Congenital Malformations: A Study of Parental Characteristics, with Special Reference to the Reproductive Process [Reprint 2016 ed.] 9781512804867

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CONGENITAL

MALFORMATIONS

MAP OF PHILADELPHIA

Legend. Showing the location of the homes of 890 families each of which possessed one or more congenitally malformed members.

T H E G Y N E C E A N H O S P I T A L I N S T I T U T E OF G Y N E C O L O G I C R E S E A R C H

CONGENITAL

MALFORMATIONS

A Study of Parental Characteristics with Special Reference to the Reproductive Process

By D O U G L A S P. M U R P H Y , M.D..F.A.C.S. Assistant Professor of Obstetrics and Associate in the Gynecean Hospital of Gynecologic Research, University of

Research Institute Pennsylvania

Philadelphia

UNIVERSITY OF PENNSYLVANIA PRESS London: Humphrey

Milfotd: 1940

Oxford

University Press

Copyright 1940 D O U G L A S P. M U R P H Y Manufactured in the United States of America Fir it printing,

¡939

Second printing,

1940

ACKNOWLEDGEMENTS The study which forma the baais for the present volume was conduoted under the auapicea of the Gynecean Hospital Inatitute of Gyneoologic Reaearoh of the University of Pennsylvania.

The author wishes to take this opportunity to express

to Dr. Charles C T Norris, Director of the Institute, his most sincere thanks and appreciation for his constant help and encouragement in the pursuit of this investigation as well as in the carrying out of the many other reaearchea completed under 'lis guidance. The cost of the study was met in part by grants from the Dr. John G. Clark Fund of the University of Pennsylvania, the Federal Works Administration, and the Local Works Division, through the co-operation of the Commonwealth of Pennsylvania Department of Health. In the Bureau of Vital Statistics of the Department of Health, the author is indebted to its former chief. Dr. Emlyn Jones, and eepecially to Misa Florence G. Hardy, Chief Statistician, Kiss Mary A. Cleckner, Chief of the Tabulation Section, and Kiss Martha V. Smith, assistant to Miss Cleckner for their co-operation and assistance.

To Miss Agnes F.

Driver, Miss Grace Earley, Mrs. Mary Dissinger, and Mrs. Kathleen Steekley thanks are due for the care with which they searched the files of death and birth certificates. The homes of the defective individuals were visited v

by Miss Dorothea Killian, Mr. Tracy Cuttle, Mr. Edward Durkin, and Mr. Milton Mazer, and the hospitals by Dr. Robert A. MacCalmont.

To each of these persons the author wishes to ex-

press his appreciation for the thoroughness of their work. The author is indebted to Mrs. Anna DePlanter Bowes, M.A., of the Philadelphia Child Health Society for assistance in composing the questionnaire dealing with diet, for analyzing the data and for writing the report on that phase of the study.

Table of

Contents

ACKNOWLEDGEMENTS

Chapter I.

Page MATERIALS A N D METHODS

1

Introduction Outline of study Locating of families Diagnosis of malformation Home visiting Hospital data Information from physicians Handling of data Amount of material Discussion

II.

FREQUENCY OF MALFORMATIONS

11

Per year Per 10,000 deaths In stillborn individuals Per 10,000 live births Among siblings Among half-siblings Among other relatives Summary

III.

NON-REPRODUCTIVE CHARACTERISTICS OF PARENTS . . . Race and color Economic and social status Consanguinous marriage General health of parents Father Mother Syphilis Parental age Maternal Paternal Parental age difference Occupation of father Summary vii

15

IV.

MATERNAL CHARACTERISTICS RELATED TO CHILDBEARING .

29

Menstruation Pelvic disease Conceptions per family Conception rate Duration of pregnancy Birth order of defective children Reproductive efficiency Intervals between pregnancies Occurrence of subsequent conceptions Summary V.

DEFECTIVE CHILD PREGNANCY

47

Contraceptive vaginal douching Month of conception Diet Anemia Hypertension and albuminuria Uterine bleeding Fetal irradiation Abnormal symptoms Fetal pathology suspected Labor complications Placenta praevia Summary VI.

CHARACTERISTICS OF OFFSPRING

66

Development of all offspring Normally developed siblings Twins Sex ratio Legal status Malformation diagnoses Duplication of malformations Among siblings Among other relatives Age at death Summary VII. VIII.

ETIOLOGY OF CONGENITAL MALFORMATIONS

84

DISCUSSION AND SUMMARY

89

REFERENCES 97

APPENDIX viii

CHAPTER I MATERIALS AND METHODS kittle is known concerning the relative frequency of congenital defects in families already possessing one malformed member. This fact was brought to the attention of the author by the experience of a colleague who delivered a patient of two monst«rs in successive pregnancies, having informed her after the birth of the first, that she was no more likely to give birth to a second one than was any woman who had never had such a n experience. In an effort to determine the frequency of defects among siblings, i.e., brothers and 6isters, the author undertook an investigation of families possessing congenitally malformed children. The present volume contains a summary and discussion of the results of that study. The word congenital, as used throughout this report, denotes present at birth and has no other significance. The term malformation means any gross, anatomical deviation from the normal, and is used interchangeably with the terms defect, anomaly, deformity, or abnormality. In outline, the plan consisted of locating families through the medium of congenital malformation diagnoses upon death certificates. The homes were visited, and the mother or the next nearest relative of the defective individual was interviewed. If the abnormal child had been born or had died in a hospital, the records of the institution were examined. Information from these sources was augmented by data upon birth certificates and in some cases, by correspondence with the physicians who had signed the certificates. It was necessary to limit the study to families in which a malformed child had died, because diagnoses and addresses upon death certificates offered the only means for locating a large series of families possessing defective offspring. For the purpose of this study, the fact that the malformed child was dead did not appear to be important. The investigation was further restricted to Philadelphia families in which the malformed children had died during the five years between January 1, 1929 and December 31, 1933. Philadelphia families were used, to make it feasible to visit the homes. A five year period was selected in order to have a large enough number of families to be statistically satisfactory. The five year period immediately preceding 1

$he beginning of the study was chosen in order to minimize the loss of families which results from the normal shifting of population* Locating of Families» The death certificates were on file in the Bureau of Vital Statistics of the State Department of Health at Harrisburg, Pennsylvania, where they were examined by clerks familiar with them. These workers transcribed to duplicate official forms, the essential data on every certificate which bore any notation of a congenital -naiformation, whether it was cited as the chief, or only as the contributing, cause of death. Diagnoses which the searchers were uncertain about were referred to the Chief Statistician of the Bureau for decision. If the latter was in doubt, the matter was referred to the author. The data upon available birth certificates of the deceased, defective individuals likewise were transcribed to duplicate official forms. Both certificates were checked for errors of omission and commission. Vihen found, these certificates were submitted to the county registrars for additions and corrections. Diagnosis of Malformation. The next steps in the handling of the death certificates were: To determine if there was sufficient evidence to confirm the existence of a congenital defect, and to assign to each deceased individual a single, chief diagnosis in cases in which more than one defect was present. This was done to simplify the handling of the material. The existence of a malformation was considered confirmed under either of two conditions: If the defect was visible at birth, or if solely internal, its presence had been disclosed either by operation or necropsy. Certificates satisfying these criteria form the basis for the study; the remaining ones were discarded. The chief diagnosis was selected in the following manner: If an external defect was present, it was selected; if two or more external defects existed, the most serious one was chosen; in cases in which there were no external defects, but in which two or more internal malformations existed, the most serious of these was used. Home Visiting. The home of each family which had possessed a deceased, defective member was visited, provided it was within or near the city limits. The visiting, carried out by four, fourth year medical students, vra.s started six months after the death of the last defective individual in the series, 2

and was completed approximately four months later. The visitors were supplied with a five page questionaire to be filled out at the interview, the contents of which were as follows: The home all available operation was than when the

visitor rarely experienced difficulty in securing information, although in certain instances, cogotten more readily from the mother when alone, father was present.

Hospital Data. In approximately 8 out of 10 instances, the defective child was either born or had died in a hospital. All hospital records were summarized by a recent medical graduate, who was supplied with Page VI of the questionnaire. Information from Physicians. In some cases, certain facts could not be secured without ccmmunicating with the physicians who had signed the certificates. This was done by letter or telephone, but usually by interview. Handling of Data. Facts from all sources were assigned identification numbers and in this form were assembled upon special code sheets. From the latter they were transferred to punch cards for mechanical sorting. The punches in the cards were checked carefully against the code sheets by a worker with long experience in the handling cf medical, statistical material. Summaries of the data were then secured by running the punch cards through a tabulating machine. Amount of Material. From January 1, 1929 to December 31, 1933 there were 130,132 deaths and stillbirths from all causes in Philadelphia. Among the certificates for these deaths, 1,476 recorded congenital malformations, of which 890 possessed confirmed diagnoses. The latter, however, represented only 884 families, since in each of six families two malformed children had died during this period of time. Birth certificates were located for 787, or 88.4 per cent, of the 890 defective individuals. There were 546 home visits made at which it was possible to to secure most of the desired information; although only in the case of 501 families was the outcome of every conception determined. The interview was most satisfactory when it was possible to interview the mother. In families in which for some reason she could not be consulted, less information was secured. In 495 cases, it was possible to examine hospital records of the birth or death of the malformed child. These records, however, did not represent in every case families that had received a heme visit.

3

QUESTIONNAIRE - PAGE I.

Child's Name;

G.H.I. No.

Birth Year:

Diagnosis:

Mother's Name:

Address: New Address:

Hospitals: (delivery)

(death)

Physicians: (delivery)

(death)

Mother Non-Pelvic Diseases:

Menses: a.

(specify)

Onset

Duration -

Irregularities:

No

Yes

Pelvic Operations or Treatments: No Yes Details

Year:

Other. Pelvic Complaints: Details:

Interval Year of Onset:

(curettage especially)

Hospital Name:

No

Yes

Year:

Other Hospitals or Physicians Attended:

QUESTIONNAIRE - PAGE II.

Previous Marriage:

No

Yes

Results of Pregnancies:

During the Above Pregnancy: a.

General Illnessess:

No

Yes

Details

Kind of Treatment: b.

Uterine Bleeding; Start:

c.

No

Yes Duration:

Pelvic Radium or X-ray Treatment:

No

Yes

Name of Hospital:

d.

Unusual Pregnancy Symptoms:

No

Yes

Details:

e.

Was Fetal Pathology Suspected before Labor? When? Why?

Relatives with Birth Marks or Underdevelopment: (State relation and describe defect.) 5

No

Yes

QUESTIONNAIRE - PAGE III

Father a.

Birth Year:

Trade or Occupation:

b.

Unemployment

No

c.

Other Possible Sources of Family Income:

d.

Previous Marriage:

Yes

No

How long?

Yes

Result of any Conceptions:

e.

Health before This Conception:

Good

Poor

Details:

f.

Names of Any Hospitals Attended at Any Time:

g.

Relatives with Marks or Underdevelopment: (Give relationship and describe defect)

Cousin Marriages:

(Mother 4 Father) Yes

No

(Mat. G. P.) Yes

No

Estimate of Economic Status: Very poor

Poor

Well-to-do

Moderate circumstances Rich

6

(Pat G.P.) Yes No

QUESTIONNAIRE - PAGE IV.

Food Questions a.

How much milk do you use daily in any way? None

b.

1 cup

2 cups

3 cups

4 cups

What green vegetables do you like and eat?

How often?

Once or twice daily?

Once or twice weekly?

c. What other vegetables do you like and eat?

d.

What fruit do you like and eat?

e.

How much bread do you generally eat? slices per meal.

How often?

What kind of bread?

f.

What foods do you like best and eat most

g.

How much coffee do you generally drink? n

u

"

"

tea

n

u

"

"

beer, wine or other such drinks

do you take daily?

h.

How often?

often?

cups. cups>

glasses

Did you eat about like this when you were pregnant? Yes No Differences:

7

QUESTIONNAIRE

- PAGE V .

Cause

i

O Z

O Z

o Z

o Z

Z

o

o Z

0 Z

£ >•

£ >-

>£

£ >•

t >-

S S"

£

1 >

S >•

s >•

»

D

C

Q

Q

Q

Q

o

D

o

Q

Q

z

Z

z

Z

Z

Z

•Z

z

Z

z

Z

i Z

a.

a.

a.

a,

a.

B.

eu

c-

C.

û-

1

** -5

'i M ;

J

*J

J

J

J

J

J

a.

C/3 , C/> ! C/3 ' C/5 J

1

1 J

1

i

!

1

1

i 1

i

J

c o s

Child's Nome

31

ft.

1 Birth Order

« Ql» I I S B.

Condition of Offspring •t End of Pregnancy

S

Date of Birth

!

Pregnancies

O H

o z

Yes

>• ot

O

Z

1

s

o Z

Yes

X H o

Healthy

i c i

1

£ o

Present Condition of Normal Children

i è

*o-c

Now Alive

x u

! i i

Unhealthy (Diagnosis)

-e a u Q ï o Z

_

m

•i-

J VO 1

r-.

00

o

; ! ' — , r*

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QUESTIONNAIRE - PAGE VI. Mother's Name:

G.H.I . No:

Hospital Name:

Hosp. No.:

From Pregnancy Record Last Menses Date:

N.R.

Unusual or Exaggerated Symptoms or Signs:

N.R.

Presentation:

N.R.

(vertex)

Duration of Labor:

(breech)

(other)

N.R.

(hours)

N.R.

Labor Complications:

From Laboratory Record Mother's Wassermann or Kahn Test:

Positive

Negative

N.R.

Cord

Positive

Negative

N.R.

De scrib e:

N.R.

"

"

Mother's R. B. C. :

"

"

:

N.R.

Mother's Urine Abnormalities;:

None

Hgb. Yes

Mother's Highest Blocd Pressure During Pregnancy:

N.R.

From Infant's Record Operation:

No

Yes

N.R.

Necropsy:

No

Yes

N.R.

Summarize congenital defects: If no operation or necropsy, on what signs or symptoms was the diagnosis based? N.R. No Record available. Remarks: 9

During the course of the home visiting, 45 additional defective offspring were discovered. Of the latter, 17 were living. The remaining ones had died prior to January 1, 1929. These 45 individuals, added to those located through the medium of death certificates, gave a total of 935 defective persons, concerning each of which some facts were obtainable. It is obvious that all sources of information were by no means available for every family. This fact explains the wide differences in the totals forming the basis for the various analyses which follow.

DISCUSSION Death certificates offered the only means for locating a large series of families possessing congenitally malformed offspring. This source material, naturally had its limitations: It was impossible to interview the family at the time that the malformed individual was alive, and in a few cases, undoubtedly, the nature of the defect may have been misunderstood by the physician who treated the defective person. However, the chief interest of the investigation did not center about the exact nature and extent of maldevelopment of the congenitally malformed individual, but rather with the reproductive activity of the parents. In this respect a considerable degree of success was attained, in that the mother of the defective child was interviewed in most of the families that were located, and her full co-operation was secured in most instances. The locating of the certificates was performed by workers with previous experience in the handling of such material. Their knowledge of medical terms, and their personal interest were an invaluable aid. The home visiting also was carried out by trained individuals who likewise were interested in the investigation, and who reported daily to the author. The closeness of contact of the author with the enumerators was a distinct advantage. The planning of the code sheets and the punch cards was done with the advice of the members of the Bureau of Vital Statistics. This fact, together with the careful checking of the punch cards with the code sheets by a person experienced in handling such material, increased further the value of the study.

10

CHAPTER

II

F R E Q U E N C Y OF M A L F O R M A T I O N S Deaths of Malformed Persons Per Year. There were 1,476 death certificates bearing confirmed and unconfirmed diagnoses of congenital defects for the five years covered by the survey. These were distributed by years as follows: 315, 318, 306, 306, and 231. The constancy in the number of individuals listed during each of the first four years of the study suggests that we were dealing with a sample of adequate size. The small number of deaths of defective persons in the last year could be explained on the basis of the smaller number of deaths from all causes during that time.

Table 1. Malformations Among Live and Stillborn Deceased Individuals Deceased Individuals Condition at Birth

All

Malformed

Malformed per 10,000

Number

Number

Number

Live Born Stillborn

122,654 7,478

668 222

54 297

Total

130,132

890

68

Legend. Showing (a) the number of deaths and stillbirths which took place in Philadelphia, between January 1, 1929 and December 31, 1933, and (b) the number of these individuals whose death certificates recorded the existence of a congenital defect. Note the high incidence of malformation in the individuals who were stillborn.

Deaths of Malformed Individuals in Relation to All Deaths» Among 130,132 consecutive certificates for deaths and stillbirths from all causes in Philadelphia during the five year period covered by the survey, the 1,476 bearing diagnoses of gross congenital defects represented approximately 113 per 11

10,000. Of the latter, 586, or 39.7 per cent, bore diagnoses which were not confirmed. These included 527 noting congenital heart disease, 44 recording pyloric stenosis, 8 listing intestinal obstruction, 3 biliary obstruction, and 2 each noting malformations of the lungs or kidneys. The certificates with unconfirmed diagnoses were omitted from further consideration. The remaining 890 satisfactorily diagnosed ones represented approximately 68 deaths and stillbirths of defective individuals per 10,000 deaths and stillbirths from all causes, as indicated in table 1. Among the live born, deceased individuals, 54 per 10,000 were defective; among the stillborn ones, 297 were malformed. Therefore, malformations were observed in stillborn individuals nearly 5.5 times as often as in live born persons. The Manual of the International List of the Causes of Death (i93l), which is the standard followed in tabulating mortality statistics in the United States, cites congenital malformation as a cause of death only in the case of live born individuals. Therefore, the 222 stillborn, defective persons, representing approximately 25 per cent of all malformed persons for whcm death certificates were found, would be listed merely as stillbirths in United States Government statistics. Deaths of Malformed Individuals in Relation to Live Births. In the five years covered by the survey, there were 166,451 live births in Philadelphia. The 890 deceased, defectives represented 53 per 10,000 of live births. Of the 890 deceased persons, only 739 were born in the city during the survey period. One hundred and eight were born outside of the city but died within it, and 43 were born in the city, but prior to January 1, 1929. If this group of 43 is added to the 739, it might counterbalance the group born in the city during the survey period, but who died after December 31, 1933, and who therefore were not included in the present figures. The resulting figure of 782 gives a rate of approximately 47 births of malformed individuals per 10,000 of all live births in Philadelphia, or about one in 213. Malformations Among Siblings. The incidence of conception after the birth of the first malformed child was learned for 501 mothers. Of this group, 226 experienced no subsequent conceptions, whereas 275 mothers, or approximately 55 per cent, each bore one or more later offspring, having between them a total of 431 subsequent conceptions. The outcome of each of these conceptions was known. Among the 275 mothers, 25 had one and 9 had two additional malformed children. These 34 mothers who gave birth to subsequent defective offspring represented 12.3 per cent of all those who conceived after the birth of the first malformed child. 12

Of the 431 subsequent pregnancies, 331, or 77 per cent, ended in the birth of full term, normally developed children. The remaining 100 pregnancies ended in 42 miscarriages where the fetal development was unknown, 9 premature births, 6 stillbirths, and 43 live born, malformed offspring. These unsuccessful pregnancies represented nearly one in four of those which followed the births of the first defective child. The 43 pregnancies ending in the birth of malformed offspring represented approximately 10 per cent of the total subsequent pregnancies. There were 331 live born, normally developed children, 43 live born with defects, and 9 live born but premature, giving a total of 383 live born children. The defective offspring represented 11.2 per cent of the latter, or a birth rate of 1,120 malformed children per 10,000 of all subsequent live births. Since the birth rate of defective persons in the general population was demonstrated to be approximately 47 per 10,000 of live births, the rate in families already having one defective child was approximately twenty-four times greater. Malformations Among Half-Siblings. Thirty-nine fathers had been married more than once. Of this number, 36 had been married twice and 3 had been married three times. From the 42 previous marriages had come 30 offspring, of which 2 were defective. In one case, the child by each wife exhibited a congenital defect of the intestine. In the second instance, the defective child by the first wife was hydrocephalic, whereas the child by the second wife suffered from meningo-myelocele. There were 2 9 mothers who had been married more than once. Of these, 28 had been married twice and one had been married three times. By the previous husbands, these mothers gave birth to a total of 64 offspring, all of which were normal. The above figures give a total of 94 offspring resulting from 72 previous marriages either of the mother or of the father of the certificate children. Among these 94 offspring, there were 2 which exhibited gross, congenital defects, giving a rate of 212 malformed children per 10,000 births in these families. It is of interest to note that this rate is lower than the rate in the certificate child families, 1,120 per 10,000, and higher than the rate in the general population, 47 per 10,000. The fact that malformations occurred with greater frequency in the second marriages than in the first might be explained by the advanced ages of the parents (Chapter 3). Malformations Among Other Relatives. 13

Of 562 families

which gave information concerning congenital malformations among relatives, 39, or 6.9 per cent, recorded the existence of such defects. These malformations were evenly distributed between relatives of the mother and of the father; in no instance did defects appear simultaneously in the relatives of both parents.

SUMMARY 1) Among deaths and stillbirths from all causes in Phiadelphia during the period of time covered by the survey, approximately 68 individuals per 10,000 possessed gross congenital malformations. 2) Among all deceased, live born individuals, 54 per 10,000 were defective. 3) Among all stillborn individuals, 297 per 10,000 possessed congenital malformations. 4) Of all deceased, defective individuals, approximately 25 per cent were stillborn. 5) Approximately 47 individuals possessing congenital malformations were born alive or dead in Philadelphia per 10,000 live births. 6) In families already possessing a malformed child, the birth rate of subsequent defective offspring was approximately 1,120 per 10,000 live births, which is approximately 24 times greater than the rate in the general population. 7) The occurrence of malformations among offspring by earlier marriages appeared to be lower than in subsequent marriages, but higher than in the population-at-large. 8) Defects were noted among the relatives in 6.9 per cent of the families reporting on this point.

14

CHAPTIR III NON-REPRODUCTIVE CHARACTERISTICS OF PARENTS Race and Color. The defective individuals consisted of whites and negroes only, no other color being represented; the number of each per 10,000 live births appears in Table 2. Malformations occurred in white persons and in negroes in the ratio of 57 to 32. This preponderance of congenital defects in the white race is confirmed by United States Government Statistics dealing with Birth, Stillbirth and Infant Mortality (1927), (1928), (1929). Data from these reports were summarized and are presented graphically in Figure 1.

Table 2. Defective Individuals by Color Deceased Defective Individuals

All Live Births

Number

Per 10,000 Live Births

White Black Other

(1) 142,252 24,071 128

(2) 814 76 0

(3) 57 32 0

Total

166,451

890

53

Color

Legend. Showing distribution of malformed individuals by color, compared with all persons born alive in Philadelphia during the same period of time. Note in column 3 that the incidence of malformations among white people was nearly twice what it was in the negro race.

Economic and Social Status. At the home visit information was secured regarding: the source of family income, the home environment and the extent of education of the children. With these observations it was then possible to classify 571 families 15

Figure 1.

DEFECT DEATHS PER 1,000 OF ALL D E A T H S 0

20

40

60

80

100

120

140

ENGLAND SCOTLAND WALES DENMARK NORWAY SWEDEN GERMANY

IRELAND

CANADA

UNITED STATES

ITALY

AUSTRIA

POLAND

NOT STATED

OTHER COLORED

NEGRO

Legend. Showing the number of deaths r e s u l t i n g from c o n g e n i t a l malformations per 1,000 of a l l deaths i n the r e g i s t r a t i o n a r e a of the United States during 1927, 1928 and 1929, arranged a c cording t o the country of b i r t h of mother. Note that the n e groes e x h i b i t e d the lowest r a t e , and t h a t the other c o l o r e d races showed a very low incidence of malformations.

16

as being very poor, poor, in moderate circumstances, or w e l l to-do (Table 3.). The criteria for these groups are as follows: V e r y Poor Income. From employment over short periods, otherwise frcm charity. Environment. House badly in need of repair, furnishing poor and insufficient. Usually more than one family to a house. Change of abode frequent. Clothing shabby. Education. Secondary or less, w i t h lack of desire for enlightenment.

Table 3. Economic Rating of Families Families Economic Rating Number Very poor Poor Moderate Circumstances Well-to-do Total

|

Per cent

148 205 201 17

25,9 35.9 35.2 3.0

571

100.0

Legend. Showing the economic rating of 571 defect bearing families, based u p o n the source of family income, home environment, and the education of the children. Note small number of well-to-do families.

Poor Income.

F r o m labor, but uncertain.

Environment. Better neighborhood than in preceding class. House i n fair state of repair, better furnishings, Clothing neat. Education.

Possibly high school. 17

Moderate Circumstances. Income.

Certain.

Environment. Good neighborhood. May own home. Inexpensive automobile, rugs, piano, radio, etc. Clothing stylish. Education.

High school, or better.

Well-to-do Income.

Professional man or owner of business.

Environment. Best neighborhood, expensive home, servants, automobile. Clothing expensive. Education.

As much as desired.

Economic status also was measured in terms of unemployment of the heads of the families. Data upon this point, available for 494 families, have been arranged in Table 4. according to color.

Table 4. Heads of Defect Families b^ Unemployment and Color Heads of Families Defect

Color Number

All Philadelphia

Per cent Unemployed

Per cent Unemployed

Reported _ 494 30.4 29.0 456 30 •White 38 47.0 Colored 48 Legend. Showing incidence of unemployment of heads of 494 defect bearing families, by color, compared with families picked at random by a governmental agency. Note similarity of figures for the two groups.

In the right hand column of this table are presented control figures for unemployment in the general population of Philadelphia, which were collected by the Pennsylvania State Emergency Relief Board (1934) six months before the date of the 18

present survey. Since there did not appear to be any unusual incidence of unemployment in the malformation families, it might be assumed that they represented a more or less vertical section through all economic levels i n the population. A n extremely low social and economic group is that represented b y destitute w o m e n , illegitimately pregnant, and m a r ried mothers of the same class. S u c h a combined group w a s studied in a hospital, whose function it is to care largely for individuals of this type. During the period of time that 1,947 consecutive, live births took place i n t h i s institution, 22 m a l f o r m e d individuals were born. This number represents a b i r t h rate of approximately 113 malformed individuals per 10,000 of all live births. This birth rate is more t h a n twice the birth rate of malformed persons (47 per 10,000) i n the general population. The figures from this hospital w o u l d suggest t h a t malformations occur w i t h unusual frequency in f a m i lies of poor economic and social status. Consanguinous Marriage. Of the 553 families giving d a t a upon this question, only 10, or 1.8 per cent gave a history of marriage between relatives. I n two instances the parents of the defective child w e r e first cousins and in one case second cousins. The remaining 7 relationships were as follows: a) Grandfathers were first cousins, b) Parents w e r e t h i r d cousins, c) The father was a cousin of the mother's grandmother. d) Maternal and paternal grandparents w e r e first cousins, e) The father's parents were first cousins, f) P a ternal grandparents w e r e first cousins, g) Maternal grandparents were second cousins. General Health of Parents. The general health of the father and mother was investigated w i t h respect to the existence of any chronic or prolonged illnesses, at the time of conception of the malformed child. Of 569 fathers who reported, only 53 (9.3 per cent), suffered from chronic poor health; of 640 mothers, only 56 (8.7 per cent) were unhealthy. The parents suffered from 118 diseases; those which occurred at least twice are listed i n Table 5. No correlation could be made out between chronic p a r e n t a l disease and congenital malformation in the offspring. Positive Blood Wassermann Reactions. The blood W a s s e r m a n reaction of 324 mothers w a s secured f r o m the hospital records. Of these w o m e n , 285 were white and 39 were negro. Among the former, 23, or 8.0 per cent, exhibited positive reactions.

19

w h e r e a s among the negro w o m e n 17, or 43.6 per cent, did so, the average for the two races being 12.3 per cent. Clark (1932) states t h a t among 27,131 individuals included i n a serological survey made i n six s o u t h e r n states, 19.5 per cent gave a positive W a s s e r m a n n reaction. S i n c e only 12.3 per cent of the mothers of the m a l f o r m e d c h i l d r e n d i d so, there was apparently no u n u s u a l frequency of syphilis i n these individuals.

Table 5. Chronic Illnesses of 109 Parents at Conceptions of Defective

Children Diseases of

Illnesses

Reported Pulmonary tuberculosis Alcoholism Syphilis Heart disease 'Sickly' S t o m a c h trouble Cough Nephriti s General w e a k n e s s Nervousness Thyroid deficiency Neurasthenia Anemia Diseases not repeating

Fathers

Mothers

62

56

10 8 7 6 4 3 2 0 0 0 0 0 0

6 0 7 9 0 0 0 6 5 4 3 3 3

22

10

Legend. Recording the chronic illnesses experienced b y 53 fathers and 56 mothers a t the time t h a t their congenitally m a l formed children were conceived. Note that chronic illnesses occurred w i t h about equal frequency i n b o t h parents and that the parents suffered in general from the same diseases.

A s has b e e n noted above, congenital malformations are nearly twice as common in the w h i t e race as i n the b l a c k race.

20

Syphilis, on the other hand, was found to be much more frequent in the negroes. On the basis of these observations, it would appear that syphilis plays no role in the causation of congenital malformations. Parental Age. The relation of parental age to the occurrence of malformations was studied from two points of view: the age of the mother at the birth of the malformed child, and the difference in ages of the parents. Maternal Age. The ages of 570 mothers at the births of 607 of their congenitally malformed children, and 1,584 of their normally developed offspring, were determined. The data are considered under the following headings: a) Maternal age at birth of first normal and at birth of first defective child. b) Early versus late marriage and the intervals before the birth of the first normal, and before the birth of the first defective child. c) Ratio of defective to normal offspring at various maternal ages.

a) Maternal Age at Birth of First Normal and at Birth of First Defective Child. There were 466 families, each of which contained at least one normally developed child, as well as a malformed one, and in which families, data on the maternal age at the births of both were available. The average age of the mothers at the time of marriage was 21.1 years; at the birth of the first normal child it was 23 years; whereas the first defective child was not born until the average age was 28,4 years. The first normal child, on the average, was born 17.4 months after marriage, whereas the first defective one was not born until a period of 77.9 months had elapsed. In other words, the first defective infant appeared 60.5 months, or approximately 5 years, after the birth of the first normal child. It is apparent from these figures that: The first child was more often normal than defective, and the interval between marriage and the birth of the first defective child was of sufficient length to have permitted the birth of four offspring. The length of this interval is of interest in view of the observation that defective offspring appear with 21

u n u s u a l frequency after the b i r t h of the fourth child i n a family (Chapter IV). b ) Early Versus Late Marriage a n d I n t e r v a l Before B i r t h of First Normal a n d Before B i r t h of First Defective C h i l d . The interval b e t w e e n m a r r i a g e a n d the b i r t h of the first n o r m a l child, and the interval b e t w e e n marriage a n d the b i r t h of t h e first defective child w e r e compared for two groups of w o m e n w h o s e average ages a t marriage w e r e separated b y a n interval of t e n years (Appendix 1.), as s h o w n i n Table 6 a n d Figure 2 .

Table 6. Early Versus Late Marriage and Interval Before B i r t h of First Normal a n d Before Birth of First Defective Child i n Two E q u a l - S i z e d Groups of Mothers Mothers

Number

Average Age at Marriage, Years

Average N u m b e r of Pregnancies

(1) 45 45

(2) 16.8 26.8

(3) 3.08 2.09

Average Interval F r o m Marriage to B i r t h of First Normal Child, Months

Defective Child, Months

(4) 15.3 21.0

(5) 87.2 59.0

Legend. Showing average interval b e t w e e n marriage a n d the birth of the first normal and of the first defective child, respectively, for two groups of mothers w h o s e average ages a t marriage differed by 10 y e a r s . Note i n column 5 t h a t the average interval b e t w e e n marriage and the b i r t h of the first defective child w a s longer i n the case of the y o u n g e r mothers t h a n for the older group.

The y o u n g e r mothers h a d an average of 3.08 pregnancies, whereas the older group h a d a n average of only 2.09 pregn a n c i e s . The y o u n g e r mothers had their first defective children after a longer interval following marriage than, did the older ones, i n spite of the fact t h a t they h a d their first 22

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The distribution of the observed normal individuals (Table 11, column 4) was determined by subtracting the observed defective individuals (column 3) in each birth rank from the total of all individuals in that rank (column 2). The following values were then computed for the observed distributions (Table 14). The standard deviation of the difference between mean ranks of the observed normal and the observed malformed individuals was calculated by the formula given by Penrose ('fr) ^^ka) and found to be 0.12. The distribution of the expected normal individuals by birth rank was then determined in the same way as for the observed normal individuals from the data in Table 13, column 2 and Table 11, col-umi 2. The mean birth ranks for both the observed and the expected distributions are given in Table 15. The mean rank of the expected malformed (2.46) is 1.13 ranks ahead of the expected normals (3.59). In other words, if it is assumed that the malformed are distributed at random by birth rank, one would expect that the mean birth rank of the malformed would, in our families, be 1.13 ranks ahead of the mean birth rank of the normal individuals. The observed malformed, however, are only 0.33 rank ahead of their normal siblings. Therefore the observed malformed individuals occurred 0.80 rank later than would be expected if they were distributed at random. Since the average displacement of the observed malformed in relation to their normals (0.80) is more than six timea the standard deviation of the difference between the mean ranks of malformed and normals (0.12), this displacement is statistically significant. It may be conoluded that the malformed individuals in this group are, on the average, later bora than would be expected by chance. Table 14. Observed Distribution

Malformed (M) Normal (N) All (T)

Number

Mean Rank

Standard Deviation

582 1,475 2,057

3.02 3.25 3.26

(-) 2.32

—

Place-in-Family of Second Malformed Sibling in Relation to Birth of First Defective Child. As has been 3hown above, it happens not infrequently that two or more siblings may be mal35

formed. Also it has been demonstrated that malformed individuals tend to be born late in families. These findings raise the question as to the place-in-family of a second malformed sibling with respect to the birth of the,first defective offspring. Will a subsequent defective offspring be the next child to the first malformed sibling, or is it more likely tc be born still later in the family? Light is thrown upon this question by the data appearing in Table 50. Here are listed 40 families, each having at least two malformed offspring, and in which families the birth order of all siblings was known. Of the 40 second malformed offspring, 22, or more than half, arose from the conceptions which followed immediately after the birth of the first malformed child. From this it would appear that the second malformed child is more likely to result from the first conception to follow the birth of the malformed child than to result from a later conception. Table 15. Observed and Expected Pi stributi ons

Malformed Normal All

Observed

Expected

3.02 3.35 3.26

2.46 3.59 3.26

If, however, the number of conceptions which followed the birth of the first malformed offspring is taken into consideration, the place-in-family of the second defective sibling will be found to be different. The place-in-family of the second defective sibling is shown in Table 16. Column 1 lists the places-in-family following the birth of the first malformed child. Column 2 shows the observed places-in-family of the 40 second defective offspring. Column 3 gives the expected distributions of these children had they been distributed throughout these subsequent places-in-family according to the laws of chance, using the Greenwood-Yule reconstruction (Appendix 4). Column 4 gives the ratio of observed to expected distributions. From these figures it is evident that the second malformed child appeared more often than would be expected in the second and third positions, rather than in the first position immediately after the conception of the first malformed sibling. The place-in-family of the second malformed child was also computed for the series of families listed in table 51. Again it was found that the second malformed child was most likely to appear late in the family, rather than immediately after the birth of the first defective sibling. 36

Table 16. Place-in-Family of Second Malformed Child Place-in-Family After Birth of First Malformed Child (1) First Second Third Fourth Fifth Sixth Seventh

Second Malformed Child Distribution Observed

Expected

(2) 22 7 8 1 0 1 1

(3) 28.7 5.7 3.7 0.5 0.3 0.3 0.1

Col. > 2 Col. 3 (4) 0.77 1.23 2.16 -

Legend. Showing place-in-family of second, malformed sibling in relation to that of first, defective child, in 40 families listed in Table 50. Each family considered to be complete with birth of its second, malformed member. In column 2, the observed distribution of the second, malformed children; in column 3 their expected distribution, had they occurred according to the laws of chance; in column 4, the ratio of observed to expected distribution. Note in column 4 that the second, malformed child appeared in the second and third places-in-family after the birth of the first malformed child more often than would be expected, and less often than would be expected in the first place-in-family.

Reproductive Efficiency Before and After the Conception of Malformed Children. Miscarriages, premature births, and stillbirths were observed in a number of families. The place-infamily of these unsuccessfully ending pregnancies, designated "disturbed" pregnancies, was studied. The investigation was limited to families with only one malformed child, ones having more than one offspring, and ones in which both parents had been married only once. This selection confined the analysis to 405 families. In them there were 1,732 conceptions, of which 1,094 or 63.2 per cent, terminated normally with live born, fully developed offspring. There were 405 malformed offspring, and 233 conceptions which ended in miscarriages, premature births, or stillbirths. The place-in-family of the 233 disturbed pregnancies, in relation to the pregnancies whioh ended in the birth of the malformed offspring, are shown in Table 17, and in Figure 5. 37

Figure 5. 1.50

-2

-I

+1

+2

+3

BIRTH POSITION Legend. Graphic presentation of data appearing in Table 17, column 7. Cross-hatched bars record ratio of observed, combined, miscarriages, premature births and stillbirths, to their "expected" frequency, arranged according to their place-infamily, in relation to the place-in-family of the malformed child. Plus one position represents first conception after, and minus one the conception immediately preceding that which ended in the birth of the malformed child. Note the highest incidence of these abnormally ending pregnancies in the positions next to the malformed child.

38

Table 17. Place-in-Family of Disturbed Pregnancy in Relation to Malformation Pregnancy Disturbances of Pregnancy Observed Expected PlaceCol. 5 Combined Combined inFamily Miscar- Still- Pre- Miscarriages, Miscarriages, Col.6 mature stillbirths, stillbirths, riages births births premature premature births births (1) -12 -11 -10 - 9 - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 + + + + + +

1 2 3 4 5 6

Total

Number Number Number (3) (2) (4) 0 1 0 1 1 0 1 1 0 1 2 1 0 1 1 1 2 0 4 6 1 0 9 2 3 5 2 8 IS 6 6 19 4 15 45 14

Number (5) 1 2 4 2 3 11 11 10 29 29 74

Number (6) 0.63 0.63 2.33 2.75 4.94 7.14 9.63 12.58 17.98 25.41 35.75 56.60

8 3 0 0 0

6 3 0 0 0 0

0 0 0

40 12 3 0 0 0

37.66 13.79 3.65 0.71 0.17 0.17

147

49

37

233

232.52

2y

2

5 1 0

39

(7)

0.86 1.45 0.41 0.42 1.14 0.88 0.56 1.14 0.81 1.30 1.06 0.87 0.82 0.00

0.00 0.00 -

In table 17 the heavy face, horizontal line indicates the place-in-family of the congenitally m a l f o r m e d child. The minus numbers i n column 1 represent the conceptions w h i c h preceded the defective child; plus numbers those w h i c h followed. The - 1 p o s i t i o n represents the conception immediately preceding, and + 1 the one immediately following the defective child. The figures in columns 2, 3, a n d 4 represent the observed m i s carriages, stillbirths and premature births, a n d i n column 5 t h e y are combined. The expected frequency of the combined miscarriages, stillbirths a n d premature births in column 5, h a d t h e y occurred at random, is shown i n c o l u m n 6. The ratio of the observed to the expected figures is s h o w n in column 7. O n the basis that 1.0 is normal expectancy, the figures in c o l u m n 7 show that the disturbances of p r e g n a n c y (column 5) occurred more often t h a n expected i n the positions close to the defective child, and less o f t e n i n the more distant positions. The small number of families studied accounts for the ratios greater t h a n 1.0 found i n the - 3 , - 6 a n d - 9 positions. The latt e r distribution w a s computed b y the use of the Greenwood-Yule (1914) reconstruction.

Since all disturbed pregnancies i n each family w e r e counted i n the total of column 5, a n d since i n column 6, each family w a s counted once for each disturbance n o t e d i n column 5, the totals of these two columns are necessarily approximately equal. Had the observed disturbances occurred w i t h random frequency, the figures i n each b i r t h p o s i t i o n i n column 5 w o u l d have been, for all practical purposes, identical w i t h tho3« i n column 6. This identity w o u l d have p r o d u c e d a ratio i n column 7 of 1.0 for ecch b i r t h position.

The figures i n column 7 show t h a t the disturbed pregnancies i n the p o s i t i o n - 1 and + 1 , immediately adjacent to the defective child, occurred more often t h a n w o u l d be expected. In the birth p o s i t i o n immediately preceding that of the defective child, the observed disturbances w e r e the m o s t frequent, being n e x t most common i n the p o s i t i o n immediately following that of t h e defective child. I n the m a j o r i t y of the more distant p o -

40

sitions, the disturbances occurred less often than would be expected by chance. Three of the distant positions, -3, -6, -9, showed a greater frequency than would be expected. These are believed to be false values, due to the small number of families forming these groups. Considering the relative sizes of the observed frequencies in the -1 and -2 positions, column 5, it is evident that the frequency in the -1 position is approximately two and one-half times that of the -2 position. These figures refer to the combined miscarriages, stillbirths, ana premature births. If these combined disturbances are sub-grouped, as shown in columns 2, 3, and 4, the following is observed: The frequency of miscarriages alone in the -1 position is more than twice as great as in the -2 position; the frequency of stillbirths in the -1 position is two and one-half times as great as in the -2 position; and the frequency of premature births in the -1 position is over three times as large as in the -2 position. The close proximity of the miscarriages, stillbirths, and premature births to the position of the defective child suggests that they v.'ere individually determined by a common cause, and by the same CL-.use which in all probability brought about the congenital malformations in the fari_lies in this group. The finding of the disturbance so often in the pregnancy immediately preceding that which resulted in the deformed child, suggests that the appearance of a disturbed pregnancy should give the obstetrician cause to suspect the possible existence of a congenital malformation during the course of the subsequent pregnancy. Intervals Between Pregnancies. The intervals in months preceding the births of the malformed offspring were compared with those preceding the births of their normally developed siblings. In case a pregnancy preceded a pregnancy, the interval was timed from the month of the preceding delivery to the month of the following conception. In the event of a first pregnancy, it was counted from the month of marriage to the month of conception. In case the mother married twice, and had children by both husbands, the interval preceding the birth of the first child by the second husband was measured from the date of the second marriage. In a few instances, the duration of prematurely ending pregnancies was not known. In these cases, miscarriages were estimated as having occurred at the end of 3 months periods, and premature births at the end of 7 months intervals. With these facts, then, it is possible to determine, in months.

41

the lengths of the non-pregnant intervals which preceded the conceptions of b o t h the congenitally malformed offspring and those of their normally developed siblings. The preceding intervals were determined for 2,146 p r e g nancies w h i c h occurred in a consecutive series of 531 families. Of these pregnancies, 584 terminated i n the birth of malformed children, and 1,562 i n the birth of normally developed siblings. The number and percentage of pregnancies ending i n the b i r t h of congenitally malformed children can be compared w i t h similar figures for their normally developed siblings i n Table 18, arranged according to the lengths of the non-pregnant intervals. The percentage relationship between these distributions is expressed graphically i n Figure 6. F r o m these data it is apparent that: The malformed children had a tendency to be b o r n after longer non-pregnant intervals, on the average, them, did their normally developed brothers and sisters, and an Table 18. Intervals Intervals in Months 1 13 25 37 49 61 73 85 97

(1) -12 - 24 - 36 - 48 - 60 - 72 - 84 - 96 - -

Total

Total Number

Between Pregnancies

Siblings Mai Jformed Number Per cent

(2) 1,213 547 189 79 50 26 12 3 27

(3) 285 130 66 31 33 14 6 1 18

2,146

584

(4) 23.5 23.8 34.9 39.2

J[ >

61.2

-

Normal Number Per cent (5) 928 417 123 48 17 12 6 2 9 1^62

(6) 76.5 76.2 65.1 60.8

> 38.8

J -

Legend. Showing the distribution of malformed and normal siblings of 531 mothers, arranged according to the length of the non-pregnant interval w h i c h preceded tho birth of each sibling. Note that where the non-pregnant intervals are 49 months or more i n length, the proportion of malformed siblings is decidedly greater t h a n where the intervals are shorter.

exceedingly large percentage of malformed offspring w e r e b o r n after non-pregnant intervals of more t h a n four years duration.

- 42 -

Occurrence of Subsequent Conceptions. The birth of a m a l f o r m e d child undoubtedly makes parents apprehensive regarding the development of any subsequent offspring, and no doubt, in certain cases, leads to the avoidance of pregnancy. A t the home visits the attitude of the parents vas not elicited routinely. Some mothers accented their misfortunes Philosophically, attributing the birth of the defective child to the "Will of God" and merely hoped for better luck next time. In a number of instances, fear was expressed, although it did not appear to dominate the picture in most families. Figure b. 100

75 ui < t-

¡5 o

50

te

ui a

25

0 1-12

13-24

25 - 36

37-48

0VER48

MONTHS

MALFORMED I I NORMAL Legend. Graphic presentation of data appearing i n columns 4 and 6, table 18. Base line indicates non-pregnant intervals in months. Vertical bars represent percentage of malformed and normal siblings. Note tendency for pregnancies ending i n m a l f o r m e d offspring to follow the longer non-pregnant intervals, especially where the intervals are very long.

-

43 -

In 485 instances, there w a s definite knowledge as to the occurrence of subsequent pregnancy. I n these cases, the m o t h er and father h a d lived together since the b i r t h of the m a l formed child, and no p r o l o n g e d attempt h a d b e e n made to avoid pregnancy. The incidence of conception, arranged according to the duration of observation of each family, is recorded in table 19. Table 19. Incidence of Conception Following B i r t h of Congenitally M a l f o r m e d Child Interval Between B i r t h of Defective Child and Home Visit Months (1) 1-12 13 - 24 25 - 36 37 - 48 49 - 60 Over 60 Totals

Mothers Conceptions Total

With

Without

Number Number Per cent Number Per cent (2) (3) (4) (5) (6) 23 4 19 17.4 82.6 107 33 74 30.8 69.2 101 50 51 50.5 49.5 99 65 34 34.4 65.6 81 30 51 37.0 63.0 0 74 00.0 74 100.0 485

277

-

208

-

Legend. Showing the incidence of conceptions following the b i r t h of the m a l f o r m e d child, arranged according to the length of time the families w e r e under observation. Note i n column 4 the progressive increase in the incidence of conception the longer the p e r i o d of observation, a n d the fact that every mother observed for over five years experienced a subsequent conception. Of the 485 families, 208 experienced no subsequent conceptions, w h e r e a s 277, or 57 per cent, did so. It is of interest that the conception rate increased i n relation t o d u r a t i o n of observation, and that all mothers w h o w e r e observed for more t h a n five years ultimately conceived. This latter occurrence might be explained on one of several grounds: E i t h e r fear gradually disappeared, or it w a s overcome b y the desire to have a child, or contraception failed to be effective. The number of subsequent conceptions also w a s studied; as can be seen f r o m the data i n Table 20, ninety-four or approximately 34 p e r cent of the 277 families experienced at least two subsequent conceptions.

- 44 -

Table 20. Conceptions Per Family A f t e r Birth of Congenitally Malformed Child Interval Between Birth of Defective Child a n d Home Visit Total

Families Number of S u b s e q u e n t Conceptions 1

2

3

4 33 50 65 51 74

4 33 43 40 33 30

6 19 15 23

6 3 7

277

183

63

16

4

5

More t h a n 5

4

5

5

5

5

5

Months 1-12 13 - 24 25 - 36 37 - 48 49 - 60 Over 60 Totals

1

Legend. Showing the number of conceptions experienced b y the 277 mothers (table 19) w h o conceived following the b i r t h of the defective child. Note t h a t 94, or approximately 34 percent, experienced two or more subsequent conceptions.

A correlation w a s sought between the occurrence of subsequent conceptions and the extent and seriousness of the defect. It w a s thought that malformations w h i c h involved the b o d y surface might be more likely to produce fear, and hence avoidance of conception t h a n ones w h i c h w e r e disclosed only at necropsy or operation. The incidence of subsequent conception w a s practically the same i n both groups. The r e l a t i o n of economic status to subsequent conceptions w a s investigated. It is a generally accepted fact that people in higher economic levels have smaller families t h a n people w h o are less w e l l off. This fact is borne out i n the p r e s e n t figures w h e r e it appeared that following the b i r t h of the defective child, 63.8 per cent of those classified as poor or v e r y poor conceived, w h e r e a s among those grouped as being i n moderate circumstances or w e l l - t o - d o , only 46.5 per cent did so. In this connection it is of interest that in the case of the 40 families having two or more m a l f o r m e d children, as shown i n Table 50, conceptions occurred after the b i r t h of the second m a l f o r m e d child in 21, or in more t h a n 50 per cent of instances.

- 45 -

SUMMARY 1 ) No significant relationship w a s found to exist between the occurrence of malformations and menstrual abnormalities, previous maternal pelvic disease, or rapidly repeated childbearing. 2) Malformed offspring w e r e born prematurely more than four times as often as their normally developed siblings. 3 ) Later born children w e r e found to be malformed more than their earlier born siblings.

often

4 ) In families having mere than one defective child, the second defective sibling was more likely to be born late in the family than to result from the conception w h i c h t o o k place immediately after the birth of the first defective sibling. 5) Miscarriages, stillbirths, and premature births occurred more often than would be expected by chance in the pregnancies immediately preceding and following the pregnancy which resulted in the birth of a congenitally malformed child. 6) The birth of the malformed child w a s preceded by a period of relative sterility more often than w a s the birth of its normally developed sibling. 7) All families observed for 5 years experienced at least one conception following the birth of the malformed child.

-

46

-

CHAPTER V DEFECTIVE CHILD

PREGNANCY

Contraceptive Vaginal Douching. It has been suggested that the sperm cell may be so injured by the chemical in a contraceptive, vaginal douche that, although fertilization might not be prevented, the development of the embryo might suffer as a result. With this possibility in mind, some of the mothers were questioned upon the use of douches. Of 345 reporting, 88, or only 25.5 per cent, used contraceptive, vaginal douches routinely at the time that the malformed child was conceived. Of this number, 23 used plain water, and 55, or only 16 per cent of the 345 women, used a chemical douche. The chemicals used in these douches are listed in Table 21. Table 21. Qhftjni p.a 1 Douches Number of Douches

Chemical Lysol •Unstated Physicians prescriptions Zonite Baking Soda Boric acid Soap Sabia Creolin

23 17 6 5 5 3 3 2 2 66

Total

Legend. A list of the chemicals used in contraceptive, vaginal douches which were being employed routinely by 55 mothers at the time that they conceived their malformed offspring.

The use of chemical douches by so few women suggests that douches played little if any role in the etiology of the defects . * Chiefly patented preparations

- 47 -

W h e t h e r a chemical douche could injure a sperm cell w i t h o u t first destroying its power of being able to fertilize the egg cell - is a n unanswered question. deRenyi and Murphy (1932) recently studied the effect of r a d i u m u p o n the m a m m a lian egg. They concluded that the first power of the egg to be destroyed by irradiation w a s its power to become fertilized. Such might very likely be the case w i t h respect to the effect of a chemical u p o n the sperm cell. If it w e r e , t h e n it w o u l d be unnecessary for the user of a douche to w o r r y about the possible injurious effect of any chemical, contraceptive solution u p o n the development of future offspring. Month of Conception. The month of conception w a s calculated for 935 m a l f o r m e d individuals, and for 1,590 of their normally developed siblings. The distribution of these individuals, b y the months of their conceptions, are presented in Table 22 and Figure 7. Table 22. I.lonth of Conception of Congenitally Malformed Children and of Their Normally Developed Siblings Children Defective January February March April May June July August September October November December Total

Normal

Number

Per cent

79 64 79 70 79 89 89 83 72 79 75 77

8.45 6.84 8.45 7.49 8.45 9.52 9.52 8.88 7.69 8.45 8.02 8.24

130 133 127 157 134 117 121 132 116 133 147 143

8.18 8.36 7.99 9.88 8.43 7.36 7.61 8.30 7.30 8.36 9.24 8.99

935

100.00

1590

100.00

Number

Per cent

The conceptions w e r e distributed fairly evenly throughout the year, but there w a s a slight preponderance of the conceptions of malformed individuals in the summer months, and of their normally developed siblings in spring months. O n the other hand, Petersen (1934) found a preponderance of conceptions of malformed individuals in the spring months. The relatively - 48 -

Figure

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Legend. Showing a) b i r t h order of congenitally m a l f o r m e d children, b) family size, c) sex of e a c h child, d) incidence of m i s c a r r i a g e s , including abortions, a n d e) the chief diagnosis of e a c h congenitally m a l f o r m e d child, in each of 19 families having at least two m a l f o r m e d siblings, as reported by correspondence w i t h physicians living outside of Philadelphia. Note the d u p l i c a t i o n of malformations in the first 10 families.

-

79

-

Table 52. Incidence of Child Defect Among Relatives Dêfect in Relative Certificate Child

Diagnosis

Same as certificate child

Different from certificate child

Number

Number

Number

(1) Hydrocephalus

(2) 7

(3) 5

(4) 2

Spina bifida

7

3

4

1 Pyloric stenosis 1 Dislocation of shoulder 1 (a) Absence of eye (b) Hydrocephalus 1 No description

Cleft palate and harelip

5

4

1

1 Absence of ear

Heart disease

4

1

3

1 Spinal defect 1 Extremity defect 1 No description

Pyloric stenosis

4

1

3

1 Hydrocephalus 1 Syndactylism 1 Deaf mute

Anencephalus

3

0

3

1 Hydrocephalus 1 (a) Cleft palate (b) Hydrocephalus 1 Deaf mute

Monster undescribed

2

0

2

1 Pyloric stenosis 1 (a) Syndactylism (b) Missing fingers

1

0

1

1 Hemangioma

1

0

1

1 Harelip with absence of tooth

Rectovaginal fistula

1

0

1

1 Heart defect

Stricture of ureter

1

0

1

1 Harelip

Intestinal obstruction

1

0

1

1 No description

Hydrocephalus spina bifida

1

1

0

Folydactylism

1

1

0

39

16

23

Meningocele Atresia of Bsophagus

Total

Diagnosis (5) 1 Harelip 1 Extremity defeot

(a) and (b) - Designate two relatives of one child. Legend. Showing the frequency with whioh the del'eot observed in the certificate child duplicated in its distant relative. Column 1 records the nature of the defect seen in the certificate child; column 2, the number of certificate children exhibiting each type of anomaly, column 3, the number of distant relatives possessing the same defect as the certificate child, column 4, the number of distant relatives possessing non-duplioating defects, and column 5, the nature of the latter. Note in the total line that in 16 out of 39 instanoes, or in 41 per oont of cases, the distant relative possessed the same defect as the certificate Child. -

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having the defective relative on the father's side, the defect duplicated in only 4 instances. If these figures are correct - that duplication of defects occurred on the mother's side almost three times as often as on the father's side of the family - it might be inferred that the characteristics of the mother have a more pronounced influence upon the offspring than do those of the father. Table 53. Relationship of Malformed Relative to Defective Certificate Child

by

Number of Certificate

Child Families Defect in relative

Cousin Aunt Uncle More than one relative Great aunt Step-sibling Father Grandfather Great uncle Not stated Total

Number of certificate child families

Same as certificate child

Different from certificate child

13 8 7

4 7 1

9 1 6

3 2 2 1 1 1 1

1 1 1 0 0 1 0

2 1 1 1 1 0 1

39

16

23

Legend. Showing the relationship between the certificate child and its congenitally defective, distant relative, in the case of the 39 families recorded in table 52. Note that duplication of the certificate child defect occurred most often where the relative was an aunt.

From these findings the following observations are made: Malformations have a strong tendency to duplicate among siblings, and among more distant relatives. Duplication involves all types and degrees of defect. These observations support the hypothesis that congenital defects arise prior to fertilization and hence are hereditary in origin.

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Age of Defective Individual at Time of Death. The ages of the 890 defective individuals for whom death certificates were available at the time of death are given in Table 54. Approximately 25 per cent of them were stillborn, and a total of more than 90 per cent were either stillborn or died within one year of birth. Table 54. Age of Defective Individual at Time of Death Individuals Age

Cumulative Total

Stillborn Less t h a n 1 hour Remainder of 1st day M It It week tt II II month II II II year Before 7 years Before 15 years After 15 years

Number

Number

Per cent

222 36 54 116 118 260 58 16 10

222 258 312 428 546 806 864 880 890

25.0 29.0 35.1 48.1 61.4 90.6 97.1 98.9 100.0

Legend. Recording the age of the malformed individuals at the time of death. Note the large proportion of stillborn individuals (25%), and ones stillborn or dying under 1 year of age (90.6%).

SUMMARY 1) In the 826 families for w h i c h information was available approximately one-third of the offspring exhibited gross, congenital malformations. 2) The normally developed siblings of the malformed offspring did not exhibit unusual frequency of any diseases, or die from unusual causes. 3)

Certain defects afflicted one sex more often than the other.

4) Among the defective children, there was no greater incidence of illegitimacy t h a n w a s observed in the general population. -

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5) Approximately 77 per cent of the defective individuals exhibited a malformation which affected only one part of the body. 6) In 80 per cent of instances, the malformation was visible without recourse to operation or necropsy. 7) Defects which involved the central nervous system were most numerous, hydrocephalus being the most common diagnosis. 8) Among defects of the gastro-intestinal tract, pyloric stenosis was the most frequently recorded. 9) Harelip and cleft palate were the most common defects involving primarily the musculo-skeletal system. Club-foot was also a very common finding, although it was usually not classified as a chief diagnosis. 10) In families possessing two or more malformed offspring, the defect in the first-born, malformed member duplicated in a subsequent, malformed sibling in nearly one-half of instances. 11) In families in which a distant relative exhibited a defect, the malformation in the defective child duplicated in the distant relative in approximately one-half of instances. 12) Of the 890 malformed individuals who were studied, about 25 per cent were stillborn, and about 90 per cent were either stillborn or died within a year of birth.

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CHAPTER VII THE ETIOLOGY O F CONGENITAL MALFORMATIONS It is said that development results f r o m the interaction between inherited tendencies contained w i t h i n the egg substance itself, and the external conditions w h i c h surround and act upon this substance (Mall 1908). It is common knowledge that m a n y congenital abnormalities are inherited. The question arises, however, as to whether all defects have their origin in this m a n n e r , or whether some of them m a y be due to disturbances w i t h i n the environment of the otherwise normal ovum. A number of observations support the idea that m a n can influence the environment of the ovum sufficiently to modify its growth. S t o c k a r d subjected the eggs of fish, during early stages of development, to the a c t i o n of w e a k solutions of alcohol. The resulting embryos exhibited m a r k e d abnormalities in the structure of the central nervous system and organs of special sense. B a g g (1922)likewise m o d i f i e d the growth of the eye and b r a i n of rat embryos by exposing them to radium irradiation. M u r p h y (1929) assembled evidence that radium and roentgen exposure w i l l arrest the growth of the h u m a n embryo, microcephaly being the m o s t common sequel. W i t h respect to spontaneously occurring malformations, Mall (1908) found a h i g h incidence of abnormalities among aborted, h u m a n embryos, and ones from tubal gestations. The very large number of pathologic embryos found in the tubal pregnancies w a s one of the strongest arguments to him that they were not the result of germinal influences, but due to unsuitable external conditions. It is c o n c e i v a b l e , however, that the pathologic embryos examined b y M a l l m a y have acquired their unusual maternal relationships as a result of abnormal germinal characteristics. In such a n event, the ensuing maldevelopment w o u l d have been due primarily to hereditary causes. It is generally agreed, therefore, that m a n y congenital malformations are inherited, also that the development of the ovum can be m o d i f i e d under experimental conditions. The evidence does not appear to be entirely convincing, however, that

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spontaneously occurring abnormalities can be due to environm e n t a l factors. The present analysis deals w i t h certain of the characteristics of the families that have b e e n discussed above. These are assembled in order to show the relative importance of heredity and environment in the production of congenital defects in m a n . The familial characteristics having a possible bearing upon the etiology of the physical abnormalities are considered under two headings: (A) Environment and (B) H e r e d i t y . (A)

Environment

The frequency w i t h w h i c h certain of the environmental characteristics occurred is given in Tablé 55. Table 55. Familial Characteristics Relating to Environment

Characteristic

Families Studied Number

Characteristic Present Per cent

Chronic illness of father Chronic illness of m o t h e r Positive maternal W a s s e r m a n n Previous maternal pelvic -disease Previous atypical m e n s t r u a t i o n Preconceptional douching Unbalanced diet

569 640 324 628 654 345 545

9.3 8.8 12.4 10.8 12.5 25.5 40.0

Legend. Showing the frequency of certain familial characteristics relating to environment. Note the relative infrequency of t h e s e attributes, w i t h the possible exception of a n unbalanced diet.

A l t h o u g h no control data were available, these attributes did not appear to occur unusually often. Frequency of Reproduction. In the group of 208 families, e a c h of w h i c h had two or more children born before the birth of the congenitally m a l f o r m e d child, the reproduction rate w a s no greater than in the series of control families having normally developed offspring.

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Month of Conception. The m o n t h of conception of the 935 malformed individuals showed a slight preponderance of such conceptions in the summer m o n t h s , but comparing these figures w i t h those of other authors, there seemed to be no reason to believe that the conception of m a l f o r m e d offspring occurs w i t h unusual frequency in any one season of the y e a r . Diet. A l t h o u g h the diets of the m o t h e r s w h e n pregnant w i t h their m a l f o r m e d children were inadequate from many points of view, it w a s not possible to correlate defiencies in diet w i t h the occurrence of m a l f o r m e d children. Coincidence of M a l f o r m a t i o n W i t h Placenta Praevia. There w a s n o unusual coincidence of placenta praevia in association w i t h the 741 m a l f o r m a t i o n pregnancies reported above.

(B)

Heredity

Color. Congenital m a l f o r m a t i o n w a s observed in the white families w i t h nearly twice the frequency as it was observed in the negro race. M a t e r n a l A g e . The proportion of defective to normal offspring at different maternal ages w a s found to be as follows: (a) lowest w h e n the m o t h e r s w e r e b e t w e e n 20 and 25 years of age; (b) more or less constant w h e n they were between 15 and 30 y e a r s of age; (c) increasing from year to year w h e n the m o t h e r had passed 30; (d) greatest after the mother had passed 40 y e a r s of age, at w h i c h time the ratio of defective to normally developed children w a s approximately three times or more that noted before the m o t h e r s were 30 years old. B i r t h Order of M i s c a r r i a g e s , Premature Births, and Stillbirths. The m i s c a r r i a g e s , premature births and stillbirths took place immediately before and after the birth of the m a l f o r m e d child more often t h a n w o u l d be expected by chance. Relative Sterility Before B i r t h of M a l f o r m e d Child. A long period of relative sterility occurred four times more o f t e n immediately preceding the conception of malformed offspring than it did preceding the births of their normally developed brothers and sisters. Frequency of M a l f o r m a t i o n s Among Brothers and Sisters. In the general population, m a l f o r m a t i o n s occurred in the ratio of 1 m a l f o r m e d child for every 213 live births« In families hay— -

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ing one malformed child,another appeared in every eight subsequent live births. Duplication of Malformations Among Brothers and Sisters. The defect observed in the first malformed child reappeared in a subsequent malformed brother or sister in 46 per cent of instances. Duplication of Malformations Among Pistant Relatives. In 39 cases, a distant relative of the malformed child exhibited a congenital malformation. The latter defect was identical with that observed in the malformed child in 41 per cent of instances. Duplication of Rare Defects. Maldevelopment occurs more frequently in the left dome of the diaphragm than in the right dome. One mother gave birth in successive pregnancies to two children each exhibiting an absence of the right dome. Duplication of Defects Through Two Wives. Harelip and cleft palate are more common on the left than on the right. One father had a child with a right-sided harelip and cleft palate by each of two wives. Malformations According to Sex. Certain malformations had a predilection for one sex or the other. Discussion. The observations dealing with environmental factors offer no proof that environment plays a role in etiology. This may be due to the limitations inherent in the study. For example, such defects as amputations, which are believed to be due to amniotic bands, did not appear in the series of abnormalities which formed the basis for this investigation» On the other hand, characteristics relating to heredity point to it as the most likely place of origin of malfornation. These fall into four groups: color, sex ratio, reproductive inefficiency, and the character of the defects which were seen in brothers and sisters. Abnormalities were observed in white persons twice as frequently as in negroes, which fact would support the theory of a germinal origin for congenital defects. This high frequency of malformations in whites is of interest in view of the fact that syphilis is much more common in negroes. It

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might be concluded, from these observations, that syphilis is not a n etiological factor. Certain defects afflicted one sex m o r e often than the other. If spontaneously occurring m a l f o r m a t i o n s arise, primarily, from environmental influences, it w o u l d seem that the sexes should be affected w i t h equal frequency. Reproductive inefficiency w a s indicated b y : a) the long period of relative sterility frequently observed immediately preceding the b i r t h of the m a l f o r m e d child, b) the nearness of miscarriages, premature b i r t h s , and stillbirths to the m a l formation pregnancy, c) the h i g h incidence of malformed offspring b o r n to older m o t h e r s , and d) the increased frequency of congenital defects among brothers and sisters. Since these evidences of reproductive w e a k n e s s , in very m a n y cases, operated over a period of years, it seems likely that their origins rested upon defects w i t h i n the germ cells, rather than upon abnormality in the environment. Perhaps the single m o s t convincing piece of evidence in favor of heredity is the frequent d u p l i c a t i o n of defects in brothers and sisters. This w a s observed in the case of the more unusual, and m o r e serious m a l f o r m a t i o n s , as well as in the more common types of less serious ones. From this investigation it is not possible to conclude that spontaneously occurring, human, congenital malformations do not arise from factors inherent in the environment of the ovum. O n the other hand, no evidence w a s found to confirm this theory. All of the available data point to disturbances in the germ cells prior to fertilization as the factors primarily responsible for m a l d e v e l o p m e n t .

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88

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CHAPTER VIII DISCUSSION AND SUMMARY As w a s indicated in the introduction, the present study w a s u n d e r t a k e n originally to determine the frequency of m a l formations among brothers and sisters. The findings indicate that not only are m a l f o r m a t i o n s m u c h more frequent among siblings t h a n in the population at large, but also that the malformations of siblings are very prone to be identical. The extension of the original purpose of the study to include other phases of the reproductive capacity of the parents of malformed offspring, has b r o u g h t to the foreground the question of w h a t m i g h t , for a better expression, be termed "reproductive efficiency". For a discussion of this subject it is convenient to classify all m a t i n g s as b e i n g either efficient or inefficient. Efficient M a t i n g s . A n efficient m a t i n g m i g h t be considered one in w h i c h reproduction occurs at w i l l : all offspring are carried to term, are b o r n alive, and are b o t h mentally and physically normally d e v e l o p e d . Inefficient M a t i n g s . A n inefficient m a t i n g is one which does n o t conform to the above standard. In such a case there m a y be a m a l f o r m e d child or some other reproductive error. The inefficient m a t i n g s m i g h t be subdivided according to the degrees or kind of inefficiency w h i c h they exhibit. For purposes of description it m i g h t be w e l l t o predicate at least three degrees of inefficiency, i.e., (A) (B) (C). Inefficiency Degree (A) The m a t i n g s in t h i s group are the most.efficient of the inefficient ones. Here are to be found normal offspring together w i t h a m a l f o r m e d one. In such a family there m a y be a large n u m b e r of children all b u t one of w h i c h are normally developed, and the m o t h e r has not experienced any m i s c a r r i a g e s , premature b i r t h s or stillbirths. Inefficiency Degree (B) This m a t i n g is less efficient them Degree (A) but m o r e efficient t h a n Degree (C). There m a y be normal children, besides the m a l f o r m e d one, but in addition the m o t h e r m a y exhibit one or m o r e miscarriages,

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premature births or stillbirths. period of relative sterility.

This w o m a n exhibits no

Inefficiency Degree (C) This m a t i n g is less efficient than that of Degree (B). In such a family there may be normal children as well as a m a l f o r m e d one, but in such a mating there m a y be a very long period of relative sterility, w h i c h is m o s t likely to immediately precede the birth of the malformed child. The m o s t inefficient m a t i n g on the other hand, would be the one in w h i c h reproduction fails to occur. The present study indicates that the couples w h o give rise to m a l f o r m e d offspring are reproducing inefficiently, and in the future they m a y again give evidence of this w e a k ness. W i t h these considerations in m i n d the physician must decide how he will answer questions w h i c h , naturally, will be asked by the parents of a congenitally malformed child. He m a y tell them that they have a greater chance of having another m a l f o r m e d child t h a n other couples, and that the chance of having another defective child will be increased if one or b o t h of the parents are w e l l advanced in years. The parents m i g h t be told that the occurrence of a malformation depends upon the character of the egg or sperm before fertilization rather t h a n upon any influences acting upon the already fertilized egg; that malformations are not due to syphilis or any other disease of the parents. Just what he will say will depend u p o n circumstances.

SUMMARY 1) Gross congenital m a l f o r m a t i o n s as recorded upon death certificates afflict approximately one in every 213 of individuals who are b o r n alive. 2) About 25 per cent of congenitally malformed persons are stillborn. 3) The m a l f o r m a t i o n rate among white persons is about twice the rate found among n e g r o e s . 4) In families already possessing a malformed child, the b i r t h of a subsequent m a l f o r m e d offspring takes place w i t h a frequency which is in the neighborhood of twenty-five times greater than that of the general population. 5) There is no unusual frequency of malformations among the illegitimate.

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6) It is difficult to e s t a b l i s h any definite relationship between the occurrence of congenital m a l f o r m a t i o n s and economic and social status, a l t h o u g h the evidence suggests that malformations m a y be a little more frequent in the lower classes of the population. 7) There appears to be no unusual frequency of chronic illness at the time of conception in either the mother or father of deformed offspring. 8) Syphilis, as indicated by W a s s e r m a n n test of the blood, does not afflict the m o t h e r s of congenitally m a l f o r m e d offspring, more often than those of children w h o are normally developed at birth. 9) The older the m o t h e r the more likely she is to give birth to a congenitally m a l f o r m e d child. 10) A w i d e difference between the ages of the parents, does not occur among the parents of malformed children, w i t h any greater frequency t h a n in the general population. 11) No correlation is to be found b e t w e e n the occurrence of congenital malformations in the offspring and the occupation of the father. 12) The mothers of m a l f o r m e d children exhibit n o unusual frequency of pelvic disease prior to the conception of their malformed children. 13) There is no unusual frequency of reproduction before the conception of malformed children. 14) The malformed child is less likely to go to t e r m t h a n is the normally developed sibling. 15) The child born later in a family is more likely to be congenitally malformed them is an older brother or sister. 16) In families containing two m a l f o r m e d siblings, the subsequent defective child is more likely to be b o r n later in the family t h a n it is t o be the next child in order of b i r t h to the first defective sibling. 17) In families possessing congenitally malformed children and in w h i c h miscarriages, premature births and stillbirths occur, the latter are unusually likely to occur close to the time that the m a l f o r m e d child is b o r n rather t h a n v e r y early or very late in the reproductive life of the m o t h e r .

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18) Periods of relative sterility are very likely to precede the birth of congenitally m a l f o r m e d children. 19) M a n y m o t h e r s did not conceive after the b i r t h of their defective offspring; none of this group w a s under observation for as long as five y e a r s . Every w o m a n w h o w a s followed for that length of time experienced, d u r i n g or after that period, one or m o r e subsequent conceptions. This observation suggests that a n y fear of giving b i r t h to a subsequent, m a l f o r m e d o f f spring failed to prevent conception after a five year period had elapsed. 20) Contraceptive vaginal douches were employed by very few m o t h e r s in the present series. 21) There is no evidence to support the hypothesis that congenitally m a l f o r m e d individuals are concerned w i t h unusual frequency at any one season of the y e a r . 22) The m o t h e r s of the m a l f o r m e d offspring were not especially unhealthy. 23) Therapeutic, pelvic radium or roentgen irradiation during pregnancy, or before conception were not employed in the treatment of the w o m e n forming the basis for this study. 24) W h e n pregnant w i t h their m a l f o r m e d offspring, the most commonly observed alterations in the physiology of the m o t h ers w e r e : polyhydramnios and abnormality of fetal movement. 25) The pregnancies associated w i t h the b i r t h of a congenitally m a l f o r m e d child exhibited no unusual frequency of placenta praevia. 26) The normally developed siblings exhibited no unusual m o r b i d i t y or m o r t a l i t y . 27) Certain m a l f o r m a t i o n s afflicted one sex more than the other. 28) The fect in without nervous

central n e r v o u s system w a s the seat of the chief deabout 60 per cent of cases; hydrocephalus w i t h or spina b i f i d a accounted for the great m a j o r i t y of these system lesions.

29) I n families possessing two or more m a l f o r m e d siblings the d e f e c t in the subsequent offspring w a s identical w i t h that in the previous defective sibling, in approximately 50 per cent of instances.

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30) Of all of the m a l f o r m e d individuals studies, approximately 90 per cent were either stillborn or died w i t h i n a year of b i r t h . 31) The diets of the m o t h e r s of the defective children were found to be significantly lacking in adequate amounts of calcium, phosphorous, iron and vitamins B, C and D. 32) The observations w h i c h have been made during the course of the present investigation lead to the general conclusion that gross, human, congenital m a l f o r m a t i o n s arise solely from influence w h i c h affect the germ cells prior to fertilization. No evidence is available to indicate that they result from factors w h i c h operate for the first time after fertilization has taken place.

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REFERENCES Bagg, H. J. 1932. Disturbances in mammalian development produced by radium emanation. Am J. Anat., 30: 133-154. Birth, stillbirth, and infant mortality statistics for the birth registration area of the United States for 1927, 1928, and 1929. Washington: U.S. Government Printing Office. Clark, T. 1932. The control of syphilis in southern rural areas. Chicago. Julius Rosenwald Fund. Das, K. 1934. Twin pregnancy. Demographic and ethnic study. J. Obst. & Gynec. Brit. Emp., 41: 227-255. deRenyi, G. S., M . deRenyi, and D. P. Murphy. 1932. Preconception ovarian radium irradiation of the albino rat (Mus norvegicus albinus). A biological study. Am. J. Roentgenol. & Radium Therap., 28: 764-783. Eddy, W. H. 1937. Address before the Philadelphia Dietetic Association, December. Genova, A. 1923. Di un caso raro di monstruosita fetali multiple e placenta previa. Ann. di Ostet. e Ginec., 45: 374-386. Greenhill, J. P. 1923. The association of fetal monstrosities and deformities with placenta praevia. Surg., Gynec. & Obst., 36: 227-231. Greenwood, M., and Yule, G. U. 1914. On the determination of size of family and of the distribution of characters in order of birth from samples taken through members of sibships. J. Roy. Stat. Soc., 77: 179-197. Kellogg, F. A.

1935.

Personal communication.

ii Kraul, L. 1926. 1927. Uber Placenta praevia. Wehnsehr., 77: 285-290.

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League of Nations Technical Commission of the Health Committee, Resort on the Physiological Bases of Nutrition, 1936, League of Nations Publications Department, Geneva. Lieberman, B. L. 1926. An analysis of seventy-nine cases of placenta previa. Am. J. Obst. 4 Gynec., 11: 814-823. Mall, F. P. 1908. A study of the causes underlying the origin of human monsters (Third contribution to the study of the pathology of human embryos.). J. Morph., 19: 3-368. Manual of the International List of Causes of Death. Fourth revision, Paris, 1929. 1932. Washington: U.S. Government Printing Office. Murphy, D. P. 1929. The outcome of 625 pregnancies in women subjected to pelvic radium or roentgen irradiation. Am. J. Obst.