CONTEXT:

There is increasing use of antidepressants in pregnancy and hence children exposed in utero. Contradictory studies exist in the literature in which researchers report on the potential impact of antenatal antidepressant exposure on subsequent child motor development.

OBJECTIVE:

Our objective in this systematic review and meta-analysis was to determine whether antenatal antidepressant exposure increases the risk of impaired motor development in children.

DATA SOURCES:

We searched PsychINFO, Embase, Medline, PubMed, and Scopus up to July 24, 2017.

STUDY SELECTION:

English-language cohort and case control studies in which researchers report primary data from a motor assessment of infants or children after any antidepressant exposure in pregnancy were included.

DATA EXTRACTION:

Of the 329 studies identified, there were 160 articles screened, 24 were included in the systematic review, and 18 met inclusion criteria for the meta-analysis.

RESULTS:

The total pooled results were based on random effects models and revealed a significant association between exposure to antidepressants during pregnancy and overall occurrence of poorer motor outcomes in children (effect size = 0.22; 95% confidence interval = 0.07 to 0.37) with a moderate degree of heterogeneity (I2 = 56.6%).

LIMITATIONS:

There was variation in the measurement both of exposure and motor development across the identified study, and few followed up to later childhood or beyond.

CONCLUSIONS:

A small increased risk of poorer motor development may exist for children who are exposed to antidepressant medications during pregnancy. However, the marked methodological variation among studies and the limited control for possible confounds warrants cautious interpretation of these findings.

Researchers in epidemiologic studies report point prevalence rates of depression during pregnancy ranging between 8.5% and 11%, with up to 12.7% of women having an episode of major depression during pregnancy.1 Rates of antidepressant prescribing during pregnancy have increased significantly over the last 10 to 15 years, with estimates revealing an increase of between fourfold and 16-fold.2,3 In part, this increase may be explained by research findings of an association between untreated maternal depression and risks to both the mother4,6 and developing child.7,11 Furthermore, cessation of antidepressants before pregnancy has been shown in some studies to significantly increase the risk of relapse during the pregnancy.12 

A large number of studies have examined the potential risk of structural abnormalities in the fetus after antidepressant exposure during pregnancy, with mixed results.13,15 Researchers in an increasingly well-established body of literature have also addressed the immediate physiologic effects of pregnancy-related antidepressant exposure in the neonate.16,17 Importantly, the longer-term neurodevelopmental outcomes for the child are less well known. Some findings are nevertheless beginning to emerge as the children of mothers who were prescribed antidepressants during pregnancy progress through their early childhood and school years. In broad terms, studies in which researchers have considered these longer-term effects can be divided into those who have looked at the impact on cognitive,18,19 motor,20,21 neurobehavioral, and emotional development.22,23 

Specifically, in terms of motor outcomes, several early studies revealed that fetal exposure to antidepressant medication may be associated with an impairment of motor processes in infancy and early childhood.20,21 Researchers in more recent studies using better methodologies have obtained conflicting results.24,26 Nevertheless, there is sufficient biological plausibility to postulate that fetal exposure to antidepressants may impact on future motor development. Serotonin is important in the regulation of multiple aspects of development in the human brain, including neurogenesis, migration, and differentiation.27 It also plays a role in regulating the development of its own serotonergic neurons.28 Moreover, it has been established that selective serotonin reuptake inhibitor (SSRI) medication readily crosses the placenta and blood-brain barrier.29 Given that this barrier is not fully mature or competent until after birth, there is significant potential for the altering of serotonin signaling and the development of serotonin circuitry.30 In animal models, fluoxetine-exposed rats have demonstrated impaired motor performance, which is shown to be associated with an altered structure of striatal and cortical neurons.31 Such structural changes are yet to be identified in humans, but they constitute a possible physiologic basis for the proposed impact of antidepressants on fetal brain circuitry.

Importantly, children with clinically significant motor impairment suffer a number of negative psychosocial consequences, including poorer scores on attention and learning,32 lower perceived self-efficacy, lower perceived levels of social support, lower ratings of self- worth, and higher levels of anxiety than matched controls.33 Furthermore, researchers in a recent meta-analysis have concluded that motor deficits during development, particularly impaired coordination, may represent an early marker of risk for the development of schizophrenia, especially in those with a familial risk of the disorder.34 Given these far-reaching potential consequences of motor impairment, establishing the presence or absence of motor impairment and, if present, the degree of severity in children who were exposed to antidepressants in utero is of importance.

Although there are a few systematic reviews of the literature on the relationships between prenatal antidepressant exposure and subsequent developmental outcomes,35,36 none of these reviews has been focused solely on motor outcomes and the potential implications of motor deficiencies for a child’s well-being. Therefore, our objective in this study was to assess and critically evaluate, through an up-to-date systematic review and meta-analysis of the published literature, whether in utero antidepressant exposure increases the risk of impaired motor development in infants and children compared with those who were not exposed to antidepressants during pregnancy. Considering the methodological diversity and limitations evident in the included studies, we also examined whether the effect on motor outcomes changed in subgroups of studies in which researchers report on different measures of motor assessment and further explored other potential predictors of heterogeneity, including the study quality.

To address these issues, a systematic review of the literature was performed by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. After this, a meta-analysis of findings was undertaken. To ensure a comprehensive search of the literature, a computerized search of multiple electronic databases was conducted. These databases included PsychINFO, Embase, Medline, PubMed, and Scopus. Each database was searched from its start date to July 24, 2017. Keywords and their combinations used were as follows: “antidepressants or selective serotonin reuptake inhibitors or SSRI/SRI/SNRI,” “pregnant/pregnancy,” “infant/child,” and “(motor/psychomotor/neuromotor) development” (Supplemental Information). Reference lists, including those of relevant review articles and meta-analyses, were searched for additional studies not already identified in the initial database search.

Researchers’ studies were included in the systematic review if they (1) reported primary data, (2) were published in the English language, (3) were studies involving humans, (4) used and described an accepted measure of motor performance, and (5) reported on infant or child motor development outcomes after any antidepressant exposure in pregnancy. Studies were excluded if they were individual case studies, conference abstracts, or proceedings without a related publication; reviews or meta-analyses of the literature; or were solely focused on motor outcomes in the neonatal period.

For the purposes of the subsequent meta-analysis, additional inclusion criteria were as follows: (1) included a control group of women who were not exposed to antidepressant medication during pregnancy and (2) provided sufficient raw data to perform effect size (ES) calculations.

It became apparent from our systematic review of the literature that only a small number of studies included a comparison group of infants of women with depression who did not receive antidepressant medication during pregnancy either as the sole control group or as an additional comparison group along with healthy controls. Therefore, in the main meta-analysis, we only included studies with data available for a healthy control group of women who were not exposed to antidepressant medication to ensure uniformity with the majority of available studies.

Titles and abstracts were examined for all studies identified by using the keyword search. When the inclusion criteria were met, the full-text article was retrieved. A second researcher reviewed those articles that were identified for inclusion as well as those for which ambiguity existed about their inclusion or exclusion from the systematic review. Information extracted from all the studies (when available) included the authors, year of publication, study design, sample size, demographic and clinical characteristics of participants, details of antidepressant exposure (type, dose, and timing of exposure during pregnancy), details pertaining to the timing, method of and age at motor assessment, and primary and secondary outcomes.

For the meta-analysis, we further extracted from the published studies the raw data to calculate the ES for each study. When repeated measures of motor assessment occurred in the same study population, and/or when subdomains of the motor assessment were reported, we preferentially extracted summary measures of motor performance at the latest available time point of assessment. When fine and gross motor data were reported separately within the same study, in the absence of the availability of a summary measure, the fine motor domain was used. In the absence of the necessary data being available in the published study, we contacted authors requesting the appropriate raw data.

To enable variability in study results to be critically evaluated, the methodological quality of the included nonrandomized studies was assessed by using the Newcastle-Ottawa Quality Assessment Scale (NOQAS).37 Each study was allocated a star rating in multiple categories: (1) “selection” of cases or cohort, (2) “comparability” of cases and controls (or cohorts), and (3) “exposure” (for case control studies) or “outcome” (for cohort studies). Total scores were assigned to each study for a maximum possible rating of 9 stars. Quality ratings were performed before conducting the analyses. Irrespective of the NOQAS score, we included all studies that met inclusion criteria in the main analysis.

Data were analyzed by using Stata (Stata Corp, College Station, TX) and examined for both fixed and random effect models. The metan package and metareg were used in all analyses. We divided studies into subgroups. Those in which researchers used a standardized measure of motor development, such as the Bayley Scales of Infant Development (BSID), were compared with studies in which researchers drew on population data and made use of parent self-report or clinician report of motor abilities. This distinction is referred to as “data type” in the meta-regression reported below. Publication bias was assessed through the use of a funnel plot.

We identified 320 articles using the described literature search methodology with an additional 9 published studies obtained by review of reference lists and consultation with experts in the field. After duplicate removal, 160 unique articles were identified, of which 126 were excluded after extensive title and abstract review. In total, 34 full-text articles were assessed for eligibility. Ten articles were subsequently excluded (Fig 1). Of the excluded articles, 3 were excluded because researchers either did not use an accepted measure of motor performance38,39 or did not clearly report on the procedures for the assessment of motor development.40 Researchers in 4 of the excluded studies reported on other outcomes of interest,41,44 those in 1 reported only neonatal outcomes,45 and those in 2 provided insufficient data,18,46 leaving 24 articles for inclusion in the qualitative synthesis (Table 1).

FIGURE 1

Identification of studies for inclusion in the meta-analysis.47 

FIGURE 1

Identification of studies for inclusion in the meta-analysis.47 

TABLE 1

Psychomotor Development Studies That Satisfied the Criteria for Inclusion in the Systematic Review

StudyStudy Design and NGroups ComparedAge at TestingMedicationMotor MeasureQuality Rating (of 9)
Reebye et al48  Prospective cohort Exposure to SSRI alone (n = 24) 2 mo SSRI only: paroxetine fluoxetine sertraline BSID-II 
 N = 61 Exposure to SSRI and benzodiazepine (n = 14)     
  No depression and no psychotropic medication (n = 23)  SSRI and clonazepam   
Nulman et al19  Prospective Tricyclics (n = 46) Between 15 mo and 71 mo Amitriptyline (39%) BSID-II (PDI) up to 30 mo of age 
 N = 122 Fluoxetine (n = 40)  Imipramine (26%)   
    Clomipramine (15%) MSCA after 30 mo of age  
  No psychiatric or MDD history and no exposure to medications (n = 36)  Desipramine (6.5%)   
    Nortriptyline (6.5%)   
    Doxepin (4%)   
    Maprotiline (2%)   
    Fluoxetine (20–80 mg per d): n = 40; 100% of group   
Simon et al49  Retrospective case control Exposure to SSRIs during pregnancy (n = 185) Birth to 2 y Fluoxetine (33%) Pediatrician health monitoring with diagnosis by physician and formal motor development evaluation 
 N = 788 No exposure to SSRIs during pregnancy (n = 185)  Amitriptyline (17%)   
    Imipramine (12%)   
  Exposure to TCA during pregnancy (n = 209)  Doxepin (9%)   
    Nortriptyline (8%)   
    Sertraline (8%)   
    Paroxetine (7%)   
    Desipramine (6%; some multiple exposures)   
  No exposure to TCA during pregnancy (n = 209)     
Casper et al20  Controlled, cohort comparison MDD diagnosis during pregnancy and treated with SSRIs (n = 31) Between 6 mo and 40 mo Sertraline (48%) BSID-II 
  MDD diagnosis during pregnancy but no SSRI treatment (n = 13)  Paroxetine (26%) PDI and BRS  
    Fluoxetine (23%)   
    Fluvoxamine (3%)   
 N = 44      
Mortensen et al21  Retrospective cohort No medication (n = 755) 7–10 mo ADs not specified BOEL test 
  ADs (n = 50)     
 N = 1095 Benzodiazepines (n = 82)     
  Antiepileptics (n = 145)     
  Neuroleptics (n = 63)     
Oberlander et al50  Prospective cohort  Exposure to SSRI alone (n = 28) 2 mo and 8 mo SSRI alone BSID-II PDI score 
 N = 69 Exposure to SSRI and benzodiazepine (n = 18)   Paroxetine (61%)   
     Fluoxetine (25%)   
     Sertraline (14%)   
  Nonexposed control group (n = 23)  SSRI and clonazepam   
     Paroxetine (89%)   
     Fluoxetine (11%)   
Oberlander et al51  Prospective cohort Prenatal exposure to SSRIs only (n = 11) 2 mo and 8 mo Paroxetine (71%) BSID-II (PDI) 
 N = 63 Prenatal and postnatal exposure (via breastfeeding) to SSRIs (n = 30)  Fluoxetine (19.5%)   
  No psychotropic agents and no history of maternal mental illness (n = 22)  Sertraline (19.5%)   
Pedersen et al52  Large-scale, population-based pregnancy cohort  No severe depressive symptoms and no SSRI exposure during pregnancy (n = 81 042) 6 mo and 19 mo Fluoxetine (25.5%) Computer-assisted telephone interviews with mothers reporting on motor development milestones 
  Depressive symptoms during pregnancy but no SSRI exposure (n = 489)  Citalopram (26%)   
 N = 81 946 Depressive symptoms during pregnancy and SSRI exposure (n = 415)  Paroxetine (23%)   
    Sertraline (25.5%)   
Klinger et al53  Prospective cohort SSRI exposure with NAS at birth (n = 30) 2–6 y (no additional details provided) Fluoxetine DDST-II gross motor and fine motor scores 
 N = 82 SSRI without NAS at birth (n = 52)  Paroxetine   
    Citalopram   
    Sertraline   
    Fluvoxamine   
    Venlafaxine   
Casper et al25  Cohort comparison SSRI exposure during first trimester (n = 14) Average : 14 mo Sertraline (36%) BSID-II PDI 
  SSRI exposure during second and/or third trimester (n = 18)  Fluoxetine (33%)   
 N = 55 SSRI exposure during first, second, and third trimester (n = 23)  Paroxetine (27%)   
    Citalopram (4%)   
Galbally et al54  Prospective case control MDD and exposure to ADs at any time during pregnancy (n = 22) 18–35 mo postpartum At first trimester BSID-III 
 N = 41 No exposure to ADs during pregnancy (n = 19)   No medications (50%)   
     Sertraline (19%)   
     Venlafaxine (9.5%)   
     Citalopram (7.1%)   
     Fluoxetine (2.4%)   
     Escitalopram (2.4%)   
     Mianserin (2.4%)   
     Mirtazapine (2.4%)   
     Paroxetine (2.4%)   
Suri et al55  Prospective, naturalistic, blinded cohort MDD history and AD (unspecified type) use during pregnancy (n = 33) Within first wk (n = 59) and at 6–8 wk (n = 57) Sertraline 90.5±50.3 mg (36%) BNBAS 
  MDD history without AD (unspecified type) use in pregnancy or discontinued (n = 16)  Fluoxetine 22.5±7.5 mg (38%)   
 N = 64 No exposure to AD (unspecified type) and no psychiatric history (n = 15)  Other ADs (unspecified type; 26%)   
Johnson et al56  Prospective controlled Pregnancy exposure to antipsychotics (n = 22) 6 mo Unspecified AD medication INFANIB 
 N = 309 Pregnancy exposure to ADs (n = 202)     
  No exposure to psychotropic agents in pregnancy (n = 85)     
Batton et al57  Retrospective case control Preterm infants (<36 and sixth-sevenths wk) 24 mo and/or 36 mo Paroxetine (9.5%) BINS 
  Exposed to SSRIs (n = 19)  Fluoxetine (28.5%) BSID (pre-2006)  
 N = 38 Preterm infants not exposed to SSRIs (n = 19)  Sertraline (43%)   
    Citalopram (9.5%) BSID-III (post- 2006)  
    Escitalopram (9.5%)   
de Vries et al58  Prospective observational SSRI-exposed infants (n = 63) Assessed during first wk after birth and again at 3–4 mo Paroxetine (43%) GMs and an MOS 
 N = 107 Nonexposed infants (n = 44; included 9 with depression and/or anxiety)  Citalopram (22%)   
    Venlafaxine (16%)   
    Fluoxetine (13%)   
    Sertraline (3%)   
    Changed medications (3%)   
Hanley et al59  Prospective cohort Mood disorder and SRI use during pregnancy (n = 31) 10 mo Paroxetine (13%) BSID-III 
 N = 83 No exposure to SRIs during pregnancy (n = 52)     
    Fluoxetine (10%)   
    Sertraline (16%)   
    Venlafaxine (38%)   
    Citalopram (23%)   
Austin et al24  Controlled, prospective longitudinal cohort AD (unspecified type) exposure of mother during pregnancy (n = 35) 18 mo Sertraline (31%) BSID-III 
  No history of mood disorder and no AD (unspecified type) exposure during pregnancy (n = 23)  Fluoxetine (17%)   
 N = 58   Citalopram (14%)   
    Dothiepin (14%)   
    Venlafaxine (11%)   
    Escitalopram (6%)   
    Paroxetine (3%)   
    Fluvoxamine (3%)   
Santucci et al60  Longitudinal, observational cohort No MDD and no SRI exposure (n = 98) 12 wk, 26 wk, 52 wk, and 78 wk, corrected for prematurity Sertraline (33%) BSID-II PDI and MQI 
  MDD during pregnancy but no SRI exposure (n = 27)     
 N = 166 MDD and SRI exposure during pregnancy (n = 41)  Fluoxetine (24%)   
    Escitalopram (16%)   
    Citalopram (11%)   
    Venlafaxine (11%)   
    Fluvoxamine (2%)   
    Paroxetine (2%)   
Galbally et al26  Prospective case-controlled AD (unspecified type) use during mother’s pregnancy (n = 20) 4 y Before attrition Movement ABC 
  No depression and no AD (unspecified type) use during pregnancy (n = 21)   SSRI (84%)   
 N = 41    SNRI (9%)   
     TCA (3%)   
     NaSSA (3%)   
Handal et al61  Large-scale, population-based, prospective cohort No SSRI exposure (n = 50 544) 3 y SSRI medications not specified Maternal reports of gross and fine motor skills using selected items from the ASQ 
  Prepregnancy SSRI use only (n = 479)     
 N = 51 404 SSRI use during 1 pregnancy phase (n = 222)     
  Prolonged SSRI use (n = 159)     
Hurault-Delarue et al62  Observational  Exposed to psychotropic medications in utero (n = 493) 9 mo and again at 24 mo Most common ADs (unspecified type) were as follows: General practitioner or pediatrician ratings on 14 items of psychomotor development 
 N = 32 796 No exposure to psychotropic medications in utero (n = 32 303)   Amitriptyline   
     Paroxetine   
     Fluoxetine   
     Venlafaxine   
     Imipramine   
Brown et al63  Prospective birth cohort Exposed to SSRIs during pregnancy (n = 15 596) Mean: 7.73 y Fluoxetine Medical examination by physician recorded in the Finnish Hospital Discharge Register 
 N= 56 340 MDD history without AD (unspecified type) use during pregnancy (n = 9537)  Citalopram   
  No MDD and no AD (unspecified type) exposure during pregnancy (n = 31 207)  Paroxetine   
    Sertraline   
    Fluvoxamine   
    Escitalopram   
Partridge et al64  Cross-sectional cohort Pregnancy exposure to SRI (n = 15) 4–5 y Sertraline (64%) Kinematic analysis of reach-and-drop task 
  Untreated MDD during pregnancy (n = 10)  Citalopram (24%)   
 N = 40 Unexposed control group (n = 15)  Escitalopram (4%)   
Galbally et al65  Population specific longitudinal cohort AD (unspecified type) use during pregnancy (n = 31) 6 mo Before attrition or exclusion ASQ 
  Ceased AD (unspecified type) use during pregnancy (n = 11)   SSRI (78%)   
 N = 42    SNRI (22%)   
StudyStudy Design and NGroups ComparedAge at TestingMedicationMotor MeasureQuality Rating (of 9)
Reebye et al48  Prospective cohort Exposure to SSRI alone (n = 24) 2 mo SSRI only: paroxetine fluoxetine sertraline BSID-II 
 N = 61 Exposure to SSRI and benzodiazepine (n = 14)     
  No depression and no psychotropic medication (n = 23)  SSRI and clonazepam   
Nulman et al19  Prospective Tricyclics (n = 46) Between 15 mo and 71 mo Amitriptyline (39%) BSID-II (PDI) up to 30 mo of age 
 N = 122 Fluoxetine (n = 40)  Imipramine (26%)   
    Clomipramine (15%) MSCA after 30 mo of age  
  No psychiatric or MDD history and no exposure to medications (n = 36)  Desipramine (6.5%)   
    Nortriptyline (6.5%)   
    Doxepin (4%)   
    Maprotiline (2%)   
    Fluoxetine (20–80 mg per d): n = 40; 100% of group   
Simon et al49  Retrospective case control Exposure to SSRIs during pregnancy (n = 185) Birth to 2 y Fluoxetine (33%) Pediatrician health monitoring with diagnosis by physician and formal motor development evaluation 
 N = 788 No exposure to SSRIs during pregnancy (n = 185)  Amitriptyline (17%)   
    Imipramine (12%)   
  Exposure to TCA during pregnancy (n = 209)  Doxepin (9%)   
    Nortriptyline (8%)   
    Sertraline (8%)   
    Paroxetine (7%)   
    Desipramine (6%; some multiple exposures)   
  No exposure to TCA during pregnancy (n = 209)     
Casper et al20  Controlled, cohort comparison MDD diagnosis during pregnancy and treated with SSRIs (n = 31) Between 6 mo and 40 mo Sertraline (48%) BSID-II 
  MDD diagnosis during pregnancy but no SSRI treatment (n = 13)  Paroxetine (26%) PDI and BRS  
    Fluoxetine (23%)   
    Fluvoxamine (3%)   
 N = 44      
Mortensen et al21  Retrospective cohort No medication (n = 755) 7–10 mo ADs not specified BOEL test 
  ADs (n = 50)     
 N = 1095 Benzodiazepines (n = 82)     
  Antiepileptics (n = 145)     
  Neuroleptics (n = 63)     
Oberlander et al50  Prospective cohort  Exposure to SSRI alone (n = 28) 2 mo and 8 mo SSRI alone BSID-II PDI score 
 N = 69 Exposure to SSRI and benzodiazepine (n = 18)   Paroxetine (61%)   
     Fluoxetine (25%)   
     Sertraline (14%)   
  Nonexposed control group (n = 23)  SSRI and clonazepam   
     Paroxetine (89%)   
     Fluoxetine (11%)   
Oberlander et al51  Prospective cohort Prenatal exposure to SSRIs only (n = 11) 2 mo and 8 mo Paroxetine (71%) BSID-II (PDI) 
 N = 63 Prenatal and postnatal exposure (via breastfeeding) to SSRIs (n = 30)  Fluoxetine (19.5%)   
  No psychotropic agents and no history of maternal mental illness (n = 22)  Sertraline (19.5%)   
Pedersen et al52  Large-scale, population-based pregnancy cohort  No severe depressive symptoms and no SSRI exposure during pregnancy (n = 81 042) 6 mo and 19 mo Fluoxetine (25.5%) Computer-assisted telephone interviews with mothers reporting on motor development milestones 
  Depressive symptoms during pregnancy but no SSRI exposure (n = 489)  Citalopram (26%)   
 N = 81 946 Depressive symptoms during pregnancy and SSRI exposure (n = 415)  Paroxetine (23%)   
    Sertraline (25.5%)   
Klinger et al53  Prospective cohort SSRI exposure with NAS at birth (n = 30) 2–6 y (no additional details provided) Fluoxetine DDST-II gross motor and fine motor scores 
 N = 82 SSRI without NAS at birth (n = 52)  Paroxetine   
    Citalopram   
    Sertraline   
    Fluvoxamine   
    Venlafaxine   
Casper et al25  Cohort comparison SSRI exposure during first trimester (n = 14) Average : 14 mo Sertraline (36%) BSID-II PDI 
  SSRI exposure during second and/or third trimester (n = 18)  Fluoxetine (33%)   
 N = 55 SSRI exposure during first, second, and third trimester (n = 23)  Paroxetine (27%)   
    Citalopram (4%)   
Galbally et al54  Prospective case control MDD and exposure to ADs at any time during pregnancy (n = 22) 18–35 mo postpartum At first trimester BSID-III 
 N = 41 No exposure to ADs during pregnancy (n = 19)   No medications (50%)   
     Sertraline (19%)   
     Venlafaxine (9.5%)   
     Citalopram (7.1%)   
     Fluoxetine (2.4%)   
     Escitalopram (2.4%)   
     Mianserin (2.4%)   
     Mirtazapine (2.4%)   
     Paroxetine (2.4%)   
Suri et al55  Prospective, naturalistic, blinded cohort MDD history and AD (unspecified type) use during pregnancy (n = 33) Within first wk (n = 59) and at 6–8 wk (n = 57) Sertraline 90.5±50.3 mg (36%) BNBAS 
  MDD history without AD (unspecified type) use in pregnancy or discontinued (n = 16)  Fluoxetine 22.5±7.5 mg (38%)   
 N = 64 No exposure to AD (unspecified type) and no psychiatric history (n = 15)  Other ADs (unspecified type; 26%)   
Johnson et al56  Prospective controlled Pregnancy exposure to antipsychotics (n = 22) 6 mo Unspecified AD medication INFANIB 
 N = 309 Pregnancy exposure to ADs (n = 202)     
  No exposure to psychotropic agents in pregnancy (n = 85)     
Batton et al57  Retrospective case control Preterm infants (<36 and sixth-sevenths wk) 24 mo and/or 36 mo Paroxetine (9.5%) BINS 
  Exposed to SSRIs (n = 19)  Fluoxetine (28.5%) BSID (pre-2006)  
 N = 38 Preterm infants not exposed to SSRIs (n = 19)  Sertraline (43%)   
    Citalopram (9.5%) BSID-III (post- 2006)  
    Escitalopram (9.5%)   
de Vries et al58  Prospective observational SSRI-exposed infants (n = 63) Assessed during first wk after birth and again at 3–4 mo Paroxetine (43%) GMs and an MOS 
 N = 107 Nonexposed infants (n = 44; included 9 with depression and/or anxiety)  Citalopram (22%)   
    Venlafaxine (16%)   
    Fluoxetine (13%)   
    Sertraline (3%)   
    Changed medications (3%)   
Hanley et al59  Prospective cohort Mood disorder and SRI use during pregnancy (n = 31) 10 mo Paroxetine (13%) BSID-III 
 N = 83 No exposure to SRIs during pregnancy (n = 52)     
    Fluoxetine (10%)   
    Sertraline (16%)   
    Venlafaxine (38%)   
    Citalopram (23%)   
Austin et al24  Controlled, prospective longitudinal cohort AD (unspecified type) exposure of mother during pregnancy (n = 35) 18 mo Sertraline (31%) BSID-III 
  No history of mood disorder and no AD (unspecified type) exposure during pregnancy (n = 23)  Fluoxetine (17%)   
 N = 58   Citalopram (14%)   
    Dothiepin (14%)   
    Venlafaxine (11%)   
    Escitalopram (6%)   
    Paroxetine (3%)   
    Fluvoxamine (3%)   
Santucci et al60  Longitudinal, observational cohort No MDD and no SRI exposure (n = 98) 12 wk, 26 wk, 52 wk, and 78 wk, corrected for prematurity Sertraline (33%) BSID-II PDI and MQI 
  MDD during pregnancy but no SRI exposure (n = 27)     
 N = 166 MDD and SRI exposure during pregnancy (n = 41)  Fluoxetine (24%)   
    Escitalopram (16%)   
    Citalopram (11%)   
    Venlafaxine (11%)   
    Fluvoxamine (2%)   
    Paroxetine (2%)   
Galbally et al26  Prospective case-controlled AD (unspecified type) use during mother’s pregnancy (n = 20) 4 y Before attrition Movement ABC 
  No depression and no AD (unspecified type) use during pregnancy (n = 21)   SSRI (84%)   
 N = 41    SNRI (9%)   
     TCA (3%)   
     NaSSA (3%)   
Handal et al61  Large-scale, population-based, prospective cohort No SSRI exposure (n = 50 544) 3 y SSRI medications not specified Maternal reports of gross and fine motor skills using selected items from the ASQ 
  Prepregnancy SSRI use only (n = 479)     
 N = 51 404 SSRI use during 1 pregnancy phase (n = 222)     
  Prolonged SSRI use (n = 159)     
Hurault-Delarue et al62  Observational  Exposed to psychotropic medications in utero (n = 493) 9 mo and again at 24 mo Most common ADs (unspecified type) were as follows: General practitioner or pediatrician ratings on 14 items of psychomotor development 
 N = 32 796 No exposure to psychotropic medications in utero (n = 32 303)   Amitriptyline   
     Paroxetine   
     Fluoxetine   
     Venlafaxine   
     Imipramine   
Brown et al63  Prospective birth cohort Exposed to SSRIs during pregnancy (n = 15 596) Mean: 7.73 y Fluoxetine Medical examination by physician recorded in the Finnish Hospital Discharge Register 
 N= 56 340 MDD history without AD (unspecified type) use during pregnancy (n = 9537)  Citalopram   
  No MDD and no AD (unspecified type) exposure during pregnancy (n = 31 207)  Paroxetine   
    Sertraline   
    Fluvoxamine   
    Escitalopram   
Partridge et al64  Cross-sectional cohort Pregnancy exposure to SRI (n = 15) 4–5 y Sertraline (64%) Kinematic analysis of reach-and-drop task 
  Untreated MDD during pregnancy (n = 10)  Citalopram (24%)   
 N = 40 Unexposed control group (n = 15)  Escitalopram (4%)   
Galbally et al65  Population specific longitudinal cohort AD (unspecified type) use during pregnancy (n = 31) 6 mo Before attrition or exclusion ASQ 
  Ceased AD (unspecified type) use during pregnancy (n = 11)   SSRI (78%)   
 N = 42    SNRI (22%)   

Movement ABC, Movement Assessment Battery for Children; AD, antidepressant; ASQ, Ages and Stages Questionnaire; BINS, Bayley Infant Neurodevelopmental Screener; BNBAS, Brazelton Neonate Behavior Assessment Scale; BOEL, blicken orienterar efter ljudet; BRS, Behavioral Rating Scale; BSID, Bayley Scales of Infant Development; DDST-II, Denver Developmental Screening Test II; GM, general movement; INFANIB, Infant Neurologic International Battery; MDD, major depressive disorder; MOS, motor optimality score; MQI, Motor Quality Index; MSCA, McCarthy Scales of Children’s Abilities; NaSSA, noradrenergic and specific serotonergic antidepressant; PDI, Psychomotor Development Index; SNRI, serotonin and norepinephrine reuptake inhibitor; SRI, serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

For the meta-analysis, an additional 6 studies were excluded. Of these, 3 were excluded because they did not contain a control group without antidepressant exposure,25,53,65 1 did not have a healthy control group for comparison,20 and researchers in 1 used the same cohort of children that was later published as a follow-up study.54 We excluded the initial article in keeping with our prescribed methodology to use only the results from the latest available time point of assessment. The final study was excluded after consultation with all the authors because there was no summary measure available that was suitable for inclusion in the meta-analysis.64 

Overall, we pooled results from 18 studies. The ES for poorer motor outcomes after in utero antidepressant exposure was 0.22 (95% confidence interval [CI] = 0.07 to 0.37; Fig 2). On further subanalysis determined a priori, researchers in 7 studies reported outcomes of motor assessment with categorical data. The pooled ES from these studies was significant (ES = 0.40; 95% CI = 0.18 to 0.62). The 11 studies in which researchers report continuous data resulted in a nonsignificant ES of 0.08 (95% CI = −0.11 to 0.26).

FIGURE 2

Effects of antidepressant exposure on child motor development. ES is a standardized mean difference. Fixed and random effects are calculated for each subgroup separately and then overall. D+L, random effect calculated by using the DerSimonian and Laird model in Stata; ID, identification; I-V, the fixed effect calculated by using the inverse variance method in Stata.

FIGURE 2

Effects of antidepressant exposure on child motor development. ES is a standardized mean difference. Fixed and random effects are calculated for each subgroup separately and then overall. D+L, random effect calculated by using the DerSimonian and Laird model in Stata; ID, identification; I-V, the fixed effect calculated by using the inverse variance method in Stata.

Heterogeneity measures were significant, both for the total pooled analysis (I2 = 56.6; P = .002) and the analysis of the categorically reported data of motor assessment outcomes (I2 = 67.4; P = .005; Fig 2). The studies reporting motor assessment outcomes with continuous rather than categorical data for motor development demonstrated an I2 value of 34.2 (P = .125). Heterogeneity between these 2 subgroups was also significant (P = .018). Meta-regression analyses of potential predictors of heterogeneity, including the NOQAS, year of publication, and type of data obtained from motor assessment (ie, categorical or continuous), were performed. Only the type of data was a significant predictor of heterogeneity (P = .033; Table 2).

TABLE 2

Sources of Heterogeneity in the Meta-Analysis

EffectESSEt-valueP (Significance)95% CI
Quality −0.039 0.074 −0.53 .606 −0.199 to 0.121 
Year −0.005 0.018 −0.30 .772 −0.044 to 0.033 
Data type −0.422 0.177 −2.38 .033 −0.805 to −0.039 
Constant 11.817 35.951 0.33 .748 −65.851 to 89.485 
EffectESSEt-valueP (Significance)95% CI
Quality −0.039 0.074 −0.53 .606 −0.199 to 0.121 
Year −0.005 0.018 −0.30 .772 −0.044 to 0.033 
Data type −0.422 0.177 −2.38 .033 −0.805 to −0.039 
Constant 11.817 35.951 0.33 .748 −65.851 to 89.485 

A funnel plot was produced to examine publication bias. This revealed no indication of publication bias and is presented in Fig 3.

FIGURE 3

Evaluation of publication bias. A funnel plot with pseudo 95% CIs is shown.

FIGURE 3

Evaluation of publication bias. A funnel plot with pseudo 95% CIs is shown.

Our objective in this systematic review and meta-analysis was to investigate the possible relationship between antidepressant exposure in utero and subsequent motor development outcomes in infants and children. The total pooled result of our meta-analysis reveals a small effect (0.22) in the direction of an increased risk of poorer motor scores and outcomes in children who are exposed to antidepressant medications during pregnancy. However, the overall study-to-study variation is moderate (I2 = 56.6%); therefore, these initial findings require further qualification.

With the exception of de Vries et al,58 researchers in the 6 other studies reported categorical data for motor outcomes and used indirect observation of assessment measures by parents or clinicians as reported through structured interviews or through database or chart review21,49,52,61,63. Because of the nature of these studies, blinding of assessor was mostly not appropriate or possible. In contrast, researchers in the 11 studies in which continuous data were reported primarily used standardized measures of motor assessment.19,24,26,48,50,51,55,57,59,60 All were determined by direct observations from a limited number of trained assessors as part of the research team, the majority of whom were blinded to exposure status. When these 2 groups are analyzed separately, only the studies in which researchers report categorical data from clinician and/or parent ratings continue to exhibit a negative effect on motor outcomes (ES = 0.40; 95% CI = 0.18 to 0.62). Those reporting continuous data from standardized testing do not (ES = 0.08; 95% CI = −0.11 to 0.26). Furthermore, measures of heterogeneity are substantially less in the latter group (I2 = 67.4% versus I2 = 34.2%), with our subsequent meta-regression tests confirming that only the type of measure (ie, standardized testing versus clinician and/or parent rating) is a significant predictor of heterogeneity.

The methodological limitations of the individually included studies help to explain the moderate-to-large degree of heterogeneity observed in our analysis. In the included studies alone, there are 13 different methods used to quantify motor performance. Only Galbally et al26 used a standardized and specific neuropsychological measure of motor development, the Movement Assessment Battery for Children, which has been established to have high test-retest reliability and moderate construct validity as a motor measure.66 In comparison, the BSID was most commonly used among the included the studies and is widely considered the reference standard for the measurement of infant and toddler development, but its motor subscale has been less clearly validated against other measures of motor assessment.67 Other methods used to assess motor outcomes included screening measures with motor components but not specific subscales (eg, BOEL [blicken orienterar efter ljudet] test), clinical assessment (eg, general practitioner or physician), maternal reports, and combinations of the aforementioned. Aside from the difficulty this creates in comparing results among studies, some of the clear limitations of these measures include their lack of validity as a measure of motor performance and lack of blinding of the assessors to knowledge about in utero pregnancy exposure to antidepressant medications.

The timing and duration of the antidepressant exposure during pregnancy also differs greatly across studies. It is possible that the cumulative duration of exposure or the timing of exposure in combination with the fetus’s stage of central nervous system development may explain some of the differences across studies, but there is insufficient evidence from the existing research to draw such conclusions. Like most studies in which researchers investigate the potential for adverse outcomes secondary to medication use, limitations pertaining to the establishment of medication compliance and associated confirmation of exposure are present. Methods such as self-report are susceptible to recall bias, and pharmacy dispensation records do not guarantee that a medication has actually been taken.

Confounding by indication and severity are particularly problematic in the original studies. Researchers in only 5 of the 24 studies included in the systematic review attempted to address this by including a second control group of women who had depression but were unmedicated during pregnancy.20,52,55,60,63 Researchers in 1 additional study designated a comparison group of prepregnancy SSRI users without continued use during pregnancy.61 The incorporation of such control groups within well-designed studies is important for interpretation purposes. Given that depression in the mother has been associated with a multitude of adverse outcomes in the child, including infant cognitive and motor development issues,10 developmental delay,7 lower adolescent IQ, and increased likelihood of emotional and disruptive behavior disorders,8 untangling the effects of depression versus those of antidepressant exposure is a necessity. Furthermore, for those studies in which researchers rely on maternal report of child motor problems, the impact of maternal depression on ratings of the child requires consideration in design and interpretation of studies.

Limitations in the design of our meta-analysis include the use of data for fine motor outcomes over gross motor outcomes when only the total scores for each were reported in the published studies. Only 324,59,61 of the included studies in the meta-analysis are impacted by this. Further post hoc analyses could be performed to ensure that these alternative data do not change the overall result of our study. If anything, we would expect to have underestimated the effect of in utero antidepressant exposure on the impairment of motor development. Hanley et al59 identified statistically significant poorer gross but not fine motor scores. Researchers in the other 2 studies found similar nonsignificant results for both fine and gross motor assessments. The use of these gross motor scores would therefore be unlikely to influence our findings. In addition, as with any review of the literature, it is possible that a number of studies may have been missed, including those published in non–English-speaking journals or in databases not included in the electronic search.

Although there were identified studies in which researchers found differences in motor development in exposed children, the clinical relevance of these findings has been questioned. Despite the existence of statistical differences or small-to-moderate ESs, in at least 5 of the studies included in our systematic review and meta-analysis, the researchers note that raw scores still mostly fell within normal developmental ranges or differences were not discernable on clinical examination.25,52,54,60,61 Therefore, even with the results of our meta-analysis, the clinical significance of our finding remains somewhat unclear. It is possible that our findings predominantly reflect differences in mean scores within the normal developmental range rather than clinically significant impairments in functioning.

An interesting subset of studies that have been identified through our systematic review are those in which researchers have followed up on the development of children who exhibited symptoms of neonatal abstinence syndrome (NAS) at birth after antidepressant exposure in pregnancy. A number of the symptoms characterizing this syndrome are of a motor nature, including tremors, jitteriness, and poor muscle tone. There is considerable disagreement about whether these symptoms represent an acute withdrawal syndrome or are the result of structural changes that have occurred to the fetal brain secondary to the in utero antidepressant exposure. It follows then that neonates who suffer from this syndrome might be at greater risk of impaired motor development in childhood. At present, researchers in 4 studies included in our systematic review have examined motor outcomes in these children, with varying results.26,50,53,65 Two of these studies did not meet inclusion criteria for our meta-analysis,53,65 and thus quantifying these results is difficult. Future work in which researchers investigate the long-term motor as well as other developmental outcomes in children exhibiting NAS at birth would be clinically useful. If such a relationship exists, this would provide clarity about which children are at risk and allow for appropriate monitoring of and follow-up in this population.

Researchers in most of the included studies performed outcome assessments at a young age. Given that researchers in only 3 studies26,63,64 investigated motor development in children solely after 3 years of age, this remains a significant gap in the literature. It is likely that at the moment, any abnormalities of motor development occurring in later years related to in utero antidepressant exposure would be overlooked. Furthermore, the assessment of motor capacity in young infants is imprecise, and measures such as BSID have limited predictive validity for later motor outcomes. Of course, research to date has been limited by the relatively recent increase in the prescription of SSRIs during pregnancy2,3 and the subsequent availability of these populations for long-term follow-up of developmental outcomes in children. With a number of large population-based cohorts now being established,52,61,62 researchers will be better positioned to draw conclusions about longer-term developmental outcomes going forward. Until such results are available, the results of our meta-analysis reveal that general practitioners and pediatricians involved in the care of children who are exposed to antidepressant medication during pregnancy might routinely ask about progress toward the achievement of motor milestones with appropriate follow-up if parents report concerns.

In this systematic review and meta-analysis, we provide a timely synthesis of the available literature on the relationship between antidepressant exposure in utero and subsequent motor development in infants and children. Our finding of a small association between antidepressant exposure in pregnancy and poorer motor outcomes in children is limited by the vast differences in methodological design in the included studies. This clearly highlights the need for future researchers to design larger, methodologically rigorous studies that include a pregnant, unmedicated control group with depression (when ethically and clinically appropriate) in addition to a standard, unmedicated control group without depression; in which they accurately and prospectively record the timing and duration of antidepressant exposure in pregnancy; and in which they manage offspring longitudinally into older childhood or adolescence using robustly administered neuropsychological measures of motor development. In view of increasing prescription rates for antidepressants during pregnancy, the lack of such studies, particularly when trends toward poorer motor outcomes observed in this meta-analysis exist, is concerning. Currently, these findings are unlikely to warrant alterations to the current antidepressant prescribing guidelines during pregnancy. However, there may be some benefit in the monitoring of at-risk children. Further research will better enable clinicians and patients to make informed, evidence-based decisions on this matter.

     
  • BSID

    Bayley Scales of Infant Development

  •  
  • CI

    confidence interval

  •  
  • ES

    effect size

  •  
  • NAS

    neonatal abstinence syndrome

  •  
  • NOQAS

    Newcastle-Ottawa Quality Assessment Scale

  •  
  • SSRI

    selective serotonin reuptake inhibitor

Dr Groves undertook the systematic review of the literature and collated this for analysis and prepared the initial draft of the manuscript; Dr Lewis conceived and undertook the meta-analysis and reviewed and revised the manuscript; Dr Galbally designed and supervised the study, reviewed the included articles, and critically reviewed and revised the manuscript; and all authors contributed to the concept of the article, drafted the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

We thank the library staff at Fiona Stanley Hospital and Graylands Hospital for their assistance.

1
Gavin
NI
,
Gaynes
BN
,
Lohr
KN
,
Meltzer-Brody
S
,
Gartlehner
G
,
Swinson
T
.
Perinatal depression: a systematic review of prevalence and incidence.
Obstet Gynecol
.
2005
;
106
(
5, pt 1
):
1071
1083
[PubMed]
2
Andrade
SE
,
Raebel
MA
,
Brown
J
, et al
.
Use of antidepressant medications during pregnancy: a multisite study.
Am J Obstet Gynecol
.
2008
;
198
(
2
):
194.e1
194.e5
[PubMed]
3
Jimenez-Solem
E
,
Andersen
JT
,
Petersen
M
, et al
.
Prevalence of antidepressant use during pregnancy in Denmark, a nation-wide cohort study.
PLoS One
.
2013
;
8
(
4
):
e63034
[PubMed]
4
Beck
CT
,
Records
K
,
Rice
M
.
Further development of the postpartum depression predictors inventory-revised.
J Obstet Gynecol Neonatal Nurs
.
2006
;
35
(
6
):
735
745
[PubMed]
5
Chatillon
O
,
Even
C
.
Antepartum depression: prevalence, diagnosis and treatment [in French]
.
Encephale
.
2010
;
36
(
6
):
443
451
[PubMed]
6
Kurki
T
,
Hiilesmaa
V
,
Raitasalo
R
,
Mattila
H
,
Ylikorkala
O
.
Depression and anxiety in early pregnancy and risk for preeclampsia.
Obstet Gynecol
.
2000
;
95
(
4
):
487
490
[PubMed]
7
Deave
T
,
Heron
J
,
Evans
J
,
Emond
A
.
The impact of maternal depression in pregnancy on early child development.
BJOG
.
2008
;
115
(
8
):
1043
1051
[PubMed]
8
Hay
DF
,
Pawlby
S
,
Waters
CS
,
Sharp
D
.
Antepartum and postpartum exposure to maternal depression: different effects on different adolescent outcomes.
J Child Psychol Psychiatry
.
2008
;
49
(
10
):
1079
1088
[PubMed]
9
Marmorstein
NR
,
Malone
SM
,
Iacono
WG
.
Psychiatric disorders among offspring of depressed mothers: associations with paternal psychopathology.
Am J Psychiatry
.
2004
;
161
(
9
):
1588
1594
[PubMed]
10
Murray
L
,
Stein
A
.
The effects of postnatal depression on the infant.
Baillieres Clin Obstet Gynaecol
.
1989
;
3
(
4
):
921
933
[PubMed]
11
Paulson
JF
,
Keefe
HA
,
Leiferman
JA
.
Early parental depression and child language development.
J Child Psychol Psychiatry
.
2009
;
50
(
3
):
254
262
[PubMed]
12
Cohen
LS
,
Altshuler
LL
,
Harlow
BL
, et al
.
Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment.
JAMA
.
2006
;
295
(
5
):
499
507
[PubMed]
13
Galbally
M
,
Gentile
S
,
Lewis
AJ
.
Further findings linking SSRIs during pregnancy and persistent pulmonary hypertension of the newborn: clinical implications.
CNS Drugs
.
2012
;
26
(
10
):
813
822
[PubMed]
14
Pedersen
LH
,
Henriksen
TB
,
Vestergaard
M
,
Olsen
J
,
Bech
BH
.
Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study.
BMJ
.
2009
;
339
:
b3569
[PubMed]
15
Grigoriadis
S
,
VonderPorten
EH
,
Mamisashvili
L
, et al
.
Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence.
J Clin Psychiatry
.
2013
;
74
(
4
):
e293
e308
[PubMed]
16
Salisbury
AL
,
O’Grady
KE
,
Battle
CL
, et al
.
The roles of maternal depression, serotonin reuptake inhibitor treatment, and concomitant benzodiazepine use on infant neurobehavioral functioning over the first postnatal month.
Am J Psychiatry
.
2016
;
173
(
2
):
147
157
[PubMed]
17
Grigoriadis
S
,
VonderPorten
EH
,
Mamisashvili
L
, et al
.
The effect of prenatal antidepressant exposure on neonatal adaptation: a systematic review and meta-analysis.
J Clin Psychiatry
.
2013
;
74
(
4
):
e309
e320
[PubMed]
18
Nulman
I
,
Rovet
J
,
Stewart
DE
, et al
.
Neurodevelopment of children exposed in utero to antidepressant drugs.
N Engl J Med
.
1997
;
336
(
4
):
258
262
[PubMed]
19
Nulman
I
,
Rovet
J
,
Stewart
DE
, et al
.
Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study.
Am J Psychiatry
.
2002
;
159
(
11
):
1889
1895
[PubMed]
20
Casper
RC
,
Fleisher
BE
,
Lee-Ancajas
JC
, et al
.
Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.
J Pediatr
.
2003
;
142
(
4
):
402
408
[PubMed]
21
Mortensen
JT
,
Olsen
J
,
Larsen
H
,
Bendsen
J
,
Obel
C
,
Sørensen
HT
.
Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuroleptics, and anti-epileptics.
Eur J Epidemiol
.
2003
;
18
(
8
):
769
771
[PubMed]
22
Misri
S
,
Reebye
P
,
Kendrick
K
, et al
.
Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications.
Am J Psychiatry
.
2006
;
163
(
6
):
1026
1032
[PubMed]
23
Oberlander
TF
,
Reebye
P
,
Misri
S
,
Papsdorf
M
,
Kim
J
,
Grunau
RE
.
Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy.
Arch Pediatr Adolesc Med
.
2007
;
161
(
1
):
22
29
[PubMed]
24
Austin
MP
,
Karatas
JC
,
Mishra
P
,
Christl
B
,
Kennedy
D
,
Oei
J
.
Infant neurodevelopment following in utero exposure to antidepressant medication.
Acta Paediatr
.
2013
;
102
(
11
):
1054
1059
[PubMed]
25
Casper
RC
,
Gilles
AA
,
Fleisher
BE
,
Baran
J
,
Enns
G
,
Lazzeroni
LC
.
Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development.
Psychopharmacology (Berl)
.
2011
;
217
(
2
):
211
219
[PubMed]
26
Galbally
M
,
Lewis
AJ
,
Buist
A
.
Child developmental outcomes in preschool children following antidepressant exposure in pregnancy.
Aust N Z J Psychiatry
.
2015
;
49
(
7
):
642
650
[PubMed]
27
Gaspar
P
,
Cases
O
,
Maroteaux
L
.
The developmental role of serotonin: news from mouse molecular genetics.
Nat Rev Neurosci
.
2003
;
4
(
12
):
1002
1012
[PubMed]
28
Whitaker-Azmitia
PM
.
Serotonin and brain development: role in human developmental diseases.
Brain Res Bull
.
2001
;
56
(
5
):
479
485
[PubMed]
29
Kim
J
,
Riggs
KW
,
Misri
S
, et al
.
Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding.
Br J Clin Pharmacol
.
2006
;
61
(
2
):
155
163
[PubMed]
30
Whitaker-Azmitia
PM
.
Role of serotonin and other neurotransmitter receptors in brain development: basis for developmental pharmacology.
Pharmacol Rev
.
1991
;
43
(
4
):
553
561
[PubMed]
31
Lee
LJ
,
Lee
LJ
.
Neonatal fluoxetine exposure alters motor performances of adolescent rats.
Dev Neurobiol
.
2012
;
72
(
8
):
1122
1132
[PubMed]
32
Dewey
D
,
Kaplan
BJ
,
Crawford
SG
,
Wilson
BN
.
Developmental coordination disorder: associated problems in attention, learning, and psychosocial adjustment.
Hum Mov Sci
.
2002
;
21
(
5–6
):
905
918
[PubMed]
33
Skinner
RA
,
Piek
JP
.
Psychosocial implications of poor motor coordination in children and adolescents.
Hum Mov Sci
.
2001
;
20
(
1–2
):
73
94
[PubMed]
34
Burton
BK
,
Hjorthøj
C
,
Jepsen
JR
,
Thorup
A
,
Nordentoft
M
,
Plessen
KJ
.
Research review: do motor deficits during development represent an endophenotype for schizophrenia? A meta-analysis.
J Child Psychol Psychiatry
.
2016
;
57
(
4
):
446
456
[PubMed]
35
Suri
R
,
Lin
AS
,
Cohen
LS
,
Altshuler
LL
.
Acute and long-term behavioral outcome of infants and children exposed in utero to either maternal depression or antidepressants: a review of the literature.
J Clin Psychiatry
.
2014
;
75
(
10
):
e1142
e1152
[PubMed]
36
Gentile
S
,
Galbally
M
.
Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review.
J Affect Disord
.
2011
;
128
(
1–2
):
1
9
[PubMed]
37
Wells
GA
,
Shea
B
,
O’Connell
D
, et al
. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. 2009. Available at: www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed Octover 6, 2016
38
Nulman
I
,
Koren
G
,
Rovet
J
, et al
.
Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression.
Am J Psychiatry
.
2012
;
169
(
11
):
1165
1174
[PubMed]
39
Nulman
I
,
Koren
G
,
Rovet
J
,
Barrera
M
,
Streiner
DL
,
Feldman
BM
.
Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study.
J Clin Psychiatry
.
2015
;
76
(
7
):
e842
e847
[PubMed]
40
Heikkinen
T
,
Ekblad
U
,
Kero
P
,
Ekblad
S
,
Laine
K
.
Citalopram in pregnancy and lactation.
Clin Pharmacol Ther
.
2002
;
72
(
2
):
184
191
[PubMed]
41
El Marroun
H
,
White
TJ
,
Fernandez
G
, et al
.
Prenatal exposure to selective serotonin reuptake inhibitors and non-verbal cognitive functioning in childhood.
J Psychopharmacol
.
2017
;
31
(
3
):
346
355
[PubMed]
42
Karam
F
,
Sheehy
O
,
Huneau
MC
, et al
.
Impact of maternal prenatal and parental postnatal stress on 1-year-old child development: results from the OTIS antidepressants in pregnancy study.
Arch Women Ment Health
.
2016
;
19
(
5
):
835
843
[PubMed]
43
DiPietro
JA
,
Novak
MF
,
Costigan
KA
,
Atella
LD
,
Reusing
SP
.
Maternal psychological distress during pregnancy in relation to child development at age two.
Child Dev
.
2006
;
77
(
3
):
573
587
[PubMed]
44
Yoshida
K
,
Smith
B
,
Craggs
M
,
Kumar
RC
.
Fluoxetine in breast-milk and developmental outcome of breast-fed infants.
Br J Psychiatry
.
1998
;
172
:
175
178
[PubMed]
45
Costei
AM
,
Kozer
E
,
Ho
T
,
Ito
S
,
Koren
G
.
Perinatal outcome following third trimester exposure to paroxetine.
Arch Pediatr Adolesc Med
.
2002
;
156
(
11
):
1129
1132
[PubMed]
46
Harrington
RA
,
Lee
LC
,
Crum
RM
,
Zimmerman
AW
,
Hertz-Picciotto
I
.
Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay.
Pediatrics
.
2014
;
133
(
5
). Available at: www.pediatrics.org/cgi/content/full/133/5/e1241
[PubMed]
47
Moher
D
,
Shamseer
L
,
Clarke
M
, et al;
PRISMA-P Group
.
Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
Syst Rev
.
2015
;
4
:
1
[PubMed]
48
Reebye
PN
,
Morison
SJ
,
Panikkar
H
,
Misri
S
,
Grunau
RE
.
Affect expression in prenatally psychotropic exposed and nonexposed mother–infant dyads.
Infant Ment Health J
.
2002
;
23
(
4
):
403
416
49
Simon
GE
,
Cunningham
ML
,
Davis
RL
.
Outcomes of prenatal antidepressant exposure.
Am J Psychiatry
.
2002
;
159
(
12
):
2055
2061
[PubMed]
50
Oberlander
TF
,
Misri
S
,
Fitzgerald
CE
,
Kostaras
X
,
Rurak
D
,
Riggs
W
.
Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure.
J Clin Psychiatry
.
2004
;
65
(
2
):
230
237
[PubMed]
51
Oberlander
TF
,
Grunau
RE
,
Fitzgerald
C
,
Papsdorf
M
,
Rurak
D
,
Riggs
W
.
Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure.
Pediatrics
.
2005
;
115
(
2
):
411
425
[PubMed]
52
Pedersen
LH
,
Henriksen
TB
,
Olsen
J
.
Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.
Pediatrics
.
2010
;
125
(
3
). Available at: www.pediatrics.org/cgi/content/full/125/3/e600
[PubMed]
53
Klinger
G
,
Frankenthal
D
,
Merlob
P
, et al
.
Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome.
J Perinatol
.
2011
;
31
(
9
):
615
620
[PubMed]
54
Galbally
M
,
Lewis
AJ
,
Buist
A
.
Developmental outcomes of children exposed to antidepressants in pregnancy.
Aust N Z J Psychiatry
.
2011
;
45
(
5
):
393
399
[PubMed]
55
Suri
R
,
Hellemann
G
,
Stowe
ZN
,
Cohen
LS
,
Aquino
A
,
Altshuler
LL
.
A prospective, naturalistic, blinded study of early neurobehavioral outcomes for infants following prenatal antidepressant exposure.
J Clin Psychiatry
.
2011
;
72
(
7
):
1002
1007
[PubMed]
56
Johnson
KC
,
LaPrairie
JL
,
Brennan
PA
,
Stowe
ZN
,
Newport
DJ
.
Prenatal antipsychotic exposure and neuromotor performance during infancy.
Arch Gen Psychiatry
.
2012
;
69
(
8
):
787
794
[PubMed]
57
Batton
B
,
Batton
E
,
Weigler
K
,
Aylward
G
,
Batton
D
.
In utero antidepressant exposure and neurodevelopment in preterm infants.
Am J Perinatol
.
2013
;
30
(
4
):
297
301
[PubMed]
58
de Vries
NK
,
van der Veere
CN
,
Reijneveld
SA
,
Bos
AF
.
Early neurological outcome of young infants exposed to selective serotonin reuptake inhibitors during pregnancy: results from the observational SMOK study.
PLoS One
.
2013
;
8
(
5
):
e64654
59
Hanley
GE
,
Brain
U
,
Oberlander
TF
.
Infant developmental outcomes following prenatal exposure to antidepressants, and maternal depressed mood and positive affect.
Early Hum Dev
.
2013
;
89
(
8
):
519
524
[PubMed]
60
Santucci
AK
,
Singer
LT
,
Wisniewski
SR
, et al
.
Impact of prenatal exposure to serotonin reuptake inhibitors or maternal major depressive disorder on infant developmental outcomes.
J Clin Psychiatry
.
2014
;
75
(
10
):
1088
1095
[PubMed]
61
Handal
M
,
Skurtveit
S
,
Furu
K
, et al
.
Motor development in children prenatally exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study.
BJOG
.
2016
;
123
(
12
):
1908
1917
[PubMed]
62
Hurault-Delarue
C
,
Damase-Michel
C
,
Finotto
L
, et al
.
Psychomotor developmental effects of prenatal exposure to psychotropic drugs: a study in EFEMERIS database.
Fundam Clin Pharmacol
.
2016
;
30
(
5
):
476
482
[PubMed]
63
Brown
AS
,
Gyllenberg
D
,
Malm
H
, et al
.
Association of selective serotonin reuptake inhibitor exposure during pregnancy with speech, scholastic, and motor disorders in offspring.
JAMA Psychiatry
.
2016
;
73
(
11
):
1163
1170
[PubMed]
64
Partridge
MC
,
Salisbury
AL
,
LaGasse
LL
.
Fine motor differences and prenatal serotonin reuptake inhibitors exposure.
J Pediatr
.
2016
;
175
:
144
149.e1
65
Galbally
M
,
Spigset
O
,
Johnson
AR
,
Kohan
R
,
Lappas
M
,
Lewis
AJ
.
Neonatal adaptation following intrauterine antidepressant exposure: assessment, drug assay levels, and infant development outcomes.
Pediatr Res
.
2017
;
82
(
5
):
806
813
[PubMed]
66
Croce
RV
,
Horvat
M
,
McCarthy
E
.
Reliability and concurrent validity of the movement assessment battery for children.
Percept Mot Skills
.
2001
;
93
(
1
):
275
280
67
Connolly
BH
,
Dalton
L
,
Smith
JB
,
Lamberth
NG
,
McCay
B
,
Murphy
W
.
Concurrent validity of the Bayley Scales of Infant Development II (BSID-II) Motor Scale and the Peabody Developmental Motor Scale II (PDMS-2) in 12-month-old infants.
Pediatr Phys Ther
.
2006
;
18
(
3
):
190
196

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Galbally has previously received honoraria for speaking from Lundbeck; the other authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data