JPediatr(RioJ).2017;93(5):437---438
www.jped.com.br
EDITORIAL
A
closer
look
at
the
fetal
programming
hypothesis
with
obstetric
ultrasound
夽
,
夽夽
Uma
análise
mais
profunda
da
hipótese
de
programac
¸ão
fetal
com
ultrassom
obstétrico
Henning
Tiemeier
ErasmusMedicalCenterRotterdam,DepartmentofChildandAdolescentPsychiatry,Rotterdam,Netherlands
Most, if not all, pregnant women in developed countries willhaveanultrasoundexaminationtotimepregnancyand assessthehealthanddevelopmentoftheembryoorfetus. Nonetheless,surprisinglyfewcohortstudieshaveused rou-tinehealth care or researchultrasound datato test their hypotheses.Repeatedultrasoundassessmentsduring preg-nancyoffertheopportunity toexaminetheassociationof intra-uterine exposures with fetalgrowth and the associ-ation of fetal growth patternswith child outcomes. Most studiesoffetalprogrammingsimplyrelyonaproxy measure-mentoffetalgrowth:maternalor midwifereportofbirth weight.Birthoutcomesareonly crudesummarymeasures offetalgrowthandcannotprovideinformationongrowth acrossdifferent timesin pregnancy.Furthermore, individ-ualsmayreachthesamebirthweightthroughdifferentfetal growthtrajectories.Pintoetal.aretobecomplimentedfor theusestandardized clinicalultrasoundconductedbyone cliniciantotestanimportantpublichealthquestion:do chil-drenofanxiousordepressedmothershaveaworsestartto lifeevenbeforetheyareborn?1
夽 Pleasecitethisarticleas:TiemeierH.Acloserlookatthefetal
programminghypothesiswithobstetricultrasound.JPediatr(Rio
J).2017;93:437---8.
夽夽SeepaperbyPintoetal.inpages452---9.
E-mail:[email protected]
Depressionandanxietyduringpregnancyhavebeen asso-ciated with numerous poor child outcomes, but several importantquestionsremain:howmuchoftheobserved asso-ciation between maternal psychiatric problems and child development is due to confounding by lifestyle or back-ground factors such as socio-economic status; how much isduetogeneticeffectsonmaternalpsychopathologyand childdevelopment;istheprenataldevelopmentparticularly vulnerabletodepressionoranxietyinspecificperiods;and cantheeffectsofanxietyordepressionbedifferentiated?
Inthepastyears,wehavewitnessedseveralapproaches toaddress thecausalityof intra-uterineexposure associa-tions;someof thesecast doubtonthefetalprogramming hypothesis. Sibling designs suggest that many potential side-effects of antidepressant drug use during pregnancy probably reflect background risks.2 Comparative tests of the associations of paternal and maternal exposure dur-ing pregnancy suggest that the association of maternal depressionwithADHDcanbestbeexplainedby confound-ingfactors,aspaternaldepressionwassimilarlyassociated withthisoutcome.3Sometimes,geneticvariantsrelatedto anexposurecanhelpidentifywhetheranassociationofan intrauterineexposurewithachildoutcomeiscausal. How-ever,suchaMendelianrandomizationapproachistricky,as pregnancyconstitutesashortexposureperiodtomaternal genes.Nonetheless,thisapproachprovidedinitialevidence thatevenverymoderatealcoholconsumptionduring preg-nancyhasnegativeeffectsonchild development.4Others
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438 TiemeierH
have usedfrequently repeatedmeasures of depression to identify a time during pregnancy when the offspring is particularlyvulnerable--- but resultssuggest that the vul-nerability does not vary.5 Pinto et al. address another question important to ourcausal understanding1: arethe observed associations of depression and anxiety specific? Theirresults are in line with observationsfrom the work ofourandothergroups,thatanxietyduringpregnancy typ-icallyhasmuchstrongereffectsonchilddevelopmentthan depression.6 Interestingly, pregnancy-specific anxiety has beenincreasinglyrecognizedasanimportantriskfactorfor neurodevelopmental outcomes. In contrast, the observed associations attributed todepressive symptoms are often betterexplainedby confounders,comorbid anxiety symp-toms, or postnatal depression. Moreover, as Pinto et al. rightlyemphasize,itmattershowsymptomsaremeasured, astraits,asstates,andifthesameorspecificinstruments areused.1
Finally,Iwouldliketopoint outthattheeffectsizeof theobservedassociationbetweenanxietyduringpregnancy andfetalweightgaininthepresentstudyisimprobable.A childborntoananxiousmotherintheCentroHospitalardo Portowasmorethan800glighteratbirththanachildofa non-anxiousmother.1Evengiventhewideconfidence inter-val,this effectsizeis notrealistic.Theauthors discussed selectionbias--- apossibleexplanation,butIamconvinced thatthiseffectsizeismorelikelytoreflectachance find-ing or a confounding factor. Henrichs et al., in a much larger,verywellcontrolledstudy intheNetherlands using repeatedobstetric ultrasound assessments,observed that motherswithsignificant symptomsofanxietyduring preg-nancyhadfetuseswhogrewataratethatwas3.2g/week lower.7 This study from my group was embedded in the Generation R Study (‘‘R’’ stands for Rotterdam), a large longitudinal,population-basedcohort followingmorethan 8000 children from fetal life onwards. There have been multiple time points of data collection on that cohort, withdata at age 10 yearsmost recently completed. The repeatedfetalultrasounds, combined withdetailed preg-nancyquestionnaires,offeredGenerationRresearchersthe mostuniqueopportunities.Moreover,formanymothersthe ultrasoundassessmentswerethereasonstoparticipatein the cohort in the first place; in the early 2000s, routine obstetricultrasoundwasnotapart ofthe regular health-care system, nor was it reimbursed by the insurers. The GenerationRresearchersstudiedtrajectoriesoffetalhead growth to test whether maternal exposures during preg-nancyhadanimpactonearlyneurodevelopment.Notonly maternal depression andanxiety, but alsosmokingduring pregnancy, maternal serotonin-specific reuptake inhibitor (SSRI)use,lackoffolicacidsupplementation,andcannabis exposure all negatively affected fetalhead growth.8 Fur-thermore, this data was used to address the association
betweenintrauterinegrowthtrajectoriesandchild develop-ment,adoptingsimilarstatisticaltechniquesasPintoetal. Wefoundsupportforarelationofintrauterineheadgrowth withobservedmotordevelopment,butnotwithbehavioral or emotional problemsof infants andpreschoolchildren.9 However, morestudies addressing the importantquestion ofifandhowanxietyanddepressionofthemotherduring pregnancyaffecttheoffspringarenecessary.Thestudyby Pintoetal.isawonderfulreminderthatobstetricultrasound isatoolunderutilizedbyresearcherstohelpanswerthese questions‘‘veryrelevanttopublichealth’’.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
References
1.Pinto TM, Caldas F, Nogueira-Silva C,Figueiredo B. Maternal depressionandanxietyandfetal-neonatalgrowth.JPediatr(Rio J).2017;93:452---9.
2.FuruK,KielerH,HaglundB,EngelandA,SelmerR,Stephansson O,etal.Selectiveserotoninreuptakeinhibitorsandvenlafaxine inearlypregnancyand riskofbirthdefects:populationbased cohortstudyandsiblingdesign.BMJ.2015;350:h1798.
3.VanBatenburg-EddesT,BrionMJ,HenrichsJ,JaddoeVW, Hof-man A, Verhulst FC, et al. Parental depressive and anxiety symptomsduringpregnancyandattentionproblemsinchildren: a cross-cohort consistency study. J Child Psychol Psychiatry. 2013;54:591---600.
4.MurrayJ,BurgessS, ZuccoloL,HickmanM,GrayR,LewisSJ. Moderatealcoholdrinking inpregnancyincreases riskfor chil-dren’spersistentconductproblems:causaleffectsinaMendelian randomisationstudy.JChildPsycholPsychiatry.2016;57:575---84.
5.LahtiM,SavolainenK,TuovinenS,PesonenAK,LahtiJ,Heinonen K,etal.Maternaldepressive symptomsduringandafter preg-nancy and psychiatric problems in children. JAm Acad Child AdolescPsychiatry.2017;56,30---9.e7.
6.vanBatenburg-EddesT,deGrootL,HuizinkAC,SteegersEA, Hof-manA,JaddoeVW,etal.Maternalsymptomsofanxietyduring pregnancyaffectinfantneuromotordevelopment:the Genera-tionRstudy.DevNeuropsychol.2009;34:476---93.
7.Henrichs J, Schenk JJ, Roza SJ, van den Berg MP, Schmidt HG, Steegers EA, et al. Maternal psychological distress and fetalgrowthtrajectories:theGenerationRstudy.PsycholMed. 2010;40:633---43.
8.TiemeierH,VeldersFP,SzekelyE,RozaSJ,DielemanG,Jaddoe VW,etal.TheGenerationRstudy:areviewofdesign,findings todate,andastudyofthe5-HTTLPRbyenvironmental interac-tionfromfetallifeonward.JAmAcadChildAdolescPsychiatry. 2012;51,1119---35.e7.
