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Cadernos de Saúde Pública

ISSN 1678-4464

36 nº.2

Rio de Janeiro, Fevereiro 2020


REVISÃO

Exposição intrauterina a antidepressivos e risco de transtornos de neurodesenvolvimento e psiquiátricos: uma revisão sistemática

Jessica Salvador Areias de Araujo, Isabella Fernandes Delgado, Francisco José Roma Paumgartten

http://dx.doi.org/10.1590/0102-311X00026619


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RESUMO
O estudo teve como objetivo investigar se a exposição intrauterina a antidepressivos (ADs) aumenta o risco de transtornos do espectro autista (TEA), transtorno de déficit de atenção e hiperatividade (TDAH), esquizofrenia e outros transtornos mentais e déficits cognitivos e de desenvolvimento em lactentes e pré-escolares. Foram realizadas buscas nas bases PubMed, EMBASE e BIREME/BVS para identificar estudos sobre associações entre o uso de ADs durante a gestação e transtornos de neurodesenvolvimento e psiquiátricos. Vinte estudos trataram de riscos de TEA e/ou TDAH, enquanto 30 focaram em déficits cognitivos e de desenvolvimento em lactentes ou pré-escolares. A maioria dos estudos não detectou associação entre AD na gestação e TEA, depois de ajustar as razões de risco para depressão ou outros transtornos psiquiátricos maternos. Alguns estudos mostraram que a depressão materna, quer tratada ou não, aumenta o risco de TEA. Sete entre oito estudos não detectaram aumento de risco de TDAH associado à exposição intrauterina a inibidores seletivos da recaptação da serotonina, o AD mais comumente utilizado. Não foram encontradas evidências consistentes entre o uso de AD na gestação e déficits de desenvolvimento neurocognitivo em lactentes ou pré-escolares. Em quase todos os estudos, permaneceu um confundimento residual por indicação (gravidade da depressão). A revisão sistemática não encontrou evidências consistentes de que os ADs na gestação aumentassem o risco de TEA, TDAH ou déficits de desenvolvimento neurocognitivo. Entretanto, alguns estudos evidenciaram que a depressão materna aumenta o risco de TEA.

Antidepressivos; Depressão; Transtorno do Espectro Autista; Transtorno do Déficit de Atenção com Hiperatividade; Gravidez


 

Introduction

Depression is a common but serious disorder characterized by a constellation of symptoms, namely, insomnia or hypersomnia, anhedonia, feelings of worthlessness, deep sadness and excessive guilt, extreme fatigue, loss of energy, diminished ability to concentrate and to make decisions, loss or increase of appetite and/or weight, psychomotor retardation or agitation, and suicidal thoughts and attempts 1.

In 2015, the World Health Organization (WHO) estimated that 322 million people, or 4.4% of world's population, suffered from depression 2. By 2030 depression will become the leading cause of global burden of disease as measured by the disability-adjusted life years (DALY) 2. Depression is nearly 1.7-fold more common in females than in males and vulnerability to it increases in pregnancy and puerperium when many women experience their first depressive episode, or have a recurrent manifestation of a previously diagnosed disorder 3. It affects up to 10%, or even more, of pregnant women and mothers who have recently given birth 4. Although depression is treatable, only approximately 12% of depressed pregnant women receive adequate treatment 5.

There is little consensus about the management of depression in pregnancy and reluctance to prescribe antidepressants (ADs) to pregnant women arises mostly from unresolved concerns regarding their risks to the unborn child 6. Accumulated evidence from observational investigations and meta-analyses indicates that maternal use of selective serotonin reuptake inhibitors (SSRI) in the first trimester of gestation entails a slightly higher risk of congenital malformations, particularly of heart defects 7. Some studies revealed associations of use of non-SSRIs with adverse pregnancy outcomes other than congenital anomalies, such as preterm delivery, low birth weight and perinatal complications 8,9. A recent systematic review, however, found no consistent differences between AD-treated and untreated patients in the risk level for poor pregnancy outcomes, such as small-for-gestational-age babies, spontaneous abortions and preterm births 10.

Concerns about harmful effects of maternal depression and its pharmacological treatment on the unborn child go beyond the endpoints evaluated at term pregnancy and neonatal period. It is thought, for instance, that antenatal exposure to ADs might increase the risk of neurodevelopmental disorders such as autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, and/or cognitive deficits 11. This notion is plausible because the fetal brain undergoes a process of rapid cell proliferation and migration, synaptogenesis and circuitry formation. Considerable experimental and clinical evidence apparently links dysfunctions of serotoninergic transmission to disruption of neural network shaping and subsequent appearance of neurodevelopmental disorders 12,13. It is of note that the most commonly prescribed antidepressants inhibit, either selectively or non-selectively, serotonin uptake from the synaptic cleft. Serotonin acts as a nervous tissue growth factor and, by doing this, it modulates neural plasticity and network formation in the developing brain 13. Serotonin-dependent shaping of neural circuitry provides an insight into a possible mode of action by which antenatal exposure to serotonin reuptake inhibitors might increase the risk of neurodevelopmental disorders. Along this line, Rotem-Kohavi et al. 14 recently reported findings of a possible neural correlate of epidemiologic associations between antenatal exposure to SSRIs and neurodevelopmental disorders. Using a resting-state functional magnetic resonance imaging, the authors noted that, compared with healthy control infants and infants whose depressed mothers did not receive antidepressants, newborns prenatally exposed to SSRIs exhibited a hyperconnectivity in auditory resting-state networks.

Several cohort and case-control studies addressed a potential association between antidepressant drug use by pregnant women and neurodevelopmental disorders such as ASD and ADHD in their children 15. These studies arrived at conflicting conclusions about whether or not antenatal exposure to antidepressants is associated with ASD or ADHD. There is far less information about risks of neurodevelopmental disorders other than ASD and ADHD, such as mental illnesses of later onset and long-term cognitive deficits.

Eight reviews of observational studies showed a positive association between exposure to ADs (SSRIs) in utero and ASD 16,17,18,19,20,21,22,23, whereas two studies found no evidence of association or inconsistent findings 24,25. Whether these associations were causal, however, remained unclear. Three reviews evaluated whether prenatal AD exposure was associated with ADHD and found no evidence of a causal link 25,26,27. Only one recent review examined whether AD use in pregnancy was associated with neurodevelopmental outcomes other than ASD and ADHD 28.

Autistic disorders are as a rule diagnosed around 3-4 years of age, and last throughout the individuals' life 29. They are characterized by symptoms such as deficits of social interaction and communication, limited and repetitive patterns of behavior, poor eye contact, lack of response to his/her name and/or indifference to caregivers, difficulty to express his/her emotions or feelings, apparent indifference to the feelings of others, inability to start a conversation or keep one going, and others 29. Some children with ASD have learning disabilities whereas others show normal to high intelligence, yet having great difficulty to communicate or apply what they learned. Both genetic and environmental factors seem to contribute to ASD susceptibility and severity 29. According to current estimates, ASD affects approximately 1% of people, being more frequently diagnosed in boys than in girls. There is no effective therapy for ASD, nor are there effective means to prevent it 29. Identification of environmental risk factors for ASD is, therefore, a public health goal of utmost importance.

ADHD is characterized by difficulty in paying attention and or hyperactivity/impulsivity 30. It is about 2-fold more frequent in boys than in girls, generally diagnosed in children under the age of 12 years, and lasts throughout the persons' life. Most patients have combined attention deficit and hyperactivity symptoms, and their enhanced distractibility and impulsivity impairs school performance and social skills 30,31. Although ADHD pathophysiology remains unclear, its symptoms show a good response to treatment with dopaminergic drugs. ADHD is one of the most prevalent childhood psychiatric disorders, affecting 5-7% children, when diagnosed by DSM-IV criteria, and 1-2% when diagnosed by WHO's (ICD-10) criteria 30,31. Overdiagnosis and overtreatment of ADHD, however, is a matter of debate.

The objective of this review was to answer a question of relevance for both public health and clinical practice: Is there epidemiologic evidence suggesting that prenatal exposure to ADs increases risks of ASD, ADHD, other psychiatric disorders of later onset and neurodevelopmental deficits in the exposed offspring? A well-founded response to this question would enable physicians and health authorities to make informed decisions about the use of antidepressant drugs to treat maternal depression in pregnancy. A corollary aim of the systematic review was to disclose research gaps requiring further epidemiology studies.

This study adds to existing reviews due to its broader research question, encompassing ASD, ADHD, psychiatric disorders of later onset and other neurodevelopmental outcomes, and because it reviewed a greater number of observational studies and critically appraised their methodological limitations.

Methods

This review followed the recommendations of the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 32, and was registered with PROSPERO 2018 (CRD42018080950).

Search strategy and study selection

A systematic search on PubMed, EMBASE, BIREME/BVS (Virtual Health Library - Brazil) electronic databases identified epidemiologic studies addressing the association of ADs in pregnancy with neurodevelopmental disorders in the offspring. The search covered the period between the inception of the database and December 2nd, 2018 (PubMed and BIREME/BVS), or January 1st, 2019 (EMBASE). The BIREME/BVS database includes articles published in periodicals indexed in the Latin American and Caribbean Literature on Health Sciences (LILACS). We also conducted a manual screening of reference lists of articles, reviews, and other documents, to identify additional studies potentially eligible for reviewing. There was no restriction regarding the language of the article. The search strategy combined Medical Subject Heading (MeSH; https://www.ncbi.nlm.nih.gov/mesh) terms for the pharmacological classes of antidepressants (with their variations) with pregnancy (or gestation) and with MeSH terms for neurodevelopmental disorders and cognitive skills (and variations). To design the search strings, Boolean connectors “AND” and “OR” were used for combining the search terms. Term combinations and the full search strategy are shown in Figure 1 and Supplementary Material - Appendix 1 (http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-app1-e00026619_3711.pdf).

 

 

Figure 1 Design of systematic review search strings (MeSH terms) with Boolean connectors “AND” and “OR”.

 

Inclusion criteria

Studies were eligible for inclusion if they investigated, in children born to mothers with any exposure to AD in pregnancy, outcomes such as diagnoses of ASD, ADHD, mental disorders (schizophrenic, affective or anxiety disorders), or emotional, internalizing and externalizing behaviors, speech and language, intelligence, neuromotor development, or any other form of cognitive functioning, assessed at least 3-4 weeks after birth, using scales or any other method. Internalizing behaviors (or disorders) are children's negative behaviors characterized primarily by processes focusing inward (on the self) such as anxiety, fearfulness, social withdrawal, somatization and depression. Contrasting with internalizing behaviors, externalizing behaviors are directed outwards (the external world) such as hostility, antisocial behavior, and aggression.

Exclusion criteria

Articles were not eligible for reviewing if they met any of the exclusion criteria, namely, in vivo studies conducted in animals, in vitro/ex-vivo investigations, ecologic and non-analytic epidemiology studies, cross-sectional studies, case-reports, case-series, letters, editorials, reviews, meta-analyses, notes, comments, clinical guidelines, opinion papers, full-paper not available, and articles not available in English, Portuguese, Spanish, German or French.

As shown in Figure 2, selection of retrieved studies (after excluding duplicates) for reviewing was a two-step screening process: at first, publications were screened by titles and abstracts and, if deemed potentially eligible, at a subsequent phase full articles were retrieved and read. Two reviewers independently screened retrieved studies for eligibility and, if they did not reach a consensus after extensive discussion, a third reviewer was asked to resolve it.

 

 

Figure 2 PRISMA flowchart of selection of studies for inclusion in the review.

 

Data extraction

Based on the STROBE statement checklist of items that should be included in reports from observational studies 33, two reviewers extracted a predetermined set of data from each study selected for review. Extracted data included first author's name, publication year, geographic location, study period, sample size, drug exposure (type of antidepressant and pharmacological class), period of exposure during pregnancy, strengths and limitations of the study, findings, outcome with risk estimates and 95% confidence intervals (95%CI), adjusted confounders, and study conclusions. A third reviewer examined the compiled data and study summaries, and differences between reviewers were resolved with discussion.

Assessment of the methodological quality

The assessment of study quality was based on the Newcastle-Ottawa Scale (NOS) for observational (case-control and cohort) epidemiology studies 34. NOS consists of eight items grouped into three domains for selection, comparability and outcome and two reviewers independently assessed each of the studies assigning a score (maximum score = 9) to the study quality. Any discrepancy between reviewers was resolved by a third reviewer.

Data synthesis

For each outcome evaluated, we present the characteristics and findings of all included studies. A qualitative (narrative) synthesis of the evidence for ASD, ADHD and other neurodevelopmental outcomes responded the research question. It took into account not only the results of the reviewed studies but also their methodological limitations and residual confounding. We considered undertaking a quantitative synthesis for ASD and ADHD. Nonetheless, we did not perform a meta-analysis because of the heterogeneity in design and characteristics of the included studies and the fact that several studies (national-based cohorts) used the same national data source (registry) with overlapping of data collection times.

Results

As shown in the PRISMA flow diagram of study selection process Figure 2, of the 50 studies included in the review, 20 addressed risks of ASD and ADHD while 30 investigated risks of developmental and cognitive impairments in infants, toddlers and preschool children. One Finnish study investigated the impact of gestational exposure to SSRIs on offspring psychiatric disorders including not only ASD and ADHD, but also anxiety and depression in early adolescents 35.

Autism spectrum disorders

Five out of 16 studies evaluating whether prenatal ADs increased risks of ASD found no increase in risk 35,36,37,38,39. Three studies detected a weak association of AD in pregnancy with ASD that were no longer significant when risk estimates were adjusted for confounding factors such as maternal depression or history of psychiatric disorders 40,41,42. Hagberg et al. 43 found a significant association of ASD with antenatal AD, when the unexposed offspring (no AD, no history of depression) was compared with a group exposed to both AD and maternal depression in pregnancy. No increase in risk of ASD was evident, however, when unexposed offspring was compared with offspring of pregnant women who received AD for disorders other than depression 43. Six cohort and case-control (nested in population-based cohorts) investigations, on the other hand, found a modest association of antenatal AD with ASD 44,45,46, ASD in boys 47, and ASD without intellectual disability 48,49. One of the reviewed studies evaluated whether antenatal exposure to SSRI was associated with higher scores for autistic traits in children 50. El Marroun et al. 50 found a modest association between maternal (self-reported) use of SSRIs in pregnancy and higher scores for autistic traits in infants assessed by child behavior checklists and a social responsiveness scale. Since depressed women are likely to overestimate problems with their children, and a residual confounding by indication of SSRIs (severity of depression) remained, associations of SSRI use in pregnancy with higher scores for autistic traits in infants may be non-causal.

Attention deficit/hyperactivity disorders

Four out of 8 studies that examined possible associations between AD in pregnancy and ADHD found no association between exposure and outcome 35,37,42,51. Three studies revealed no association of ADHD with maternal use of SSRIs, yet they found that this disorder was - weakly to moderately - associated with prenatal exposure to non-SSRIs, tricyclic ADs (TCA) and atypical antidepressants.

Figueroa 52 found that maternal use of SSRIs and ADs other than bupropion in pregnancy did not increase the risk of ADHD in children aged 5 years or younger. Antenatal bupropion, on the other hand, was moderately associated with ADHD especially when exposure occurred in the 2nd trimester of gestation. Bupropion inhibits both norepinephrine (NE) and dopamine (DA) reuptakes and, additionally, releases these neurotransmitters into the synaptic cleft. It also acts as a nicotinic receptor antagonist 53. This atypical antidepressant is used in combination with another AD, when patients are resistant to SSRI, and as an adjunct therapy for smoking cessation, weight loss and ADHD 54,55,56. Boukhris et al. 57 found that TCA in the 2nd/3rd trimesters of pregnancy was weakly associated with ADHD, even after adjustment for maternal history of depression. A territory population-based study by Man et al. 58 found that non-SSRI use in pregnancy was associated with a modest increase in the risk of ADHD in the offspring, yet a subsequent sibling analysis showed no association.

Finally, a case-control study by Clements et al. 41 found a modest association of ADHD with prenatal exposure to SSRIs & non-SSRIs, especially during the 1st trimester of gestation. This association was significant even after adjustment of risk estimates for maternal history of depression.

Quality assessment

The quality of cohort and case-control studies selected for review ranged from fair to very good (NOS scores 6 to 9), and 16 and 8 of them investigated risks of ASD and/or ADHD, respectively, in children born to AD-treated pregnant women Tables 1 and 2. The reasons for lower assessments (fair quality) were lower scores in Selection (2) and Comparability (1), and Outcome (1) and Comparability (1) domains for one case-control 44 and one cohort 50 study, respectively (Supplementary Material - Appendix 2: http://cadernos.ensp.fiocruz.br/site/public_site/arquivo/suppl-app2-e00026619_2540.pdf).

 

 

Tab.: 1
Table 1 Maternal use of antidepressant medication during pregnancy and risk of autism spectrum disorders in children prenatally exposed.

 

 

 

Tab.: 2
Table 2 Maternal use of antidepressant medications in pregnancy and risk of attention deficit/hyperactivity disorders in prenatally exposed children.

 

Mental disorders of later onset

Malm et al. 35 found that prenatal exposure to SSRIs modestly increased risks of depression in the offspring (SSRI exposed vs. non-exposed, after adjustment for maternal psychiatric disorder; HR = 1.78; 95%CI: 1.12-2.82). In this Finnish national register-based cohort study, cumulative incidence of diagnoses of depression was determined up to adolescence (age of 14) 35. Notwithstanding the attempt to adjust risk estimates for records of maternal history of psychiatric illnesses, the severity of maternal depressive disorder remained as a residual confounding. It is of note that association of SSRIs with depression among the offspring was also detected (adjusted HR = 1.84; 95%CI: 1.14-2.97) for preconception exposures (i.e., SSRIs discontinued in pregnancy). In this study, the authors found no association of SSRI in pregnant women with anxiety in children prenatally exposed 35. No other study examined a possible association between antenatal exposure to ADs and psychiatric disorders of later onset (adolescents and young adults) such as schizophrenia 59, and affective and anxiety disorders 60.

Developmental and cognitive deficits

Thirty out of 50 studies selected for review focused on the development and/or cognitive deficits in infants, toddlers and preschool children that might have arisen from prenatal exposures to ADs Table 3. A majority of these 30 studies found no association between prenatal ADs (mostly SSRIs) and deficits of IQ and/or cognitive 61,62,63,64,65,66,67,68,69, language 70, and behavior development 65,71,72,73,74. Some studies, however, indicated that the maternal depressive disorder, regardless of whether it is treated with ADs or not during pregnancy, may slightly increase the risks of deficits of IQ and language development 62, language competence 75, and/or behavior development 76,77.

Six studies evaluated the impact of prenatal ADs (mostly SSRI) on levels of internalizing and/or externalizing behaviors in preschool children. One study found that both prenatal SSRI and depression increased risks of externalizing behaviors while SSRI increased risks of internalizing behaviors 67. Another investigation indicated that prenatal SRI predicts internalizing but not externalizing behaviors in early childhood 78. Oberlander et al. 79 found that antenatal SSRI and depression are not associated with the child's externalizing behavior while current maternal mood predicts it. Two additional studies found no association between prenatal SSRIs or ADs with internalizing 80 and externalizing behaviors 81. Overall, the foregoing findings showed no consistent association of antenatal SSRIs and depression with children's internalizing or externalizing behaviors.

 

 

Tab.: 3
Table 3 Maternal use of antidepressant drugs in pregnancy and developmental and cognitive deficits in infant and toddlers.

 

Discussion

Residual confounding by indication and severity of depression

A residual confounding by indication was a shortcoming with major impact on the interpretation of most research findings. ADs are indicated mainly for the treatment of depressive disorders and so the possibility exists that associations resulted from the maternal depression for which the drug was prescribed and not from the pharmacological intervention. In other words, reported associations between children's neurodevelopmental disorders (ASD and ADHD) and maternal use of ADs in pregnancy may be non-causal. A few studies did not control confounding by indication at all and simply compared the offspring of AD-treated depressed mothers with the offspring of untreated and non-depressed pregnant women. These studies generally found a higher risk of ASD/ADHD among children prenatally exposed to ADs. In most studies, however, investigators made an attempt to control this confounding in the statistical analysis by adjusting risk ratios for effects of dichotomous presence or absence of maternal depression or history of psychiatric disorders, or yet, by also making a maternal sibling sub-cohort analysis.

It is fair to think that depression entailing prescription for AD is probably more severe than the disorder of patients not receiving pharmacological intervention. The lack of adjustment for severity of depression may have led to spurious associations of AD exposure in pregnancy with any analyzed outcome, if there is a causal link between the outcome (ASD, ADHD or other neurodevelopmental disorder) and the mother's major depressive illness.

Depression and risks of ASD, ADHD and neurodevelopmental impairment

The notion that maternal depression might be an independent risk factor for adverse pregnancy outcomes and offspring neurodevelopmental disorders is not only plausible but it is also consistent with findings from observational studies. Systematic reviews, with or without meta-analysis, found that untreated depression, anxiety and/or perceived stress during pregnancy were associated with small increases in the risk of adverse pregnancy outcomes such as preterm births, low birth weights and small-for-gestational-age infants 82,83. Untreated depression also causes effects on the developing fetus such as hyperactivity, irregular fetal heart rate and altered EEG patterns 84. The impact of maternal depression on child development and mental health has been far less explored. Nonetheless, some researches provided indirect evidence for such association of unmedicated maternal depression with ASD. A strong evidence along this line was provided by studies showing that preconception-only maternal exposure to ADs increased risks of ASD in the offspring 36,37,41,45. AD therapy before pregnancy indicates that these women suffered from a depressive disorder severe enough to require a pharmacological intervention. It is difficult to foresee, on the other hand, how a preconception-only exposure to ADs could have any detrimental effect on the further development of the conceptus. Moreover, associations of ASD with AD use in pregnancy detected by several studies proved to be nonsignificant after adjustment for maternal psychiatric disorders. Recently, Hagberg et al. 43 found that untreated depression, but not AD use in pregnancy for disorders other than depression, increased risks of ASD in the offspring. Using the duration of the last episode of depression as a proxy for disorder severity, the authors noted that risk of ASD increased with increasing severity of maternal depression. Collectively, these findings are consistent with the interpretation that a maternal history of depression might be an independent risk factor for ASD.

Seven studies found that maternal depression in pregnancy and/or after birth, regardless of whether it is treated or untreated, might impair child development 62,67,75,76,77,79,80. These findings showed that, as noted for ASD and ADHD, the non-adjustment of risk ratios for severity of depression may have led to spurious associations of antenatal AD with deficits in the cognitive and behavioral development of infants and preschool children.

Genetics and mother-child interaction

Both inheritable genetic traits and depression-caused abnormal mother-child interaction might provide plausible explanations for associations between maternal depression and enhanced risks of neurodevelopmental and psychiatric disorders in the offspring.

Affective disorders have well-established genetic components and family studies indicated 2- to 3-fold increases in lifetime risk of major depression among first-degree relatives 85,86. A recent genome-wide association meta-analysis identified 44 genetic risk loci for major depressive disorders and strongly suggested the existence of biological processes common to major depression and schizophrenia. The genome analysis indicated that some biological processes might be common to major depression and other psychiatric disorders such as ASD and ADHD 86. In the study by Malm et al. 35, for instance, inherited risk factors for major depression were lurking variables that might have influenced the apparent association between SSRI use in pregnancy and depressive disorders in the adolescent offspring. Although the association was significant after adjustment for maternal psychiatric illness, the authors did not adjust risk ratios for severity of maternal depression. SSRI use in pregnancy could have been a surrogate or marker for more severe maternal depressive disorders and, as mentioned, major depression has a genetic and inheritable component.

Furthermore, various studies provided evidence that depression can adversely affect mother-child bonding as well as the child's development and mental health 87.

Sibling analysis designs are useful to investigate associations thought likely to suffer confounding arising from genetics and environmental postnatal factors, including the detrimental effects of maternal depressive symptoms on mother-child interaction. In principle, such strategy to control potential confounding in the design of the study seems to be better than merely adjusting risk ratios in the statistical analysis using dichotomous data on the presence/absence of maternal history of depression. Nonetheless, a possible disadvantage of sibling analysis in a sub-cohort of population-based cohorts is that it drastically reduces the sample size and thus the statistical power of the analysis. In all sibling analyses conducted by reviewed studies, no association of ADs in pregnancy with ASD was found 38,40,42,43, nor was it detected with ADHD 42,51,58.

Non-differential misclassification of exposure

A notable shortcoming common to all reviewed studies is a potential non-differential misclassification of exposure status due to lack of confirmation of the actual drug intake in pregnancy. Exposure assessment (binary exposure) took into account records of drug prescription and dispensing, but no study confirmed patients' adherence to AD treatment. The exposure status relevant for the outcome of interest is not merely a matter of using or not ADs during pregnancy. The effect of exposure on the outcome is likely to depend on the magnitude (dose), timing and adherence to prescribed pharmacotherapy. Nonadherence to prescribed medication and, particularly, poor AD adherence is a challenging issue in psychiatric practice. It is estimated that up to approximately 50% of psychiatric patients, including those with major depression prematurely discontinue drug therapy 88,89. Nonadherence with medication is also a common problem among pregnant women whose drug-taking behavior can be negatively influenced by concerns about harmful effects of the pharmacological therapy on the unborn child, among other factors 90. The influence of concomitant pregnancy and depressive illness on the high rates of nonadherence with medication noted in either condition alone is unclear. At any rate, non-differential misclassification of exposure is likely to bias towards the null estimates of detrimental effects of prenatal AD exposure on offspring's health.

National scenarios

Another potential drawback of the reviewed cohort or case-control studies is the fact that nearly all of them used data from nationwide (or territory-based) health registries (e.g., Scandinavian countries, Finland, Hong Kong), or large databases from health insurance companies (e.g., United States, United Kingdom). These studies investigated associations between exposure and outcomes in people living in a few highly developed countries and findings might be somewhat different for distinct exposure scenarios and populations from Asia, Africa and Latin America.

Publication bias and searching strategy

In principle, publication biases may misdirect the qualitative and/or quantitative synthesis of any systematic review. It is unlikely, however, that any good quality observational study on the topic addressed by this systematic review would have remained unpublished. The possibility exists, on the other hand, that the adopted searching strategy (search strings and databases) was not effective to identify all relevant studies. To verify whether the search strategy failed to identify articles of interest, we compared the set of studies included in this review with those analyzed by previous systematic reviews. Nine reviews conducted between 2014 and 2018 examined a possible association of ADs in pregnancy with ASD 16,17,18,19,20,21,22,23,24. Our review about ASD risks covered not only all studies included in the previous reviews but also analyzed two more studies than the most recently published review. Two reviews, both published in 2018, addressed the risks of ADHD 26,27. Again, this study covered not only all studies included in published reviews but one more than those examined by one of the two previous reviews. Two reviews published in 2011 91 and 2018 28, including 5 and 7 studies, respectively, evaluated risks of neurodevelopmental disorders arising from prenatal exposures to ADs. Except for one study 92, this review analyzed all studies included in previous reviews and 23 additional articles. Suri et al. 92 found no association of AD in pregnancy with neurobehavioral outcomes and their study was included in the review by Prady et al. 28.

The foregoing comparison with previous reviews suggests that this updated review, encompassing the three outcomes of interest, did not fail to retrieve and include any relevant study about potential associations between prenatal exposure to AD and risks of ASD, ADHD and neurodevelopmental disorders.

SSRIs and neurodevelopmental outcomes

Studies of associations of ADs in pregnancy with impaired neurocognitive and behavioral development during infancy and early childhood were heterogeneous regarding the design, instruments used to assess neurocognitive development outcomes and child age at assessment. Overall, their findings indicated that antenatal exposure to SSRI did not impair further child development. Many of these studies used scales to assess child development such as the Bayley Scales of Infant Development (BSID) for infants with ages ranging from one to 42 months. BSID has high reliability and validity but, unless the scores are very low, its predictive value for long-term intellectual and motor disabilities is questionable 93,94,95. The clinical relevance of significant yet small differences in BDSI scores detected by some studies is unclear.

Since observational studies have limitations for controlling confounding and making causal inferences, a prospective, randomized, placebo-controlled, double-blinded clinical trial is under way in Sweden to clarify whether a SSRI (sertraline) and/or depression in pregnancy might in fact affect child neurocognitive development. The primary objective of this trial is to assess cognitive development at 2 years of age using the BSID-III scale. The recruitment of pregnant women for this study (MAGDALENA study protocol) will be finished in 5 to 6 years' time 96.

Concluding remarks

This study found no consistent evidence of association between antenatal exposure to ADs and increased risks of ASD, ADHD, psychiatric illnesses, and cognitive and or developmental deficits in preschool children.

The conclusion that prenatal exposure to SSRIs and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) does not predict risks of ASD is particularly robust. It is of note that results from some studies strongly suggested that maternal depression, regardless of whether it is treated or untreated during pregnancy, increases risks of ASD in the offspring. A recent population-based cohort study (mother-newborn pairs from Manitoba, Canada, born 1996-2009 with follow-up through 2014) found no association (HR = 0.92; 95%CI: 0.42-2.03) between antenatal exposure to SSRI or SNRI and ASD 97. This study was not included because only a conference abstract was available when the review was completed.

As commented before, eight reviews of observational studies found a positive association of ASD with use of SSRIs in pregnancy 16,17,18,19,20,21,22,23. At least four of these studies highlighted that maternal psychiatric condition was a major confounding 18,20,22,23 or that causality remained to be confirmed 17. Two additional reviews found no association 24, or pointed out that a residual confounding by indication and inconsistent findings precluded a conclusion about risks of ASD 25. Along the same line, three reviews concluded that a residual confounding by indication cannot be ruled out as an explanation for observed associations of prenatal AD exposure with ADHD 25,26,27. Only one review 28 evaluated studies that compared behavioral and neurodevelopmental outcomes for children whose mothers took ADs during pregnancy with those whose mothers suffered from mental disorders but did not take medication. This study 28 found very limited evidence indicating that gestational use of ADs might impair behavioral and neurodevelopmental outcomes in the offspring.

Overall, findings from this study and those from other systematic reviews addressing risks of poor pregnancy outcomes and developmental disorders do not support concerns on the risks of SSRIs/SNRIs for the unborn child.

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