34 Williamson et al., Neurodevelopmental outcome

J. Perinat. Med.10 (1982) 34

Early neurodevelopmental outcome of low birth weight infantssurviving neonatal intraventricular hemorrhage*

W. Daniel Williamson, Murdina M. Desmond, Geraldine S. Wilson, Leora Andrew,Joseph A. Garcia-Prats

From the Sections of Developmental Pediatrics and Neonatology,Department of Pediatrics, Baylor College of Medicineand the Leopold L. Meyer Center for Developmental Pediatrics,Texas Children's Hospital, Houston, Texas

1 Introduction

Neonatal intraventricular hemorrhage has emergedäs one of the most important and frequently en-countered lesions in the central nervous System ofthe prematurely born infant [1]. Intraventricularhemorrhage is known to contribute significantly toneonatal mortality and morbidity. However, in-formation regarding its effects on the long-termoutcome of survivors is limited. This report de-scribes the early neurodevelopmental Status oftwenty-eight low birth weight infants survivingsymptomatic neonatal intraventricular hemorrhagedocumented by computerized tomography andrelates outcome to gestational age and grade ofhemorrhage based on severity and location [2].

2 Subjects and methods

2.1 Subjects

Subjects were low birth weight infants with doc-umented intraventricular hemorrhage (IVH) caredfor in the Neonatal Intensive Gare Unit (NICU) ofTexas Children's Hospital (TCH) between Januaryl, 1977 and December 31, 1978. Computerizedtomography (CT) to diagnose intraventricularhemorrhage was carried out in the presence of the

This manuscript was presented at the Perinatal Intra-cranial Hemorrhage Conference December 13, 1980Washington, D. C.

Curriculum vitae

w. DANIEL WILLIAM-SON, born in 1948, re-ceived both his B. S. in ed~ucation and M. D. frontLouisiana State University.Fottowing his pediatrictrainingat the Medical Uni-versity of South Carolina,he had two years offellow-ship training in develop-mental pediatrics withMURDINA M. DESMOND,Baylor College of Medicine, Houston. He remains on thefaculty there. His major interests include follow-up ofpremature infants surviving intraventricular hemorrhageand infants with congenital infections, äs well asdevisingeducational programs for handicapped children. Dr. WIL-LIAMSON was the 1978-80 WATCH-Mary ElizabethPatton Fellow in Pediatrics, Subspecialty Studiesf TexasChildren 's Hospital

following findings: unexpected fall in hematocrit,tense anterior fontanelle, unexplained deteriora-tion in respiratory or metabolic Status, apnea/bradycardia, change in activity level Or tone, sei-zures, and blood in the cerebrospinal fluid. Theroutine scanning of all low birth weight infantswas not practiced.During the period covered by this report, the in-cidence of intraventricular hemorrhage docu-mented by CT scan in infants of birth weightsbelow 1,500 grams was 41%. The survival rate ofall infants with documented IVH was 44%.

0300-5577/82/0010-0005$02.00© by Walter de Gruyter & Co. · Berlin · New York

Williamson et al., Neurodevelopmental outcome 35

During the study period, thirty-five prematureinfants weighing less than 2,000 grams survivingIVH confirmed by CT scan were cared for in theNICU. Of the thirty-five, two were excludedfrom this study because of concomitant con-genital infections (rubella, Listeria), three (oneseverely handicapped) were lost to follow-up aftersix months because of family relocation and twowere not seen following nursery discharge. Theremaining twenty-eight children (85% of thoseeligible) constitute the study group who enrolledfor longitudinal follow-up in the Leopold MeyerCenter for Developmental Pediatrics, Texas Chil-dren's Hospital.The TCH nursery is a regional referral Level IIIunit and only three of the study patients were in-born. APGAR scores ranged from l to 8 (median5) at one minute and 4 to 9 (median 6) at fiveminutes. All infants were initially referred to theNICU for management of respiratory distress. Allbut one (Patient No. 3) required mechanicalVentilation.The mean gestational age for the group was 28.9weeks (ränge 25 to 35 weeks) and mean birthweight was 1,179 grams (ränge 700 to 1,930grams). Seventeen infants were male and elevenwere female. Paternal social class (HOLLINGS-HEAD'S classification) [3] was distributed äs fol-lows: 27% - Class II, 31% - Class III, and 42% -Class IV.The postnatal age at which intraventricular hemor-rhage was clinically suspected ranged from one toten days. The mean age when computerized tomo-graphy was performed to confirm the hemorrhagewas six days; all but one infant (Patient No. 17)was scanned at least once during the first fourteendays of life. The extent of hemorrhage on CT scanwas graded using the system of PAPBLE et al. [2]:Grade I — supependymal hemorrhage, Grade II —intraventricular hemorrhage without ventriculardilatation, Grade III - intraventricular hemorrhagewith ventricular dilatation, and Grade IV — intra-ventricular hemorrhage with parenchymal hemor-rhage.

2.2 Methods

The follow-up consisted of neurologic and devel-opmental assessments done at the ages of three,

six, nine, eighteen, and thirty months by a multi-disciplinary team. This report describes the find-ings noted at the patients7 visits between thirteenand thirty-four months Chronologie age (mean19.7 months). The outcome categorizations (nor-mal, suspect, abnormal) assigned after these assess-ments were based on neurologic and developmen-tal functioning.Neurologic fmdings classified äs suspect includedmild disturbances of muscle tone, coordination ormotor development, delayed language skills, shortattention span or increased motor activity [4, 5].Neurologic findings categorized äs abnormal wereblindness, hearing loss, hydrocephalus, cerebralpalsy and seizure disorder.Developmental performance was assessed utilizingthe GESELL Developmental Schedules [6] for in-fants under eighteen months corrected age or theBAYLEY Scales of Infant Development [7] forolder infants. (Two children were assessed byother measures. See Tab. I.) The GESELL Adap-tive Developmental Quotient (DQ) was scaled äsfollows: 1) normal, > 85,2) suspect, 75 to 84, or3) abnormal, < 74. The BAYLEY Mental Index(MDI) was ranked äs follows: 1) normal, > 84.2)suspect, 68 to 83, and 3) abnormal, < 67.A child considered "normal" had a normal neurol-ogic examination äs well äs a normal develop-mental assessment for corrected age. The term"multihandicap" indicates the child had bothsignificant developmental delay and abnormalneurologic findings.

3 Results

3.1 Neurologic and developmental Status

Individual clinical findings are summarized inTab. I.Cerebral palsy was noted in nine infants(32%). Seven of these had quadriparesis, one haddiplegia, and one had hemiparesis correlating withan area of porencephaly.Post-hemorrhagic hydrocephalus developed ineight infants. Seven required shunting procedures.(Patient No. 25 developed ventricular dilatation atsixteen months of age, but has not yet requiredshunting.) Three infants with shunts (PatientNo. 17, 22, 24) later demonstrated microcephaly.

J. Perinat. Med. 10 (1982)

36 Williamson et al., Neurodevelopmental outcome

Tab. I. Low birth weight infants surviving IVH: Relation of clinical findings to grade of.hemorrhage, birth weight andgestational age.

GradeoflVH

I

II

III

IV

CaseNo.

12

3456

7

8

910

11

12

1314

15

16

17

1819

20

2122

23

24

25

262728

Birthweight(Gras.)

7001510

10151060980800

1260

1320

12001260

1500

1330

15901360

700

1320

1330

9001023

1930

1320760

1180

1070

1060

12501360930

Gest.age(Weeks)

2729

26262728

30

30

3032

32

31

3528

26

27

28

2828

34

2825

27

28

30

303l"29

Agelast seen(Months)

1420

21181514

19

20

1320

26

19

2124

24

34

18

2125

18

2218

19

21

19

161419

Neurologic findings

Blind, spastic quadriparesis

Spastic quadriparesisAsymmetrie tone; delayedfine motor and language skillsShort attention span; delayedfine motor skillsShort attention span; delayedfine motor and language skills

Delayed fine motor andlanguage skillsHydrocephalus with shunt;delayed language skillsHydrocephalus with shunt;hypertonic lower extremities

Mixed Hearing loss;severe strabismusShort attention span; delayedfine motor skills; poorbalance; toe walkingBlind; spastic quadriparesis;hydrocephalus with shunt,infantile spasmsSpastic quadriparesisDelayed fine motor skills; mildhypertonic lower extremitiesHydrocephalus with shunt

Spastic diplegjaBlind; spastic quadriparesis;hydrocephalus with shunt,infantile spasmsBlind; quadriparesis, hydro-cephalus with shunt, infantilespasms ; neurosensory HearinglossHydrocephalus with shunt;spastic hemiparesisArrested hydrocephalus;generalized seizuresDelayed language skills

Spastic quadriparesis

DQ/MDI

<50107

13193

<5085

103

111

8197

98

84

113112

<50

95*

<50

93 .104**

100

108<50

<50

56

89

807150

Outcomecategory

.

Abnormal (MH)1*Normal

NormalNormalAbnormal (MH)1"Suspect

Suspect

Suspect

SuspectSuspect

Abnormal

Abnormal

NormalNormal

Abnormal (MH)1"

Suspect

Abnormal (MH)1*

AbnormalSuspect

Abnormal

AbnormalAbnormal (ΜΗ)1*

Abnormal (MH)1"

Abnormal (MH)1*

Abnormal

SuspectAbnormalAbnormal (ΜΗ)1"

* McCarthy General Cognitive Index** Stanford-BinetLQ.MHT Multihandicap J. Perina t. Med. 10 (1982)

Williamson et al., Neurodevelopmental outcome 37

24

28 32 3640Gestational Age

10 20 30 40 60 80 100Age, weeks

Fig. 1. Measurement of head circumference demonstrating occurrence of microcephaly following post-hemorrhagehydrocephalus in low birth weight infant with Grade III intraventricular hemorrhage (Patient No. 22) [13a].

The occurrence of microcephaly in a patient withearlier, shunted post-hemorrhagic hydrocephalusis illustrated by the head circumference curve ofPatient No. 22 (Fig. 1). Three of the eight withhydrocephalus had no other major neurologic ordevelopmental abnormalities, and a fourth had ageneralized seizure disorder but normal develop-ment. The remaining four infants with hydro-cephalus were multihandicapped. Three of thesedeveloped infantile spasms beginning at five, eightand nine months Chronologie age.Neurosensory deficits included blindness second-ary to cicatricial retinopathy of prematurity infour infants and hearing loss in two. (One infantwas both deaf and blind.)Seventeen patients (61%) had developmentalquotients within the normal ränge and two (7%)in the suspect ränge. Nine (32%) showed delayeddevelopment; eight of these were multihandi-capped.On the basis of both neurologic examination anddevelopmental testing, five infants were considerednormal and eight suspect (Tab. II). Fifteen infantswere abnormal; eight of these were multihandi-capped.

3.2 Social and economic impactThe stresses experienced by the families during thefollowup period were intense and cumulative.

Tab. II. Short term outcome related to grade of IVH in28 low bkth weight infants assessed at mean age of 19.7months.

Outcome

NormalSuspectAbnormal(Multi-handicap)Total

No. patientsGrade IVHI II III

1 4 00 5 21 3 4

(D (D (2)

2 12 6

IV

b17

(4)

8

TotalNo.

58

15(8)

28

Per-cent

18%28%54%

(28%)

They appeared related to many factors, i.e. theearly birth, the prolonged nursery stay (mean 74days, ränge 42—141), the many medical problemsfollowing nursery discharge and the high costs ofnursery hospitalization (initial costs ranging from$ 25-125,000). Subsequent rehospitalizationswere not uncommon — to date sixteen of thetwenty-eight infants have required thirty-threerehospitalizations.The impact of these survivors on the Communitymay be illustrated by the referral during infancyof thirty-six percent (ten of twenty-eight) of thestudy population to Intervention programs inCommunity agencies. These infants will also

J. Perinat. Med. 10 (1982)

38 Williamson et al., Neurodevelopmental outcome

qualify for special education in public school atage three in accordance with Public Law 94-142(Education for All Handicapped Children's Act)[8].

3.3 Clinical correlations

In this study, two flndings were signiflcant. First,the incidence of abnormal outcome was signifi-cantly higher among infants with Grade III or IVhemorrhage (79%) than among infants withGrade I or II hemorrhage (29%) (X2 with Yatescorrection = 5.166; .01 <P < .025). Second, themean gestational age of the eight multihandi-capped infants (27.0 weeks) was significantly lessthan that of the remaining twenty infants (29.7weeks) (STUDENT'S t Test: t = 3.754; .001 <P<.01; two-tailed significance level).The incidence of abnormal outcome in infantswith birth weights below 1,000 grams was high(86%) regardless of grade of hemorrhage. Ab-normal outcome for infants with birth weightsgreater than 1,000 grams appeared to be moredirectly related to the grade of hemorrhage thanto birth weight. (Abnormal outcome in infantswith birth weight greater than 1,000 grams: 0%(0/1) Grade I, 20% (2/10) Grade II, 50% (2/4)Grade III, 83% (5/6) Grade IV.) These trendscould not be statistically correlated because of thesmall sample size.

4 Discussion

Although intraventricular hemorrhage is generallyconsidered to be a major contributor to the neo-natal morbidity and mortality of very low birthweight infants, its specific association with out-come in survivors is only sparcely documented inthe literature [9,10]. The single detailed report onearly outcome related to grade of hemorrhageappearing in the literature to date is that ofKRISHNAMOORTHY et al. [9], who report a seriesof fifteen infants, eighty percent of whom hadlesser degrees of hemorrhage (Grade I or II). Themean gestational age for the group was 32 weeks.Our study group, in contrast, is equally divided

between those with sevQip hemorrhage (GradesIII/IV) and those with less severe grades (GradesI/II) and has a lower mean gestational age (28.9weeks).In the present study, infants with Grades I and IIhemorrhage had significantly better early outcomethan those with Grade III or IVhemorrhage,a find-ing consistent with that of KRISHNAMOORTHY.Our study indicates that poorest outcome (multi-handicapped Status) is also related to extremeprematurity (gestational age < 27 weeks).Four clinical findings in this study are of specialnote. First, the outcome of infants with post-hemorrhagic hydrocephalus appeared more di-rectly related to gestational age and to initial gradeof hemorrhage than to the presence or absence ofhydrocephalus itself. Second, head growth dimin-ished rapidly in three patients who had earliershunted hydrocephalus, with the eventual develop-ment of microcephaly. Third, blindness secondaryto cicatricial retinopathy of prematurity (ROP)occurred in 14% of our patients, a high incidencefor low birth weight infants in general [11]. Anassociation between cicatricial ROP and IVH hasbeen suggested, which may account for the highincidence noted in this study [12]. Fourth, in-fantile spasms emerged during the follow-upperiod in three of our patients, a finding not pre-viously reported in IVH survivors. Since eachinfant was of low birth weight and experiencedsignificant perinatal asphyxia (factors previouslyconsidered predisposing to infantile spasms) [13],a direct association between IVH and infantilespasms cannot be presumed.Although forty-six percent of the study groupwere categorized äs normal or suspect and did notdemonstrate statte abnormalities when last eva-luated, they will remain at risk for perceptual-motor deficits, motor clumsiness, and disorders ofattention, learning/language, and behavior [14-18]. It is possible that these disorders, whichreportedly have a high incidence in prematureinfants, may in part be residua related to theoccurrence or secondary effects of earlier intra-ventricular hemorrhage. Only the long-term fol-low-up of survivors can clarify this point.

J. Perinat. Med. 10 (1982)

Williamson et al., Neurodevelopmental outcome 39

Summary

This article reports the follow-up findings in ·28 pre-terminfants who survived symptomatic neonatal intraventricu-lar hemorrhage and were cared foi in the Neonatal Inten-sive Gare Unit of Texas Children's Hospital, Houston.The severity of hemorrhage noted on CT scan was gradedusing the system of PAPILE, et al. [2].The mean gestational age for the group was 28.9 weeks(ränge 25 to 35 weeks) and mean birth weight was 1,179grams (ränge 700 to 1,930 grams). Seventeen infantswere male and eleven were female. Paternal social class(HOLLINGSHEAD's classification) was distributed äsfollows: 27% class II, 31% class III, and 42% class IV.Follow-up consisted of neurologic examination andmultidisciplinary developmental assessment. The outcomecategorizations (normal, suspect, abnormal) were basedon both neurologic and developmental functioning. Achild considered "normal" had a normal neurologicexamination and developmental function within thenormal ränge for corrected age. The term "multihandi-capped" indicated both significant developmental delayand abnormal neurologic findings.At a mean age of 19.7 months, five infants were con-sidered normal (18%), eight suspect (28%), and fifteenabnormal (54%). (Tab. II). Eight abnormal infants were

multihandicapped. Cerebral palsy was noted in nineinfants (32%). (Tab. I). Post-hemorrhagic hydrocephaluswas noted in eight; seven required shunting. Three infantswith shunts later demonstrated microcephaly. (Fig. 1).Three developed infantile spasms. Neurosensory deficitsincluded blindness (secondary to cicatricial retinopathy ofprematurity) in four infants and Hearing loss in two. Atleast one-third of the study group will require specialeducation by age three years.Two significant findings emerged in this study. First, theincidence of abnormal outcome was higher among infantswith Grades HI and IV hemorrhage (79%) than amonginfants with Grades I or II hemorrhage (29%) (.OK P <.025). Second, the mean gestational age of the eightmultihandicapped infants (27.0 weeks) was significantlybelow that of the remaining twenty infants (29.7 weeks)(.001 < P < .01).Although forty-six percent of the study group did nothave static abnormalities when evaluated, they remain atrisk for disorders of language, learning and behavior.Longterm follow-up of these infants is planned to deter-mine if these disorders may, in part, be related to theoccurrence or secondary effects of earlier intraventricularhemorrhage.

Keywords: Infantile spasms, intraventricular hemorrhage, very low birth weight infants.

Zusammenfassung

Neurologische Komplikationen und Entwicklungsstörun-gen bei Kindern nach überlebter neonataler Ventrikelblu-tungWir berichten über die Nachuntersuchungen an 28 Früh-geborenen, die eine neonatale Ventrikelblutung überleb-ten und in der Intensivüberwachungseinheit des Texas

Chüdren's Hospital, Houston, behandelt wurden. DerUmfang der Ventrikelblutung wurde computertomogra-fisch festgestellt und nach dem Schema von PAPILE etal. klassifiziert [2].Das mittlere Gestationsalter in dieser Gruppe lag bei28.9 Wochen (25 bis 35 Wochen), das mittlere Geburts-gewicht bei 1179 g (700 bis 1930 g). 17 Kinder warenmännlich, 11 weiblich. Die Aufteilung in soziale Klassennach HOLLINGSHEAD ergab: Klasse II 27%, Klasse III31%, Klasse IV 42%.Die Nachuntersuchung bestand aus neurologischen Prü-fungen und multidisziplinären Entwicklungstesten. Beider Kategorisierung (unauffällig, suspekt, auffällig) wur-den sowohl die neurologischen Befunde wie auch die Er-gebnisse aus den Entwicklungstesten zugrunde gelegt.Ein als ,normaT eingestuftes Kind hatte einen unauffälli-gen neurologischen Status und befand sich entwicklungs-mäßig innerhalb der normalen Streubreite einer auf seinAlter bezogenen Vergleichsgruppe. Eine Mehrfachbehin-derung diagnostizierten wir, wenn sowohl eine signifi-kante Entwicklungsverzögerung wie auch ein auffälligerneurologischer Status vorlagen.

Mit einem mittleren Alter von 19.7 Monaten wurden5 Kinder (18%) als unauffällig, 8 (28%) als suspekt und15 (54%) als auffällig eingestuft (Tab. II). Bei 8 Kindernlag eine Mehrfachbehinderung vor, bei 9 Kindern (32%)eine Cerebralparese (Tab. I). 8 Kinder zeigten einen post-hämorrhagischen Hydrocephalus, 7 von ihnen brauchteneinen Shunt. Hiervon hatten 3 später einen Mikrocephalus(Fig. 1). Bei 3 Kindern entwickelten sich Spasmen.An neurosensorischen Störungen fand sich bei 4 Kinderneine Amaurosis infolge der narbigen Retinopathie undGehörverlust bei 2 Kindern. Schließlich benötigte einDrittel unser Untersuchungsgruppe eine spezielle erzie-herische Betreuung ab dem 3. Lebensjahr. Unsere Unter-suchung zeigt 2 bedeutsame Fakten:1. Unter den Kindern mit Hämonhagien vom Typ III undIV war die Komplikationsrate mit 79% wesentlich höherals in der Gruppe mit Hämorrhagien vom Typ I und II,wo sie bei 29% lag (0.01 < p < 0.025),2. Das mittlere Gestationsalter bei den 8 mehrfach Be-hinderten lag mit 27 Wochen deutlich unter dem mittle-ren Gestationsalter der übrigen 20 Kinder, das mit 29.7Wochen anzugeben ist (0.001 < p < 0.01). Auch wenn46% der Kinder zum Untersuchungszeitpunkt keine sta-tomotorischen Auffälligkeiten zeigten, tragen sie ein ho-hes Risiko, Sprach-, Lern- und Verhaltensstörungen zuentwickeln. Eine Langzeituntersuchung ist geplant, umletztlich bestimmen zu können, ob die Störungen als di-rekte Folge der Ventrikelblutung oder als sekundäre Ef-fekte des Traumas anzusehen sind.

Schlüsselwörter: Niedriges Geburtsgewicht, Spasmen im Kindesalter, Ventrikelblutung.

J. Perinat. Med. 10 (1982)

40 Williamson et al., Neurodevelopmental outcome

Resume

Etüde du developpement neurologique piecoce, d'enfantsprematures ayant survecu a une hemoirhagie intra-ventriculaire neonataleCet article donne les resultats etudies de 28 enfantsprematures ayant survecu une hemoirhagie intiaventricul-aire neonatale ayant ete traites dans le "Neonatal Intens-ive Gare Unit of Texas Children's Hospital ä Houston." Laseverite de ITiemorrhagie vue sur le CT scan 6tait evalueeselon le Systeme de PAPILE et al. [2]. La duree moyennede la grossesse pouf ce groupe etait de 28,9 semaines(compris entre 25 et 35 semaines) et le poids moyen ä lanaissance de 1,179 grammes (s'etalant de 700 a 1,930 gr.)17 enfants etait de sexe male et 11 de sexe femelle.Les classes sociales (selon la classification de HOLLINGS-HEAD s'etablissaient comme suit: 27% de classe II, 31%de classe III et 43% de classe IV.Les examens de contröle consistaient en tests neuro-logiques, et une evaluation du developpement par method-es multidisciplinaires.La categorisation (normal, suspect, anormal) etait baseesur le fonctionnement neurologique et le developpement.Pour un enfant soit considere comme normal il devaitavoir un examen neurologique normal et un developp-ement correspondant aux normes corrigees en fonctionde son äge. Le terme plurihandicape signifait un developp-ement retarde et un examen neurologique anormal. ATage de 19,7 mois, 5 enfants furent consideres commenormaux (18%), 8 comme sirspects (28%) et 15 comme

anormaux (54%) (Tab. II). 8 enfants anormaux etaientplurihandicapes. La paralysie cerebrale (CP) fut constateedans le cas de 9 enfants (32%) (Tab. I). Une hydrocephaliepost-hemorrhagique fut constatee dans 8 cas dont 7requirent un pontage. Trois enfants avec pontage^present-erent plus tard une microcephalie (Fig. 1). 3 ont developpedes spasmes infantils. Des defidts neuro-sensitifs,comprenant la cedte (suite a une retinopathie dcatricielledu premature) se sont developpees chez 4 enfants et lasurdite chez 2 enfants. Au moins un tiers de ces enfantsauro besoin d'une education speciale a Tage de 3 ans.Deux f aits remarquables emergent de ette etude.1: L'incidence de resultats anormaux etaient plus eleveedans le cas dTiemorrhagie des enfants issusidesgroupes IIIet IV (79%) que ceux des groupes I et II (29%) (0,01 <p < 0,025)2: la duree moyenne de la grossesse de 8 enfants pluri-handicapes (27 semaines) etait significativement plusbasse que celle des 20 autres (29,7 semaines) (0,001 <p < 0,01). Parmi les 46% qui ne presentaient pasd'anomalies statiqües lors de l'examen, subsiste le risquede presenter des desordres du langage, de la faculted'apprendre et des troubles du comportement.Une surveillance ä long terme de ces enfants est prevuepour determmer si ces desordres peuvent, en partie, etrerelies a l'apparition des effets secondaires d'une hemorr-hagie intraventriculaire precoce.

Mots-cles: Enfants prematures, hemoirhagie intraventriculake, spasmes infantiles.

Acknowledgements: The authors thank Doctor L. PAUL GERSON, Neuroradiologist, Texas Children's Hospital, forgrading the CT scans. We express appreciation to the Meyer Center staff, particularly SUSANTHURBER, LYNDA ARMSTRONG, and SHIRLEY NORTHROP, for their participation, toEVELYN KROULIK, PHYLLIS GUTIERREZ, and BARBARA NASH for preparation of thismanuscript and to Doctors ALAN PERCY, JANICE GODDARD and MARVIN FlSHMAN formanuscript review.This work was supported by grants from the LlLLIAN KAISER LEWIS FOUNDATION, theHAMMAN FOUNDATION, the MCASHAN FUND, and MCT NO. ooo,436.

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W. Daniel Williamson, M. D.Meyer Center for Developmental PediatricsTexas Chüdren's HospitalHouston, Texas 77030/USA

J. Perinat. Med. 10 (1982)