INTRODUCTION — Pregnant women with psychiatric illnesses are often treated with antidepressant drugs. As an example, studies of pregnant women in Europe have found that antidepressants were used by approximately 3 percent [1-5], and in the United States by 8 percent [6-9]. The most commonly used and studied drugs are selective serotonin reuptake inhibitors (SSRIs) [1,2,6-13].

Antidepressants cross the placenta and fetal blood brain barrier. Prenatal exposure thus involves potential risks of teratogenesis, preterm birth, low birth weight, and pregnancy complications (eg, spontaneous abortion and postpartum hemorrhage), as well as postnatal effects (eg, persistent pulmonary hypertension of the newborn).

This topic reviews the potential adverse consequences that may be associated with using SSRIs during pregnancy, including teratogenicity, preterm birth, low birth weight, pregnancy complications, and perinatal mortality. The potential adverse antenatal effects of antidepressants other than SSRIs, postnatal outcomes among infants exposed in utero to antidepressants, principles of teratology, choice of treatment for depressed pregnant patients, safety of antidepressants in lactating women, and treatment of postpartum depression are discussed separately:

●(See "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors".)

●(See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes".)

●(See "Birth defects: Approach to evaluation".)

●(See "Severe antenatal unipolar major depression: Choosing treatment".)

●(See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding".)

●(See "Severe postpartum unipolar major depression: Choosing treatment".)

QUALITY OF EVIDENCE — Information about the risks of antidepressant drugs during pregnancy comes from low to moderate quality studies. No randomized trials have been conducted; instead, the evidence is based upon observational studies that can yield associations confounded by measured and residual (unmeasured) factors [10,14,15]. Observational studies include retrospective case-control studies, which carry the risk of recall bias. In addition, population based registry studies typically rely upon prescription databases that may misclassify exposure, given that women may not take a prescribed drug. Some studies did not precisely define outcomes, or grouped together different types of malformations across a range of severity from mild to severe. Other studies did not specify the antidepressant dose or timing of use during the antenatal period. Some observed associations between exposure and outcome are based upon a small number of exposed and affected infants, and some associations may occur by chance due to an excessive number of comparisons.

Associations between fetal exposure to antidepressants and adverse outcomes that are found in observational studies may be confounded by many factors [10,11,16,17]:

●Pregnant women who were psychiatrically ill and took antidepressants were often compared with pregnant women who were healthy; thus, observed associations between prenatal exposure to antidepressants and pregnancy outcomes may be confounded by exposure to maternal psychiatric illness.

●Another potential confound is severity of illness; among pregnant women with depression or anxiety, the mental disorder is typically more severe in patients who are prescribed antidepressants than patients not prescribed antidepressants.

●Other potential confounds in women prescribed antidepressants for a particular disorder include comorbid general medical and psychiatric illnesses, and use of other medications (eg, benzodiazepines and antipsychotics).

●Ascertainment (surveillance) bias may exist such that congenital defects, which might have otherwise gone undetected, are discovered in offspring of women using antidepressants because they are more likely to undergo prenatal and postnatal ultrasonography, echocardiography, and thorough postnatal physical examination. Thus, there may be a greater likelihood that malformations are detected, especially mild defects, such as small ventricular septal defects that often close during childhood.

Teratogenicity — Teratogens are thought to consistently cause similar types of malformations across studies [10]. However, studies of antidepressant exposure and adverse pregnancy outcomes often yield conflicting results and fail to show a pattern. Observed associations that are inconsistent across studies are less likely to represent a true effect.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) — The selective serotonin reuptake inhibitors (SSRIs) include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. The adverse pregnancy risks of antidepressants have been more widely studied in SSRIs than other antidepressant drugs; in one study of women who used antidepressants during the first trimester (n >64,000), SSRIs were prescribed for 72 percent [11].

Although SSRIs differ in their pharmacologic properties, the pregnancy outcomes observed for the different drugs (usually from underpowered analyses) are comparable, suggesting that the impact of SSRIs is likely a class effect of the SSRI drugs. Thus, composite data on SSRIs are generally used for the primary analyses of outcomes.

The pharmacology, administration, and side effects of SSRIs are discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

Teratogenicity — Most studies indicate that SSRIs as a group are not major teratogens and are not associated with birth defects [5,10,11,13,18-25]. In studies that have observed an association between SSRI exposure and congenital anomalies, the magnitude of the increased risk was small [26].

Evidence regarding SSRIs (as a drug class) and teratogenicity include the following observational studies [27]:

●A national registry study (nearly 1,300,000 births) compared infants who were exposed to SSRIs in early pregnancy (n >10,000) with infants not exposed [23]. After adjusting for potential confounds (eg, maternal age, smoking, and body mass index), the analyses found that the risk of severe congenital malformations was comparable in the two groups.

●A subsequent study of national registries from multiple countries identified infants who were exposed to SSRIs or venlafaxine during the first trimester (n >36,000) and infants who were not exposed (n >2,100,000); the analysis controlled for several potential confounding factors, such as maternal age, smoking, diabetes, and use of other medications (eg, antiepileptics) [25]. The incidence of major birth defects was greater for exposed infants than unexposed infants (3.7 versus 3.2 percent). However, this clinically small increase was not observed in analyses that adjusted further for potential family related confounding factors by analyzing siblings (2288 infants) discordant for both exposure and birth defects. The sibling controlled analysis found that exposure was not associated with an increased risk of major birth defects; this suggests that the increased risk observed in the initial analysis was due to residual confounding (other, unmeasured factors that were not controlled for in the analysis).

●A meta-analysis of 12 studies compared infants of mothers who used antidepressants during pregnancy (n >50,000; largely SSRIs) with infants who were not exposed (n >1,200,000) [28]. The risk of congenital malformations was comparable for the two groups.

Cardiac defects — One finding that has been reported in multiple studies of SSRIs is the potential for a small increased risk of cardiovascular defects [28,29]; however, several other studies have found no association between antenatal exposure to SSRIs and heart defects [11,13,23,26,30].

Observational studies that have found an association between prenatal exposure to antidepressants and a small increased risk of cardiovascular defects include the following:

●A meta-analysis of 13 studies compared infants of mothers who used antidepressants (n >20,000; largely SSRIs) during pregnancy with infants who were not exposed (n >1,500,000) [28]. The risk of congenital cardiac malformations was increased in the group that was exposed to antidepressants (relative risk 1.4, 95% CI 1.1-1.7). Given that the baseline risk for cardiovascular malformations in unexposed infants is approximately 5 in 1000, a relative risk increase of 1.4 would result in an absolute risk of 7 in 1000 live births.

●A meta-analysis of 10 studies found that the risk of risk of congenital cardiac malformations was greater in infants exposed to SSRIs in utero (n >22,000), compared with unexposed infants (n >2,300,000) (odds ratio 1.32, 95% CI 1.01-1.73) [29]. For every 1000 children in each group, there were 2 more cases of cardiac defects in the exposed group (absolute risk difference). However, heterogeneity across studies was moderate to large.

It is worth noting that the observed malformations include anomalies such as small ventricular septal defects, which often close during childhood.

Observational studies that found antenatal SSRI exposure was not associated with an increased risk of cardiac defects include the following:

●A study of an insurance claims database compared infants born to depressed mothers who received SSRIs during the first trimester (n >36,000) with infants whose depressed mothers were not treated with antidepressants (n >180,000) [11]. Propensity scoring was used to match the two groups with regard to a large set of observed potential confounders (eg, maternal age, obesity, and substance use disorders; depression severity; chronic maternal illnesses; and use of other medications). The risk of congenital cardiac defects was similar among infants exposed to SSRIs compared with unexposed infants.

●A national registry study (nearly 1,300,000 births) compared infants who were exposed to SSRIs in early pregnancy (n >10,000) with infants not exposed [23]. After adjusting for potential confounds, the analyses found that the specific risk of cardiovascular defects was comparable for the two groups.

●A subsequent study of national registries from multiple countries identified infants who were exposed to SSRIs or venlafaxine during the first trimester (n >36,000) and infants who were not exposed (n >2,100,000); the analysis controlled for several potential confounding factors, including family related confounding factors by analyzing siblings (2288 infants) discordant for both exposure and birth defects [25]. The incidence of cardiac defects was not increased in babies exposed to antidepressants.

Pregnancy complications

Spontaneous abortion — SSRIs appear to be associated with little to no risk for spontaneous abortion (miscarriage):

●A national registry study identified pregnant women with depression who were treated with SSRIs or other antidepressants (n >22,000 pregnancies), or were not treated with these drugs (n >1800 pregnancies) [31]. The analysis controlled for potential confounding factors (eg, maternal age, use of other medications, and drug abuse), and found that the risk of miscarriage in the two groups was comparable.

In a second study using the same registry data, women exposed to SSRIs in the first 35 days of pregnancy (n >22,000) were compared with women who discontinued SSRI treatment 3 to 12 months prior to conception (n >14,000) [32]. The incidence of miscarriage was comparable in the exposed group and the control group (13 and 14 percent).

●Two independent meta-analyses each used the same set of observational studies, but found contradictory results, suggesting that the association between antenatal exposure to SSRIs and spontaneous abortion was small or nonexistent. In one meta-analysis of three observational studies that included pregnant women who took SSRIs (n >1000) or did not (n >4000), there was only a trend for an association between SSRI exposure and miscarriage (odds ratio 1.47, 95% CI 0.99-2.17) [33]. The second meta-analysis, using the same three observational studies, found that SSRIs were associated with an increased risk for miscarriage (odds ratio 1.60, 95% CI 1.01-2.53) [29].

Hypertensive disorders of pregnancy — The association of SSRIs with hypertensive disorders of pregnancy is at most small, and multiple studies have found that SSRIs are not associated with an increased risk of hypertension of pregnancy:

●A study of a nationwide insurance claims database found that among pregnant women with depression, the incidence of preeclampsia was identical for women who were treated with SSRIs during the second and third trimesters (n = 19,000), and women who received no antidepressants (n = 59,219) (5 percent in both groups) [34]. In addition preeclampsia occurred in fewer women treated with SSRIs than women treated with serotonin-norepinephrine reuptake inhibitors (n = 1216) or tricyclics (441) (5 versus 9 and 11 percent).

●A national registry study identified pregnant women with psychiatric disorders (primarily depressive disorders or anxiety disorders), and compared outcomes in women exposed to antenatal SSRIs (n >15,000) with women who were not exposed (n >9000) [5]. After adjusting for potential confounding factors, the risk of hypertension of pregnancy was comparable in the exposed and unexposed groups (5.2 versus 4.5 percent).

●A study using healthcare utilization databases identified pregnant women with depression who were either treated with SSRIs between gestational weeks 10 and 20 (n >3000), or who received no antidepressants (n >65,000) [35]. After adjusting for potential confounders (eg, maternal age, depression, and use of other psychotropic drugs), there was a trend for a greater incidence of preeclampsia in women exposed to SSRIs, compared with controls (3 and 2 percent of women; relative risk 1.22, 95% CI 0.97-1.54).

Postpartum hemorrhage — Multiple observational studies suggest that SSRIs are associated with bleeding, including postpartum hemorrhage:

●A study of a nationwide insurance claims database identified pregnant women with mood or anxiety disorders (primarily depression), who were either treated with SSRIs at the time of delivery (n >11,000) or were not treated with antidepressants in the five months before delivery (n >69,000) [36]. The analyses controlled for potential confounding factors (eg, maternal age, coagulopathies, and use of other medications), and found that postpartum hemorrhage occurred in more women who were exposed to SSRIs than women who were not (4 versus 3 percent).

●In a study that examined hospital records of pregnant women who delivered live born babies vaginally, postpartum hemorrhage occurred in more women who used SSRIs during pregnancy (n = 500), compared with women who did not (n >39,000) (18 versus 9 percent) [37]. In addition, the volume of blood loss was slightly greater in women exposed to SSRIs than controls (484 versus 398 mL in nonusers).

●A study of administrative health data for pregnant women examined the incidence of postpartum hemorrhage in those with late gestation exposure to antidepressants (n = 558; primarily SSRIs or venlafaxine), and women with psychiatric disorders who were not dispensed antidepressants (controls; n = 1292) [38]. Hemorrhage occurred in more women who were exposed to antidepressants than controls (16 versus 11 percent).

Additional information about bleeding as a side effect of SSRIs is discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Bleeding'.)

Preterm birth — Observational studies of pregnant women indicate that exposure to SSRIs is associated with preterm birth (eg, <37 weeks gestational age) and a small reduction in gestational age at birth [39]:

●A meta-analysis of 18 studies (n >1,200,000 pregnant women) found that SSRI exposure was associated with preterm birth (relative risk 1.7, 95% CI 1.5-2.0) [40], consistent with a prior meta-analysis of 13 studies (odds ratio 1.6) [33].

●A meta-analysis of 15 studies (number of pregnant women not reported) found that exposure to antidepressants (mostly SSRIs) was associated with a reduction in gestational age at birth [33]. However, the mean difference in gestational age between exposed and unexposed infants was approximately three days, which is probably not clinically significant. A subsequent study also found that delivery occurred three days earlier in women exposed to SSRIs [37].

The effect of SSRIs upon preterm delivery may be related to the timing of exposure. In a meta-analysis of 41 observational studies (n >5,000,000 pregnant women) that controlled for potential confounding factors (eg, maternal age, smoking, alcohol use, and history of prematurity), first trimester exposure to antidepressants (mostly SSRIs) was not associated with preterm birth [41]. However, third trimester exposure was associated with premature delivery (odds ratio 2.0, 95% CI 1.6-2.4); controlling for depression did not eliminate the effect. However, heterogeneity across studies was large.

Although the weight of the evidence indicates that exposure to SSRIs is associated with preterm birth, inconsistent results have been reported. As an example, a national registry study identified pregnant women with psychiatric disorders (primarily depressive disorders or anxiety disorders), and compared outcomes in offspring exposed to antenatal SSRIs (n >15,000) with offspring who were not exposed (n >9000) [5]. After adjusting for potential confounding factors (eg, maternal age at delivery, use of other medications, and chronic general medical illnesses), the risk of preterm birth was lower in the exposed neonates than unexposed neonates (4.7 versus 5.4 percent).

Low birth weight — It is not clear if use of SSRIs during pregnancy is associated with low birth weights:

●A meta-analysis of 9 observational studies (n >1,200,000 pregnant women) found that exposure to SSRIs was associated with low birthweight (<2500 g) (relative risk 1.5, 95% CI 1.2-1.8) [40]. Heterogeneity across studies was significant.

●A meta-analysis of 20 studies (number of pregnant women not stated) found that birth weights were lower in babies of mothers who took antidepressants (mostly SSRIs) than babies of all mothers who did not [33]. However, the mean difference between exposed and unexposed babies was 74 g, a small difference that is unlikely to be clinically significant. In addition, when depressed mothers who took antidepressants during pregnancy were compared with depressed mothers not exposed to antidepressants (six studies), the association between antidepressant exposure and lower birth weight was no longer statistically significant.

Apgar score — Exposure to SSRIs and other antidepressants is associated with reduced Apgar scores (calculator 1) in observational studies, but the clinical significance is not clear:

●A meta-analysis of 14 studies found that Apgar scores at five minutes were lower among infants exposed in utero to antidepressants (mostly SSRIs), compared with unexposed infants [33]. However, the mean difference between the two groups was only 0.2 points, which is probably not clinically significant.

●A subsequent study identified pregnant women with psychiatric disorders (primarily depressive disorders or anxiety disorders), and compared outcomes in offspring exposed to SSRIs during the second and/or thirds trimester with offspring who were not exposed [5]. After adjusting for potential confounding factors, the risk of five-minute Apgar scores <7 was greater in the exposed neonates than unexposed neonates (odds ratio 2.2, 95% CI 1.7-2.7).

Perinatal death — Multiple studies suggest that SSRIs are not associated with an elevated risk of perinatal death [42]. As an example, a study of national registries from five countries (n >1,600,000 births) included more than 29,000 mothers who filled an SSRI prescription during pregnancy; among the births, there were more than 6000 stillbirths, 3600 neonatal deaths, and 1500 postnatal deaths [43]. After controlling for potential confounding factors (eg, maternal age, smoking, diabetes, and psychiatric illness), the analyses found that the risks of stillbirth, neonatal death, and postnatal death were each comparable for women who used or did not use SSRIs.

Postnatal effects — Potential neonatal problems such as the neonatal behavioral syndrome, neurodevelopmental effects, and persistent pulmonary hypertension of the newborn are discussed separately. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes".)

Specific SSRIs — We do not consider one SSRI as "safer" or "less safe" to use during pregnancy than another, with the possible exception of paroxetine. Several studies have found that paroxetine was associated with a small increased risk for congenital cardiovascular malformations; however, other studies have found no such risk. (See 'Paroxetine' below.)

Few studies have had sufficient power to evaluate the risks associated with specific SSRIs, including the more widely studied medications, such as citalopram, fluoxetine, paroxetine, and sertraline. Newer (eg, escitalopram) and less frequently used SSRIs (eg, fluvoxamine) have been less well studied. Even across studies that have assessed individual SSRIs, there is substantial inconsistency in the type and magnitude of adverse events reported, which may suggest that the observed associations are less likely to represent a true effect [10].

The following sections review studies of teratogenicity and pregnancy complications for specific SSRIs.

Citalopram

Teratogenicity — Exposure to citalopram appears to be associated with little to no risk of birth defects [10,13,20,25,44-47]. As an example:

●In a national registry study (n >1,000,000 pregnant women) that adjusted for potential confounds (eg, maternal age, smoking, and body mass index), citalopram exposure early in pregnancy (n >3900) was not associated with severe birth defects (analyzed collectively), and was not associated specifically with cardiovascular defects [30].

●A study of a nationally representative sample of live births found that the rate of major congenital anomalies was comparable for children exposed to citalopram during the first trimester (n >1900) compared with children of mothers with unmedicated depression (n >23,000) [21]. In addition, the rate of major cardiac anomalies was comparable for the two groups.

●A meta-analysis of seven observational studies found that the incidence of congenital malformations in babies who were exposed (n >7000) or not exposed (n >2,300,000) in utero to citalopram was comparable [29]. In addition, the rate of major malformations and the rate of cardiac anomalies were each comparable for the two groups.

Although other observational studies have found an association between early pregnancy exposure to citalopram and birth defects [26,48,49], the type of defect varied across studies, which suggests the findings did not represent true effects [10], and that citalopram is not a major teratogen [50].

Pregnancy complications — Most studies have found that citalopram is not associated with any major pregnancy complications, except for postpartum hemorrhage:

●Spontaneous abortion – Multiple studies suggest that citalopram is not associated with spontaneous abortion [32]. As an example, a national registry study identified pregnant women with depression, and found that the risk of spontaneous abortion was comparable in women who were treated with citalopram and women who were not exposed to antidepressants [31].

●Hypertensive disorders of pregnancy – Multiple studies suggest that citalopram is not associated with hypertensive disorders of pregnancy [51]. As an example, a study of an insurance claims database found that among pregnant women with depression, the risk of preeclampsia was comparable for women who were treated with citalopram during the second and third trimesters (n >1000) and women who received no antidepressants (n >59,000) [34].

●Postpartum hemorrhage – A study of pregnant women with mood or anxiety disorders in a nationwide insurance claims database found that use of citalopram at the time of delivery (n >800) was associated with postpartum hemorrhage (relative risk 1.5, 95% CI 1.1-2.0) [36].

Escitalopram

Teratogenicity — Several studies suggest that escitalopram is not associated with teratogenic effects [10,47]:

●A meta-analysis of three observational studies found that the incidence of congenital malformations in babies who were exposed (n >600) or not exposed (n >1,700,000) in utero to escitalopram was comparable [29]. In addition, the rate of major malformations and the rate of cardiac anomalies were each comparable for the two groups.

●A subsequent study using a nationally representative database found that the incidence of major congenital anomalies was comparable for children exposed to escitalopram during the first trimester (n = 333), and for children of mothers with unmedicated depression (n >23,000) [21]. In addition, the rate of major cardiac anomalies was comparable for the two groups.

●Another subsequent study collected data from national registries from multiple countries (n >2,100,000 pregnancies) and controlled for several potential confounding factors; neither major malformations overall nor cardiac malformations specifically were increased among infants exposed to escitalopram during the first trimester (n >3900) [25].

Prenatal exposure to escitalopram has been studied less than that of citalopram, fluoxetine, paroxetine, and sertraline [11,30]; however, the safety data for citalopram may apply to escitalopram (which is the s-enantiomer of citalopram).

Pregnancy complications — Escitalopram does not appear to be associated with any major pregnancy complications, except for postpartum hemorrhage:

●Spontaneous abortion – Multiple studies suggest that escitalopram is not associated with spontaneous abortion [32]. As an example, a national registry study identified pregnant women with depression, and found that the risk of spontaneous abortion was comparable in women who were treated with escitalopram and women who were not exposed to antidepressants [31].

●Hypertensive disorders of pregnancy – A study of an insurance claims database found that among pregnant women with depression, the risk of preeclampsia was comparable for women who were treated with escitalopram during the second and third trimesters (n >1000) and women who received no antidepressants (n >59,000) [34].

●Postpartum hemorrhage – A study of pregnant women with mood or anxiety disorders in a nationwide insurance claims database found that use of escitalopram at the time of delivery (n >1000) was associated with postpartum hemorrhage (relative risk 1.6, 95% CI 1.2-2.1) [36].

Fluoxetine

Teratogenicity — Most observational studies have not found an association between use of fluoxetine during pregnancy and an increased risk of birth defects [10,13,21,49,52,53]. As an example, a meta-analysis of four studies (n >1,200,000 births) compared infants of mothers who used fluoxetine during pregnancy (n >52,000) with infants who were not exposed, and found that the risk of congenital malformations overall was comparable for the two groups [28].

In addition, multiple studies suggest that antenatal exposure to fluoxetine is not associated specifically with congenital cardiovascular malformations [21,26,49,54]:

●A meta-analysis of four studies (nearly 1,600,000 births) compared infants of mothers who used fluoxetine during pregnancy (n >17,000) with infants who were not exposed, and found that the risk of congenital heart malformations was comparable for the two groups [28].

●A subsequent study compared infants born to depressed mothers who received fluoxetine during the first trimester (n >8000) with infants whose depressed mothers were not treated with antidepressants (n >180,000) [11]. Propensity scoring was used to match the two groups with regard to observed potential confounders. The risk of congenital cardiac defects was comparable among infants exposed to fluoxetine compared with unexposed infants.

Nevertheless, some studies suggest that fluoxetine may be associated with a small increased risk of teratogenicity [54]:

●A meta-analysis of six observational studies found that the incidence of major congenital malformations was greater in babies who were exposed in utero to fluoxetine (n >3000), compared with unexposed babies (n >1,200,000) (odds ratio 1.3, 95% CI 1.1-1.5) [29]. For every 1000 children in each group, there were 7 more cases of malformations in the exposed group (absolute risk difference). In addition, the rate of cardiac anomalies was greater in exposed offspring (odds ratio 1.6, 95% CI 1.1-2.3; absolute risk difference of 4 per 1000).

●A subsequent study of national registries from multiple countries identified infants who were exposed to fluoxetine during the first trimester (n >6200) and infants who were not exposed (n >2,100,000); the analysis controlled for several potential confounding factors [25]. The risk of major birth defects was greater for exposed infants than unexposed infants (odds ratio 1.3, 95% CI 1.1-1.4), as was the risk of cardiac defects (odds ratio 1.3, 95% CI 1.1-1.6).

●A subsequent case-control study examined the antenatal use of fluoxetine in mothers of infants with birth defects (n >17,000 cases) and mothers of infants without birth defects (n >9000 controls) [47]. The analysis controlled for potential confounding factors (eg, maternal obesity and smoking), and found that exposure to fluoxetine during the first trimester was greater in babies with congenital anomalies than babies with no defects. As an example, exposure was greater among infants (n = 27 cases) with right ventricular outflow tract obstruction compared with controls (odds ratio = 2.0, 95% credible interval 1.4-3.1). Nevertheless, the authors concluded that the absolute risk was small; if the association is causal, the absolute risk would increase from 1 per 1000 children to 2 per 1000.

It is worth noting that in both studies, the association between use of fluoxetine and birth defects may be due to residual confounding. (See 'Teratogenicity' above.)

Pregnancy complications — Fluoxetine does not appear to be associated with any major pregnancy complications, except for postpartum hemorrhage:

●Spontaneous abortion – Multiple studies suggest that fluoxetine is not associated with spontaneous abortion [32]. As an example, a national registry study identified pregnant women with depression, and found that the risk of miscarriage was comparable in women who were treated with fluoxetine and women who were not exposed to antidepressants [31].

●Hypertensive disorders of pregnancy – Multiple studies suggest that fluoxetine is not associated with hypertensive disorders of pregnancy [51]. As an example, a study of an insurance claims database found that among pregnant women with depression, the risk of preeclampsia was comparable for women who were treated with fluoxetine during the second and third trimesters (n >5000) and women who received no antidepressants (n >59,000) [34].

●Postpartum hemorrhage – A study of pregnant women with mood or anxiety disorders in a nationwide insurance claims database found that use of fluoxetine at the time of delivery (n >3000) was associated with postpartum hemorrhage (relative risk 1.5, 95% CI 1.3-1.8) [36].

Fluvoxamine

Teratogenicity — No association between first trimester fluvoxamine exposure and teratogenicity has been found, but this drug has been studied less than other SSRIs [11,30]. A meta-analysis of four observational studies found that the incidence of congenital malformations in babies who were exposed (n >400) or not exposed (n >1,600,000) in utero to fluvoxamine was comparable [29]. In addition, the rate of major malformations and the rate of cardiac anomalies were each comparable for the two groups.

Pregnancy complications — A case-control study of administrative health data found that fluvoxamine was not associated with pregnancy induced hypertension; however, the number of exposures to fluvoxamine for the entire sample of cases plus controls was small [51].

Paroxetine

Teratogenicity — Although some evidence suggests that paroxetine may be associated with a small absolute increase in congenital heart defects [19,55], results across different observational studies are inconsistent [10].

Studies that suggest first trimester use of paroxetine is not associated with an excess risk of congenital cardiac anomalies include the following [13,26,49,56,57]:

●One study analyzed an insurance claims database to compare infants born to depressed mothers treated with paroxetine during the first trimester (n >8000) with infants whose depressed mothers were not treated with antidepressants (n >180,000) [11]. Propensity scoring was used to match the two groups with regard to observed potential confounders. The risk of congenital cardiac defects was comparable among infants exposed to paroxetine compared with unexposed infants.

●In a study of national registries from multiple countries (n >2,100,000 pregnancies) that controlled for several potential confounding factors, the risk of cardiac malformations among infants (n >2800) exposed to paroxetine during the first trimester and infants not exposed was comparable [25].

●A study used prospectively collected data to compare the incidence of cardiovascular birth defects following exposure to paroxetine (n = 1174) with the incidence following exposure to drugs that are considered safe in pregnancy (n = 1174); the rate of defects for both groups was 0.7 percent [58].

However, several studies support an association between in utero paroxetine exposure and cardiac defects [47,48,59]. Although the results suggest an increased risk of at least 40 to 70 percent, the absolute risk was small:

●A meta-analysis of seven studies (n >1,600,000 births) compared infants of mothers who used paroxetine during pregnancy (n >18,000) with infants who were not exposed [28]. The risk of congenital cardiovascular malformations was greater in the exposed infants than unexposed infants (relative risk 1.4, 95% CI 1.1-1.9).

A second meta-analysis of seven studies found similar results; cardiac defects were observed in more infants exposed to paroxetine in utero (n >4000), compared with unexposed infants (n >2,300,000) (odds ratio 1.5, 95% CI 1.1-1.9 [29]. For every 1000 children in each group, there were 3 more cases of cardiac defects in the exposed group (absolute risk difference).

●A meta-analysis of seven studies (n >16,000 live births) found that first trimester exposure to paroxetine (n >2600) was associated with an increased risk of cardiac malformations (odds ratio 1.7, 95% CI 1.2-2.4) [16]. However, this increase may have been related to a detection bias; women who took SSRIs during pregnancy underwent 30 percent more prenatal ultrasound examinations than women not on antidepressants. In addition, infants who were exposed during pregnancy had twice as many echocardiograms in the first year of life than unexposed infants.

●A study of a nationally representative sample of live births compared children exposed in utero to paroxetine during the first trimester (n = 1200) with children of depressed women who were not treated with medications (n >23,000) [21]. After adjusting for potential confounds (eg, maternal age, smoking, and body mass index), the analysis found a trend for a greater rate of congenital heart anomalies in the group exposed to paroxetine (odds ratio 1.7, 95% CI 1.0-2.8).

Pregnancy complications — Exposure to paroxetine does not appear to be associated with spontaneous abortion; different studies have yielded contradictory results regarding exposure to paroxetine and hypertensive disorders of pregnancy. Paroxetine seems to be associated with postpartum hemorrhage.

●Spontaneous abortion – Multiple studies suggest that paroxetine is not associated with spontaneous abortion [32]. As an example, a national registry study identified pregnant women with depression, and found that the risk of miscarriage was comparable in women who were treated with paroxetine and women who were not exposed to antidepressants [31].

●Hypertensive disorders of pregnancy – It is not clear if paroxetine is associated with hypertensive disorders of pregnancy due to conflicting findings across studies:

•A study of an insurance claims database found that among pregnant women with depression, the risk of preeclampsia was comparable for women who were treated with paroxetine during the second and third trimesters (n >3000) and women who received no antidepressants (n >59,000) [34].

•An observational study of administrative health data examined use of paroxetine among pregnant women with pregnancy induced hypertension (n >1200 cases) and pregnant women without pregnancy induced hypertension (n >12,000 controls), and controlled for potential confounding factors (eg, maternal age, depression, and use of other medications) [51]. Although exposure to paroxetine was greater in women with hypertension than controls (odds ratio 1.81, 95% CI 1.02-3.23), there were only 18 cases of hypertension with exposure to paroxetine.

●Postpartum hemorrhage – A study of pregnant women with mood or anxiety disorders in a nationwide insurance claims database found that use of paroxetine at the time of delivery (n >2000) was associated with postpartum hemorrhage (relative risk 1.4, 95% CI 1.1-1.7) [36].

Sertraline

Teratogenicity — Several reviews have found that in most studies, early pregnancy exposure to sertraline was not associated with major congenital abnormalities overall, nor with cardiovascular malformations in particular [10,54]. Studies that found sertraline was not associated with birth defects include the following [13,21,30,47]:

●A meta-analysis of six observational studies found that the incidence of congenital malformations in babies who were exposed (n >4000) or not exposed (n >2,300,000) in utero to sertraline was comparable [29]. In addition, the rate of major malformations and the rate of cardiac anomalies were each comparable for the two groups.

●A subsequent study of an insurance claims database compared infants born to depressed mothers treated with sertraline during the first trimester (n >11,000) with infants whose depressed mothers were not treated with antidepressants (n >180,000) [11]. Propensity scoring was used to match the two groups with regard to observed potential confounders. The risk of congenital cardiac defects was comparable among infants exposed to sertraline compared with unexposed infants.

●Another subsequent study collected data from national registries from multiple countries (n >2,100,000 pregnancies) and controlled for several potential confounding factors; the risk of major birth defects among infants (n >7000) exposed to sertraline during the first trimester and infants not exposed was comparable, as was the risk of cardiac defects [25].

Among the relatively few studies that found an increased risk for some birth defects, the absolute risk appeared to be low [60].

Pregnancy complications — Sertraline does not appear to be associated with any major pregnancy complications, except for postpartum hemorrhage:

●Spontaneous abortion – Multiple studies suggest that sertraline is not associated with spontaneous abortion [32]. As an example, a national registry study identified pregnant women with depression, and found that the risk of spontaneous abortion was comparable in women who were treated with sertraline and women who were not exposed to antidepressants [31].

●Hypertensive disorders of pregnancy – Multiple studies suggest that sertraline is not associated with hypertensive disorders of pregnancy [51]. As an example, a study of an insurance claims database found that among pregnant women with depression, the risk of preeclampsia was comparable for women who were treated with sertraline during the second and third trimesters (n >7000) and women who received no antidepressants (n >59,000) [34].

●Postpartum hemorrhage – A study of pregnant women with mood or anxiety disorders in a nationwide insurance claims database found that use of sertraline at the time of delivery (n >4000) was associated with postpartum hemorrhage (relative risk 1.3, 95% CI 1.1-1.5) [36].

SSRIS PLUS BENZODIAZEPINES — It is not clear if the combination of SSRIs and benzodiazepines is associated with major congenital malformations. In two registry studies, infants exposed to SSRIs plus benzodiazepines in early pregnancy (n = 406 and 359) were compared with infants not exposed to either drug [23,61]. One study found that the combination was associated with an elevated risk of congenital heart disease [61], whereas the other study did not [23]. A third registry study found that the combined use of SSRIs or venlafaxine plus benzodiazepines during the first trimester did not increase the risk of birth defects [25].

Additional information about the teratogenic and postnatal effects of benzodiazepines is discussed separately. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Benzodiazepines'.)

ANTIDEPRESSANTS OTHER THAN SELECTIVE SEROTONIN REUPTAKE INHIBITORS — The potential adverse antenatal consequences that may be associated with antidepressants other than selective serotonin reuptake inhibitors are discussed separately. (See "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors".)

OTHER MEDICATIONS AND ECT — The teratogenic and postnatal effects of anticonvulsants, antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy (ECT) are discussed separately. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of AEDs on the fetus and neonate' and "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy".)

BREASTFEEDING — The safety of antidepressants in lactating women is discussed separately. (See "Safety of infant exposure to antidepressants and benzodiazepines through breastfeeding".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)

SUMMARY

●Options for treating depressed pregnant patients include psychotherapy and pharmacotherapy. The risks of untreated moderate to severe maternal major depression, to both the mother and fetus, often outweigh the risks associated with antidepressants. (See "Severe antenatal unipolar major depression: Choosing treatment".)

●The most commonly used antidepressants during pregnancy are selective serotonin reuptake inhibitors (SSRIs). (See 'Introduction' above.)

●Information about the risks of antidepressants during pregnancy comes from low to moderate quality studies. The antenatal risks of SSRIs have been more widely studied than other antidepressants. (See 'Quality of evidence' above and 'Selective serotonin reuptake inhibitors (SSRIs)' above.)

●First trimester exposure to SSRIs is associated with a low risk of teratogenicity, and individual SSRIs as well as SSRIs as a group are not considered major teratogens. Although some data suggest that SSRIs (particularly paroxetine) may be associated with a small absolute increase in congenital heart defects, several studies have found no such association. (See 'Teratogenicity' above.)

●Observational studies of pregnant women have consistently found that exposure to SSRIs is associated with preterm birth (eg, <37 weeks gestational age), and a small reduction in gestational age at birth that is probably not clinically significant. It is not clear if SSRIs are associated with low birth weight. (See 'Preterm birth' above and 'Low birth weight' above.)

●SSRIs do not appear to be associated with an elevated risk of miscarriage, and do not appear to greatly increase the risk for hypertensive disorders of pregnancy. However, SSRIs are associated with postpartum hemorrhage. (See 'Spontaneous abortion' above and 'Hypertensive disorders of pregnancy' above and 'Postpartum hemorrhage' above.)

●SSRIs do not appear to be associated with perinatal death. (See 'Perinatal death' above.)

●We do not consider one SSRI to be safer or less safe than another to use during pregnancy, with the possible exception of paroxetine. Several studies have found that paroxetine was associated with a small increased risk for congenital cardiovascular malformations; however, other studies have found no such risk. (See 'Specific SSRIs' above and 'Paroxetine' above.)