PROSPECTIVE EXPERIENCE WITH MATERNAL RUBELLA AND THE ASSOCIATED CONGENITAL MALFORMATIONS

F ou@owi@c an Australian epidemic of rubella in 1940, Gregg1 first observed the association between maternal rubella and certain congenital defects. Since then, evidence for a causal relationship has ac cumulated but the true frequency of re sulting malformations has been difficult to assess. Swan et a12 estimated the risk to be nearly 100% if rubella occurred in the first few months of pregnancy. This conclusion was based on retrospective data, usually by observing malformed children whose mothers were then found to have had ru bella during pregnancy. Normal progeny were easily overlooked by this approach, thus exaggerating the apparent risk. These observations, however, stimulated a great interest in environmental factors and their possible deleterious effects on pregnancy.

PATIENT MATERIAL AND PROCEDURES

The Fetal Life Study3'4 began in 1946 to evaluate factors related to abortion, stillbirth, prematurity, infant mortality and congenital malformations. Study cases consisted of all pregnant women registered in the ante partum clinic of the Sloane Hospital for Women within

the first 14 weeks following the onset of their

last menstrual period. At their initial visit, and at all subsequent visits to the ante partum clinic, they were questioned in detail by the Study personnel regarding the events of their pregnancy. In addition, patients were re quested to call the Study office if they devel oped or were exposed to anyone with a fever, rash or specific infectious disease. Examination of the patient at the time of the illness was made if the patient came to the hospital. The services of a visiting nurse and contact with the attending physician were used to document cases in the home. If the diagnosis of rubella

was accepted, continued follow-up of these pa

tients differed in no way from that of the gen

eral Study population. The infants were exam ined carefully by a pediatrician of the Study team on the first or second day of life. Follow up visits were scheduled for 6 and 12 months of age with special emphasis on the detection of malformations. Postmortem examinations were made whenever possible in all cases of

abortion, stillbirth or infant death.

The Fetal Life Study has enrolled approxi mately 10,000 pregnant women during the past 13 years, and in 18 instances a diagnosis of rubella was recorded as having occurred

during pregnancy. Seven additional cases of

maternal rubella were included which pre sented themselves to the ante partum clinic too

late to be included in the Fetal Life Study.

However, they were followed in the same man ner. The diagnosis of rubella was made by a

physician in 18 of these 25 cases. The other seven had no physician in attendance. Four of these cases, however, had known contact with rubella or secondary cases in the family. These cases are listed in Table I. Seventeen of these women were white and eight were Negro (Cases 3, 11, 15, 16, 17, 18, 23, 25).

Exposure to rubella occurred during 95

other pregnancies which were similarly fol

lowed (Table II).

OBSERVATIONSFROM THE

FETAL LIFE STUDY

PregnanciesComplicated by Rubella

The rubella infections are timed as the gestational week of onset from the first day of the last menstrual period. It should be realized that this is not an exact measure ment of fetal age, because the relation of the menstrual cycle to conception may vary. In the first 4 weeks of pregnancy, two diag

This investigation was supported by The Fetal Life Study, Research Grant (RG-4194) from the Human

Embryology and Development Division, Public Health Service.

ADDRESS:(G.W.M.) Fetal Life Study,622 West 168th Street,New York32, New York.

PsmAmIcs, August 1960

200

PROSPECTIVE

EXPERIENCE

WITH MATERNAL RUBELLAAND

THE ASSOCIATEDCONGENITAL MALFORMATIONS

Richard H. Michaels, M.D., and Gilbert W. Mellin, M.D.

CaseL.M.P. *DiagnosisG

@ e

Iwnal Weekof RubellaCompleted

Gesta tional Week at DeliveryBirth

JVeighl (gm)SexFollow upResult15/1/57Physician1433,660F1

yrNormal live-born22/

9/55History327—FP.M.fSpontaneous

abortion31/25/51Physician519—MP.M.Spontaneous abortion43/15/55Physician524—MP.M.Spontaneous

abortion(rightlung—Q

lobes)53/17/55Physician6392,610F24

yrPatent ductus

arteriosus61/15/55Physician728—FP.M.Spontaneous

abortion78/10/55Physician7422,510M2

yrCardiac anomaly.

Microcephaly83/11/55Physician8412,470F8

yrPatent ductus

arteriosus92/12/51Physician8403,120F7

yrNormal live-born101/27/59Physician10351,520

,500M MBirthBirthNormal

live-born twin Normal live-born twin111/

3/58Physician11372,220F6 moNormal

live-born122/14/57History11422,635F14

yrNormal

live-born1312/26/46Physician12392,570F1

yrNormal live-born141/11/49History13392,850F1

yrNormal live-born1512/

5/54History15404,045MBirthNormal

live-born161/

3/58Physician17413,500F6 moNormal

live-born174/

1/56Physician18393, 225F2 yrNormal

live-born1812/

2/57Physician18393,490M6 moNormal

live-born191/18/58History18362,860F8

moNormal live-born2011/14/50Physician18403,360M1

yrNormal live-born218/

5/56Physician19388,080M24 yrNormal

live-born2211/21/57Physician23413,290M6

moNormal live-born2312/14/47History25372,530F1

yrNcrmal live-born2410/14/49History28393,080FBirthNormal

live-born258/29/47Physician32383,750M1

yrNormal live-born

TABLE I

PREGNANCIES COMPLICATED BY RUBELLA COLLECTED IN FETAL LIFE STUDY, 1946—1959

* Date of last menstrual period. t P.M.—Postmortem.

noses of rubella were reported. One infec tion occurred during the last menstrual period, and a normal infant was later de livered. The other infection in the third ges tational week was followed by a spontane ous abortion. The seven pregnancies com !@plicated by rubella in the fifth through eighth week resulted in three spontaneous abortions, three malformed live-born in fants and one normal live-born infant. Ru bella infection after the eighth week in 16 instances revealed no abnormalities in a

imited follow-up period.

Two children with malformations had a patent ductus arteriosus. In neither case was a cardiac murmur heard at birth, al though each child had three separate ex

aminations, one of which was done by a pediatrician of the Fetal Life Study. Both infants had definite heart murmurs in the second month. This is consistent with our previous findings on the development of heart murmurs.5 In each case the diagnosis was confirmed and the lesion successfully repaired at operation in Babies Hospital.

One child was microcephalic, having a

head circumferenceof 41 cm and a chest

Gesta tionoi Week of ExposureTotal

CasesNormal

.

Live bornStill

births and

Malformations Abor

tions

TABLE II

PREGNANCIES FOLLOWED IN FETAL LIFE STUDY COMPLICATED BY EXPOSURE TO RUBELLA

WITHOUT OVERT ILLNESS

ology, Carnegie Institution of Washington, Baltimore, Maryland, and one was examined

by the Department of Pathologyin Babies

Hospital. Three specimens were extremely macerated and revealed no gross malforma

tions. The remaining fetus had a right lung with only two lobes.

No therapeuticabortionsor stillbirthsoc

curred in this series of pregnancies compli cated by rubella.

Rubella Exposure

There have been reports8'7 of anomalies of the “¿rubellasyndrome― following ex posure to rubella during pregnancy, but without overt maternal rubella. Rubella in fections without rash have been expected from epidemiologic experience, and this is supported by evidence from volunteer studies.8'9 From the Fetal Life Study 95 mothers were found to have been exposed to rubella without obvious illness (Table II). How many of these mothers had had previous rubella infections could not be de termined.

In the spring of 1955 there was a high incidence of rubella in New York City. Of 653 infants born into the Study from March 1955 to March 1956, none were found to have cataracts although all live-born infants had routine ophthalmologic examinations at birth.

SUMMARY OF SELECTEDPROSPECTIVE

STUDIESIN THE LITERATURE

Criteria for Selection

A review of other prospective studies in

respectto malformationratewas made using

the following criteria:

1) The diagnosis of rubella was made and recorded before delivery.

2) The diagnosis of rubella was made by a physician in most instances.

3) At least one careful follow-up examina tion of the progeny was made in most cases.

4) The timing of maternal rubella is known by week or month of gestation for the fetal deaths, normal live-born infants and the affected offspring.

Among the published prospective studies,

1 1 —¿ —¿

2 1 —¿ 1

3 2 1 1

4 5 5 —¿

5 1 1 —¿

6 3 3 —¿

7 7 7 —¿

8 5 5 —¿

9 2 2 —¿

10 3 3 —¿

11 5 3 —¿

12 3 1 —¿

13 4 2 —¿

14 8 7 1

15 7 6 1

16 5 5 —¿

17 2 2 —¿

18 5 5 —¿

19 2 2 —¿

20 4 4 —¿

21 1 1 —¿

22 4 4 —¿

23 2 1 —¿

Anencephalic

Tr-esoph. fistula

Extra nipple

Hypospadias

Inguinal hernia Anencephalic

Absent distal pha langes of both great toes

24 1 —¿ —¿ Webbed toes, 2nd

and 3rd

25 1 1 —¿ —¿

26 3 2 —¿ Hypospadias

27 1 1 —¿ —¿

1 1

I I —¿

I I —¿

I I —¿

2 2 —¿ —¿

1 1 —¿ —¿

Total 95 81 6 9

changes in the precordial lead compatible with right ventricular enlargement.

Of the four spontaneous abortions, three were sent to the Department of Embry

30 33 34

35

Reference No.Number

of

CasesGesialionalWeek of RubellaGestational

R@alt Month of Rubella

TABLE III

CASES OMITTED FROM THE REVIEW OF THE LITERATURE ON PREGNANCIES COMPLICATED BY RUBELLA WITHIN THE FntsT 16 WEEKS

22141Stillbirth: congenital cardiac

lesion.272—1Therapeutic abortion.22152Family

lostsight of.28162Macerated

stillborn.24I62Not traced.26I62Died

age 5 weeks: certified cause pneumonia. Not examined

personally.23282Therapeutic abortion.232It)2Therapeutic

abortion.@7I—2Therapeutic

abortion.221123Missed

abortion: fetus died shortly after ru bella

infection.279—3Therapeutic

abortion.2510—1—3Lost

from study.2548—1—3Therapeutic

abortion.221134Family

lost sight of.241144At

3 years 5 months soft systolic murmur

heard. Diagnosed as “¿possiblemild grade pulmonary

stenosis.―261144Mongolism.261164Stillbirth:

no specificcausefound at necropsy.243——Therapeutic

abortion.

one'° was excluded because of the inclusion of retrospectively-collected cases. Others'@1@

were eliminated because of lack of published information pertaining to the timing of rubella and the follow-up examination of offspring. Some 17-19were not included because the diag nosis of rubella was not made by a physician

in most of the cases. Two20'2' were eliminated because the cases were included in subsequent reports.

Six reports were used in the present sum

mary.22-279 Only live-born infantsf resulting from pregnancies complicated by rubella within the first 16 weeks from the first day of

the last menstrual period were included. Our experience indicates that stillbirths in general have an unusually high incidence of malfor mations4 and many of these can be detected only at necropsy. The effect of maternal rubella on rates of abortion and stillbirths requires

more extensive and intensive investigation. Clinically, the malformation risk among live

° We wish to thank Dr. Greenberg for supplying

us with the monthly breakdown of his previously re ported cases.

t This includesneonataldeaths.

born infants is an important figure.

Cases with inadequate follow-up were also

excluded. Also one infant with mongolism26 was excluded because of the improbability of a causal relationship with maternal infec tion.28—30

In another situation, with the information available, we were not able to determine

whether the child was normal or abnormal.24

The cases omitted from this review are listed in Table III.

The reviewed cases are presented in Table IV and summarized in Table V.

Results

This combined prospective series was analyzed according to the frequency of mal formations among live-born infants result ing from pregnancies complicated by ru bella, and the number of malformations per affected child.

26252Normal23162Congenital

heart, multiple facial anomalies23162Harelip-cleft

palate, congenital heart24I62Bilateral

cataract, microcephalyFLS162Patent

ductus arteriosus22,

23, 24,

26462NormalFLS172Cardiac

anomaly, microcephaly22,

26272Normal23182Bilateral cataract24182Megalocornea

with atrophy of iris, patent ductus arteriosusFLS182Patent

ductus arteriosus22,

‘¿23,24,26,

FLS68‘2Normal2714—2Normal24193Neonatal

death. Necropsy showed cardiac defects: ab normal division of truncus arteriosus, tricuspid atresia and patent interventricular

septum.22,

23, 24, FL$10103Normal (FLS-Twins)22,

26,

FLS5II3Normal221123Neonatal

death. Died 3 days. Congenital cardiac lesions.231123Harelip-cleft

palate22, 23, 24,

FLS5123Normal2723—3Normal26I134Partial

bilateral deafness26,

FLS3134Normal22, 23, 24, 266144Normal22,

24, FIS4154Normal23,

244164Normal

TABLE IV

REVIEW OF PREGNANCIES COMPLICATED BY RUBELLA WITHIN THE FIRST 16 WEEKS RESULTING IN LIVE-BORN INFANTS

(;e.vtationai Number (If

Reference No. (‘ares Week of Rubella

Gestational Month of Rubella

Resu!t

22

22

22, 26, FLS*

26

26 26 26 25 25 25, 26

1 Bilateral cataract, microphthalmus, thromhocytopenic purpura

1 1 1 Cataract of right eye

5 1 1 Normal

1 2 1 Bilateral cataract, harsh systolic murmur over precord ium. Per hospital: “¿suggestiveof ventricular septal de fect.― Died 3 mo, cause congenital heart (lisease. No necropsy.

3 1 Bilateral cataract, microphthalmus

1 3 1 Normal

1 4 1 Patent interventricular septum, severe bilateral deafness ‘¿2 4 1 Bilateral cataract, congenital heart disease. (Twins)

4 1 Bilateral cataract, microphthalmus

3 4 1 Normal

* Fetal Life Study.

formation rate appears to decline inversely to the duration of the pregnancy at the time of the rubella infection. Among live-born

infants resulting from pregnancies compli

cated by rubella in the first 4 weeks, there

was an incidenceof 47% (8/17);in the fifth

Reference No.Gestationat

Time of Maternal Rubella1stMonth

P2nd 3rd4th1—4Weeks

5—8 9—1213—1622

23 24 25 26

27

FetalLifeStudy2/4* 0/0 0/0 3/5 3/7

0/0

0/10/3

1/4

3/6 1/8

2/4 1/4

0/12 0/14

0/5 0/2

0/2 0/9

3/4 0/50/3

0/3 0/5

—¿

1/5

—¿

0/2Total8/17

(47%)8/36

3/46

(22%) (7%)1/18(6%)

congenital heart lesions as single malforma tions weights these figures.

Table VII presents a summary of specific malformations found in live-born infants in relation to the time of maternal rubella.

DISCUSSION

The association of maternal rubella and congenital malformations is now generally accepted. However, malformation rates ranging from 7 to 70% have recenfly been re ported for the first trimester.19'2' Table V suggests that difference in incidence by month of gestation is great enough to vary first trimester rates, depending on the fre

quency distribution of the study population during this time. Clarification of this re lationship will require further prospective observations and more accurate technical definitions.

A prospective approach is fundamental in eliminating bias in case selection. Observa tions may begin either with the pregnancy which may later be complicated by rubella, or with the diagnosis of rubella which may be complicating a pregnancy. Ideally, in either event, all observations should begin before the pregnancy terminates, whether in an abortion, stillbirth or live-born in fant. If pregnancies complicated by rubella are tabulated only at term, early abortions and stillbirths will not be noted. Further more, a large number of therapeutic abor tions in a study population will also add bias, as it would tend to eliminate those in which the rubella was a definite and early complication of pregnancy. Since the attack rate of rubella during pregnancy is low, most of the published prospective observa tions have begun with the diagnosis of ru bella rather than pregnancy. Although this has been a more efficient approach, it has not provided adequate control observations of pregnancies not complicated by rubella.

Documentation of the diagnosis of rubella (the cause) and of the presence of malfor mations (the effect) is also an important consideration in evaluating the risk. A phy sician, for study purposes, diagnosing ru TABLE V

SUMMARY TABLE OF THE FREQUENCY OF MAL FORMATIONS AMONG LIVE-BORN INFANTS

RESULTING FROM PREGNANCIES COM PLICATED BY RUBELLA

* Number malformed/lolal live births.

in the thirteenth through sixteenth weeks, 6% (1/18).° In a recent review of some of

the prospective studies summarized here,

Hill26 found similar malformation rates for the first months of pregnancy. Other inves tigations have not found this trend.'9'3' However, the data are not comparable.

The relationship between the number and type of individual malformations and the duration of pregnancy at the time of the rubella infection is presented in Table VI. When multiple cardiac anomalies occurred, they were considered as single malforma tions. Using this approach, 32 malforma

tions were found among the 20 affected live

born children, 8 having one anomaly and 12 having two. Table VI reveals that double malformations were more commonly associ ated with early maternal rubella than were single malformations. The arbitrary classi fication of bilateral cataracts with microph thalmia as double malformations and all

* Among 5,638 live-births and neonatal deaths in

the FetalLife Study (1946-1953),7.4% of the infants

Osa MALFORMATION

1 Cataract right eye― 1

Totals 16

Patent ductua ar- 1

teriosusFLS*

8 Patent ductus ar teriosus@18 1 8 Bilateral cataract― I

39

Cardiac defects― 1

19 harelip-cleft pal- 1

ate―

12 Congenital cardiac 1 lesions―

313

Partial bilateral 1 dealness―

1Two

MALFORMATIONS 1 Bilateral cataract 1

Microphthalmus―

S Bilateral cataract 1 Microphthalmua'S

4 Bilateral cataract I Microphthalmus―

2 Bilateral cataract I

Congenital heart―

4 Bilateral cataract 2 Congenital heart―

4 Patentinterventric

ular septum I Severe bilateral

deafness―

Totals 76

Congenital heart I Multiple facial

anomalies―

6 Congenital heart I

Harelip-cleft pal

palate―

6 Bilateral cataract I

Microcephaly―

7 Cardiac anomaly I

Microcephaly9'@

8 Megalocornea with atrophy of iris 1 Patent ductus ar

teriosus3'

5Total

malformations 13 Total affected infants 8 Total normal infants 913

8 283

3 431

1 17

206 1@UBELLA

TABLE VI

MALFORMATIONS PER LIVE-BORN INFANT BY TIME OF MATERNAL RUBELLA

Fourth Month or 1d—16 Gestational Weeks

(Jest. . Number

JJ'eek Malfi)rmat,on Infants

First Month or 1—4

Geatational Weeks

SecondMonth or 5-8

Gestational Weeks

Third Month or 9-12

Gestationsil Weeks

(Jest. . Number

Week Malformation Infants (Jest.

Ireek Malformahon Number (Jest.Infants Week Malformation Number_Infants

Fetal Life Study.

bella during pregnancy is performing a dif

ferent function from the physician making a clinical diagnosis and routinely reporting

an infectious disease—asis the patient diag

nosing herself and filling out a question naire. These influences may result in either over- or under-diagnosis of rubella. In this

regard, there was an interesting patient

(not included in this series) who was en

rolled in the Fetal Life Study in 1948 and delivered a child with congenital heart dis ease and cataract. Her interview records list a minor respiratory infection in the sixth

week of gestation. Retrospectively, both the

patient and her family physician recalled a rash, but a definite diagnosis was never made. On the other hand, another study of

pregnancies complicated by rubella25 cover ing the same geographic area and similar years (1949-1955), but beginning with re ports of maternal rubella, failed to record any of the cases found in the Fetal Life

Study which began its observations with

the pregnancy.

At present the diagnosis of rubella is en tirely clinical with the occasional aid of an

epidemic situation. No specific laboratory

confirmation is yet available. In fact, the basis of viral etiology of rubella rests pri marily on studies with animals and human volunteers.8'9 Furthermore, the definite pos

sibility of clinical confusion has arisen with the discovery of other agents giving similar

1stP2nd3rd4thMonthMonthMonthMonth(1—4(5—8(9—1P2(13—16Weeks)Weeks)Weeks)Weeks)Cardiac

anomalies462—Cataracts72——Microphthalmus3———Megalocornea

withatrophy

of iris—I——Deaf nessI——IHarelip-cleft palate—11—Multiple

facial anom

alies—I——Microcephaly—2——Totals151331

of deafness following pregnancies compli cated by rubella, but few cases were diag nosed within the first year. Jackson and Fisch3' found approximately 30% of the children resulting from pregnancies in which the rubella occurred within the first 16 weeks had auditory deficits. The subtle ties of mental retardation and dental anom alies also are not obvious early in life.

Geographic and temporal influences also must be considered. There is no evidence that the teratogenic effect of the rubella virus is constant in different areas and in different years, since strains of rubella virus cannot be detected and compared. Two longitudinal studies, the present Study (1946-1959) and that reported by Green berg (1949@1955),25 were simultaneously conducted in the New York City area. In both series the year 1955 appeared out standing. Eight of our 25 cases occurred in that year; this group included 3 of the 4 spontaneous abortions and all 3 of the mal formed infants in our series. The three anomalous offspring from Greenberg's series were also from the year 1955.

Other influencing factors may be the increased accuracy of diagnosis during epi demics, or chance variation due to the small sample.

CONCLUSIONS

More complete reporting of prospectively followed pregnancies complicated by ru bella is necessary. Important factors often missing are: the date of the last menstrual period, the method of documenting the diagnosis, the gestational week of the on set of rubella rather than the trimester, the duration of the pregnancy, the birth weight of the infant, and the duration of follow-up before classifying an infant as normal or abnormal.

Control populations also must be ob served to determine the incidence of mal formations in the general population.

Objective technical means of diagnosing rubella and comparing various strains of the virus must be developed before the diagnosis can be made with certainty and TABLE VII

SPECIFIC MALFORMATION IN RELATION TO TIME OF MATERNAL RUBELLA

teroviruses have been associated with ex anthems.'2 Preliminary investigation of ECHO 9 virus infection during pregnancy, utilizing serologic techniques, indicates no increase in the risk of malformation or fetal death.33

Many malformations are discovered only

the consistency of the teratogenic effects of different strains can be established.

SUMMARY

The Fetal Life Study (1946-1959) re corded 25 instances of rubella infection dur ing pregnancy. Exposure to rubella oc curred during 95 other pregnancies. The results of these pregnancies and the follow up of the infants is reported.

A summary of other prospective studies reported in the literature is also presented. The incidence and number of malforma tions per live-born child are discussed in relation to the time of maternal rubella during pregnancy. There appeared to be a decreasing risk of malformation in live-born infants from 47% (8/17) in the first 4 weeks, 22% (8/36) in the fifth through eighth weeks, to 7% (3/46) in the ninth through twelfth weeks. Although the trend appears to be definite, the Fetal Life Study and the six other studies summarized are quite diverse and the samples are small.

It is suggested that prospective observa tions be more completely reported and con trol observations also be made. There is dire need of objective laboratory techniques for the diagnosis of rubella.

Addendum

Since our request to Dr. Greenberg for addi tional information in June, 1959, a more com plete report of his cases has appeared in the literature (Siegel, M., and Greenberg, M.: Fetal death, malformation and prematurity after ma ternal rubella. Results of a prospective study, 1949-1958. New England J. Med., 262:389, 1960).

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PROSPECTIVE EXPERIENCE WITH MATERNAL RUBELLA AND THE

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