the effect of prenatal antidepressant exposure on neonatal adaptation a systematic review and...

8/13/2019 The Effect of Prenatal Antidepressant Exposure on Neonatal Adaptation a Systematic Review and Metanalysis

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e309J Clin Psychiatry 74:4, April 2013

F W M H

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The Effect of Prenatal Antidepressant Exposure onNeonatal Adaptation: A Systematic Review and Meta-Analysis

Sophie Grigoriadis, MD, PhD, FRCPC; Emily H. VonderPorten, MPH; Lana Mamisashvili, MSW;

Allison Eady, BA; George Tomlinson, PhD; Cindy-Lee Dennis, PhD; Gideon Koren, MD, FRCPC, FACMT;Meir Steiner, MD, PhD, FRCPC; Patricia Mousmanis, MD, CCFP, FCFP; Amy Cheung, MD, MSc, FRCPC;and Lori E. Ross, PhD

ABSTRACT

Objective:Conflicting reports on potential risks of

antidepressant exposure during gestation for the infant

have been reported in the literature. This systematic review

and meta-analysis on immediate neonatal outcomes were

conducted to clarify what, if any, risks are faced by infants

exposed to antidepressants in utero. Subanalyses address

known methodological limitations in the field.

Data Sources:MEDLINE, EMBASE, CINAHL, and PsycINFOwere searched from their start dates to June 2010. Various

combinations of keywords were utilized including, but not

limited to, depressive/mood disorder, pregnancy/pregnancy

trimesters, antidepressant drugs, and neonatal effects.

Study Selection:English language and cohort and case-

control studies reporting on a cluster of signs defined as

poor neonatal adaptation syndrome (PNAS) or individual

clinical signs (respiratory distress and tremors) associated with

pharmacologic treatment were selected. Of 3,074 abstracts

reviewed, 735 articles were retrieved and 12 were included

in this analysis.

Data Extraction:Two independent reviewers extracteddata and assessed the quality of the articles.

Results:Twelve studies were retrieved that examined PNAS

or the signs of respiratory distress and tremors in the infant.

There was a significant association between exposure to

antidepressants during pregnancy and overall occurrence

of PNAS (odds ratio [OR]=5.07; 95% CI, 3.257.90; P


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Grigoriadis et al

ClinicalPoints

Antidepressant exposure during pregnancy may be

associated with poor neonatal adaptation syndrome (PNAS)

in the infant.

Antidepressant exposure during pregnancy may be

associated with respiratory distress and tremors in the infant.

Clinicians must inform and prepare women taking

antidepressants during pregnancy that their infant may

show signs of PNAS and, in case they occur, how they

will be managed.

DATA SOURCES AND STUDY SELECTION

This study is part of a larger program of research exam-ining the effect of perinatal antidepressant medication useas well as depression itself on outcomes; the methods havebeen described in detail elsewhere.13Briefly, 2 professionallibrarians, with expertise in the areas of psychiatry andpsychopharmacology, completed the literature searches

independently. Various combinations of keywords wereutilized, including but not limited to depressive/mooddisorder, pregnancy/pregnancy trimesters, antidepressantdrugs, and neonatal effects(full list of keywords providedin supplementary material). The databases and vendorsused included MEDLINE (Ovid), MEDLINE In-Process(Ovid) to access current literature (keyword searching only),PsycINFO (American Psychological Association; Ovid),CINAHL (Nursing; Allied Health), EMBASE (ExerptaMedica, Elsevier; Ovid), and Scopus (Elsevier) to accesscurrent literature (keyword searching only). Each databasewas searched from its start date to June 30, 2010. Reference

lists in reviews and meta-analyses were searched but did notproduce any further references.

Inclusion and Exclusion Criteria

Cohort and case-control studies were included in themeta-analysis if they (1) were published in the English lan-guage; (2) reported original data; (3) reported on neonataleffects following any antidepressant exposure, including(but not limited to) selective serotonin reuptake inhibitors,tricyclic antidepressants, and monoamine oxidase inhibi-tors; (4) included a comparison group of pregnant womennot exposed to the antidepressant examined; and (5) pro-

vided sufficient data to calculate an effect size if it was notprovided. Because of the volume of potentially eligiblestudies, we excluded abstracts and conference proceedingsand did not search for unpublished data. The followingoutcomes were included in this meta-analysis: PNAS, respi-ratory distress, and tremors as defined by the authors of theoriginal publication. During the review of the literature, itbecame clear that many definitions are used for the clus-ter of signs identified as PNAS and that the wide varietyof signs included in studies of PNAS makes it difficult topool studies for a meta-analysis. We included all studies thatdefined PNAS as the presence of 1 or more of the followingsigns: tremors or shaking, jitteriness, shivering, agitation,

irritability, increased or decreased muscle tone, poor feed-ing, excessive weight loss, seizures, tachypnea or respiratorydistress, hypothermia, or hypoglycemia. We specificallyselected signs of respiratory distress (respiratory distressortachypneawhen respiratory distress was not listed as a sign)and tremors (or shakingif tremors was not listed as a sign)for further examination, as these signs were deemed the mostimportant clinically, based on feedback by our advisory com-

mittee of key stakeholders (including representatives frompsychiatry, family medicine, obstetrics, neonatology, publichealth, patient advocacy, and policy) that was assembled forthis program of research.

DATA EXTRACTION

The data extraction and quality assessment processesemployed in this research program have been described indetail elsewhere.13In brief, 2 independent research assistantsscreened the titles and abstracts of articles, relevant abstractswere reviewed, and those articles meeting inclusion criteriawere retrieved. Data extraction forms were modeled after

the Strengthening the Reporting of Observational Studies inEpidemiology (STROBE) statement14to record relevant datafrom all eligible studies. The extracted data included source,study design, participants (sample, control, demographicsand clinical characteristics), inclusion/exclusion criteria,antidepressants examined, dosage, duration of exposure,primary and secondary outcomes, outcome assessmentmethods, and loss to follow-up. For publications in whichnot all data were provided, we contacted the authors withrequests for raw data. We extracted adjusted estimates andtheir variances where they were available. If no adjustedestimates were provided, crude ORs or differences in means

(and sample variances) were computed from the publisheddata. We added 0.5 to all cells in studies with a 0 cell countwhen calculating the OR.

Quality Assessment

The quality assessment tool used for this investigationhas been described in detail elsewhere.13In brief, the Sys-tematic Assessment of Quality in Observational Research(SAQOR) was based on existing quality assessment instru-ments, including the checklist developed by Downs andBlack15and the Newcastle-Ottawa Scale,16and adapted toassess the specific criteria necessary for evaluation of data

presented in this area of research. Research staff evaluateda total of 19 criteria under the following categories for eachstudy by outcome: (1) sample, (2) control group, (3) qualityof exposure/outcome measure, (4) follow-up, and (5) dis-torting influences.The last category specifically includedassessment as to whether analyses controlled for depres-sion, other psychotropic medications, and other potentiallyrelevant confounders, such as smoking, alcohol, and illicitdrug use. On the basis of scores on the quality criteria evalu-ated, a final quality rating (high, moderate, low, very low)was assigned by using a modification of the Grading of Rec-ommendations Assessment, Development and Evaluation(GRADE) system.17High, moderate, and low were deemed


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above quality threshold, whereas the very low were belowquality threshold. Data extraction and quality assessmentresults for each study were compared between raters, withany differences discussed with the principal investigatorsuntil consensus was reached.

Statistical Analyses

In the few cases in which adjusted hazard ratios or rela-tive risks were reported, we treated these as estimated oddsratios. The DerSimonian and Laird random-effects modelwas used to obtain pooled estimates of the OR for binaryoutcomes and the weighted mean difference for continu-ous outcomes.18When only 2 studies published data on anoutcome, we used a fixed-effects pooled estimate. Publica-tion bias was assessed by visual inspection of funnel plotsdepicting the individual study estimates (on the log scalefor ORs) against their standard error. Further, the numberof unpublished studies (k) was estimated by using theL estimator developed by Duval and Tweedie.19In brief, if

k was 1 or more, then k studies were imputed by reflectionof the k largest effects around the summary estimate. Thestandard errors of the k reflected studies were used for thek imputed ones and the summary OR was reestimated inthis expanded dataset. If k was estimated to be 0, then therewas no evidence for publication bias. For studies with pub-lication bias, Duval and Tweedies trim-and-fill method19was used to estimate exposure effects after adjusting forpotential publication bias. Between-study heterogeneity wasassessed by Cochrane Qand visual inspection of forest plotsand quantified by I2.

A nonsignificant Q and small I2 suggest a commonunderlying effect and that variations in estimated study

effects are due only to random variation and not true study-to-study variation (heterogeneity). I2can be interpreted asthe proportion of the total variance due to heterogeneity.In one interpretation, I2= 25% represents a low degree ofheterogeneity; 50%, a moderate degree; and 75%, a highdegree.20Subgroup analyses were run (regardless of whetherQwas significant) to explore sources of heterogeneity by

examining within-group effects and between-group differ-ences in pooled effects based on several study characteristicschosen a priori: whether a convenience sample was used (ie,not consecutive or random sample), study quality (ie, thoseabove threshold compared with those below), timing ofexposure, and the use of adjusted data. The metafor pack-age21in R (2.14.2)22was used for the statistical analyses.

RESULTS

Of the 3,074 abstracts reviewed, 2,339 were excluded basedon title and abstract. In total, 735 articles were retrieved andassessed for eligibility and 15 articles met the inclusion crite-

ria (Figure 1).

23

Of these, 3 articles were excluded because 1did not have a control group without antidepressant use forthis outcome,51 did not report on the necessary outcomes,24and 1 did not have a comparable outcome measure,25leaving12 studies for inclusion in the quantitative analysis (Table1).8,10,12,2634Most studies reported data on more than 1 out-come (8 reported on neonatal adaptation syndrome overall,9 on respiratory signs, and 4 on tremors or shaking). Sevenstudies used a convenience sample, while 5 studies usedeither a population- or hospital-based sample. Eleven of the12 studies were above our quality threshold. Seven studiesconfirmed third trimester or late exposure. Three studiesprovided adjusted data.

Figure 1. Identification of Independent Studies for Inclusion in Meta-Analysis (adapted fromPRISMA 2009 flow diagram23)

3,073 Records identified throughdatabase searching

1 Additional record identifiedthrough other sources

2,339 Records excluded3,074 Records screened

12 Studies included inquantitative synthesis

(meta-analysis)

735 Full-text articlesassessed for eligibility

Identification

Screening

Eligibility

Inc

luded

723 Full-text articles excluded, with reasons

75 Nonpharmacologic interventions

178 Risk factors for antenatal depression

242 Impact of maternal depression

120 Postpartum treatment

47 Case reports/series

39 Other outcomes of interest

20 Insufficient data

2 PNAS but not an outcome of interest oroutcome measure not adequate


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Strengths and Limitations

The strength of our work rests on the attention paid topotential confounding factors and consideration of meth-odology. The research examining the potential effects ofprenatal antidepressant exposure has been criticized forweak methodology in general37and for neglecting to accountfor potential confounders known to affect pregnancy out-comes. In response, we pooled estimates for all studies, usingadjusted data where possible, and then examined the effect ofmoderator variables that we identified a priori. We assessedthe studies for the effect of using convenience samples (ie,

those that were not recruited using consecutive or randomsampling strategies) and whether study quality affectedinterpretation. Moreover, we contrasted results by usingpooled estimates for studies that did and did not adjust forconfounders the authors of the original publication deemedimportant. We examined the data for a potential effect fortiming of exposure,38as it has been suggested that third tri-mester exposure may be an important factor in whether theneonate displays PNAS.10 Most of the moderator variablesdid not appear to affect the significance of the results, a find-ing that suggests a genuine effect of the antidepressants, asalmost all subanalyses remained significant and not sig-

nificantly different from one another, except one. The useof convenience samples did appear to result in statisticallyhigher OR for respiratory distress than the studies that didnot use convenience samples. Given that the conveniencesamples were ones that were not based on random or con-secutive sampling, they may have been biased in favor of theinfant displaying respiratory distress and inflating the OR.Regardless, the analysis with nonconvenience samples wasalso statistically significant. Overall, the data exhibit a robusteffect, with consistently elevated ORs over 2 suggesting theresults are clinically significant as well.39The robustness ofthe OR is reassuring, as it is unethical to conduct the goldstandard of randomized controlled trials with pregnant and

Figure 2. Exposure to Any Antidepressant and the Risk of Poor Neonatal Adaptation Syndrome a

Study

Odds

Ratio 95% CI

Weight

(fixed), %

Weight

(random), %

Costei et al,262002 7.26 0.8959.09 4.5 4.5

Laine et al,272003 6.93 1.5331.38 8.6 8.6

Oberlander et al,102004 4.59 0.9522.31 7.9 7.9

Levinson-Castiel et al,82006 52.67 3.09898.14 2.5 2.5

Ferreira et al,30

2007 3.10 1.337.24 27.4 27.4

Maschi et al,322008 3.67 1.1611.58 14.9 14.9

Boucher et al,312008 7.00 3.2015.31 32.2 32.2

Rampono et al,342009 2.53 0.1255.55 2.1 2.1

Fixed-effects model 5.07 3.257.90 100

Random-effects model 5.07 3.257.90 100

Heterogeneity: I2=0%, 2=0,P=.6174

aMeta-analysis results for all studies.

0.01 0.1 1 10 100

higher ORs for the convenience samples and studies belowquality threshold.

Publication Bias

We did not find evidence for the presence of publicationbias in our main PNAS analysis; heterogeneity was not sig-nificant, the funnel plot appeared symmetric around 5, and,when the L estimator of Duval and Tweedie was used,19theredid not appear to be missing studies. There did appear tobe publication bias for the individual symptoms analyses,although the impact was minor on the estimates. For the

respiratory distress analysis, the adjusted OR, which wasderived from the trim-and-fill procedure,19was 2.00 (95%CI, 1.592.52; P< .0001). The trim-and-fill procedure yieldedan adjusted OR of 5.17 (95% CI, 2.1112.73; P< .003) for thetremors outcome.

DISCUSSION

The objective of this study was to determine if any rela-tionship exists between prenatal antidepressant exposureand poor immediate neonatal outcomes. The results of ourmeta-analysis suggest that there is a genuine increased riskfor PNAS. Moreover, as this syndrome appears not to be

uniformly defined, we further examined 2 specific clinicalsigns, namely, respiratory distress and tremors; a significantassociation was also shown for the aforementioned signs andthe infant having been exposed to antidepressants in utero.To our knowledge, ours is the first meta-analysis to examinePNAS as a syndrome as well as individual signs with anti-depressant exposure at any point in pregnancy. Our results aresimilar to those of Lattimore and colleagues,11despite theirinclusion of only 3 studies (Hendrick et al,35Chambers et al,5and Goldstein et al36) of their pooled 6 that did not provideunexposed control group data. We did not include Zeskindet al,25which was included in the Lattimore et al analysis,11because the frequency of tremors was not provided.


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depressed women to definitively determine any potentialadverse effects of these medications, and we are still cur-rently limited to observational research.

It is important to note that not all of the studies includedin this meta-analysis defined PNAS in the same way; 2 usedan objective scoring system to measure it, although eachapplied the system slightly differently, and 1 used a scale(ie, Levinson-Castiel,8 Rampono,32 and Laine25). Severalresearchers have identified different clusters of signs thatthey found to be associated with antidepressant exposureduring pregnancy. The studies included in this meta-analysishad significant overlap in the clinical signs they identified,but they were also diverse. We also assessed the presence of2 individual signs that experts in our advisory committeeagreed are highly specific to this syndrome, at least clini-cally, and they were also significant. Although we analyzed

the 2 individual signs to circumvent the diversity in the waythe syndrome was operationalized at the time the originalstudies were conducted, this method can also be considered

a limitation of our meta-analysis, as the signs we chose maynot be universally accepted as always occurring in this syn-drome. Although we grouped studies according to timing ofexposure, we were able to segregate only those that did anddid not report third trimester exposure. Thus, the studiesin the not confirmed category had infants exposed fromany trimester of pregnancy, which could have included thethird.

It is important that future studies specify timing of expo-sure by trimesters of pregnancy to definitively determinewhether timing is an important factor for the emergenceof PNAS. Moreover, future studies should objectively mea-sure PNAS, preferably with a validated assessment measure.

Table 2. Exposure to Any Antidepressant and Risk of Poor Neonatal Adaptation Syndrome (PNAS) or Signs: Meta-AnalysesResults

TotalSample

Size

Within Group

No. ofStudies

No. ofCases

Heterogeneity Effect of Moderator

Analysis OR (95% CI)a PValueQ(df)

Within PValue I2(%)Q(df)

Between PValue I2(%)

PNAS overall

All studies 8 270 959 5.07 (3.257.90) < .0001 5.357 .617 0.0Study type

Convenience sample 6 167 693 3.96 (2.286.85) < .0001 1.305 .935 0.0 1.41 .237 26.0Not convenience sample 2 103 266 11.89 (2.0967.76) .005 1.811 .179 45.0

Study qualityAbove quality threshold 7 185 813 4.34 (2.537.45) < .0001 4.386 .625 0.0 0.971 .325 18.0Below quality threshold 1 85 146 7.00 (3.2015.31)b < .0001

Timing of exposureExposed late 5 226 794 5.13 (2.869.21) < .0001 4.984 .290 20.0 0.000531 .982 0.0Unsure/not exposed late 3 44 165 5.20 (1.8614.57) .002 0.372 .831 0.0

ConfoundersAdjusted findings 2 181 312 4.74 (2.1410.52) < .0001 1.911 .167 48.0 0.071 .794 1.0Unadjusted findings 6 89 647 5.46 (2.7210.97) < .0001 3.365 .644 0.0

Respiratory distress

All studies 9 23,224 676,186 2.20 (1.812.66) < .0001 12.98 .116 38.0Study type

Convenience sample 4 78 349 4.18 (2.297.60) < .0001 2.403 .493 0.0 5.41 .020 42.0Not convenience sample 5 23,146 675,837 2.01 (1.762.30) < .0001 4.84

4

.304 17.0Study quality

Above quality threshold 8 23,174 676,040 2.20 (1.792.72) < .0001 12.67 .081 45.0 0.01 > .999 0.0Below quality threshold 1 50 146 2.50 (1.145.49)b .022

Timing of exposureExposed late 6 5,536 76,657 2.64 (1.694.14) < .0001 7.945 .160 37.0 0.61 .440 5.0Unsure/not exposed late 3 17,688 599,529 2.14 (1.602.86) < .0001 4.852 .089 59.0

ConfoundersAdjusted findings 2 16,410 583,939 2.24 (1.752.86) < .0001 0.091 .770 0.0 0.021 .880 0.0Unadjusted findings 7 6,814 92,247 2.30 (1.723.08) < .0001 12.156 .059 51.0

Tremors

All studies 4 106 482 7.89 (3.3318.73) < .0001 5.413 .144 44.5Study type

Convenience sample 2 34 216 11.31 (0.63204.37) .100 3.701 .054 73.0 0.031 .857 1.0Not convenience sample 2 72 266 8.59 (4.1417.81) < .0001 0.761 .384 0.0

Study quality

Above quality threshold 3 82 336 6.74 (2.3919.03) .0003 4.112 .128 51.0 0.781 .376 14.0Below quality threshold 1 24 146 15.31 (3.4568.06)b .0003Timing of exposure

Exposed late 4 106 482 7.89 (3.3318.73) < .0001 5.413 .144 44.5Unsure/not exposed late 0 0 0

ConfoundersAdjusted findings 0 0 0Unadjusted findings 4 106 482 7.89 (3.3318.73) < .0001 5.413 .144 44.5

aPooled effect size estimated using random-effects model.bPooled effect size estimated using fixed-effects model.


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The decision of whether or not to use antidepressantmedication requires weighing the risks of the effects ofdepression itself as well as the effects of the medication onthe fetus, neonate and child; beneficial effects on the motherand risk of relapse if medication is discontinued must also bereviewed. Both mother and baby must be considered in anydecision. Women who choose to use antidepressant medica-tion while pregnant must be counseled that the infant may

develop PNAS, and that, to date, data suggest this syndrome isusually transient, although more severe symptoms have beenreported. The woman and her family must be supported intheir decision regarding the use of antidepressant medica-tion and assured that should complications arise, they will beidentified and treated immediately. This work highlights theongoing need to collaborate with the entire health care teamand in particular increase the awareness of neonatologistsof antidepressant exposure in the infant such that appropri-ate care is expeditiously provided if necessary. Moreover, thefamily may require ongoing support if a prolonged neona-tal intensive care unit admission occurs; arrangements for

such can be more quickly arranged if clinicians have priorknowledge.

Drug names:citalopram (Celexa and others), clonazepam (Klonopin andothers), fluoxetine (Prozac and others), fluvoxamine (Luvox and others),mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva, and others),sertraline (Zoloft and others), trazodone (Oleptro and others), venlafaxine(Effexor and others).

Author affiliations:Department of Psychiatry, Womens College Hospital,Toronto (Dr Grigoriadis and Mss VonderPorten, Mamisashvili, and Eady);Womens College Research Institute, Toronto, (Drs Grigoriadis and Dennis);Department of Psychiatry, University Health Network, and Clinical TrialsResource Center, Toronto General Research Institute (Dr Grigoriadis);Department of Psychiatry, Sunnybrook Health Sciences Center, Toronto(Drs Grigoriadis and Cheung and Mss VonderPorten and Mamisashvili);Sunnybrook Research Institute, Toronto (Drs Grigoriadis and Cheung);

Department of Psychiatry (Drs Grigoriadis, Dennis, Cheung, and Ross),Department of Medicine (Dr Tomlinson), Faculty of Nursing (Dr Dennis),Departments of Pediatrics, Pharmacology, Pharmacy, and Medical Genetics(Dr Koren), and Institute of Medical Sciences (Dr Steiner), Universityof Toronto, Toronto; Center for Innovation in Complex Care, TorontoGeneral Hospital, Toronto (Dr Tomlinson); Division of Clinical Decision-Making and Health Care, Toronto General Research Institute, Toronto(Dr Tomlinson); Motherisk Program, The Hospital for Sick Children, Toronto;and Departments of Medicine, Pediatrics and Physiology/Pharmacology,University of Western Ontario, London (Dr Koren); Departments ofPsychiatry and Behavioural Neurosciences and Obstetrics and Gynecology,McMaster University; Womens Health Concerns Clinic, St Josephs Hospital;and St Josephs Healthcare, Hamilton (Dr Steiner); Healthy Child DevelopmentProgram, Ontario College of Family Physicians, Toronto; York CentralHospital, Richmond Hill; and Markham Stouffville Hospital, Markham (DrMousmanis); and Center for Addiction and Mental Health, Toronto (Dr Ross),

Ontario, Canada. Dr Grigoriadis is now with the Department of Psychiatry,Sunnybrook Health Sciences Center, and Sunnybrook Research Institute,Toronto. Mss VonderPorten and Mamisashvili are with the Department ofPsychiatry, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.

Author contributions:Conception and design: Drs Grigoriadis and Ross; dataanalysis and interpretation: Drs Grigoriadis, Tomlinson, Ross, Dennis, Koren,Steiner, Mousmanis, and Cheung and Mss VonderPorten, Mamisashvili,and Eady; drafting or revision of the manuscript: Drs Grigoriadis, Ross,Tomlinson, Dennis, Koren, Steiner, Mousmanis, and Cheung and MssVonderPorten, Mamisashvili, and Eady; and approval of the final versionof t he manuscript for publication: Drs Grigoriadis, Ross, Tomlinson,Dennis, Koren, Steiner, Mousmanis, and Cheung and Mss VonderPorten,Mamisashvili, and Eady. Drs Grigoriadis and Ross had full access to all ofthe data in the study and take responsibility for the integrity of the data andthe accuracy of the data analysis.Potential conflicts of interest:In the last 5 years, Dr Grigoriadishas receivedhonoraria as a consultant and a member of an advisory committee or for

lectures from Wyeth Pharmaceuticals, GlaxoSmithKline, Pfizer, Servier, EliLilly Canada, and Lundbeck; and has received research grant support fromthe Canadian Institutes of Health Research (CIHR), Ontario Ministry ofHealth, Ontario Mental Health Foundation, and CR Younger Foundation.Dr Steiner has been a consultant to AstraZeneca, Azevan, Servier, BayerCanada, and Lundbeck; has received grant/research support from CIHR,Pfizer, Eli Lilly, and Lundbeck; and has received honoraria from the Society forWomens Health Research and AstraZeneca. Drs Tomlinson, Dennis,Koren,Mousmanis, Cheung, and Ross and Mss VonderPorten, Mamisashvili, andEadyhave no f inancial disclosures to report.Funding/support:This research was funded by a Research Syntheses grantfrom the CIHR, KRS-83127, and the Ontario Ministry of Health andLong-Term Care through the Drug Innovation Fund, grant # 2008-005.Dr Grigoriadis has a new investigator award in womens health research fromthe CIHR in partnership with the Ontario Womens Health Council, awardNOW-88207. Dr Ross is supported by a new investigator award from CIHRand the Ontario Womens Health Council, award NOW-84656. In addition,support to the Center for Addiction and Mental Health for salary of scientistsand infrastructure has been provided by the Ontario Ministry of Health andLong-Term Care.Disclaimer:The views expressed here do not necessarily reflect those of theMinistry of Health and Long-Term Care.Previous presentations:Preliminary results of this study were presentedat the Motherisk Update 2012 (paper title: The effect of antidepressantmedications on mothers and babiesan updated systematic analysis);May 23, 2012; Toronto Ontario, Canada Canadian Psychiatric AssociationConference (paper title: Evidence-based discussion guide for antidepressant

treatment in depressed pregnant and postpartum women); October 1315,2011; Vancouver, British Columbia, Canada Canadian Institutes for HealthResearch, Innovations in Gender, Sex and Health Research Conference (papertitles: [1] Effects of in utero exposure to antidepressant medication duringpregnancy: a meta-analysis and [2] Short-term and long-term impact ofuntreated maternal depression on the child); November 2223, 2010; Toronto,Ontario, Canada Canadian Psychiatric Association Conference (paper t itle:Outcomes associated with antidepressant medication use during pregnancy:a meta-analysis); September 2326, 2010; Toronto, Ontario, Canada 36thAnnual Meeting of the North American Society for Psychosocial Obstetricsand Gynecology (poster title: Preliminary results from the Reproductive LifeStages Algorithm Project: use of antidepressant medication during pregnancyand lactation: development of an evidence-based decision tool); February1013, 2010; Richmond, Virginia Organization for the Study of SexDifferences 3rd Annual Meeting (poster title: An evidence-based algorithmto quantify risk-benefit decision-making for use of antidepressant medication

during pregnancy and lactation); June 46, 2009; Toronto, Ontario, Canada

35th Annual Meeting of t he North American Society for PsychosocialObstetrics and Gynecology (poster title: Use of antidepressant medicationduring pregnancy and lactation: development of an evidence-based decisiontool); February 47, 2009; New Haven, Connecticut Canadian College ofNeuropsychopharmacology Annual Meeting (poster title: An evidence-basedalgorithm to quantify risk-benefit decision-making for use of antidepressantmedication during pregnancy and lactation. Research in progress: currentstate of knowledge); June 69, 2008; Toronto, Ontario, Canada.

Acknowledgments:The authors thank their advisory committee membersfor providing valuable input and lending their expertise to this project:Hiltrud Dawson, RN (Health Nexus, Toronto, Canada); Michael Dunn, MD(Sunnybrook Health Sciences Center, Toronto, Canada); Adrienne Einarson,RN (The Hospital for Sick Children, Toronto, Canada); Alicja Fishell, MD(Womens College Hospital, Toronto, Canada); Jasmine Gandhi, MD (OttawaHospital, Ottawa, Canada); Jan Kasperski, RN, MHSc (Ontario College of

Family Physicians, Toronto, Canada); Sidney Kennedy, MD (University HealthNetwork, Toronto, Canada); Diane Meschino, MD (Womens College Hospital,Toronto, Canada); Irena Nulman, MD, PhD (The Hospital for Sick Children,Toronto, Canada); Sagar Parikh, MD (University Health Network, Toronto,Canada); Paula Ravitz, MD (Mount Sinai Hospital, Toronto, Canada); SarahRomans, MD (University of Otago, Wellington, New Zealand); Simone Vigod,MD (Womens College Hospital, Toronto, Canada); Jennifer Blake, MD(Sunnybrook Health Sciences Center, Toronto, Canada); and Karen Wade, RN,MScN (Toronto Public Health, Toronto, Canada). The authors would also liketo thank Lindsay Witton, MSW (Womens College Hospital, Toronto, Canada);Maura OKeefe, MSW (Womens College Hospital, Toronto, Canada); andSvetlana Emelianova, MD (North York General Hospital, North York, Canada)for providing their feedback during many research meetings. Sheila Lacroix,MLS (Center for Addiction and Mental Health, Toronto, Canada), and AniOrchanian-Cheff, MISt (University Health Network, Toronto, Ontario),devised search strategies and completed literature search. The authors alsothank Alex Kiss, PhD (Sunnybrook Health Sciences Center, Toronto, Canada),


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for performing preliminary meta-analyses and Jenna McKay, BA (WomensCollege Hospital, Toronto, Canada), and Kimberly Radford, BA (WomensCollege Hospital, Toronto, Canada), for assisting with data extraction andquality assessment processes. Dr Kennedy has received research funding orhonoraria in the past from AstraZeneca, Biovail, Eli Lilly, GlaxoSmithKline,Janssen-Ortho, Lundbeck, Pfizer, St Jude Medical, and Servier. Ms Einarsonhas conducted research funded by an unrestricted grant from Eli LillyCanada. Dr Nulman has held a CIHR Collaborative grant with Duchesnay.Dr Parikh has had education or research grants or served on advisory boardsor as a speaker for AstraZeneca, Apotex, Biovail, Bristol-Myers Squibb, CIHR,Canadian Network for Mood and Anxiety Treatments, Canadian PsychiatricAssociation, GlaxoSmithKline, Genpharm, Janssen, Eli Lilly, Lundbeck,Novartis, Pfizer, and Wyeth. There were no conflicts of interest or relevantfinancial disclosures reported by any of the other acknowledged individuals.

Additional information:This work was carried out at the Departments ofPsychiatry, Womens College Hospital, University Heath Network, Center forAddiction and Mental Heath, and University of Toronto, Toronto, Ontario,Canada.Supplementary material:See accompanying pages.

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Editors Note:We encourage authors to submit papers forconsideration as a part of our Focus on Womens Mental

Health section. Please contact Marlene P. Freeman, MD, [email protected].

Supplementary material follows this article.


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Copyright 2013Physicians Postgraduate Press, Inc.

Supplementary Material

Article Tit le: The Effect of Prenatal Antidepressant Exposure on Neonatal Adaptation: A SystematicReview and Meta-Analysis

Author(s): Sophie Grigoriadis, MD, MA PhD, FRCPC; Emily H. VonderPorten, MPH; LanaMamisashvili, BSc (Hons); Allison Eady, BA; George Tomlinson, PhD; Cindy-Lee Dennis,PhD; Gideon Koren, MD, FRCPC, FACMT; Meir Steiner, MD, PhD, FRCPC; PatriciaMousmanis, MD, CCFP, FCFP; Amy Cheung, MD, MSc, FRCPC; and Lori E. Ross, PhD

DOI Number: 10.4088/JCP.12r07967

List of Supplementary Material for the article

1. Keywords Keywords

2. eFigure 1 Exposure to any antidepressant and the risk of respiratory distress in the neonate: meta-analysis results for all studies

3. eFigure 2 Exposure to any antidepressant and the risk of tremors in the neonate: meta-analysisresults for all studies

DisclaimerThis Supplementary Material has been provided by the author(s) as an enhancement to the published article. Ithas been approved by peer review; however, it has undergone neither editing nor formatting by in-house editorialstaff. The material is presented in the manner supplied by the author.


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neonate: meta-analysis results for all studies. Abbreviations: see Figure 2.


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Keywords

Antenatal Antidepressant (search words: Major Depression; Depression; depressive disorder,mood disorder, dysthymic disorder, pregnancy, trimester, pregnancy unplanned/unwanted, prenatalcare, pregnant women; antenatal/pregnant/prenatal/perinatal/puerperal; Neonatal withdrawal,

neonatal abstinence syndrome, poor adaptation syndrome, neonatal adaptation, prenatal

exposure/delayed effects, substance withdrawal symptoms, spontaneous abortion, miscarriage,fetus, fetal, neonatal, newborn, infant, infant outcome; maternal outcome, suicide, maternalsuicide; premature birth, premature delivery, neurocognitive outcome or development, neurological

outcome or development, infant development/child development, abnormalities, drug induced;attachment/mother/maternal, maternal behaviour; prenatal exposure, first trimester

pregnancy/second trimester pregnancy/third trimester pregnancy/pregnancy complication;

Tricyclic Antidepressant Drugs/Antidepressant Drugs/SSRIs/Monoamine OxidaseInhibitors/Pregnancy*)

Antenatal Non Drug(search words: Psychotherapy/ Brief Psychotherapy/InterpersonalPsychotherapy; Support Groups; Counseling; Interpersonal Therapy or Interpersonal

Psychotherapy; Supportive Therapy or Narrative Therapy; Cognitive Therapy or Cognitive

Behavioral Therapy; Psychoeducational or Psychodynamic; Psychosocial Intervention orPsychological Intervention; Psychosocial care, psychosocial rehabilitation, primary prevention,

social support, prevention, therapy; Motivational Interview; emotion-focused counseling, non-

directive counseling; Major Depression/Depression; Pregnancy/Prenatal or Antenatal)

Antenatal Risk Factors for Depression(search words: Major Depression; depressive disorders,dysthymic disorders, Depression; Pregnancy; unwanted/unplanned pregnancy, adolescent

pregnancy, Prenatal or antenatal; Risk Assessment/ Risk Management/ At Risk Populations/ Risk

Factors; Protective Factors; psychosocial support, social support)

Postnatal Antidepressant(search words: depressive disorder/mood disorder, dysthymic disorder;postpartum/postnatal; Major Depression; Depression; Tricyclic Antidepressant

Drugs/Antidepressant Drugs/SSRIs/Monoamine Oxidase Inhibitors)

Lactation / Breastfeeding: Postpartum Depression, Antidepressants, etc. (search words: Breastmilk, Breast Feeding/ Lactation/ Lactating, weaning; Depression, puerperal depression, postpartumdepression, dysthymic disorders, depressive disorders; breast milk and antidepressants,Antidepressant Drugs/Antidepressants*)

Postnatal Non Drug (search words: Postpartum, postnatal; pregnancy, Psychotherapy/ BriefPsychotherapy/Interpersonal Psychotherapy; Support Groups; Counseling; Interpersonal Therapy

or Interpersonal Psychotherapy; Supportive Therapy or Narrative Therapy; Cognitive Therapy orCognitive Behavioral Therapy; Psychoeducational or Psychodynamic; Psychosocial Intervention or

Psychological Intervention; psychological rehabilitation, social support, psychoeducational

support, Motivational Interview; non-directive counseling, emotion-focused counseling, cognitive

rehabilitation, psychotherapeutic techniques, Major Depression/Depression; Postnatal)

Risk Factors for Postpartum Depression(search words: Postpartum/postnatal, postpartumperiod, prevention/control, therapy, psychosocial care, social support, psychosocial rehabilitation,psychosocial intervention; risk assessment/risk management, at risk populations, risk factors,

primary mental health prevention, protective factors, unwanted/unplanned pregnancy, pregnancy;depressive disorders, dysthymic disorders; Postpartum Depression/ Risk Assessment/At Risk

Populations/Risk Factors/Risk Management; Protective Factors; child development, attachment

behaviour, infant/child behaviour, maternal behaviour, untreated depression, neurocognitivedevelopment, mother-child relations, infant care, neurological/neurocognitive development).

the effect of prenatal antidepressant exposure on neonatal adaptation a systematic review and...

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