Selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors in pregnancy: Infant and childhood outcomes

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In Canada, the annual and lifetime prevalence of major depressive disorder (MDD) in the general population is 4.7% and 11.3%, respectively ^[1]. Women have a greater annual prevalence of MDD compared with men (4.9% versus 2.8%) ^[1]. Perinatal depression, occurring during pregnancy and in the first year postpartum, is one of the most common morbidities of pregnancy and the postnatal period, with an estimated prevalence of 7.5% during pregnancy and 6.5% in the first 3 months postpartum ^[2][3]. When minor depressive disorders are considered, these rates increase to 18.4% and 19.2% respectively ^[2][3]. Similarly, the overall prevalence of a clinical diagnosis of any anxiety disorder is 15.2%, and 4.1% for a generalized anxiety disorder ^[4]. The prevalence for self-reported anxiety symptoms is 18.2%, increasing to 24.6% in the third trimester ^[4]. Postnatally, the prevalence of anxiety symptoms overall is 15% ^[4]. If untreated, maternal depression and anxiety can affect the pregnancy (e.g., via poorer nutrition and medical care, increased smoking, or substance misuse), the newborn (e.g., being small for gestational age, born preterm, greater rates of neonatal intensive care unit (NICU) admission, lower rates of breastfeeding ^[5]-[8]), infant development (e.g., lower quality mother-infant interactions, and later, higher rates of emotional, behavioural, and academic problems ^[9][10]), maternal mental health (e.g., MDD relapse ^[11]), and family functioning ^[2][10][12].

Although non-pharmacological treatments are considered first line ^[2][12], pharmacological therapy may be required. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants in pregnancy ^[13]. In the United States and Europe, 6% and 3.8% of women take an SSRI or SNRI respectively during pregnancy, with lesser prevalence before pregnancy or in the first trimester compared with later in pregnancy ^[13]-[15]. It is important to balance the risks and benefits of SSRI and SNRI use in pregnancy and postpartum versus the risks of inadequately treating maternal depression or anxiety on the health of the mother, her pregnancy, family life, and child health. Discussions about a person’s intent to become pregnant and the safety of treatments during pregnancy should be part of assessing, managing, and counselling women of childbearing age with experience of depression or anxiety ^{[2][12][16][17]}. Together with individualized assessment and discussion of options with a clinician, families can access helpful online resources at mothertobaby.org and medicinesinpregnancy.org.

This statement updates a previous CPS document on the risks of exposure to SSRIs or SNRIs in pregnancy on infant outcomes ^[18] with additional information on risks for neurodevelopmental outcomes. The following questions have helped to focus recommendations:

1. Are SSRI and SNRIs safe to use in pregnancy regarding risk for congenital malformations, pregnancy outcomes (preterm birth and low birth weight (LBW)), poor neonatal adaption syndrome (PNAS), persistent pulmonary hypertension of the newborn (PPHN), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD)?
2. What monitoring is required in the neonatal period for infants exposed to SSRI or SNRIs in utero?
3. Should mothers using an SSRI or SNRI breastfeed?

Literature search strategy

Search strategies were conducted in October 2018, using MEDLINE, EMBASE, CINAHL, and Cochrane Database of Systematic Reviews to capture the literature published since the previous statement review ^[18]. The following search terms were used: selective serotonin reuptake inhibitors or SSRI, OR serotonin-norepinephrine reuptake inhibitors or SNRI, AND pregnancy or expectant mothers, OR postnatal period or postpartum, OR pregnancy complications. Bibliographies were also reviewed for pertinent references. An important limitation of the literature is that the use of SSRI and SNRIs during pregnancy is a marker for a population of women with different risk factors from the general population of pregnant women ^[9][19]. Most studies are thus confounded by indication and an inability to fully control for underlying maternal depression, severity of depression, or risk factors associated with maternal depression. Available human data from population-based epidemiological studies or systematic reviews are presented when available. Text and tables cite these studies first, followed by systematic reviews by year of publication, with the most recent studies first.

Are SSRIs and SNRIs safe to use in pregnancy?

Congenital malformations

Information on the possible teratogenic effects of individual SSRIs or SNRIs has been controversial, whether based on studies of population or meta-analysis (Table 1).

Using multicentre, population-based, case-control data from the United States, sertraline was the most commonly used SSRI, and no association of sertraline with any specific congenital malformation in infants has been found ^[20]. Paroxetine has been associated with anencephaly, atrial septal defects (ASDs), right ventricular outflow tract obstruction (RVOTO) defects, gastroschisis, and omphalocele ^[20]. Fluoxetine has been associated with RVOTO defects and craniosynostosis ^[20]. Similarly, using a population-based, case-control study of 12 European registries, SSRI exposure in the first trimester of pregnancy was associated with ano-rectal atresia or stenosis, gastroschisis, renal dysplasia, and clubfoot ^[21]. SSRI exposure was also associated with congenital heart defect (CHD), particularly tetralogy of Fallot and Ebstein’s anomaly ^[21]. Although these analyses strongly supported the validity of such associations, the increase in absolute risk was small. On the other hand, a multinational population-based cohort study using sibling-controlled analysis within five Nordic countries found no substantial increase in prevalence of overall congenital malformation or any congenital cardiac malformation among infants exposed to SSRIs or to venlafaxine, an SNRI, in utero ^[22]. Study authors concluded that results from both the adjusted and sibling-controlled analyses indicate against a teratogenic effect for SSRIs and venlafaxine ^[22].

Several meta-analyses have associated SSRIs with teratogenic risk. One recent study found that pregnant women who were exposed to SSRIs during the first trimester were at increased risk for having an infant with CHD ^[23]. Another, older study found an increased risk for major malformations but not CHD ^[24]. Yet another found no association with major malformations but did find an association with CHD and septal defects ^[25]. One meta-analysis of prospective cohort studies also did not associate first trimester SSRI use with developing CHD ^[26]. Regarding specific SSRIs, fluoxetine ^[24][27] and paroxetine ^[24][25][28] have been associated with higher risk for major malformations and cardiovascular malformations (both septal defects and non-septal defects) in meta-analyses, whereas sertraline and citalopram were not associated with either ^[24]. In other meta-analyses, fluoxetine was not shown to be associated with either major malformations ^[25] or cardiac malformations ^[25][29]. All the studies referenced here were limited by inability to fully control for confounding or ascertainment or detection bias (or both).

To summarize, it remains difficult to determine whether SSRIs or SNRIs are associated with increased risk for teratogenic effects, because while some studies appear to demonstrate an association, others clearly do not. Importantly, however, when an association has been found, the absolute risk was low and the number needed to treat to harm (NNTH) was high. 

Pregnancy outcomes

In two large population studies from Nordic countries, there was no association with antenatal SSRIs and stillbirths or neonatal deaths after adjusting for confounders ^[30][31]. In several systematic reviews and meta-analyses, antidepressant and SSRI or SNRI use during pregnancy were associated with preterm birth (<37 weeks) (19,32-35) and LBW (<2500 g) ^[33]. Second and third trimester exposure increased the risk for preterm birth ^[19]. The pooled mean difference in weeks was -0.45 (95% CI -0.64 to -0.25) and the mean difference for birth weight was -74g (95% CI -117 to -31) ^[34]. The authors of these meta-analyses cautioned against over-interpreting the clinical significance of such associations ^[34], due to heterogeneity of samples ^[33] and residual confounding ^[19]. By contrast, using a population-based national birth cohort, treatment with SSRIs during pregnancy was related to a lower risk for late preterm birth (OR 0.84, 95% CI 0.74 to 0.96), very preterm birth (OR 0.52, 95% CI 0.37 to 0.74), and caesarean section (OR 0.70, 95% CI 0.66 to 0.75) ^[36].

Poor neonatal adaptation syndrome (PNAS)

PNAS, also referred to as neonatal withdrawal syndrome and serotonin discontinuation syndrome, has been described in up to 30% of newborns exposed to maternal SSRI or SNRI use in utero, particularly during the third trimester ^[37]. Symptoms include poor muscle tone, tremors, jitteriness, irritability, seizures, feeding difficulties, sleep disturbances, hypoglycemia, and respiratory distress ^[37][38]. Although the mechanism of PNAS is not completely understood, symptoms may relate to either a withdrawal from maternal SSRI or SNRI exposure, or overstimulation from serotonin toxicity ^[37][38]. One systematic review and meta-analysis described an association between exposure to antidepressants and PNAS (OR 5.07, 95% CI 3.25 to 7.90; p<0.001), respiratory distress (OR 2.20, 95% CI 1.81 to 2.66; p<0.001), and tremors (OR 7.89, 95% CI 3.33 to 18.73; p<0.001) ^[37]. Similarly, a second comparable study reported a risk ratio (RR) of 3.0 (95% CI, 2.0 to 4.4) of late gestational SSRI exposure for PNAS ^[38].

Persistent pulmonary hypertension of the newborn (PPHN)

PPHN is the final common pathway for a variety of risk factors and insults (e.g., congenital malformations, premature birth, meconium aspiration syndrome, caesarean section) that can cause pulmonary underdevelopment, maldevelopment, or poor postnatal adaptation. In PPHN, vascular resistance in the newborn lung fails to decrease after birth, resulting in right-to-left shunting of blood though fetal channels, decreased pulmonary blood flow, and hypoxia. Infants can present with a wide range of breathing difficulties, from mild respiratory distress to severe respiratory failure requiring intubation and ventilation. In both large cohort studies ^[39][40] and one systematic review and meta-analysis ^[41], SSRIs taken late in pregnancy have been associated with increased risk for PPHN, although the absolute risk is low (Table 2). Studies differ by diagnostic criteria, definition, severity of PPHN, and controls for confounders. The biological mechanism for association with PPHN is believed to relate to higher circulating levels of serotonin in the fetus, causing vasoconstriction and smooth muscle proliferation in pulmonary vasculature ^[41].

Neurodevelopmental outcomes

Several studies have examined the association between prenatal exposure to SSRIs or SNRIs and autism spectrum disorders (ASD) in children ^{[35][42]-[44]}. Although there may be an association of increased risk ^[44], this relationship has not been found consistently ^[35][42][43] (Table 3). Weakness of association may be explained by confounding by indication for medication use. More recent studies have adjusted for confounding and used sibling and exposure-before-pregnancy comparisons. Genetic factors, familial environment, and maternal mental illness history could each contribute to ASD risk ^{[35][42]-[44]}. Similarly, in a population-based cohort study of first trimester antidepressant use, ADHD was diagnosed in 12.63% exposed versus 5.46% unexposed children by 15 years of age (International Classification of Diseases ^[ICD]-9 and ICD-10 coding), hazard ratio (HR) 2.21 (95% CI 2.01 to 2.39). This finding was more attenuated in the sibling-comparison analysis: HR 0.99 (95% CI 0.79 to 1.25) ^[35].

What monitoring is required in the neonatal period for infants exposed to an SSRI or SNRI in utero?

Review of the literature’s conflicting results for congenital malformation risk (and for cardiac malformation risk in particular) does not support recommending either routine fetal echocardiogram during pregnancy or routine echocardiogram of newborns exposed to SSRIs during the first trimester of pregnancy. Rather, all newborns being assessed for safe discharge ^[45][46], should have received routine pulse oximetry testing to detect critical congenital heart disease (CCHD) ^[47]. Focused and possibly repeated assessment is especially important for infants presenting with PPHN, where clinical examination remains the mainstay of detection.

For PNAS, symptoms usually begin within hours of delivery, resolve within days to 2 weeks post-birth, and are generally mild and self-limiting ^[37][38][48]. Some clinicians use a modified Finnegan score to assess severity of symptoms ^[37][48][49], although this tool has not been validated for this purpose, and no other standardized tool is available. Based on cohort studies and expert opinion, some study authors have recommended observing infants for 24 h to 48 h post-birth, preferably with their mothers ^[50][51]. Managing neonates with PNAS includes providing a quiet environment, swaddling, skin-to-skin care, and frequent small feeds ^[38]. Breastfeeding should be encouraged and supported ^[37][49]. Discontinuation or tapering of antidepressants near term is unwarranted ^[16][37]. In some rare cases (<1%), anticonvulsant treatment, fluid management, and respiratory support may be required ^[13][38]. Hypoglycemia (blood glucose <2.6 mmol/L) has been reported to be more common in infants with PNAS ^[48][52]. Infants of SSRI-treated mothers were more likely to require admission to a NICU ^[36][52]: 13.7% for exposed newborns versus 8.2% non-exposed newborns ^[52]. Long-term sequelae after PNAS have not been well studied ^[37].

Should mothers using an SSRI or SNRI breastfeed?

There is abundant evidence to support treating maternal depression during the postpartum period with SSRIs ^[2][53][54]. Women with perinatal depression ^[9] and exposure to SSRIs during pregnancy ^[55] are less likely to initiate and sustain breastfeeding. Most evidence regarding the safety of SSRI or SNRI use during breastfeeding has been drawn from case reports or case series, without a comparison population or controlling for confounders ^{[2][12][56][57]}. Data on possible effects of SSRI or SNRI exposures in breast milk on infant outcomes and development are also lacking ^{[2][12][56][57]}. Breastfeeding is not contraindicated during treatment with SSRI or SNRIs, however. The transfer of both medications into breast milk is known to be low, and uptake by the infant even lower ^[54][56][57]. Sertraline is favoured over other medications for nursing mothers, with fluoxetine being less preferred ^[54][56][57].

The many benefits of breastfeeding must be considered when decision-making around SSRI or SNRI use during pregnancy or postpartum. Most study authors recommend that when mothers have been treated for depression successfully during pregnancy, the same drug should be used in the postpartum period, because discontinuation or switching treatments at this vulnerable time could lead to relapse ^[54][56]. Monitoring infant feeding and growth, and watching for symptoms of possible toxicity (e.g., poor feeding and low weight gain), is also recommended ^[12][54].

Conclusions

Overall, maternal use of an SSRI or SNRI to treat depression during pregnancy is safe for, and well tolerated by the fetus, whereas untreated maternal depression or anxiety is associated with adverse outcomes for both mother and newborn. Most women who continue SSRI or SNRI treatment during pregnancy have healthy babies. There may be increased risk for PNAS, which is typically self-limiting and treatable by non-pharmacological means. Mothers should be encouraged and supported to breastfeed their infants during treatment with an SSRI or SNRI. The literature is inconsistent regarding the safety of in-utero exposure to SSRIs or SNRIs, including neonatal and neurodevelopmental risks. The interplay among medication-related factors, maternal depression, and genetic and social factors is confounding, while methodological constraints may further limit study results. Data from large prospective studies using adequate sample sizes and appropriate comparisons and adjustments for confounding are still required to establish the iatrogenic effects of SSRI or SNRI type, dosing, timing, and duration during pregnancy and beyond.

Recommendations for clinicians

• Although non-pharmacological treatments are considered first line, mothers and families must be supported when deciding to use an antidepressant medication during pregnancy or in the postpartum period. Untreated maternal depression or anxiety can adversely affect pregnancy, the newborn, child development, and family functioning.
• Women who use an SSRI or SNRI during pregnancy should be counselled that the overall risk for congenital malformations or persistent pulmonary hypertension is low.
• Women who use an SSRI or SNRI during pregnancy should be counselled that the infant may develop poor neonatal adaptation syndrome, though symptoms are usually mild and transient, and respond to a quiet environment, swaddling, skin-to-skin care, and frequent feeding, and typically resolve within days to 2 weeks post-birth.
• Women who use an SSRI or SNRI during pregnancy should be reassured that behavioural concerns such as autism spectrum disorder and attention-deficit hyperactivity disorder have not been convincingly associated with exposure to these medications in utero.
• No specific monitoring is recommended for newborns or children who were exposed to an SSRI or SNRI in utero or while breastfeeding. Routine discharge planning and later well child visits should be the same as for non-exposed healthy term and late preterm infants.
• The benefits of breastfeeding are well established and should be encouraged and supported for mothers using an SSRI or SNRI during pregnancy and in the postpartum period.

Acknowledgements

This position statement has been reviewed by the Community Paediatrics, Drug Therapy and Hazardous Substances, and Mental Health and Developmental Disabilities Committees of the Canadian Paediatric Society. It was also reviewed by members of the Society of Obstetricians and Gynaecologists of Canada (SOGC), Family Physician Advisory (FPA), Clinical Practice Obstetrics (CPO), and Maternal Fetal Medicine (MFM) committees.

CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE

Members: Nicole Anderson MD (Resident Member), Heidi Budden MD (Board Representative), Mireille Guillot MD (Resident member), Leonora Hendson MD, Thierry Lacaze-Masmonteil MD, PhD (past Chair), Brigitte Lemyre MD, Souvik Mitra MD, Michael R. Narvey MD (Chair), Vibhuti Shah MD
Liaisons: Radha Chari MD, The Society of Obstetricians and Gynaecologists of Canada; James Cummings MD, Committee on Fetus and Newborn, American Academy of Pediatrics; William Ehman MD, College of Family Physicians of Canada; Danica Hamilton RN, Canadian Association of Neonatal Nurses; Roxanne Laforge RN, Canadian Perinatal Programs Coalition; Chantal Nelson PhD, Public Health Agency of Canada; Eugene H. Ng MD, CPS Neonatal-Perinatal Medicine Section
Principal authors: Leonora Hendson MD, Vibhuti Shah MD, Sandra Trkulja

References

Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.