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Journal Club www.AJOG.org
1
icrocephaly associated with congenital heart defect: Barbu et alsabelle Wilkins, MD; George A. Macones, MD, MSCE, Associate Editor
he article below summarizes a roundtable discussion of a study published in this issue of the Journal in light of its methodology, relevance to practice, and
mplications for future research. Article discussed:
arbu D, Mert I, Kruger M, Bahado-Singh RO. Evidence of fetal central nervous system injury in isolated congenital heart defect: microcephaly at birth.m J Obstet Gynecol 2009;201:43.e1-7.
he full discussion appears at www.AJOG.org, pages e7-12.
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DISCUSSION QUESTIONS
What was the study question?
What was the study design?
How were cases and controlsidentified?
Do the conclusions correspond withearlier work?
Why are these findings biologicallyplausible?
What challenges accompany aprospective study design?
What might be the best antenataltesting in this population?
How will these findings shape patientcounseling and care?
rom the Department of Obstetrics andynecology, Division of Maternal-Fetaledicine, University of Illinois College ofedicine at Chicago, Chicago, IL:
oderatorsabelle Wilkins, MDrofessor and Director
iscussantsaria Colon, MD
ellow
eredith Cruz, MDourth-year resident
oa Qato, MDhird-year resident
ennifer Damlichourth-year medical student
002-9378/free2009 Published by Mosby, Inc.
oi: 10.1016/j.ajog.2009.05.018
uSee related article, page 43
18 American Journal of Obstetrics & Gynecology
ongenital heart defects (CHDs) arerelatively common, occurring in
bout 1% of live births, according to themerican Heart Association. Obstetri-ians are generally aware of who may bet risk, and we know how to screen pa-ients with prenatal imaging studies.hose of us who perform or interpret
hose studies may know a bit more aboutlassification of lesions, but few accepteduidelines exist for antenatal manage-ent, and once these babies are deliv-
red, neonatologists and pediatric cardi-logists take over. Prenatal consultationsith these services are usually confined
o discussions of how to follow the fetusor prenatal heart failure or worsening ofardiac status and planning for delivery;or example, determining whether a spe-ialized center is essential and how im-ediate neonatal resuscitation will pro-
eed.Most obstetricians know little about
he long-term outcome of babies whoave had a CHD diagnosed before birth.side from cardiac disorders, these pa-
ients have a higher than expected inci-ence of neurodevelopmental delay.hile this may be related to a variety of
eonatal and childhood incidents, in-luding intraoperative events duringorrective cardiac surgery, a growingody of medical literature points to pos-ible in utero origins for this damage.
USEFUL SIGN
o how do we study whether or not aetus was neurologically damaged intero? Barbu and colleagues, the authorsf the article discussed in this month’seeting of the Journal Club, used neo-
atal microcephaly as a marker for in
tero compromise. In this retrospective aJULY 2009
ospital-based study, the researchersooked at all babies with a diagnosis ofHD who had been born at Children’sospital of Michigan. They retrieved in-
ormation about birthweight and headircumference, looked for associatednomalies, such as syndromes or chro-osomal abnormalities, and eliminated
ases with other potential explanationsor developmental delay or small headircumference. Finally, they went back tohe maternal records for demographicnformation to eliminate confounders.
The authors found that the mean headircumference was significantly smallern neonates with CHDs compared withontrols. Because the absolute amountf the difference was small, they also
ooked at the rate of microcephaly andound that it was more common than itas among control infants. Their defini-
ion of microcephaly was a head circum-erence below the 3rd percentile, andhey adjusted for gestational age. Oneould expect approximately 3% of their
ontrols to have microcephaly. In fact,he rate was quite a bit higher at 8%. Ifhis is a chance finding, their abnormalesults would be more significant. How-ver, it does raise the question of whetherheir population has other factors that
ight interfere with the generalizabilityf the findings.Overall, it appears that significantlyore neonates with CHD had micro-
ephaly when compared with controls.his very worrisome and importantnding is similar to what other groupsave discovered. Once the authors ana-
yzed these results by type of CHD, theyearned that the associations were trueor some CHDs and not others. For ex-
mple, hypoplastic left heart was linkedww
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www.AJOG.org Journal Club
ith microcephaly but aortic stenosisas not.
MALL BABIES; BIG QUESTIONS
fter data from neonates who were smallor gestational age (SGA) were removedrom the calculations related to specificefects, only the association between co-rctation/aortic arch hypoplasia and mi-rocephaly remained significant, and itas slightly less significant than it hadeen when all neonates were consideredogether. The researchers attributed theoss of significance in the relationshipsetween microcephaly and tetralogy ofallot and hypoplastic left ventricle withhe resulting small sample size. This ismportant, since the definition of micro-ephaly is less clear in infants with intra-terine growth retardation (IUGR).owever, it is possible that IUGR, in it-
elf, is a risk factor for poor outcome;hat it might contribute disproportion-tely to a poor prognosis. For example,ight it be possible that the lost associa-
ion between microcephaly and specificHDs was not a result of small sample
ize but to a lower prevalence of micro-ephaly among neonates who had aHD but were of normal size? Perhaps
he group of neonates who were SGAhould be studied separately, as well. Athis time, the best in utero evaluationnd management of a fetus with IUGRnd an associated congenital anomalyas yet to be determined.
HALLENGES AHEAD
hen investigating the limitations of aetrospective study, it is always temptingo ask for a prospective trial to follow uphe findings. The study by Barbu et alaises many important questions includ-ng whether compromised fetuses can bedentified before delivery, what form the
ompromise takes, whether the process fan be monitored and/or interrupted,nd whether aggressive intervention inhe natural history of these disorders im-roves outcome. In studying the associ-tion between microcephaly and CHDs,here are some obvious limitations to arospective approach. First, we would
ikely not ascertain all cases of CHD, asany go undetected prenatally. Further-ore, it is also difficult to make a pro-
pective diagnosis of IUGR and micro-ephaly.
Presumably, the only way to preventngoing damage is to identify a fetus atisk and intervene to correct the prob-em. The authors suggest that once a di-gnosis of a CHD and microcephaly areade, follow-up might include non-
tress testing, biophysical profiles, andoppler studies of blood flow to theead. Yet, it is not clear that testingould determine which fetuses wouldltimately have a neurologic insult orhich would be at risk of an insult thatas yet to occur. At present, correcting
nadequate oxygenation is only possiblehrough early delivery, but prematuritylso has a clear association with develop-ental delay. In short, we are far from
eing able to make clinical recommen-ations based on findings from thistudy.
Another issue of concern is the likeli-ood of false-positive results with ante-atal testing. Though the suggested testseem like reasonable, noninvasive, mon-toring tools, all forms of antenatal test-ng have a false-positive rate. Again, theesults could lead to iatrogenic prematu-ity, and this could add to the burden ofhe infant’s physical condition, sinceremature babies with cyanotic CHDave a poorer prognosis than those whoave been delivered at term.Our difficulty, therefore, does not lie
n the way Barbu and colleagues per-
ormed the study, but rather in what we,JULY 2009 Am
s clinicians, should do with the infor-ation it provides. This study advances
ur knowledge of the natural history ofhese disorders but offers no firm guid-nce on how the data should be appliedo our patients. The authors correctlytate that their tentative recommenda-ions for antenatal testing and consider-tion of early delivery are, at the mo-ent, without adequate support.
ournal Club members wholeheartedlygreed with this point and were ex-remely concerned about the potentialownside of these recommendations.onetheless, this necessary work fur-
hers our understanding of these disor-ers, their progression in utero, and howhey adversely affect the fetus. Generally,he group found the work to be a wel-ome advance. However, we felt thendings could not be used to formulateecommendation for obstetric manage-ent. Our Journal Club panel was not
onvinced that early delivery would leado better outcomes, and therefore, wegreed that it was not indicated in theseabies.This article explores a new and essen-
ial field. The fetus is often cared for in atepwise fashion by specialists, whereashe best approach to understanding andending to these patients is to offer a con-inuum of care from a team of providersho bring their own viewpoints to the
able. Still, even when a team of experts isn place, its members often do not havehe detailed information about the natu-al history of a given fetal disorder, andhis makes it difficult to determine theest therapeutic plan. The work byarbu and colleagues emphasizes that
his is indeed the case with CHDs, but itlso gives us a better insight into the chal-enges ahead. f
erican Journal of Obstetrics & Gynecology 119