The Beginnings of Perinatal Medicine 9783110317954, 9783110317909

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Erich Saling, Monika Dräger, Jens H. Stupin (Eds.) The Beginnings of Perinatal Medicine

Hot Topics in Perinatal Medicine

| Edited by Joachim W. Dudenhausen

Volume 4

Erich Saling, Monika Dräger, Jens H. Stupin (Eds.)

The Beginnings of Perinatal Medicine | In collaboration with the International Academy of Perinatal Medicine (IAPM)

Editors Prof. Dr. med. Erich Saling, FRCOG Prof. em. of Perinatal Medicine Charité University Medicine Berlin Erich Saling-Institut for Perinatal Medicine, Berlin c/o Vivantes Klinikum Berlin-Neukölln Rudower Str. 48, 12351 Berlin, Germany e-mail: [email protected] www.saling-institut.de/eng/

Dr. med. Jens H. Stupin Scientific Assistant Consultant in Obstetrics and Gynecology Clinic of Obstetrics Charité University Medicine Berlin Campus Virchow-Klinikum Augustenburger Platz 1, 13353 Berlin, Germany e-mail: [email protected]

Dr. med. Monika Dräger Scientific Assistant Erich Saling-Institut for Perinatal Medicine, Berlin c/o Vivantes Klinikum Berlin-Neukölln Rudower Str. 48, 12351 Berlin, Germany e-mail: [email protected] In collaboration with the International Academy of Perinatal Medicine (IAPM) The book has 38 figures and 3 tables. ISBN 978-3-11-031790-9 e-ISBN (PDF) 978-3-11-031795-4 e-ISBN (EPUB) 978-3-11-038212-9 Library of Congress Cataloging-in-Publication Data A CIP catalog record for this book has been applied for at the Library of Congress. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.dnb.de. © 2014 Walter de Gruyter GmbH, Berlin/Munich/Boston The publisher, together with the authors and editors, has taken great pains to ensure that all information presented in this work (programs, applications, amounts, dosages, etc.) reflects the standard of knowledge at the time of publication. Despite careful manuscript preparation and proof correction, errors can nevertheless occur. Authors, editors and publisher disclaim all responsibility and for any errors or omissions or liability for the results obtained from use of the information, or parts thereof, contained in this work. The citation of registered names, trade names, trade marks, etc. in this work does not imply, even in the absence of a specific statement, that such names are exempt from laws and regulations protecting trade marks etc., and therefore free for general use. Typesetting: le-tex publishing services GmbH, Leipzig Printing and binding: CPI books GmbH, Leck ♾ Printed on acid-free paper Printed in Germany www.degruyter.com

Contents Erich Saling, Monika Dräger, Jens H. Stupin 1 Preface and introduction | 1 Erich Saling and Monika Dräger 2 Fetal heart activity and measurements of labor activities | 5 2.1 Scientific precursors | 5 2.1.1 Development of the stethoscope | 5 2.1.2 Recognition of the existence of fetal heart sounds | 5 2.1.3 First attempts to register the fetal heart beats | 6 2.1.4 Measurement of the intrauterine pressure during labor | 8 2.2 Early stages: “modern” cardiotocogram (CTG) | 11 2.3 Later developments | 18 Erich Saling and Monika Dräger 3 Fetal blood analysis (FBA) | 23 3.1 Precursors | 23 3.2 Fetal blood analysis (FBA) | 23 3.3 Further developments | 24 3.3.1 Pulse oxymetry | 25 3.4 Excursion: Physiological concepts in connection with fetal blood analysis | 25 3.4.1 “Brain sparing effect” | 25 3.4.2 “Maternogenic” increase of metabolic acidity in the fetus | 25 Monika Dräger and Erich Saling 4 Amniotic fluid interventions and examinations | 29 4.1 Knowledge about the significance of meconium in the amniotic fluid | 29 4.2 Amniocentesis | 30 4.3 Amnioscopy | 31 J. Bennebroek Gravenhorst 5 Prevention of Rh-immunization | 35 5.1 History | 35 5.1.1 First descriptions and discovery of the pathogenesis | 35 5.1.2 First exchange transfusions | 36

vi | Contents 5.2 5.3 5.4 5.5

Attempts to affect the immune system | 36 Intrauterine transfusion | 37 Rh-immune prophylaxis | 37 Later developments | 38

Asim Kurjak 6 Sonography | 41 6.1 Ian Donald – Pioneer of ultrasound in obstetrics and gynecology | 41 6.2 Parallel early developments in the USA, Japan, and Russia | 45 6.3 The ultrasonic boom in the 1960s | 46 6.3.1 The development and use of new ultrasound devices: the Vidoson® real-time scanner and articulated-arm compound contact scanner SSD-10 | 46 6.3.2 The work of Alfred Kratochwil | 48 6.3.3 The Kossoff group: first use of ultrasound in the diagnosis of fetal malformation and further technical innovations | 49 6.3.4 Ultrasound in the diagnostics of pregnancy assessment | 50 6.4 The implementation of Doppler ultrasound | 52 6.5 Later developments and future perspectives | 53 6.5.1 The founding of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and the first journal in this field | 53 6.5.2 From the scan of fetal movements to the diagnosis of fetal well-being due to Doppler ultrasound | 53 6.5.3 The implementation of 3D ultrasound | 54 6.5.4 Use of ultrasound in the diagnostics of malformation and preterm delivery | 55 Amos Grünebaum 7 Measures in cases of threatened prematurity | 59 7.1 Tocolysis | 59 7.1.1 Introduction | 59 7.1.2 Medications for tocolysis | 59 7.1.3 Later developments – tocolysis today | 61 7.1.4 Conclusions | 62 7.2 History of induction of lung maturation | 62 7.2.1 Antecedent of fetal lung maturation | 62 7.2.2 Early stages of fetal lung maturation 1940s–1960s | 63 7.2.3 From 1970s till today | 63 7.2.4 Conclusion | 65

Contents |

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Noelia Zork and Mary E. D’Alton 8 Diagnosis of genetic defects | 69 8.1 Introduction | 69 8.2 Early stages of clinical diagnostics: Fetoscopy versus ultrasound | 69 8.3 The implementation of amniocentesis (AC) | 70 8.4 The implementation of chorionic villus sampling (CVS) | 70 8.5 Later developments in diagnostics: Ultrasound guided CVS and amniocentesis (AC) | 71 8.6 Alpha-fetoprotein in maternal serum as non-invasive diagnostic tool | 73 8.7 The triple and quadruple screens | 74 8.8 The return of ultrasound | 74 8.9 The combined screening | 74 8.10 New directions: Cell-free DNA (cfDNA) testing in maternal blood and chromosomal microarray | 75 Monika Dräger and Erich Saling 9 Assessment of the newborn immediately after delivery | 79 9.1 Apgar-score | 79 9.1.1 Precursors | 79 9.1.2 Apgar-score | 79 9.2 Assessment of the biochemical state of the newborn | 82 9.2.1 Precursors – chemical and physiological scientific background | 82 9.2.2 Blood gas analysis and pH-measurement in the newborn | 82 9.2.3 Stanley James and Virginia Apgar | 83 9.3 Attempts to modify the Apgar-score and completion of the assessment of the newborn | 83 Anne Greenough and Anthony D. Milner 10 Neonatological part of perinatal medicine | 87 10.1 Introduction | 87 10.2 Resuscitation | 87 10.2.1 Precursors in the eighteenth and nineteenth century | 87 10.2.2 Beginnings of current neonatal resuscitation practices | 89 10.2.3 “Alternative” approaches | 90 10.2.4 Scientific comparison of different methods | 90 10.2.5 Supplementary oxygen | 90 10.2.6 Refilling anesthetic bag | 91 10.2.7 Change in pressure limiting valves | 91 10.2.8 Later developments and recommendations | 91

viii | Contents 10.3 10.3.1 10.3.2 10.3.3 10.3.4 10.3.5 10.3.6 10.4 10.4.1 10.4.2 10.4.3 10.4.4 10.4.5 10.5

Mechanical ventilation | 92 Intermittent positive airway pressure | 92 Negative external inhalation | 93 Bronchopulmonary dysplasia | 94 Outcomes of mechanical ventilation | 94 Altering inflation times and rates | 94 Later developments | 96 Exogenous surfactant therapy | 97 Physiological background | 97 Identification of the chemical structure of surfactant | 97 Methods for assessing surfactant | 98 Hormones and the surfactant system | 99 Surfactant therapy | 99 Conclusions | 100

Jens H. Stupin 11 History of clinical structures and development of the Perinatal Care System | 105 11.1 Introduction | 105 11.2 Historical precursors of a structural reform | 105 11.2.1 The need for the establishment of antenatal care at the end of the 19th century | 105 11.2.2 John William Ballantyne’s plea for a pro-maternity hospital | 106 11.3 Erich Saling’s proposals for reforms in obstetrics: Early attempts to a structural reform | 108 11.4 International developments as the answer to Saling’s proposals | 109 11.5 Later developments and evolution of an integrative Perinatal Care System | 112 Erich Saling and Monika Dräger 12 History of first activities such as training, publications, foundation of very first congresses and societies | 115 12.1 New section in medicine: First activities | 115 12.2 First local educational activities | 116 12.3 Later developments | 120

Contents | ix

Jose M. Carrera 13 History of the International Academy of Perinatal Medicine (IAPM) | 121 13.1 Introduction | 121 13.2 The first steps | 121 13.3 The roots of the Academy | 122 13.4 Foundation of the IAPM | 123 13.5 Identity, mission, and objectives of IAPM | 124 13.5.1 Mission | 124 13.5.2 Objectives of the IAPM | 125 13.6 Activities of the IAPM | 126 Index of Names and cited Authors | 127 Subject Index | 131

List of contributors Prof. Mary E. D’Alton, MD Willard C. Rappleye Professor of Obstetrics and Gynecology Chair, Department of Obstetrics and Gynecology Director, Obstetric and Gynecologic Services Columbia University College of Physicians & Surgeons Department of Obstetrics & Gynecology 622 West 168th Street, PH 16-28 New York, NY 10032, United States of America e-mail: [email protected]

Prof. José Maria Carrera Secretary General of “International Academy of Perinatal Medicine” President of “Matres Mundi” Calle Ganduxer 8, ático Barcelona 08021, Spain e-mail: [email protected]

Prof. Dr. med. Amos Grünebaum, MD, FACOG Director of Obstetrics Department of Obstetrics and Gynecology, New York Weill Cornell Medical College 525 East 68th Street, Suite J-130, New York, NY 10065, United States of America e-mail: [email protected]

Prof. Asim Kurjak, MD, PhD Professor of Obstetrics and Gynecology, Medical School Universities of Zagreb and Sarajevo, Rector, DIU Libertas International University DIU Libertas International University Sv. Dominika 4 20000 Dubrovnik, Croatia e-mail: [email protected]

Prof. Jack Bennebroek Gravenhorst, PhD, MD, Prof. em. Leiden University Medical Center (LUMC) Guest Scientist, Applied Scientific Research (TNO), Dpt Child Health Schipholweg 77–89 2316 ZL Leiden, The Netherlands e-mail: [email protected]

Prof. Anthony D. Milner, MD, FRCP, FRCPCH, DCH Division of Asthma, Allergy & Lung Biology, MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, UK Corresponding author: Professor A Greenough 4th Floor Golden Jubilee Wing, King’s College Hospital Denmark Hill, London, SE5 8RS, UK e-mail: [email protected]

Prof. Anne Greenough, MD, FRCP, FRCPCH, DCH, FKC Division of Asthma, Allergy & Lung Biology, MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, UK 4th Floor Golden Jubilee Wing, King’s College Hospital Denmark Hill, London, SE5 8RS, UK. e-mail: [email protected]

Noelia Zork, MD Clinical Fellow, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center Division of Maternal Fetal Medicine Department of Obstetrics and Gynecology Columbia University Medical Center 622 W. 168th St. PH 16-66 New York, NY 10032, United States of America e-mail: [email protected]

Erich Saling, Monika Dräger, Jens H. Stupin

1 Preface and introduction

For the obstetricians of the younger generation, it is hardly imaginable, how obstetrics was without the methods and measures, which they use today in their daily work. One of the aims of this book is to describe how these methods came into being, but the main emphasis is to illustrate how a complete new medical field, namely “Perinatal Medicine” has developed. This book about the “Beginnings of Perinatal Medicine” concerns a historically unique new field of applied medicine in so far as for the very first time the application of human medicine has been brought forward in the phase before the great biological event of birth, and also in a new widely unknown region, namely in the intrauterine space. We should be aware that since the beginning of our obstetrical profession, the most impressive evolutionary event was the great change from the predominantly mother-oriented obstetrics with its considerable amount of operative character to a combined widespread complex of human medicine: becoming not only motheroriented but also embryo- and fetal-oriented obstetrics. Before the 1960s, very little – nearly nothing – could be known before birth with regard to the questions: what is the infant’s condition, what is his state of health, and in what state it will be born. But from the 1960s onward, the fetus became a real patient, in addition to its mother. Now some comments about the terminology: The term “perinatal” already goes back to 1935 when the German pediatrician M. Pfaundler defined the “perinatal period” [1]. He did not create the term “Perinatology” as has been later wrongly published [2]. It is rather difficult to find out when the term “Perinatology” was used for the first time. When we started at the beginning of the 1960s to prepare the very first book on prenatal medicine, we wanted to use also a suitable term for this new part of obstetrics which still was not existing. Our idea was to express our directed focus to the unborn infant within obstetrics. So we created the up-to-now unknown term “Ped-Obstetrics”: ped from the Greek word child (𝜋𝛼𝜏𝜍) and combined it logically with our conventional field, with obstetrics. The editor of our later published book did not accept this new created term, rather he preferred a German title. We agreed, it was “Das Kind im Bereich der Geburtshilfe.” Directly translated: “The infant within obstretrics.” In 1966, Dobbs and Gairdner used the term “foetal medicine” for the first time [3]. This term was not extensive enough, because the term “Fetus” does not include the embryonic period. We therefore preferred the term “Prenatal Medicine.” This is terminologically undisputed. The original mostly used term “Perinatal Medicine” was cre-

2 | Erich Saling, Monika Dräger, Jens H. Stupin ated by us in 1967 [4]. In the 1970s, in Anglo-American terminology the term “Maternofetal-medicine” was introduced. The actual start of “Perinatal Medicine” can be assessed at the time period from the middle of the last century onward, with the works of Bevis, Liley, and Saling – as stated by Dobbs and Gairdner [3], see Chapter 3 (Fetal blood analysis). However, names such as Apgar and James, Caldeyro-Barcia and Hon, Donald and Kratochwil, and Liggins, Maeda and Hammacher have also to be named. The first editor of this book (Erich Saling) is one of the last living pioneers of this time. In the 1960s and early 1970s, the importance of this new evolution has been rapidly recognized and the enthusiasm for these breakthroughs has been overwhelming. A new interdisciplinary field of scientific and applied medicine, the “Prenatal” and “Perinatal Medicine,”, respectively, has grown up and accordingly changed conventional obstetrics to the modern one. Because of the enormously growing content of this new science, we have concentrated our presentation mainly on the early stages of perinatal medicine. Up to the end of the 1960s the following main fields were in the foreground: – to assess fetal heart activity, mostly the frequency, – to examine amniotic fluid, mainly by amniocentesis and later by amnioscopy, – to achieve the first direct approach to the fetus in the form of sampling and analyzing fetal blood from the presenting part, – to assess the state of the newborn immediately after delivery and – if necessary – its resuscitation and ventilation, and – at the end of the 1960s ultrasonography started for widespread clinical use. The period covered in this book has the main emphasis on the time up to the early 1970s. However, both scientific precursors and later developments have been mentioned briefly in several contributions, whenever appropriate. For example, with regard to cardiotocography, we included the first auscultation of the fetal heart by Major in 1818. Another emphasis was the applicability of a given method on a larger scale. We therefore included only a few basic research methods and hardly mentioned any methods that were not eventually used for routine practice (that did not lead to methods used for routine practice). The idea for this book has two origins: the first editor, Professor Saling, gave a main lecture on November 8, 2011 at the 10th World Congress of Perinatal Medicine in Punta del Este/Uruguay about “History of Perinatal Medicine – Early Stages.” Professor Joachim Dudenhausen, who at the De Gruyter Publisher edits a new series of socalled Hot topics, found the lecture worth publishing on this basis as a special book. At about the same time, Prof. José Carrera, the Secretary General of the International Academy of Perinatal Medicine (IAPM), planned to prepare a history book about “Perinatal Medicine” as part of the activities of the IAPM. The best solution was to combine both ideas in this common project. Because of the cooperation of the International Academy of Perinatal Medicine in planning and preparing this book, we allowed some

1 Preface and introduction

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more space for its history than we allowed for the history of other scientific communities. As editors, three generations have been working together: Prof. Saling, as one of the last living pioneers¹ describes in the first part of this preface the profound evolutionary changes in our discipline and he contributed from “first hand” many historical details, that otherwise might have been lost forever; Dr. Dräger, as a close co-worker of Prof. Saling, who during the past years has immersed herself deeply into the history of perinatal medicine, was able to contribute substantially to the book; and Dr. Stupin, also from Berlin, as an obstetrician of the “younger generation” was able to bring the “today’s view” into the planning of our book. For several chapters, we could win competent experts as authors for concerned fields. The styles of the contributions have their own character – reflecting the individuality of the authors and their approaches to their scientific fields. We only did slight editing and so the different flavor of the contributions has been kept. We hope that the book provides not only historical information with the perspective of how things developed and what is actually still in use today, but also contains information which might be relevant for the younger generation. Of course, history is always subjective. This is not only because of the personal biases and emphasis of the editors and authors, but also due to many facts. Sometimes, for example, it just depends on the languages that the author or researcher can read. For example, many publications regarding our so-called precursors of perinatal medicine were published in German and the first works of Prof. Caldeyro-Barcia have been published in Spanish (so particularly some important “precursors” might have been overlooked and may be detected later from future historical researchers). We hope that the research about the history of perinatal medicine will grow in a similar manner as perinatal medicine itself has grown.

Bibliography [1] Pfaundler M. Studien über Frühtod, Geschlechtsverhältnis und Selektion, I. Mitteilung: Zur intrauterinen Absterbeordnung. Z. Kinderheilk. (European Journal of Pediatrics) 1935,57,185–227. (http://www.springerlink.com/content/f41nq2km5548q577/?p= df3876d6d72f404c93b687d5fa4252c6). ger. [2] López DO, Marin SR, González EF. Terminology in perinatal medicine. In: Carrera JM, ed. Recommendations and Guidelines for Perinatal Medicine, 2007,19–25 (English). [3] Dobbs RH, Gairdner D. Foetal Medicine – who is to practice it?, Editorial. Arch Dis Childh 1966, 41,453 (English). [4] Saling E. Vorschläge zur Neuordnung der Geburtshilfe [Proposals for new regulations in obstetrics]. Geburtsh. Frauenheilk. 1967,27,572–585 (German).

1 A list of Prof. Saling’s main scientific contributions can be found on www.saling-institut.de/eng/

Erich Saling and Monika Dräger

2 Fetal heart activity and measurements of labor activities

The most important historic precursor of indirect approaches to the fetus has been fetal heart rate diagnostics. One might say that it concerns the historically oldest part of intrauterine diagnostics. For thousands of years, estimating the state of the unborn infant has only been possible by palpating the fetal movements. This allowed an answer to the question “Is it alive?”. However, the question (if asked at all) whether the infant might be endangered could not been answered with this method. The start of a change goes back to the early 19th century with the auscultation of fetal heart rates and later with further methods.

2.1 Scientific precursors 2.1.1 Development of the stethoscope The evaluation of the fetal heart rate activity would not have been possible without the invention of the stethoscope in 1816 by René Laennec (1781–1826). He first used a roll of paper for the auscultation of lung and heart of his patients. Later he developed a wooden stethoscope (wooden tube) [1]. However, at that time it did not become widely used.

2.1.2 Recognition of the existence of fetal heart sounds In 1818, Mayor¹ remarked during a lecture on auscultation of fetal heart sounds [3] by placing the ear on the maternal abdomen, and in 1821 Lejumeau de Kergaradec reported in more detail on simple auscultation of fetal heart sounds with a stethoscope [4]. Both interpreted the sounds as a definite sign that the fetus is alive. In 1833 Kennedy from Dublin published a monumental monograph on the observations of obstetric auscultation of the fetal heart [5]. Goodlin (1979) comments on Kennedy’s achievements: “Although some of his views on the significance of fetal distress have not stood the test of time (. . . ) most of his clinical impressions regarding

1 To our knowledge, Mayor himself did not publish his findings, but according to [2] the editor of the Bibliothéque universelle des Sciences remarks on an apparently verbal statement of Mayor.

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Fig. 2.1. (a) Dr Adolphe Pinard, Source: Wikipedia [11, 35]; (b) Nurse using a Pinard horn in Uganda. Source: [36] (© [37]).

the significance of various FHR patterns appear compatible with current concepts.” (Goodlin 1979 [6, p. 324]) According to Goodlin, Kennedy included, for example, Bodson’s statement that the most ominous fetal heart rate pattern was “slowness of its return when a contraction is passing on.” Later authors attempted to define the range of normal and pathological heart rate frequencies, for example, in 1862 Hüter [7], in 1865 Katz [8], and in 1882 Ziegenspeck [9]. In 1893, von Winckel included diagnostic recommendations in his text book to define today’s so-called fetal distress, for instance, “the presence of bradycardia below 100 bpm and tachycardia with more than 160 bpm.” [10, translation by us]. The first stethoscope specially designed to listen to the fetal heart beats was developed in 1895 by the French obstetrician Adolphe Pinard (1844–1934, see Figure 2.1 (a)). “Pinard horns” are still in use worldwide (see Figure 2.1 (b)) [11].

2.1.3 First attempts to register the fetal heart beats 2.1.3.1 Fetal cardiography Recording of the fetal heart beats started in 1890 when Pestalozzi [12] recorded heart beats by a sphygmograph for the first time. (A sphygmograph is a device, that was originally developed to record the pulse rate.)

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Fig. 2.2. ECG machine according to Einthoven: “string galvanometer,” with each of the patients limbs in containers of salt solutions from which the ECG was recorded. The picture shows an early commercial ECG machine, built in 1911 by the Cambridge Scientific Instrument Company (Christoph Zywietz, A Brief History of Electrocardiography – Progress through Technology) to measure the human electrocardiogram according to the standards developed by Einthoven. Source: Wikipedia [13].

2.1.3.2 Fetal electrocardiogram Preceding the fetal electrocardiogram (FECG), the ECG was developed as a method itself. In 1843, Carlo Matteucci discovered that the activity of the heart is based on electric processes. In 1882, Augustus Desiré Waller recorded for the first time an ECG. The instruments for recording an ECG were substantially improved in 1903 by Willem Einthoven, who introduced it into clinical practice. In Figure 2.2, you can see a commercial ECG according to Einthoven [13]. Cremer [14] was successful in recording the first FECG in 1906, in which the small fetal signals (orange arrows in Figure 2.3) could be differentiated from the bigger ones of the mother (green arrows). This is in so far remarkable, as since Einthoven’s improvements in 1903 the ECG (from adults) was usually recorded with a “string galvanometer,” with each of the patient’s limbs in containers of salt solutions from which the ECG was recorded (see Figure 2.2), because metal electrodes directly applied to the skin had the problem of the huge electrical resistance. However, Cremer used spe-

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fetus mother

fetus

mother

time line

Fig. 2.3. First FECG recorded in 1906 by Cremer [14] (with explanations in color by us).

cial electrolytic chlorinated silver electrodes for his fetal electrocardiogram – one electrode within the vagina and one at the outer abdominal wall of the mother.

2.1.3.3 Phonocardiogram In 1908, Hofbauer and Weiss [15] recorded the first phono-cardiogram. Beruti from Buenos Aires developed a phonocardiograph that could be applied in clinical practice. He combined the microphone with a telephone and already predicted in 1927 that in the future the obstetrician would be able to monitor the pregnant patient from the distance [16].

2.1.4 Measurement of the intrauterine pressure during labor Today, registration of the fetal heart activity is recorded in most cases – particularly during labor combined with the registration of labor activity. Therefore, some milestones of the measurement of labor activity should be mentioned: First measurement of the intrauterine pressure during labor started in Germany in 1872 with Schatz [17]. He used a transcervically inserted balloon. In Figure 2.4 (a) you can see his equipment and in Figure 2.4 (b) some records. Josef Zander wrote in his

2 Fetal heart activity and measurements of labor activities

Ballon which is inserted transcervically into the uterus

Fig. 2.4. (a) Tocodynamometer from Schatz.

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10 | Erich Saling and Monika Dräger

Fig. 2.4. (b) First records.

overview about milestones in gynecology and obstetrics [18] about Schatz (translation by us): “The gynaecologist Friedrich Schatz (1841–1920), (. . . ), developed already in 1872 a tocodynamometer for intern measurement of the pressure during labor. Even according to modern standard, his results have to be admired.” [18, p. 58]

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In 1948, the first amnoicentesis for the direct measurement of intrauterine pressure has been published by Alvarez and Caldeyro-Barcia [19, 20], see Chapter 4, Amniotic fluid-examniations.

2.2 Early stages: “modern” cardiotocogram (CTG) The two outstanding pioneers of modern electronically based fetal heart rate surveillance are Caldeyro-Barcia (Figure 2.5) and Hon (Figure 2.6). In 1957, Hon succeeded in separating the fetal signals out of the abdominally recorded maternal and fetal complexes and thus laid the basis for modern cardiography, see Figure 2.7 [21, 22]. Caldeyro-Barcia was also a pioneer of uterine physiology and pathophysiology. In 1958 Caldeyro-Barcia and his co-workers were the first to record the fetal heart rate in combination with uterine contractions [23, 24]. This was the initial step of modern heart rate monitoring, for cardiotocography. The fetal heart rate was recorded directly from an anencephalic fetus (see Figure 2.8). In Figure 2.9, you can see the records. According to Goodlin [6], in the 1950s and early 1960s, different intrauterine electrodes have been used by several authors, such as Smyth (1953) from England, Sureau

Fig. 2.5. Prof. Roberto Caldeyro Barcia © open for public use, with kind permission of Ofelia, the spouse of Prof. Roberto Caldeyro Barcia.

Fig. 2.6. Prof. Edward Hon © [38].

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a

b

a

b

Fig. 2.7. Hon and Hess 1957: Important step for the clinical utilization of abdominal ECG by selective graphic representation of fetal signals. This was achieved by apparative cancellation of maternal ECG-signals from common maternal-fetal records. In the figure above (Fig. 1) you see the apparative concept. In the figure below (Fig.2) you see two records with a two-channel electrocardiograph. The upper channels (a) show the maternal and fetal ECG (M-F), the lower channels (b) just the fetal ECG after cancellation of the maternal ECG (F); © figure taken from [21], with kind permission of AAAS (Science).

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Fig. 2.8. In 1958, first simultaneous registrations of the fetal heart rate and uterine contractions by Caldeyro-Barcia and co-workers [23]: a direct electrode was placed at the anencephalic fetus, the reference electrode on the abdominal wall of the mother. The intrauterine pressure was measured directly with an electrode after transabdominal puncture of the amniotic cavity. © Archivos Ginecologia y Obstetrica, with kind permission.

(1956) from France, Kaplan and Toyama (1958) from the USA, and Ross (1961) from Australia. In 1963 Edward Hon [25] introduced a clip electrode fixed on the fetal scalp for direct fetal electrocardiotocography which later made widespread clinical use possible. All these registrations of the fetal heart rate combined with the recording of the intrauterine contractions required the usage of complicated huge equipment and could therefore only serve experimental and some physiological considerations. They have hardly been suitable for widespread routine clinical use. In Figure 2.10, you can see such a large piece of equipment for heart rate and uterine contraction recording in

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Fig. 2.9. Recordings obtained with the methods depicted in Figure 2.8 by combined measurement of intraamniotic pressure and fetal heart rate frequency [23]. © Archivos Ginecologia y Obstetrica, with kind permission.

Fig. 2.10. In the early stages of cardiotocography, huge computers have been necessary. (The picture was taken in 1998 during the visit of the first author in the Roberto Caldeyro-Barcia’s Museum in Montevideo.) © Saling.

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Fig. 2.11. Prof. Konrad Hammacher accompanied by his spouse Dr Monika Hammacher, receiving the Maternity Prize in 1969; with kind permission.

Fig. 2.12. Hammacher 1964: Selective evaluation of heart beat frequency by comparisons of the time intervals between two successive first heart beats and two successive second heart beats [39], figure taken from: [40] © Hammacher, with kind permission of his spouse.

Roberto Caldeyro-Barcia’s Museum in Montevideo which the first author visited again in 1998. The real breakthrough leading to later practical clinical usage was made in the 1960s when Hammacher (see Figure 2.11) in cooperation with Hewlett and Packard was successful in developing suitable transportable equipment, called cardiotocograph, which was based on the phonocardiographic principle. It enabled the elimination of all disturbing noises by electronically controlled comparisons of the time interval between two successive first heart beats and two successive second heart beats, see Figure 2.12. In this way, in 1962 Hammacher laid the theoretical and practical bases for later widespread reliable routine electronic registration of the fetal heart rate [26]. Equipment for widespread use was not available until 1968 (see Figure 2.13). But from then on cardiotocography developed rapidly into a surveillance method used all over the world.

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Fig. 2.13. Transportable cardiotocograph developed by Hammacher in cooperation with Hewlett and Packard suitable for clinical use. The picture shows one of the earlier models (8020A); © Saling.

Two other pioneers in cardiotocography have been Maeda (see Figure 2.14) from Japan and Mosler from Germany. They have been the first to use the Doppler principle as basic impulses for heart rate recording. In Figure 2.15, you can see the first CTG machine that was produced by Toizu Co. with Maeda’s advice in 1965. Maeda was one of the first to use Doppler CTG in 1969, see Figure 2.16 [27]. The other pioneer using Doppler CTG was Mosler (Figure 2.17) in Germany, also in 1969 [28]. In Figure 2.18, you can see his records. Excursion: Cardiotocography compared with fetal blood analysis Shortly after cardiotocography became available for routine use, together with our fetal blood analysis, which had been developed 8 years earlier, we examined the fetal acid base situation when pathological heart rate patterns have been present. When we met with Caldeyro-Barcia in October 1964 in Montevideo, we already performed together the first combined examinations on 3 fetuses. Later, in 1968, when cardiotocography became available for routine use we started the first study and in so far the very first clinical use of combined assessment of the fetus by cardiotocography and fetal blood analysis in 146 cases [29]. We were surprised that in a considerable number of the cases, even with bradycardia, there have been normal pH values. We continued this comparative study and presented the results with more cases in 1970 at the second European Congress of Perinatal Medicine in London. In 52 cases with bradycardia with less than 120 bpm there have been normal or preacidotic pH values in 67% and only in 33% acidotic pH values [30]. Many later studies have confirmed this weakness of cardiotocography.

2 Fetal heart activity and measurements of labor activities

Fig. 2.14. Prof. Kazuo Maeda; © Saling.

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Fig. 2.15. 1965 the first CTG machine commercialized by TOIZU Co. Maeda provided them with many useful ideas for its production; © with kind permission of Prof. Kazuo Maeda.

Fig. 2.16. Doppler CTG in the 16th week of pregnancy. (Maeda et al., 1969, 173 [27]; © with kind permission of Prof. Maeda.

18 | Erich Saling and Monika Dräger

Fig. 2.17. Prof. Karl-Heinz Mosler; © Karin Mosler, with kind permission.

Fig. 2.18. Doppler CTG-record, published by Mosler in 1969 [28]; ©: Experentia by Mural, Alexander von. Reproduced with permission of Verlag Birkauser, via Copyright Clearance Center.

2.3 Later developments In the meantime, considerable progress has been achieved particularly by the introduction of computer assessment of cardiotocograms. A pioneer in this field was Dawes and his working group with Visser and Redman who in 1978 already started to evaluate different patterns of cardiotocograms by the use of computers, published in 1981 [31] (Quoted in: [32]). In this regard we learned from Prof. Redman a humorous anecdote: he suggested to Prof. Dawes in 1977 that computerized analysis of the human FHR would be a good undertaking. Professor Dawes at first doubted that this would be so but soon changed his mind.

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Another published method which has some potential diagnostic value is fetal ECG and here the ST-waveform analysis, the so-called STAN. With the clinical realization that cardiotocography alone is an insensitive index of asphyxia, the interest went back to the FECG waveform in the sense of a discriminator of fetal heart rate changes. As a result in the late 1980s and 1990s, the STAN (ST-waveform analysis concept of intrapartum fetal surveillance under the auspices of the Swedish physiologist and neonatologist Karl Gustav Rosén, could be developed [33, 34]. However, up to now the STAN system did not find its way to a wide clinical routine application.

Bibliography [1] [2] [3] [4]

[5]

[6] [7] [8] [9]

[10] [11] [12]

[13] [14]

[15]

Wikipedia. Stethoskop, 2014. (Accessed March 3, 2014, at http://de.wikipedia.org/wiki/ Stethoskop). Gültekin-Zootzmann B. The history of monitoring the human fetus. J. Perinat. Med. 1975,3, 135–144 (English). Bibliothéque universelle des Sciences, Belles-lettres, et Arts, faisant suite à la Bibliothéque Britannique. Vol 9, Sciences et Arts, “Melanges.” Genéve, 1818 (French). Kergaradec MJAL de. Mémoire sur l’Auscultation appliquée à l’Etude de la Grossesse ou Recherches sur deux nouveaux signes propres á faire reconnaitre plusieurs circonstances de l’Etat de Gestation; lu à l’Académie royal de médecine, dans sa séance générale du 26 décembre 1821. Paris, 1822 (French). Kennedy E. Observations of Obstetrical Auscultation. Dublin, Hodges and Smith, 1833, 288 p. Available from: http://books.google.de/books?id=lXdTAAAAcAAJ&printsec=frontcover&hl= de{#}v=onepage&q&f=false (English). Goodlin RC. History of fetal monitoring. Am. J. Obstet. Gynecol. 1979,133,323–352 (English). Hüter V. Über den Fötalpuls. Mschr. Geburtsk. 1862,18,23 (German). Katz J. Der Fötalpuls und sein Verhältnis zur operativen Geburtshülfe [Medizinische Dissertation]. Marburg, 1865 (German). Ziegenspeck R. Welche Veränderungen erfährt die fötale Herztätigkeit regelmäßig und unter der Geburt? Auszug aus einer gekrönten Preisschrift [Medizinische Dissertation]. Jena. Quotation from: Gültekin-Zootzmann (1975), 1882 (German). Winckel F v. Lehrbuch der Geburtshülfe. 2nd edn. Leipzig, Verlag von Veit & Comp., 1893 (German). Wikipedia. Adolphe Pinard, 2012. (Accessed March 3, 2014, at http://en.wikipedia.org/wiki/ Adolphe_Pinard) (English). Pestalozzi E. Graphische Darstellung des fötalen Herzimpulses, Verhandlungen der gynäkologischen Section des X. interantionalen medic. Congresses in Berlin vom 4. bis 9. August 1890. Archiv für Gynäkologie 1891,39,137 (German). Wikipedia. Elektrokardiogramm, 2012. (Accessed March 3, 2014, at http://de.wikipedia.org/ wiki/EKG) (German). Cremer M. Ueber die direkte Ableitung der Aktionsströme des menschlichen Herzens vom Oesophagus und über das Elektrokardiogramm des Föten. Münch Med Wochenschr 1906,53, 811–813 (German). Hofbauer J, Weiss O. Photographische Registrierung der fötalen Herztöne. Zentralbl Gynakol 1908,(13),429–431 (German).

20 | Erich Saling and Monika Dräger [16] Beruti JA. Fernauskultation und Registrierung der fetalen Herztöne, Gegenwärtiger Stand der Versuche. Arch Gynakol 1927,132,52–57 (German). [17] Schatz F. Beiträge zur physiologischen Geburtskunde. Arch Gynakol 1872,3,58–144,174–182 (plus Tafel 1–5) (German). [18] Zander J. Meilensteine in der Gynäkologie und Geburtshilfe – 100 Jahre Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. In: Beck L, ed. Zur Geschichte der Gynäkologie und Geburtshilfe. Aus Anlaß des 100jährigen Bestehens der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe. Berlin, Springer, 1986, 27–62. ISBN: 3-540-16338-7 (German). [19] Alvarez H, Caldeyro-Barcia R. Estudios sobre la fisiología de la actividad contráctil del útero humano. Primera comunicación. Nueva técnica para registrar la actividad contráctil del útero humano grávido. Archivos de Ginecologia y Obstetrica (Urugay) 1948,7,7–24. spa. [20] Alvarez H, Caldeyro-Barcia R. Fisiologia de la Actividad contractil del utero humano gravid. Cuarta communication. Adaptacion del “Tono” Uterino a las variaciones de volumen de su contenido. Archivos de Ginecologia y Obstetrica (Urugay) 1948,VII,139–151 (Spanish). [21] Hon EH, Hess OW. Instrumentation of fetal electrocardiography. Science 1957,125,553–554 (English). [22] Hon EH. The electronic evaluation of the fetal heart rate; preliminary report. Am. J. Obstet. Gynecol. 1958,75,1215–1230 (English). [23] Poseiro JJ, Caldeyro-Barcia R. Estudio de la anoxia fetal intrauterina mediante el ECG fetal y el registro continuo de la frequenca cardiaca fetal. Archivos de Ginecologia y Obstetrica (Urugay) 1958,XVI,105–111 (Spanish). [24] Caldeyro-Barcia R. Estudio de la anoxia fetal intrauterina mediante el ECG fetal y el registro continuo de la frecuencia cardíaca fetal., III Congr. Lat. Amer. Obst. Ginec., México, Vol. 2 1958, 388–390 (Spanish). [25] Hon EH. Instrumentation of fetal heart rate and fetal electrocardiography. II. A vaginal electrode. Am. J. Obstet. Gynecol. 1963,86,772–784 (English). [26] Hammacher K. Neue Methode zur selektiven Registrierung der fetalen Herzschlagfrequenz [New method for the selective registration of the fetal heart beat.]. Geburtsh Frauenheilk 1962, 22,1542–1543 (German). [27] Maeda K, Kimura S, Fukui Y, et al. Pathophysiology of the fetus. Fukuoka, Fukuoka printing, 1969 (English). [28] Mosler KH. Dauerüberwachung der fetalen Herzaktion unter der Geburt mittels Ultraschall [[Continuous monitoring, using ultrasonics, of fetal heart actions during birth]]. Experientia 1969,25,222–223 (German). [29] Saling E. Elektronische und biochemische Überwachung der Feten unter der Geburt [Electronic and biochemical surveillance of the fetus during birth]. Bull. Soc. R Belge. Gynecol. Obstet. 1968,38,289–299 (German). [30] Saling E. The Measurement of Fetal Heart-Rate and Acid-Base Balance. In: 2nd European Congress of Perinatal Medicine. Basel, Karger, 1970 (English). [31] Dawes GS, Visser GH, Goodman JD, Redman CW. Numerical analysis of the human fetal heart rate: the quality of ultrasound records. Am. J. Obstet. Gynecol. 1981,141,43–52 (English). [32] Pardey J, Moulden M, Redman CWG. A computer system for the numerical analysis of nonstress tests. Am. J. Obstet. Gynecol. 2002,186,1095–1103 (English). [33] Rosén KG, Lindecrantz K. STAN–the Gothenburg model for fetal surveillance during labour by ST analysis of the fetal electrocardiogram. Clin. Phys. Physiol. Meas. 1989,10,51–56 (English). [34] Norén H, Luttkus AK, Stupin JH, et al. Fetal scalp pH and ST analysis of the fetal ECG as an adjunct to cardiotocography to predict fetal acidosis in labor – a multi-center, case controlled study. J. Perinat. Med. 2007,35,408–414. (doi:10.1515/JPM.2007.097) (English).

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[35] Unknown. Adolphe Pinard (1844–1934). (Accessed April 4, 2014, at http://ihm.nlm.nih.gov/ images/B21311). [36] Wikipedia. Pinard horn, 2012. (Accessed March 3, 2014, at http://en.wikipedia.org/wiki/ Pinard_horn) (English). [37] Pinard horn used by a US Army Reserve nurse in Uganda, This image was originally posted to Flickr by US Army Africa at http://flickr.com/photos/36281822@N08/4034859430. It was reviewed on 13 July 2012 by the FlickreviewR robot and was confirmed to be licensed under the terms of the cc-by-2.0., 2012. [38] Hon EH, Caldeyro-Barcia R, Saling E. Editors’ preface. J. Perinat. Med. 1973,1,3–6 (English). [39] Hammacher K. Fetale Herzschlagfrequenz und intrauterine Hypoxie, (35. Verhandlungsbericht der Deutschen Gesellschaft für Gynäkologie in München 1964). Arch Gynakol 1965,202,353– 356 (German). [40] Hammacher K. Einführung in die Cardiotokographie – ein Kurs für Hebammen. 5th edn. Bremen, Verlag Wilhelm Schnitz Druck, 2000 (German).

Erich Saling and Monika Dräger

3 Fetal blood analysis (FBA)

3.1 Precursors The precursors of fetal blood analysis (FBA) are almost the same as those for blood gas analysis and pH measurement in the newborn. We therefore refer here to Section 9.2 (Assessment of the biochemical state of the newborn). However, the first examination of the fetal blood has not been made for blood gas analysis or pH measurement, but in order to gain blood for serological and hematological examinations in cases of fetal erythroblastosis. For precursors of the prevention of Rh-immunization, please refer to Chapter 5 (Prevention of Rh-immunization). Using the principle of Tödt [1] for O2 measurement, in 1961, Saling and Damaschke developed a rapid method to measure the blood O2 saturation in microsamples [2], see below.

3.2 Fetal blood analysis (FBA) Eight years before cardiotocography and ultrasonography became available for widespread routine application. The first direct approach to the human fetus that could already be used for routine clinical practice had been achieved: this was the moment of the birth of intrauterine medicine. It was on June 21, 1960 (published 1961) when we started sampling and examining the fetal blood from its presenting part to assess specifically the state of the respiratory supply of the fetus [3, 4] (Reprinted as “Classic pages in obstetrics and gynecology” in English in the AJOG [5]). It was only a tiny incision into the fetal scalp (see Figure 3.1); nevertheless, it was a decisive step to open up the intrauterine space to direct medical exploration. It was the beginning of a new concrete science namely of prenatal medicine or in the stricter sense fetal medicine. We started to analyze fetal blood in several directions. The first were serological and hematological examinations in cases of fetal erythroblastosis such as [6]: – Race-Coombs test, – blood group determination, – cross-matching with donor blood and hematological examinations such as hemoglobin, – hematocrit, etc. These examinations enabled us to start with the blood exchange in severely affected cases some minutes after birth which up to then had never been possible so early.

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Fig. 3.1. Fetal blood analysis, © Erich Saling.

Shortly afterwards, we started with the examinations of fetal acid base balance and blood gas analysis [4] and these examinations changed the character of the supervision of the fetus fundamentally, for instance, the consequences for termination of labor under the view of fetal indication. Consequently, the fetus became for the first time a real patient apart from his mother and obstetrics underwent an essentially new character. The clinical and scientific interest increased very fast particularly in the younger generation of colleagues. We also found acceptance from abroad, so, for example, a few years later Dobbs and Gairdner, two British pediatricians [7] published in 1966 the now historical comment: “With the advent of the techniques of amnioscopy and foetal blood sampling developed by Saling, and of amniocentesis and fetal transfusion due to Bevis and to Liley, we witness the end of the long period of fetal inaccessibility, and we hopefully believe, the start of the science of foetal medicine.”

3.3 Further developments Through the course of the years FBA became a gold standard of biochemical assessment of the fetus during labor. As FBA only allows random tests, there have been attempts to also introduce continuous methods [8]. But up to now, none of them has been successful for widespread use.

3 Fetal blood analysis (FBA) |

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3.3.1 Pulse oxymetry Here it should be mentioned that Albert and Renate Huch together with Lübbers in 1972 developed a method for continuous transcutaneous measurement of pO2 [9], which later became an important method in intensive care in neonatologic units and it was also a preliminary step for later continuous measuring of oxygen saturation by pulse oximetry in the fetus during labor.

3.4 Excursion: Physiological concepts in connection with fetal blood analysis 3.4.1 “Brain sparing effect” In connection with the fetal blood examinations the first author developed in 1966 a concept of oxygen-conserving adaptation of the fetal circulation to hypoxemia, later by others erroneously called “brain-sparing effect.” In fact, it is not just a “brainsparing effect,” but also a heart and adrenal sparing effect [10, 11], see Figure 3.2. Oxygen deficiency in the fetus leads to oxygen-conserving adaptation of its circulation. The advantage of this response is that, in spite of the reduction of available oxygen, the supply and function of the heart and brain are maintained at the expense of a considerable decrease in oxygen consumption by other less vital organs. In the meantime, many confirmations by Doppler examinations have been published for instance from our side [12].

3.4.2 “Maternogenic” increase of metabolic acidity in the fetus Such a physiological – sometimes pathophysiological – situation in the relationship between mother and fetus which we discussed many decades ago [13, p. 129] can still be of clinical interest. Fetal metabolic acidity increase may namely also be caused by the passage of organic acids, mainly lactic acid, from the mother to the fetus. This can be the case when the parturient is in stress. A typical situation would be a slow decrease of fetal pH values in combination with only slightly suspicious CTG patterns. Additional controls of maternal acid–base values can easily clear up the background. Only when the fetus shows signs of an additional hypoxic complication should the situation be considered as critical. It seems unlikely that maternal hyperlactemia alone can cause serious fetal disturbance in the absence of other complications.

b

Fig. 3.2. Concept of oxygen-conserving adaptation of the fetal circulation to hypoxemia, © Erich Saling, source: [14, Fig. 83 a/b, p. 140–141], with kind permission of Thieme publisher.

a

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Bibliography [1]

[2] [3] [4]

[5]

[6] [7] [8] [9] [10] [11] [12]

[13] [14]

Tödt F. Elektrochemische Sauerstoffmessungen, Konzentrationsmessungen oxydierender und reduzierender Stoffe durch galvanische Modellelemente. Berlin, de Gruyter, 1958, 212 p (German). Saling E, Damaschke K. Neue Mikro-Schnell-Methode zur Messung des Blutsauerstoffes auf elektrochemischem Wege. Klin. Wochenschr. 1961,39,305–306 (German). Saling E. Neue Untersuchungsmöglichkeiten des Kindes unter der Geburt (Einführung und Grundlagen). Zentralbl Gynakol 1961,83,1906–1907 (German). Saling E. Neues Vorgehen zur Untersuchung des Kindes unter der Geburt, Einführung, Technik und Grundlagen. Archiv für Gynäkologie 1962,197,108–122. (http://www.springerlink.com/ content/q78l55k2w6133154) (German). Saling E. Neues Vorgehen zur Untersuchung des Kindes unter der Geburt. Einführung, Technik, Grundlagen, Classic Pages in Obstetrics and Gynecology. Am. J. Obstet. Gynecol. 2006,194, 895–899. (doi:10.1016/j.ajog.2005.04.049) (German). Saling E. Pränatale Feststellung der Erythroblastose. Geburtsh Frauenheilk 1961,21,694–696 (German). Dobbs RH, Gairdner D. Foetal Medicine – who is to practice it?, Editorial. Arch Dis Childh 1966, 41,453 (English). Stamm O, Latscha U, Janacek P, Campana A. Kontinuierliche pH-Messung am kindlichen Kopf post partum and sub partu. Z Geburtshilfe Perinatol 1974,178,368–376 (German). Huch R, Lübbers DW, Huch A. Quantitative continuous measurement of partial oxygen pressure on the skin of adults and new-born babies. Pflugers Arch. 1972,337,185–198 (English). Saling E. Die O2 -Sparschaltung des fetalen Kreislaufes [O2 conservation by the fetal circulation]. Geburtsh Frauenheilk 1966,26,413–419 (German). Saling E. Oxygen-conserving adaptation of the foetal circulation. In: Apley J, ed. Modern Trends in Paediatrics, Butterworths, 1970, 51–68 (English). Arabin B, Saling E. Die “Sparschaltung” des fetalen Kreislaufs dargestellt anhand von eigenen quantitativen Doppler-Blutflussparametern [Economy circuit of fetal circulation illustrated on the basis of personal quantitative Doppler blood flow parameters]. Z Geburtshilfe Perinatol 1987,191,213–218 (German). Saling E. Foetal and Neonatal Hypoxia in relation to Clinical Obstetric Practice. London, Edward Arnold (Publishers) Ltd., 1968, 181 p (English). Saling E. Das Kind im Bereich der Geburtshilfe, Eine Einführung in ausgewählte aktuelle Fragen. Stuttgart, Thieme, 1966, 219 p (German).

Monika Dräger and Erich Saling

4 Amniotic fluid interventions and examinations

The following history of amniotic fluid examinations, respectively, interventions concerns: – Knowledge about the significance of meconium in the amniotic fluid, – Amniocentesis, – Amnioscopy.

4.1 Knowledge about the significance of meconium in the amniotic fluid It is very likely that at least some knowledge about the connection between meconiumstained fluid and endangered status of the infant has been achieved very early in medical history. This also illustrates the Latin name meconium, which derives from the Greek μήϰων, poppy juice or opium, and may refer “either to its tarry appearance that may resemble some raw opium preparations” [1] or to “Aristotle’s observation of the association between meconium staining of the amniotic fluid and a sleepy state or neonatal depression” [2]. According to Goodlin [3], in 1833, Kennedy from Dublin in his monography on obstetric auscultation already made accurate reflections upon the significance of meconium-stained fluid [4]. And in 1858, Schwartz from Germany in his monography wrote in detail about his examinations on the occurrence of meconium stained fluid [5]. He reached to the following conclusion (translation by us): “In infants, who have died at or immediately after birth and in seemingly dead infants, who recovered, preterm loss of fetal excrements is the rule, however, it is more often in the former than the latter,” [5, p. 266]. However, for a long time, the occurrence of meconium-stained fluid could only be assessed after amniorrhexis (or from the middle of the 20th century onwards in single cases after an amniocentesis). Routine assessment of the color of the amniotic fluid in order to detect meconium started only with the introduction of amnioscopy (see Section 4.3).

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4.2 Amniocentesis Amniocentesis was regarded as a sacrilegious breach of the inner sanctum of the uterus. There were only occasional case reports of its use in polyhydramnios: The first to report about amniocentesis as a means of decompressing a hydramnion were for example Lambl in 1881 [6] and Schatz in 1882 [7]. In 1930, Menees [8] performed the first amniography by injecting contrast medium into the amniotic cavity. In 1948, the first amniocentesisesis for measurement of intrauterine pressure was published by Alvarez and Caldeyro-Barcia (see Figure 4.1) [9, 10]. In 1952, Bevis [11] used amniocentesis for diagnosing Rh-erythroblastosis. This was an important prerequisite for two important methods developed by Liley in Australia: (1) first spectrophotometric analysis of amniotic fluid in 1961 [12] and (2) treatment of severe Rh-disease afflicted preterm fetuses developed in 1963. Liley and coworkers performed an intrauterine blood transfusion into the fetal peritoneal cavity [13]. With this treatment, Liley became the pioneer of fetal therapy. It is also of interest that Finn in 1961 developed the idea of destroying merged fetal Rh-positive erythrocytes [14]. This made him the pioneer of sensitization prophylaxis of erythroblastosis. From the 1960s onwards with the help of amniocentesis diagnoses of other diseases also became possible. For more details, please also refer to Chapter 8, Diagnosis of genetic defects. Amniocentesis for the detection of meconium or bile pigments in the amniotic fluid: In 1956, in 23 women with suspected toxicosis or postmaturity Lesinski performed amniocentesis to gain amniotic fluid. In cases of green fluid, he performed cesarian section [15]. Also in 1956, Hoffbauer [16] performed amniocentesis in cases of erythroblastosis and in 1962 Kubli [17] performed amniocentesis in order to identify an endangered status of the fetus.

Fig. 4.1. Alveraz & Caldeyro-Barcia (1948): First amniocentesis for measurement of intrauterine pressure (scheme) [10]. © Archivos Ginecologia y Obstetrica, with kind permission.

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4.3 Amnioscopy A quite different amniotic fluid examination is amnioscopy (see Figure 4.2) which the second author introduced in 1961 (first published in 1962) [18]. Amnioscopy enabled the obstetrician to assess amniotic fluid through the intact membranes at the forewaters during the last weeks of pregnancy. The main aspects have been to eval-

Fig. 4.2. Amnioscopy after Saling [18] (figure from: [23]): Introduction of the tube (above) and observation of the forewaters (below); © Erich Saling. © Reproduced from [23, Fig. 1, p. 473] with permission of BMJ Publishing Group Ltd.

Fig. 4.3. Amnioscopy after Saling [18]: findings and assessment: (a) Normal finding: (here: milky amniotic fluid with large vernix flakes and a hair strain of the fetus) = not increased risk; (b) Meconium-stained amniotic fluid = increased risk; Figure: © Erich Saling.

32 | Monika Dräger and Erich Saling uate the color of amniotic fluid and its content. Amnioscopy is a method to differentiate between fetuses of not increased risk concerning their respiratory supply from the mother, or with increased risk for example, when meconium-stained amniotic fluid or lack of amniotic fluid has been diagnosed (see Figure 4.3 (a) and (b)). Before ante-partum cardiotocography became available in 1968 induction of labor in cases of pathological amnioscopical findings was recommendable because of the obviously increased risk for these fetuses. This consequently reduced the incidence of seriously endangered infants. However, today also amnioscopy is still used for various indications [19–22].

Bibliography [1] [2] [3] [4]

[5] [6] [7] [8] [9]

[10]

[11] [12] [13] [14] [15] [16]

Wikipedia. Meconium, 2013. (Accessed November 11, 2013, at http://en.wikipedia.org/wiki/ Meconium). Fanaroff AA. Meconium aspiration syndrome: historical aspects. Journal of perinatology: official journal of the California Perinatal Association 2008,28,S3–S7 (English). Goodlin RC. History of fetal monitoring. Am. J. Obstet. Gynecol. 1979,133,323–352 (English). Kennedy E. Observations of Obstetrical Auscultation. Dublin, Hodges and Smith, 1833, 288 p. Available from: http://books.google.de/books?id=lXdTAAAAcAAJ&printsec=frontcover&hl= de{#}v=onepage&q&f=false (English). Schwartz H. Die vorzeitigen Athembewegungen; ein Beitrag zur Lehre von den Einwirkungen des Geburtactes auf die Frucht., 1858 (German). Lambl D. Ein seltener Fall von Hydramnios. Zentralbl Gynakol 1881,5,329–334 (German). Schatz F. Eine besondere Art von einseitiger Polyhydramnie mit anderseitiger Oligohydramnie bei eineiigen Zwillingen. Arch Gynakol 1882,19,329–369 (German). Menees TO, Miller JE, Holly LE. Amniography. Am J Roentgneol 1930;(2). 363 (English). Alvarez H, Caldeyro-Barcia R. Estudios sobre la fisiología de la actividad contráctil del útero humano. Primera comunicación. Nueva técnica para registrar la actividad contráctil del útero humano grávido. Archivos de Ginecologia y Obstetrica (Urugay) 1948,7,7–24 (Spanish). Alvarez H, Caldeyro-Barcia R. Fisiologia de la Actividad contractil del utero humano gravid. Cuarta communication. Adaptacion del “Tono” Uterino a las variaciones de volumen de su contenido. Archivos de Ginecologia y Obstetrica (Urugay) 1948,VII,139–151 (Spanish). Bevis DC. The antenatal prediction of haemolytic disease of the newborn. Lancet 1952,259, 395–398 (English). Liley AW. Liquor amnii analysis in the management of the pregnancy complicated by resus sensitization. Am. J. Obstet. Gynecol. 1961,82,1359–1370 (English). Liley AW. Intrauterine transfusion of foetus in haemolytic disease. Br Med J 1963,2,1107–1109 (English). Finn R, Clarke CA, Donohoe WTA, et al. Experimental Studies on the Prevention of Rh Haemolytic Disease. Br Med J 1961;(1).1486–1490 (English). Lesinski J. Frühdiagnose der drohenden intrauterinen Fetalanoxie mittels Amnionanstechung. Zentralbl Gynakol 1956,78,265–267. (German). Hoffbauer H. Die Bedeutung von Fruchtwasseruntersuchungen für die Diagnose und Therapie des Morbus haemolyticus neonatorum [Significance of amniotic fluid examination in diagnosis and therapy of hemolytic disease of the newborn]. Zentralbl Gynakol 1956,78,1707–1712 (German).

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[17] Kubli F. Indikation, Technik und klinische Interpretation der abdominalen Amnionpunktion 1962,22,134–143 (German). [18] Saling E. Die Amnioskopie, ein neues Verfahren zum Erkennen von Gefahrenzuständen des Feten bei noch stehender Fruchtblase [Amnioscopy, a new method for diagnosis of conditions hazardous to the fetus when membranes are intact.]. Geburtsh Frauenheilk 1962,22,830–845 (German). [19] Dudenhausen JW. Praktische Geburtshilfe. 20th edn. Berlin, de Gruyter, 2008, 470 p (German). [20] Fallahian M, Taherzadeh P, Neisani Samani E, Moghadam MP, Taheri Z. Amnioscopy Revival as a Fetal Surveillance Tool. World Journal of Laparoscopic Surgery 2009,2,4–6. (Accessed October 18, 2010, at http://www.jaypeebrothers.com/eJournalNEW/ShowText.aspx?ID=223&Type= FREE&TYP=TOP&IN=_eJournals/World%20Journal%20of%20Laparoscopic%20Surgery. jpg&IID=26&isPDF=YES) (English). [21] Saling E, Lüthje J. Amnioscopy is still of value for developing countries. In: Proceedings of Global Congress of Maternal and Infant Health, 22.-26.09.2010 in Barcelona, Spain, 2010SS2103. (Lectures) (English). [22] Saling E. Amnioscopy can still be of value in post-term cases, (Abstract). Punta del Este (Uruguay), 2011. (Accessed 2012 Jan 9). Available from: http://www.saling-institut.de/german/ 04infoph/05lit.html (English). [23] Saling E. Amnioscopy and Foetal Blood Sampling: Observations on Foetal Acidosis. Arch Dis Childh 1966,41,472–476. (Accessed November 4, 2010, at http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC2019594/pdf/archdisch01572-0022.pdf) (English).

J. Bennebroek Gravenhorst

5 Prevention of Rh-immunization

5.1 History 5.1.1 First descriptions and discovery of the pathogenesis In 1609, the first description of what appears to have been hemolytic disease of the newborn (HDN) was made by Louise Bourgeois (see Figure 5.1), a French midwife who worked at the court of King Henry IV and Queen Marie de Medicis. She described the birth of twins. The first a girl was hydropic and died immediately, while the second a boy, initially in a better condition, became jaundiced, got severe neurological symptoms and died three days later [1]. Ballantyne, in 1892, emphasized in a systematic study the characteristic appearance of the affected infants: severe anemia, organ enlargement, and yellow ascites containing bilirubin, the maternal multiparity and the

Fig. 5.1. Louise Bourgeois, 1563–1636. © Reproduced from [34] with kind permission of BMJ Publishing Group Ltd.

36 | J. Bennebroek Gravenhorst likelihood of recurrence in successive pregnancies [2]. Hydrops fetalis, anemia and kernicterus were interpreted as three aspects of the same pathology only in 1932 by Diamond et al. [3]. In 1938, Darrow extensively reviewed the subject of hemolytic disease of the newborn. She rejected all previously advanced theories save one, “the destruction of the red cells by some form of immune reaction.” The antibodies formed in the maternal organism might then pass to the child through the placenta and cause the hemolytic disease [4]. The true pathogenesis of the disease was clarified in 1940 with the discovery of the Rhesus (Rh) blood-group system by Landsteiner and Wiener and with the subsequent identification in 1941 by Levine et al. of the Rh (D) antigen [5, 6]. The Rh (D) antigen was identified in (D)-negative mothers as being the cause of the immunization, following transplacental passage of fetal (D)-positive red blood cells into the maternal circulation. The subsequent passage of maternal anti-(D) immunoglobulin G (IgG) across the placenta into the fetal circulation was recognized as the event causing the clinical symptoms of HDN. Evidence supporting this hypothesis was obtained in 1954 when Chown demonstrated fetal hemoglobin in the maternal circulation [7].

5.1.2 First exchange transfusions In 1925, Hart performed the first successful exchange transfusion on an erythroblastotic infant as a treatment. His experiments were ignored and it took 25 years before the procedure was repeated by Wallerstein and acknowledged as a standard therapy for HDN [8, 9]. The methods of transfusion have later been refined, for example, by Saling, who in 1959 exchanged the blood via the aorta abdominalis and in 1961 with the help of two catheters [10, 11], which allows the most gentle exchange. In addition, the introduction of the fetal blood analysis allowed already serological examinations of the fetal blood during labor which made it possible to start therapy immediately after birth [12].

5.2 Attempts to affect the immune system Some authors have claimed an improvement in perinatal outcome and a reduced need for exchange transfusions in immunized women treated with doses of promethazine ranging from 25 to 500 mg daily. Others found no beneficial effect of promethazine in treated patients compared with matched controls [13, 14]. High-dose intravenous immunoglobulin (IVIG) has been shown to be effective in the treatment of thrombocytopenic purpura during pregnancy [15]. Its mode of action is possibly by inhibition of antibody synthesis and blockade of antibody transport across the placenta. Although the limited experience suggests a possible beneficial effect of IVIG in red cell alloimmunization there is much doubt on the cost-effectiveness of this extremely expen-

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37

sive treatment. Plasma exchange, during which volumes of plasma were removed, has been recommended but its value in preventing severe fetal hemolysis has never been proven [16].

5.3 Intrauterine transfusion The introduction of intrauterine transfusions by William Liley in 1963 has dramatically changed the outlook for the very preterm fetus with hemolytic disease [17]. Refinements in technique and especially the use of modern ultrasound equipment have facilitated the procedure and improved the results [18]. The concept of this treatment is that red cells are absorbed from the fetal peritoneal cavity and enter the circulation [19]. By infusing Rh (D)-negative-packed cells, fetal anemia is corrected and delivery may be postponed to a more mature stage of pregnancy. The procedure may be started as early as 21–22 weeks of gestation and can be repeated if necessary up to three or four times. Pregnancy can usually be continued to 34–35 weeks of gestation. Percutaneous, ultrasound-guided puncture of umbilical cord vessels was introduced in 1985 by Daffos et al. for fetal blood sampling and infusion of platelets in alloimmune thrombocytopenia [20]. The method proved to be relatively safe and could easily be adapted for intravascular blood transfusions. The intravascular approach has the advantage of providing accurate data regarding the degree of fetal anemia and the severity of the disease. This approach appeared to be superior to the intraperitoneal infusion of red blood cells and has a high survival rate (86%) [21].

5.4 Rh-immune prophylaxis Levine et al. did not only identify the Rh (D) antigen, but they also described in 1941 that when ABO incompatibility exists between mother and infant, fetal blood cells are rapidly eliminated from the maternal circulation as a result of damage by the maternal A or B isoagglutinins [6]. This explains the finding that Rh-immunization is significantly more common in ABO-compatible couples than in those which are incompatible. In 1961, Stern demonstrated that the administration of anti-D IgG could prevent sensitisation to the Rh (D) antigen [22] which supported the findings of Levine. During the same period the successful studies in Rh (D)-negative male volunteers formed the experimental basis for clinical trials in pregnant Rh (D)-negative women [23, 24]. Clarke in the UK and Freda in the USA in 1965 published experimental evidence that post-partum administration of anti-D IgG decreased the incidence of anti-Rh (D) immunization from 12–13% to 1–2% [25, 26]. There appeared to be a direct proportional relationship between the volume of Rh (D)-positive red blood cells found in the maternal circulation and the incidence

38 | J. Bennebroek Gravenhorst of anti-Rh immunization. It has been estimated that 0.1 ml is already sufficient to induce the formation of antibodies [27]. Feto-maternal transfusion most frequently occurs during labor and delivery, but also after abortion and after some obstetric interventions (manual placenta removal, chorionic villous biopsies amniocentesis, cordocentesis and external version). The amount of fetal blood in the maternal circulation can be determined by the acid elution test described by Kleihauer et al. [28]. Pollack calculated that 20 μg anti-Rh (D)/1 ml erythrocytes or 10 μg anti-Rh (D)/1 ml full blood is necessary to prevent immunization [29]. Usually, the amount of fetomaternal hemorrhage does not exceed 4 ml of red cells and the administration of 100–200 μg will be sufficient to prevent immunization. Sometimes after spontaneous birth, cesarean section or manual placenta removal, large feto-maternal hemorrhages take place necessitating larger doses of anti-(D) immunoglobulin.

5.5 Later developments Later it became evident that Rh (D)-negative women, despite postnatal prophylaxis still developed anti-(D) antibodies in, 0.8–1.5%, because of small transplacental hemorrhages during pregnancy [30]. Results of clinical studies have suggested that routine antenatal immunoprophylaxis in the 28th and or 34th week of pregnancy in addition to postnatal prophylaxis further decreases the risk of Rh(D) alloimmunization [31]. In North America and several European countries, antenatal Rh prophylaxis with anti-(D) IgG immunoglobulin is provided for all nonsensitized Rh(D)-negative pregnant women unless the father of the baby is known to be Rh(D)-negative. Dosing schedule and methods of administration whether antenatal or postnatal vary as a result of divergent clinical practises in individual countries [31]. Anti-Rh-(D) immunoglobulin is produced by industrial fractionation from pools of donor plasma obtained from volunteers who have been immunized with Rh (D) antigen. Nowadays, fetal blood-group genotyping using cell free fetal DNA isolated from maternal plasma makes it possible to detect the fetal red blood-group genotype at 12 weeks of pregnancy and therefore is an important tool to prevent unnecessary administration of anti-Rh(D) immunoglobulin [32]. The current available evidence demonstrates that antenatal anti-(D) immune prophylaxis, besides being a cost-effective strategy, is able to further reduce the incidence of sensitization to (D) antigen down to about 0.2% [33].

Bibliography [1] [2] [3]

Bourgeois L. Observations diverses sur la stérilité perte de fruict foecondité accouchements et maladies des femmes et enfants nouveaux naiz. Paris, 1609. Ballantyne JW. The diseases and deformities of the fetus. Edinburgh, Oliver and Boyd, 1892. Diamond LK, Blackfan KD, Baty JM. Erythroblastosis fetalis and its association with universal edema of fetus, icterus gravis neonatorum, and anemia of the newborn. J Pediatr 1932,30, 269–309.

5 Prevention of Rh-immunization |

[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]

[16] [17] [18] [19] [20]

[21]

[22] [23] [24] [25] [26] [27] [28]

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Darrow RR. Icterus gravis (erythroblastosis neonatorum). An examination of etiologic considerations. Arch Path 1938,25,378 Landsteiner K, Wiener AS. An agglutinable factor in human blood recognized by immune sera for Rhesus blood. Proc Soc Exp Biol Med 1940,43,223–229. Levine P, Katzin EM, Burnham L. Isoimmunization in pregnancy: its possible bearing on the etiology of erythroblastosis fetalis. JAMA 1941,116,825–827. Chown B. Anaemia from bleeding of the fetus into the mother’s circulation. Lancet 1954,1, 1213–1215. Hart AP. Familial Icterus Gravis of the new-born and its treatment. Can Med Assoc J 1925, 15(10),1008–1011. Wallerstein H. Treatment of severe erythroblastosis by simultaneous removal and replacement of the blood of the newborn infant. Science 1946,103,583–584. Saling E. Austauschtransfusion bei Neugeborenen über die Aorta abdominalis. Geburtsh Frauenheilk. 1959,19,230–235. Saling E. Die zwei-Katheterverfahren für den Blutaustausch beim Neugeborenen. Dtsch med Wochenschr 1961,86,294–298. Saling E. Pränatale Feststellung der Erythroblastose. Geburtsh Frauenheilk 1961,21,694–696. Gusdon JP. The treatment of erythroblastosis with promethazine. J Reprod Med. 1981,26,454– 458. Stenchever MA. Promethazine hydrochloride: use in patients with Rh isoimmunization. Am J Obstet Gynec 1978,130,665–668. Mizunuma H, Takahashi Y, Taguchi H, et al. A new approach to idiopathic thrombocytopenic purpura during pregnancy by high dose immunoglobuline G infusion. Am J Obstet Gynec1984, 148,218–219. Fraser ID, Bennet MO, Bothamley JE, Airth GR. Intensive antenatal plasmapheresis in severe rhesus isoimmunization. Lancet 1976,1,6–8. Liley AW. The administration of blood transfusions to the fetus in utero. Triangle Sandoz J Med Sc, 1966,7,184–189. Buscaglia M, Ferrazzi E, Zulian, G, Caccamo, ML, Pardi G. Ultrasound contributions to the management of the severely isoimmunization fetus. J Perinat Med 1968,14,51–58. Mellish P, Wolman IJ. Intraperitoneal blood transfusion. Am J Med Sci 1958,235,717–725. Daffos F, Capella-Pavlovski M, Forestier F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet Gynec 1985,153, 655–660. Kamp van IL, Klumper FJCM, Meerman RH, Oepkes D, Scherjon SA, Kanhai HHH. Treatment of fetal anemia due to red cell alloimmunization with intrauterine transfusions in the Netherlands, 1988–1999. Acta Obstet Gynecol Scand 2004,83,731–737. Stern K, Davidson I, Masaitis L. Experimental studies on Rh immunization. Am J Clin Pathol 1956,26,833–843. Clarke CA, Donohue WTA, McConnell RB, et all. Further experimental studies on the prevention of Rh haemolytic disease. BMJ 1963,II,979–984. Freda J, Gorman JG, Pollack W. Successful prevention of sensitization in man with an anti-Rh gamma2-globulin antibody preparation: a preliminary report. Transfusion 1964,4,26–32. Clarke CA, Sheppard PM. Prevention of rhesus haemolytic disease. Lancet 1965,2,343. Freda VJ, Gorman JG, Pollack W. Prevention of rhesus haemolytic disease. Lancet 1965,2,690. Zipurski A, Israels LG. The pathogenesis and prevention of Rh immunization. Can Med Ass J 1964,97,1245–1257. Kleihauer E, Braun E, Betke K. Demonstration von fetalem Hämoglobin in den Erythrocyten eines Blutausstrichs. Klien Wochenschr 1957,35,637–638.

40 | J. Bennebroek Gravenhorst [29] Polack W, Ascari WQ, Crispen JF, O’Connor RR, Ho TY. Studies on Rh prophylaxis.II. Rh immune prophylaxis after transfusion with Rh-pos blood.Transfusion 1971,11,340–344. [30] McMaster C. On prevention of Rh immunizationVox Sang 1979,37,50–64. [31] Liumbruno GM, D’Alessandro A, Rea F, PicciniV, et al. The role of antenatal immunoprophylaxis in the prevention of maternal-fœtal anti-Rh (D) alloimmunisation. Bloodtransfus 2010,8,8–16. [32] Scheffer PG, de Haas M, van der Schoot, CE. The controversy about controls for fetal blood group genotyping by cell free DNA in maternal plasma. Curr Opin Haematol 2011,18,467–473. [33] Bowman JM. The prevention of Rh immunization. Trans Med Rev 1988,2,129–150. [34] Dunn PM. Louise Bourgeois (1563–1636): royal midwife of France. Arch. Dis. Child. Fetal Neonatal Ed. 2004,89,F185–F187.

Asim Kurjak

6 Sonography

6.1 Ian Donald – Pioneer of ultrasound in obstetrics and gynecology Without any doubt, this chapter should start with a short text dedicated to the pioneer in this field. Ian Donald, by the invention of diagnostic ultrasound, has changed the face of obstetrics and gynecology in the middle of the 20th century (Figure 6.1). Hardly any area in medicine has experienced such dramatic technical advances during the past four decades as diagnostic ultrasound. The development of high-resolution 2D probes and improvements in color Doppler ultrasound have been critical milestones in the recent history of sonographic diagnosis. Especially in prenatal diagnosis and gynecology, ultrasound has become an indispensable, non-invasive diagnostic tool. With the recent advent and evolution of three-dimensional (3D) ultrasound technology during the past 20 years, we now stand at a new threshold of non-invasive diagnosis [1–3]. The diagnostic ultrasound origins go back to maritime history. Donald’s often stated preference for the term ‘sonar’ (which stands for ‘sound navigation and ranging’) when referring to ultrasonic echography is based on his acknowledgement of this historical fact. In 1954, Ian Donald was appointed Regius Professor of Midwifery at the University of Glasgow. Later he became professor of obstetrics and gynecology at the Queen

Fig. 6.1. Ian Donald with the first real-time probe and Diasonograph.

42 | Asim Kurjak Mother’s Hospital. On arrival in Glasgow Donald soon set about trying to learn something about the energy properties of ultrasound and managed to borrow from an engineering firm a powerful ultrasonic generator situated in a bath of carbon tetrachloride in which it created massive turbulence. He then suspended samples of unclotted blood in it for varying periods and then, by cell counting, determined the degree of hemolysis. One of Donald’s initial clinical frustrations on coming to Glasgow was the problem of the woman with a grossly distended abdomen in which the traditional methods of clinical diagnosis were simply inadequate. Those were the days of massive tumors, both ovarian and uterine, of ascites whether cardiac, neoplastic or hepatic in origin, and of obesity such as one seldom sees today. Donald always remembered that hot sunny afternoon of July, 21, 1955 when he took to the factory some specimens of the last few days, in the boots of two cars, large ovarian cysts and uterine fibroids, calcified and plain. The firm very thoughtfully provided a truly massive piece of prime steak as a control material. He wanted to know whether a metal flaw detector could show up on A-scan, suggesting the difference between a cyst and a solid myoma. To his surprise and delight the differences were exactly as his reading had led him to expect, the cysts showing clear margins without intervening echoes because of their fluid content and the fibroid progressively attenuating the returning echoes. Returning to the problematic female abdomen, dramatic, life-saving success soon came their way. Donald was invited to see a woman who had a grossly distended abdomen, believed to be due to massive ascites as a result of malignant portal obstruction. A barium meal X-ray had revealed a carcinoma of stomach and her case was regarded as hopeless with progressive anemia from incessant hematemesis and rapid loss of weight. His own clinical examination of this very tense abdomen fully supported the physician’s diagnosis. He expected to find on A-scan examination a mass of bowel echoes in the central abdomen due to the presence of contained gas. All he could demonstrate was a clear space with a very strong echo so that he began to doubt the validity of the technique. At operation he found a mammoth-sized mucinous cystadenoma which was entirely benign. Her recovery was immediate. Vomiting and hematemesis ceased, the X-rays were declared to be an artefact, and she put on weight and remained well for many years. Even though early results of ultrasound were disappointing and the enterprise was greeted with a mixture of scepticism and ridicule, this dramatic case where ultrasound saved a patient’s life made people take the technique seriously. ‘From this point’, Ian Donald wrote, ‘there could be no turning back’ [4]. His incursion into the study of pregnancy did not begin until 1957. In pregnancy the only echoes of which they could be reasonably sure at that time were those provided by the fetal head. It was this which led him to undertake a series of water tank experiments in which he learned to identify the biparietal diameter and, with later development, its accurate measurement.

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True tissue differentiation was only to come many years later, especially with the development of gray scaling. Nevertheless, at this time in 1958 they could differentiate with reasonable certainty between quite a variety of gynecological tumors and ascites both benign and malignant (the latter having a characteristically bizarre appearance) and, of course, gross obesity. They could also demonstrate fetal echoes in utero, particularly the fetal head provided the uterus was enlarged above the level of the symphysis pubis. Donald’s team first went to peer-reviewed literature in The Lancet of 7th June 1958 under the arid title ‘Investigation of Abdominal Masses by Pulsed Ultrasound’ [5] and he regarded this as one of the most important papers he had ever written, noteworthy also because there had, so far, been no subsequent need to repeal anything he had then written. Indeed this was probably the most important paper on medical diagnostic ultrasound ever published. Ten years later all doubts had been cast away and Ian Donald was able to review the early history of ultrasound in a characteristic, forthright manner. ‘As soon as we got rid of the backroom attitude and brought our apparatus fully into the Department with an inexhaustible supply of living patients with fascinating clinical problems, we were able to get ahead really fast. Any new technique becomes more attractive if its clinical usefulness can be demonstrated without harm, indignity or discomfort to the patient’ [4]. In 1959, Ian Donald noted that clear echoes could be obtained from the fetal head and began to apply this information. Within the next few years it became possible to study pregnancy from beginning to end and diagnosis of complications like multiple pregnancy, fetal abnormality and placenta praevia (which causes life-threatening hemorrhage) became possible. Professor Donald had gathered around him a team of talented young doctors and technologists, including the research engineers John Fleming and Angus Hall, who were engaged by the University. Tom Brown, at the age of 24, invented and constructed with Ian Donald the prototype of the world’s first Compound B-mode (plan-position indication, PPI) contact scanner in 1957. The transducer operated at 2.5 MHz. The prototype was progressively improved to become the Diasonograph® manufactured commercially by Smith Industrials of England which had taken control of the Kelvin and Hughes Scientific Instrument Company in 1961 [4]. The automatic B-scanner was completed in 1960 and Donald and his team were able to identify and measure biparietal diameter accurately. The biparietal cephalometry had a remarkable development. The glimpses which they obtained with a hand-held probe left insufficient time to measure the distance between the relevant blips from the parietal eminences on the cathode-ray tube face. Accordingly, his colleague Brown borrowed from his employers a two-channel-gated flaw alarm unit which triggered a solenoid-operated polaroid camera from whose photographs measurements could be accurately made. This was an ingenious device with which it was hoped to simplify biparietal cephalometry in the course of random searching in the region of the anterior fetal parietal bone. A physicist, Tom Duggan,

44 | Asim Kurjak joined the team. He introduced electronic cursors consisting of bright-up dots which could be placed by knob manipulation on the leading edges of the blips and provide a digital read-out of the distance between them. This proved even more accurate and saved money on photographic materials. Bertil Sunden from Sweden was Donald’s first distinguished foreign pupil to whom he taught all he then knew. He returned to Lund with his own apparatus and contributed greatly to the subject, mainly in the identification of twins by counting fetal heads and in recognizing the characteristic features of hydramnios. Donald’s experience grew in a number of directions, most notably of all perhaps in the rapid and easy diagnosis of hydatidiform mole. From 1962 onwards, Donald’s team had established contact with Joe Holmes and his colleagues in Denver with whom a successful cooperation and association has been maintained ever since. Both groups made research to identify the placenta as an extension of the principles underlying the diagnosis of hydatidiform mole. A really important breakthrough occurred in 1963 when a nervous patient presented herself for examination with extremely full bladder. This at once made possible visualization of the pelvic viscera, even though not enlarged, since it had the effect of displacing gas containing and therefore impenetrate bowel out of the field and also provided a built-in viewing tank without interfering with the ultrasonic picture. With full bladder even the contents of a normal size uterus could have been then studied. Early pregnancies, normal, abnormal, aborting and continuing could have been then studied serially in great detail from the fifth week onwards and they soon collected a mass of material. Donald published the various appearances throughout prenatal development in an article in the Journal of Pediatrics in 1969. By the early 1970s, Donald’s team began to recognize the phenomenon of ovum blighting and published their findings on the subject in 1972. Hugh Robinson came on the scene to replace Stuart Campbell who had done so much to import sonar to a city like London. Robinson’s most significant contributions were the determination of the fetal crown-rump length and its accurate relation to early gestational age and the positive identification of early fetal heart movement by time motion display. These provided the concrete evidence of continuing fetal life long before ultrasonic Doppler studies become worthwhile. In 1974, a scan converter and accessories were linked up with Donald’s standard Diasonograph B-scanner. This immediately made gray scaling possible. The quality of the pictures as regards organ outline remained as good as ever but also, by different shades of gray, gave a far better indication of tissue characterization. This facility has opened up a whole new avenue of approach, especially in the study of tissue parenchyma. Finally, just before his retirement in 1976, there came on the scene a whole crop of real-time scanning machines. Recent technological breakthroughs in diagnostic ultrasound have surpassed all expectations. With these advances, clinicians now have the tools needed to contend

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with many significant diagnostic challenges. The rapid improvement in ultrasound image quality that has occurred, particularly over the past 20 years, has enabled us all to a degree that was thought inconceivable at Donald’s time. What is undeniable however are the dramatic changes by the advent of color Doppler, power Doppler and more recently 3D and 4D imaging. The simultaneous development of ultrasound contrast has also widened the diagnostic armamentarium at our disposal. The Ian Donald Inter-University School of Ultrasound bears testament to globalization in its most successful and worthwhile form. The school was founded by Asim Kurjak in Dubrovnik in 1981. In the preface of the first edition in 2004 [6], we were proud to announce that the school had grown to eight branches. Since then, the growth has been meteoric and now consists of more than 80 national branches throughout the world, and it is now considered one of the largest and most important ultrasound schools in the world. The reason for this success has been the tireless and selfless efforts of the world’s leading authorities in ultrasound who are willing to dedicate their valuable time without reimbursement to teach sonologists and sonographers throughout the world. The teachers put national, religious, political, and other parochial considerations aside as they strive to improve the care of all women and fetal patients. Our politicians in all of the more than 80 countries represented in the school have much to learn from the purity of spirit that exists throughout the international family of Ian Donald schools. It is not overstating the fact to say that Donald’s innovation has changed the thinking of our age. The magnitude of this step alone is incalculable. Indeed, diagnostic ultrasound, more than any other modern technique, has made manifest that the fetus is a patient virtually from conception [1–3].

6.2 Parallel early developments in the USA, Japan, and Russia According to Woo [4], Holmes, Stewart Taylor, Horace Thompson and Kenneth Gottesfeld in Denver published their important work in clinical ultrasound. They published some of the earliest papers on ultrasound in obstetrics and gynecology from North America. In 1962, Douglass Howry moved to Boston where he worked at the Massachussetts General Hospital until his death in 1969. Woo wrote about the development of ultrasound in Japan. He mentioned two surgeons at the Juntendo University in Tokyo, Kenji Tanaka and Toshio Wagai, who together with Shigeru Nakajima (director of the Japan Radio Company), Rokuro Uchida (physicist) and chief engineer had started to consider the use of ultrasound in the diagnosis of intracranial disease. They collaborated with the Nihon Musen Radiation and Medical Electronics Laboratory. In 1950, the laboratory became the Aloka® Company headed by Uchida Nakajima. In 1949, Uchida was the one who built Japan’s first ultrasonic scanner which operated in the A-mode and was modified from a metal-flaw detector.

46 | Asim Kurjak Another important figure who was involved in their research was Yoshimitsu Kikuchi who was at that time Professor at the Research Institute of Electrical Communications at the Tohoku University in Sendai. In 1952, the team started their formal work in ultrasound imaging. Aloka® Company was successful in producing Japan’s first commercial medical A-scanner, the SSD-2 and the water-bag B-scanner, the SSD-1 in 1960. To quote Woo, ‘The application of ultrasound in obstetrical and gynecological diagnosis started around 1956 with the A-scan basing on a vaginal approach and later B-scans at around 1962 basing on the use of the “one-point contact-sector scanner” in the PPI format. Early commercial water-bag scanners were being produced by Aloka® and Toshiba® in the early 1960s’. In another part of the world, at around the same time, in the early 1960s, N. D. Selezneva, whose teacher was S. Y. Sokolov, the famous Soviet scientist, published her work in ultrasound in gynecology in the former USSR. Scientists from the Central Institute of Advanced Training in Medicine from Moscow, Khentov, Khlestova and Skorunskii, followed Selezneva and published numerous papers from the field of obstetrics and gynecology from 1965 onwards. Their work was based on using A-mode and later on using B-mode equipment made at the USSR Scientific Research Institute of Medical Instruments and Equipment. However, almost all of these publications were in the Russian language.

6.3 The ultrasonic boom in the 1960s From 1966 onwards, research in obstetric and gynecologic ultrasound and its application significantly developed. Numerous centers, especially in Europe, United States and Japan, were involved in studying the application of ultrasound diagnosis in obstetrics and gynecology.

6.3.1 The development and use of new ultrasound devices: the Vidoson® real-time scanner and articulated-arm compound contact scanner SSD-10 Woo’s investigation of the history of ultrasound showed that the advent of the realtime scanners was such an important innovation that it completely changed the practice of ultrasound scanning. According to Woo, the first real-time scanner, better known as ‘fast B-scanners’ at that time, was developed by Walter Krause and Richard Soldner (with Paetzold and Kresse) and manufactured as the Vidoson® by Siemens Medical Systems of Germany, in 1965 (Figure 6.2). Hofmann, Holländer and Weiser at the Westphalian Wilhelms University in Münster, Germany published its first use in obstetrics and gynecology in 1966 in the German language. Hofmann and Holländer’s paper in 1968 on ‘Intrauterine diagnosis of hydrops fetus universalis using ultra-

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Fig. 6.2. The Vidoson 635 by Siemens Medical Systems, Germany, 1965. The transducer housing is mounted on a mobile gantry and rigidly connected to the main console. The scanning frequence was 2.25 MHz. Scaling and caliper functions were not present, with kind permission from Deutsches Museum, Bonn.

sound’, also in German, is probably the first paper in the medical literature describing formally the diagnosis of a fetal malformation using ultrasound. It has been recorded that in 1969, Malte Hinselmann, using the Vidoson® , demonstrated the universal visualization of fetal cardiac action from 12 weeks onwards. The Vidoson® kept its popularity in the next 10 years or so and was used in many scientific works done in centers throughout Europe. Its initial popularity was based more on the possibility for the operator to display and study movements (e.g., fetal cardiac motion, gross body movements and fetal breathing movements) than on the resolution of the images. In 1978, in Charleroi, Belgium, the International Symposium on Real-time Ultrasound in Perinatal Medicine was organised. It was noted that the most of presented work were based on results from the Vidoson® [4]. We have to mention Louis M. Hellman, Mitsunao Kobayashi, Ross Brown, George Leopold, Roy Filly, Roger Sanders, Arthur Fleischer, Kenneth Taylor, Fred Winsberg, John Hobbins and William Cochrane. They were very active from the early 1970s onwards and contributed significantly to the application of obstetric and gynecologic ultrasound. Winsberg was particularly interested in real-time scanners. In 1970, he initiated the use of the German Vidoson® real-time scanner in Montreal, Canada, at the McGill University.

48 | Asim Kurjak One of the earliest textbooks in sonography was ‘Atlas of Ultrasonography in Obstetrics and Gynecology’, authors Kobayashi, Hellman and Cromb, published in 1972. In Japan, one of the most active was Juntendo University in Tokyo where Shigemitsu Mizuno, Hisaya Takeuchi, Koh Nakano and Masao Arima experimented with new versions of the A-mode transvaginal scanner [4]. As Woo described, ‘The first ultrasound scan of a 6-week gestational sac by vaginal A-scan was reported in the Japanese language in 1963. From 1962, the group worked extensively with the water-bag B-scanner, the Aloka SSD-1 and was very active in many areas and producing a huge number of research publications, ranging from early pregnancy diagnosis to cephalometry to placentography. They also reported on a large series of pelvic tumors in 1965, and in the following 2 years switched from the waterbag contact scanner to the articulated-arm compound contact scanner, the SSD-10. Another group consisting of Tanaka, Suda and Miyahara started researches into the different stages of pregnancy in 1964’. Shigemitsu Mizuno, Hisaya Takeuchi and their team also demonstrated in 1965 an endovaginal scanner for pelvic examination using the plan-position indication (PPI) B-mode format. The device was manually rotated and the resulting display was very similar to a circular military ‘radar’ display. Used either transrectally or transvaginally, it was capable of producing some meaningful pictures of the pelvic organs. See Hisaya Takeuchi for a list of early work from the group. The Japan Society of Ultrasonics in Medicine was officially formed in 1962. In the 1970s, important work started at the Tottori University, Toyko under Kazuo Maeda, particularly on Doppler fetal cardiotocography and at the University of Toyko under Shoichi Sakamoto. Toshiba® produced their first A-mode scanner, the SSA-01A and the compound contact B-scanner, the TSL system in 1967. Hitachi® produced their first A-mode (EUA-1) and B-mode scanner (EUB-1) in 1971 and 1972, respectively [4].

6.3.2 The work of Alfred Kratochwil We have to mention the work of Alfred Kratochwil (Figure 6.3). At the Second University Frauenklinik in Vienna, Austria, he started working on placental localisation with the A-mode scanner. He acquired the same from Paul Kretz, the founder of KretzTechnik AG in Zipf, Austria. After he learned of Ian Donald’s work with the B-scan, he started to collaborate with the company to develop a similar device. The company adapted model 4100, which was originally designed for ophthalmologic use, to carry an articulated-arm gantry for the abdominal B-scan mode. It was reported that he initially tried to use it on localising pelvic recurrences in patients who underwent radical surgery for carcinoma of the cervix, and also on a variety of obstetric conditions. In 1972, Kratochwil was successful in visualization of ovarian follicles with static B-mode ultrasound.

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Fig. 6.3. Alfred Kratochwil using the A-scan, © Prof. Kratochwil, with kind permission.

According to Woo, Kratochwil became a very productive user of the instrument, publishing many early papers. In his department in Vienna, he also established training courses in ultrasound in which from 1968 onwards hundreds of radiologists and obstetricians learned about the applications of ultrasonography. He was one of the most productive investigators in Europe and significantly and constantly assisted to KretzTechnik AG to improve their designs. It is worth mentioning that the ‘First World Congress on Ultrasonic Diagnostics in Medicine’ was held in Vienna in 1969 and the second in Rotterdam in 1972. Both meetings gathered clinicians and scientists involved in ultrasound and resulted in its further development and application.

6.3.3 The Kossoff group: first use of ultrasound in the diagnosis of fetal malformation and further technical innovations It is important to mention that in 1959 the Ultrasonic Research Section at the National Acoustic Laboratory was established in Sydney, Australia and its goal was to form a center of technical expertise in the field of medical ultrasound [4]. George Kossoff was working with William Garrett, a gynecologist from the Royal Hospital for Women in Sydney. In 1959, Kossoff introduced the water-coupling CAL echoscope, perfected it in 1962. It was modified for breast scanning as well. Since 1959 the team consisting of George Kossoff, chief physicist and director of the Ultrasonic Research Section was involved and most successful in inventing and refining ultrasound apparatus for a variety of purposes including ophthalmic applications. David Robinson joined the group in 1961. It was at the Ultrasonics symposium held in Illinois the next year that they presented their first obstetrics scans. It was in 1968 that

50 | Asim Kurjak Garrett, Robinson and Kossoff published ‘Fetal anatomy displayed by ultrasound’ using the water-bath CAL echoscope. This was one of the first papers announcing the future role of ultrasound in the diagnosis of fetal malformations. Another paper was published in 1970 reporting a case of fetal polycystic kidneys at 31 weeks of gestation. Woo [4] wrote that ‘The most important innovation in ultrasound imaging subsequent to the invention of the compound contact scanner was the advent of the scan converter. The cathode ray tube had a low dynamic range of about 16 decibels. The application of true gray scaling had evolved from the work of the Kossoff group. Together with William Garrett and two brilliant engineers, George Radovanovitch and David Carpenter, Kossoff published their new scan converter with gray scale capabilities in 1973, basing on work which they had already started in 1969’. The team developed sophisticated annular dynamic phased arrays which were installed in the mark II water-coupling echoscope. It is well known that in 1975, according to Woo, ‘they constructed the UI Octoson, a rapid multi-transducer water-bath scanner which had then incorporated the new scan-converter, improved annular array transducers and more powerful computing electronics that had allowed for superior compound scans to be completed in less than 1 second. The scanning mechanism of the Octoson is completely immersed in the coupling tank’. At the two meetings – at the International Biological Engineering meeting held in Melbourne in 1971, and at the World Congress of Ultrasonic Diagnosis in Medicine held in Rotterdam in 1973 – the group reported gray-scale obstetric scans. The team was strengthened by David Carpenter who joined the Section in 1968, and headed the Engineering Research subsection, and by Stanley Barnett, a physiologist who published extensively on ultrasound bioeffects.

6.3.4 Ultrasound in the diagnostics of pregnancy assessment As Woo [4] elegantly described, ‘the A-mode scan had been used for early pregnancy assessment (detection of fetal heart beat), cephalometry and placental localisation in Europe, Britain, United States, Japan, China, USSR, Poland and Australia in the early 1960s, the measurement of the biparietal diameter (BPD) having been invented by Ian Donald in 1961 and further expanded in his department by James Willocks, basing on improvements in the “bright-up” markers and the electronic caliper system. The measurements were done “blindly” without actually seeing the structures under study. Visualizing the gestational sac by B-mode ultrasound was first described by the Donald and MacVicar team in 1963. The first ultrasound scan of a 6-week gestational sac by vaginal A-scan was reported in the Japanese language in 1963. In 1965, they were able to demonstrate a 5-weeks gestational sac. The gestational sac diameters in the assessment of fetal maturity was described by Lou M. Hellman and M. Kobayashi in 1969 and by Pentti Jouppila (Finland), Salvator Levi (Brussels) and E. Reinold (Vienna) in 1971

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in relation to early pregnancy complications. Kobayashi also described the ultrasonic appearance of extra-uterine pregnancy using bi-stable B-mode ultrasound in 1969’. In 1970, a large series of patients where fetal death in utero was diagnosed solely on bistable ultrasound scan was reported by Kenneth Gottesfeld in Denver. One of the vital uses of ultrasonography is the ability to detect and confirm whether the fetal cardiac action is present in early pregnancy. Detection of fetal heartbeat by the A-scan and audio Doppler ultrasound had been variously reported, e.g., Wang in 1964 reported M-mode from 10 weeks, Kratochwil in 1967 vaginal A-scan from 7 weeks, Bang and Holm in 1968 A- and M-mode from 10 weeks. However, only in 1972, Hugh Robinson in Glasgow, using the improved instrumentation, achieved 100% detection of fetal cardiac action as early as from 7 weeks onwards. Using B-scan ultrasound, Robinson was able to locate the fetus and then observe the heartbeat with a direct beam in A- and M-mode. Such a step forward enabled better management of early pregnancy bleeding and in threatened miscarriages. In 1966, the Denver group reported B-mode placentography as well as the Donald group one year later. It is known that in 1963 the same group described ultrasonic diagnosis of molar pregnancies [4]. In 1968, Stuart Campbell published a historic paper entitled ‘An improved method of fetal cephalometry by ultrasound’ in which he described the use of A- and B-mode scan in measuring the fetal biparietal diameter. This method became standard practice in an ultrasound examination. It is important to state that Hugh Robinson in Glasgow, a research registrar at that time, in 1973 described measurement of the fetal crown-rump length. With new machines, life size magnification of the images was possible and thus accurate measurement on early embryos was enabled. With further investigation and ultrasonic findings, the Scottish group in 1972 developed the concept of ‘blighted ovum’ in obstetrics. It was Ian Donald who first described it in 1967. This concept has significantly changed the management of pregnancies with vaginal bleeding in the first trimester. In 1965, Horace Thompson was the one who presented measurement of the thoracic circumference (TC) as a method to study fetal grows. The accuracy of such measurement was within 3 cm in 90% of the patients. Several years later, in 1972, the thoracic circumference was re-introduced by Manfred Hansmann who correlated it with the birth weight of the fetus. Hansmann also presented intrauterine transfusion under ultrasonic guidance. Woo [4] wrote that ‘William Garrett and David Robinson in Sydney had also reported on measurement of the fetal trunk area as a means to assess fetal size. The group used a water-bath Echoscope which by 1970 had already incorporated some degree of gray scale capability allowing for better visualization of the fetal trunk’. Stuart Campbell, using static B-scan, published two important papers in Lancet. The first one, published in 1972, reported the diagnosis of an anencephalic fetus at 17 weeks while the second one, published in 1975, reported the diagnosis of spina bifida.

52 | Asim Kurjak Another important parameter was introduced by the Campbell group in 1975. It was the measurement of the abdominal circumference, since then the most important single parameter to assess fetal weight and nutrition. Circumference measurements of the fetal trunk are considered superior to diameter measurements as the former is less affected by the change in shape of the fetal body. It was not until 1979 that Margi Mantoni and Jan Fog Pederson in Copenhagen first described the visualization of the yolk sac, using the static B-scan [4].

6.4 The implementation of Doppler ultrasound It is important to mention various applications of Doppler ultrasound. In 1955, Wild and Reid had invented and described the use of A-mode trans-vaginal and trans-rectal scanning transducers. Using a KretzTechnik A-mode vaginal scanner, Alfred Kratochwil in Austria was able to report on fetal heart pulsation at slightly over 6 weeks menstrual age. Since 1977, Robert Gill together with the Kossoff group performed quantitative measurements of human blood flow velocities with the Octoson® . He was able to determine that the flow in the fetal umbilical vein increased with gestational age; however, it remains constant at around 103 ml per min per kg fetal weight. We should be aware that some factors (e.g., operator’s skill, fetal position, blood vessel diameter and angle of insonation) influenced the accurate measurement of flow volumes and flow velocities in the fetal blood vessels and thus made it impractical. Sturla Eik-Nes and Karel Marsal developed in 1980 in Norway the first hand-held linear-array real-time apparatus coupled with range-gated Doppler and were able to document blood flow velocities in the fetal aorta. The use of the new apparatus enabled them in 1983 to report the volume flow through the umbilical vein. In Oulu, Finland, Pentti Jouppila and Pertti Kirkinen group was very active. They worked with quantitative blood flow velocities in the umbilical vein and were able to report a significant reduction in flow in growth-retarded fetuses. Their findings from 1981 showed that in fetuses with severe growth retardation the quantitative umbilical venous flow was unrecordable. In 1984, they concluded that there was a significant negative correlation between umbilical venous flow and the cord hemoglobin. An important breakthrough happened in 1985 when an advertisement of the first machine with real-time color flow mapping capabilities from Aloka® (SSD-880CW) appeared in medical journals. Later in the same year, Toshiba® was next with their SSH-65A. Asim Kurjak in Croatia, using the Aloka® machine, was the first to introduce the application of color flow Doppler in fetal assessment, publishing his work in 1987 [4].

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6.5 Later developments and future perspectives 6.5.1 The founding of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and the first journal in this field Stuart Campbell with his colleagues Asim Kurjak, Manfred Hansmann, Yuriy Wladimiroff and Ivica Zalud, soon started the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) in 1990 and held its first world congress in the following year. He also became the founding editor of the Society’s official journal, Ultrasound in Obstetrics and Gynecology (UOG). The first issue of this journal was published in January 1991. UOG is an international, peer-reviewed journal. Published monthly, the journal includes original papers, case reports, reviews, editorial and opinion articles, and a letters column.

6.5.2 From the scan of fetal movements to the diagnosis of fetal well-being due to Doppler ultrasound By the introduction of real-time scanners research on body movements and breathing movements of the fetus became possible. Dawes and Boddy from the Nuffield Institute of Medical Research at Oxford University in England initiated the study of fetal breathing movements in the early 1970s. They considered that the presence or absence of breathing movements as well as their amplitude and intervals, is indicative of fetal well being. In early to mid-1970s, other groups from different centers, such as Karel Marsal group from University Hospital at Malmo (Sweden), the Tchobroutsky group at the Maternite de Port-Royal in Paris, the Wladimiroff group in Rotterdam, and the Trudinger group in Australia, joined the research and started to use real-time apparatus. Further investigations and research were done and reported. One of them was done by Stuart Campbell’s group at the King’s College Hospital in London. This active group reported in 1983 the evaluation of utero-placental flow velocity waveforms in compromised pregnancies with duplex Doppler, and described the ‘frequency index profile’. Another center was the one in Utrecht (The Netherlands) where Reuwer in 1984 first discussed the ominous significance of absent end-diastolic flow in the umbilical artery. Later in 1986 and 1987, the Campbell group, including work from Hackett and Cohen-Overbeek, was able to prove that absence of end-diastolic flow in the fetal descending aorta plays a significant prognostic role. In Australia, it was Brian Trudinger who in 1986 revealed that abnormal Doppler waveform patterns tended to preceed abnormal cardiotocographic traces. According to Woo [4], ‘in the same year the Wladimiroff group reported the value of middle cerebral artery waveforms in the assessment of severely compromised fetuses. Sanjay Vyas working at King’s College Hospital in England described the use of renal artery waveforms in 1989. The value of fetal venous blood flow in the assessment of fetal compromise was first suggested by

54 | Asim Kurjak Torvid Kiserud in Bergen, Norway in 1991. Giuseppe Rizzo at the Universita di Roma Tor Vergata in Italy furthered expounded the usefulness of the ductal venus velocimetry in fetal acidemia and cardiac decompensation’ [4]. Until the mid-1980s, Doppler ultrasound was not applied in gynecology. In 1985, Kenneth Taylor from Yale described blood flow in the ovarian and uterine arteries. In 1989, in Croatia, Asim Kurjak successfully introduced the use of transvaginal color Doppler in the assessment of pelvic circulation.

6.5.3 The implementation of 3D ultrasound Fast development of ultrasonic and computer technology enabled work on 3D visualization to begin in the early 1980s [4]. The Japanese experts were leading in 3D technology. Thus the Institute of Medical Electronics at the University of Tokyo was the first to report on a 3D ultrasound system in 1984. One of expert was successful in obtaining 3D fetal images by processing the raw 2D images on a mini-computer in 1986. According to Woo [4], ‘their setup was reported in the Acta Obstetrica et Gynaecologica Japonica. Baba, with Kazuo Satoh and Shoichi Sakamoto at the Saitama Medical Center, described the improved equipments in 1989 in which they used a traditional real-time convex array probe from an Aloka SSD280 scanner mounted on the positionsensing arm of a static compound scanner (Aloka M8U-10C)’. The contribution of Eberhard Merz from the Center for Diagnostic Ultrasound and Prenatal Therapy at University of Mainz (Germany) should be mentioned. In 1995, Merz successfully demonstrated the usefulness of multiplanar orthogonal imaging as well as surface views and transparent views in the diagnosis and confirmation of fetal surface and skeletal anomalies such as cleft lips and complex multiple malformations. He and his co-workers reported a large series of over 600 cases of fetal diagnosis using 3D ultrasound. In 1997, his team reported on the diagnosis of facial anomalies using transvaginal 3D scans. Medison® , which had acquired KretzTechnik® in 1996 continued to produce more advanced versions of the Voluson series of scanners that produced some of the best 3D images in the market. Bernard Benoit in Nice, France working in collaboration with KretzTechnik® , published some of the earliest, most stunning and convincing 3D images in the mid-1990s using prototype Voluson scanners. His pictures had been responsible for drawing the attention of many to this new scanning modality [4]. The development of transvaginal 3D probes has further enhanced its value in the early diagnosis of congenital malformations. In the article by Asim Kurjak and his team, ‘Three-dimensional sonography in prenatal diagnosis: a luxury or a necessity?’, he concluded, ‘. . . the main advantages of three-dimensional ultrasound in perinatal medicine and antenatal diagnosis include scanning in the coronal plane, improved assessment of complex anatomic structures, surface analysis of minor defects, volumetric measuring of organs, “plastic” transparent imaging of fetal skeleton, spatial presentation of blood flow arborization and,

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finally, storage of scanned volumes and images. It is our decided opinion that threedimensional sonography has gained a valuable place in prenatal diagnosis, becoming a necessity for every modern perinatal unit . . . ’. Dolores Pretorius published on its usefulness and techniques in 1998. The Croatian group led by Asim Kurjak and Sanja Kupesic expounded this new diagnostic entity further. Their book ‘Three-Dimensional Power Doppler in Obstetrics and Gynecology’ was published in 2000.

6.5.4 Use of ultrasound in the diagnostics of malformation and preterm delivery Kypros Nicolaides at King’s developed the single operator two-hands method and became a leading figure in cordocentesis exploring many important aspects of fetal physiology and pathophysiology. With the advent of color flow mapping, the technique has become even more accessible. In 1992, Nicolaides and his group at King’s published the landmark paper where the measurement of nuchal translucency between 11 and 14 weeks was used to screen for Down syndrome. He demonstrated the importance of likelihood ratios in the detection. The group later on turned out some of the most important data regarding the application of nuchal translucency measurements including risk estimates and the quantization of the measurement into gestational-age related multiples of the median (MoM). We should also mention Ilan E. Timor-Tritsch, who was working in Israel and later on at New York University. He reported frequently on fetal anatomy and anomalies which he systematically studied using high-resolution transvaginal transducers in the first trimester. Timor-Tritsch opened up a new area in fetal ultrasound diagnosis, that of ‘sono-embryology’. Transvaginal 3D work on early fetal anatomy and malformations had also come out of Timor-Tritsch’s center in New York. Frank Chervenak defined the jugular lymphatic obstruction sequence for cystic hygroma in the New England Journal of Medicine which presaged the classic work of Nicolaides with nuchal translucency and he published pioneering works in Lancet and other journals on hydrocephalus and other anomalies of the fetal neural axis. However, his timeless contribution is the development of the field of perinatal ethics with its myriad applications to ultrasound screening, diagnosis, and management. Roberto Romero, during his tenure at Yale University and subsequently at the Perinatology Research Branch of NICHD/NIH, has made seminal contributions to the development and application of obstetrical ultrasound. Early contributions included the description of the discriminatory hCG zone [8] and other sonographic findings in the diagnosis of ectopic pregnancy, and studies in fetal anatomy, physiology, biometry and growth, as well as dysmorphology. The book Prenatal Diagnosis of Congenital Anomalies [9] became the first treatise systematically describing fetal anomalies by

56 | Asim Kurjak organ system, was a reference for ultrasound units worldwide, and became a medical best seller. He also played an important role in improving the technique for invasive procedures, such as sonographic-guided amniocentesis [10], percutaneous umbilical blood sampling (PUBS) [11], and diagnostic and therapeutic endoscopic procedures. The studies of the uterine cervix as a predictor of preterm delivery [12] led to the conduction of the PREGNANT trial [13] and the demonstration that vaginal progesterone could reduce the rate of preterm delivery in patients with a short cervix, providing compelling evidence to support routine risk assessment of cervical length to decrease the rate of preterm birth. Romero also made important contributions to the use of three- and four-dimensional ultrasound in the fetus, with particular emphasis on fetal echocardiography [14, 15]. His unit developed several algorithms for interrogating the fetal heart, the most recent of which has been Fetal Intelligent Navigation Echocardiography (FINE) [16], a method that allows automatic display of the standard diagnostic planes of the fetal heart from a single spatiotemporal image correlation (STIC) volume. Another more recent focus has been the utilisation of MRI to study not only fetal anatomy and dysmorphology, but also neural connectivity [17]. Most recent promising development is fetal neurology in which both structural and functional assessment of fetal brain development resulted in introduction of KANET test (Kurjak Antenatal Neurodevelopmental Test) which is now investigated in ten international universities. Pooh and Kurjak recently published the book on Fetal Neurology [18]. The history of obstetrics sonography is a never-ending story. This author is aware that many names are not mentioned but the limited space in this book did not allow including them.

Bibliography Due to limited space we list here only the essential citations. In case of further interest in details, we kindly ask the reader to contact the chapter’s author for more specific information. [1] Kurjak A. Ultrasound scanning – Prof. Ian Donald (1910–1987). Eur J Obstet Gynecol Reprod Biol 2000,90,187–189. [2] Kurjak A, Chervenak FA. Editorial – Fiftieth anniversary of the first Donald publication. Donald School J Ultrasound Obstet Gynecol 2008,4,iii–iv. [3] Donald Eide TJ. Life with Father. The early years with Ian Donald. Donald School J Ultrasound Obstet Gynecol 2011,4,xii–xvi. [4] Woo J. A short history of the development of Ultrasound in Obstetrics and Gynecology. (Accessed February 20, 2014, at http://www.ob-ultrasound.net) [5] Donald I, McVicar J, Brown T. Investigation of abdominal masses by pulsed ultrasound. Lancet 1958,271,1188–1195. [6] Kurjak A, Chervenak FA. Donald School Textbook of Ultrasound in Obstetrics and Gynecology. New Delhi, India, Jaypee Brothers Medical Publishers, 2004. [7] Kurjak A, Hafner T, Kos M, Kupesic S, Stanojevic M. Three-dimensional sonography in prenatal diagnosis: a luxury or a necessity? J Perinat Med 2000,28,194–209.

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[9] [10]

[11] [12]

[13]

[14]

[15]

[16]

[17]

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Romero R, Kadar N, Jeanty P, Copel JA, Chervenak FA, DeCherney A, Hobbins JC. Diagnosis of ectopic pregnancy: value of the discriminatory human chorionic gonadotropin zone. Obstet Gynecol 1985,66,357–360. Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins JC. Prenatal Diagnosis of Congenital Anomalies. New York, USA, Appleton-Century-Croft, 1988. Romero R, Jeanty P, Reece EA, Grannum P, Bracken M, Berkowitz R, Hobbins JC. Sonographically monitored amniocentesis to decrease intraoperative complications. Obstet Gynecol 1985, 65,426–430. Hobbins JC, Grannum PA, Romero R, Reece EA, Mahoney MJ. Percutaneous umbilical blood sampling. Am J Obstet Gynecol 1985,152,1–6. Romero R. Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment. Ultrasound Obstet Gynecol 2007,30,675–686. Hassan SS, Romero R, Vidyadhari D, Fusey S, Banter J, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O’Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW; for the PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, doubleblind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011,38,18–31. Gonçalves LF, Lee W, Chaiworapongsa T, Espinoza J, Schoen ML, Falkensammer P, Treadwell M, Romero R. Four-dimensional ultrasonography of the fetal heart using spatio temporal image correlation. Am J Obstet Gynecol 2003,189,1792–1802. Espinoza J, Kusanovic JP, Gonçalves LF, Nien JK, Hassan S, Lee W, Romero R. A novel algorithm for comprehensive fetal echocardiography using 4-dimensional ultrasonography and tomographic imaging. J Ultrasound Med 2006,25,947–956. Yeo L, Romero R. Fetal Intelligent Navigation Echocardiography (FINE): a novel method for rapid, simple, and automatic examination of the fetal heart. Ultrasound Obstet Gynecol 2013, 42,268–284. Thomason M, Dassanayake M, Shen S, Katkuri Y, Alexis M, Anderson A, Yeo L, Mody S, Hernandez-Andrade E, Hassan S, Studholme C, Jeong JW, Romero R. Cross-hemispheric functional connectivity in the human fetal brain. Sci Trans Med 2013,5,173ra24. Pooh RK, Kurjak A. Fetal Neurology. New Delhi, India, Jaypee Brothers Medical Publishers, 2008.

Amos Grünebaum

7 Measures in cases of threatened prematurity

7.1 Tocolysis 7.1.1 Introduction The word “tocolysis” is a derivative of two Greek words: toketos, which means labor and lysis, which means to bring something to an end. The term tocolysis did not emerge until 1964 where it was coined by Mosler [1] at the “Symposion über Physiologie und Pathologie der Wehentätigkeit.” Tocolytics are medications used to suppress contractions and labor. Originally, tocolytics were used with the aim to prolong pregnancy in the cases of actual or threatened preterm delivery to suppress contractions and delay delivery, either (a) for prolonged periods of time and (b) since the 1970s for a short time period to allow medications given for lung maturation to work efficiently against the neonatal complications of prematurity. Up to now, the aim to delay delivery for a prolonged period of time has not been fulfilled, however, in the field of prolonging for shorter periods of time, several indications have been developed (see Section 7.1.3, Later developments).

7.1.2 Medications for tocolysis Over the last 6–7 decades, many drugs have been used to achieve tocolysis in the attempt to prolong pregnancy. Most have eventually been found to be ineffective and their use has been abandoned. Morphine or other sedative drugs were traditionally used in the futile attempt to suppress preterm labor. In the 1950 10th edition of Williams Obstetrics [2] the authors said: “One of the most common errors made in the management of premature labor is to administer morphine or some other sedative drugs. It is not only futile but often followed in a few hours by the delivery of a heavily drugged infant.” In 1975, the 15th edition of Williams Obstetrics [3] mentioned the following for treatment of preterm labor: Bed rest; progestational agents: progesterone and 17-hydroxy-progesterone caproate; antiprostaglandins: indomethacin and aspirin; and beta-adrenergics: ritodrine, salbutamol, and orciprenaline. The 1985 17th Williams Obstetrics edition [4] provided additional medications like ethanol, magnesium sulfate plus ritodrine, isoxuprine, and terbutaline.

60 | Amos Grünebaum 7.1.2.1 Relaxin Relaxin was introduced for the treatment of preterm labor by Abramson and Reid in 1955 [5]. The authors reported a 100% success rate in the five women treated. In 1957, McCarthy et al. [6] used a control group and found no difference between the treatment and control group. Surprisingly, others investigated whether relaxin could cause contractions and enhance cervical ripening and therefore be used for the augmentation of labor [7].

7.1.2.2 Alcohol Fritz Fuchs [8] was among the first in the late 1950s and 1960s to promote the use of ethanol/alcohol for the treatment of premature labor. For ethanol to be effective, blood levels between 1.2 and 1.8 g/l were necessary, well above the legal limit for intoxication. In the late 1970s there were many investigations done on the use of ethanol in arresting preterm labor until the use of alcohol was eventually abandoned due to concerns about maternal side effects including nausea and fetal alcohol syndrome.

7.1.2.3 Progesterone As early as 1959, Fuchs [9, 10] reported success with using progesterone for the treatment of premature labor. Liggins showed equally good results [11]. Da Fonseca [12] found a role for progesterone in treating preterm labor.

7.1.2.4 Ritodrine The only drug ever approved by the FDA for the treatment of preterm labor was ritodrine, a beta-mimetic relaxant. Early studies showed promise in the early 1970s that ritodrine could be successfully used in arresting preterm labor [13]. However, subsequent studies [14] showed no clear benefits and significant maternal side effects significantly associated with betamimetics were pulmonary edema, cardiac arrhythmias, and hypokalemia; therefore, ritodrine fell out of favor as the primary agent for tocolysis [15].

7.1.2.5 Magnesium Sulfate Magnesium sulfate was first introduced in 1965 by Dumont [16]. It has been used since the 1960s for pre-eclamptic patients mostly to prevent pre-eclamptic seizures, and was investigated in the 1960s as tocolytic agent [17, 18]. Elliott [18] in 1983 said: “MgSO4 was found to be a successful, inexpensive, and relatively nontoxic tocolytic agent that had few side effects.” Spisso [19] in 1982 concluded: “Magnesium sulfate is considered to be effective tocolytic agent having minimal adverse effects in managing patients at risk for premature delivery.”

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While magnesium sulfate has been used for treating preterm labor for decades, it was eventually found in several trials to not be effective in preventing the preterm birth. The results of the MAGPIE trial suggest that magnesium sulfate is not successful in preventing preterm births [20]. A 2013 Cochrane database review concluded: “There is not enough evidence to show any difference between magnesium maintenance therapy compared with either placebo or no treatment, or alternative therapies (ritodrine or terbutaline) in preventing preterm birth after an episode of threatened preterm labour.” [21] 7.1.2.6 Beta-Agonists The 1960s saw research interest in beta-agonist agents, such as nylidrine, isoxsuprine, and orciprenaline to suppress uterine contractility. None of the many agents studied have ever fulfilled the hopes that were pinned on them, but they resulted in the availability of a large number of agents to suppress uterine contractility which included agents such as aspirin, sodium salicylate, flufenamic acid, sulindac, and indomethacin. Fenoterol, was introduced in Germany in 1970, and in 1982 Jung [22] proclaimed that it was the most widely used and best-explored betaagonist agent in Europe and it was used in combination with many other agents to counteract some of its side effects or to enhance its activity. 7.1.2.7 Calcium Channel Blockers Calcium channel blockers such as nifedipine have been researched extensively as tocolytics [23]. Nifedipine was introduced in 1977 appear to be among the more efficacious and safer drugs that are currently being used for tocolysis [24], but the lack of good quality evidence available for these tocolytics and reports of cardiovascular side effects may limit their usefulness in the treatment of preterm labor. 7.1.2.8 Bed rest Bed rest has long been recommended as a “tocolytic” to prevent preterm birth though there is no evidence that it is beneficial in preventing preterm birth [25, 26].

7.1.3 Later developments – tocolysis today Saling [27] was the first to suggest the use of tocolytics for short relaxation of the uterus to help in external cephalic version, including for patients with prior cesarean section [28]. Additional indications for tocolysis include its use for intrauterine resuscitation, short-term use in cases of uterine hyperstimulation [29] and abnormal fetal tracings [30].

62 | Amos Grünebaum Today, tocolytics are often used to buy a short time period of 24–48 h for the administration of betamethasone, a glucocorticoid drug which greatly accelerates fetal lung maturity and prevents other neonatal complications of prematurity. As of 2014, betamimemtics are not routinely used for extended periods of time in preterm labor to prolong pregnancy but only for limited periods to complete a course of bethamethasone. A Cochrane review [31] concluded that “Betamimetics help to delay birth, which may give time to allow women to be transferred to tertiary care or to complete a course of antenatal corticosteroids. However, multiple adverse effects must be considered.” Atosiban (Tractocile) has been successfully used in Europe for tocolysis and may have some advantages especially over fenoterol but is not FDA approved and is not in use in the United States. Romero [32] showed that natural vaginal progesterone has been found to be successful in women with a history of prior preterm births as well as those with singleton gestation, history of preterm birth, and a short cervix (< 25 mm).

7.1.4 Conclusions The history of tocolysis is based on incomplete studies, premature conclusions, and recommendations, and investigations of dozens of agents that eventually turned out to be ineffective, or even worse, harmful. The wide range of tocolytic agents in use over the last 5–6 decades is testament to the fact that there is still no ideal drug available for tocolysis and there is often disagreement among physicians who either believe that tocolysis is an excellent tool or that it is useless and even harmful. Despite the existence of a plethora of drugs, and the expenditure of billions of dollars in tocolytics there has not been an actual reduction in preterm births, and in fact during the height of using tocolytics there has been an increase in preterm births. Advances in neonatal care and the use of glucocorticoids prior to preterm births will make tocolysis less useful for extended used, except for short-term 24–48 h pregnancy prolongation.

7.2 History of induction of lung maturation 7.2.1 Antecedent of fetal lung maturation What we consider today “preterm” or “premature” was not considered equivalent in the 19th century. In the 1800s, medical writers used the words “premature and weak infants” or “weaklings” for short to describe infants that today would be considered premature [33].

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These infants were considered to have a lack of energy and those dying from respiratory distress would have been diagnosed as having “congenital lung atelectasis” secondary to breathing problems. It was unclear whether that was due to immaturity or was a congenital problem. Premature mortality was hidden by the overall high infant mortality in the late 19th century which was 15–20% of all infants before their first birthday in the United States. Until the 1910 census in the United States this premature mortality was not analyzed separately from other causes of infant mortality [34]. The first significant challenge to this equilibrium between doctor and mother was the invention in Paris of a medical technology directed at premature infants, the incubator. Its invention was associated with the French obstetrician Stephane Tarnier, who in the 1870s sought to find a means to warm the numerous premature infants who routinely succumbed to hypothermia on the wards of Paris’s Maternité Hospital. In the early 20th century, American pediatricians like Hess became more interested in premature infants and he developed an electrical “heated bed” for a premature infant [35]. The role of the obstetrician in improving the outcomes of premature infants was mainly confirmed to advising women to work less and to shift from treating preterm infants to preventing preterm births. Pinard in Paris thought that the best strategy of preventing prematurity was a maternity leave for working women [36].

7.2.2 Early stages of fetal lung maturation 1940s–1960s The 1940s and 1950s saw emerging research of what was at that time called “hyaline membrane disease” a newborn disease which eventually was called “respiratory distress syndrome (RDS)” [37–39]. Some details about the physiological background are also discussed in Section 10.4 (Exogenous surfactant therapy). The original concept that pulmonary maturation can be induced by glucocorticoids came as a direct result of research done by Moog [40] showing the effect of glucocorticosteroids on the intestine. The analogy between intestine and lung was made by Buckingham et al. [41], and in 1969 Liggins [11] reported that parturition was induced about 80% earlier than the normal sheep’s gestation by infusing dexamethasone into fetal lambs and the premature lambs became viable. Liggins suggested that this precocious lung maturity might be an example of corticosteroid induction of the enzyme activity similar to Moogs previous observations in intestines.

7.2.3 From 1970s till today In 1972, Liggins [42] was the first to show that corticosteroids may prevent RDS in premature human infants by accelerating fetal lung maturation.

64 | Amos Grünebaum Subsequently, Fargier et al. [43] reported in 1974 that prenatal corticosteroid treatment was successful in reducing the RDS. The time period between 1975 and 1976 was especially fruitful when dozens of studies in different countries [44–48] were published confirming the beneficial effect of corticosteroid treatments to enhance the fetal lung maturation However, it took another 25 years for antenatal glucosteroid treatment to become mainstream. Today, after over 45 years of research, the beneficial effect of antenatal corticosteroids on fetal lung maturation has been documented. Over a dozen of randomized trials [49] confirmed the original 1972 findings of Liggins. The main reason for this prolonged time period of acceptance was among other issues the concern that the potential benefits of glucosteroid treatment were outweighed by concerns for potential risks. In 1979, Olsen [50] concluded in a review of using glucosteroids for fetal lung maturation that the long-term effect on newborns needed to be examined. He mentioned that steroid therapy of commercial livestock might potentially result in a product that is unmarkable and recommended that before external glucosteroids are used in humans cost/benefit decision must be performed. These concerns were eventually alleviated when studies showed no long-term adverse outcomes in infants exposed to glucocorticosteroids in utero [51]. Antenatal corticosteroid therapy leads to architectural and biochemical changes that improve both lung mechanics (maximal lung volume, compliance) and gas exchange. These changes are primarily the result of accelerated morphologic development of type 1 and type 2 pneumocytes [52–56]. Antenatal steroid in combination with postnatal surfactant remains the mainstay of prevention and therapy for RDS in preterm infants. Steroids stimulate (via the fibroblast-pneumonocyte factor) production of surfactant phospholipids by alveolar type II cells, enhance the expression of surfactant-associated proteins, reduce microvascular permeability, and accelerate overall structural maturation of the lungs. In addition to the positive effect of antenatal glucosteroids on lung development, prenatal steroids have also show to have a positive effect on other complications of prematurity. Prenatal steroid treatment has been shown to reduce the frequency of PDA, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia. These are the most important and frequent morbidities that reduce the quality of life for the very low birth weight survivor. Though there may be some suggestions from animal studies that show a potential effect of long-term steroids on fetal long-term outcome, there are without clearly demonstrable and no known major adverse effects for the human mother or child from corticosteroid treatment, and the cost/benefit ratio strongly and clearly favors treatment when preterm delivery is anticipated [57]. The Cochrane database confirmed that prenatal glucosteroids are successful in preventing complications from preterm births [49]. Major organizations such as the National Institutes of Health (NIH) in 1994 and 2000 [58, 59], the Royal College of Medicine in 1996 [60], and the American College of Obstetricians and Gynecologists

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(ACOG) in 2011 [61] have recommended antenatal corticosteroid treatment for women at risk for preterm delivery prior to 34 weeks of gestation to reduce the morbidity and mortality associated with preterm birth.

7.2.4 Conclusion We have come a long way since Liggins first confirmed in the early 1970s that prenatal glucosteroids aid in improving outcomes of preterm infants. Today there are two main strategies available for the prevention of neonatal RDS in cases of preterm delivery: antenatal administration of glucosteroids that accelerate fetal lung maturation, and prophylactic treatment with surfactant soon after birth. The efficacy and the safety of each of these therapeutic regimens have been well documented in large randomized clinical trials which indicate that, in preterm babies there is not only a lowered risk of RDS but also a lowering of other complications such as frequency of IVH, necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia.

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Mosler KH, Schwalm H. [Comparative investigations of tocolytic and relaxant substances in the isolated uterus]. Zentralbl Gynakol 1965,87,603–613. [2] Williams JW, Eastman NJ., eds. Williams Obstetrics. 10th edn. New York, USA, AppletonCentury-Crofts, 1950. [3] Williams JW, Pritchard JA, MacDonald PC., eds. Williams Obstetrics. 15th edn. New York, USA, Appleton-Century-Crofts, 1976. [4] Williams JW, Pritchard JA, MacDonald PC, Gant NF., eds. Williams Obstetrics. 17th edn. Norwalk, Conn., USA, Appleton-Century-Crofts, 1985. [5] Abramson D, Reid DE. Use of relaxin in treatment of threatened premature labor. J Clin Endocrinol 1955,15,206–209. [6] McCarthy JJ, Erving HW, Laufe LE. Preliminary report on the use of relaxin in the management of threatened premature labor. Am J Obstet Gynecol 1957,74,134–138. [7] MacLennan AH, Green RC, Bryant-Greenwood GD, Greenwood FC, Seamark RF. Ripening of the human cervix and induction of labour with purified porcine relaxin. Lancet 1980,1,220–223. [8] Fuchs F. Effect of alcohol on threatened premature labor. Am J Obstet Gynecol 1967,99,627– 637. [9] Fuchs F, Stakemann G. [Treatment of threatened premature delivery with high doses of progesterone; an attempt at reduction of neonatal mortality]. Ugeskr Laeger 1959,121,566–568. [10] Fuchs F, Stakemann G. An endeavour to reduce neonatal mortality through treatment of threatened premature labour with large doses of progesterone. Acta Paediatr 1959,48,(Suppl 118), 29–30. [11] Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969, 45,515–523. [12] Da Fonseca EB, Bittar RE, Damião R, Zugaib M. Prematurity prevention: the role of progesterone. Curr Opin Obstet Gynecol 2009,21,142–147.

66 | Amos Grünebaum [13] Wesselius-de Casparis A, Thiery M, Yo le Sian A, Baumgarten K, Brosens I, Gamisans O, Stolk JG, Vivier W. Results of double-blind, multicentre study with ritodrine in premature labour. Br Med J 1971,3,144–147. [14] The Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the betaadrenergic agonist ritodrine. N Engl J Med 1992,327,308–312. [15] Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev 2006,25,CD003927. [16] Dumont M. Traitement des douleurs utérine gravidiques par le lactate de magnésium. Lyon Med 1965,213,1571–1582. [17] Petrie RH. Preterm parturition. Tocolysis using magnesium sulfate. Semin Perinatol 1981,5, 266–273. [18] Elliott JP. The use of magnesium sulfate as the primary tocolytic agent to prevent premature delivery. Am J Obstet Gynecol 1982,142,840–845. [19] Spisso KR, Harbert GM Jr, Thiagarajah S. Magnesium sulfate as a tocolytic agent. Am J Obstet Gynecol 1983,147,277–284. [20] The Magpie Trial Collaboration Group. Do women with pre-eclampsia, and their babies benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002,359,1872–1873. [21] Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2013,5,CD000940. [22] Jung H. General remarks on treatment with betamimetics. In: Jung H, Lamberti G., eds. Betamimetic drugs in obstetrics and perinatology. Stuttgart, Germany, Georg Thieme, 1982. [23] Andersson KE, Ingemarsson I, Ulmsten U, Wingerup L. Inhibition of prostaglandin-induced uterine activity by nifedipine. Br J Obstet Gynaecol 1979,86,175–179. [24] Pryde PG, Janeczek S, Mittendorf R. Risk-benefit effects of tocolytic therapy. Expert Opin Drug Saf 2004,3,639–654. [25] Sosa C, Althabe F, Belizán J, Bergel E. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 2004,1,CD003581. [26] Crowther CA. Hospitalisation and bed rest for multiple pregnancy. Cochrane Database Syst Rev 2001,1,CD000110. [27] Saling E, Müller-Holve W. J. External cephalic version under tocolysis. J Perinat Med 1975,3, 115–122. [28] Pluta M, Giffei JM, Saling E. [External version of the foetus from breech presentation in patients in condition following abdominal caesarean section (author’s transl)]. Z Geburtshilfe Perinatol 1981,185,121–123. [29] Egarter CH, Husslein PW, Rayburn WF. Uterine hyperstimulation after low-dose prostaglandin E2 therapy: tocolytic treatment in 181 cases. Am J Obstet Gynecol 1990,163,794–796. [30] Klöck FK, Chantraine H. [Possibilities and limits of the intrauterine reanimation (author’s transl)]. Z Geburtshilfe Perinatol 1975,179,401–419. [31] Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2014,2,CD004352. [32] Romero R, Yeo L, Miranda J, Hassan SS, Conde-Agudelo A, Chaiworapongsa T. A blueprint for the prevention of preterm birth: vaginal progesterone in women with a short cervix. J Perinat Med 2013,41,27–44. [33] Baker JP. The incubator and the medical discovery of the premature infant. J Perinatol 2000,20, 321–328. [34] Meckel RA. Save the Babies: American Public Health Reform and the Prevention of Infant Mortality, 1850 –1929. Baltimore, USA, Johns Hopkins University Press, 1990,166–171.

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[35] Hess JH. An electric-heated water-jacketed infant incubator and bed, for use in the case of premature and poorly nourished infants. JAMA 1915,64,1068–1069. [36] Pinard A. Rapport sur la puériculture dans ses périodes initiales. In: Commission de la Depopulation: Seánces 1902–1903. Melun, France, Imprimerie Administrative, 1903, 28–29. [37] Lynch MJ, Mellor LD. Hyaline membrane disease of newborn premature lungs; a new approach. J Pediatr 1955,47,275–286. [38] Dawson JR. The pathogenesis of hyaline membrane disease of the newborn; a preliminary report. Minn Med 1955,38,514–518. [39] Karlberg P, Cook CD, O’Brien D, Cherry RB, Smith CA. Studies of respiratory physiology in the newborn infant. II. Observations during and after respiratory distress. Acta Paediatr 1954,43, Suppl,397–411. [40] Moog F. The functional differentiation of the small intestine. III. The influence of the pituitaryadrenal system on the differentiation of phosphatase in the duodenum of the suckling mouse. J Exp Zool 1953,124,329. [41] Buckingham S, McNary WF, Sommers SC, Rothschild J. Is lung an analog of Moog’s developing intestine? I. Phosphatases and pulmonary alveolar differentiation in fetal rabbits. Federation Proc 1968,27,328. [42] Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of RDS in premature infants. Pediatrics 1972,50,515–525. [43] Fargier P, Salle B, Baud, Gagnaire JC, Arnaud P, Magnin P. Value of antepartum treatment with glucocorticoids. Nouv Presse Med 1974,3,1595–1597. [44] Siebert W, Meitinger C. Prevention of respiratory distress syndrome with betamethasone. Preliminary communication. Geburtshilfe Frauenheilkd 1975,35,130–133. [45] Farrell PM, Kotas RV. The prevention of hyaline membrane disease: new concepts and approaches to therapy. Adv Pediatr 1976,23,213–269. [46] Wauer RR, Grauel EL, Hengst P. Prevention of neonatal respiratory distress syndrome through the administration of prednisolone in the fetal period. Zentralbl Gynakol 1976,98,769–773. [47] Horváth I, Méhes K, Fias I, Szmodits S. Prevention of respiratory distress syndrome by antenatal maternal steroid treatment. Acta Paediatr Acad Sci Hung 1976,17,303–306. [48] Caspi E, Schreyer P, Weinraub Z, Reif R, Levi I, Mundel G. Prevention of the respiratory distress syndrome in premature infants by antepartum glucocorticoid therapy. Br J Obstet Gynaecol 1976,83,187–193. [49] Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006,3,CD004454. [50] Olsen EB. Role of glucosteroids in lung maturation. J Anim Sci 1979,49,225–238. [51] Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: long-term follow-up. J Pediatr 1984,104,259–267. [52] Smolders-de Haas H, Neuvel J, Schmand B, Treffers PE, Koppe JG, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up. Pediatrics 1990,86,65–70. [53] Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995,173,254–262. [54] Ballard PL. Hormonal regulation of surfactant in fetal life. Mead Johnson Symp Perinat Dev Med 1978,14,25–39. [55] Walther FJ, David-Cu R, Mehta EI Polk DH, Jobe AH, Ikegami M. Higher lung antioxidant enzyme activity persists after single dose of corticosteroids in preterm lambs. Am J Physiol 1996,271 (2 Pt 1),L187–L191. [56] Polk DH, Ikegami M, Jobe AH, Sly P, Kohan R, Newnham J. Preterm lung function after retreatment with antenatal betamethasone in preterm lambs. Am J Obstet Gynecol 1997,176,308–315.

68 | Amos Grünebaum [57] Shields JR, Resnik R. Fetal lung maturation and the antenatal use of glucocorticoids to prevent the respiratory distress syndrome. Obstet Gynecol Surv 1979,34,343–363. [58] Report on the Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. U.S. Department of Health and Human Services, Public Health Service, NIH Pub No. 95-3784,1994. [59] Antenatal Corticosteroids Revisited: Repeat Courses. National Institutes of Health Consensus Development Conference Statement August 17–18, 2000. (Accessed August 29, 2013, at http: //www.consensus.nih.gov/2000/2000AntenatalCorticosteroidsRevisted112html.htm) [60] RCOG Guidelines. Number 7. ACS to prevent respiratory distress syndrome. London, UK, Royal College of Obstetricians and Gynaecologists, 1996. [61] ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 475: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2011,117 (2 Pt 1),422–424.

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8 Diagnosis of genetic defects

8.1 Introduction Ever since the botanist and monk Gregor Johann Mendel observed the hereditary patterns of pea plants in the mid-1800s, other scientists have worked to discover and understand the genetic basis of disease. In 1909, Johannsen coined the term ‘gene’ in his book Elemente der Exakten Erblichkeitslehre [1]. More than 40 years later, Watson and Crick described the structure of deoxyribonucleic acid (DNA), which had only recently been discovered to be responsible for transmitting hereditary characteristics [2]. One of the earliest documents outlining the inheritance of congenital defects was written in 1753 by Pierre Louis de Maupertuis, in which he noted the inheritance of polydactyly in a German family [3]. Much later, in 1959, the link between chromosomal abnormalities and genetic syndromes began to gain greater awareness with the publication of ‘The chromosomes in a patient showing both mongolism and the Klinefelter syndrome’ by Ford and co-workers in The Lancet [4]. Through a series of additional discoveries [5], a strong interest in prenatal genetic diagnosis was born.

8.2 Early stages of clinical diagnostics: Fetoscopy versus ultrasound One of the first methods for making such diagnoses was ultrasound. Ian Donald, an obstetrician, and Tom Brown, an engineer, collaborated to develop the obstetric ultrasound. Donald published his first paper in 1958 entitled ‘Investigation of abdominal masses by pulsed ultrasound’ where he described their examination of 100 patients. The article included 12 pictures from B-Mode sonograms, including a gravid uterus, ovarian cysts, fibroids and ascites [6]. A more detailed discussion about the history of ultrasound can be found in Chapter 6 (Sonography). During the initial years of ultrasound, insufficient resolution for detecting congenital and genetic defects limited its role in prenatal diagnosis. This shortcoming led doctors to pioneer a way to directly visualize the external anatomy of the fetus. In 1954, a Swedish physician, Westin, reported his successful technique of transcervical fetoscopy using a 10-mm hysteroscope in patients undergoing termination in the midtrimester. In his letter to the editor, he noted that he was able to observe differences in fetal limb movements and the appearance of the umbilical vein [7]. Mandelbaum later developed the transabdominal approach for fetoscopy, in which he attempted to

70 | Noelia Zork and Mary E. D’Alton perform an intrauterine transfusion for fetal hemolytic disease [8]. And in 1972 and 1973, Valenti directly sampled fetal tissue by obtaining fetal blood and skin during fetoscopy [9]. That same year, Scrimgeour was the first to coin the term ‘fetoscopy’ to describe the work of his predecessors and his own technique of introducing a 2.2 mm scope through the uterus during laparotomy [10]. But as the resolution and availability of ultrasound improved, fetoscopy fell out of favour as a means of prenatal genetic diagnosis.

8.3 The implementation of amniocentesis (AC) During the early development of fetoscopy, less invasive methods for directly testing fetal cells were being explored. In 1956, Fuchs and Riis were the first to use amniocentesis, without the aid of ultrasound, as a method of directly analysing fetal cells [11]. Through this method, they were able to determine fetal sex based on the principle that female fetuses had several times more sex chromatin than male fetuses. This method was later used for the prenatal diagnosis of sex-linked disorders [12]. In 1966, Steele and Breg studied the feasibility of culturing fetal cells obtained by amniocentesis for karyotype. They collected a total of 52 specimens by abdominal amniocentesis in 35 patients who were suspected to have a fetus with erythroblastosis fetalis. They discovered that fetal cells obtained from amniocentesis were ‘hardy’ enough and of sufficient quantity to be cultured and karyotyped [13]. Shortly afterwards, Jacobson and Barter reported on the first prenatal diagnosis of a familial balanced translocation. [14]. In a letter to the editor of The Lancet in 1968, Valenti et al. described the first documented case of the prenatal diagnosis of Down syndrome using amniocentesis in the pregnancy of a woman who was a known carrier of a balanced translocation [15]. Soon after, amniocentesis began to be increasingly available to patients with high-risk conditions for genetic defects. For a more detailed review of the history of amniocentesis, refer to Chapter 4 (Amniotic fluid interventions and examinations).

8.4 The implementation of chorionic villus sampling (CVS) As previously noted, by the 1970s, amniocentesis was regarded as the gold standard for diagnosis of chromosomal abnormalities. However, because amniocentesis could not be safely performed before the second trimester, other methods for earlier diagnosis were being developed. In the 1960s, amniocentesis was used relatively frequently in Scandinavia due to the accessibility of mid-trimester abortions. Jan Mohr, a Norwegian physician and geneticist, was one of the most experienced in prenatal diagnosis at that time [16]. Mohr, along with Niels Hahnemann, began working on a technique that could result in earlier diagnosis of genetic defects. In explaining the need for their

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investigation, they wrote ‘On considerations regarding the mental and physical health of the mother, and also for legal reasons, it seems essential to establish such a diagnosis as early in pregnancy as possible’. In 1968, using a 6 mm endoscope transcervically, they reported a 96% success rate of obtaining chorionic cells [17]. But despite their success, this technique fell by the wayside due to the high rate of bleeding, infection and failed culturing of cells. Their idea would only be further developed in the mid-1970s. Although chorionic villus sampling (CVS) was still in its infancy, amniocentesis and ultrasound were widely available for prenatal diagnosis. In 1974, approximately 3000 women had an amniocentesis performed in the United States [18]. By the mid1970s, the possibilities of genetics and prenatal diagnosis were generating enthusiasm. In an article in Science from 1974 entitled ‘Brave New World?’, the author looked to the future and asked if even earlier diagnosis of genetic defects would become a reality [19]. As he suspected, the years following would be vital in the advancement of the field.

8.5 Later developments in diagnostics: Ultrasound guided CVS and amniocentesis (AC) In the 1970s, a new found interest in early genetic diagnosis led Chinese researchers to publish their experience with CVS to diagnose fetal sex. Their approach was transcervical, using a 3 mm metal catheter, guided only by tactile sensation (see a 1.5 mm catheter used for CVS in Figure 8.1). Researchers in the United States attempted to replicate this approach via endocervical lavage, but Goldberg and colleagues were only able to obtain maternal cells. They concluded that first trimester prenatal diagnosis was ‘not feasible at this time’ [20].

Fig. 8.1. Catheter (1.5 mm) used for CVS, developed in the early 1980s. © Courtesy of Ronald Wapner.

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Fig. 8.2. Ultrasound image of CVS, early 1980s. © Courtesy of Ronald Wapner.

Fig. 8.3. Still from instructional video for CVS from 1983. © Courtesy of Ronald Wapner.

With the advent of real-time sonography, the technique of CVS improved (see an ultrasound image of CVS in Figure 8.2). In 1982, a Soviet group reported their experience using a 1.7 mm diameter embryo–fetoscope to biopsy 165 patients, some with continuing pregnancies. This was the first reported use of ultrasound guidance with CVS. They documented no spontaneous abortions and were able to determine fetal sex [21]. The technique was perfected by Simoni and colleagues in 1983. They described four different methods of sampling the chorion in patients undergoing pregnancy termination. One of these methods used a long, plastic, 1.2 mm-wide cannula under ultrasound guidance. Using this method, they had a 96% success rate and no amniotic sac perforations [22]. Shortly thereafter, the World Health Organization established a working group on first trimester fetal diagnosis and informally sponsored an international registry to prospectively track these procedures. By 1984, over 3000 CVS procedures (Figure 8.3 shows an instructional video) had been reported to the registry. This registry and large

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prospective randomized trials from around the world helped in establishing the safety of this procedure.

8.6 Alpha-fetoprotein in maternal serum as non-invasive diagnostic tool While amniocentesis was useful in diagnosing chromosomal defects, it did little to aid in the diagnosis of congenital anomalies. The measurement of alpha-fetoprotein (AFP) in maternal serum and amniotic fluid would later expand the role of amniocentesis and aid in the diagnosis of neural tube defects [23]. In the early 1970s, a pair of geneticists in Edinburgh, Brock and Sutcliffe, began investigating the proteins found in amniotic fluid. They found that while most proteins originated from maternal serum, AFP did not. Brock and Sutcliffe analysed amniotic fluid obtained at delivery or by amniocentesis in a cohort of patients with pregnancies affected by an open neural tube defect. They matched the samples with normal controls and discovered markedly elevated levels of AFP in the fluid of anencephalic fetuses [24]. These findings were significant because in some areas of the United Kingdom 1% of neonates were found to have neural tube defects [3]. A year later, amniotic fluid AFP was being performed routinely in the United Kingdom in women with a history of neural tube defects. Multiple reports in the years to come would further underscore the association between elevated maternal serum AFP levels and open neural tube defects. These corroborations led to a multi-centre study in the United Kingdom in which serum AFP was measured in 18,684 pregnancies [25]. The results of this study established the basis for the now standardized timing and interpretation of the maternal serum AFP test. Second trimester screening for neural tube defects would soon became an established practice. Amniocentesis and CVS – the standard tests for prenatal diagnosis – were being offered only to women of advanced maternal age due to their higher risk for aneuploidy. The majority of chromosomally abnormal children, however, were being born to younger mothers. This reality led practitioners to search for ways to screen for fetal chromosomal defects and congenital anomalies in mothers with little apparent risk. At the New York State Birth Defects Symposium in 1983, Merkatz presented data showing that mothers with chromosomally abnormal fetuses had lower serum AFP levels. A year later, Cuckle et al. published a study that showed significantly decreased levels of AFP in maternal serum at 14 to 20 weeks in women with pregnancies specifically affected by trisomy 21 [26].

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8.7 The triple and quadruple screens Some years later, using the knowledge that human chorionic gonadotropin (hCG) was abnormal in spontaneous abortions affected by aneuploidy, Bogart showed that hCG was often elevated in pregnancies with chromosomal abnormalities [27]. In 1988, researchers found significantly lower levels of maternal serum estriol in Downsyndrome-affected pregnancies [28]. Shortly thereafter, Wald was able to correctly identify 60% of pregnancies with Down syndrome by combining all three tests – AFP, hCG and estriol – with maternal age [29]. By the early 1990s, a prospective study using these three analytes and maternal age for second trimester screening showed similar results [30]. The utility of combining these analytes was validated by larger studies, and the test became known as the ‘triple screen’. Within a few years, elevated levels of inhibin were also observed in these pregnancies, and it was combined with the triple screen to make the ‘quadruple screen’ [31]. As the triple and quadruple screens were becoming standard practice in the second trimester, researchers were investigating analytes that could be used for screening in the first trimester. In 1992, Wald and colleagues reported on the correlation of low pregnancy associated plasma protein A (PAPP-A) in the first trimester and Down syndrome [32]. HCG was later combined with PAPP-A to form the first trimester screen.

8.8 The return of ultrasound During the 1980s and 1990s, ultrasound technology was also steadily improving. Practioners began performing routine second trimester ultrasounds to screen for major congenital anomalies indicative of a genetic defect. Published sensitivity rates have varied depending on the screened population, falling as low as 13%. But more recent data suggest that, with a trained sonographer, its sensitivity is closer to 70% [33]. The resolution of transvaginal ultrasound has improved such that first trimester evaluation for anomalies is now a possibility and may one day become standard practice [34].

8.9 The combined screening By 2001, almost 75% of perinatologists in the United States were using only the triple screen test to screen for chromosomal abnormalities, while 40% of the remaining practitioners were screening in the first trimester [38]. Wald continued to search for the best non-invasive test. He was the first to publish on the association between the first trimester screen and nuchal translucency. He used three already published databases to combine the components of each test and he argued that this method was more accurate than the second trimester screen alone [39]. In the early 2000s, Wapner et al. conducted a multi-centre trial and demonstrated the effectiveness of

8 Diagnosis of genetic defects | 75

combined screening [40]. During this time, various methods to interpret these results emerged, including the integrated and stepwise sequential screen. With the objective of individually assessing these various screening modalities, the FASTER trial would ultimately show that the first trimester screen with nuchal translucency at 11 weeks performed better than the quadruple screen and that the integrated and sequential screens also had high rates of Down syndrome detection [41]. These studies had a dramatic impact on the practice of screening for chromosomal defects. A 2007 survey of perinatologists in the United States showed that 97% were now performing first trimester screening [42].

8.10 New directions: Cell-free DNA (cfDNA) testing in maternal blood and chromosomal microarray The field of genetics and prenatal diagnosis has advanced quickly over the last several years. Notably, the discovery of intact fetal cells and cell-free fetal DNA in maternal blood has opened up new possibilities that would have previously been hard to imagine. The advent of massive parallel genomic sequencing has made the non-invasive prenatal diagnosis of aneuploidy a reality. Several studies have validated its high accuracy, with one industry-sponsored study showing a sensitivity of 100%, 97% and 79% for detecting Trisomy 21, 18, and 13, respectively [43]. Another new technique used in prenatal diagnosis is chromosomal microarray (i.e., molecular karyotyping, array-based comparative genomic hybridisation). This method uses a molecular probe to detect chromosomal deletions and duplications, abnormalities that are usually unable to be seen on karyotype. Only recently has microarray made its transition into prenatal diagnosis. This test was shown by Wapner et al. to provide additional clinically significant information useful for diagnosing genetic syndromes in almost 2% of pregnancies with standard indications for genetic testing and in 6% of cases with a prenatally diagnosed congenital anomaly [44]. The field of prenatal diagnosis has advanced exponentially over the last 50 years. Today, we are able to diagnose genetic disorders and syndromes in ways that would have been impossible even 5 years ago. These advancements have been enabled not only by the dedicated work of individual scientists and physicians but also by collaborations that point to the increasingly interdisciplinary frontier of medical genetics.

Bibliography [1] [2] [3]

Johannsen W. Elemente der exakten Erblichkeitslehre mit Grundzügen der biologischen Variationsstatistik. 3rd edn. Jena, Germany, G. Fischer; 1926. O’Dowd MJ, Philipp EE. The history of obstetrics and gynaecology. New York, USA, Parthenon Publishing Group, 1994. Harper PS. A short history of medical genetics. Oxford, UK, New York, USA, Oxford University Press, 2008.

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Ford CE, Jones KW, Miller OJ, Mittwoch U, Penrose LS, Ridler M, Shapiro A. The chromosomes in a patient showing both mongolism and the Klinefelter syndrome. Lancet 1959,1,709–710. Carr DH. Chromosome anomalies as a cause of spontaneous abortion. Am J Obstet Gynecol 1967,97,283–293. Donald I, Macvicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet 1958,1,1188–1195. Westin B. Hysteroscopy in early pregnancy. Lancet 1954,264,872. Mandelbaum B, Pontarelli DA, Brushenko A. Amnioscopy for prenatal transfusion. Am J Obstet Gynecol 1967,98,1140–1143. Valenti C. Antenatal detection of hemoglobinopathies. A preliminary report. Am J Obstet Gynecol 1973,115,851–853. Scrimgeour J. Other techniques for antenatal diagnosis. In: Antenatal diagnosis of genetic disease. Edinburgh, UK, Churchill Livingstone, 1973, 169. Fuchs F, Riis P. Antenatal sex determination. Nature 1956, 177,330. Cederqvist LL, Fuchs F. Antenatal sex determination. A historical review. Clin Obstet Gynecol 1970,13,159–177. Steele MW, Breg WR, Jr. Chromosome analysis of human amniotic-fluid cells. Lancet 1966,1, 383–385. Jacobson CB, Barter RH. Intrauterine diagnosis and management of genetic defects. Am J Obstet Gynecol 1967,99,796–807. Valenti C, Schutta EJ, Kehaty T. Prenatal diagnosis of Down’s syndrome. Lancet 1968,2,220. Rothenberg KH, Thomson EJ. Women and prenatal testing: facing the challenges of genetic technology. Columbus, OH, USA, Ohio State University Press, 1994. Mohr J. Foetal genetic diagnosis: development of techniques for early sampling of foetal cells. Acta Pathol Microbiol Scand 1968,73,73–77. Group TNNRfAS. Midtrimester amniocentesis for prenatal diagnosis. Safety and accuracy. JAMA 1976,236,1471–1476. Motulsky AG. Brave new world? Science 1974,185,653–663. Goldberg MF, Chen AT, Ahn YW, Reidy JA. First-trimester fetal chromosomal diagnosis using endocervical lavage: a negative evaluation. Am J Obstet Gynecol 1980,138,436–440. Kazy Z, Rozovsky IS, Bakharev VA. Chorion biopsy in early pregnancy: a method of early prenatal diagnosis for inherited disorders. Prenat Diagn 1982,2,39–45. Simoni G, Brambati B, Danesino C, Rossella F, Terzoli GL, Ferrari M, Fraccaro M. Efficient direct chromosome analyses and enzyme determinations from chorionic villi samples in the first trimester of pregnancy. Hum Genet 1983,63,349–357. Abelev GI. Production of embryonal serum alpha-globulin by hepatomas: review of experimental and clinical data. Cancer Res 1968,28,1344–1350. Brock DJ, Sutcliffe RG. Alpha-fetoprotein in the antenatal diagnosis of anencephaly and spina bifida. Lancet 1972,2,197–199. Wald NJ, Cuckle H, Brock JH, Peto R, Polani PE, Woodford FP. Maternal serum-alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Report of U.K. collaborative study on alpha-fetoprotein in relation to neural-tube defects. Lancet 1977,1,1323–1332. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet 1984,1,926–929. Bogart MH, Pandian MR, Jones OW. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn 1987,7,623–630. Canick JA, Knight GJ, Palomaki GE, Haddow JE, Cuckle HS, Wald NJ. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down’s syndrome. BJOG 1988,95, 330–333.

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[29] Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, Haddow JE, Knight GJ, Palomaki GE, Canick JA. Maternal serum screening for Down’s syndrome in early pregnancy. BMJ 1988,297,883–887 [30] Phillips OP, Elias S, Shulman LP, Andersen RN, Morgan CD, Simpson JL. Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha-fetoprotein, hCG, and unconjugated estriol: a prospective 2-year study. Obstet Gynecology 1992,80,353–358. [31] Spencer K, Wallace EM, Ritoe S. Second-trimester dimeric inhibin-A in Down’s syndrome screening. Prenat Diagn 1996,16,1101–1110. [32] Wald N, Stone R, Cuckle HS, Grudzinskas JG, Barkai G, Brambati B, Teisner B, Fuhrmann W. First trimester concentrations of pregnancy associated plasma protein A and placental protein 14 in Down’s syndrome. BMJ 1992,305,28. [33] Levi S. Ultrasound in prenatal diagnosis: polemics around routine ultrasound screening for second trimester fetal malformations. Prenat Diagn 2002,22,285–295. [34] Timor-Tritsch IE, Fuchs KM, Monteagudo A, D’Alton M E. Performing a fetal anatomy scan at the time of first-trimester screening. Obstet Gynecol 2009,113,402–407. [35] Benacerraf BR, Barss VA, Laboda LA. A sonographic sign for the detection in the second trimester of the fetus with Down’s syndrome. Am J Obstet Gynecol 1985,151,1078–1079. [36] Bronshtein M, Rottem S, Yoffe N, Blumenfeld Z. First-trimester and early second-trimester diagnosis of nuchal cystic hygroma by transvaginal sonography: diverse prognosis of the septated from the nonseptated lesion. Am J Obstet Gynecol 1989,161,78–82. [37] Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 1998,352, 343–346. [38] Egan JF, Kaminsky LM, DeRoche ME, Barsoom MJ, Borgida AF, Benn PA. Antenatal Down syndrome screening in the United States in 2001: a survey of maternal-fetal medicine specialists. Am J Obstet Gynecol 2002,187,1230–1234. [39] Wald NJ, Hackshaw AK. Combining ultrasound and biochemistry in first-trimester screening for Down’s syndrome. Prenat Diagn 1997,17,821–829. [40] Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, Platt L, Mahoney M, Johnson A, Hogge WA, Wilson RD, Mohide P, Hershey D, Krantz D, Zachary J, Snijders R, Greene N, Sabbagha R, MacGregor S, Hill L, Gagnon A, Hallahan T, Jackson L; First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003,349,1405–1413. [41] Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D’Alton ME; First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005,353,2001–2011. [42] Fang YM, Benn P, Campbell W, Bolnick J, Prabulos AM, Egan JF. Down syndrome screening in the United States in 2001 and 2007: a survey of maternal-fetal medicine specialists. Am J Obstet Gynecol 2009,201,97,e1–e5. [43] Bianchi DW, Platt LD, Goldberg JD, Abuhamad AZ, Sehnert AJ, Rava RP; MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012,119,890–901. [44] Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012,367,2175–2184.

Monika Dräger and Erich Saling

9 Assessment of the newborn immediately after delivery

9.1 Apgar-score 9.1.1 Precursors The term asphyxia or birth asphyxia has been defined quite differently. In any case, the term itself, deriving from the Greek and meaning literally “without pulse,” is quite problematic. According to Goldstein 1980 [1], this “infelicity of etymology” was already pointed out by N. J. Eastman. For a more detailed discussion see Goldstein 1980 [1]. Already in 1861, Little, in his famous paper On The Influence of Abnormal Parturition, Difficult Labours, Premature Birth, and Asphyxia Neonatorum, on the Mental and Physical Condition of the Child, Especially in Relation to Deformities also pointed out the difference between what was later called “asphyxia pallida” and “asphyxia livida.” He wrote: “. . . the pallor indicating greater prostration and greater tendency to cessation of nerve-life and death,” [2]. However, until the 1950s, there have been only vague terms available to evaluate the clinical state of the newborn. For example, terminologies like “vigorous,” “moderately,” or “severely asphyxiated” have been used. Not only the terminology has been insufficient, but the complete system of definition. To illustrate this, let us quote from Apgar’s famous publication from 1953: “The endpoints which have been used previously in the field of resuscitation are ‘breathing time’ defined as the time from delivery of the head to the first respiration, and ‘crying time’ the time until establishment of a satisfactory cry [3]. Other workers have used the terms mild, moderate and severe depression [4] to signify the state of the infant. There are valid objections to these systems . . . Evaluation of the breathing time is difficult. A satisfactory cry is sometimes not established even when the infant leaves delivery room . . . Mild, moderate and severe depression of the infant leaves a margin for individual interpretation” (Apgar 1953, [5, p. 260]).

9.1.2 Apgar-score Virginia Apgar (Figure 9.1), one of the first anesthetists of her time, conducted research in obstetrical anesthesia. She was especially interested in the effects of maternal anes-

80 | Monika Dräger and Erich Saling

Fig. 9.1. Virgina Apgar 1972 in Berlin © Erich Saling.

thesia on the newborn, and in lowering the neonatal mortality rates [6]. It became clear to her, “. . . that in many cases, newborns could be saved if anyone bothered to examine them closely just after birth . . . The Apgar score, as it later became known, had its origins in a medical resident’s question: How would one do a standard, rapid assessment of a newborn’s condition? Apgar . . . jotted down five objective points to check: (1) heart rate, (2) respiration, (3) muscle tone or activity, (4) reflex response to stimulation, and (5) color. These were the standard signs monitored by anesthesiologists during surgeries. . . . ” [7] These five points have been developed by Apgar into a scoring system for newborns (Table 9.1). Table 9.1. Apgar score. Redrawn after Apgar et al. 1958 [8], with addition of the words for the Epigram APGAR (in bold) [7]: *Score of 10 indicates infant in best possible condition. Sign

Score*

0

1

2

Appearance (Color)

Blue, pale

Body pink, extremities blue

Completely pink

Pulse (Heart rate)

Absent

Slow (< 100 per minute)

> 100 per minute

Grimace (Reflex irritability, Response of skin stimulation to feet)

No response

Some motion

Cry

Activity (Muscle tone)

Limp

Some flexion of the extremities

Well flexed

Respiration (Respiratory effort)

Absent

Weak cry; hypoventilation

Good, strong cry

9 Assessment of the newborn immediately after delivery

| 81

In 1952, Apgar presented her results derived from 1.021 infants at the 27th Annual Congress of Anesthetists and in 1953 in the now famous publication A Proposal for a New Method of Evaluation of the Newborn Infant [5]. During the next years, Apgar and her colleagues (James, Holaday, and others) scored more than 15 000 infants and published the results in 1958 [8]. Here is a quote from the summary: “The score was found to be a measure of the relative handicaps suffered by infants born prematurely, delivered spontaneously at term, delivered by cesarean section, or subjected to other obstetrical and anesthetic hazards. The lower scores were generally associated with chemical findings characteristic of asphyxia in the blood obtained by umbilical catheterization. The score was especially useful in judging the need for resuscitative measures, such as respiratory assistance” (Apgar 1958, p. 1985 [8]). The epigram APGAR (derived from the first letters of: “appearance, pulse, grimace, activity, respiration,” Table 9.1) was introduced in 1961 [7]. Within the following years, the Apgar-score became a widespread method and is at present a standard method used in most newborns worldwide.

9.1.2.1 Excursion: coauthor’s critique of the Apgar-score Nevertheless the Apgar-score had from its very beginning weaknesses such as subjective influence. However, more objective parameters have been reasons for criticisms. So for instance, heart rate assessment has been disputed because of its doubtful validity. This is in so far as an asphyxiated infant may have a normal heart rate, while bradycardia does not necessarily indicate asphyxia. As Hubert Römisch found out in our department, in a doctoral thesis in the 1970s [9], the use of heart frequency within the Apgar-score is a hardly suitable parameter because the frequency of heart rate is highly dependable from the onset, existence, and quality of respiration respectively from the “respiratory efforts.” Further it depends for which period, this means, for how many seconds the baby’s heart rate is recorded and for which period, this means for how many seconds. Confusing clinical results are the consequence when no standard conditions are respected. The Apgar-score is a typical example for using a popular method in a not critical enough way and knowing its weaknesses. Better results could be expected when the weak parts would be replaced or better suitable included. So for instance, the filling of the umbilical vessels show a suitable index of the baby’s condition, namely good correlation with acid-base status [10].

In 2001, Casey et al., after examining more than 100 000 infants, drew the conclusion: “The value of the Apgar score has become controversial because of attempts to use it as a predictor of the neurologic development of the infant, a use for which it was never intended. For example, the use of the Apgar score to identify birth asphyxia is a misapplication, since conditions such as congenital anomalies, preterm birth, and administration of drugs to the mother can result in low scores that are not reflective of asphyxia” (Casey 2001, [11, p. 467]). Therefore “The Apgar scoring system remains as relevant for the prediction of neonatal survival today as it was almost 50 years ago” (Casey 2001, [11, p. 467]).

82 | Monika Dräger and Erich Saling

9.2 Assessment of the biochemical state of the newborn 9.2.1 Precursors – chemical and physiological scientific background Diagnosing the status of the fetus (and newborn) with the measurement of blood gas analysis and acid base analysis would not have been possible without various previous scientific discoveries. The most important stepping stones have been: – 1774: Discovery of oxygen by the Reverend Priestley (Birmingham) and further understanding of this discovery in 1789 by the Paris chemist Lavoisier [12, 13]. – 1667: Walter Needham postulates that the placenta acts in place of the lung (quoted in Kohlschütter 1849 [14]). – Schwartz (1858) examined the blood of healthy newborns and newborns with “verminderter Lebensenergie” (English: “depressed life energy”). He drew correct conclusions from the color of the blood to the state of oxygenation and observed that the poorer the state of the born infant was, the darker was its umbilical blood (Schwartz 1858, p. 223 [15]). – 1909: The Danish chemist Sørensen introduces the concept of pH [16, 17].

9.2.2 Blood gas analysis and pH-measurement in the newborn 9.2.2.1 Arvo Henrik Ylppö Already at the beginning of the last century, the Finish pediatrician Arvo Henrik Ylppö published in German journals important articles on the biochemical assessment of the newborn: – In 1919, Ylppö [18] published about physiology, clinical aspects, and destiny of the prematurely born. – In 1924, in his publication “Beitrag zur Azidosis bei Neugeborenen” (English: Contribution about the acidosis of the newborn) [19] published results concerning the hydrogen ionic concentration in the umbilical blood of newborns – thus laying the ground for further research in this area. – In 1924,¹ Ylppö [19] published his observation that fresh-born babies show an “azidotische Labilität,” translated: “acidotic instability” and he used also the term “Azidosebereitschaft des Neugeborenen,” translated: “tendency of newborns to acidosis.” At that time, his views have been discussed controversially and he found both opponents [20] as well as researchers, taking his work further [21].

1 Ylppö must have said something similar already in his publications of 1914 and 1916, as Hasselbalch (1917) and Seham (1919) refer to these works. However, we could not get hold of these publications.

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83

9.2.2.2 N. J. Eastman From 1930 to 1936, N. J. Eastman published the series Fetal blood studies [22–25] and some other articles. He investigated the oxygen concentration and oxygen delivery in umbilical and maternal blood [22], and the lactate in cord blood, all immediately after birth [23]. For a more detailed overview about Eastmans achievements, please refer to Goldstein 1980 [1].

9.2.2.3 Sir Joseph Barcroft In 1954, Sir Joseph Barcroft coins the expression of “Mount Everest in utero” on the basis of oxygen content and -saturation measurements in the cord blood. “. . . , the lowest recorded levels of arterial oxygen in adult humans are similar to those of a fetus and were recorded just below the highest attainable elevation on the Earth’s surface: the summit of Mount Everest ” [26, 27].

9.2.3 Stanley James and Virginia Apgar In their groundbreaking publication The acid-base status of human infants in relation to birth asphyxia and the onset of respiration from 1958, the American neonatologist James in cooperation with Virginia Apgar and others combined the score later named after Apgar with extensive cord blood examinations. The aim of their study was “ . . . to evaluate the birth status of the infant and to time the onset of respiration in relation not only to the the aterial oxygen saturation but also to the carbon dioxide tension (pCO2 ), the pH, and the total available buffer. Although the pH and pCO2 have been measured previously, they have not been considered as reflecting the duration of an episode of asphyxia” (James 1958, p. 379 [28]). The first publications included results of 101 infants, several publications with more infants followed. In the course of these studies, James, together with Apgar, in 1958 also published about the first catheterization of umbilical vessels [28]. Not knowing about each other, in the same year we have performed catheterizations of umbilical vessels in the course of our activities to develop new gentle methods for blood exchange in newborns [29, 30].

9.3 Attempts to modify the Apgar-score and completion of the assessment of the newborn In 1960, the coauthor developed fetal blood analysis (see Chapter 3, Fetal blood analysis). This enabled him to study more in detail the biochemical “events” particularly during labor [31–33].

84 | Monika Dräger and Erich Saling Table 9.2. The modified Scoring system after Saling (1965) [10]. Table redrawn after Saling 1968 [34]. This newborn got a total score of 9. Score

3

Umbilical cord vessels Trunk colour Tone and movement Respiration in the first 90 s

2

  Turgid –

  Pink Cyanotic

  Strong Good

  Crying Regular (occasional cry)



1

0

Filled

Collapsed

Mattled

Pink

Diminished

Absent

Gasping

Absent

Total score: 9

The coauthor modified the Apgar-scoring system (Table 9.2) and completed it with another additional more objective subsidiary scoring system in which four parameters have been assessed using a stopwatch [34]. These were: the first breath, the first cry, start of regular spontaneous respiration, and the start of skin reddening. For all of them normal time limits had been calculated before. Additionally the coauthor has introduced the most important parameter for this kind of assessment of the fresh born immediately after delivery, namely the combination of a modified Apgar-score as assessment of the clinical resp. physical state with the measurement of pH-values in the umbilical vessels, particularly in the arteries as an assessment of the biochemical state of the newborn. This was the first time that for a systemic routine assessment values of acid base balance of the newborn have been combined with clinical parameters (modified Apgar-score) and also with the results of pH-measurements of fetal blood during labor (Table 9.3). In the meantime, the evaluation of acid–base values in umbilical vessels particularly in the arteries are to a high degree accepted as relatively good reliable parameters, Table 9.3. Summary of all results obtained inclusively the results of fetal blood analysis (FBA) (table redrawn after Saling 1968: Fetal and neonatal Hypoxia (p. 173)). Column (A): Results of FBA (going from top to bottom): the time in hours (h) and minutes (min) before birth, actual pH and pH qu 40 of the most acidotic (antepartum) fetal blood samples. Column (B): umbilical arterial actual pH and pH qu 40. Columns (C) and (D): Points achieved in the main and subsidiary scoring system. Summary of the infant’s condition (A) (B) (C) Ante partum: h min UA

Points main scoring system

(D)

Points subsidiary scoring system

act. pH pH qu 40* *pH qu40 means the pH after equilibration with 40 mm pCO2 , representing the metabolic acidity

9 Assessment of the newborn immediately after delivery |

85

also for the assessment of the clinical state of the newborn, and they allow the up to now best suitable prognosis for the later development of an individual.

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[20]

Goldstein P. Birth Asphyxia. In: Smith GF, Vidyasagar D, eds. Historical Review and Recent Advances in Neonatal and Perinatal Medicine, Mead Johnson Nutritional Division, 1980, Chapter 11. Available from: http://www.neonatology.org/classics/mj1980/ch11.html. Little WJ. On the influence of abnormal parturition, difficult labours, premature birth, and asphyxia neonatorum, on the mental and physical condition of the child, especially in relation to deformities. Trans Obstet Soc London 1861,3,293 f. Hapke FB, Barnes AC. The obstetric use and effect of fetal respiration of nisentil. Am. J. Obstet. Gynecol. 1949,58,799–801. Eckenhoff JE, Hoffman GL. N-allyl normorphine: an antagonist to the opiates. Anesthesiology 1952,13,242–251. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg 1953,32,260–267. eng. National Library of Medicine. The Virginia Apgar Papers – Biographical Information. (Accessed January 24,2013, at http://profiles.nlm.nih.gov/ps/retrieve/Narrative/CP/p-nid/178). National Library of Medicine. The Virginia Apgar Papers – Obstetric Anesthesia and a Scorecard for Newborns, 1949–1958. (Accessed February 24, 2014, at http://profiles.nlm.nih.gov/ ps/retrieve/Narrative/CP/p-nid/181). Apgar V, Holaday DA, James LS, Weisbrot IM, Berrien C. Evaluation of the newborn infant; second report. JAMA 1958,168,1985–1988. Römisch H. Die Aussagekraft der Herzschlagfrequenz von Neugeborenen unmittelbar vor der Geburt [Inauguraldissertation]. Berlin: Freie Universität Berlin, 1970, 23 p. Saling E. Zustandsdiagnose beim Neugeborenen unmittelbar nach der Geburt [[Diagnosis of the condition of the newborn immediately after birth]]. Gynaecologia 1965,160,133–156. ger. Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N. Engl. J. Med. 2001,344,467–471. eng. Lavoisier AL. Traité Elementaire de Chimie. Paris, Citation from Obladen (2005),1789. Obladen M. History of Surfactant up to 1980. Biol Neonate 2005,87,308–316. Kohlschütter O. Einiges über die Nabelschnur als häufige Ursache des Todes des Kindes während der Geburt. In: Wittlinger WH, ed. Analekten für die Geburtshülfe. Quedlinburg und Leipzig, Druck und Verlag Gottf. Basse, 1849,142–169. (vol. 1). Schwartz H. Die vorzeitigen Athembewegungen; ein Beitrag zur Lehre von den Einwirkungen des Geburtactes auf die Frucht., 1858. ger. Sorensen SPL. Enzymstudien. II, Über die Messung und die Bedeutung der Wasserstoffionenkonzentration bei enzymatischen Prozessen. Biochem. Zeitschr 1909,21,131–304. Wikipedia. pH-Wert, 2013. (Accessed February 24, 2014). Ylppö A. Zur Physiologie, Klinik und zum Schicksal der Frühgeborenen. Z. Kinder-Heilk. 1919, 24,1–110. Ylppö A. Beitrag zur Azidosis bei Neugeborenen.: Über den Anteil der verschiedenen Blutbestandteile (Hämoglobin, Blutkörperchen, CO2 , Serumsalze) an der Regulation der Blutreaktion. Acta Paediatrica 1924,3,235–260. Hasselbalch KA. Über die wahre Natur der “acidotischen Konstitution” des Neugeborenen. Biochem. Zeitschr. 1917;(80). 251–258.

86 | Monika Dräger and Erich Saling [21] Seham M. The acidotic state of normal new-borns. Am. J. Dis. Child. (American journal of diseases of children) 1919;(18). 42–50. [22] Eastman NJ. Foetal Blood studies I. The oxygen relationship of umbilical cord blood at birth. Bull. J. Hop. Hosp. 1930,47,221–230. [23] Eastman NMC. Foetal Blood studies II. The lactic acid content of umbilical cord blood under various conditions. Bull. J. Hop. Hosp. 1931,48,261–268. [24] Eastman NJ. Foetal Blood Studies III. The chemical nature of asphyxia neonatorum and its bearing on certain practical problems. Bull. J. Hop. Hosp. 1932,50,39–50. [25] Eastman NCEDLA. Foetal blood studies IV. The oxygen and carbon dioxide dissociation curves of foetal blood. Bull. J. Hop. Hosp. 1933,53,246–254. [26] Martin DS, Khosravi M, Grocott MPW, Mythen MG. Concepts in hypoxia reborn. Crit Care 2010, 14,315. [27] Barcroft J. Researches on pre-natal life. Oxford, Blackwell, 1946,292 p. eng. [28] James LS, Weisbrot IM, Prince CE, Holaday DA, Apgar V. The acid–base status of human infants in relation to birth asphyxia and the onset of respiration. J. Pediatr. 1958,52,379–394. eng. [29] Saling E. Austauschtransfusion bei Neugeborenen über die Aorta abdominalis, Diskussionsvortrag. [Der Tagungsbericht ist leider nicht mehr auffindbar], 1958. (7. Tagung der Deutschen Gesellschaft für Bluttransfusion). [30] Saling E. Austauschtransfusion bei Neugeborenen über die Aorta abdominalis [Exchange transfusion in newborn infants through the abdominal aorta]. Geburtsh Frauenheilk 1959, 19,230–235. ger. [31] Saling E. Neues Vorgehen zur Untersuchung des Kindes unter der Geburt, Einführung, Technik und Grundlagen. Archiv für Gynäkologie 1962,197,108–122. (http://www.springerlink.com/ content/q78l55k2w6133154). ger. [32] Saling E. Die Blutgasverhältnisse und der Säure-Basen-Haushalt des Feten bei ungestörtem Geburtsablauf. Z Geburtshilfe Gynäkol 1963,161,262–292. [33] Saling E. Microblutuntersuchung am Feten. Klinischer Einsatz und Erste Ergebnisse [Microblood Studoes on the Fetus. Clinical Application and 1st Results]. Z Geburtshilfe Gynakol 1964,162,56–75. ger. [34] Saling E. Foetal and Neonatal Hypoxia in relation to Clinical Obstetric Practice. London, Edward Arnold (Publishers) Ltd., 1968,181 p. eng.

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10.1 Introduction The three areas of neonatal respiratory medicine which have had most impact on the survival of newborn infants are resuscitation at birth, mechanical ventilation, and exogenous surfactant therapy. This chapter describes the developments in those areas up to the late 1970s. For some historic views about premature infants and some stepping stones in their treatment please refer to the beginning of Section 7.2.

10.2 Resuscitation Neonatal asphyxia has been recognized for many centuries. In the sixteenth century BC the Papyrus Ebers commented on the prognosis of a baby immediately after birth [1], “If it cries nee, it will live, if it moans ba, it will die.” The latter presumably referring to the expiratory grunting of an infant with respiratory distress [2]. Although many infants commence regular respiration within seconds after delivery, there are some, either as a result of asphyxia before delivery or prematurity, fail to adapt at birth and as a result, die. There has been interest in finding techniques to prevent that adverse outcome for over 2000 years, but the basis for current approaches have their origin in the eighteenth century.

10.2.1 Precursors in the eighteenth and nineteenth century In 1752 Smellie and in 1754 Pugh, both obstetricians [3] described their experiences of resuscitating apnoeic newborn infants using endotracheal tubes and mouth-to-tube inflation. There was, however, concern expressed regarding the use of exhaled air and hence Hunter devised a bellows system to avoid it. Nevertheless, mouth-to-tube inflation continued to be in favor. Chaussier, an obstetrician in Paris [3] and Blundell, an obstetrician at Guy’s Hospital [4] both described their experiences of intubation with straight endotracheal tubes, inserted using a finger in the infant’s pharynx to guide the tube, and then mouth-to-tube inflation. Blundell [4] described in detail the case of a pregnant woman who was run over and killed by a horse and carriage outside Guy’s Hospital. He carried out an immediate caesarean section and intubation and mouth-to-tube inflation of the infant and reported “In thirteen minutes from the last respiration of the mother, the child was taken out. In fifteen minutes from the last res-

88 | Anne Greenough and Anthony D. Milner piration of the mother, I began the artificial respiration. During fifteen minutes longer I continued it, ultimately resuscitating the child completely, and had due care been taken it would probably have been living still.’” Other techniques to resuscitate an infant at that time included following insufflation of warm human breath through a tube into the infant’s mouth – “sucking the infant’s nipples, tickling its soles, giving it a warm bath, burning the umbilical cord, rectal insufflation of tobacco smoke and placing the infant into a chicken carcass” [5]. Obladen [2] has reported on earlier resuscitation processes. He states “The proper sequence of resuscitating measures was regarded to be important as pointed out in Rau’s teaching book for midwives” and reports from Rau’s teaching book, which was published in 1807 [6]: “Do not cut the umbilical cord immediately unless ruptured from the placenta, but start to resuscitate the infant before . . . You may have the pleasure to see life returning even after hours. Therefore, you should not resign too early in your efforts . . . The proper measures are as follows: ‘(1) Remove any mucus from the infant’s mouth; (2) Wrap the infant’s extremities in warm towels and rub his precordial area with a cloth soaked with warm wine; (3) When no effect is seen within 5 min, bring the infant into a lukewarm bath. The water should reach the arms, the head is to be held upright . . . (5) Blow air into the mouth, using a specifically designed tube or a quill, while closing its nostrils. This must be performed by a healthy person, and a small quantity of air should be blown only, but repeatedly; (6) Apply an enema of water and wine, or of pure wine; (7) Take the infant out of the bath, place it on a dry towel, and drip cold water onto its chest; (8) Hold strong smelling things close to its nose, e.g., ammonia, spirit, a fresh split onion, or horseradish; (9) Drip some warm wine or brandy into its mouth; (10) If all this did not help, burn its foot soles with a hot iron or with glowing coal. If you reach your goal earlier on and the life returns, omit the stronger procedures, but return the infant into the lukewarm bath and gently rub its chest until the breathing has become regular’” (Rau 1807, translated in Obladen [2, p. 145]) The use of mouth-to-mouth and mouth-to-tube resuscitation of newborn infants appears to have been lost partly as a result of the reports of pneumothoraces [7, 8]. Subsequent resuscitation techniques consisted of moving the infant’s arms up and down [9] or swinging the infant slowly from a vertical to a head down position [10]. This was continued in some units until after the Second World War and is not dissimilar from the technique often used today to stimulate newly born lambs to breathe. Tank ventilators were first introduced in the 1870s which were difficult to use in the labor suite. A commercially constructed “Pulmotor” for automatic mechanical mask ventilation powered by oxygen under pressure was developed in 1907 [11]. A “Baby Pulmotor” (Figure 10.1(a) and (b)) was developed in 1914 and remained in use in many European delivery rooms up to the 1950s [12]. In 1928, Flagg [13] described a battery powered infant laryngoscope with a straight blade. Shortly, thereafter Foregger [14] developed and manufactured different types of infant laryngoscopes and endotracheal tubes.

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Fig. 10.1. (a) Dräger-Baby-Pulmotor (photograph taken from Schröder 1914 [103], with kind permission of Dräger company). (b) Schematic diagram of the mechanism of the Baby-Pulmotor (figure taken from Schröder 1914 [103], with kind permission of Dräger company).

10.2.2 Beginnings of current neonatal resuscitation practices Current neonatal resuscitation practices can be dated back to 1928, when Yandell Henderson in the United States [15] published his experience using a face mask, a flow of oxygen, a t-piece for intermittent obstruction, and a blow-off pressure measuring system consisting of a side tube immersed in up to 30 cm H2 O. In 1928, Flagg [16] added to the technique by describing his straight tube neonatal laryngoscope and method of intubation with the same pressure limiting device. He suggested using a pressure limit of 8 in. of water pressure (approximately 20 cm H2 O) with a combination of oxygen and carbon dioxide, on the assumption that the carbon dioxide would stimulate respiration. No data were given on the efficacy of either of these approaches. An alternative approach was described by Blaikely and Gibberd, two obstetricians at Guy’s Hospital in 1935 [17]. This consisted of intubation with a relatively narrow endotracheal tube. This was followed by an inflation of up to 35 cm H2 O; as there was a considerable leak around the tube, they calculated that an inflation pressure of approximately 15 cm H2 O was generated. It was maintained until the infant commenced breathing, often after several minutes, effectively giving high levels of continuous positive airway pressure (CPAP), a technique which 70 years later is under investigation [18].

90 | Anne Greenough and Anthony D. Milner 10.2.3 “Alternative” approaches Few units adopted these techniques until the late 1950s. One possible reason for this was that the care of the newborn was gradually transferred from the obstetrician to pediatricians who had no experience of intubation and looked to techniques requiring less technical skills. One approach was the Bloxsom positive pressure oxygen-air lock [19]. Infants with asphyxia were placed in a metal chamber with a plastic viewing window. The oxygen level was raised to 60%, humidified and warmed. The pressure in the chamber was then increased to three pounds of pressure for 30–40 s, then reduced to one pound pressure for 15 s before the cycle was repeated. This apparently reduced the mortality of infants treated by 25% compared to historical controls. An alternative approach was to deliver oxygen to the gastrointestinal tract on the assumption that oxygen would then be absorbed into the blood [20]. Seven case histories were described but there were no controls in the original paper [20]. A study by James et al. [21] in 1963 highlighted that there was no evidence of the transfer of oxygen from the gastrointestinal tract into the systemic blood flow in 9 asphyxiated or 20 healthy controls, concluding that the technique had nothing to offer. Treatment with sodium bicarbonate was proposed by Usher [22]. Nonrandomized studies [23–25] seemed to support its use, but a randomized trial [26] showed no benefit.

10.2.4 Scientific comparison of different methods In 1960, Saling [27] published findings comparing the value of different methods of treating asphyxia as assessed by measuring the umbilical artery and vein blood oxygen content. He found that thorax compression, mouth-to-mouth breathing and also intragastric oxygen were ineffective, but that intubation and ventilation using 100% oxygen led to a more rapid response than was seen in spontaneously breathing infants. He also recommended that the cord should be left uncut for as long as possible and that there should be no delay in commencing resuscitation after the delivery of asphyxiated infants.

10.2.5 Supplementary oxygen Chaussier [28] recommended that infants should be resuscitated with oxygen rather than inhaled air. The use of oxygen during resuscitation became popular throughout Europe [29, 30]. Hyperbaric oxygen was recommended by Hutchison and colleagues in 1963 [31]. This consisted of raising the ambient oxygen to up to 3 atm for 30 min after placing the asphyxiated infant in a compression chamber. A randomized trial was then carried out comparing hyperbaric oxygen therapy to intubation and intermittent

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positive pressure ventilation. There were no significant differences in mortality between the two groups, but the numbers were small with 15 deaths in the intubated infants and 19 in the hyperbaric group. The authors claimed that the main benefit of hyperbaric oxygen therapy was that less skill was required.

10.2.6 Refilling anesthetic bag In 1958, the refilling anesthetic bag was introduced, which in combination with a pressure relief valve and face mask provided an alternative device for first line resuscitation [32]. Karlberg et al. [33] had shown in 1954 that many term infants generated inspiratory pressures greater than 20 cm H2 O with their first breath. In 1969, Hull examined the inflation pressures generated when a fixed inspiratory volume (40 ml) was used to inflate the lungs of term asphyxiated infants. The 40 ml was based on the inspiratory volumes from spontaneously breathing infants as measured by Karlberg and colleagues. Hull found that the inflation pressures varied, but often exceeded 30 cm H2 O [34].

10.2.7 Change in pressure limiting valves By the late 1960s, infants were resuscitated in a manner very similar to that recommended by Flagg [16] 40 years before, with peak pressures of 30 cm H2 O and inspiratory and expiratory times of 1 s using a water column to limit inflation pressures. In 1973, a paper by Hey and Lenney [35] demonstrated that pressures generated using such a column of water as a blow-off device were very variable and highly dependant on the gas flow rate, pressures often exceeding 50 cm H2 O with flow rates of 10 l/min. This and problems associated with the possible growth of Pseudomonas led rapidly to the replacement of the water columns by spring-loaded pressure limiting valves.

10.2.8 Later developments and recommendations Since the mid-1970s, there have been a number of developments including the introduction of national and international advisory boards on resuscitation of the newborn, for example, the International Liaison Committee on Resuscitation (ILCOR) which report regularly [36]. They have advised that peak pressures of 30 cm H2 O should be used initially in term asphyxiated infants and 20–25 cm H2 O for prematurely born infants due to anxieties about barotrauma, which has been well documented in prematurely born animal models. There remains doubt whether positive end expiratory pressure should be used although this is now standard in many units, limiting infla-

92 | Anne Greenough and Anthony D. Milner tion pressures to as low as 15 cm H2 O [37]. There also remains doubt whether the first few inflations should be prolonged, particularly in preterm infants [36]. Two areas have been clarified. Despite the animal experiments carried out by Dawes et al. [38] in 1968, showing that the use of 100% oxygen led to a more rapid recovery from hypoxia, there is now strong evidence that 100% oxygen leads to a higher mortality rate in asphyxiated term infants compared to the use of air [39]. The optimal oxygen concentration for use in preterm infants remains to be defined, but most units are now commencing with 30% [39]. The other area clarified by well-conducted controlled trials is that suction at birth should not be used for active infants born with meconium stained amniotic fluid [40].

10.3 Mechanical ventilation Alexander Graham Bell invented a negative pressure jacket to ventilate neonates in 1869 [41]. Subsequently, a variety of tank ventilators were developed [42]. In 1907, Dräger and Hume [43] released the “Pulmotor,” a mobile short-term respirator that applied alternating positive–negative pressure which remained in use in the delivery suites for half a century. An infant Drinker ventilator, providing external negative pressure to the thorax, was developed for use in the delivery suite in 1907, but it was not until 1953 that the ventilator was modified to provide on-going respiratory support in the neonatal unit [44]. The device consisted of a water spirometer connected to a new Drinker-type ventilator with an improved facial seal. The spirometer measured tidal volume at the face and was connected to an electrical switching system so that a negative pressure was only developed by the ventilator as the infant breathed in. Thus, this device was the first infant triggered ventilator.

10.3.1 Intermittent positive airway pressure Benson and colleagues [45] subsequently reported in 1958 the successful use of intermittent positive airway pressure (IPPV) in three infants with respiratory distress syndrome (RDS). They carried out tracheotomies on the infants and used curare to eliminate spontaneous respiratory efforts. This was followed in 1960 by a single case report of an infant with RDS who survived after two periods of IPPV using a Stephenson ventilator, an adult volume limited device with variable pressure support. The infant was ventilated via an end tracheal tube and curare was not used [46]. The main therapy for RDS at this time, however, was to treat the accompanying metabolic acidosis with sodium bicarbonate and glucose and was known at the Usher regime [47, 48]. Delivoria-Papadopoulos and Swyer [49] reported the outcome of 18 infants in whom IPPV was commenced when they were considered to be about to die and had

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mean arterial pH values of 6.7. They were initially intubated, but had tracheotomies after 36 to 72 h, if they were still alive and continuing to require IPPV. Only one infant survived and was alive 6 months later, the infant had required 9 days of IPPV. They concluded that ventilation was only likely to be successful if commenced before the infants were in a terminal state. The same group then reported the results of IPPV using a Bird mark 8 ventilator via an end tracheal tube, commencing once mask resuscitation was no longer effective in infants with RDS [50]. The infants’ gestational ages ranged from 26 to 40 weeks. All seven infants who required IPPV before 8 h died. Seven of the 13 who commenced IPPV 28–52 h after birth survived and only one had abnormal neurodevelopment at follow up. From their experience, they recommended that IPPV should be commenced when the respiratory rate was below 30 or above 160/min, the PaCO2 was above 80 mmHg or the oxygen below 40 mmHg despite administration of 100% oxygen. In 1965, the Stanford University group [51] reported their experiences of providing prolonged IPPV via an end tracheal tube to 18 infants with RDS. They used a Bennett PR2 ventilator for periods of up to 9 days. In those infants whose respiratory efforts were too weak to trigger the adult ventilator, the trigger was set to maximum sensitivity resulting in auto cycling. This provided an unstable form of ventilation, with any change in ventilator settings altering the respiratory rate. Eleven of the 18 infants survived, including one with a birth weight of 1020 g. A year later, Reid and Mitchell [52] reported their experiences providing IPPV to 12 prematurely born infants with severe apnoea. All but one survived after 1 to 11 days of respiratory support. The same group then set up the first reported randomized trial comparing the Usher regime with IPPV given via an end tracheal tube [53]. The infants were recruited at 3 to 4 h of age. Both groups initially received the Usher regime, but this was discontinued in those receiving IPPV. Eight of the 10 infants in the IPPV group survived compared to only two of 10 in those receiving the Usher regime (𝑝 = 0.012) [53]. Thirteen infants in the trial had a birth weight less than 2 kg at birth; seven of the eight on the Usher regime died compared to none of the five in the IPPV group.

10.3.2 Negative external inhalation In 1967, a group of anesthetists and pediatricians at Columbia University published a randomized trial of negative external ventilation [54]. Entry criteria were a birth weight above 1000 g, less than 24 h old and signs of RDS. The infants received either incubator care or respiratory support provided by a locally modified Drinker ventilator. The trial was terminated after 54 infants had been recruited as there was no evidence that either therapy provided an advantage. In addition, there were considerable technical problems in maintaining a face mask seal and monitoring arterial blood gases. The trial was further complicated by 18 of the infants in the incubator care group receiving

94 | Anne Greenough and Anthony D. Milner tracheal intubation and IPPV. Eleven of those 18 showed no response, seven initially improved but only one survived. The main difference between the two therapies was that those receiving incubator care died on average 16 h earlier, but this difference was not statistically significant. 10.3.3 Bronchopulmonary dysplasia In the same year, Northway and colleagues [55] described the features of a chronic pulmonary disease which followed respiratory support for RDS. This team defined four stages of chest radiograph findings, ranging from the “whiteout” seen in acute RDS to a destructive appearance with extensive fibrosis and cystic changes. They concluded that these changes resulted from the exposure of immature lungs to a high oxygen concentration [55]. This was disputed by a group at Great Ormond Street who reported similar findings in a group of infants born at term with congenital heart disease who had received very high inflation pressures, often exceeding 60 cm H2 O, but never more than 60% oxygen [56]. This suggested that barotrauma was more likely to be responsible than oxygen toxicity for the abnormalities seen on the chest radiograph. 10.3.4 Outcomes of mechanical ventilation 10.3.4.1 Inflation and ventilator rates In 1968, the group at University College Hospital, London [57] reported their results of providing IPPV via an end tracheal tube in 40 infants over an 18 month period. They used the Bennett PR2 and rates of 70 to 80/min, but with inflations maintained for two to three seconds at 20 min intervals, that regime was proposed to reduce atelectasis. Over the study period, 284 infants had been admitted to the neonatal unit. Fourteen were considered unsalvageable and died without receiving respiratory support. The indications for therapy were apnoea, collapse, gasping and a heart rate of less than 60/min. The infants first received tactile stimulation for 1–2 min, if that failed the infant was intubated and manually ventilated for 5–15 min. Only if the latter intervention failed was ventilator support commenced. Twenty eight of the 40 ventilated infants died. In retrospect, the authors considered that there was no prospect of survival in 12 of the infants as they had associated anomalies such as pulmonary hypoplasia or congenital heart disease or were severely asphyxiated at birth. Forty-three percent of the remaining 28 infants survived. 10.3.5 Altering inflation times and rates The first study of the effects of altering inflation pressures and ventilator rates was reported by Cave-Smith and colleagues from Stanford USA in 1969 [58]. Six infants with RDS who fulfilled their blood gas results criteria for needing ventilation were recruited. They were ventilated either using a Bennett PR2 or a modified Harvard small

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animal respiration pump. The ventilators were set such that the infants did not make any respiratory efforts and a fixed 1:1 inspiratory:expiratory ratio (I:E ratio) was used. The infants were ventilated for 12 min through a combination of increased or reduced ventilator rates with reduced or increased inflation pressures with the aim of keeping the alveolar ventilation constant. They found that that both high inflation pressures and low respiratory rates resulted in improvements in arterial oxygenation. This was followed by a more extensive study [59] examining the effects of altering ventilator settings on the blood gases of infants with RDS. Six infants were recruited and the Bennett PR2 ventilator used. Ventilator rates of 30 and 80/min, peak pressures of 25 and 30 cm H2 O and I:E ratios of 1:1, 2:1, and 4:1 were compared. Rates of 80/min were less effective than rates of 30/min. Increasing the inflation pressures and altering the I:E ratio from 1:1 to 2:1 or 4:1 improved arterial oxygenation. Reynolds stressed that this pattern of ventilation should be restricted to the first few days after birth as prolonging its use could compromise cardiac output as the lung compliance improved and could lead to gas trapping. That pattern of ventilation, that is, slow rates and reverse I:E ratios, was subsequently widely accepted in the United Kingdom and often in Europe.

10.3.5.1 Positive end expiratory pressure The next development was providing IPPV with positive end expiratory pressure PEEP via an end tracheal tube [60]. The results of using this combination in 120 infants with either birth asphyxia or RDS from a 3 year period were reported [61]. A pediatric Engstrom volume limited ventilator was used. A maximum CPAP of 12 cm H2 O was used in addition to IPPV. Only two of the 26 infants recruited failed to improve initially, but 14 infants subsequently died [61]. An expiratory valve, to provide positive end expiratory pressure (PEEP), was used for the later part of the study period. Survival rates rose from 23% in 1969 to 70% in 1971. In those with a birth weight between 1 and 1.5 kg, survival rates rose from 0% to 50% over the same period. In 1973, DeLemos and colleagues explored the effects of increasing levels of PEEP on 25 infants who were receiving IPPV via an endotracheal tube for RDS [62]. Twenty of the 25 infants studied had progressive increases in their oxygenation as the level of PEEP was increased, sometimes up to as much as 20 cm H2 O, but that this was accompanied by a progressive increase in arterial CO2 levels and a decrease in cardiac output. They noted that PEEP levels of 5 cm H2 O had no adverse effects, but recommended that the PEEP level used should be carefully adjusted according to the effect on the arterial blood pressure. In 1973, Herman and Reynolds [63] investigated the effects of altering PEEP and I:E ratios in nine infants ventilated for RDS. They found that increasing the I:E ratio had a greater positive effect on arterial oxygen tension than providing PEEP. They suggested that this was because increasing the inflation time had a greater effect on the mean airway pressure and resulted in less CO2 retention. They also demonstrated a very striking inverse linear relationship between the mean airway pressure and the alveolar-arterial oxygen difference.

96 | Anne Greenough and Anthony D. Milner 10.3.6 Later developments Manginello et al. in 1978 [64] compared volume cycled ventilation with IPPV in a randomized trial which included 20 infants with RDS. Both forms of ventilation were similarly effective in correcting the metabolic acidosis and with regard to CO2 clearance. IPPV with an I:E ratio of 1:1 and a square pressure wave form, however, was more effective in raising arterial oxygen levels, as a result of much higher mean airway pressures. Seven of the 10 receiving volume limited ventilation died compared to only two of those on the IPPV regime. The beneficial effects of increasing the mean airway pressure already found in 1973 by Herman and Reynolds [63] were subsequently confirmed in 1979 by a study of 12 infants by Boros [65]. A Bourns ventilator was used which could provide I:E ratios of 4:1 or 1:4 and 1:1. In the 1–1 mode, the ventilator had a peak pressure hold mode, which allowed extending the inflation time and hence increased the mean airway pressure. Although there was a small increase in oxygenation on increasing the I:E ratio from 1:4 to 1:1, oxygenation more than doubled when the peak pressure was held. Boros was also able to demonstrate a linear relationship between mean airway pressure and oxygenation [65]. In the 1980s, there was a focus on the very high rate of pneumothoraces, that is 50% in some units. The use of prolonged inflation times was shown to increase the likelihood of the infant actively expiring [66], which increased the likelihood of a pneumothorax. In a randomized trial it was demonstrated that amongst infants actively expiring use of a neuromuscular blocking agent could significantly reduce the occurrence of pneumothoraces [67]. An alternative approach was to shorten the inspiratory time to 0.5 s or less and increase the respiratory rate to at least 60/min to match the infants spontaneous breathing pattern and promote synchrony between the infant’s breathing and delivery of positive pressure inflations and so avoid active expiration [68]. Subsequently, to further promote synchrony patient-triggered ventilation has been developed for infants with triggering devices including sensors detecting abdominal wall movement or changes in respiratory flow and more recently diaphragmatic EMG from sensors placed in the oesophagus. Ventilators are also now available which use the infant’s flow signal to terminate inflation (pressure support ventilation) which further reduce the likelihood of active expiration. A further “trigger” mode is proportional assist ventilation in which inflation pressures are provided in phase with the infant’s tidal volume (elastic unloading) and/or flow (resistive unloading). In addition, high-frequency oscillation is available. Despite the introduction of all these new ventilation techniques, although survival rates of even very prematurely born infants are now high, the problem highlighted by Northway et al. [55], BPD, remains a common complication as is chronic respiratory morbidity.

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10.4 Exogenous surfactant therapy In 1835, Jorg [69] published a monograph on RDS highlighting that the disease occurred almost exclusively in prematurely born infants and those with birth asphyxia, weakness and right to left shunting contributed to its pathogenesis.

10.4.1 Physiological background Von Neergaard in 1929, a tuberculosis physician, was the first to demonstrate that lungs could be inflated with greater ease if saline rather than gas was used to distend the lungs [70]. The next significant finding was by Pattle, an English physicist, who investigated the properties of pulmonary oedema fluid. In 1955, he reported that the bubbles in the fluid were very stable, persisting for up to 60 min. Using a rabbit model, he found that silicone antifoams had no effect on the stability of the bubbles in the pulmonary oedema fluid, but they were affected by pancreatin and trypsin. He concluded that the bubbles must be surrounded by an insoluble protein which was generated in the alveoli and had the effect of reducing surface tension to zero [71]. He suggested that hyaline membrane disease might be due to a lack of surface tension reducing substances. At the same time, groups in North America working in collaboration [72–74] using Wilhelmy balance techniques also found that the surface tension within the lungs of healthy animals was very low, decreasing as lung volume was reduced. This was the opposite of what was predicted from the Laplace formula, which states that if there is a sphere with a water/gas interface, the pressure within the sphere is inversely related to the radius provided the surface tension remains constant, i.e., pressure = 2* surface tension/radius. The effect noted to occur in bubbles from lung liquid was not seen when serum was substituted for the lung fluid [73]. The relevance of those findings became obvious in 1957 when Avery and Mead [75] published their studies showing that the lung fluid from infants who had died from hyaline membrane disease had high surface tension values. They concluded, as had Pattle, that RDS resulted from a lack of a surface tension lowering compound, that is surfactant, leading to stiff lungs and unstable alveoli.

10.4.2 Identification of the chemical structure of surfactant The next phase in the history of surfactant was the identification of its chemical structure. Klaus and colleagues [76] in 1961 were amongst the first to recognize that surfactant was predominantly a lipoprotein, and also contained small amounts of proteins. It was initially considered that the lipoprotein, dipalmitoyl phosphatidylcholine (DPPC) which makes up approximately 60% of surfactant, was responsible for the sur-

98 | Anne Greenough and Anthony D. Milner face tension lowering effects as it performed well in Wilhelmy balance studies [77]. By 1974, however, it became apparent that there were other constituents of surfactant including other phospholipids such as monoenoic PC and anionic phospholipids which were also important, as DPPC spread more slowly than the whole lung fluid [78]. Up to 10% of surfactant was found to be nonserum proteins, although as late as 1974 their functions were unknown [79]. There was evidence, however, that the presence of protein content improved the surface tension reducing properties of surfactant. It was not until the mid-to-late 1980s that four proteins were identified, SP-A, SP-B, SP-C, SP-D, and demonstrated that both SP-B and SP-C aid spreading [80] and that SP-A enhanced their effects [81]. In 1954, Macklin [82] was the first to suggest that the bulky type 2 pneumocytes in the alveolar membrane were the site of surfactant production. This was confirmed 8 years later by Klaus and colleagues who isolated a mitochondrial fraction in lung fluid and showed this to have surface tension lowering activity [83].

10.4.3 Methods for assessing surfactant The early studies investigating the surface tension lowering of surfactant used the Wilhelmy balance [71], in which the substance is spread over a water filled Teflon-coated trough. There is a movable boom across the trough, which allows the area of spread and hence the concentration of the substance being investigated to be altered. A transducer attached to the boom measured the surface tension. In 1977, Enhorning and colleagues described the pulsating bubble method [84]. Using that method, a bubble of the fluid under examination is mounted on a fine three-way tube system. One of the limbs is attached to a pressure transducer, the other to a pumping system so that the bubble can be “ ventilated” at a rate of 20/min. This provided information on the effect of distention and contraction of the bubble and the extent to which the substance differed from the Laplace relationship. Neither of the above techniques have found a place in clinical care [85]. An alternative method for assessing surfactant was described by Gluck and colleagues in 1971 [86]. It consisted of collecting amniotic fluid, separating the surfactant using chloroform and methanol and centrifugation, and then calculating the ratio of lethicin to sphingomyelin using a densitometer. Values above two were associated with surfactant maturity. Results below two were less specific, although the lower the result, the more likely the infant was to develop RDS. A simpler method, which gained popularity in the 1970s, was to collect gastric fluid from the infants after delivery, shake it, and observe how long the bubbles persisted, a technique which Pattle would have approved [71].

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10.4.4 Hormones and the surfactant system The role of hormones in maturing the surfactant system in immature fetuses was first noted by Moog in 1953 [87] and pursued by Liggins in 1969 [88]. He was investigating the effects of ACTH and cortisol on the delivery of premature lambs. The main finding was that delivery was accelerated, but he also noticed that the lambs were more likely to be alive after premature delivery and some had aerated lungs, suggesting that the lungs were more mature than expected. The following year he published similar results after treating the pregnant yews with dexamethasone [89]. Those results were confirmed by deLemos and colleagues [90]. This was followed, in 1972, by a randomized controlled trial by Liggins and Howie to examine the effects of antepartum glucocorticoid treatment in the prevention of RDS [91]. Sadly it was not until the mid-1990s that administration of antenatal glucocorticoid treatment to women at risk of premature delivery was generally adopted. The results of initial studies investigating the effects of thyroxine were also promising. In 1973, Wu and colleagues reported that thyroxine had a maturing effect on the type 2 pneumocytes of fetal rabbits [92]. Rooney and co-workers highlighted similar results when thyroid releasing hormone, which unlike thyroxine crosses the placenta readily, was given to pregnant rabbits [93]. Unfortunately subsequent large randomized studies involving over 2,000 pregnant women failed to show any benefit [94, 95]. 10.4.5 Surfactant therapy Once the composition and function of surfactant was known, it was inevitable that surfactant replacement therapy would be attempted. The results of initial studies, however, were disappointing. Both Robillard and colleagues [96] and Chu and coworkers [84] did not have positive results when giving DPPC as nebulized solutions. In contrast, Enhorning and Robertson, who administered surfactant derived from adult rabbit lung washings before their first breath via a tracheostomy tube to rabbits born after 28 days gestation demonstrated benefit. The surfactant administration was achieved by squeezing the thorax. The treatment led to prolonged fetal survival and improved lung expansion compared to administration of saline [98]. They then repeated the experiment but gave the surfactant as a pharyngeal injection avoiding the need for a tracheostomy. This also had positive results, although was less effective [99]. The first report of successful treatment with exogenous surfactant of infants with RDS was 7 years later. In 1980, Fujiwara and colleagues [100] used a mixture of naturally occurring surfactant lipids and synthetic lipids containing dipalmitoyl phosphatidylcholine and phosphatidyl glycerol. This was given to ten prematurely born infants who were less than 20 h old and had RDS Their gestational ages ranged from 28 to 33 weeks. Ten millilitres of the suspension was put into the endotracheal tube and then the infants received “bag and tube” ventilation with 100% oxygen. All 10 had dramatic improvements in their arterial oxygen tension and the mean inspired oxygen concentration could be reduced from 0.8 to 0.4. Two of the infants subsequently died,

100 | Anne Greenough and Anthony D. Milner but neither from a respiratory-related cause. The benefits of surfactant therapy were confirmed in randomized controlled trials by Enhorning and colleagues in 1985 [101], the Fujiwara group in 1990 [102] and subsequently by many others. Since then there have been numerous randomized studies attempting to define the optimal formulation, timing and the number of doses.

10.5 Conclusions Resuscitation of asphyxiated infants at birth is usually very effective. Since the 1970s changes include use of air rather than 100% oxygen and the more widespread use of CPAP. The use of mechanical ventilation has led to increased survival of even the most immature infants. Sophisticated ventilators have been developed which use the infant’s own respiratory patterns to control the rate and often the inflation time; other new modes have been developed. Nevertheless, BPD and chronic respiratory morbidity remain common and further studies are required to identify the optimum techniques for those infants at highest risk. Although surfactant research dates back to the 1920s, it was not until the 1990s that surfactant replacement therapy was used extensively resulting in improvements in survival and reductions in acute complications. Studies, however, are still needed to determine the optimum formulation and delivery technique.

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Jens H. Stupin

11 History of clinical structures and development of the Perinatal Care System

11.1 Introduction¹ During the 1960s, a significant increase in basic and clinical research regarding the pregnant mother and her fetus occurred. An increase of knowledge about the fetus has become greater in this decade than in any other period throughout the history of human medicine. Obstetricians took on a unique role in the entire field of medicine; as physicians for two patients at the same time, for both mother and fetus. It was the beginning of an ongoing fundamental structural metamorphosis in obstetrics, from predominantly mother-oriented medicine, with its considerable amount of operative character to combined mother-, embryo- and fetus-oriented medicine with the widespread concept of a new intrauterine medicine [1, 2]. Several centers and hospital departments specifically dedicated to this new scientific field appeared and developed in several places across the globe (e.g. Berlin, Montevideo, London, New York, etc.). This was one of the most impressive evolutionary events in the history of medicine, the birth of a new medical subspecialty, later referred to as ‘Perinatal Medicine’ [3], which would require immediately clinical and structural changes.

11.2 Historical precursors of a structural reform 11.2.1 The need for the establishment of antenatal care at the end of the 19th century At the end of the 19th century, obstetrics still remained a relatively young field of dubious professional status and obstetricians still struggled for recognition. Normally, they met their patients for the first time if called in by the attending midwife in the cases of difficult labor or obstructed delivery [4]. A special ward for pregnant women existed only at the Salpetrière in Paris, which also had the first refuge for abandoned pregnant women opened in 1892 by Madame Becquet [5]. In Edinburgh, Dr. Haig Ferguson opened a similar refuge for unmarried pregnant women, associated with the Royal Maternity Hospital in 1899. Asylum and rest in late pregnancy surprisingly reduced the incidence of eclampsia and prematurity. The 1 This introduction is on the basis of former statements of Prof. E. Saling.

106 | Jens H. Stupin benefits were so great that the married women from the Maternity Hospital soon demanded similar attention. Visits by midwives to expectant mothers in their homes in the later months of pregnancy followed. But there was a growing demand for this care and the need for outpatient antenatal clinics [4].

11.2.2 John William Ballantyne’s plea for a pro-maternity hospital More than 100 years ago, at the beginning of the 20th century, John William Ballantyne (1861–1923) (Figure 11.1), a lecturer in midwifery and gynecology at the Medical College for Women, Edinburgh, and also a lecturer on antenatal pathology and teratology at the University of Edinburgh [6], studied these promising results of medical care and supervision of pregnant women. He became one of the first, who recognized that pregnancy outcome is related to availability, quality and organization of health care. After studying medicine at the University of Edinburgh which he graduated in 1883, Ballantyne turned his attention to gynecology and obstetrics while still a student. In 1889, he graduated with a medical doctorate (MD) having a thesis on Some Anatomical and Pathological Conditions of the Newborn Infant in their Relation to Obstetrics. He became resident in the gynecological wards of the Royal Infirmary and in the Royal Maternity Hospital. Following 5 years as assistant at the university, he be-

Fig. 11.1. John William Ballantyne (1861–1923).

11 History of clinical structures and development of the Perinatal Care System |

107

Fig. 11.2. First page of J. W. Ballantyne’s ‘A Plea for a Pro-Maternity Hospital’, 1901.

came assistant professor at the Extramural School, and in 1916 assistant professor for the female medical students of the Edinburgh University. He was appointed assistant physician at the Royal Maternity Hospital in 1900 and was the chief physician from 1904 to 1919 [7]. His lectures and publications culminated in the magnum opus called A Manual of Antenatal Pathology and Hygiene, published in two extensive volumes in 1902 (about the fetus) [8] and 1904 (about the embryo) [9]. In 1901, he published A Plea for a Pro-Maternity Hospital, a concept of vital importance in the development of antenatal care [10] (Figure 11.2). During a time where pregnant women needing hospitalization were admitted under the care of general physicians without expertise in obstetrics and existing maternity institutions generally turned away preparturient women, he proposed a ‘pro-maternity hospital’ for women with complicated pregnancies which would accept patients at any stage of pregnancy diagnosed with complications or abnormal obstetric histories. According to Ballantyne, the expectant mother should be subject to clinical observation and management ‘on behalf of her unborn child’ [10]. In October 1901, Ballantyne’s ‘plea’ was answered when the directors of the Edinburgh Royal Maternity Hospital with the help of a £1000 donation by a generous donor², set aside a single bed for the ‘purpose of the treatment of the diseases peculiar to, or accidental during, pregnancy’ [4, 7]. Later the single bed had to be expanded to an antenatal department making Ballantyne the first to have hospital beds for antenatal patients. Doctors and nurses and even patients themselves realized the value of pre-maternity care. In April 1915, the first pre-maternity and infant welfare center under his direction was started in the hospital under the name of ‘Infant and Pregnancy Consultations for Expectant Mothers’. In 1917, Ballantyne was appointed ‘extra physician in charge of the ante-natal department’ [7]. Similar developments in Boston and Paris led to the establishment of antenatal clinics there.

2 Dr. Freeland Barbour, gynecological physician to the Edinburgh Royal Infirmary and president (1894/95) of the Edinburgh Obstetric Society

108 | Jens H. Stupin Ballantyne was a pioneer in organizing pregnancy care, being one of the first in his field to focus attention not just on the technology of childbirth and its after-effects, but on diseases during pregnancy and the damages they cause to the fetus and the health of the mother. He anticipated the modern approach of positive maternal and child health through good antenatal care and the prevention of disease [11]. Thereby he was well ahead of his time and undoubtedly the forerunner of the antenatal clinic of today [12, 13].

11.3 Erich Saling’s proposals for reforms in obstetrics: Early attempts to a structural reform At the end of the 1960s, after much progress was made, the time for reforms of clinical structures was overdue. In 1967, for the first time Erich Saling published fundamental recommendations for a structural reform and reorganization in gynecology and obstetrics and the setting up of units of modern obstetrics in Germany under the title: Vorschläge zur Neuordnung der Geburtshilfe (Proposals for New Regulations in Obstetrics) [3] (Figure 11.3). He was the first who recognized that old-fashioned structures were not only a hindrance for medical and scientific progress but also had a role in high perinatal mortality. Saling recommended establishing a new subdiscipline within women’s departments, concentrating on mother and fetus. In detail, he proposed the following five principal points [3]:

Fig. 11.3. First page of E. Saling’s ‘Proposals for New Regulations in Obstetrics’, 1967, © Prof. Saling.

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1.

2. 3.

4.

5.

Practicing gynecologists should select cases of high-risk pregnancy and send these patients to a specially equipped clinic for obstetrics and perinatal medicine for special outpatient care. Cases without increased risk could be managed at home or in smaller departments with less specialized equipment. A departmental system should be introduced, establishing at least three medically independent units within the field of gynecology such as conservative and operative gynecology, obstetrics and perinatal medicine, and gynecological endocrinology. The coordination of the different units within a clinic of obstetrics and gynecology should be in the hands of an executive director. A sufficient number of specially equipped regional obstetric departments (accessible within one and half hour) for the antenatal care and delivery of patients with a prognostic risk should be established. Such departments should have adequate staff, a laboratory which is operational around the clock, have facilities for immediate operative deliveries, and should have a chief who specializes only in obstetrics and is well versed in the modern methods of intrauterine diagnosis such as amnioscopy and micro-blood analyses of the fetus. To improve the research in obstetrics, the strained facilities of the university departments should be relieved by obstetric research departments affiliated with university departments but relieved from undergraduate teaching responsibilities.

These recommendations never advocated a separation of the specialty into obstetrics and gynecology, or the development of an autonomous ‘foetus doctor’, as discussed by Dobbs and Gairdner [2]. In a later paper on structural problems, Saling underlined that ‘mother and child must continue to be considered as a unit; the care of each being of equal importance’ [14]. However, this reform initiative has not been accepted in Germany, but was seen as a provocation. It caused resistance and was literally blocked by the conservative older generation of gynecologists in Germany. Traditional attitudes dominated, such as the idea that every gynecologist and obstetrician should be familiar with the entire field of women’s medicine. The conflict lasted for decades, prevented any structural reforms for a long time, and restrained scientific research in this field [15].

11.4 International developments as the answer to Saling’s proposals While recognition stalled within Germany, the progress in this new field of medicine achieved in Germany was acknowledged on an international level.

110 | Jens H. Stupin Realization of structural consequences began at a relative early stage in the United States. In 1969, the American Board of Obstetrics and Gynecology organized a meeting to determine the feasibility of subspecialty certification or boards in obstetrics and gynecology. In the same year, the American Board of Obstetrics and Gynecology did establish divisions of Maternal–Fetal Medicine, Oncology and Reproductive Endocrinology. Edward J. Quilligan was appointed the first head of the Division of Maternal– Fetal Medicine and became one of the principal founders of the subspecialty in the United States [16]. One of the purposes of this division was to improve the healthcare of mother and fetus suffering from diseases peculiar to or related to gestation by improving the organization and distribution of patient care [17]. Five years after Saling’s groundbreaking contribution, in 1972, the first ‘Units of Maternal–Fetal Medicine’ agreeing with his recommendations were established in the United States and many other countries followed [18]. The setting up of these units made successful the consequent use of the prenatal part of perinatal medicine within the framework of the complete field of obstetrics and gynecology. The medical success of this structural transformation served as a paradigm back in Germany, where the first center for perinatal medicine was also established in 1972 at University Hospital Frankfurt/Main (Goethe University). Two years prior to this, on February 1, 1970, at Charité Hospital, Berlin (former German Democratic Republic) a neonatal intensive care unit was established inside of the Clinic of Obstetrics and Gynecology, within walking distance of the labor ward. Thus the life-threatening transport of newborns between the labor ward and the neonatal intensive care unit (distance 1.5 km) could be avoided [19, 20]. This could be considered as the predecessor of the later established center for perinatal medicine at the same clinic, mainly lacking of a pediatric surgery. The initiative for this formation was started by Ingeborg Rapoport, the first holder of a chair for neonatology in Germany and Europe [20]. Already in 1968, she framed as one primary object of this construct the prophylaxis and clinical care of preterm births [20, 21]. As early as 1970, a center for perinatology with emphasis on scientific activities was founded in Montevideo (Figure 11.4). The first ‘Latin-American Center of Perinatology’ (CLAP, Centro Latinoamericano de Perinatologia y Desarrollo Humano) was created by a group comprised of professionals with mother’s and newborn’s health and led by one of the most influential obstetricians of the 20th century, Roberto CaldeyroBarcia (1921–1996). The foundation was supported by an agreement between the Ministry of Public Health, the University of Uruguay, the Pan-American Health Office (PAHO) and the Regional Office of the WHO. This also shows that in general Latin America and in particular Uruguay played an important role in the development in this new field [22]. In Sweden, the first research professorships in perinatal medicine were established at Karolinska University Stockholm and the University of Uppsala in 1972 and 1973, respectively. Gösta Rooth (1918–2008) at the University of Uppsala was the first holder of a chair in perinatal medicine in Europe. At the beginning, the two Swedish

11 History of clinical structures and development of the Perinatal Care System | 111

Fig. 11.4. Latin-American Center of Perinatology (CLAP), Montevideo, with kind permission of Ofelia Stajano de Caldeyro.

perinatal groups in Stockholm and Uppsala had research commitments and basically no clinical appointments, but later the members of the groups held clinical positions in the Departments of Obstetrics and Gynecology [23]. In Zurich, Switzerland, Albert Huch (1934–2009) together with his wife Renate Huch and neonatologist Gabriel Duc established the so-called Zurich Model of Perinatal Medicine in 1978, an integrative model of special perinatal care and clinical research that became an example for other European countries. A key factor of this clinic was the actual closeness between labor ward and neonatal intensive care unit [24, 25].

112 | Jens H. Stupin

11.5 Later developments and evolution of an integrative Perinatal Care System With the establishing of ‘Maternal–Fetal Units’, during the 1970s the American College of Obstetricians and Gynecologists (ACOG) together with the American Academy of Pediatrics (AAP) became convinced that a system or organized approach to perinatal care could improve pregnancy outcomes [26]. These organizations formed together with the National Foundation-March of Dimes, the American Medical Association and the American Academy of Family Physicians to create an ad hoc ‘Committee on Perinatal Health’ to design recommendations for a systems approach. These recommendations were released in 1976 under the title ‘Toward Improving the Outcome of Pregnancy: Recommendations for the Regional Development of Maternal and Perinatal Health Services’ [27]. The publication focused on the third trimester and neonatal period and on the hospital and inpatient sectors primarily. A three-level categorization of perinatal services to introduce co-operative interaction and organization into a system was proposed, enhancing the conception of Erich Saling from 1967 [28]. As result in the mid-1980s, the perinatal regionalization, including the broadly accepted three-level concept of organization, had been implemented throughout the United States [26]. Finally in 2005, 38 years after Saling’s proposals and after the establishment of numerous centers for perinatal medicine in Germany, the first governmental directive to establishing such centers was legislated [29]. The modern centers for perinatal medicine around the world highlight that Ballantyne’s and Saling’s intentions and aims were realized. They provide specialized care to pregnant patients, offering advanced perinatal diagnostic services and compassionate care. The staff combines insight from different medical specialties – obstetrics, perinatology, diagnostic radiology, ultrasonography and genetics – giving the patients comprehensive, multidisciplinary care during the pregnancy.

Bibliography [1] [2] [3] [4] [5] [6]

Saling E. Das Kind im Bereich der Geburtshilfe [The infant within the field of obstetrics]. Stuttgart, Germany, Thieme, 1966. Dobbs RH, Gairdner D. Editorial: Foetal medicine – Who is to practise it? Arch Dis Child 1966, 41,453. Saling E. Vorschläge zur Neuordnung der Geburtshilfe [Proposals for new regulations in obstetrics]. Geburtshilfe Frauenheilkd 1967,27,572–585. Reiss HE. Historical insights: John William Ballantyne 1861–1923. Hum Reprod Update 1999,5, 386–389. Browne FJ. Antenatal and postnatal care. Chapter 1: The history and development of antenatal care. 6th edn. London, UK, J A. Churchill Ltd., 1946. Philip AGS. Historical perspectives: Perinatal profiles: John William Ballantyne: Scottish obstetrician and prolific writer. Neoreviews 2008,9,e503–e505.

11 History of clinical structures and development of the Perinatal Care System

[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

[19]

[20] [21]

[22] [23] [24] [25] [26] [27]

[28]

[29]

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Obituary. John William Ballantyne, M.D., F.R.C.P.E., F.R.S.E. Br Med J 1923,1,213–216. Ballantyne JW. A manual of antenatal pathology and hygiene of the foetus. Vol. 1, Edinburgh, UK, William Green and Sons, 1902. Ballantyne JW. A manual of antenatal pathology and hygiene of the embryo. Vol. 2, Edinburgh, UK, William Green and Sons, 1904. Ballantyne JW. A plea for a pro-maternity hospital. Br Med J 1901,1,813–814. Ballantyne JW. An address on the new midwifery: preventive and reparative obstetrics. Br Med J 1923,1,617–621. Ballantyne JW. The maternity hospital, with its antenatal and neo-natal departments. Br Med J 1921,1,221–224. Dunn PM. Dr. John Ballantyne (1861–1923): perinatologist extraordinary of Edinburgh. Arch Dis Child 1993,68,66–67. Saling E. Structural classification of the obstetric part of perinatal medicine. International discussion of a medical-political question. J Perinat Med 1974,2,219–221. Saling E. The first 40 years – a subjective review. J Perinat Med 2001,29,275–280. Quilligan EJ. Perinatal medicine in the United States. In: Kurjak A, Chervenak FA, eds. Textbook of Perinatal Medicine, Vol. 1, 2nd edn. Abingdon, UK, Informa Healthcare, 2006, xxxviii-xl. The American Board of Obstetrics and Gynecology. Bull Div Matern-Fetal Med 1973. Saling EZ. Birth and youth of prenatal and perinatal obstetrics. In: Kurjak A, Chervenak FA, eds. Textbook of Perinatal Medicine, Vol. 1, 2nd edn. Abingdon, UK, Informa Healthcare, 2006, xxv–xxxiii. Wauer RR. Die Entwicklung der Neonatologie als Teil der Perinatologie an der Universitätsfrauenklinik der Charité in Berlin-Mitte. In: David M, Ebert AD, eds. Geschichte der Berliner Universitäts-Frauenkliniken. Berlin, Germany, New York, USA, de Gruyter, 2010,88–130. Wauer RR. Inge Rapoport – Nestorin der deutschen Neonatologie. Sitzungsberichte der Leibniz-Sozietät der Wissenschaften zu Berlin 2013, 115,37–59. Syllm-Rapoport I. [Recommendations of the Society for Perinatal Medicine of the GDR for the special care of newborns in postnatal primary critical conditions (first 2 hours of life)]. Z Arztl Fortbild (Jena) 1972,66,121–128. CLAP-The Latin-American Center of Perinatology, Women’s and Reproductive Health. (Accessed March 25, 2014, at http://www.clap.ops-oms.org) Rooth G. Perinatal medicine in Sweden. J Perinat Med 1974,2,222–223. Zimmermann R. Akademischer Bericht 2009. Klinik für Geburtshilfe. Zurich, Switzerland, Universität Zürich, 2009. Vetter K, Dudenhausen JW. Albert Huch – Leben aus dem Widerspruch. Nachruf. Z Geburtsh Neonatol 2009,213,120. Little GA. Structure of perinatal care systems. In: Kurjak A, ed. Textbook of Perinatal Medicine, Vol. 1. London, UK, New York, USA, The Parthenon Publishing Group, 1998, 159–164. Committee on Perinatal Health. Toward improving the outcome of pregnancy (TIOP#1): Recommendations for the regional development of maternal and perinatal health services. White Plains, New York, USA, National Foundation-March of Dimes, 1976. Frigoletto FD, Little GA, eds. Guidelines for perinatal care. 2nd edn. Elk Grove, Washington, USA, American Academy of Pediatrics, American College of Obstetricians and Gynecologists, 1988. Gemeinsamer Bundesausschuss (G-BA). Vereinbarung über Maßnahmen zur Qualitätssicherung der Versorgung von Früh- und Neugeborenen nach § 137 Abs. 1 Satz 3 Nr. 2 SGB V. BAnz Nr. 205 (S. 15 684),28.10.2005.

Erich Saling and Monika Dräger

12 History of first activities such as training, publications, foundation of very first congresses and societies

12.1 New section in medicine: First activities From the beginning of the 1960s, fetal blood analysis and amnioscopy fundamentally changed clinical and scientific obstetrics, which has been similarly stated as the beginning of “Fetal Medicine” by both the British pediatricians Dobbs and Gairdner [1]. In so far in addition to the established care of the mother, the fetus received for the first time high attention and became a real patient. This can be proven by studying obstetrical textbooks published in the late 1950s. There were only single pages which concern the state or the safety of the fetus. Just a few years later in 1966 [2], the first author published the very first real book of this new field with the title: Das Kind im Bereich der Geburtshilfe (“The infant within the field of obstetrics”). In 1968, this book was translated into English – unfortunately

a

b c

d

Fig. 12.1. Development of publications in the field of perinatal medicine. (a) Only a few pages in obstetrical textbooks published in the late 1950s. (b) Saling (1966) very first real book of this new field with the title: “Das Kind im Bereich der Geburtshilfe” (“The infant within the field of obstetrics”). (c) Translated in 1968 into English – unfortunately under a not quite suitable title: “Foetal and Neonatal Hypoxia in relation to Clinical Obstetric Practice” [3]. (d) Textbook of Perinatal Medicine which has been edited by Prof. Asim Kurjak at the end of the last century [4] [5]. © Erich Saling.

116 | Erich Saling and Monika Dräger under a not quite suitable title: “Foetal and Neonatal Hypoxia in relation to Clinical Obstetric Practice” [3]. In this decade – in the 1960s – the obstetrician took over an exclusive task within the entire field of medicine, namely to be a physician for two patients at the same time, for both mother and the fetus. It was a great principle change from mother-oriented obstetrics to an additionally fetal-oriented new concept. How immensely this field has grown since that time is presented by the huge Textbook of Perinatal Medicine which has been edited by Asim Kurjak at the end of the last century [4, 5]. We have tried to illustrate this tremendous development in Figure 12.1. In 1973, we founded the very first Journal of Perinatal Medicine in Berlin. Roberto Caldeyro-Barcia, Edward Hon, and Stanley James as neonatologist joined us as invited editors [6].

12.2 First local educational activities As already mentioned, starting at the beginning of the 1960s, the character of obstetrics fundamentally changed. We became physicians not just for the parturient alone, but increasingly also for the unborn infant. In 1963, in our unit we started one week international introductory courses in modern obstetrics and perinatal medicine (Figure 12.2). In the first year, we had participants from eight European countries. In Figure 12.3, you see the practical training in fetal blood sampling; the fetal head is replaced by a tennis ball.

Fig. 12.2. Introductory courses in modern obstetrics and perinatal medicine in Berlin Neukölln. Figure taken at the fourth course in 1964. © Erich Saling.

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Fig. 12.3. Training of fetal blood sampling; fetal head is replaced by a tennis ball. © Erich Saling.

When Joseph Bieniarz, the German speaking co-worker of Caldeyro-Barcia read our first publications, the team of Montevideo contacted us and started to prepare the first international meeting on a high scientific level which took place in Uruguay, in Montevideo in October 1964 (with a small group of participants, see Figure 12.4, including Caldeyro-Barcia (5), Hon (4) James (3), and the first author (7).) The very first national scientific society in cooperation with other disciplines – mainly neonatology – has been founded by us on February 6th 1967 in Berlin. It was the German Society of Perinatal Medicine. It is of particular interest that when founding this society, we included other quite different disciplines apart from obstetrics and neonatology. Also there were representatives from anesthesiology, pathology, physiology, pediatric surgery, and even from veterinary obstetrics. The foundation of the first national society of Perinatal Medicine, the German, can be considered as the birth of the official public corporation of Perinatal Medicine. In November of the same year, we organized the very first national congress of Perinatal Medicine, also in Berlin (Figure 12.5). One year later, in 1968, the second national corporation in this field was founded. It was the Society of Perinatal Medicine of the German Democratic Republic (former East Germany).

118 | Erich Saling and Monika Dräger

Fig. 12.4. Meeting in Montevideo. First row, from left to right: 1. Juan Poseiro (Uruguay), 2. Edward Quilligan (USA, 3. L. Stanley James (USA), 4. Edward H. Hon (USA), 5. Roberto Caldeyro-Barcia (Uruguay), 6. F. Kubli (Germany), 7. Erich Z. Saling (Germany), 8. Karlis Adamsons (USA), Second row, from left to right: 9. Name unknown to us, 10. Name unknown to us, 11. Molly Towell (USA), 12. J. Esteban-Altirriba (Spain), 13. D. Fonseca (Uruguay), 14. L. Escarcena (Uruguay), 15. S. V. Pose (Uruguay), 16. C. Méndez-Bauer (Uruguay). Third row, from left to right: 17. O. Alvarez (Uruguay), 18. O. Althabe (Uruguay), 19. R. Schwarz (Argentina) © of the original picture: family of Prof. Caldeyro-Barcia, with kind permission of Ofelia, the spouse of Prof. Caldeyro-Barcia (numbers inserted by the authors).

1. Deutscher Kongress für Perinatale Medizin in Berlin am 25. November 1967

Fig. 12.5. First national congress of Perinatal Medicine, Berlin 1967 © Erich Saling.

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a

b

Fig. 12.6. (a) Cover and (b) title page of the program of the first “European Congress of Perinatal Medicine, 28th–30th March, 1968, in the Congress Hall, Berlin.” The statue on the cover is the Maternity Statue, designed by Mme. Hélène Guastalla, Paris (more background details are available in [7]. Since 1969 a small copy of the statue was awarded to each winner of the Maternity Prize of the German Society of Perinatal Medicine and since 1976 to each winner of the European Maternity Prize, awarded from the European Association of Perinatal Medicine to outstanding scientists. © Erich Saling.

Also in 1968, after our initiative, the very first international scientific meeting took place. It was the first European Congress of Perinatal Medicine in Berlin (Figure 12.6). The first international interdisciplinary society has consequently then been founded on March 30th 1968. It was the European Association of Perinatal Medicine, more historic details see in the common publication with Prof. Gian Carlo DiRenzo about the history of the European Association of Perinatal Medicine, published in 1996 [7]. This was in so far the beginning of the international official public corporation of perinatal medicine. After 1968, a large number of national and also a considerable number of international societies of this new field have been founded.

120 | Erich Saling and Monika Dräger

12.3 Later developments With regard to international societies, the foundation of the society The Fetus as a Patient in 1984 has been particularly important. In 1991, the first World Congress of Perinatal Medicine was held in Tokyo under the chairmanship of Shoichi Sakamoto and during this congress, the World Association of Perinatal Medicine (WAPM) was founded In 2005, the International Academy of Perinatal Medicine (IAPM) was founded. As this book has been compiled and published in cooperation with the IAPM, we asked the secretary general of IAPM, José Carrera, to write a contribution about the history of it (see Chapter 13).

Bibliography [1] Dobbs RH, Gairdner D. Foetal Medicine – who is to practice it?, Editorial. Arch Dis Childh 1966, 41,453 (English). [2] Saling E. Das Kind im Bereich der Geburtshilfe, Eine Einführung in ausgewählte aktuelle Fragen. Stuttgart, Thieme, 1966,219 p. (German). [3] Saling E. Foetal and Neonatal Hypoxia in relation to Clinical Obstetric Practice. London, Edward Arnold (Publishers) Ltd., 1968, 181 p. (English). [4] Kurjak A, ed. Textbook of Perinatal Medicine, A comprehensive guide to modern clinical perinatology. London, New York, The Parthenon Publishing Group, 1998, 2 vol. (English). [5] Kurjak A; Chervenak FA, eds. Textbook of Perinatal Medicine. 2nd edn. London, Informa Healthcare, 2006, 2 vol., 2304 p. ISBN: 1842143336 (English). [6] Hon EH, Caldeyro-Barcia R, Saling E. Editors’ preface. J. Perinat. Med. 1973,1,3–6 (English). [7] Saling E, Di Renzo GC. Perinatal care in Europe, A history of the European Association of Perinatal Medicine. New York, Parthenon, 1996. ISBN: 1850709130.

Jose M. Carrera

13 History of the International Academy of Perinatal Medicine (IAPM)

13.1 Introduction The foundation of the International Academy of Perinatal Medicine (IAPM) was undoubtedly not just an historic event, but also a formidable demonstration of coherence, generosity, opportunity, and friendship. The decision of three large world scientific societies¹ to combine their efforts, in order to create a common forum for academic debate, was an act that does credit to those who made it possible: The Presidents of the three organizations (Profs. Asim Kurjak, Aris Antsaklis, and Frank Chervenak), and the father of Perinatal Medicine, Prof. Erich Saling, who accepted the presidency of the new institution. These men clearly demonstrated their remarkable foresight, their open and innovative spirit, their love for Perinatal Medicine, and their capacity to quickly reach agreements.

13.2 The first steps The idea of founding an academic institution that would bring together most of the outstanding personalities of the world’s Perinatal Medicine, came up for the first time in Osaka, Japan, in 2003, on the occasion of the 6th World Congress of Perinatal Medicine. The Secretary General of the World Association of Perinatal Medicine (WAPM), Dr. Jose M. Carrera, during an informal dinner with a small group of friends belonging to several scientific societies convinced them of the need for an institution whose mission would go beyond that of the scientific societies to which they belonged and could serve as a space for reflection and dialogue, a corporation such as a stable senate that would pick up personalities from all over the world. It was proposed, among other things, that this corporation ought to be the conscience of the world’s Perinatology. The majority of those present, reflected positively on the idea and requested Prof. José. M. Carrera to explore possibilities and to work in a theoretical project. In November 2004, at a meeting in Budapest, Hungary, under the auspices of Prof. Zoltan Papp, the three Presidents (Profs. Asim Kurjak for the WAPM, Aris Antsaklis for the European Association of Perinatal Medicine, and Frank 1 The World Association of Perinatal Medicine (WAPM), the European Association of Perinatal Medicine, and the International Society “The Fetus as a Patient.”

122 | Jose M. Carrera

Fig. 13.1. Preparatory meeting for IAPM in New York, December 14th, 2004 (from left: Profs. Erich Saling, Frank Chervenak, Asim Kurjak, and José Carrera) © Erich Saling.

Chervenak for the International Society The Fetus as a Patient) successfully agreed to start the project, and produced a list of potential fellows and establishing the grounds for a possible constitution. Finally, in December 2004 (Figure 13.1), the texts for the founding of the IAPM were revised, amended, and finally approved, as well as the list of regular fellows and the composition of the board of directors.

13.3 The roots of the Academy The roots of the IAPM are: The World Association of Perinatal Medicine (WAPM), which brings together specialists of Perinatal Medicine from all over the world was founded in Tokyo, Japan on November the 6th, 1991. Their first president was Prof. Schouichi Sakamoto (Japan). Up to now (2014) there have been 11 World Congresses. Its official journal is The Journal of Perinatal Medicine, chief editor is Prof. Joachim W. Dudenhausen (W. de Gruyter, Berlin). The European Association of Perinatal Medicine was founded in Berlin by Prof. Erich Saling on March 30th, 1968, during the 1st European Congress of Perinatal Medicine. This was the first official international public corporation of Perinatal Medicine. It is composed of several very active study groups and it organizes the European Congress of Perinatal Medicine every 2 years. Its official magazine The Journal of Maternal Fetal and Neonatal Medicine is headed by Profs. Gian C. Di Renzo and Dev Maulik.

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The International Society “The Fetus as a Patient” was founded in 1984 by a very prestigious group of Perinatal Medicine specialists. The founder president was Prof. Asim Kurjak (Croatia). The society holds an annual international congress as well as several advanced training courses for postgraduates in Maternal Fetal Medicine. The official Journal is Fetal Diagnosis and Therapy led by Prof. Wolfgang Holzgreve (Karger, Basel). With the later inclusion of Prof. Hirosichi Nishida to the Board of Directors of the IAPM, (2006) the prestigious Federation of Asia and Oceania Perinatal Societies (FAOPS), founded in 1980, and including 17 countries is also represented in our Academy. It is an old tradition that new academies (both domestic and international) are sponsored by an old Academy. In the case of IAPM, this function has been performed by the Royal Academy of Medicine of Catalonia. Its current President, Prof. Jacint Corbella, in his capacity of the President of the Academy was the President of the foundation ceremony.

13.4 Foundation of the IAPM The foundation ceremony (Figure 13.2) was held on May 25th, 2005. The presidential table was comprised of: Profs. Jacint Corbella (President of the Royal Academy of Medicine of Catalonia), Asim Kurjak (President of the WAPM), Aris Antsaklis (President of the European Association of Perinatal Medicine), Frank Chervenak (President of the International Society The Fetus as a Patient), and Jose M. Carrera (Secretary General of the WAPM). Academic fellows of the Royal Academy that were to serve as academic godfathers of the future regular fellows were Profs. Angel Ballabriga Aguado and José M. Dexeus Trias de Bes. Prof. Jacint Corbella, President of the Royal Academy, opened the session and gave a word of salutation to the Board of Directors of IAPM. Then the Secretary General of the WAPM read the Foundation Charter of the Academy, after which Prof. Asim Kurjak read the list of the 10 regular fellows proposed by his association. Following this, Prof. Aris Antsaklis named the 10 personalities proposed by the European Association of Perinatal Medicine and Prof. Frank Chervenak proposed 10 regular fellows on behalf of the International Society The Fetus as a patient. They too entered the compound preceded by the godfathers. The second part of the ceremony consisted of the solemn oath of each new regular fellow, and the award of the symbols (medal and diploma) of their new academic status. The following board has been elected: Prof. Saling as President, as Vice Presidents: Profs. Asim Kurjak, Frank Chervenak, Aris Antsaklis, as Secretary General: Prof. José Carrera and as Treasurer Prof. Birgit Arabin.

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Fig. 13.2. Foundation ceremony. © José Carrera.

13.5 Identity, mission, and objectives of IAPM The IAPM is a scientific, international, and independent nonprofit-making academic institution for the study, evaluation, dialogue, and promotion of Perinatal Medicine across the world.

13.5.1 Mission The mission of the International Academy of Perinatal Medicine is guided by the international ethical concept of fiduciary responsibility to protect and promote the health of pregnant women, fetal patients, and newborns globally. In adopting this ethical concept as its foundation, the Academy seeks to transcend differences of national origin, history, religion, ethnicity, gender, and race. In furtherance of this mission, the Academy is committed to provide evidencebased and ethically justified advice on scientific, clinical, research, and health policy matters related to Perinatal Medicine.

13 History of the International Academy of Perinatal Medicine (IAPM) |

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13.5.2 Objectives of the IAPM The objectives of the Academy are as follows: 1. To promote the study of scientific principles and practical applications in Perinatal Medicine. 2. To promote research and education in reproductive health, conducting courses and workshops either by itself or through sister organizations. 3. To develop and improve the exchange of information and dialogue, in accordance with the academic principles mentioned, convening an annual scientific conference to discuss the most current and conflicting issues. 4. To foster international aid to developing countries to actively promote maternal and child health care across the world. This objective shall be done through Matres Mundi. 5. To maintain an adequate relationship with societies and institutions involved in Perinatal Medicine. The logo of IAPM brings together the items that symbolize the objectives of the Academy: a pregnant mother with a child in her arms (Figure 13.3). – For specific characteristics of the IAPM, please refer to www.iaperinatalmedicine.org/Mission,%20Identity%20and%20Objectives.htm – For information about decision-making structures, and a list of regular, associate and honorary members, please refer to: www.iaperinatalmedicine.org/Basic%20Organization.htm www.iaperinatalmedicine.org/The%20International%20Council.htm

Fig. 13.3. Logo of the IAPM. © IAPM.

126 | Jose M. Carrera

13.6 Activities of the IAPM Apart from the statutory annual meetings, activities carried out by the IAPM include: symposia and courses, the preparation of statements, humanitarian work, and collaboration with other academies and scientific societies. Humanitarian Activities: A collaboration between the IAPM and the charitable organization Matres Mundi culminated in the signing of an “Agreement” in May 2006 stating that Matres Mundi is the humanitarian agency of the IAPM. The International School of Perinatal Medicine for Africa (ISPEMA) was founded (Barcelona, December 10th, 2012) as the result of the collaboration between the IAPM and Matres Mundi and most international societies of Perinatal Medicine. Its basic goals are to increase the number and training of healthcare professionals involved in Perinatal Medicine. Presidential Award: In 2005, the so-called International Academy of Perinatal Medicine’s Presidential Award was instituted. It is symbolized by the presentation of a “Golden Amnioscope.” The “Presidential Award” recognizes figures who have contributed to the overall development of Perinatal Medicine, based on their original scientific publications and their contribution to the development of IAPM. The first to receive the Presidental Award have been Prof. Asim Kurjak and Prof. José Carrera.

Selected References [1] Matres Mundi International, Carrera J. M. International Academy of Perinatal Medicine (IAPM), History, Organization, Activities. Barcelona, Spain: Matres Mundi, 2008 (English). [2] Matres Mundi. International Cooperation Agency for Maternal and Infant Health. Barcelona, 2009 (English). [3] World Association of Perinatal Medicine (WAPM). History, Organization and Activities. Secretary General Office. Barcelona, Spain, 2005 (English). [4] International Academy of Perinatal Medicine http://www.iaperinatalmedicine.org/index.htm (24.02.2014) (English).

Index of Names and cited Authors A Abramson, E. 60 Aguado, A. B. 123 Alvarez, H. 11 Antsaklis, A. 121, 123 Apgar, V. 2, 79, 83 Arabin, B. 123 Arima, M. 48 Avery, M. E. 97 B Ballantyne, J. W. 35, 106–108 Bang, J. 51 Barcroft, J. 83 Barnett, S. 50 Barter, R. H. 70 Baty, J. M. 38 Bell, A. G. 92 Benoit, B. 54 Benson, F. 92 Betke, K. 39 Bevis, D. C. 2, 30 Bieniarz, J. 117 Blackfan, K. D. 38 Blaikely, J. B. 89 Bloxsom, A. P. 90 Blundell, J. 87 Boddy, K. 53 Bogart, M. H. 74 Boros, S. J. 96 Bourgeois, L. 35 Braun, E. 39 Breg, W. R. Jr. 70 Brock, D. J. 73 Brown, R. 47 Brown, T. G. 43, 69 C Caldeyro-Barcia, R. 2, 11, 110, 116, 117 Campbell, S. 44, 51, 53 Carpenter, D. 50 Carrera, J. M. 2, 120–123, 126 Casey, B. M. 81 Cave-Smith, P. C. 94 Chaussier, F. 87, 90

Chervenak, F. A. 55, 121–123 Chown, B. 36 Chu, J. 99 Clarke, C. A. 37 Cochrane, W. 47 Cohen-Overbeek, T. 53 Corbella, J. 123 Cremer, M. 7 Crick, F. 69 Cromb, E. 48 Cuckle, H. S. 73 D Da Fonseca, E. B. 60 Daffos, F. 37 Damaschke, K. 23 Darrow, R. R. 36 Dawes, G. S. 18, 53 de Kergaradec, M. J. A. L. 5 de Lemos, R. A. 95, 99 de Maupertuis, P. L. 69 Delivoria-Papadopoulos, M. 92 Dexeus Trias de Bes, J. M. 123 Di Renzo, G. C. 119, 122 Diamond, L. K. 36 Dobbs, R. H. 1, 24, 109, 115 Donald, I. 2, 41, 69 Dräger, M. 3, 92 Dudenhausen, J. W. 2, 122 Duggan, T. 43 Dumont, M. 60 E Eastman, N. J. 79, 83 Eik-Nes, S. 52 Einthoven, W. 7 Enhorning, G. 98–100 F Filly, R. 47 Finn, R. 30 Flagg, P. J. 88, 89, 91 Fleischer, A. 47 Fleming, J. 43 Foregger, R. 88

128 | Index of Names and cited Authors Fuchs, F. 60, 70 Fujiwara, T. 99 G Gairdner, D. 1, 24, 109, 115 Garrett, W. 49 Gibberd, G. F. 89 Gill, R. 52 Gluck, L. 98 Goldberg, M. F. 71 Goldstein, P. 79, 83 Goodlin, R. C. 5, 11, 29 Gottesfeld, K. 45, 51 Guastalla, H. 119 H Hackett, G. A. 53 Hahnemann, N. 70 Hall, A. 43 Hammacher, K. 2, 15 Hansmann, M. 51, 53 Hart, A. P. 36 Hellman, L. M. 47, 50 Henderson, Y. 89 Herman, S. 95, 96 Hess, J. H. 63 Hey, E. 91 Hinselmann, M. 47 Hobbins, J. 47 Hofbauer, J. 8 Hoffbauer, H. 30 Hofmann, D. 46 Holaday, D. A. 81 Holländer, H. J. 46 Holm, H. H. 51 Holmes, J. 44, 45 Holzgreve, W. 123 Hon, E. H. 2, 11, 13, 116, 117 Howie, R. N. 99 Howry, D. 45 Huch, A. 25, 111 Huch, R. 25, 111 Hull, D. 91 Hunter, J. 87 Hutchison, J. H. 90 Hüter, V. 6 J Jacobson, C. B. 70 James, L. S. 2, 81, 83, 90, 116, 117

Johannsen, W. 69 Jorg, E. 97 Jouppila, P. 50, 52 K Karlberg, P. 91 Katz, J. 6 Kennedy, E. 5, 29 Kergaradec, M. J. A. L. de 5 Khentov, R. A. 46 Khlestova, R. A. 46 Kikuchi, Y. 46 Kirkinen, P. 52 Kiserud, T. 54 Klaus, M. H. 97, 98 Kleihauer, E. 38 Kobayashi, M. 47, 50 Kohlschütter, O. 82 Kossoff, G. 49 Kratochwil, A. 2, 48, 51 Krause, W. 46 Kubli, F. 30 Kupesic, S. 55 Kurjak, A. 45, 52–54, 56, 116, 121, 123 L Laennec, R. 5 Lambl, D. 30 Landsteiner, K. 36 Lavoisier, A. L. 82 Lenney, W. 91 Leopold, G. 47 Lesinski, J. 30 Levi, S. 50 Levine, P. 36, 37 Liggins, G. C. 2, 60, 63, 65, 99 Liley, A. W. 2, 30, 37 Little, W. J. 79 Lübbers, D. W. 25 M Macklin, C. C. 98 Maeda, K. 2, 16, 48 Mandelbaum, B. 69 Manginello, F. P. 96 Mantoni, M. 52 Marsal, K. 52, 53 Matteucci, C. 7 Maulik, D. 122

Index of Names and cited Authors

Mayor, F. I. 5 Mead, J. 97 Mendel, G. J. 69 Menees, T. O. 30 Merkatz, I. R. 73 Merz, E. 54 Mitchell, R. G. 93 Miyahara, S. 48 Mizuno, S. 48 Mohr, J. 70 Moog, F. 63, 99 Mosler, K. H. 16, 59 N Nakajima, S. 45 Nakajima, U. 45 Nakano, K. 48 Needham, W. 82 Neergaard, K. van 97 Nicolaides, K. 55 Nishida, H. 123 Northway, W. H. 94 O Obladen, M. 88 P Pattle, R. E. 97 Pederson, J. F. 52 Pestalozzi, E. 6 Pfaundler, M. 1 Pinard, A. 6, 63 Pollack, W. 38 Pooh, R. K. 56 Pretorius, D. 55 Priestley, J. 82 Pugh, B. 87 Q Quilligan, E. J. 110 R Radovanovitch, G. 50 Rapoport, I. 110 Rau, G. M. W. L. 88 Redman, C. W. 18 Reid, D. E. 60 Reid, D. H. S. 93 Reinold, E. 50

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Reuwer, P. J. H. M. 53 Reynolds, E. O. R. 95, 96 Riis, P. 70 Rizzo, G. 54 Robertson, B. 99 Robillard, E. 99 Robinson, D. E. 49–51 Robinson, H. 44, 51 Romero, R. 55, 62 Römisch, H. 81 Rooney, S. A. 99 Rooth, G. 110 Rosén, K. G. 19 S Sakamoto, S. 48, 54 Saling, E. 1, 2, 23, 36, 90, 108, 109, 112, 117, 121 Sanders, R. 47 Satoh, K. 54 Schatz, F. 8, 30 Schwartz, H. 29, 82 Scrimgeour, J. 70 Selezneva, N. D. 46 Simoni, G. 72 Skorunskii, I. A. 46 Smellie, W. 87 Sokolov, S. Y. 46 Soldner, R. 46 Sørensen, S. P. L. 82 Stanford University group 93 Steele, M. W. 70 Stern, K. 37 Stupin, J. H. 3 Suda, I. 48 Sunden, B. 44 Sutcliffe, R. G. 73 Swyer, P. R. 92 T Takeuchi, H. 48 Tanaka, K. 45 Tanaka, M. 48 Tarnier, S. 63 Taylor, K. 47, 54 Taylor, S. 45 Tchobroutsky, C. 53 Thompson, H. 45, 51 Timor-Tritsch, I. E. 55

130 | Index of Names and cited Authors Tödt, F. 23 Trudinger, B. 53 U Uchida, R. 45 Usher, R. H. 90 V Valenti, C. 70 van Neergaard, K. 97 Visser, G. H. 18 von Winckel, F. 6 Vyas, S. 53 W Wagai, T. 45 Wald, N. J. 74 Waller, A. D. 7 Wallerstein, H. 36 Wang, X. F. 51

Wapner, R. 74, 75 Watson, J. 69 Weiser, P. 46 Weiss, O. 8 Westin, B. 69 Wiener, A. S. 36 Willocks, J. 50 Winckel, F. von 6 Winsberg, F. 47 Wladimiroff, Y. 53 Wu, B. 99 Y Ylppö, A. H. 82 Z Zalud, I. 53 Zander, J. 8 Ziegenspeck, R. 6

Subject Index 3D ultrasound 41, 54 A abdominal circumference 52 ABO incompatibility 37 acid base analysis 82 acid-base status 83 acidosis of the newborn 82 acidotic instability 82 ACTH 99 Alcohol 60 alpha-fetoprotein (AFP) 73 altering inflation times and rates 94 American Academy of Pediatrics (AAP) 112 American Board of Obstetrics and Gynecology 110 American College of Obstetricians and Gynecologists (ACOG) 112 amniocentesis 30, 56, 70, 73 amniocentesis (AC) 70 amniography 30 amnioscopy 31, 115 amniotic fluid 29, 73 A-mode 45 A-mode scanner 48 A-mode transvaginal scanner 48 anencephalic fetus 51, 73 anesthetic bag 91 aneuploidy 73–75 antenatal care 105, 107, 108 antiprostaglandins 59 Apgar-score 79 A-scan 51 asphyxia 79, 87 assessment of the newborn 79 Atosiban 62 B Baby Pulmotor 88 balanced translocation 70 Bed rest 59, 61 Bennett PR2 ventilator 93 beta-agonist agents 61 betamethasone 62 betamimemtics 62

betamimetics 60 biochemical state of the newborn 84 biparietal diameter 42, 50 – fetal 51 Bird mark 8 ventilator 93 birth asphyxia 79 blood exchange in newborns 83 blood flow velocities 52 blood gas analysis 23, 24, 82 blood vessels – fetal 52 B-mode 48, 50, 69 B-mode scanner 48 Bourns ventilator 96 brain sparing effect 25 breathing movements – fetal 47 bronchopulmonary dysplasia 65, 94 B-scanner 44 C calcium channel blockers 61 caliper system – electronic 50 cardiac motion – fetal 47 cardiography – fetal 6 cardiotocogram (CTG) 11 – Doppler 16 catheterization – umbilical 81 catheterization of umbilical vessels 83 cell-free DNA (cfDNA) 75 cell-free fetal DNA 75 centers for perinatal medicine 112 cephalometry 48, 50 – biparietal 43 chorion 72 chorionic cells 71 chorionic villus sampling 71 chorionic villus sampling (CVS) 70 – ultrasound guided 71 chromosomal abnormalities 69, 70, 74 chromosomal defects 73, 75

132 | Subject Index chromosomal deletions 75 chromosomal microarray 75 clinical structures 105 color flow Doppler 52 combined screening 74, 75 compound contact scanner 48, 50 computer assessment of cardiotocograms 18 congenital anomalies 73–75 congenital defects 69 congenital malformations 54 congress of Perinatal Medicine 117 continuous positive airway pressure (CPAP) 89 cordocentesis 55 corticosteroid treatment – antenatal 65 corticosteroids – antenatal 64 cortisol 99 crown-rump length – fetal 44, 51 D Das Kind im Bereich der Geburtshilfe 1, 115 delivery – preterm 59 deoxyribonucleic acid (DNA) 69 dexamethasone 63, 99 diagnosis – non-invasive 41 – prenatal 41 diagnostic tool – non-invasive 73 Diasonograph® 43 dipalmitoyl phosphatidylcholine 99 dipalmitoyl phosphatidylcholine (DPPC) 97 Doppler CTG 16 Doppler ultrasound 52 Down syndrome 55, 70, 74, 75 Dräger-Baby-Pulmotor 89 Drinker ventilator 93 ductal venus velocimetry 54 duplex Doppler 53 dysplasia – bronchopulmonary 94 E echocardiography – fetal 56 ectopic pregnancy 55

educational activities 116 electrocardiogram 7 – fetal 7 end diastolic flow – absent 53 endovaginal scanner 48 erythroblastosis 23, 30, 35 estriol 74 ethanol 60 ethics – perinatal 55 European Association of Perinatal Medicine 119, 121, 122 European Congress of Perinatal Medicine 122 external cephalic version 61 F Federation of Asia and Oceania Perinatal Societies (FAOPS) 123 fenoterol 61, 62 fetal acid base balance 24 fetal blood analysis 16, 115 fetal blood analysis (FBA) 23 fetal blood sampling 23 – percutaneous 37 Fetal cardiography 6 fetal cells 70, 75 fetal head 42 fetal heart rate diagnostics 5 Fetal Medicine 115 fetal surface 54 fetal well-being 53 feto-maternal hemorrhage 38 Fetoscopy 69 Foetal and Neonatal Hypoxia in relation to Clinical Obstetric Practice 115 foetal medicine 1 G genetic defect 69, 70, 74 genetic disorder 75 genetic syndrome 69 genetic testing 75 German Society of Perinatal Medicine 117 gestational sac 50 glucocorticoid 62, 63 glucocorticosteroid 63 glucosteroid 65 Golden Amnioscope 126

Subject Index |

gray scale 50 gray scaling 44 growth-retardation 52 H health care 106, 110 heartbeat – fetal 51 hemolytic disease – fetal 70 hemolytic disease of the newborn (HDN) 35 high-risk pregnancy 109 hormones and the surfactant system 99 human chorionic gonadotropin (hCG) 74 hydramnios 44 hydrocephalus 55 hydrops fetalis 36 hypoxemia 25 I Ian Donald Inter-University School of Ultrasound 45 immaturity 63 infant Drinker ventilator 92 infant within obstretrics 1 inflation – mouth-to-tube 87 inflation and ventilator rates 94 inheritance 69 inhibin 74 Intermittent positive airway pressure (IPPV) 92 International Academy of Perinatal Medicine (IAPM) 120 International Academy of Perinatal Medicine’s Presidential Award 126 International School of Perinatal Medicine for Africa (ISPEMA) 126 International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) 53 intrauterine pressure – measurement 8, 30 intrauterine transfusion 70 intraventricular hemorrhage (IVH) 65 J Journal of Perinatal Medicine 116 K karyotype 70 karyotyping 75

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L labor activity – registration 8 Laplace formula 97 Laplace relationship 98 laryngoscope 89 Latin-American Center of Perinatology 110 lung maturation 59, 62, 65 M Magnesium sulfate 60 malformation – fetal 49 Maternal–Fetal Medicine 110 Maternal–Fetal Units 112 Maternity Statue 119 Materno-fetal-medicine 2 Maternogenic increase of metabolic acidity 25 Matres Mundi 126 mechanical ventilation 92 – outcomes 94 meconium 29, 30 middle cerebral artery waveforms 53 miscarriages 51 M-mode 51 modern obstetrics 116 Montevideo 117 mortality – perinatal 108 – premature 63 movements – fetal 53 multiple pregnancy 43 N necrotizing enterocolitis (NEC) 65 negative external inhalation 93 neonatal intensive care unit 110, 111 neural tube defects 73 nifedipine 61 nuchal translucency 55, 74 O O2 -measurement 23 obstetrical textbooks 115 obstetrics – mother-oriented 1 Octoson® 52 outpatient care 109

134 | Subject Index oxygen – concentration 83 – delivery into the gastrointestinal tract 90 – discovery 82 – hyperbaric 90 – supplementary 90 oxygen-conserving adaptation 25 P pCO2 83 Ped-Obstetrics 1 Perinatal Care System 105, 112 Perinatal Medicine 1, 105 – terminology 1 perinatal medicine 109, 110, 116 perinatal period 1 Perinatology 1 pH 83 pH measurement 23 phonocardiogram 8 phosphatidyl glycerol 99 pH-values in the umbilical vessels 84 placenta praevia 43 placentography 48, 51 pneumocytes 64 pneumothorax 96 pO2 – measurement transcutaneous 25 positive end expiratory pressure (PEEP) 95 positive pressure oxygen-air lock 90 power Doppler 45 pregnancy – extra-uterine 51 pregnancy assessment 50 pregnancy associated plasma protein A (PAPP-A) 74 pre-maternity care 107 prematurity 59 prenatal diagnosis 69, 70, 73, 75 prenatal genetic diagnosis 69 Prenatal Medicine 1 Presidential Award 126 pressure limiting valves 91 preterm delivery 55, 65 preterm labor 59, 61, 62 progesterone 56, 59, 60, 62 publications on Perinatal Medicine 115 Pulmotor 88, 92 Pulse oxymetry 25

Q quadruple screen 74, 75

R real-time scanner 46 real-time sonography 72 refilling anesthetic bag 91 Relaxin 60 renal artery waveforms 53 respiratory distress syndrome 87 respiratory distress syndrome (RDS) 65, 92 resuscitation 79, 87 – beginnings of practices 89 – comparison of different methods 90 – intrauterine 61 – precursores 87 Rh-blood group system 36 Rh-erythroblastosis 30 Rh-immune prophylaxis 37 Rh-Immunization 35 Rh-incompatibility 35 ritodrine 59, 60 Royal Academy of Medicine of Catalonia 123

S scan converter 50 scientific societies 117 scoring system – after Saling 84 – modified Apgar scoring system 84 – subsidiary 84 serological and hematological examinations 23 Society of Perinatal Medicine of the German Democratic Republic 117 sodium bicarbonate 90 sono-embryology 55 sonography 41 sphygmograph 6 spina bifida 51 SSD-1 46 SSD-2 46 STAN 19 stethoscope 5 structural reform 105, 108 ST-waveform analysis 19 subsidiary scoring system 84 surfactant 64, 65

Subject Index |

surfactant system – and hormones 99 surfactant therapy 97, 99 T Tank ventilator 88 Textbook of Perinatal Medicine 116 The Fetus as a Patient 120, 122 The Journal of Maternal Fetal and Neonatal Medicine 122 The Journal of Perinatal Medicine 122 thoracic circumference 51 thyroxine 99 tocolysis 59, 60, 62 transcervical fetoscopy 69 transducer 43 transfusion – exchange transfusion 36 – feto-maternal 38 – intrauterine 37, 51 transvaginal transducers 55 triple screen 74 Trisomy 21 75 U ultrasound 41, 45, 46, 50, 69 – diagnostic 41

ultrasound guidance 72 Ultrasound in Obstetrics and Gynecology (UOG) 53 umbilical artery 53 umbilical vein 52 Units of Maternal–Fetal Medicine 110 use Doppler CTG 16 Usher regime 92, 93 uterine contractility 61 utero-placental flow velocity waveforms 53 V ventilation, mechanical 92 Voluson 54 W Wilhelmy balance 98 World Association of Perinatal Medicine 121 World Association of Perinatal Medicine (WAPM) 120, 122 World Congress of Perinatal Medicine 120 Y yolk sac 52 Z Zurich Model of Perinatal Medicine 111

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