Version June 2024
INTRODUCTION — Depressive disorders and anxiety disorders occur in approximately 10 to 15 percent of pregnant women and can have short- and long-term deleterious effects upon the mother, child, and family [1-4]. Although patients with mild to moderate illness may respond to psychotherapy, patients with severe (eg, suicidality or psychosis), chronic, or recurrent syndromes often require pharmacotherapy.
The decision to prescribe antidepressants for pregnant patients requires clinicians to weigh the negative impact of untreated mood and anxiety disorders against the adverse effects of antidepressants. Although the risks to infants and children from antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) appear to be small to nonexistent, the potential risks are uncertain due to the lack of high quality data on the impact of these drugs. The complexity of managing pregnant women with mood and anxiety disorders requires coordinated efforts among psychiatrists, primary care clinicians, obstetricians, and pediatricians.
Maternal use of SSRIs and SNRIs during pregnancy is estimated at roughly 8 percent [5]. SSRIs and SNRIs are first- and second-line medications for depressive and anxiety disorders, as well as other disorders such as obsessive-compulsive disorder and posttraumatic stress disorder. In addition, these antidepressants are often combined with second-generation antipsychotics for treating bipolar major depression in pregnant women.
When studying the long-term effects of antenatal antidepressants, it is difficult to disentangle medication effects from other factors, such as pre-existing and ongoing maternal psychiatric illness. Women with psychiatric symptoms in pregnancy are at high risk for postpartum depression and anxiety, and thus for impaired mother-infant interactions that are associated with delayed developmental in the offspring [4]. Maternal depression and anxiety can be chronic and recurrent [6], so the impact upon children can extend beyond the immediate postnatal phase.
This topic reviews the association between antenatal exposure to SSRIs and SNRIs and the risk of abnormalities in growth, motor skills, and cognition in the offspring. Antenatal exposure to SSRIs and SNRIs and neonatal outcomes, as well as the risk of psychopathology in the offspring, are discussed separately. The antenatal use of antidepressants and risk of teratogenicity and adverse pregnancy outcomes are also discussed separately, as are the clinical features and choice of treatment for antenatal depression, and the risks of exposure to antenatal depression:
●(See "Mild to moderate episodes of antenatal unipolar major depression: Choosing treatment".)
●(See "Severe antenatal unipolar major depression: Choosing treatment".)
●(See "Antenatal depression: Pregnancy and neonatal outcomes".)
●(See "Antenatal depression: Risks of abnormal infant and child development".)
●(See "Antenatal depression: Risks of cognitive impairment and psychopathology in the offspring".)
INTERPRETING THE EVIDENCE — The evidence regarding the potential risk of antenatal exposure to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors is limited due to several factors. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes", section on 'Interpreting the evidence'.)
TERATOGENICITY — The teratogenicity of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors is discussed separately. (See "Antenatal use of antidepressants and the potential risk of teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors".)
PREGNANCY OUTCOMES — The effects of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors on pregnancy outcomes, including spontaneous abortion, stillbirth, length of gestation, fetal growth, and neonatal mortality, are discussed separately. (See "Antenatal use of antidepressants and the potential risk of teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors".)
NEONATAL EFFECTS — The association between antenatal exposure to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, and neonatal outcomes, are discussed separately. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes".)
GROWTH — Antenatal selective serotonin reuptake inhibitor (SSRI) exposure does not appear to affect postnatal growth of infants, based upon limited data. A prospective observational study assessed infants age 12 months who were born to mothers with antenatal unipolar major depression that was treated with SSRIs (n = 46), mothers with antenatal depression that was not treated (n = 31), and mothers who were neither depressed nor treated with SSRIs during pregnancy (n = 97) [7]. Weight, length, and head circumference were comparable for the three groups of infants. In addition, a second prospective observational study of children (n = 55, mean age 14 months) who were exposed in utero to SSRIs found that duration of exposure was not associated with weight, length, and head circumference [8].
MOTOR SKILLS — Due to conflicting results across studies, it is not clear if antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with delayed or impaired childhood motor skills [9]. As a result, it is generally thought that the risk of abnormal motor function is small to nonexistent and that this risk is outweighed by the risks of untreated moderate to severe antenatal depression [10].
Evidence that suggests antenatal exposure to SSRIs is not associated with impaired motor function includes the following [11]:
●In a review of four observational studies of children aged four years and older, none of the studies found an association between in utero exposure to antidepressants and motor development [12]. As an example, a national registry study identified pregnant women who used SSRIs (n >15,000) and pregnant women with psychiatric disorders who did not use SSRIs (n >9000); the offspring were followed for up to 14 years after birth [13]. After controlling for potential confounding factors (eg, parental age and history of psychiatric diagnoses, and maternal smoking), the analyses found that the frequency of motor disorders (eg, impaired fine and gross motor coordination) in the exposed and unexposed children was comparable (0.7 and 0.6 percent).
●A prospective study included children of mothers who were treated for antenatal depressive disorders with antidepressants (n = 35) and children of mothers who had no history of mood disorders and who were not treated with psychotropic drugs (n = 23) [14]. The majority of antidepressants were SSRIs, and the children were assessed at a mean age of 19 months. Fine and gross motor development were each comparable in the two groups.
●A prospective study recruited pregnant women treated for depression with antidepressants (n = 415, treated primarily with SSRIs) and pregnant women with untreated depression (n = 489) [15]. The offspring were assessed at an average age of 6 months and again at 19 months. After adjusting for potential confounding factors (eg, maternal age, birth outcomes, and postnatal depression), the analyses found that general gross motor activity at 6 months in exposed and unexposed infants was comparable (odds ratio 1.3, 95% CI 0.9-1.5). At 19 months, fine motor and gross motor function were also comparable.
However, other studies suggest that antenatal exposure to SSRIs may be associated with a small increased risk of abnormal motor skills [8,16]:
●One prospective study included infants who were exposed in utero to SSRIs or venlafaxine (n = 31) for treatment of maternal depressive disorders, and infants who were not exposed (n = 52) [17]. The infants were assessed at 10 months of age. After controlling for potential confounding factors (pre- and postnatal maternal depression, and antenatal smoking and alcohol use), the analyses found that gross motor functioning was worse in the exposed infants. However, fine motor development in the exposed and unexposed infants was comparable.
●A second prospective study assessed motor function in infants who were exposed in utero to SSRIs (n = 58) or not exposed (n = 44); assessments were conducted during the first week of life (median age three days) [18]. After controlling for potential confounding factors (eg, maternal depression and anxiety during the third trimester, education, and infant gestational age), the analyses found that abnormal motor function was present in more exposed than unexposed infants (59 versus 33 percent). However, the infants were assessed again at age three to four months, at which point impaired motor function was comparable in exposed and unexposed infants (5 and 0 percent). The initial finding during the first week of infant life probably represented the transient syndrome of poor neonatal adaptation, which is associated with in utero exposure to SSRIs and SNRIs during the third trimester. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes", section on 'Poor neonatal adaptation'.)
●Another prospective study included children aged three years with either prolonged in utero exposure to SSRIS (eg, 29 weeks; n = 159 children) or no exposure (n >51,000), and assessed fine and gross motor development through maternal reports [19]. After adjusting for potential confounding factors (eg, parental education and maternal depression and smoking), the analyses showed that exposure was weakly associated with motor development delays that were not clinically significant. In addition, the analyses did not adjust for severity of depression; thus, severe depression may have been associated with motor skills delay, rather than the medication used to treat the illness. The investigators concluded that the findings did not warrant withholding medications indicated for antenatal depression.
COGNITION
General cognition — Multiple observational studies consistently suggest that antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) is not associated with impairment of general cognitive functioning in children [8,11,14,20,21]:
●A review of in utero exposure to antidepressants and general cognition identified five prospective studies of children aged four years and older; the studies included children exposed in utero to antidepressants (total n = 166), children exposed in utero to untreated maternal depression (n = 460), and unexposed children (n = 5545) [12]. In each of the five studies, prenatal exposure to antidepressants was not associated with cognitive performance.
●A prospective study recruited pregnant women treated for depression with antidepressants (n = 415, treated primarily with SSRIs) and pregnant women with untreated depression (n = 489) [15]. The offspring were assessed at an average age of 19 months. After adjusting for potential confounding factors (eg, maternal age, birth outcomes, and postnatal depression), the analyses found that cognitive functioning (eg, correctly aligning a picture) in exposed and unexposed infants was comparable (odds ratio 1.0, 95% CI 0.7-1.4).
●A prospective study included infants who were exposed in utero to SSRIs or venlafaxine (n = 31) for treatment of maternal depressive disorders, and infants who were not exposed (n = 52) [17]. The infants were assessed at 10 months of age. After controlling for potential confounding factors (pre- and postnatal maternal depression, and antenatal smoking and alcohol use), the analyses found that cognitive development in the exposed and unexposed infants was comparable.
Language — It is not clear whether antenatal exposure to SSRIs is associated with slightly impaired language skills, due to inconsistent results across studies.
Some studies have found that antenatal exposure to SSRIs is not associated with an increased risk of language disorders:
●A prospective study recruited pregnant women treated for depression with antidepressants (n = 415, treated primarily with SSRIs) and pregnant women with untreated depression (n = 489) [15]. The offspring were assessed at an average age of 19 months. After adjusting for potential confounding factors (eg, maternal age, birth outcomes, and postnatal depression), the analyses found that language development (eg, using two-word sentences) in exposed and unexposed infants was comparable (odds ratio 1.2, 95% CI 0.8-1.7).
●A prospective study included children of mothers who were treated for antenatal depressive disorders with antidepressants (n = 35) and children of mothers who had no history of mood disorders and who were not treated with psychotropic drugs (n = 23) [14]. The majority of antidepressants were SSRIs; the children were assessed at a mean age of 19 months. Receptive and expressive language were each comparable in the two groups.
●A prospective study included infants who were exposed in utero to SSRIs or venlafaxine (n = 31) for treatment of maternal depressive disorders, and infants who were not exposed (n = 52) [17]. The infants were assessed at 10 months of age. After controlling for potential confounding factors (pre- and postnatal maternal depression, and antenatal smoking and alcohol use), the analyses found that receptive and expressive language were each comparable in the exposed and unexposed infants was comparable.
Evidence that suggests antenatal exposure to SSRIs may be associated with a small increased risk of delays in language development includes the following [9]:
●A national registry study identified pregnant women who purchased SSRIs (n >15,000) and pregnant women with psychiatric disorders who did not purchase SSRIs (n >9000); the offspring were followed for up to 14 years after birth [13]. After controlling for potential confounding factors (eg, parental age and history of psychiatric diagnoses, and maternal smoking), the risk of speech/language disorders (eg, articulation disorder or receptive language disorder) was comparable in the exposed and unexposed children (hazard ratio 1.20, 95% CI 0.97-1.49). When the analyses were restricted to women who purchased SSRIs at least twice during pregnancy, suggesting that they actually took the medication, the risk of speech/language disorders was modestly greater in the exposed than unexposed children (hazard ratio 1.4, 95% CI 1.1-1.7). Further analyses that used indirect proxies of depression severity also found that SSRI exposure was associated with an increased risk of speech/language disorders. Nevertheless, the association may be confounded by severity of depression and may also be due to residual confounding by variables that were not included in the analyses, such as postpartum depression. The absolute risk of speech/language disorders in both groups was relatively small (less than 2 percent in each group).
●A prospective study at a perinatal psychiatric clinic included pregnant women (n = 102) treated with SSRIs or SNRIs and pregnant women not treated with these antidepressants (n = 76); most women (87 percent) received psychotropic drugs [21]. The offspring were assessed between the ages of 2.5 to 5.5. After controlling for potential confounding factors (eg, maternal and child age, lifetime maternal mental illness, and antenatal use of other psychotropic drugs), the analyses found that expressive language was modestly worse in exposed than unexposed children, and that longer antenatal exposure to SSRIs and SNRIs was associated with greater impairment.
●A prospective observational study (n >51,000 pregnancies) examined exposure to SSRIs during three time periods (from pregnancy week 0 to week 18, week 19 to week 29, and pregnancy week 30 until the child was six months old); language competence was assessed in the offspring at the age of three years [22]. After controlling for potential confounding variables (eg, parental education and maternal depression before and during pregnancy), the analyses found that prolonged antenatal SSRI exposure for two or more periods (n = 161 pregnancies) compared with no use was associated with a delay in language competence in children age three years (relative risk 2.3, 95% CI 1.2-4.4). However, children of mothers with anxiety and depression throughout pregnancy also had an increased risk of delayed language competence by age three years (relative risk 1.8, 95% CI 1.4-2.4). In addition, the authors did not report the statistical significance of the association between SSRI use and language delay after accounting for postnatal anxiety and depression symptoms. Thus, residual confounding may explain the observed association between antenatal SSRI exposure and language delay.
Intelligence — Antenatal exposure to SSRIs does not appear to be associated with decreases in general intellectual functioning, which is typically assessed by measuring the child’s intelligence quotient (IQ) [9]. A review of in utero exposure to antidepressants and IQ identified five prospective observational studies of children aged three years and older (total n = 404) [12]. The results indicated that factors such as maternal IQ and/or maternal depression, rather than prenatal exposure to antidepressants, predict child IQ. As an example:
●A study compared children of mothers with antenatal depression treated with SSRIs (n = 62), children of mothers with antenatal depression treated with venlafaxine (an SNRI, n = 62), and children of mothers with antenatal depression that was not treated with antidepressants (n = 54) [23]. The mean IQ scores were comparable for the three groups. However, the IQ of these three groups of children were lower than the mean IQ score of a fourth group of children born to mothers who were not depressed and not treated with antidepressants (n = 62), suggesting that maternal depression rather than antenatal exposure to SSRIs or venlafaxine may affect intelligence.
●The same research group conducted a study of 45 sibling pairs, one of whom was exposed to SSRIs and/or SNRIs during gestation and one of whom was not; this approach accounted for shared genetic and environmental factors [24]. The antidepressants were prescribed for antenatal depressive disorders, and IQ was assessed in the children between the ages of three to six years. After controlling for potential confounding factors (eg, child’s age, birth order, and severity of maternal depressive episodes during pregnancy and after delivery), the analyses found that the Full Scale IQ in the exposed and unexposed siblings was comparable (103 and 106). However, higher maternal IQ was associated with higher offspring IQ.
Intellectual disability — Antenatal exposure to SSRIs does not appear to be associated with intellectual disability (IQ <70 plus functional impairment). A national registry study identified children of mothers who used SSRIs during pregnancy (n >3000) and children who were not exposed (n >170,000) [25]. The children were followed for an average of eight years following birth. After controlling for potential confounding factors (eg, parental age, education, and psychiatric diagnoses), the analyses found that intellectual disability in the exposed and unexposed children was comparable (relative risk 1.48, 95% CI 0.98-2.23).
Educational achievement — It is not clear whether antenatal exposure to SSRIs is associated with diminished educational achievement, due to conflicting results across national registry studies that included pregnant women who filled prescriptions for SSRIs. However, the best evidence suggests that exposure is not associated with adverse outcomes:
●One study identified pregnant women with depressive disorders who either used SSRIs (n >15,000) or did not use SSRIs (n >9000); the offspring were followed for up to 14 years after birth [13]. After controlling for potential confounding factors (eg, parental age and history of psychiatric diagnoses, and maternal smoking), the analyses found that the frequency of scholastic disorders (eg, reading disorder or disorder of mathematical skills) in the exposed and unexposed children was comparable (0.4 and 0.6 percent).
●A subsequent study of children and adolescents included youth with no antenatal exposure to antidepressants (n >560,000) and youth exposed in utero to SSRIs (n >8000) [26]. After controlling for potential confounding factors (eg, parental psychiatric history and maternal prescription fill for other psychotropic drugs), the analyses found that language test scores were comparable in the two groups. Conversely, mathematics test scores were lower in the group exposed to antenatal SSRIs; however, the difference was small, and the clinical significance was uncertain. In addition, this study lacked the methodologic advantage of the first study, which included only women with depressive disorders.
PSYCHOPATHOLOGY — Antenatal exposure to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors and the risk of psychopathology in the offspring is discussed separately. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Risk of psychopathology in the offspring".)
SUMMARY
●For infants and children who are exposed in utero to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), it is not clear whether the drugs are associated with risks of adverse developmental outcomes due to the lack of high quality studies. (See 'Introduction' above and "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes", section on 'Interpreting the evidence'.)
●Antenatal SSRI exposure does not appear to affect postnatal growth of infants. (See 'Growth' above.)
●SSRIs may be associated with minor delays or impairments in childhood motor skills, but there are inconsistent results across studies. (See 'Motor skills' above.)
●Multiple observational studies consistently suggest that antenatal exposure to SSRIs and SNRIs is not associated with impairment of general cognitive functioning in children. (See 'General cognition' above.)
●Prenatal exposure to SSRIs may be associated with minor impairments in language skills, but there are inconsistent results across studies. (See 'Language' above.)
●Antenatal exposure to SSRIs does not appear to be associated with decreases in intellectual functioning as assessed by measuring the child’s intelligence quotient. (See 'Intelligence' above.)
●Although results across different studies are inconsistent, the best evidence suggests that antenatal exposure to SSRIs does not appear to be associated with scholastic disorders. (See 'Educational achievement' above.)
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