Develop. Med. Child Neurol. 1972, 14, 585-591

The Risk of Handicap due to Birth Defect in Infants of Very Low Birthweight

Ann Stewart

Introduction Rawlings and co-workers (197 1) have

recently reported an improved survival rate and prognosis for infants of very low birthweight (< 1.5kg) and suggested that this indicated that much of the long-term handicap observed previously in these children (Drillien 1967) would have been preventable with modern methods of care. If this interpretation was correct, it would suggest that the incidence of handicapping congenital malformations in these infants was not unduly raised. We have, therefore, examined our study group of very low birthweight infants (< I .5kg) born since 1966 and the records and autopsy reports of the children who died during the same period, in the Neonatal Unit of University College Hospital, London, to establish the incidence of birth defects and their effect on the long-term prognosis of the survivors of very low birthweight.

Study Population During the years 1966-70, 123 infants

of birthweight less than 1,501g were born in University College Hospital and were immediately transferred , without selection, to the Neonatal Unit. In addition, 72 other infants of birthweight less than 1,501g were admitted from hospitals in

the London area. Their admission was requested because the infants were of very low birthweight and were, therefore, con- sidered to require intensive care. Because of the particular interest of the staff of the Unit, it is likely that some of these infants were selected for the presence of respira- tory problems, both by those requesting the admission and those accepting it, but in general, acceptance depended princi- pally on the availability of a cot. The 195 infants to be studied were the result of 178 pregnancies (Table I), of which 148 were single and 30 were multiple births. These included sextuplets, two sets of trip- lets, twelve sets of twins, and thirteen infants whose co-twin either weighed more than 1 *5kg at birth or was not admitted, usually because it had been stillborn or had died too soon after birth for transfer from another hospital.

Ninety-eight of the infants survived more than twenty-eight days, 64 of them being University College Hospital born and 34 outside admissions, and are the subjects of a follow-up study of growth and development (Rawlings et al. 1971). The youngest survivor was born on November 1, 1970. The remaining 97 infants died, 89 within the first twenty- eight days of life, and eight later, but

Medical Research Council Human Biochemical Genetics Unit, The Galton Laboratory, University College, 4 Stephenson Way, London NW1.

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1972, 14

TABLE I Distribution of study population

Single pregnancies Multiple pregnancies All pregnancies 1 Totals I Survivors Deaths Survivors Deaths i Survivors Death

U.C.H. born .. . . 44 43 20 (12)* 16 (10) 64 (56) 59 (53) 123 (109) Outside admissions . . ~ ;: 1 ;: 1 4

24 (16) 23 (14) 98 (90) 97 (88) 195 (178) 1 7 (4) I 34 1 38 (35) 1 72 (69) 1 I Whole population . .

~~ ~

* Numbers in brackets refer to number of pregnancies where this differs from number of infants.

before the end of the first year of life. Transient abnormalities considered to be Thirty-eight (39 per cent) of the 98 sur- associated with immaturity were not con- vivors were non-Caucasian. There were no sidered to be birth defects. The samples of data about the ethnic groups of the infants urine were also examined to exclude who died. galactosaemia.

In addition to the initial clinical exami- Methods nation, 83 of the 97 infants who died (85

We have used the term ‘birth defects’ to per cent) had autopsies performed by Dr. include structural abnormalities and genet- Taghizadeh, and his reports were the source ically determined metabolic abnormalities of data for all 83 infants. Of the 14 infants present from birth. ‘Normal variants’ as on whom autopsy was not performed, defined by Marden et a!. (1964) were not eleven were infants of less than 27 weeks included except where two or more gestation who died shortly after admission variants occurred in the same infant. Such without any surface evidence of abnormal- an infant was considered to be abnormal ity other than immaturity. and was described as having ‘multiple minor abnormalities’. Cardiac murmurs Results without other evidence of congenital heart Twenty-six (13 per cent) of the 195 disease were not included, neither were infants had recognisable birth defects umbilical or inguinal hernias. Major (Tables I1 and 111). Sixteen of these infants defects were defined as those defects which survived and ten died. The birth defect was interfered with normal function and were considered to be a major one in eleven of further subdivided into those which were the 26 affected infants. Six of the seven remediable and those which caused perm- major defects in the dead infants were the anent malfunction or ‘handicap’. cause of, or contributed to the cause of

All infants were examined clinically on death. Two (2 per cent) of the 98 survivors admission to the Neonatal Unit and any had handicaps which were a consequence birth defects recorded in the case notes. of their birth defects. The handicaps in- Survivors were subsequently examined on cluded partial sight due to cataracts, discharge and at follow-up visits (Rawlings probably associated with mental retarda- et al. 1971). Thus, ‘birth defects’ include tion, and VI nerve paralysis due to D u h e s those defects diagnosed at birth and later. syndrome. Table I11 shows the distribution All survivors had samples of blood and of birth defects amongst infants born in urine examined by paper chromatography University College Hospital, and those for abnormalities of amino acid metabol- admitted from other hospitals, for both ism, with particular reference to phenyla- survivors and dead infants from single and lanine, tyrosine, leucine and isoleucine. multiple pregnancies.

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ANN STEWART

TABLE I1 Birth defects

Minor defects: Naevus .. .. . . . . Skin defect. . . . .. . . Plagiocephaly . . . . .. Spindle fingers . . . . . . Undescended testis . . . . Wardenburg’s syndrome . . . . Multiple minor defects . . . . Horseshoe kidney . . . . . . Squint (without eye abnormality)

-

.. . . . . .. .. . . .. . . . .

Major defects: Squint with paralysis (Duines) . . . . Cataracts with mental retardation . . Cleft lip and palate . . . . . . Cong. heart disease-alone . . .. Cong. heart disease-with abnormal brain Malrotation of the gut . . . . . . Hypospadias . . . . . . . . Potter’s syndrome . . Down’s syndrome and duodenal’atresia Perforation of the colon . . . . ..

U.C.H. born ~ Outside admission

Deaths Deaths

(M) signifies that the infants resulted from multiple pregnancy; (H) signifies handicapping defect.

Twenty-five (13 per cent) of the study population had birth weights below the 10th percentile on Lubchenco’s grid (Lub- chenco et al. 1963) and were therefore classified as ‘light for dates’ (LFD). The 20 surviving LFD infants were the result of 13 single and 7 multiple pregnancies, and included two members of the sextuplets. Thus, 20 per cent of the group of 98 survivors in this study population were LFD. Four of the five LFD infants who died were the result of single pregnancies, and one was a member of a twin pair. Seven (28 per cent) of the LFD infants had birth defects. Four of these infants survived, including one who had cataracts and mental retardation, another who had multiple malformations, namely facial skin tags, micrognathns and strawberry naevi, and two who had major but remed- iable defects (cleft lip and palate and hypospadias). The three LFD infants who died were considered at birth to have

multiple birth defects. However, birth defect was the cause of death in only one of these infants, who was found at autopsy to have a perforation in an abnormal colon.

Birth defects were recorded in the case notes of 42 (3 per cent) of the 1,500 infants weighing more than 2-5kg, born in University College Hospital during 1969. Twenty-one (1.5 per cent) of these were major defects.

Discussion Thirteen per cent of the group of very

low birthweight infants under study had recognisable birth defects. This figure does not differ significantly (p = 0.15) from the incidence of 9 . 1 per cent reported by Yerushalmy et al. (1965) in their low- birthweight group (< 1.6kg). Thirty-nine per cent of the survivors were non- Caucasian and included all other ethnic groups. There are few data on the com- parative incidence of birth defects amongst

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1972, 14

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ethnic groups, but it is likely that, for all birth defects, it does not differ significantly (Chung et a/. 1968, Stewart el a/. 1969), although ethnic (Chung et al. 1968) and regional variations have been reported in the incidence of specific defects, such as polydactyly and those due to neural tube anomalies (Stevenson et al. 1966). Six (38 per cent) of the sixteen birth defects in our survivors occurred in non-Caucasians, which suggests that the ethnic composition of our group has not affected the overall incidence of birth defects.

The only available control data for our group were derived from a retrospective search through the case notes. Three per cent of the 1,500 infants weighing more than 2.5kg who were born in University College Hospital in 1969 were reported to have a birth defect, suggesting a consid- erable excess of birth defects in the very low birthweight group. However, Kennedy (1967), in a review of the world literature on the incidence of congenital malforma- tions, showed that the reported incidence depended on the method of ascertainment. He showed that when some form of direct examination of the infant was made, the incidence was three times greater than that calculated from retrospective examination of hospital records. He also quoted the unique study reported by McIntosh el al. (1954) who found that the incidence of malformations doubled when the study population was re-examined at age one year. It would therefore be meaningless to compare the data from a repeatedly examined group of infants who have undergone intensive care and subsequent detailed follow-up or autopsy, with those derived retrospectively from the case notes of potentially normal infants who were not all re-examined after leaving hospital. It appears more reasonable to examine the potential of the recorded birth defects to affect prognosis and to evaluate this as a ‘risk factor’ similar to hyaline membrane

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ANN STEWART

disease or disseminated intravascular co- agulation.

Eleven (6 per cent) of our study group of 195 very low birthweight infants had sericus birth defects potentiaIIy capable of affecting prognosis. Seven of these died and in six the defect was the cause of death. Six per cent of the 97 deaths in the group were therefore due to birth defects. However, of the four survivors with serious birth defects, two were com- pletely remediable (cleft lip and palate, and hypospadias), leaving two infants (or 2 per cent of the 98 survivors) with handi- caps due to birth defects. One of these (in a LFD infant) is serious, and as a conse- quence the child will require special schooling.

The incidence of birth defects did not differ significantly in either the survivors (p=0.2) or deaths (p=0.2) between those born in University College Hospital and those admitted from other hospitals. Thus, the incidence of handicapping birth de- fects in this group of 98 very low birth- weight (< 1.5kg) survivors is only 2 per cent.

The collection of a larger series of infants of birthweight < 1 * 5kg presents considerable difficulties, as only one per cent of the total newborn population of University College Hospital, London (and < 1 per cent in the series reported by Yerushalmy ef al. (1965)) are of such very

low birthweight. It therefore seems reason- able to examine the incidence of handicap due to birth defect in our 98 survivors of very low birthweight in order to discover why it differs from that reported by earlier workers. The overall incidence of abnor- mality in the University College Hospital survivors is < 15 per cent (Rawlings et al. 1971, Stewart 1972). This figure may be compared with an incidence of > 40 per cent (Drillien 1969) for the infants of birthweight < I .5kg referred to in the earlier reports (Drillien 1965, 1968). If, as has been suggested (Rawlings el al. 1971) this difference is due to the introduction of modern methods of postnatal care, the majority of abnormalities previously ob- served must have been acquired after birth. The relatively low incidence of handicap due to birth defect (2 per cent) reported here is in agreement with this suggestion.

Acknowledgements: It is a pleasure to acknow- ledge the help and encouragement that Prof. L. B. Strang and Dr. E. 0. R. Reynolds have given during the preparation of this report, in addition to allowing me to study the infants and case records in their care. I am also grateful to Dr. Taghizadeh for the autopsy reports and to Dr. D. Cusworth for the reports on the plasma and urinary amino acid chromatograms. Finally, I should like to thank Sister J. March and her staff in the Children’s Outpatient and Records Depart- ment, and Sister L. M. Collins, Sister J. Langham, Sister A. Blake and Sister M. Rowlands and their staff in the Neonatal Unit, all of University College Hospital, without whose help this report would have been impossible.

SUMMARY

The relationship between birth defects (congenital malformations and genetically determined metabolic errors) and long-term handicaps has been examined in a group of 195 infants of very low birthweight (< 1.5kg). The overall incidence of birth defects in the whole group was 13 per cent. The incidence was 16 per cent in the 98 survivors and 10 per cent among the 97 infants who died. Two per cent of the survivors had long-term handicaps due to a birth defect. Thus, contrary to earlier suggestions, birth defect did not appear to be a major cause of long-term handicap in this group of infants of very low birthweight.

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1972, 14

RGSUMI~ Risque de handicap par anornalie de naissance chez les enfants de trPs faible poids de naissance

La relation entre anomalies de naissance (malformations congknitales et erreurs mCta- boliques d’origine genCtique) et handicap A long terme a Ctt CtudiCe sur un groupe de 195 enfants de t r b faible poids de naissance (moins de 1,5 k) La frkquence des anomalies de naissance dans le groupe entier ttait de 13 pour cent. Elle Ctait de 16 pour cent chez les 97 survivants et 10 pour cent chez les enfants qui moururent. 2 pour cent des survivants prisenthrent des handicaps a long terme liCs aux anomalies de naissance. Ainsi, contraire- ment aux suggestions antkrieures, les anomalies de naissance ne semblent pas &tre une cause majeure de handicap dans ce groupe d’ enfants de trks faible poids de naissance.

Z USAM MENFASS UNG Das Risiko einer Schadigung auf Grund eines Geburtsschadens bei Kindern rnit sehr niedrigem

Geburtsge wicht Bei einer Gruppe von 195 Kindern mit sehr niedrigem Geburtsgewicht (1,5 kg) wurde die

Beziehung zwischen Geburtsschaden (angeborene Mi Bbildungen und genetisch bedingte metabolische Defekte) und Dauerschadigungen untersucht. Bei 13 Prozent dieser Gruppe kamen Geburtsschaden vor. Von den 98 Uberlebenden waren es 16 Prozent und von den 97 Verstorbenen 10 Prozent. 2 Prozent der uberlebenden zeigten Dauerschadigungen bedingt durch einen Geburtsschaden. Entgegen fruherer Behauptungen scheinen also Geburtsschiiden bei diesen Kindern mit sehr niedrigem Geburtsgewicht kein Hauptgrund fur Dauerschadigungen zu sein.

RESUMEN

El riesgo de rninusvalia debida a un defecto de nacirniento en nifios con un peso de nacirniento muy bajo

En un grupo de 195 niiios de un peso de nacimiento muy bajo (< 1,5 kg) se ha examinado la relacion entre defectos de nacimiento (malformaciones conghitas y errores metabblicos gentticamente determinados) y minusvalias a largo plazo. La incidencia global de 10s defectos de nacimiento en todo el grupo fue del 13 por ciento. La incidencia fue del 16 por ciento en 10s 98 supervivientes y 10 por ciento en 10s 97 que murieron. Dos por ciento de 10s supervivientes tenian minusvalias a largo plazo debidas a un defecto de nacimiento. Asi pues, contrariamente a sugestiones anteriores, el defecto de nacimiento no aparece como una causa mayor de minusvalia a largo plazo en este grupo de niiios de muy bajo peso de nacimiento.

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ANN STEWART

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