FormalPara Key Points

The available evidence on the association between antidepressant use during pregnancy and poor motor development in offspring is inconclusive.

The results of the reviewed studies do not suggest an association between in utero exposure to antidepressants and delayed adverse effects on intellectual ability in children.

1 Introduction

Maternal depression encompasses mild and severe non-psychotic depressive conditions affecting pregnant women and new mothers. It includes depressive episodes that occur during pregnancy and up to a year after childbirth [1, 2]. According to the World Health Organization, approximately 10% of pregnant women and 13% of new mothers (up to 12 months postpartum) experience depression [3]. The growing incidence of maternal depression imposes a substantial social and economic burden on many societies; hence, it is now recognized as a global public health issue [4].

Untreated maternal depression is associated with higher rates of pregnancy-related complications, such as premature death of the infant, and poor fetal outcomes, such as low fetal growth and increased fetal heart rate [5, 6]. Untreated depression during pregnancy is also associated with a higher risk of preterm birth (< 37 weeks) and lower birth weight (< 2500 g) than in women without depression [7]. Furthermore, having depression during pregnancy is associated with a broad range of neurodevelopmental problems in offspring, such as negative behavioral, emotional, or cognitive outcomes, intellectual disabilities, and language impairment [8,9,10,11]. Observational studies have shown that persistent depression during pregnancy is associated with increased risk of delayed cognitive and behavioral development in children and with antisocial and violent behavior in teenagers [8, 9], which emphasizes the importance of adequate maternal depression treatment during pregnancy to prevent severe adverse outcomes for mother and child.

Despite the need for appropriate treatment of maternal depression during pregnancy, there is limited information available to guide clinicians [12]. The prevalence of antidepressant use during pregnancy worldwide varies from 1.8 to 7.3% [13,14,15]. Currently, a combination of pharmacotherapy and psychotherapy is the most common treatment for moderate to severe maternal depression, while psychotherapy alone is recommended in mild cases [16,17,18]. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used antidepressants during pregnancy [16,17,18]. However, antidepressants have their own set of adverse effects on maternal and fetal outcomes. Since they can pass the placental barrier, their use during pregnancy may potentially affect the neurotransmitter systems in the brain of the offspring, and may eventually influence neurodevelopmental outcomes [19]. Consequently, clinicians often face the risk–benefit dilemma of whether to treat mothers with antidepressants during pregnancy. There is a need for a systematic examination of the published literature to provide evidence on the use of antidepressants during pregnancy and on the potential risk of neurodevelopmental outcomes in the offspring.

Studies assessing the safety of antidepressant use during pregnancy report conflicting results [12, 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. For example, several studies have linked prenatal exposure to antidepressants to attention deficit hyperactivity disorder or autism spectrum disorder in children [20,21,22,23,24,25,26,27, 31,32,33,34,35]. However, after addressing confounding bias through sibling design, the risk was moved to the null finding [33,34,35]. On the other hand, only a few studies have examined the potential impact of antidepressant use on other neurodevelopment aspects, such as cognitive and motor development, intelligence quotient (IQ), or language competence [12, 29, 36,37,38], and there is no consensus on the effect of prenatal exposure to antidepressants on motor and intellectual development in offspring [12, 29, 39,40,41,42,43,44,45,46,47,48,49,50,51].

Therefore, this systematic review aims to evaluate the available literature concerning the prenatal use of antidepressants and its potential impact on motor and intellectual development in offspring.

2 Methodology

2.1 Data Sources

A systematic literature search for the papers published before December 2020 was performed in the Cochrane Central Register of Controlled Trials, PubMed/Medline, and Google Scholar. The reference lists of the selected articles and the systematic reviews/meta-analyses identified through the search were also screened for additional publications.

2.2 Search Terms

Medical subject headings combined with relevant keywords were used to search the databases. The search terms for motor outcomes were “antidepressant” OR “tricyclic antidepressants” OR “TCA(s)” OR “selective serotonin reuptake inhibitors” OR “SSRI(s)” OR “serotonin norepinephrine reuptake inhibitors” OR “SNRI(s)” AND “children” OR “offspring” OR “pregnancy” OR “pregnant” OR “maternal” OR “prenatal” OR “antenatal” OR “gestational” AND “motor performance” OR “neuromotor performance” OR “motor activity” OR “motor skills” OR “motor outcome.”

For intellectual disabilities, the search terms were “antidepressant” OR “tricyclic antidepressants” OR “TCA(s)” OR “selective serotonin reuptake inhibitors” OR “SSRI(s)” OR “serotonin norepinephrine reuptake inhibitors” OR “SNRI(s)” AND “children” OR “offspring” OR “pregnancy” OR “pregnant” OR “maternal” OR “prenatal” OR “antenatal” OR “gestational” AND cognitive” OR “cognitive development” OR “intelligence” OR “intelligence quotient (IQ)” OR “low IQ” OR “intellectual development disorder” OR “intellectual disability” OR “mental retardation” OR “mental deficiency.”

2.3 Inclusion Criteria

We included papers that met the following criteria. The study population was children, between 0 and 18 years old, of mothers exposed to antidepressants during pregnancy. The exposure window was from 30 days before conception to the time of delivery. The exposure of interest was the mother’s use of antidepressants, including SSRIs, serotonin and noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), and tricyclic antidepressants (TCAs). We studied the transient effects of prenatal exposure to antidepressants on motor or intellectual development events that had been assessed either by medical diagnoses or by standardized psychometric instruments.

2.4 Selection of Studies

The initial search was limited to human studies published in English. The titles and abstracts of all articles found in the initial search were screened for primary evaluation. Only observational studies (cohort, case–control design, or their variants) available in full text were included. Two reviewers independently conducted the systematic literature search, screening, and reviewing of articles. Upon completion of the literature search, both reviewers shared their findings and reached a consensus for the final study selection. The current review adheres to the guidelines and checklist of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

2.5 Quality Appraisal

Once the selection process was complete, the baseline characteristics of all studies included (i.e., first author’s name, date of publication, study design, sample size, duration of antidepressant exposure, outcome measure, children’s age, and adjusted variables) were carefully examined. The methodological quality and risk of bias for each study were assessed using the Risk of Bias in Non-Randomized Studies (ROBINS-I) tool (Table 4).

3 Results

The initial literature search resulted in 813 articles. After excluding duplicates, non-English studies, and animal studies, 670 records were screened. Of these, 626 records were excluded after title/abstract screening. In total, 44 articles remained for full-text screening. Thirty articles were subsequently excluded: 20 for addressing other outcomes and ten for being reviews. Finally, 14 studies remained for use in this systematic review. Figure 1 shows the flow diagram for article selection based on PRISMA. Tables 1 and 2 present the baseline characteristics and main findings of the studies included.

Fig. 1
figure 1

PRISMA flow diagram for study selection. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses. From: Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7): e1000097. https://doi.org/10.1371/journal.pmed1000097

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Table 1 Characteristics of studies assessing the effect of antidepressants on motor development
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Table 2 Studies assessing the effect of antidepressants on intellectual disabilities
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3.1 Motor Development

3.1.1 Characteristics of the Studies Included

Ten studies examined the association between antidepressant use during pregnancy and poor motor development outcomes in offspring [39,40,41,42,43,44,45,46,47,48]. The studies operationalized adverse motor development outcomes using an observer assessment scale or diagnostic codes (Table 1). Seven studies used psychometric evaluation instruments; six studies [40,41,42, 44, 47, 48] used either the 2nd or 3rd edition of the Bayley Scales of Infant Development (BSID-II and BSID-III), and one study used the Movement Assessment Battery for Children (Movement ABC) [45]. All psychometric evaluations were conducted by trained psychologists or occupational therapists who were blinded to the infants’ exposure status. Two studies assessed motor activity in infants by observing the infants physically with activity monitoring devices and the Neonatal Behavioral Assessment Scale (NBAS) [39, 46]. Physical observations were done by trained assessors who were blinded to the infants’ exposure status. One study based its outcome assessment on medical diagnosis by physicians in specialized care units [43].

3.1.2 Antidepressant Exposure

Antidepressant exposure was ascertained from self-reported questionnaires in five studies [39, 44, 45, 47, 48], while the remaining studies obtained exposure status from medical records. Most studies (six out of nine) specifically examined the association between maternal exposure to SSRIs and adverse effects on motor outcomes [39, 41, 43, 46, 48]. The timing of antidepressant exposure during pregnancy varied between studies, and only four studies classified antidepressant exposure by trimester [39, 44, 47, 48].

3.1.3 Bayley Scales of Infant Development

Using BSID-II or BSID-III, one study showed that the fine motor function performance in offspring of healthy mothers unexposed to antidepressants was 9.4% higher than that in exposed children [42]. However, these findings were not statistically significant (Table 1). In contrast, three studies showed a statistically insignificant higher score (ranging from 0.9 to 6.1%) in fine motor functions in offspring with in utero exposure to antidepressants in comparison to offspring of unexposed healthy mothers [40, 41, 44]. Notably, none of the studies considered the cumulative in utero exposure to antidepressants, nor the timing of the exposure by trimester (except one study). Casper et al. (2011) did link longer antidepressant use during pregnancy to adverse effects on motor development in offspring [47]. However, this study did not include a control group of unmedicated women with depression; therefore, confounding by indication cannot be ruled out.

Three studies showed that the score of gross motor function performance was 9.1–12.6% lower in children with in utero exposure to antidepressants in comparison to offspring of unexposed healthy mothers [40, 42, 48]. On the other hand, two studies demonstrated slightly higher scores (1.1–7.7%) in gross motor function in children with in utero exposure to antidepressants in comparison to unexposed children of healthy mothers [41, 44].

3.1.4 Neonatal Behavioral Assessment Scale

Two small studies examined the association of in utero antidepressant exposure with early motor development using NBAS and reported inconsistent findings. Zeskind and Stephens showed worse motor performance during sleep associated with in utero exposure to antidepressant (unspecified by trimester) in comparison to no exposure with healthy mothers [46]. Similarly, there was an association between maternal exposure to antidepressant during the third trimester and adverse motor outcomes in neonates in another study [39]. However, these differences in motor activity were no longer significant when adjusted for gestational age in both studies [39, 46].

3.1.5 Movement Assessment Battery for Children

One study reported insignificant worse motor development effects (using the Movement ABC test) in offspring following antidepressant exposure during pregnancy in comparison to those born to healthy mothers with no antidepressant use [45]. The composite motor score was 3.6% lower in children with maternal exposure to antidepressants in comparison to those without exposure to antidepressant.

3.1.6 Diagnoses of Motor Disorders

Brown et al. (2016) [43] conducted a large population-based study using data on singleton live births from the Finnish Medical Birth Register using medical diagnoses as the measure of motor outcome. No significant differences were observed in motor outcomes between offspring in the antidepressant-exposed group and in the unmedicated group with mothers who had depression (hazard ratio [HR] 1.18; 95% confidence interval [CI] 0.81–1.72). The authors observed an insignificant increased risk of motor disorders in offspring of mothers with at least two antidepressant purchases compared to offspring of unexposed healthy mothers (HR 1.26; 95% CI 0.9–1.77). The risk increased with more refills of SSRI prescriptions (≥ 2) compared to only receiving one prescription; this might indicate confounding by depression severity, which the authors attempted to control for by adjusting for suicidal ideation and restricting the analysis to those with no other psychotropic agents [43].

3.1.7 Confounding Domains Assessed by the Included Studies

Table 3 shows the covariates evaluated by the studies included. Two potential confounders (maternal age and gestational age) were evaluated in all studies. Other variables controlled for in some studies including cigarette and alcohol use during pregnancy, the mother’s education level, the mother’s socioeconomic status, the mother’s IQ, and the duration of antidepressant exposure (Table 3). Nine out of ten studies assessed either the severity of the maternal depression or the maternal psychiatric history. Zeskind and Stephens’s study [46] was the only one that did not evaluate maternal depression or psychiatric comorbidity during pregnancy. The study mainly included postpartum mothers and was limited to measures of maternal treatment intensity in terms of number and duration of antidepressant use during pregnancy [46].

Table 3 Covariates controlled for/adjusted in the studies included
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3.1.8 Risk of Bias

Of the ten studies assessing motor development as an outcome of maternal exposure to antidepressants, we considered nine studies [39,40,41,42,43, 45,46,47,48] at moderate risk of bias and one study [44] at serious risk of bias (Table 4).

Table 4 Risk of bias among observational studies measuring prenatal antidepressant exposure and its potential impact on motor and intellectual development in children
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3.2 Intellectual Disabilities

3.2.1 Characteristics of the Studies Included

Five studies [45, 49,50,51,52] examined the association between maternal antidepressant exposure during pregnancy and the risk of intellectual disabilities in offspring. The studies used a psychometric instrument (BSID-II) and the McCarthy Scales of Children’s Abilities [49, 50], the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) [45, 51], or diagnostic codes [52]. The psychometric assessment was done by trained psychologists or occupational therapists blinded to the offspring’s exposure status.

3.2.2 Antidepressant Exposure

In four studies, antidepressant exposure ascertainment was done through self-reported questionnaires [45, 49,50,51]. Maternal antidepressant exposure windows were specified in two studies, where the use of antidepressants went on throughout the pregnancy, starting from the first trimester, and this was a requirement for eligibility for the study [45, 50]. The other two studies did not restrict the timing or length of antidepressant use [49, 51, 52]. Most studies (three out of five) specifically examined the association between maternal exposure to SSRIs and adverse effects on intellectual performance outcomes [49, 50, 52].

3.2.3 Wechsler Preschool and Primary Scale of Intelligence

Two studies used the WPPSI to examine the association between exposure to antidepressants during the entire pregnancy and detrimental effects on intellectual ability [45, 51]. In one study, the full IQ test score was similar between children exposed to antidepressants and unexposed children of healthy mothers (mean IQ score ± SD = 115 ± 14 vs. 115 ± 8; p = 0.92) [45]. The other study reported slightly higher full IQ scores (IQ = 112 ± 11) in unexposed children of healthy mothers than in antidepressant-exposed children (IQ = 105 ± 13) [51]. However, neither study found a statistically significant association between in utero exposure to antidepressants and adverse mental outcomes.

3.2.4 Bayley Scales of Infant Development and McCarthy Scales of Children’s Abilities

The McCarthy Scales of Children’s Abilities and the BSID were used in two studies to assess the risk of adverse effects on a child’s intellectual abilities following in utero exposure to antidepressants [49, 50]. Both studies included only mothers who used antidepressants throughout the pregnancy, starting from the first trimester. The performance in global IQ assessments was similar or slightly higher in exposed children compared to unexposed children of healthy mothers (Table 2). The results of global cognitive function assessments were comparable between exposed children and unexposed children of healthy mothers (Table 2). In both studies, there was no association between in utero exposure to antidepressants and adverse effects on the offspring’s cognitive development or intellectual ability compared to no exposure [49, 50].

3.2.5 Intellectual Disabilities Diagnosis

Viktorin et al. [52] used the Swedish national registers to conduct a retrospective cohort study comprising 179,007 infants. Infants exposed to antidepressants through their mother had a 33% higher risk of intellectual disability compared to unexposed infants of healthy mothers. However, the results were not statistically significant (relative risk 1.33; 95% CI 0.90–1.98) [52]. The specific timing of exposure to antidepressants and the length of exposure did not have an effect on the association between antidepressant exposure and intellectual disabilities in infants (Table 2).

3.2.6 Confounding Domains Assessed by the Studies Included

Table 3 highlights the covariates evaluated by the studies included that examined intellectual disabilities as an outcome. The maternal age and gestational age were evaluated by all studies. Covariates such as cigarette and alcohol use during pregnancy, the mother’s education level, the mother’s socioeconomic status, the mother’s IQ, and the duration of antidepressant exposure were considered in the studies (Table 3). Adjustment for the use of psychotropic drugs other than antidepressants occurred in three studies [50,51,52].

3.2.7 Risk of Bias

Of the five studies [45, 49,50,51,52] that examined the association between maternal antidepressant exposure during pregnancy and the risk of intellectual disabilities in offspring, we assessed two studies [51, 52] at low risk of bias, two at moderate risk of bias [45, 50], and one at serious risk of bias [49].

4 Discussion

This systematic review was conducted to examine published studies investigating the relationship between in utero exposure to antidepressants and the risk of poor motor development and intellectual disability outcomes in offspring.

The available evidence concerning the association between antidepressant use during pregnancy and the risk of adverse motor development is inconsistent. A recently published meta-analysis [30] reported a small effect (effect size = 0.22; 95% CI 0.07–0.37) in the direction of an increased risk of worse motor development outcomes in children exposed to antidepressants. However, given the marked variations in outcome measurements among the studies, particularly in methods used to quantify motor performance, the meta-analysis is subject to a moderate degree of heterogeneity (I2 = 56.6%; p = 0.002). Although the study suggested a possible association between in utero exposure to antidepressants and delayed motor development, it could not rule out the influence of different biases or of unmeasured confounding such as confounding by indication.

The results of the observational studies included found no association between antidepressant exposure during pregnancy and intellectual disability outcomes in offspring [45, 49,50,51,52]. Nulman et al. conducted a series of studies [49,50,51] to examine the differences in IQ between antidepressant-exposed and unexposed children, and found no significant association between intellectual disabilities and prenatal exposure to antidepressants. Methodologically, Nulman et al. [50] mitigated the concerns of a previous study [49] by the same authors about exposure misclassification in the first trimester by restricting the study cohorts to women who had used antidepressants throughout their pregnancy. In addition, Nulman et al.’s 2012 study [51] had fewer limitations than their previous studies [49, 50] and was assessed to be at low risk of bias using the ROBINS-I tool. This study overcame confounding by indication by including a control group of depressed mothers who did not receive antidepressants [51].

The findings summarized in this systematic review should be interpreted with caution given the many methodological limitations inherent to the observational studies included. The main problem that limits the validity of most studies is unmeasured confounding, particularly confounding by indication. In only two of the 14 studies, the researchers had an appropriate comparison group of untreated, depressed mothers to address confounding by indication [43, 51]. The risk of residual confounding is another major concern, as these studies had variation in the type of covariates adjusted or controlled for, and most studies did not control for several potential confounders in the analysis, such as the use of psychotropic drugs other than antidepressants, maternal and paternal psychiatric history, or other environmental or genetic factors. Only one study, by Brown et al. [43], controlled for maternal and paternal history of psychiatric diagnoses through matching siblings with discordant exposure status. Notably, sibling design may address time-invariant or shared confounders but may fail to address time-varying confounders. In comparison to non-sibling design, the risk of bias is higher in sibling design studies when the levels of confounders differ between the siblings [53].

Furthermore, the methods used to assess motor performance, intellectual disabilities, and the severity of the maternal depression varied greatly across studies in terms of validity and internal consistency. The BSID was the most commonly used scale for motor assessment in most studies. Other methods included the NBAS and Movement ABC. Of these, only Movement ABC is a neuropsychological test specifically for motor function impairment and has been reported to have high test–retest reliability and moderate construct validity [54] It was used in one study [45]. In contrast, although the BSID is regarded as the gold standard assessment tool for measuring the developmental functioning of infants and toddlers, its motor subscale is considered a poor predictor of later motor impairments [55].

Measures used to assess intellectual disability outcomes included the WPPSI-III, the Bayley Mental Development Index, and the McCarthy General Cognitive Index. Only the WPPSI-III is a scale specifically designed to provide a full-scale IQ score on general intellectual ability [56]. On the other hand, the type and severity of depression was assessed using a variety of scales, such as the self-rated Edinburgh Postnatal Depression Scale, the Beck Depression Inventory, the Center for Epidemiologic Studies Depression Scale, the Index of Parental Attitudes, the Global Assessment of Functioning Scale, the clinician-rated Hamilton Rating Scale for Depression, and many more. In the studies included, these scales were used either individually or in combination. Taken together, the diverse range of assessment scales and their lack of validity made the results of the studies difficult to compare.

The ascertainment of the timing and duration of the prenatal exposure to antidepressants also differed greatly between studies, leading to exposure misclassification. Because of this, we could not find conclusive evidence on the association between maternal antidepressant exposure and adverse motor or intellectual effects in offspring. The studies used different methods to collect information about antidepressant use during pregnancy, including electronic medical registry data, medical record review, and self-report; however, no study reported adherence in drug use. Hence, there is uncertainty regarding the actual use of the prescribed antidepressants.

5 Conclusion

The studies reviewed were inconclusive in their findings concerning the motor and cognitive neurodevelopmental effects of in utero antidepressant exposure. Furthermore, several methodological limitations, such as confounding by indication and a lack of adjustment for potential confounders, existed in the reviewed studies. Therefore, future studies should use a more robust methodology to help clinicians make better informed risk–benefit assessments concerning the use of antidepressants during pregnancy.