Evidence of fetal central nervous system injury in isolated congenital heart defects: microcephaly at birth

O

EcD

Ogm

Scjpmda

Rr

CA

Hrhtatepdlao

FGBBRTaDUS

R

0©d

Research www.AJOG.org

BSTETRICS

vidence of fetal central nervous system injury in isolatedongenital heart defects: microcephaly at birthiana Barbu, MD; Ismail Mert, MD; Michael Kruger, MS; Ray O. Bahado-Singh, MD

hot1m

CCtmw

BJECTIVE: We sought to ascertain the risk of reduced fetal brainrowth in cases of isolated congenital heart defect (CHD) based onicrocephaly at birth.

TUDY DESIGN: In a case-control study, head circumference wasompared in 401 newborns with isolated CHD with 401 control sub-ects. Microcephaly was defined as head circumference below thirdercentile. The rates of microcephaly in multiple different categories ofajor CHD were ascertained along with logistic regression analyses to

etermine the specific types of cardiac defects that were significantlyssociated with microcephaly.

ESULTS: Isolated CHD in the fetus was associated with an increased

m J Obstet Gynecol 2009;201:43.e1-7.

tisahhnblDinba

dgmtlssctfitascephaly at birth in sele

See Journal Club, page 118

ypoplasia, and hypoplastic left ventricle syndrome. Tetralogy of Fallotdds ratio, 2.6; 95% confidence interval, 1.1-6.3; P � .04 and coarc-

ation/aortic arch hypoplasia, odds ratio, 2.8; 95% confidence interval,.5-5.1; P � .001 were significant independent predictors oficrocephaly.

ONCLUSION: The finding of microcephaly at birth in nonsyndromicHD provides strong evidence in support of intrauterine hypoxic cen-

ral nervous system damage. Potential changes in prenatal manage-ent including aggressive antepartum surveillance and earlier deliveryarrant urgent consideration.

isk of microcephaly as were tetralogy of Fallot, coarctation/aortic arch Key words: congenital heart defect, microcephaly

ite this article as: Barbu D, Mert I, Kruger M, et al. Evidence of fetal central nervous system injury in isolated congenital heart defects: microcephaly at birth.

it

aCcgfadnartrgmdcqBvcsaimTt

igh rates of central nervous system(CNS) abnormalities have been

eported in children with congenitaleart defects (CHDs).1 Significant atten-ion has been focused on intraoperativend perioperative factors as a cause ofhese CNS abnormalities.2 Such periop-rative factors include the use of cardio-ulmonary bypass during surgery, theeep hypothermia used to induce circu-

atory arrest and low cardiac output andltered cerebral blood flow in the post-perative period.3,4

rom the Department of Obstetrics andynecology, Ohio State University (Drarbu), Columbus, OH; the Kekai Tahirurak Women’s Health Education andesearch Hospital (Dr Mert), Ankara,urkey; and the Hutzel Women’s Hospitalnd Children’s Hospital of Michigan,etroit Medical Center, Wayne Stateniversity (Mr Kruger and Dr Bahado-

ingh), Detroit, MI.

eprints not available from the authors.

002-9378/$36.002009 Mosby, Inc. All rights reserved.

oi: 10.1016/j.ajog.2009.03.029

Less attention has, however, been paido intrauterine causes of CNS abnormal-ties in isolated CHD cases. For example,ignificantly increased rates of cerebraltrophy have been reported in otherwiseealthy term newborn CHD cases thatad not undergone cardiac surgery.5 Sig-ificant hemodynamic alterations haveeen documented in fetal cerebral circu-

ation in CHD cases using prenataloppler velocimetry.6,7 These reports

ncrease the plausibility of fetal hemody-amic and blood oxygenation changeseing a significant contributor to brainbnormalities and microcephaly.

Studies have only now begun to ad-ress the issue of abnormal fetal brainrowth in CHD cases. Increased rates oficrocephaly and neurologic dysfunc-

ion have been reported in newborn iso-ated CHD cases before surgery.8 Suchtudies have mainly involved a relativelymall number of cases and only limitedategories of CHD. Two large popula-ion-based studies reported conflictingndings regarding the association be-

ween isolated CHD and microcephalyt birth. The Washington-Baltimoretudy found increased rates of micro-

cted categories of e

JULY 2009 Ameri

solated CHD9 whereas another popula-ion-based study from France did not.10

There are a number of potential vari-bles both related to and independent ofHD that could lead to the reported mi-

rocephaly. These include poor fetalrowth, known to be increased in CHDetuses, concomitant maternal medicalnd obstetric disorders, and clinical andemographic variables. The simulta-eous coexistence of � 1 cardiac anom-ly is a common occurrence. It naturallyaises the question of which of the struc-ural heart defects in such situations isesponsible for the compromised brainrowth. Finally, it is unknown whetherultiple simultaneous structural heart

efect increases the risk of microcephalyompared with a single defect. The aboveuestions require further clarification.road classifications of CHD, eg, mixings nonmixing lesions,11 cyanotic vs non-yanotic,8 and left- vs right-sided ob-truction6 rather than a specific type ofnatomic defect have been reported toncrease the risk of fetal brain damage

anifesting as microcephaly at birth.he roles and relative contributions of

his large number of potential confound-
rs remain to be systematically analyzed.
can Journal of Obstetrics & Gynecology 43.e1

moifCsncvrfDfcpbmi

MWtncl3jidW

CcscctwsmrvaavpvAscdgtpccgg

hw

dawunot

ceaa(at

ifftnpbtamfwwaalo

SA(IcScFvs

ts

RActb(.

Research Obstetrics www.AJOG.org

4

In a large case-control study, we si-ultaneously evaluated a large number

f plausible confounding variables todentify the significant independent riskactors for microcephaly in newbornHD cases. We wanted to ascertain what

pecific types of cardiac lesions were sig-ificantly associated with newborn mi-rocephaly. Further, we evaluated a wideariety of clinically significant CHD,ather than the limited categories of de-ects generally reported in the literature.etermining the risk to the developing

etal brain posed by coexistent CHDould profoundly affect clinical ap-roaches to prenatal counseling, fetaliophysical monitoring, and obstetricanagement such as timing of delivery

n CHD pregnancies.

ATERIALS AND METHODSe conducted a single-center retrospec-

ive case-control study of babies diag-osed with isolated major CHDs. Searchriteria included all liveborn babies de-ivered between Jan. 1, 1998, and March1, 2007, who were diagnosed with ma-or CHD at Children’s Hospital of Mich-gan. The majority of these babies wereelivered at Hutzel Women’s Hospital at

TABLE 1Maternal demographic, medical, anParameter CHD

Mean age, y (SD)a 28....................................................................................................................

Parity, mean (SD)a 1....................................................................................................................

Ethnicity, n (%)b..........................................................................................................

Caucasian 173..........................................................................................................

African American 157..........................................................................................................

Other 71...................................................................................................................

Diabetes, n (%)c 36...................................................................................................................

Hypertension, n (%)c 14...................................................................................................................

Substance abuse, n (%)c 22...................................................................................................................

Tobacco use, n (%)c 35...................................................................................................................

Obstetric complications (%)c..........................................................................................................

Abruption 3..........................................................................................................

Preeclampsia 11...................................................................................................................

CHD, congenital heart defect; ns, not significant.a Independent samples t test; b �2 test; c Fisher exact test.

Barbu. Evidence of fetal central nervous system injury in i2009.

ayne State University. International w

3.e2 American Journal of Obstetrics & Gynecolog

lassification of Diseases, Ninth Revisionodes of the following common CHDubtypes were used to search for studyases: d-transposition of great artery,orrected transposition of the great ar-eries, tetralogy of Fallot, coarctationith aortic arch hypoplasia, ventricular

eptal defect (VSD) (excluding small orinor defects), aortic stenosis, inter-

upted aortic arch, double outlet rightentricle, truncus arteriosus, totalnomalous pulmonary venous drainage,trioventricular septal defect, aorticalve atresia, aortic arch hypoplasia, hy-oplastic left ventricle, hypoplastic rightentricle, and pulmonary valve stenosis.total of 401 newborns were included as

tudy cases. Cardiovascular anomaly wasonfirmed by 1 or a combination of stan-ard procedures such as echocardio-ram, cardiac catheterization, and ana-omic observation of surgery orostmortem. Exclusion criteria includedhromosomal defects, presence of extra-ardiac anomalies, recognized or sug-ested genetic syndromes, and multipleestation pregnancies.A total of 401 sex- and race-matched

ealthy babies born at Hutzel Hospitalithin 3 months of the index study case

obstetric featuresControl P value

.5) 26.5 (6.5) � .001..................................................................................................................

.5) 1.4 (1.6) ns..................................................................................................................

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

1) 171 (42.6) ns..................................................................................................................

2) 157 (39.2)..................................................................................................................

7) 73 (18.2)..................................................................................................................

) 21 (5.2) .054..................................................................................................................

) 12 (3.0) ns..................................................................................................................

) 29 (7.2) ns..................................................................................................................

) 50 (12.5) ns..................................................................................................................

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

) 3 (0.7) ns..................................................................................................................

) 12 (3.0) ns..................................................................................................................

ed CHD: microcephaly at birth. Am J Obstet Gynecol

ere included. A healthy baby whose c

y JULY 2009

ate of birth was closest to the study casend having a gestational age at birthithin 1 week of the index study case wassed as the control. Control subjects hado structural anomalies and no knownr suggested genetic defects, nor werehey from multiple gestations.

The following parameters were re-orded: sex, race, maternal age at deliv-ry, gravidity, parity, maternal medicalnd obstetric disorders, gestational aget birth, newborn biometric informationhead circumference [HC], birthweight,nd body length), type of CHD, karyo-ype if available, and maternal smoking.

Study and control cases were placednto respective birthweight classes (smallor gestational age [SGA], appropriateor gestational age [AGA], large for ges-ational age [LGA]) based on publishedeonatal growth curves used.12 Microce-halic cases were determined using new-orn growth charts for appropriate ges-ational ages with microcephaly defineds HC less than the third percentile.12 Allajor or clinically significant cardiac de-

ects observed in the individual patientere recorded. The different CHD typesere further classified into groups such

s cyanotic and cyanotic lesions; mixingnd nonmixing lesions; and obstructive,eft-sided, and right-sided cardiacbstruction.

tatistical methodsll data were analyzed using software

SPSS for Windows, Version 15.0; SPSSnc, Chicago, IL). Univariate analysis ofontinuous data was conducted usingtudent independent samples t tests andategorical data were analyzed usingisher exact tests and Pearson �2. Multi-ariate analyses were conducted usingtepwise binary logistic regression.

A significance level of P � .05 was usedo determine findings as statisticallyignificant.

ESULTSs shown in Table 1, there was a signifi-ant difference in the maternal age be-ween the 2 groups with the mean ageeing lower for control vs CHD groups26.5 vs 28.2 years, respectively; P �001). Otherwise, there were no signifi-

d

2 (6.........

4 (1.........

.........

(43..........

(39..........

(17..........

(9.0.........

(3.5.........

(5.5.........

(8.7.........

.........

(0.7.........

(2.7.........

solat

ant differences observed in ethnicity,

rag

nsadwdmst[aPsm

.sctg

3apS

rpgoilad

qtspoginfonsw

www.AJOG.org Obstetrics Research

elevant medical and obstetric disorders,nd substance or tobacco use betweenroups.Table 2 lists the breakdown of the

umber and types of CHDs in thetudy group. VSD, coarctation of theorta/aortic arch hypoplasia, and-transposition of the great arteriesere the 3 most common defects withiminishing order of frequency. Theean birthweight of CHD cases was

ignificantly less than that of the con-rol group (3018.8 [722.6] g vs 3088.2639.7] g; P � .01); 38.1 (2.4) weeksnd 38.5 (2.7) weeks, study vs controls;� .05. Otherwise, there were no ob-

ervable differences with respect toean gestational age at birth and sex.The mean HC was 33.3 vs 33.6 cm, P �

04, in cases compared with controls, re-pectively. When only SGA cases wereonsidered (86 and 48 cases, respec-ively), the difference between the

TABLE 2Congenital heart defectcategories

Category of CHDNo. ofcases (%)

D-transposition of great artery 65 (16.2)...........................................................................................................

Tetralogy of Fallot 34 (8.5)...........................................................................................................

Coarctation/aortic archhypoplasia

81 (20.2)

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

VSD 101 (25.2)...........................................................................................................

Aortic stenosis 21 (5.2)...........................................................................................................

Double outlet right ventricle 24 (6.0)...........................................................................................................

Total anomalous pulmonaryvenous drainage

29 (7.2)

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

Hypoplastic right ventricle 58 (14.5)...........................................................................................................

Hypoplastic left ventricle 24 (6.0)...........................................................................................................

Pulmonary valve stenosis 44 (11.08)...........................................................................................................

Other CHDa 48 (12.0)...........................................................................................................

CHD, congenital heart defect; VSD, ventricular septaldefect.a Corrected transportation of great artery-1, complex-3,

truncus arteriosus-8, A-V canal defect-4, partial anom-alous systemic venous return-1, absent-hypoplastic ab-errant pulmonary artery-1, vascular ring-3, double inletleft ventricle-1, Ebstein anomaly-6, tricuspid regurgita-tion-2, mitral insufficiency-2, mitral valve hypoplasia,pulmonary-5, interrupted aortic arch-2, others-2.

Barbu. Evidence of fetal central nervous system injuryin isolated CHD: microcephaly at birth. Am J ObstetGynecol 2009.

roups were still statistically significant:

1 (2.7) vs 32.3 (1.6) cm, P � .003. Later,nalyses were performed to control forotential confounders including AGA vsGA status.The frequency of microcephaly in the

espective categories of CHD was com-ared with that in the entire normalroup (Table 3). As noted, in the meth-ds section, microcephaly was standard-

zed for gestational age. Tetralogy of Fal-ot, coarctation/aortic arch hypoplasia,nd hypoplastic left ventricle groupsemonstrated a significantly higher fre-

TABLE 3Type of isolated congenital heart dCase type CH

D-transposition of great artery 5...................................................................................................................

Tetralogy of Fallot 8...................................................................................................................

Coarctation/aortic arch hypoplasia 18...................................................................................................................

Ventricular septal defect 13...................................................................................................................

Aortic stenosis 2...................................................................................................................

Double outlet right ventricle 2...................................................................................................................

Total anomalies pulmonary veins 3...................................................................................................................

Hypoplastic left ventricle 11...................................................................................................................

Hypoplastic right ventricle 3...................................................................................................................

Pulmonary valve stenosis 6...................................................................................................................

Other CHD cases 8...................................................................................................................

CHD, congenital heart defect; ns, not significant.a One-sided Fisher exact test to determine whether microcep


TABLE 4Frequency of microcephaly in funcof isolated congenital heart defectCategory CHDa CHD

Overall CHD group 56/401 (14...................................................................................................................

Cyanotic 35/259 (13...................................................................................................................

Acyanotic 21/142 (14...................................................................................................................

Mixing vs controls 33/242 (13...................................................................................................................

Nonmixing vs controls 23/159 (14...................................................................................................................

Nonobstructive 9/132 (6....................................................................................................................

Left-sided obstruction 30/157 (19...................................................................................................................

Right-sided obstruction 16/109 (14...................................................................................................................

CHD, congenital heart defect; ns, not significant.a Total number of cases in particular category of CHD; b 1-side

frequently in the CHD cases.6,8,11

Barbu. Evidence of fetal central nervous system injury in i
2009.
JULY 2009 Ameri

uency of microcephaly compared withhe overall normal group (Table 3). Priortudies have evaluated whether or re-orted that the risk of poor brain devel-pmental is significantly affected by theroup category of CHD, namely cyanot-c/acyanotic13 or that cerebral hemody-amic changes in the fetus may be af-

ected by whether the CHD was mixingr nonmixing CHD,11 and whether orot the lesion is left- vs right-side ob-tructive.6 The rates of microcephalyere compared in these group categories

ct and frequency of microcephalyControl P valuea

(7.7%) 34/401 (8.5%) ns..................................................................................................................

(23.5%) 34/401 (8.5%) .007..................................................................................................................

(21.7%) 34/401 (8.5%) � .001..................................................................................................................

(12.9%) 34/401 (8.5%) ns..................................................................................................................

(9.5%) 34/401 (8.5%) ns..................................................................................................................

(8.3%) 34/401 (8.5%) ns..................................................................................................................

(10.3%) 34/401 (8.5%) ns..................................................................................................................

(18.3%) 34/401 (8.5%) .016..................................................................................................................

(12.5%) 34/401 (8.5%) ns..................................................................................................................

(13.6%) 34/401 (8.5%) ns..................................................................................................................

(16.7%) 34/401 (8.5%) ns..................................................................................................................

occurs more frequently in the CHD cases.


al categories

Control P valueb

) 34/401 (8.5%) .024..................................................................................................................

) 34/401 (8.5%) .008..................................................................................................................

) 34/401 (8.5%) ns..................................................................................................................

) 34/401 (8.5%) .002..................................................................................................................

) 34/401 (8.5%) ns..................................................................................................................

) 34/401 (8.5%) ns..................................................................................................................

) 34/401 (8.5%) ns..................................................................................................................

) 34/401 (8.5%) � .002..................................................................................................................

her exact test to determine whether microcephaly occurs more


efeD

/65.........

/34.........

/83.........

/101.........

/21.........

/24.........

/29.........

/60.........

/24.........

/44.........

/48.........

haly

solat

tion

.0%.........

.5%.........

.8%.........

.6%.........

.5%.........

8%.........

.1%.........

.7%.........

d Fis

solat


vqcp[PmCsw.occloincgss(n

c(clos

n(

mTrtghcstat

wtgnnnccs�tcytl Gynecol 2009.


4

s control group (Table 4). The fre-uency of microcephaly was signifi-antly increased in CHD overall com-ared with control subjects (56/40114.0%] vs 34/401 [8.48%], respectively;� .024). Similarly, increased rates oficrocephaly were observed in cyanoticHD, mixing type lesions, and right-

ided obstructive disorders comparedith the overall control subjects (P �

002; Table 4). Analysis of variance of theverall group did not show any signifi-ant difference in the frequency of mi-rocephaly based on obstruction (none,eft, and right) status compared with nobstruction. When SGA cases were elim-

nated, analysis of variance showed a sig-ificant difference (P � .01) with in-reased microcephaly in the affectedroups. Finally, microcephaly occurredignificantly more frequently in the left-ided (18/118 [15.3%]) vs right-sided7/80 [8.8%]; P � .02) groups amongon-SGA cases.There was a significant progressive de-

rease in mean (SD) HC from control33.6 [2.0] cm), nonmixing (33.4 [2.6]m), and mixing (33.2 [2.3] cm) cardiacesion (P � .023). Even after eliminationf SGA babies, the HC trend maintained

TABLE 5Type of congenital heart defect andexcluding small-for-gestational-agType of CHD CHD

D-transposition of great arteries 1/5...................................................................................................................

Tetralogy of Fallot 2/1...................................................................................................................

Coarctation/aortic archhypoplasia

12/6

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

Ventricular septal defect 6/7...................................................................................................................

Aortic stenosis 2/1...................................................................................................................

Double outlet right ventricle 1/2...................................................................................................................

Total anomalies pulmonaryveins

1/2

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

Hypoplastic left ventricle 5/4...................................................................................................................

Hypoplastic right ventricle 2/1...................................................................................................................

Pulmonary valve stenosis 2/3...................................................................................................................

Other CHD 5/4...................................................................................................................

CHD, congenital heart defect; ns, not significant.Fisher exact test for all measures.


ignificance: control (33.7 [2.0] cm), t


onmixing (33.9 [2.2] cm), and mixing33.6 [2.0] cm; P � .037).

SGA status likely increases the risk oficrocephaly, independent of a CHD.he analysis in Table 3 was repeated after

emoving all SGA newborns from bothhe study and control groups and sub-roup (Table 5). Coarctation/aortic archypoplasia remained significantly asso-iated with microcephaly Small sampleize likely accounted for the loss of statis-ical significance in the tetralogy of Fallotnd hypoplastic left ventricle groups af-er removal of SGA cases.

A separate series of univariate analysesere performed to identify potential fac-

ors (cardiac anomaly type, anomalyroup (eg cyanotic vs acyanotic), mater-al medical, obstetric, demographic andewborn factors) that correlated withewborn microcephaly. All potentialonfounding factors affecting micro-ephaly were taken into consideration ashown listed in Table 6. A threshold of P

.10 was used in the univariate analysiso identify independent variables for in-lusion into the logistic regression anal-sis for significant independent predic-ors of microcephaly. Stepwise binaryogistic regression analysis confirmed

equency of microcephaly,eonates

Control P value

1.8%) 20/349 (5.7%) ns..................................................................................................................

9.1%) 20/349 (5.7%) ns..................................................................................................................

18.5%) 20/349 (5.7%) .001

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

8.5%) 20/349 (5.7%) ns..................................................................................................................

11.1%) 20/349 (5.7%) ns..................................................................................................................

4.8%) 20/349 (5.7%) ns..................................................................................................................

4.8%) 20/349 (5.7%) ns

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

11.6%) 20/349 (5.7%) ns..................................................................................................................

11.1%) 20/349 (5.7%) ns..................................................................................................................

8.9%) 20/349 (5.7%) ns..................................................................................................................

12.5%) 20/349 (5.7%) ns..................................................................................................................


fre n

7 (.........

5 (.........

5 (

.........

1 (.........

8 (.........

1 (.........

1 (

.........

3 (.........

8 (.........

4 (.........

0 (.........

solat

hat birthweight status was a significant

y JULY 2009

TABLE 6Factors associated withmicrocephaly: univariate analysis

VariablePvalue

Maternal characteristics...........................................................................................................

Agea .575...........................................................................................................

Graviditya .128...........................................................................................................

Paritya .189...........................................................................................................

Race/ethnicityb .860...........................................................................................................

Sexb .074...........................................................................................................

Birthweighta � .01...........................................................................................................

Growth status, SGA vs AGAb � .001...........................................................................................................

Medical disordersa

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

Chronic hypertensiona .524...........................................................................................................

Diabetesa .667...........................................................................................................

Tobacco usea .066...........................................................................................................

Substance abusea .166...........................................................................................................

Obstetric disorderabruptiona

1.00

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

No. of obstetric disordersa .167...........................................................................................................

Newborn heart defect...........................................................................................................

Congenital heart defect .018...........................................................................................................

Cyanotic/acyanotic CHD .044...........................................................................................................

Mixing/nonmixing CHD .045...........................................................................................................

Obstruction of left outflowtract

.001

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

Obstruction of right outflowtract

� .1

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

No. of cardiac lesions .89...........................................................................................................

Tetralogy of Fallot � .05...........................................................................................................

Coarctation/aortichypoplasia

.003

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

VSD .614...........................................................................................................

Aortic stenosis 1.000...........................................................................................................

Double outlet right ventricle 1.000...........................................................................................................

Venous drainage...........................................................................................................

Hypoplastic left ventricles .081...........................................................................................................

Hypoplastic right ventricle .747...........................................................................................................

Pulmonary stenosis .623...........................................................................................................

Other types of CHD .238...........................................................................................................

AGA, appropriate for gestational age; CHD, congenitalheart defect; SGA, small for gestational age; VSD,ventricular septal defect.a Independent samples t test; b Fisher exact test.

Barbu. Evidence of fetal central nervous system injuryin isolated CHD: microcephaly at birth. Am J Obstet

icc�wac2a2tslbCm

ie1C

CTwpciecisospmclcobtpdfddoarttsri

ppsrcvmogetpf

wmwogktpCcpta

nwv.fsupldpldpii

nnfooChamp

ci

wffpRfdtcBtffufidhwaaCFiic1aiisCtmba

oafrgHppahosn

Sm


ndependent predictor of newborn mi-rocephaly: odds ratio (OR), 0.195; 95%onfidence interval (CI), 0.121-0.313; P

.001. Thus, being born with a birth-eight that is appropriate for gestational

ge reduces the risk of microcephaly bylose to 80%. Tetralogy of Fallot (OR,.6; 95% CI, 1.07-6.31; P � .04) and co-rctation/aortic arch hypoplasia (OR,.78; 95% CI, 1.50-5.15; P � .001) werehe specific cardiac anatomic defects thatignificantly and independently corre-ated with microcephaly in the new-orns. The presence of either of theseHD independently increased the risk oficrocephaly � 2.5-fold.Power analysis indicated that 128 cases

n the overall CHD and normal categoryach would have 80% power to detect a0% higher rate of microcephaly in theHD group.

OMMENThe morbidity and mortality associatedith corrective surgery for CHD has im-roved dramatically during the last 2 de-ades. Neurodevelopmental outcomesn these cases remain a concern, how-ver. In a large study of isolated CHDases, which included the most clinicallymportant defects, we found that 2 le-ions, tetralogy of Fallot and coarctationf the aorta/aortic arch hypoplasia, wereignificant independent risk factors foroor fetal brain growth manifested asicrocephaly at birth. Our findings are

onsistent with the results of fetal Dopp-er studies. Significant hemodynamichanges in the fetal cerebral circulationf CHD cases have been demonstratedy Doppler velocimetry.6,7,11 The rela-ive increase in cranial blood flow re-orted by these studies is thought to beue to reduced oxygen content resulting

rom cardiac mixing of oxygenated andeoxygenated blood as a result of the car-iac lesion or from retrograde flow of de-xygenated blood from the right heartcross the aortic isthmus and into the ce-ebral circulation.6,7 In addition, CHDhat results in reduced total blood flow tohe brain such as hypoplastic left heartyndrome could also have a similar det-imental effect. We did observe an
ncreased rate of microcephaly when hy- f
oplastic left ventricle cases were com-ared with the normal group. The re-ponse of the cerebral circulation toeduced oxygen content, whatever theause, is vasodilatation to increase flowolume and oxygen delivery. The ulti-ate consequence of decreased cerebral

xygenation could be decreased brainrowth. Fetal cranial Doppler velocim-try-based blood flow changes consis-ent with cerebral hypoxemia are re-orted to correlate significantly with

etal HC measurement.14

HC is a reliable measurement that isidely used in clinical practice.15 HCeasurement is known to correlate wellith weight, protein, and DNA contentf the brain.16 Microcephaly is a hetero-eneous disorder that has long beennown to correlate with mental retarda-ion. This is particularly the case in theresence of associated disorders such asHD.17 The finding of newborn micro-

ephaly in CHD is likely of clinical im-ortance and warrants ongoing evalua-ion of neurobehavioral function inffected cases.

A high rate of cranial ultrasound ab-ormalities, including cerebral atrophyas found in full-term infants with CHDs control subjects (59% vs 14%; P �001).5 That study was significant for theact that it excluded cases with other as-ociated abnormalities, evidence of intero distress, perinatal asphyxia, orostnatal complications and the radio-

ogic studies were performed within 2ays of birth. This provides strong em-irical evidence that significant neuro-

ogic insults occur before birth. Fetal car-iovascular compromise was posited as aotential explanation for these abnormal

ntracranial findings. Again, those find-ngs are consistent with our results.

Although the long-term impact ofewborn microcephaly in CHD caseseeds further exploration, short-term

ollow-up data indicate a negative effectn neurologic performance. In a groupf 56 newborns with a variety of majorHDs that excluded hypoplastic lefteart syndrome, extracardiac anomalies,nd asphyxia, microcephaly was docu-ented in 35.7% of cases.13 Prospective

reoperative neurologic evaluation
ound that two-thirds of microcephaly c
JULY 2009 Ameri

ases had an abnormal neurologic exam-nation result.

In a small number of CHD fetuses, ofhich 16 had tetralogy of Fallot, Dono-

rio et al7 observed a reduction of HC onetal ultrasound in this subgroup com-ared with control subjects. Similarly,osenthal9 performed a study of 276 in-

ants with isolated CHD limited to-transposition of the great artery, te-ralogy of Fallot, hypoplastic left ventri-le, and coarctation of the aorta from thealtimore-Washington infant popula-

ion study database. After taking con-ounders into consideration, the authorsound reduction in newborn head vol-me compared with birthweight in therst 3 categories of CHD. They found re-uced birthweight but relatively largeead volume for birthweight in casesith coarctation of the aorta. Our study

lso found increased rates of microceph-ly (Table 3) in these 3 categories ofHD. In a population-based study fromrance, Stoll et al10 reported a reduction

n newborn birthweight, length, and HCn a group consisting of a total of 801ases of CHD from a population of05,374 consecutive births. In contrast,mong the subgroup of 595 cases withsolated CHD, no significant reductionn birthweight, length, or HC was ob-erved. This subgroup with isolatedHD was not further broken down into

ypes of CHD and therefore did not per-it a determination of the association

etween specific isolated cardiac lesionsnd head growth

In a study of isolated CHD consistingf 46 transposition of the great arterynd 28 hypoplastic left ventricle term in-ants, Manzar et al18 reported significanteduction in newborn HC in bothroups compared with control subjects.C was significantly reduced in hypo-

lastic left heart syndrome cases com-ared with the transposition of the greatrtery group. As a group, hypoplastic lefteart syndrome cases had increased ratesf microcephaly compared with controlubjects in our study although this didot persist in logistic regression analysis.The prior studies,8,9,18 but not that of

toll et al,10 agree with our findings oficrocephaly at birth in isolated CHD

ases. There appears to be a significant


ratoafviaatneaifhto

Smis(csvwfAtDomcptdscgbtigftspObrc

A

cwWtisggdcginhbnetcddtppocaptWawltpwsnasetbp

ittfgavdat

libsbrss

fofbtNocpwtaDpnhvdrfmoidmaddnmdawcAqteFiaa

oafi


4

elationship between the type of CHDnd microcephaly. Both our study andhose of Rosenthal9 and Manzar et al18

bserved increased rates of microceph-ly in tetralogy of Fallot cases. Rosenthal9

ound head sparing in hypoplastic leftentricular cases whereas we observedncreased rates of microcephaly. Ournalysis was different from these other 2uthors because we controlled for addi-ional heart defects present in the sameewborn. It is possible that the coexist-nce of other cardiac pathologies such astrial or ventricular septal defects couldncrementally affect and, therefore, con-ound the relationship between a majoreart defect. We, unlike others, con-rolled for such confounders with the usef regression analysis.The observed association between

GA and CHD requires further com-entary. The Baltimore-Washington

nfant population-based study reportedignificantly increased rates of SGA� tenth percentile) in endocardialushion defects, hypoplastic left heartyndrome, pulmonary stenosis, and se-ere ventricular septal defect infantshen adjustments were made for con-

ounders.19 All cases had isolated CHD.similar population-based study from

he Metropolitan Atlanta Congenitalefects Program found increased ratesf intrauterine growth restriction inany types of isolated CHD with the ex-

eption of atrial septal defect and hypo-lastic left heart syndrome.20 Similarly,he New England Regional Infant Car-iac Program reported significant re-triction in birthweight of isolated CHDases.21 The relationship between fetalrowth restriction and CHD appears toe a complex one. It has been positedhat growth abnormality as the primarynsult could lead to alteration of cardio-enesis and subsequent disturbance inetal hemodynamics leading to struc-ural heart defect.22,23 Fetal growth re-triction does not alone, however, ex-lain the poor head growth in CHD.ther studies9,18 and ours controlled for

ody weight and still observed increasedates of poor head growth and micro-ephaly at birth in their CHD groups.

Our study had a number of strengths.
wide variety of CHD categories, in- a

luding a substantial number of casesithin each CHD category, was studied.e identified and systematically con-

rolled for a large number of confound-ng variables that are reportedly or plau-ibly associated with reduced headrowth. These included maternal demo-raphics, medical and obstetric disor-ers, and newborn sex. Further, CHDases were classified into functionalroups: eg, cyanotic vs acyanotic, miss-ng vs nonmixing lesions, obstructive vsonobstructive lesions. These factorsave been variously suggested to affectlood oxygenation and head growth. Fi-ally, we evaluated the impact of the co-xistence of multiple cardiac defects inhe same individual. Prior studies havelassified simultaneous multiple heartefect cases based on the predominantefect, a somewhat arbitrary designationhat risks overlooking the potential im-act and contributions of other accom-anying lesions. A general limitation ofur study was the potential for bias asso-iated with a retrospective evaluation. Inddition, this was a hospital- rather thanopulation-based case-control studyhat, by itself, has a potential for bias.

e, however, attempted to be rigorousnd systematic in matching controlsith study cases. Further, with the use of

ogistic regression analyses, we at-empted to control for a large number ofotential confounders. We excluded casesith recognized genetic syndromes, other

tructural defects and chromosomal ab-ormalities, patent ductus arteriosus,trial septal defect and small ventriculareptal defects. Based on this, it is to bexpected that the frequency distribu-ions of various categories of CHD wille skewed compared to the generalopulation.Tetralogy of Fallot is associated with

ntracardiac mixing of blood with poten-ial delivery of deoxygenated blood tohe brain. This could plausibly accountor the microcephaly observed in thisroup.19 Overall, the high association ofortic arch abnormalities with cardio-ascular malformations that lead to re-uction of flow through the ascendingorta24 and thus lead to absolute reduc-ion of oxygenated blood to the brain
nd microcephaly. Finally, hypoplastic f
y JULY 2009

eft ventricle drastically reduces or elim-nates the output of highly oxygenatedlood to the brain and elsewhere. In-tead, the oxygenated blood is replacedy somewhat deoxygenated blood thatesults from the mixing of left- and right-ided blood that is a consequence of theingle ventricle.

Our findings may have implicationsor obstetric management. The evidencef hypoxic brain insult suggests the needor systematic and early deployment ofiophysical monitoring of the CHD fe-us. Biophysical parameters such as theST and biophysical profile were devel-ped to monitor the fetus for evidence oferebral hypoxia. Preliminary data re-orting reduced HC at an average of 28.4eeks in tetralogy of Fallot cases suggest

hat early monitoring might be advis-ble.7 The use of middle cerebral arteryoppler measurements in such cases ap-ears to be a useful noninvasive tech-ique to detect and monitor cerebralypoxia. Due to its low cost and nonin-asive nature, weekly monitoring may beesirable. Because of the association witheduced fetal growth, frequent biometryor example at 2- to 3-week intervals

ight be prudent in CHD cases. An areaf concern that may need to be addressed

s the timing of delivery. Current stan-ards hold that temporizing to achieveaximal fetal weight and development,

nd to facilitate neonatal surgery is pru-ent. Evidence of cerebral hypoxia or re-uced brain growth might suggest theeed for a compromise such as docu-entation of lung maturity and earlier

elivery to limit cerebral hypoxic dam-ge. The question naturally arises as tohich categories of CHD are at signifi-

ant risk for hypoxic cerebral damage.lthough even larger studies will be re-uired to definitively answer this ques-ion, our studies combined with the lit-rature reviewed suggest that tetralogy ofallot, d-transposition of the great arter-

es, hypoplastic left ventricle syndrome,nd coarctation of the aorta are potentialppropriate categories.

An intriguing question is the relevancef these findings to fetal cardiac surgery,

fascinating and rapidly developingeld. A plausible case could be made for

etal surgical procedures that can pre-

vbaaiapctdiishpdbmv

R1oc12s33cC4sD5i

fA6cbO7Awe8Rrfa69atE1Ge1twsO1bwa1Rrd11Cd

i21hd1am1at11Sph1BdsA2CuP2Be2fl22cFaP2lRau


ent or reduce the severity of hypoxicrain injury in pertinent CHD cases. Ex-mples include early release of mitralnd aortic value narrowing to prevent ormprove hypoplastic left heart syndromend aortic hypoplasia. Safe and effectiverenatal surgical techniques will ofourse need to be developed. The au-hors readily admit that currently theata are insufficient to justify strong clin-

cal recommendations. Overall, ourdeas and suggestions with regard to ob-tetric management appear reasonable,owever, in view of the findings we re-ort. Large collaborative studies to ad-ress this phenomenon of fetal hypoxicrain injury in CHD and how this can beitigated are now warranted in our

iew. f

EFERENCES. Miller G, Vogel H. Structural evidence of injuryr malformation in the brains of children withongenital heart disease. Semin Pediatr Neurol999;6:20-6.. Ferry PC. Neurologic sequelae of open-hearturgery in children. Am J Dis Child 1987;141:09-12.. Mahle WT. Neurologic and cognitive out-omes in children with congenital heart disease.urr Opin Pediatr 2001;13:482-6.. Ferry PC. Neurologic sequelae of open-hearturgery in children: an ‘irritating question.’ Am Jis Child 1990;144:369-73.. van Houten JP, Rothman A, Bejar R. High

ncidence of cranial ultrasound abnormalities in a

ull-term infants with congenital heart disease.m J Perinatol 1996;13:47-53.. Kaltman JR, Di H, Tian Z, Rychik J. Impact ofongenital heart disease on cerebrovascularlood flow dynamics in the fetus. Ultrasoundbstet Gynecol 2005;25:32-6.. Donofrio MT, Bremer YA, Schieken RM, et al.utoregulation of cerebral blood flow in fetusesith congenital heart disease: the brain sparingffect. Pediatr Cardiol 2003;24:436-43.. Limperopoulos C, Majnemer A, Shevell MI,osenblatt B, Rohlicek C, Tchervenkov C. Neu-

odevelopmental status of newborns and in-ants with congenital heart defects before andfter open heart surgery. J Pediatr 2000;137:38-45.. Rosenthal GL. Patterns of prenatal growthmong infants with cardiovascular malforma-ions: possible fetal hemodynamic effects. Am Jpidemiol 1996;143:505-13.0. Stoll C, Alembik Y, Roth MP, Dott B, Deeeter B. Risk factors in congenital heart dis-ase. Eur J Epidemiol 1989;5:382-91.1. Modena A, Horan C, Visintine J, Chan-hasenanont A, Wood D, Weiner S. Fetusesith congenital heart disease demonstrateigns of decreased cerebral impedance. Am Jbstet Gynecol 2006;195:706-10.2. Fenton TR. A new growth chart for pretermabies: Bobson and Brenda’s chart updatedith recent data and a new format. BMC Pedi-tr 2003;16:13.3. Limperopoulos C, Majnemor A, Shevell M,osenblatt B, Rohlicek C, Tchervenkov C. Neu-

ologic status of newborns with congenital heartefects before open heart surgery. Pediatrics999;103:402-8.4. Chiung-Hsin C, Chen-Hsiang Y, Huei-hen K, Chu-Ling C, Fong-Ming C. Three-imensional power Doppler ultrasound for the
ssessment of the fetal brain blood flow 1
JULY 2009 Ameri

n normal gestation. Ultrasound Med Biol003;24:1273-9.5. Bhushan V, Paneth N. Reliability of neonatalead circumference measurement. J Clin Epi-emiol 1991;44:1027-35.6. Winick M, Rosso P. Head circumferencend cellular growth of the brain in normal andarasmic children. J Pediatr 1969;74:774-8.7. Dolk H. The predictive value of microceph-ly during the first year of life for mental retarda-ion at seven years. Dev Med Child Neurol991;33:974-83.8. Manzar S, Nair AK, Pai MG, Al-KhusaibyM. Head size at birth in neonates with trans-osition of great arteries and hypoplastic lefteart syndrome. Saudi Med J 2005;26:453-6.9. Rosenthal GL, Wilson PD, Permutt T,oughman JA, Ferencz C. Birth weight and car-iovascular malformations: A population-basedtudy; the Baltimore-Washington infants study.m J Epidemiol 1991;133:1273-81.0. Khoury M, Erickson J, Cordero JF, Mc-arthy BJ. Congenital malformations and intra-terine growth retardation: a population study.ediatrics 1988;82:83-90.1. Levy RJ, Rosenthal A, Fyler DC, Nadas AS.irthweight of infants with congenital heart dis-ase. Am J Dis Child 1978;132:249-54.2. Grant RP. The embryology of ventricularow pathogenesis in man. Circulation 1962;5:756-79.3. Jaffee OC. Abnormal organogenesis in theardiovascular system. In: Wilson JG, FraserC, eds. Handbook of teratology. Vol 2. Mech-nisms and pathogenesis. New York: Plenumress; 1977:343-63.4. Moore RJ, Oppenheimer-Dekker A, Mou-

aert AJ, Wenink AC, Gittenberger-deGroot AC,oozendaal H. The concurrence of dimensionalortic arch anomalies and abnormal left ventric-lar muscle bundles. Pediatr Cardiol 1982;2:
07-14.

Documents

Evidence of fetal central nervous system injury in isolated congenital heart defects: microcephaly at birth