Maternal use of antidepressant or anxiolytic medication during pregnancy and childhood neurodevelopmental outcomes: a systematic review.

Eur Child Adolesc Psychiatry DOI 10.1007/s00787-014-0558-3

REVIEW

Maternal use of antidepressant or anxiolytic medication during pregnancy and childhood neurodevelopmental outcomes: a systematic review Hanan El Marroun • Tonya White • Frank C. Verhulst • Henning Tiemeier

Received: 14 February 2014 / Accepted: 2 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Antidepressant and anxiolytic medications are widely prescribed and used by pregnant women for acute and maintenance therapy. These drugs are able to pass the placental barrier, and may potentially influence fetal and brain development. It is possible that exposure to prenatal antidepressants or anxiolytic medication may disturb neurotransmitter systems in the brain and have long-lasting consequences on neurodevelopment in the offspring. As all medication during pregnancy may pose a certain risk to the developing fetus, the potential benefits of the medication must be weighed against the risks for both mother and her unborn child. Therefore, information to guide patients and physicians to make a well-balanced decision for the appropriate treatment during pregnancy is needed. In this systematic review, an overview of maternal use of antidepressant or anxiolytic medication during pregnancy and

Electronic supplementary material The online version of this article (doi:10.1007/s00787-014-0558-3) contains supplementary material, which is available to authorized users. H. El Marroun (&) T. White F. C. Verhulst H. Tiemeier The Department of Child and Adolescent Psychiatry, Erasmus MC, Sophia Children’s Hospital, 3000 CB Rotterdam, The Netherlands e-mail: [email protected] T. White The Department of Radiology, Erasmus MC, 3000 CA Rotterdam, The Netherlands H. Tiemeier The Department of Psychiatry, Erasmus MC, 3000 CA Rotterdam, The Netherlands H. Tiemeier The Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, The Netherlands

childhood neurodevelopmental outcomes is provided. Some studies indicate a relation between prenatal exposure to antidepressants and adverse neurodevelopmental outcomes such as delayed motor development/motor control, social difficulties, internalizing problems and autism, but cannot rule out confounding by indication. Overall, the results of the observational studies have been inconsistent, which makes translation of the findings into clinical recommendations difficult. More well-designed observational studies and also randomized controlled trials (e.g., maintenance treatment vs. cessation) are needed to move forward and provide a comprehensive evaluation of the risks and benefits of antidepressant and anxiolytic use during pregnancy. Keywords Prenatal exposure Antidepressant medication Anxiolytic medication Child neurodevelopment

Introduction Physicians are often confronted with the difficult choice of whether or not to advise women about to taking medication during pregnancy. As all medication during pregnancy may pose a certain risk to the developing fetus, the potential benefits of the medication must be weighed against the risk for both mother and her unborn child. Depending on the type of medication, the decision to start or to recommend continued use during pregnancy can be challenging. This is especially true for antidepressant and anxiolytic medication during pregnancy, in which the risks and benefits to the developing fetus have not been well elucidated. During the reproductive years, a significant proportion of women experience depressive and anxiety disorders.

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Approximately, 8–15 % of women suffer from clinically relevant depressive or anxiety symptoms during pregnancy [1–4]. Postpartum depression occurs in 10–15 % of women [5], and this is more likely in women with a prior history of depression during pregnancy. Women with depression during pregnancy have been shown to have poor self-care, engage in less prenatal care, have less weight gain due to decreased appetite, are more likely to smoke or use alcohol, and have greater rates of self-injurious behavior [6]. There are a large number of studies demonstrating that untreated depression and anxiety during pregnancy have a negative impact on the offspring [reviewed in 7–9]. In this issue of European Journal of Child and Adolescent Psychiatry, the associations between prenatal maternal depression and different neurodevelopmental outcomes in offspring are extensively reviewed by C. Waters and colleagues. For example, untreated depression during pregnancy has been associated with low birth weight, preterm birth, and a broad range of problems later in life. These include problems involving affect, cognition, interpersonal relationships, and neuroendocrine and brain functioning. However, the literature does not prove or disapprove a direct link between prenatal exposure to depression and adverse offspring outcomes. For example, it may be possible that intergenerational transmission reflects a shared genetic risk [10]. This review focuses on prenatal exposure to antidepressant and anxiolytic medication, thus studies of the impact of depression and anxiety during pregnancy will not be presented here. Despite the high prevalence of depression and anxiety disorders in women of childbearing age, information to guide patients and physicians to make well-balanced decisions for the appropriate treatment during pregnancy is limited. Standard treatment for acute episodes of depression is short-term and medium-term therapy with antidepressant medications [11]. Antidepressants and psychotherapy are also a treatment of first choice for moderately severe depression. Most women using antidepressants or anxiolytic medication during pregnancy are on maintenance therapy. That is, treatment was not initiated because of concurrent depression, anxiety or other problems during pregnancy, but continued to prevent a possible relapse. For example, a previous study showed that about 30 % of the women who used antidepressants during pregnancy had clinically relevant depressive symptoms [12]. Doctors must advise these women and weigh the risk of relapse of chronicity and the risk for recurrence of depressive episodes, clinical guidelines recommend that treatment should be continued for 4–9 months after the acute episode, but there is evidence that continuing antidepressant treatment (maintenance therapy) up to 2 years significantly reduces the risk of relapse [13]. Hence, many pregnant women use

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antidepressant or anxiolytic medication over longer periods of time. Antidepressant and anxiolytic medications are able to pass the placental barrier [14–16], and may potentially influence fetal development. This is especially relevant during fetal life, when the brain is thought to be vulnerable, and neurotransmitters play key roles in specific neurodevelopment processes [17]. Extensive animal studies have shown that exposure to prenatal antidepressants or anxiolytic medication may impact on the development of neurotransmitter systems and have long-lasting consequences in the offspring [18–20]. However, animal studies are indicative and are not always able to mimic the clinical situation adequately. For example, one of the limitations of animal models is that SSRIs are applied to healthy pregnant animals, which do not fully represent the human situation [18]. This review will systematically evaluate the literature on the neurodevelopmental effects of prenatal exposure to antidepressant and anxiolytic medication. In addition, we will very briefly summarize the effects of prenatal exposure to antidepressant and anxiolytic medication somatic (cardiovascular, metabolic, pulmonary, endocrine) findings. Aim of the study The purpose of this study is to: (1) systematically review the literature on the early and late neurodevelopmental effects of exposure to commonly used antidepressant and anxiolytic medication during pregnancy, (2) to discuss these findings from an epidemiological and a developmental perspective and, (3) to provide clinical recommendations and suggestions for future studies.

Methods Data sources and study selection This study aims to systematically review the literature on the early and late neurodevelopmental effects of exposure to commonly used antidepressant and anxiolytic medication during pregnancy. In brief, a professional librarian and the researcher completed the literature search. The databases used to access current literature included Embase (Elsevier Life Science Solutions) and PubMed (National Center for Biotechnology Information, US National Library of Medicine). Elsevier Life Science Thesaurus Emtree, a hierarchically structured, controlled vocabulary for biomedicine and related life sciences in Embase and Medical Subject Headings (MeSH) in PubMed were

Eur Child Adolesc Psychiatry Fig. 1 Flowchart for literature retrieval

Embase search 639 references antidepressants 328 references anxiolytics 127 overlapping 840 citations

PubMed search 353 references antidepressants 131 references anxiolytics 8 overlapping 446 citations

Combined searches 1286 references 101 overlapping/duplicates 1186 citations for title/abstract screening

Title/Abstract screening 73 not in English 28 incomplete information (no abstract) 83 abstracts, conference proceedings , letters, editorials 335 no exposure to antidepressants or anxiolytics 32 no prenatal exposure (only during lactation) 165 not human studies 103 no neurodevelopmental outcomes 113 studies in pregnant women, no offspring effects studied 57 studies in non-pregnant adults 2 withdrawn article 195 citations included for further review

Further review after screening 122 reviews not included 9 articles, no full-text accessible 4 case reports excluded after careful evaluation 17 case reports included 43 controlled studies included

Added studies after reference list screening and other sources 6 controlled studies added

used for searching the existing literature. The MeSH browser was used to identify the correct MeSH terms for the searches. Each database was searched from its start date to September 30, 2013. The exact literature searches in the two databases are available upon request. Reference lists in the retrieved articles were additionally searched, and recently published studies were added, and produced six additional references (see flowchart, Fig. 1).

Inclusion and exclusion criteria A study was included in this review if it: (1) (2)

was published in the English language, reported on short- or long-term neurodevelopmental effects following any prenatal antidepressant exposure in humans, including (but not limited to) selective serotonin reuptake inhibitors, tricyclic

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(3)

antidepressants, monoamine oxidase inhibitors, and anxiolytic medication (benzodiazepines) and, was original research, including cohort studies, case– control studies, case series and case reports. Case reports are listed briefly (in the supplemental material), as case reports may shed light on new, important and unexpected side effects.

The neurodevelopmental outcomes studied in this review included psychiatric outcomes, behavioral, emotional and cognitive functioning, language development, sleep and motor development. We excluded animal studies, studies that did not evaluate antidepressant or anxiolytic agents (e.g., anti-epileptic agents), abstracts or conference proceedings, and literature reviews. We did not include unpublished data. We also searched for literature on the effects of prenatal exposure to antidepressant and anxiolytic medication on other outcomes including somatic, metabolic, immunological, endocrine, cardiovascular, and pulmonary measures. This secondary search was performed in a detailed, but not in a systematic manner.

Data extraction and quality assessment For data extraction and quality assessment, the titles and the abstracts of the articles were screened, relevant abstracts were reviewed, and those articles meeting inclusion criteria were retrieved. In addition, reference lists in the retrieved articles were additionally screened. The Systematic Assessment of Quality in Observational Research (SAQOR) [21] was based on existing quality assessment instruments [22, 23], including the checklist developed by Downs and Black [22] and the Newcastle-Ottawa Scale, [23] and adapted to assess the specific criteria necessary for the evaluation of data presented in this area of research (perinatal psychiatry). All retrieved articles were evaluated using a total of 19 criteria under the following five categories for each study by outcome: (1) sample, (2) control/comparison group, (3) quality of measurement(s) and outcome(s) (4) follow-up and (5) distorting influences [21]. On the basis of the quality scores of these categories and the design of the study, a final quality rating (high, moderate, low, very low) was assigned. This checklist is not useful for case reports, and was therefore used only for the observational studies with larger and controlled samples. High, moderate, and low quality studies were deemed ‘above quality threshold’, whereas the very low quality studies were ‘below quality threshold’. Using the criteria, none of the studies used in this systematic review were scored as ‘below quality threshold’.

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Main body Definition antidepressant and anxiolytic medication Once physicians determine that antidepressant medication is necessary, there are several antidepressants available from which to choose. Commonly used medications for the treatment of depression include: selective serotonin reuptake inhibitors (SSRIs), norepinephrine/dopamine reuptake inhibitors (NDRIs), and serotonin/norepinephrine reuptake inhibitors (SNRIs). These drugs work by inhibiting the reuptake of the neurotransmitters in the synaptic cleft [24]. Other medications are available, but used less often. These include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). MAOIs inhibit the degradation of monoamine oxidase, while TCAs act as serotonin-norepinephrine reuptake inhibitors by blocking the serotonin transporter and the norepinephrine transporter. TCAs thus increase to increase the synaptic concentration of the neurotransmitters and improve neurotransmission [24]. The latter two classes of antidepressants have poor side effects profiles and are considered less safe (during pregnancy) due to their toxicity [24]. For the treatment of anxiety disorders, both antidepressants and anxiolytic medication can be used. The main class of anxiolytic medication is benzodiazepines (BZDs), which increases the effectiveness of the neurotransmitter gammaamino butyric acid (GABA) at the GABA receptor and results in sedative, hypnotic anxiolytic, anticonvulsive and muscle relaxant properties [24]. In this paper, we will review the most commonly used antidepressants and anxiolytics, including SSRIs, SNRIs, TCAs, MAOIs, and BZDs. Epidemiology The use of antidepressants and the anxiolytics during pregnancy varies between 1–13 % [12, 25–32] and 1–11 % [33–38] in different studies, respectively. Numerous studies have reported an increase over time of antidepressant use during pregnancy [25–29]. For example, the retrospective study of Cooper and colleagues in the Unites States using data from computerized records of filled prescriptions linked to vital records (birth, death and fetal death certificates) and medical records, showed that the proportion of pregnancies with antidepressant use increased from 5.7 % of pregnancies in 1999 to 13.4 % of pregnancy in 2003 [25]. However, the participants included in this database (Tennessee’s expanded Medicaid program, Tenncare) were known to have higher rates of chronic health conditions, including mental illness and the prevalence estimate may not be generalizable.


In Europe, the prevalence estimates for antidepressant use during pregnancy are lower. For example, in Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) and the Netherlands, prevalence estimates of antidepressants’ use during pregnancy were reported to be around 1–2 % [31, 32]. In addition, studies have shown that most women continue to use antidepressants and anxiolytics throughout pregnancy. The use of these medications appears to be only marginally higher in the first trimester than in the last trimester of pregnancy [31, 33, 34]. Pregnant women using antidepressants or anxiolytics are more likely to be older [12, 25] and are more likely to use alcohol, cannabis, and smoke cigarettes during pregnancy as well [12]. Other maternal characteristics that have been shown to be associated with the use of antidepressants during pregnancy include western origin and a higher education (more than 12 years of education) [25, 39]. Indication The use of antidepressant medication cannot be equated with a diagnosis of depression, as antidepressants are prescribed for multiple reasons, including insomnia, migraine, incontinence, eating disorders, anxiety, and neuropathic pain [40]. Moreover, most women do not take antidepressants to treat an acute problem but to prevent relapse or recurrence of psychiatric problem. The same is true for anxiolytics, which in addition to being prescribed for anxiety disorders, are also prescribed for insomnia, relief of spasticity in patients with neurological illnesses, preoperative medication and deep sedation for minor operative procedures, such as in dentistry [41]. Dosing Although the general consensus is that the dose of any medication during pregnancy should be as low as possible, an interesting case study illustrated that dose requirements frequently increase during the second half of pregnancy, due to increased drug metabolism [42]. With higher plasma volume and total body water during pregnancy, the volume distribution may rise, which could increase the dose requirements necessary to sustain therapeutic drug levels [43]. Hence, if reported dosing levels during pregnancy were similar to those in non-pregnant women, it may be possible that the medication fails to produce a therapeutic effect. Nonetheless, current prescription policy does not advise altering the dose during pregnancy. Mechanisms underlying potential neurodevelopmental effects Serotonin and GABA appear in early embryogenesis as developmental signals involved in regulating the

morphogenesis of both GABA and monoamine (serotonin, norepinephrine, dopamine) systems in the brain [44, 45]. These neurotransmitters play key developmental roles in cell migration, axonal outgrowth, and synaptogenesis, and are coordinating mediators of intercellular communication in the fetus [45, 46]. With increased levels of serotonin and GABA (due to prenatal exposure to antidepressants and anxiolytics), brain morphology and function may alter. In animal models, prenatal exposure to antidepressants produces a variety of adverse neuroanatomical and behavioral consequences (reviewed in [18, 19]). In rats, prenatal exposure to antidepressants results in reduced numbers as well as reduced function of serotonergic receptors in the neonatal period; findings that persist in the mature animal. Despite the biological plausibility of neurodevelopmental alterations observed in animal models, few studies in humans have addressed possible mechanisms. Recently, two studies suggested that prenatal SSRI exposure was associated with altered levels of proteins that are involved in neurodevelopment at birth, including activin A and reelin [47, 48]. These two studies may provide insight into the underlying neurobiological changes. Behavioral, neuropsychological, and psychiatric findings Case reports and case series To date, no gross neuroteratogenic effects of antidepressants and anxiolytic medications have been identified. Our review found numerous studies investigating the associations of SSRI exposure with behavioral disturbances. The supplemental material presents 14 case reports and 3 case series that were retrieved from our systematic search. None of the studies identified reports on children exposed to benzodiazepines only. Prescribed doses reported were standard. These case reports illustrate possible neurodevelopmental side effects of antidepressants and anxiolytics such as neonatal withdrawal syndrome, seizures or seizure-like movements, problems with motor tonus and motor control, hypothermia, disorganized attachments, and other problems (see supplement for references). The large body of case reports that appeared more than a decade ago and continue to be published illustrate that unwanted neurodevelopmental effects of antidepressants during pregnancy is perceived as an important topic by clinicians. Case series can alert clinicians and researchers to unnoticed serious clinical side effects. Such descriptive case reports can indicate that prenatal exposure to antidepressant may be associated with neurodevelopmental problems early in life. Yet, it is mandatory to carefully study the potential association of prenatal exposure to antidepressants and anxiolytics with long-term

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neurodevelopmental outcomes in well-controlled larger scale studies. Controlled observational research Our systematic search retrieved 49 controlled observational studies that investigated the potential side effects of antidepressant or anxiolytic exposure during pregnancy on child neurodevelopment (see Fig. 1). These studies are summarized in Tables 1 and 2. Most of these studies are relatively small and hospital or clinic-based, though more recently large population-based studies are emerging. The latter studies are not limited to the first year of life, but have investigated longer term effects of prenatal exposure of antidepressants and anxiolytics on child development [49, 50]. Importantly, investigators are attempting to address potential limitations and biases in these pharmacoepidemiological studies. Some studies contrast the unwanted neurodevelopmental effects attributed to antidepressants with the neurodevelopmental effects of untreated depression or anxiety disorders [51–59]. Pedersen et al. [52] examined 127 children of mothers who had used antidepressants during pregnancy, 98 children of mothers with a prenatal depression without use of antidepressants, and 723 children of mothers with no prenatal depression and no use of antidepressants during pregnancy. In this study of the Danish National Birth Cohort, the association of prenatal antidepressant exposure and behavioral problems (parentreported) at the age of 4–5 years was examined. The authors reported that prenatal antidepressant exposure was not associated with abnormal scores on the Strengths and Difficulties Questionnaire (SDQ) compared with prenatal exposure to untreated prenatal depression or to no exposure. However, untreated prenatal depression was associated with abnormal SDQ scores in the subscales of conduct [adjusted odds ratio (OR) 2.3 (95 % CI, 1.2–4.5)] and social problems [adjusted OR 3.0 (95 % CI, 1.2–7.8)] compared with unexposed children. The authors concluded that prenatal antidepressant exposure was not associated with behavioral or emotional problems. However, the authors also mentioned that the study had its limitations including that parent-reported SDQ scores may not reflect actual child behavior and that the group of women with untreated prenatal depression was highly selected [52]. Other researchers attempt to infer conclusions about the specificity of the observed associations by taking into account other medications or investigating multiple subtypes of antidepressants [60–65]. For example, the study of Mortensen and colleagues performed a follow-up study based upon a regional prescription register in Denmark [64]. In this study, the researchers investigated 5 groups of children exposed to (1) antidepressants, (2) benzodiazepines, (3) anti-epileptic drugs, (4) neuroleptic drugs and (5)

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non-exposed children. In this study, the number of children varied from 8 to 24 in the exposed groups and 755 children in the non-exposed groups. A high prevalence of abnormal scores on the Boel test, a psychomotor development test, was reported in all exposed groups. However, the authors of this study acknowledged that uncontrolled and strong confounding and selection might have been underlying this high prevalence of non-optimal motor development. Furthermore, there were a few observational studies that attempted to address residual confounding of the associations between prenatal exposure to antidepressants and neurodevelopment. These studies take into account paternal mental history and paternal use of antidepressants [50, 53], or using a sibling/family-design to adjust for potential residual confounding [49, 50, 66, 67]. For example, Rai and colleagues [53] investigated not only the association between maternal antidepressant use and autism spectrum disorder (ASD), but also the association between maternal and paternal depression in relation to ASD. Interestingly, in this study, a history of maternal (adjusted OR 1.49, 95 % CI 1.08–2.08) but not paternal depression was associated with an increased risk of ASD in offspring. In addition, in a subsample with available data on medication use during pregnancy, this association was confined to women reporting antidepressant use during pregnancy (OR 3.34, 1.50–7.47, P = 0.003), irrespective of whether selective serotonin reuptake inhibitors (SSRIs) or non-selective monoamine reuptake inhibitors were reported. The investigators performed many in-depth supplemental analyses in smaller subgroups, but they acknowledged that it was not possible to conclude whether the association between antidepressant use and ASD reflects the effects of severe depression during pregnancy or a direct effect of the drug. According to the researchers, they had insufficient power to investigate this possible explanation. In addition, they acknowledged that underestimation of depression prevalence and severity may have led to partial control for confounding in the relation between antidepressant use and ASD in offspring. The family/sibling design was used in the recent work of Sorensen et al. [50]. In this study, children exposed prenatally to antidepressants had an increased risk for ASD compared to unexposed children [adjusted hazard ratio (HR) 1.5, 95 % CI 1.2–1.9]. Restricting the analysis to children of women with a diagnosis of affective disorder— to separate the effect of medication from that of the underlying indication for treatment—showed an adjusted HR of 1.2 (95 % CI 0.7–2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted HR = 1.1; 95 % CI 0.5–2.3). The authors remarked that the discordant (exposed/unexposed) sibling analyses adjust for all factors that were shared within the family, but that the discordant sibling

Design/setting

Prospective study, clinic-based


Prospective study, embedded in a study of prenatal psychotropic medication use, setting unclear

Partly prospective, partly retrospective, clinic-based

Prospective study, embedded in a study of prenatal psychotropic medication use, setting unclear

Prospective cohort, embedded in a study of prenatal psychotropic medication use, setting unclear

Prospective study, healthcare based


Nulman et al. [72]

Nulman et al. [65]

Oberlander et al. [75]

Casper et al. [79]



Misri et al. [71]


Prenatal exposure to SSRI

Study

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

Antidepressant studied/focus of study

22/14

22/14

11/22

28/23

31/13

22/23

40/36

55/84

N exposed/N non-exposed

No

Yes, of the children exposed SSRIs 9 were additionally exposed to benzodiazepine

Yes, an additional group with prenatal and postnatal exposure (n = 30)

Yes, an additional group of SSRI and benzodiazepine exposure (n = 18)

No

Yes, an additional group of SSRI and benzodiazepine exposure (n = 16)

Yes, an additional group exposed to TCA only (n = 46)

Yes, an additional group exposed to TCA only (n = 80)

Addressed confounding by indication

Table 1 Controlled observational research of exposure to antidepressants medication and neurodevelopmental outcomes

4 years

4 years

2 months

Birth, 2 and 8 months

6–40 months

Birth

15–71 months

16–86 months

Age range studied

Umbilical cord SSRI levels were associated with increased externalizing behaviors, but after adjustment for maternal depressive symptoms the association was not significant

No association with internalizing problems

Prenatal SSRI exposure was associated with blunted facial responses to pain. Prenatal ? postnatal SSRI exposure was associated with reduced parasympathetic withdrawal and increased parasympathetic cardiac modulation

Prenatal SSRI exposure (alone or in combination with benzodiazepines) was associated with transient neonatal symptoms. Development was normal at follow-up

Prenatal SSRI exposure was associated with subtle delays in psychomotor development and motor control

Prenatal SSRI exposure (only chronic) was associated with reduced behavioral pain responses and lower heart rate

No association with cognition, language or temperament

No association with global IQ, language development or behavior development

Main findings reported


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Design/setting




Cross-sectional study, clinic-based



Register study, population based



Study


Casper et al. [78]

Klinger et al. [81]

Bellisima et al. [48]

Reebye et al. [109]

Nulman et al. [58]

Ka¨lle´n and Reis [62]

De Vries et al. [77]

Smith et al. [76]

Table 1 continued

123 SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI

SSRI


6/61

63/44

3,801/300,930

62/62

22/23

24/24

All SSRI exposed, n = 30 with NAS and n = 52 without NAS were compared

55/0

33/42


No

No

Yes, eight contrast groups exposed to other CNS drugs (including benzodiazepines)

Yes, exposed to SNRI (n = 62) and exposed to untreated depression (n = 54)

Yes, exposed to SSRI ? benzodiazepine (n = 15)

No

No

No

No


At birth

First week of life, and 3–4 months of age after birth

Birth

4 years

8 months

Birth

2–6 years

12–40 months

3–4 years

Age range studied

Prenatal SSRI exposure was associated with subtle negative effects on motor development and motor control

Prenatal SSRI exposure was associated with neonatal complications, including preterm birth Prenatal SSRI exposure was associated with abnormal general movements in the first week of life, and monotonous movements between 3–4 months

Prenatal SSRI exposure was associated with a lower IQ. Prenatal SNRI exposure was also associated with a lower IQ

SSRI exposure alone was not associated with infant negative effect, but SSRI ? benzodiazepine was

SSRI-exposed children with NAS had more social problems as compared to SSR-exposed children without NAS Prenatal SSRI exposure was associated with increased levels of activin A (a neurotrophic factor and brain-damage protein) in maternal and fetal blood, and amniotic fluid

Prenatal SSRI exposure (chronic) was associated with lower scores on psychomotor development and behavioral ratings

Prenatal SSRI exposure and higher current maternal anxiety were associated with increased internalizing behaviors



Retrospective study, clinic-based

Retrospective study, population-based (case–control)

Prospective study, population based

Batton et al. [69]

Harrington et al. [84]

El Marroun et al. accepted for publication [51]

Prospective study, setting unclear

Prospective study, health care based




Warnock et al. [56]

Salisbury et al. [54]

Weikum et al. [57]

Prenatal exposure to SSRI, SNRI

Design/setting

Study

Table 1 continued

SSRI, SNRI

SSRI, SNRI

SSRI, SNRI

SSRI, SNRI

SSRI

SSRI

SSRI


32/32

36/56

10/10

31/45

69/5,531

SSRI exposure in cases: 29 exposed in 492 cases (5.9 %). SSRI exposure in typically developing controls: 11 exposed in 320 controls (3.4 %).

19/19


Yes, untreated depression (n = 21)

Yes, a contrast group of children from women with a history of major depressive disorder (n = 20)

Yes, a group of mothers and their infants exposed to untreated depression (n = 10)

No

Yes, a group of children prenatally exposed to untreated depression were included (n = 376)

Yes, a group of children with developmental delay was included. SSRI exposure in this contrast group: 8 exposed in 154 cases (5.2 %).

No


6 and 10 months

1–21 days after birth

24–60 h of age

3 months

1.5–6 years

2–5 years

36 months of age

Age range studied

Prenatal exposure was associated with altered infant speech perception. Untreated depression was also associated with altered infant speech perception

Prenatal exposure was associated with lower quality of movement and more stress signs

Prenatal exposure was associated with lower Apgar scores and abnormal crying behavior. Prenatal exposure was associated with reduced responsiveness to their infant’s pain cues. Maternal untreated depression was also associated with reduced responsiveness to their infant’s pain cues

Prenatal SSRI exposure was associated with altered HPA stress responses and reduced basal evening cortisol levels

Prenatal SSRI exposure was associated with pervasive developmental problems and increased autistic traits

No association with psychomotor development and mental development Prenatal SSRI exposure (especially first trimester exposure) was nearly three times as likely in boys with ASD relative to typically developing controls



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123

Retrospective study, clinic-based (medical records)




Leibovitch et al. [111]

Brummelte et al. [47]

Weikum et al. [112]

Weikum et al. [113]

SSRI, SNRI

SSRI, SNRI

SSRI, SNRI

SSRI, SNRI


SSRI, SNRI, TCA and other antidepressants SSRI, SNRI, and other antidepressants

Retrospective study, clinic-based (medical records)


Boucher et al. [73]

Galbally et al. [114]

Prenatal exposure to SSRI, SNRI and TCA Ka¨lle´n [61] Register study, SSRI, SNRI, TCA population based and other antidepressants

Design/setting

Study

Table 1 continued

27/27

73/73

987/573,883

26/38

32/42

25/42

401/401


No

No

Yes, subgroup analyses were performed investigating SSRI (n = 558) or TCA exposure (n = 395)

No

No

No

No


First week of life

Neonatal period

Birth

6 years

3 and 6 months

First week of life

At birth

Age range studied

Prenatal exposure was associated with discontinuation symptoms (crying, jitteriness, tremor, feeding, reflux and sneezing and sleep)

Prenatal exposure was associated with alertness alteration, altered muscular tone, tachypnea and neurological problems

Prenatal SSRI exposure was associated with preterm birth, low birth weight, respiratory distress, low Apgar scores and convulsions, but not with jaundice. Prenatal TCA exposure showed the same associations

Prenatal exposure and serotonin transporter promotor genotype were associated with executive functioning. Children prenatally exposed to SRIs with at least one short SLC6A4 allele had the best functioning

Prenatal exposure was associated with maternal interruptive behaviors in mother–child interactions. There was no association with Bayley motor and mental scales

Prenatal exposure was associated with lower levels of reelin, a protein involved in neurodevelopment

Prenatal exposure was associated with clinical symptoms, including respiratory distress, jitteriness, restlessness, feeding difficulties, regurgitations, fever C38 °C, a short cyanotic event and convulsions



SSRI, SNRI, and TCA

SSRI, SNRI, and TCA


Prospective study, population based registries

Prospective study, clinic and health care based

Register study, population-based

Galbally et al. [81]

Laugesen et al. [49]

Austin et al. [70]

Sorensen et al. [50]

Register study, population-based

Prospective study, population-based

Prospective study, population-based (case–control)

Figueroa [60]

Pedersen et al. [52]

Croen et al. [83]

SSRI, TCA and dualaction antidepressants (including SNRIs)

Antidepressants, include SSRIs, and non-SSRI

Antidepressants were categorizes 3 groups: SSRIs, bupropion, and other antidepressants

Prenatal exposure to antidepressants (alternative grouping)

SSRI, SNRI, and TCA

SSRI, SNRI, and TCA

SSRI, SNRI, and TCA

Prospective study, population-based

Pedersen et al. [59]


Design/setting

Study

Table 1 continued

Antidepressant exposure in cases: 20 exposed in 298 cases (6.7 %). Antidepressant exposure in controls: 50 exposed in 1,507 controls (3.3 %).

127/723

A total 38,074 families were included, 916 were exposed to SSRIs during pregnancy (possibly overlapping with other medications)

8,833/646,782

35/23

15,008/816,792

19/22

415/81,042


All antidepressants were evaluated as one group, but also as separate groups SSRIs vs. TCAs and/or dual-action antidepressants

Yes, untreated depression (n = 98)

Yes, different groups with psychiatric disorders and different groups with other CNS medications were included

All antidepressants were evaluated as one group, but also as separate groups SSRIs vs. TCAs and/or dual-action antidepressants

No

Yes, children not exposed in utero and born to former users (n = 45,978)

No

Yes, depression without medical treatment (n = 489)


3.5–5 years

4–5 years

5 years

5–9 years

18 months of age

Follow-up 8 years

18–35 months

6 and 19 months

Age range studied

Maternal SSRI exposure was associated with an increased risk of autism spectrum disorder. No association was found for mothers with a history of mental health treatment without SSRIs

No association with behavioral or emotional problems

Prenatal SSRI exposure was not associated with ADHD. Prenatal exposure to bupropion was associated with an increased risk of ADHD

Prenatal exposure to antidepressants was associated with an increased risk of autism spectrum disorder

No association with neurodevelopmental outcomes, such as cognition, motor and language development

Prenatal exposure to antidepressants was associated with ADHD, but the association was not causal when they conducted a family/sibling approach

Prenatal exposure to antidepressants (mostly SSRI exposure) was associated (a trend) with lower scores on fine and gross motor subscales

Prenatal exposure to antidepressants was associated with delayed motor development, albeit within the normal range



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ADHD attention deficit hyperactivity disorder, BZD Benzodiazepine, CI confidence interval, EEG electroencephalogram, HPA hypothalamic pituitary axis, IQ intelligence quotient, MAO monoamine oxidase inhibitor, NAS neonatal abstinence syndrome/symptoms, NDRI norepinephrine/dopamine reuptake inhibitor, SNRI serotonin/norepinephrine reuptake inhibitor, SRI serotonin reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, TCA tricyclic antidepressant

Prenatal antidepressant exposure was not associated with infant neurobehavioral development 1 week of age 33/15 Antidepressant, not specified Suri et al. [55]

Prospective study, clinic and health care based

Yes, a contrast group of children from women with a history of major depressive disorder (n = 16)

Prenatal and postnatal exposure to antidepressants was associated with discontinuation syndrome symptoms Infancy Of the 930 women who breastfed while taking antidepressants, 527 had taken antidepressants during pregnancy All antidepressant medication Hale et al. [115]

Cross-sectional study, convenience sample

No

Prenatal exposure to antidepressants (SSRIs and nonSSRI antidepressants) was associated with increased risk of autism without intellectual disability 0–17 years 1,679 cases/16,845 controls; the number of exposed vs. unexposed was unclear Prospective study, population-based (case–control) Rai et al. [53]

SSRI, non-SSRI

Yes, the associations of maternal/ paternal mental health history with autism spectrum disorders were also investigated

Main findings reported N exposed/N non-exposed Antidepressant studied/focus of study Design/setting Study

Table 1 continued


Age range studied


analysis may be biased (towards unity) by non-shared confounders associated with the exposure, because the siblings will tend to be also discordant for other confounding variables [68]. It is not possible to extensively portrait all studies retrieved from our systematic search in this review; therefore Table 1 summarizes the studies of prenatal exposure to antidepressant medication. Some studies report no associations between prenatal antidepressant exposure during pregnancy and adverse neurodevelopmental outcomes [52, 55, 59, 60, 65, 69–72], while others suggest specific adverse effects in children (Table 1). Prenatal exposure to antidepressants has been associated with various aspects of neurodevelopment at different time points in life. While in the first year of life, intrauterine antidepressant exposure is considered a possible risk factor for convulsions [61, 62, 73], blunted pain responses [56, 74, 75] and delayed motor development/motor control [54, 76– 80], longer term studies focus on problems in the domains of intelligence [58], social problems [81] and internalizing problems in children [82]. None of the studies reported a statistically significant association between prenatal exposure to antidepressants and language or cognitive problems [65, 70, 72]. Recently, longer term studies have focused on the association between prenatal SSRI exposure and autistic symptoms [51] and ASDs in childhood [50, 53, 83, 84]. Table 2 summarizes the studies of the associations of prenatal exposure to anxiolytic medication and neurodevelopmental outcomes. Again, some of the studies investigating the use of benzodiazepines during pregnancy report no associations with behavior or cognition [66, 67, 85], while other studies report an association between prenatal benzodiazepine exposure and motor functioning [63, 64, 86] and lower scores on mental development [87]. No meta-analyses of antidepressant or anxiolytic medication and unwanted neurodevelopment effects were conducted as the outcome measures were too diverse and the studies too heterogeneous. Somatic findings A plethora of physiological problems in newborns have been reported to occur after prenatal exposure to SSRIs, including congenital anomalies such as neural tube defects and omphalocele [88, 89], cardiovascular malformations [90], persistent pulmonary hypertension [91], preterm birth [92, 93], low birth weight [93, 94], reduced fetal head growth and head size at birth [12], lower Apgar scores [92, 95], transient respiratory problems [93, 96], gastrointestinal problems [97], and hormonal changes in cord blood (insulin-like growth factor levels, cortisol, and thyroid stimulating hormone) [98].

Eur Child Adolesc Psychiatry Table 2 Controlled observational research of exposure to anxiolytic medication and neurodevelopmental outcomes Study

Design/setting

Anxiolytic studied

N exposed/ N nonexposed


Age range studied

Findings reported

Stika et al. [85]

Retrospective study, schoolsetting (teacher reports)

Benzodiazepine

15/15

Yes, a group of children exposed to neuroleptics (n = 66) and their agematched controls (n = 66)

9–10 years

No association with behavior at school reported by the teacher

Laegreid et al. [86]

Prospective study, clinicbased

Benzodiazepine

17/29

Yes, an additional group exposed to other drugs including antidepressants, neuroleptics and antiepileptics (n = 21)

First days of life

Prenatal benzodiazepine exposure was associated (reflexes, tonus and other symptoms). Prenatal exposure to the other drugs was also associated with deviation in neurobehavior

Laegreid et al. [63]


Benzodiazepine

17/29

No

6, 10 and 18 months

Prenatal benzodiazepine exposure was associated with delayed motor functioning at 6 and 10 months, but not at 18 months. Prenatal benzodiazepine exposure was associated impaired fine motor functioning at all assessments, and with deviations in muscle tone and pattern of movements

Viggedal et al. [85]


Benzodiazepine

17/29

No

5, 10 and 18 months

Prenatal benzodiazepines exposure was associated with lower scores on mental development

Mortensen et al. [64]

Register study, population based

Benzodiazepine

82/755

Yes, children exposed to antidepressants (n = 50), anti-epileptic drugs (n = 145) and neuroleptic drugs (n = 63) were also studies

7–10 months

Prenatal exposure to any of the medications was associated with an increased risk of abnormal psychomotor development

Gidai et al. [66]

Prospective study, clinicbased (convenience sample)

Benzodiazepine

10/38,151

Yes, matched siblings (n = 12)

8–12 months

Prenatal exposure to benzodiazepines was not associated with congenital abnormalities, fetotoxicity, or neurotoxicity

Gidai et al. [67]

Prospective study, clinicbased (convenience sample)

Benzodiazepine

10/38,151

Yes, matched siblings (n = 13)

8–12 months

Prenatal exposure to benzodiazepines was not associated with intrauterine growth, cognitive status, or behavioral deviation

Similarly, the use of benzodiazepines during pregnancy has been associated with an increased risk of congenital anomalies [99] and craniofacial anomalies, such as cleftpalate [100, 101], abnormal nose, slanting eyes or abnormal ears [63]. Furthermore, prenatal benzodiazepine exposure has been studied in relation spontaneous abortions [38], preterm delivery [102], and low birth weight [102, 103]. Studies of prenatal exposure to antidepressant or anxiolytic medication in relation to somatic outcomes are

diverse in design and outcome measures. This heterogeneity makes it difficult to draw any conclusions about the potential unwanted effects of using these medications during pregnancy and to provide clear prescription guidelines. Confounding by indication and other bias In the current study, we used the SAQOR to assess the quality of a study. Although all studies included in the

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current review were of sufficient quality, none was able to obtain a good score on all 19 criteria. Interpreting the inconsistent findings summarized in this review and formulating clinical recommendations is a challenge. Synthesizing the available studies is particularly difficult, since all studies have substantial methodological weaknesses. These weaknesses pertain to sample selection (and description), choice of the index and reference group, the retrospective or prospective nature of the study, choice of outcomes measures, exposure assessment, and followup. Some of the methodological problems in these studies must certainly be kept in mind when interpreting these studies and limit the studies’ validity. The primary concern in studies examining prenatal exposure to antidepressants or anxiolytics is confounding by indication. Confounding by indication is a specific type of confounding that can occur in observational (non-experimental) pharmacoepidemiological studies of the effects or side effects of medications. As in the current review none of the studies were experimental, all of the studies were prone to some level of confounding by indication. This type of confounding arises from the fact that individuals who are prescribed or who take a given medication may be inherently different from those individuals who are not treated by medication. For example, it is more likely that pregnant women with a severe depressive disorder in the past continue to use antidepressants during pregnancy, while those with a less severe depressive disorder cease to take antidepressants before pregnancy. Second, (residual) confounding is an important issue in these studies. Some of the studies did not take into account any potential confounders in the analyses, while other studies attempted to control for confounding factors; including other use of psychotropic medications, and parental and child characteristics. Nevertheless, there could be many other important (unmeasured) factors that play a role in the association between maternal use of antidepressants or anxiolytics and neurodevelopmental outcomes that were not assessed, e.g., genetic factors, nutrition, rearing practices, stress and other medical problems during pregnancy. Methods to deal with the different biases in these pharmacoepidemiological studies will be discussed below. Third, the studies reviewed for the overview may be subject to publication bias. This is a bias stemming from what is likely to be published among what is available to be published. In general, the tendency to publish results that are positive (i.e., showing a statistically significant unwanted effect) can be different from the tendency to publish results that are negative (i.e., no unwanted effect) or inconclusive, which leads to a misrepresenting bias in the published literature. We cannot quantify publication

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bias in this review, but there are general indicators for publication bias, namely, the large variety in outcomes in the studies and that the larger studies showed smaller effects (while the smaller studies demonstrate larger effects). Finally, in many of the studies the sample size was relatively small, and even in the larger population-based studies, the number of prenatal exposed children is not very substantial. Larger sample sizes are needed to improve the identification of certain neurodevelopmental effects, so that specific abnormalities with certain antidepressants or anxiolytic medication can be determined and replicated across studies. No individual study is definitive and the presented collection of studies with mixed findings must be interpreted with caution. Recommendations Recommendations for future research The research on prenatal exposure to antidepressants and anxiolytic medications is at a crossroad. If it is to move forward, the major issue of confounding by indication must be tackled in observational studies and/or the path of randomized controlled trials (RCTs) must be taken. We will discuss the possibilities of future observational studies first. First, in the analyses of antidepressant exposure, it must become standard to adjust for the level of maternal depressive or anxiety symptoms. Arguably, adjustment for the current symptoms only may be insufficient (undercorrection), as the medication generally reduces the level of symptoms. Thus, it would be important to have information about the severity of depressive and anxiety symptoms before the patient starts the medication, which may not always be feasible. Second, in the analyses of antidepressant or anxiolytic medication, it must become standard to include an additional (matched) contrast group of children exposed to depressive symptoms or anxiety, but who did not use medication. A potential pitfall of this approach is that it may introduce a selection or referral bias by comparing to this group of children born to untreated mothers. Treatment (choice) generally is not random. Women who use medication for psychiatric problems during pregnancy are likely to be different, in terms of illness severity, socioeconomic status or other factors, from those who do not take medication during pregnancy. This comparison could easily yield an over or underestimate of the unwanted effects of the medication. A promising approach is using a sibling design in which family factors are controlled for. However, discordant siblings (exposed and unexposed to medication) are rare,


and statistical power is a common limitation in this approach. Indeed, in the few studies in this review that used a sibling design, the sample size of siblings discordant for antidepressant use is small [49, 50]. Moreover, if the siblings are discordant on the exposure, they may as well be discordant on other variables as well, which may lead to bias [68]. Another approach is to contrast the association between exposure to maternal antidepressant or anxiolytic medication and neurodevelopmental outcomes in the child with the association of paternal use of the medication during pregnancy and the same child outcomes. Using information of the father accounts for genetic confounding and for confounding by shared environmental factors. A pitfall of this strategy is that the indication for the use of antidepressant or anxiolytic medication may not be the same for men and women. Men may take antidepressants less (or more) easily than women or may be referred for treatment only when the depression is more severe. Furthermore, other medications and other outcomes should also be taken into account to comprehensively examine the specificity of the relation between prenatal exposure to antidepressant or anxiolytic medication and neurodevelopmental outcomes. For example, when investigating the effects of SSRIs, a contrasting medication could be a given medication that will not influence the serotonergic system such as an anticonvulsant drug that targets GABAergic transmission. However, different neurotransmitter systems interact with each other. Finally, some consensus about the most important research outcome is needed. In this review, we provide an overview of studies with a large variety of somatic and neurodevelopmental outcomes that range from neuromotor development, to cognition, and language. It is unclear from the studies whether the choices for these different outcomes were hypothesis-driven, data-driven or result-driven. It will be important that studies focus on a few primary outcomes in future studies. Primary outcomes should fit the age range studied, so in early childhood motor development and control may be a good primary outcome, while in the later childhood neurodevelopmental problems such as autism are a more appropriate outcome than emotional problems. To the best of our knowledge, no randomized controlled treatment trials prospectively assessed the safety of antidepressant or anxiolytic medication on the neonate and later child development. Well-designed RCTs are needed to move the field forward. Such studies are expensive, time consuming, and require considerable resources. In addition, ethical issues also need to be addressed. Women with acute depression are in need of medication, and thus stopping such treatment would be unethical. When stopping gradually with maintenance therapy there is also a substantial

risk of relapse [104], but that may be judged acceptable in carefully selected and well-informed subgroups (e.g., indication not for depression, or moderate depression in the past only). Trials should therefore be performed with women who consider stopping with their maintenance therapy rather than including women who require acute treatment. Second, it is ideal to start inclusion to the trial prior to conception. Performing the trial with women who are already pregnant has inherent problems. For example, inclusion in an RCT during the first trimester would be difficult, as the time that elapses between awareness about the pregnancy and inclusion in the RCT can easily take longer than 12 weeks. This would imply that such an RCT includes pregnant women to investigate mostly second and third trimester effects of prenatal exposure to antidepressant or anxiolytic medication. This may not be the critical period when the embryo is most sensitive to the effect of medication. Third, large samples are needed. Including a sufficiently large group of pregnant women using a specific drug to investigating a rare neurodevelopmental outcome in the off spring will be difficult. Side effects, certainly if rare, can be studied much more easily in observational than in randomized studies [105]. Thus, specific recruitment strategies for an RCT of antidepressant maintenance therapy must be developed and ethical dilemmas solved. For example, based on prescription records from pharmacies, preconception clinics or general practices with information about gender and age, researchers could approach high-risk groups (e.g., women in the age range 25–35 years who use antidepressant or anxiolytic medication for more than 1 year) in large populations. Enrichment of the sample should be achieved by including women prior to conception who have the intention to become pregnant. These women could be identified by preconception counseling or by folate prescription. Finally, it will be important to evaluate all long-term effects of the treatment cessation. For example, receiving no antidepressant or anxiolytic medication during pregnancy may indirectly affect the form of treatment and the presence of depression in the women after birth and in turn can even influence parenting. Recommendations for clinical practice Primary prevention of depression and anxiety in women of childbearing age is an important goal and can improve the health of both mother and child. Prevention measures focusing on high-risk groups typically rely on non-pharmaceutical interventions or methods. However, if women are depressed, psychotherapy and treatment with medication are the standard treatment options. The evidence presented in this review is not sufficiently strong to support any change of current practice in the treatment of

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depression and anxiety occurring during pregnancy. Yet, it is very important to explicitly mention this lack of certainty when clinicians discuss the treatment possibilities with their patients. Doctors who treat woman on antidepressant maintenance therapy, who wish to become pregnant should carefully balance the risk of relapse against the potential neurodevelopmental risk of antidepressant of anxiolytic medication during pregnancy [106]. As the risk of relapse can be substantial [104], doctors should help women weigh the benefit of treatment already observed, the severity of past episodes, and the duration of remission—to name a few criteria discussed in the treatment guidelines. Also, the availability of therapeutic alternatives must be considered. Likewise, discontinuation of any antidepressant maintenance therapy in a non-depressed pregnant woman should be very carefully evaluated. Moreover, it is important to point out that the possible critical period for effect of the medication on the embryo or fetus is very uncertain and good evidence for the timing of such a decision is lacking. Clinicians may consider longer monitoring of children exposed to antidepressant and anxiolytic medication during pregnancy, if subtle neurodevelopmental problems at birth were observed. As the literature suggests that children exposed to antidepressant or anxiolytic problems are at increased risk for delayed motor development and neurodevelopmental disorders is emerging, it may be important to monitor health and development of these children for longer periods. In conclusion, the recommendations for pregnant women when to use antidepressants or anxiolytics during pregnancy must be based on better evidence and thus further systematic studies in this area are warranted.

to better understand whether exposure to these medications during pregnancy influences neurodevelopment in the offspring. Ethical, medical and logistical aspects restrict long-term RCTs that enable examination of age- and dose-dependent exposures. Yet, such studies are urgently called for and these obstacles can be overcome. Ideally these RCTs should have long follow-up (over 10 years), begin prior to conception and must thus apply innovative patient recruitment strategies. In conclusion, further research into the long-term neurodevelopmental effects of prenatal exposure of antidepressants and anxiolytics is needed to provide information to guide in improving safe (maintenance) treatment protocols for depressive pregnant women and their children. Currently, there is insufficient evidence from good quality studies to recommend clinicians and patients not to commence or even to discontinue treatment of depressed women with SSRIs or other medication. However, clinicians and patients should carefully and individually weigh maintenance therapy against the small possible risk of neurodevelopment problems suggested by the currently available literature. Acknowledgments We gratefully thank W.M. Bramer (professional librarian at the Erasmus MC) for his extensive assistance in the systematic literature searches. The Sophia Children’s Hospital Fund (SSWO-616) supported this work financially. The Netherlands Organization for Scientific Research (NWO Brain and Cognition Program Grant 433-09-311 and VIDI Grant 017.106.370). The funding agencies had no role in the design and conduct of the study, collection, management, analyses and interpretation of the data; and preparation, review or approval of the manuscript. Conflict of interest of interest.

The authors declare that they have no conflict

Conclusion In this systematic review, we aimed to evaluate the literature on the early and late neurodevelopmental effects in children exposed to commonly used antidepressant and anxiolytic medication during pregnancy. The aim was to describe the findings in an epidemiological and a developmental perspective, and to provide clinical recommendations and suggestions for future studies. While some studies suggest an array of adverse neurodevelopmental outcomes in children exposed prenatally to antidepressants and anxiolytics, other studies show no differences. Thus, consolidating these findings into clinical recommendations based on the mixed studies in the literature remains a challenge. Synthesizing the available observational studies is difficult, because the observational studies have substantial methodological weaknesses. Improving observational studies will be an important step

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