Risks associated with in utero and lactation exposure to selective serotonin reuptake inhibitors (SSRIs)

Reproductive Toxicology 30 (2010) 249–260

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Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox

Review

Risks associated with in utero and lactation exposure to selective serotonin reuptake inhibitors (SSRIs) Maria Ellfolk a , Heli Malm a,b,∗ a b

Teratology Information Service, Helsinki University Central Hospital and HUSLAB, Helsinki, Finland Department of Clinical Pharmacology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

a r t i c l e

i n f o

Article history: Received 2 March 2010 Received in revised form 9 April 2010 Accepted 26 April 2010 Available online 4 May 2010 Keywords: SSRI Pregnancy Malformation Perinatal Neonatal adaptation Neurodevelopment, Breastfeeding

a b s t r a c t Background: Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) may increase risk for congenital malformations and adverse perinatal outcome. Objective: This article reviews the published literature on exposure to SSRIs in utero and during lactation. Methods: Literature search in PubMed. Results: There is no conclusive evidence for increased risk for malformations but paroxetine and possibly fluoxetine use in early pregnancy may be associated with a small increased risk for cardiovascular malformations. Perinatal adverse effects, including respiratory distress and neonatal adaptation problems are common in exposed infants, and an increased risk for persistent pulmonary hypertension of the newborn (PPHN) has been observed. The suspected increased risk of preterm birth, low birth weight or small for gestational age has not been confirmed. It is not clear to what extent the adverse effects observed in some studies are attributable to the drug effect or related to mother’s underlying disease and other possible confounders. The SSRIs are usually compatible with breastfeeding, however, individual variations in infant exposure may occur. © 2010 Elsevier Inc. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spontaneous abortion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Sertraline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Escitalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perinatal complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Preterm birth, low birth weight and small for gestational age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Neonatal adaptation problems, low Apgar score and admission to neonatal special care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3. Persistent pulmonary hypertension of the newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Long-term neurodevelopment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Citalopram and escitalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Teratology Information Service, Helsinki University Central Hospital and HUSLAB, Helsinki, Finland. Tel.: +35 8947176589. E-mail address: Heli.Malm@hus.fi (H. Malm). 0890-6238/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2010.04.015

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7.3. Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Sertraline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The prevalence of depression in pregnancy is approximately 10%, and up to 20% of women experience depressive symptoms during pregnancy [1]. In the last decades, the consumption of the new antidepressants, including the selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine and escitalopram), has been steadily increasing to the extent that up to 6% are using these drugs during pregnancy [2]. Few drugs and their effect on pregnancy outcome have been as extensively investigated—yet, conflicting data on congenital malformations and adverse perinatal outcome have been published. Accordingly, no definite conclusion exists if the adverse effects observed in some studies are attributable to the drug effect or related to mother’s underlying disease and other possible confounders. To address these issues and including safety of SSRI use during lactation, we have searched the literature in PubMed using search terms ‘SSRI, fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram, pregnancy, fertility, malformation, birth defect, teratogen, perinatal, neonatal, neurodevelopment, lactation, human milk’. 2. Fertility Little is known about possible effects of SSRIs on fertility. Depression per se may be related to infertility [3]. Increased prolactin secretion and galactorrhea have been associated with SSRI use in case reports [4]. A tendency to lower pregnancy rate [5] and lower pregnancy and live birth rate [6] were observed in two studies investigating exposure to SSRIs and in vitro fertilization outcome, but the numbers were small and the results did not reach statistical significance. However, in the study by Friedman et al. a higher cycle cancellation rate was observed secondary to poor ovarian response in women using SSRIs compared to nonusers. The authors speculated that SSRI drugs may interfere with the hypothalamic–gonadal axis in subtle ways [6]. Sexual dysfunction in both men and women has been reported frequently, but it is not always possible to differentiate drug-induced adverse effects from those induced by the underlying disease. Studies in men have suggested that SSRIs may damage normal sperm DNA integrity and thereby adversely affect fertility [7,8]. Lower serum gonadotropin and testosterone levels have been reported in depressed men treated with SSRIs compared to healthy men [9] but it is not known if these changes are related to depression or the medication.

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competing events, have not been considered using cumulative incidence analysis, introduced by Meister and Schaefer [15]. The referred studies address only clinically recognized pregnancy losses (approximately one-third of all post-implantation losses) which may lead to under-ascertainment of the true incidence rate. Other methodological problems include the small number of included women. While these prospective studies have not been able to adequately assess the risk for spontaneous abortions, studies based on registers are mostly retrospective and include only pregnancies ending in delivery or delivery and elective termination and do not include data on spontaneous abortions (Table 1). 4. Malformations While in vivo animal studies have been limited by maternal toxicity in terms of reduced food intake characteristic to SSRIs, they have not suggested an increased teratogenic risk [16,17]. Contrary to in vivo studies, in vitro whole embryo culture (WEC) studies have demonstrated teratogenic potential for paroxetine, and suggestive teratogenic potential for fluoxetine and citalopram [18]. Serotonin (5-HT) regulates migration of neural crest cells and studies based on WEC have demonstrated alterations in craniofacial development [18,19]. Furthermore, regulation of 5-HT by serotonin transporter (5-HTT) has been demonstrated in cell culture to play a role in heart development [20], and fluoxetine has been demonstrated to adversely affect cardiomyocyte differentiation in embryonic stem cell system [21]. Perturbed neural crest cell migration could further affect cardiac morphogenesis [18]. The SSRIs pass through the placenta with cord/maternal plasma concentrations ranging from 0.3 to 0.9 [22,23]. These drugs share common pharmacological characteristics but assessing teratogenic risk may not be relevant on a drug group level. However, several studies have analysed the SSRIs as a group, primarily due to small numbers of individual SSRIs included in the study (Table 1). The vast majority of these studies have not demonstrated an increased risk for overall major malformations [13,24–30] (Table 1) or specific malformations [28,30,31] when analysing SSRI drugs as a group. Contrary to these, Oberlander et al. found a statistically increased risk for atrial septal defects (ASDs) after exposure to serotonin reuptake inhibitors (SRIs) [32]. In that study, SSRIs were not analysed separately from venlafaxine, and information on smoking and alcohol use was lacking. A prospective study from Israel observed an increased risk for cardiac malformations [33], and a population-based register study from Denmark reported a statistically significant association with SSRI use and septal heart defects [34] (Table 1).

3. Spontaneous abortion 4.1. Fluoxetine Spontaneous abortion is a sensitive indicator of embryotoxic effects, and several studies have analysed this outcome without observing an increased risk [10–14] (Table 1 ). However, the analyses in these prospective studies have only considered crude rates of pregnancy outcome, ignoring the effect of delayed entry and left truncation, which could significantly affect the reliability of results [15]. Crude rates would only be useful if all pregnancies were observed from the very beginning [15]. Furthermore, other outcomes, including births or induced abortions considered as

The results of studies investigating fluoxetine and malformations have been contradictory. Several studies have not identified an increased risk [10,12,25,27,28,34,35]. No association between fluoxetine exposure and pooled birth defects, including cardiac defects or specific cardiac defects was observed in two case–control studies with population-based setting [28,35]. Contrary to these studies, Chambers et al. found a statistically significant risk for 3 or more minor malformations in infants exposed to fluoxetine during

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Table 1 Studies of selective serotonin reuptake inhibitors (SSRIs) and risk for spontaneous abortion and congenital malformations. Reference

Study design, number of exposed, and control group definition

Results

Comments

Pastuszak et al. 1993 [10]

Prospective cohort study - Fluoxetine, n = 128/98 (LB) Matched controls exposed to tricyclics (TCA) or nonteratogens

No significantly increased risk of major malformations or SA

Strengths - Follow-up data derived from mothers corroborated by written documentation from child’s physician Limitations - Limited power due to small numbers

Chambers et al. 1996 [11]

Prospective cohort study - Fluoxetine, n = 228/164 (LB)

No significantly increased risk for major malformations or SA

Strengths - Outcome data derived from mother, medical records and infant’s physician

Controls exposed to nonteratogens

Increased risk of >3 minor malformations in exposed (15.5%) vs. non-exposed (6.5%); P = 0.03 No increased risk for major malformations or SA compared to historic controls

Goldstein et al. 1997 [12]

Prospective cohort study by manufacturer - Fluoxetine, n = 2072/686 (LB) No control group

Kulin et al. 1998 [13]

Prospective cohort study - SSRI, n = 267/222 (LB)

Limitations - High percentage of cases lost to follow-up due to uncertain identification - Reported outcome not confirmed - No concurrent control group

No significantly increased risk for major malformations or SA

Strengths - Follow-up data derived from mothers corroborated with medical records

No significantly increased risk of major malformations

Strengths - Medication use in early pregnancy recorded prospectively Limitations - Dosage and timing of drug exposure often poorly specified

Retrospective cohort study (population-based register data) - SSRI, n = 1782/1398 exposed in first trimester Controls: pregnant women with no drug reimbursement

No significantly increased risk of major malformations for SSRIs or any individual SSRIs

Strengths - Data on pregnancy terminations due to malformation included

Prospective cohort study - Citalopram n = 132/114 (LB)

No increased risk for major malformations or SA

Strengths - Follow-up data derived from mothers corroborated with medical records

Significantly increased risk of major malformations; aRR 1.84 (95% CI 1.25–2.71)

Strengths - Attempt to focus on the most vulnerable period of development Limitations - No data on actual drug use.

Anencephaly (aOR 2.4; 95% CI 1.1–5.1), craniosynostosis (aOR 2.5; 95% CI 1.5–4.0) and omphalocele (aOR 2.8; 95% CI 1.3–5.7) associated with first trimester exposure to SSRIs A tendency for an increased risk for right ventricular outflow tract obstruction defects after paroxetine use; aOR 2.5 (95% CI 1.0–9.6) No significant association between SSRI exposure and overall congenital heart defects

Strengths - Population-based, large birth sample allowing the evaluation of several specific birth defects

A significantly increased risk for cardiac malformations; sOR 1.72 (95% CI 1.22–2.42) SSRI use during pregnancy associated with increased utilization of ultrasound and postnatal echocardiogram

Strengths - Large number of exposed

Controls exposed to nonteratogens Ericson et al. 1999 [24]

Prospective cohort study (population-based register data) - SSRI, n = 531 Controls: population birth cohort

Malm et al. 2005 [25]

Sivojelezova et al. 2005 [14]

Limitations - No data on actual drug use

Controls: one disease-matched control group and one exposed to nonteratogens Wogelius et al. 2006 [122]

Retrospective cohort study (population-based register data) - SSRI n = 1051/453 exposed during organogenesis Controls: pregnant women with no SSRI redemption

Alwan et al. 2007 [35]

Bar-Oz et al. 2007 [40]

Population-based case–control study - Cases: malformed infants n = 9622 - Controls: non-malformed cohort

1. Meta-analysis on studies of first trimester exposure to paroxetine, n = approximately 2600 (LB) 2. Rate of pre- and postnatal diagnostics evaluated from healthcare registers

Limitations - Mothers interviewed up to 2 years after the estimated date of delivery predisposing to recall bias - Case mothers interviewed more often than controls >1 year after the estimated date of delivery

Limitations - Possible heterogeneity in the studies included in the analysis

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Table 1 ( Continued ) Reference

Study design, number of exposed, and control group definition

Results

Comments

Bérard et al. 2007 [123]

Nested case–control study within a pregnant population using antidepressants

Paroxetine >25 mg/day during first trimester associated with major malformations; aOR 2.23 (95% CI 1.19–4.17) A tendency for an increased risk for cardiac malformations in dose–response analysis based on few cases (n = 5) Significantly increased risk for major malformations after first trimester exposure to paroxetine; aOR 1.89 (95% CI 1.20–2.98). No significantly increased risk of cardiovascular malformations

Limitations - Results not adjusted for smoking or alcohol use - No data on actual drug use

Paroxetine associated with an increased risk of congenital eye anomalies (RR 2.36; 95% CI 1.20–4.66) but not cardiovascular malformations

Strengths - Follow up until 1 years’ age

Cole et al. 2007 [37]

Davis et al. 2007 [26]

Cases: all infants with major malformation or cardiac malformation Controls: infants with no malformations Retrospective cohort study - Paroxetine n = 815 Controls: pregnant women exposed to other antidepressant

Retrospective cohort study - SSRI, n = 805 (paroxetine, n = 182)

Controls: unexposed to other antidepressants Källén and Otterblad- Olausson, 2007 [27]

Prospective cohort study (population-based register data) - SSRI, n = 6481 (paroxetine, n = 908) Controls: population birth cohort

Louik et al. 2007 [28]

Retrospective case control study Cases: 9849 malformed infants

Controls: nonmalformed infants

Diav-Citrin et al. 2008 [36]

Prospective cohort study - Paroxetine, n = 463 - Fluoxetine, n = 346 - Controls: exposed to nonteratogens

Strengths - Malformations confirmed from medical records Limitations - Sampling scheme originally developed for bupropion study

Limitations - Limited assessment of outcomes No increased risk for overall major malformations after exposure to SSRIs or any individual SSRI Paroxetine use linked to increased risk for all cardiovascular malformations; aOR 2.93 (95% CI 1.52–5.13) and VSD/ASD; aOR 3.23 (95% CI 1.30–6.65) Sertraline use associated with an increased risk of omphalocele; aOR 5.7 (95% CI 1.6–20.7) and cardiac septal defects; aOR 2.0 (95% CI 1.2–4.0) Paroxetine use associated with an increased risk of right ventricular outflow tract obstruction defects; aOR 3.3 (95% CI 1.3–8.8)

Strengths - Prospectively collected exposure data

Rate of cardiovascular malformations significantly higher in the fluoxetine exposed cohort; aOR 4.47 (95% CI 1.31–5.27). Rate also increased if mother smoked >10 cigarettes/day Risk for cardiovascular malformations not increased following paroxetine exposure

Strengths - Exposure data well recorded - Prenatally diagnosed anomalies resulting in ETOP included in analysis

Type of cardiovascular malformations reported varied Paroxetine use not associated with increased risk of cardiovascular birth defects

Limitations - Dosage and timing of drug exposure often poorly specified Strengths - Large size of database

Limitations - Limited numbers of specific birth defects for analysis - Mothers interviewed within 6 months of delivery, predisposing to recall bias

Limitations - Possible heterogeneity of study material and definition of outcome variables due to multicentre study design

Einarson et al. 2008 [42]

1. Analysis of prospective cohort studies - Paroxetine, n = 1174 2. Analysis of database studies - Paroxetine, n = 2061

Oberlander et al. 2008 [32]

Retrospective population based cohort study - SRI, n = 2625 (LB) Controls: no exposure to SRI or depression

SRI monotherapy associated with an increased incidence of ASD but not with overall congenital anomalies SRI in combination with benzodiazepines associated with congenital heart defects

Strengths - Adjustment for maternal illness characteristics Limitations - Diagnosis of malformations from administrative registers and not verified - No information about smoking and alcohol use

Bakker et al. 2009 [39]

Retrospective case–control study Cases: infants with isolated heart defect, n = 678 Controls: infants with genetic disorder and no heart defect, n = 615

No statistically significant increase in overall cardiac malformations after first trimester paroxetine use Significantly increased risk for isolated ASD; aOR 5.7 (95% CI 1.4–23.7)

Strengths - Mother interviewed to verify drug use obtained from pharmacy records Limitations - Adjustment to confounders limited due to small numbers

Strengths - Large number of exposed pregnancies included in the study Limitations - Heterogeneity of study material due to combining data from several countries

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Table 1 ( Continued ) Reference

Study design, number of exposed, and control group definition

Results

Comments

Einarson et al. 2009 [29]

Prospective controlled cohort - Exposed to antidepressant n = 928

Malformation risk not increased after exposure to antidepressants as a group or individual antidepressant Study able to rule out two-fold increase in cardiovascular defects after paroxetine exposure

Strengths - Detailed history of exposures and relevant other confounders - Outcome data from mothers’ interviews corroborated with infant’s physician Limitations - Each antidepressant not analysed separately due to small numbers

Matched control group exposed to nonteratogens

Merlob et al. 2009 [33]

Prospective cohort study - SSRI n = 235 Nonexposed control

Risk for cardiac malformations higher in SSRI-exposed vs. non-exposed (3.4% vs. 1.6%); RR 2.17 (95% CI 1.07–4.39)

Strengths - All newborns with persistent heart murmur examined by a pediatric cardiologist - Prospective ascertainment of exposure

Pedersen et al. 2009 [34]

Population based cohort study (national registers) - SSRI, n = 1370 (paroxetine, n = 299)

Redemption of SSRIs not associated with major malformations overall, but association observed for septal heart defects; aOR 1.99 (95% CI 1.13–3.53) Sertraline and citalopram use associated with septal heart defects; aOR 3.25 (95% CI 1.21–8.75) and aOR 2.52 (95% CI 1.04–6.10)

Strengths - Minimizing non-compliance by considering >2 redemptions as proxy of exposure Limitations - Potential confounding by indication

No increased risk for cardiac malformations in SSRI exposed infants (0.4%) vs. controls (0.8%) No cases of VSD in paroxetine-exposed pregnancies

Strengths - Single centre study with prospectively maintained database Limitations - No data on actual drug use or timing - No data on alcohol or tobacco - Outcome data restricted to immediate postnatal period

First trimester paroxetine exposure associated with an increased risk of overall major malformations; pOR 1.24 (95% CI 1.08–1.43) and cardiac malformations; pOR 1.46 (95% CI 1.17–1.82) Use of SSRI not associated with a statistically significant increase in relatively severe malformations, cardiovascular malformations or VSD/ASD Association with paroxetine exposure and cardiovascular malformations supported; aOR 1.66 (95% CI 1.09–2.53)

Limitations Analysis subject to same limitations inherent in the included epidemiologic studies

Controls: unexposed birth cohort

Wichman et al. 2009 [31]

Retrospective cohort study - SSRI, n = 808 (paroxetine, n = 119) Controls: all infants in the birth cohort not exposed to SSRIs

Wurst et al. 2009 [41]

Meta-analysis by manufacturer of studies with first trimester paroxetine exposure with control or comparator group

Reis and Källén, 2010 [30]

Prospective cohort study (population-based register data) - Antidepressant (including SSRI), n = 14 821 Controls: population birth cohort

Strengths - Exposure data collected prospectively

Limitations - Information on dose and exact timing of exposure often lacking

LB: live birth, SA: spontaneous abortion, SSRI: selective serotonin reuptake inhibitor, aRR: adjusted relative risk, 95% CI: 95% confidence interval, aOR: adjusted odds ratio, sOR: summary odds ratio, RR: relative risk, VSD: ventricular septal defect, ASD: atrial septal defect, ETOP: elective termination of pregnancy, SRI: serotonin reuptake inhibitor, pOR: prevalence odds ratio.

early pregnancy, suggestive of possible drug effect on embryonic development [11]. No increased risk of cardiac or non-cardiac malformations was observed in a cohort of 348 infants born to women who had redeemed fluoxetine prescriptions during early pregnancy [34]. A prospective cohort study from Sweden, based on national register data and including more than 900 fluoxetine-exposed pregnancies found no increased risk for major malformations compared to the population birth cohort [27]. However, a further analysis of this database, including >1550 infants exposed to fluoxetine found a marginally increased risk for relatively severe malformations (aOR 1.29; 95% CI 1.00–1.67) but no significant risk for cardiovascular defects [30]. A retrospective study from Finland, also based on national registers, did not find a statistically increased risk of overall major malformations in offspring born to women who had purchased fluoxetine during the first trimester, but among the 525 exposed infants 12 had isolated heart defects (eight of them ventricular deptal defects, VSDs), the prevalence reported to be nearly three-fold to the national prevalence of car-

diovascular malformations [25]. A significantly increased risk for major malformations overall (4.7% vs. 2.5% in controls; P < 0.05) and for cardiovascular malformations (2.8% vs. 0.6%; P < 0.05) was observed after exposure to fluoxetine in a prospective cohort study from Teratology Information Services [36] (Table 1). The risk for overall malformations was largely explained by the increase in cardiovascular malformations, which remained statistically significant after adjusting for confounders (Table 1). Of the nine cardiovascular malformations in that study, two were spontaneously closing VSDs. In addition to fluoxetine exposure, cigarette smoking (>10 cigarettes/day) was an independent risk factor for cardiovascular malformations [36]. 4.2. Citalopram The majority of studies have not identified an increased risk for malformations associated with citalopram. The Swedish data, based on national registers and including nearly 4000 exposed

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infants, did not observe an increased risk for relatively severe malformations or cardiovascular defects [30]. Similar findings have been reported from other register-based studies, case–control studies, and prospective cohort studies [14,25,28]. In a prospective cohort study, eight of 184 infants exposed to citalopram in utero were diagnosed with major malformation but the malformations varied and there was no pattern of defects [29]. Contrary to these findings, an association between citalopram use and pooled birth defects (anencephaly, craniosynostosis and omphalocele) was observed in a case–control study, based on six cases [35]. In a register-based cohort study including 460 infants, citalopram use was associated with septal hear defects (five cases) [34] (Table 1).

study by Louik et al. who reported a significantly increased risk for omphalocele and cardiac septal defects (Table 1) and also for anal atresia (aOR 4.4; 95% CI 1.2–16.4) and limb reduction defects (aOR 3.9; 95% CI 1.1–13.5) [28]. However, these findings were based on a very limited number of cases. Increased risk of cardiac septal defects was also observed in a Danish cohort study with 259 infants exposed to sertraline, with four having been diagnosed VSD [34] (Table 1). Another retrospective case–control study reported no increased risk for cardiac malformations, and a marginally increased risk but not reaching statistical significance with sertraline and pooled birth defects including anencephaly, craniosynostosis and omphalocele (aOR 2.0; 95% CI 1.0–3.9) [35].

4.3. Paroxetine

4.5. Fluvoxamine

The first signals of possible association between paroxetine and cardiovascular malformations were based on the manufacturer’s data, primarily developed to collect data on another antidepressant and, when published later, found an association between paroxetine use and overall major malformations but not a significantly increased risk of cardiovascular malformations in 815 infants when compared to those exposed to other antidepressants [37]. An increased risk of cardiovascular malformations was observed in a prospective cohort study, presented in an abstract [38]; however, when later published, a statistically increased risk was no longer observed (aOR 2.66; 95% CI 0.80–8.90) [36] (Table 1). Two case–control studies found an increased risk for right ventricular outflow defects [28,35], and one study found an increased risk for ASD but not for overall cardiac malformations [39]. In the latter study, the results were based on three exposed cases, reflected in wide confidence intervals (Table 1). An association between paroxetine and cardiovascular malformations was supported in a study based on national registers and prospectively collected exposure data, and including 1208 exposed infants [30] (Table 1). Similar results were obtained when women using potentially harmful drugs or drugs for chronic diseases known to affect pregnancy outcome were excluded from the analysis. When the subgroups of VSD and ASD were analysed separately from overall cardiovascular malformations, no statistically significant risk was longer observed (RR 1.61; 95% CI 0.83–2.82) [30]. Two meta-analyses have been performed regarding paroxetine teratogenicity: both found an increased risk for cardiac malformations [40,41] and in the latter, an association with overall major malformations was also observed [41] (Table 1). In health care register data analysis in the Bar-Oz et al. study, SSRI use during pregnancy was associated with significantly increased utilization of pre- and postnatal diagnostics. Furthermore, paroxetine was used more often for anxiety disorders than other SSRIs [40]. Both these factors may contribute as confounders. Contrary to the previously described studies, no increased risk for major malformations, cardiac malformations or septal heart defects were observed in a cohort study with 299 exposed infants [34]. A study based partly on previously published prospective cohort studies including more than 1000 exposed infants, and also on register studies including >2000 exposed infants, found no increase in cardiovascular malformations [42]. An additional prospective cohort study with exposed cases probably overlapping with the previous study found no increase in overall malformation risk or cardiovascular malformations in 148 paroxetine-exposed infants [29].

Data on fluvoxamine are much less abundant. So far no study has suggested an increased risk but the numbers have often been too small for analysis. Kulin et al. reported 26 first trimester exposures but these were analysed within the SSRI group and not separately [13] (Table 1). Another prospective cohort study reported 52 exposed infants with two malformations [29]. In a Swedish register-based study including >15 000 infants exposed to antidepressants, only 42 were exposed to fluvoxamine [30]. A comparable register-based study from Finland identified 65 infants born to mothers who had purchased fluoxetine in the first trimester with no suggestion of increased risk for major malformations (aOR 1.0; 95% CI 0.1–7.8) [25].

4.4. Sertraline No increased risk for relatively severe malformations or cardiovascular defects was observed in the Swedish register-based study with >3200 infants exposed to sertraline in early pregnancy [30]. Contradictory results were obtained in a retrospective case–control

4.6. Escitalopram There are no studies assessing the risk of malformations after in utero exposure to escitalopram. However, escitalopram is the S(+)enantiomer of the racemic citalopram, and is therefore probably comparable with citalopram. 5. Perinatal complications 5.1.1. Preterm birth, low birth weight and small for gestational age Several studies have observed an increased risk for preterm birth in SSRI-exposed pregnancies [11,26,30,43–48], whereas others have not [13,24,25,49–51]. Similarly, an increased risk for low birth weight (LBW) [44,46] or small for gestational age (SGA) [50,51] has been observed in some studies, while most studies, including a continuing data collection in the Swedish registers [30] have not suggested an increased risk in either one of these outcomes [24,25,47,49]. Only a few studies have tried to control for confounding by indication either by comparing continuous SSRI use and use only during the first or second trimester [11,25,51], by considering previous history of psychiatric illness [47] or, more specifically, by assessing maternal illness severity [50,52]. Even when controlling for maternal illness the results have been conflicting (Table 2). Two studies based on relatively large numbers did not find an increased risk for preterm birth [25,50], whereas in the latter study, SGA remained more common in the SSRI exposed infants even after adjusting for maternal illness severity [50]. Wisner et al. [48] observed an increased risk of preterm birth in pregnancies with continuous use of SSRIs and also in those with continuous depression and no SSRI exposure but the study did not assess maternal illness severity (Table 2). Depression itself is known to affect pregnancy outcome and increase the risk of pregnancy complications, including fetal growth restriction and preterm delivery [53,54]. Women using SSRIs only during the first trimester or not using them at all but having been diagnosed with depression probably suffer from less severe depression than those who continue to use

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Table 2 Studies reporting perinatal outcome in pregnancies exposed to selective serotonin reuptake inhibitors (SSRIs) and adjusting for underlying maternal illness. Reference

Study design

Results

Comments

Malm et al. 2005 [25]

Retrospective cohort study (population-based register data) SSRI drug purchase in each trimester or during the second and third trimesters (n = 360) vs. only in first trimester (n = 1010)

- No increased risk of preterm birth, LBW or SGA - Increased rate of admission to neonatal care unit (15.7% vs. 11.2%); aOR 1.6 (95% CI 1.1–2.2)

Limitations - No data on other drugs or alcohol use - Failure to compensate for multiple comparisons - Possible residual confounding by severity of underlying depression

Oberlander et al. 2006 [50]

Retrospective, population-based cohort study

Exposed to SSRIs vs. exposed to maternal depression only

Infants born to women with depression and exposed to SSRIs (n = 1451)

- No difference in preterm birth incidence - SGA and respiratory distress more common in SSRI exposed infants

Strengths - Maternal illness severity accounted for by propensity score matching Limitations - No information about length and timing of SSRI exposure

Maternal depression significantly associated with preterm birth, lower birth weight and SGA when compared to non-exposure control cohort Exposure in late gestation vs. early gestation associated with statistically significant reduction in birth weight (P < 0.04) No significantly increased risk of SGA or respiratory distress after accounting for illness severity

Strengths - Maternal illness severity accounted for propensity score matching Limitations - No data on other drugs or tobacco or alcohol use

Controls (1) Infants born to women with depression but no SSRI exposure (n = 14 234) (2) Infants born to women with neither depression nor SSRI exposure (n = 92 192) Oberlander et al. 2008 [32]

Retrospective, population-based cohort study Infants born to women exposed to SRIs (including venlafaxine) in early gestation (n = 1575) or late gestation (n = 1925)

Lund et al. 2009 [47]

Population-based, prospective cohort study Exposed to any SSRI, n = 329 Controls (1) No exposure to SSRIs and no history of psychiatric illness (nonexposed) (n = 51 770) (2) No exposure to SSRIs but previous history of psychiatric illness, n = 4902

Toh et al. 2009 [51]

Retrospective cohort study

(1) Exposed to SSRIs at any time during 2 months before conception through delivery, n = 192 - Continuing use of SSRIs after the first trimester, n = 86 (2) Exposed to non-SSRI antidepressants at any time during 2 months before conception through delivery (n = 59) Non-exposed control cohort, n = 5719 Wisner et al. 2009 [48]

Prospective, observational study Exposed to SSRIs (n = 71)

- Exposed in each trimester, n = 48 Pregnant women with major depression but no SSRI exposure (n = 36)

- Presence of major depression in each trimester, n = 14 Non-exposed, non-depressed control group (n = 131)

Length, rather than timing of exposure associated with increased risk of neonatal adverse outcome. Exposed to SSRIs vs. no exposure to SSRIs and no psychiatric illness - Increased risk of preterm delivery (8.8% vs. 4.9%); aOR 2.02 (95% CI 1.29–3.16) - Increased risk of 5-min Apgar score <8 (4.9% vs. 1.2%); aOR 4.44 (95% CI 2.58–7.63)

- Increased risk of admission to NICU (16.4% vs. 7.4%); aOR 2.39 (95% CI 1.69–3.39) No increased risk of LBW in full-term infants Similar results when compared to women with previous history of psychiatric illness No increased risk of preterm delivery in either SSRI exposure group

Limitations - No information about duration or timing (trimester) of drug exposure - Possible residual confounding by severity of underlying depression

Limitations - No information on maternal illness severity

No increased risk of SGA in those discontinuing use before the end of 1st trimester Increased risk of SGA in continuous SSRI-users (17.4% vs. 7.1%); aOR 3.01 (95% CI 1.65–5.47) Increased risk of preterm delivery in non-SSRI users; aOR 2.23 (95% CI 1.02–4.88)

Increased risk of preterm birth in pregnancies with continuous use of SSRIs (21% vs. 6%; adjusted rate ratio 5.43 (95% CI 1.98–14.84), and in continuous depression group (21%; not statistically significant) Infants exposed in utero to continuous SSRIs or continuous depression more likely to be admitted to NICU (19% and 21%) than infants in other groups (5–8%), and more likely to have 5-min Apgar score <7 (9% and 8%) than non-exposed, non-depressed controls (1%) No significant differences across exposure groups in SGA prevalence

Strengths - Intention to differentiate between the effects of major depression and SSRI use Limitations - Failure to compensate for multiple comparisons - Analyses based on small numbers and in most comparisons reaching no statistical significance

Preterm birth, delivery <37 gestational weeks. LBW, low birth weight; SGA, small for gestational age; aOR, adjusted Odds Ratio; CI, Confidence Interval; NICU, Neonatal Intensive Care Unit.

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medication throughout pregnancy, therefore, confounding by indication remains a source of bias in most studies. Discordant results regarding preterm birth obtained in two large register-based studies from Sweden and Finland raise some confusion [25,30] (Table 1). In the Swedish study, offspring exposed to SSRIs were compared to offspring of the whole pregnant population, and the results demonstrated an increased risk for preterm birth in nearly 5000 infants exposed in the second or third trimester (aOR 1.46; 95% CI 1.13–1.63) but no increased risk for LBW or SGA. Similar results were obtained among women using SRIs or tricyclic antidepressants, suggesting that the underlying illness may partially explain the results [30]. 5.1.2. Neonatal adaptation problems, low Apgar score and admission to neonatal special care Neonatal adaptation problems and need for treatment in neonatal special care unit are common in infants exposed to SSRIs during the latter half of pregnancy or the third trimester. This has been demonstrated in several studies and reports [11,25,26,43–45,55,56]. The risk for low Apgar scores has been reported to be 2–8 times higher than in non-exposed infants [44,47,48]. A meta-analysis based on published prospective cohort studies found an increased risk for poor neonatal adaptation (OR 4.04; 95% CI 1.20–19.93) and for admission to special care nursery or neonatal intensive care unit (OR 3.30; 95% CI 1.45–7.54) [57]. Again, it is not known to what extent the mother’s underlying illness may affect the neonatal outcome but low Apgar scores have also been reported in offspring of depressed women with no medication [48] (Table 2). It has been suggested that discontinuing drug treatment some weeks before delivery could lower the risk for neonatal adaptation problems, however, a recent study demonstrated that stopping drug treatment 2 weeks before delivery did not improve neonatal outcome when maternal illness severity was considered [58]. A recent, well-conducted, prospective cohort study included 60 infants with prolonged exposure to SSRIs in utero and 60 non-exposed controls [56]. Only women with no other potentially harmful exposures were included in the study. Of the neonates exposed to SSRIs in that study, eight demonstrated severe and 10 demonstrated mild symptoms of neonatal abstinence syndrome compared to none in the control group. It is not quite clear if the neonatal symptoms present drug withdrawal or drug toxicity. At least some of the neonatal problems have been attributed to high drug concentrations in the newborn [59] and high serotonergic activity, possibly modified by genetic polymorphisms in the CYP450 enzymes or enzymes involved in catecholamine metabolism and serotonin transporter activity [60–63]. One recent case report described a neonate exposed to paroxetine in utero, with severe symptoms including tremor and rigidity, who was genotyped to be a poor metaboliser of CYP2D6, the enzyme responsible for paroxetine metabolism [61]. 5.1.3. Persistent pulmonary hypertension of the newborn Persistent pulmonary hypertension of the newborn (PPHN) is characterized by failure of the normal circulatory changes that occur after birth. Elevated pulmonary vascular resistance causes venous blood to divert partly through fetal channels (ductus arteriosus and foramen ovale) into the systemic circulation, thereby bypassing the lungs and resulting in inadequate pulmonary perfusion and consequent respiratory distress and hypoxemia. PPHN is a rare, but life-threatening condition with a prevalence of 1–2/1000 births and a mortality rate of approximately 10% [64]. It occurs most often in full-term or post-term babies with conditions such as meconium aspiration or birth asphyxia. Caesarean delivery, diabetes and asthma have been associated with an increased risk for

PPHN [65]. Recently, also exposure to SSRI drugs in utero has been associated with increased risk for PPHN. The first report came from Chambers et al. who reported two infants with PPHN diagnosis in 73 infants exposed to SSRIs during the third trimester compared to none in controls [11]. Thereafter, an increased risk for PPHN has been observed in three further studies. Chambers et al. observed an association between exposure to SSRIs during the latter half of pregnancy and PPHN in a retrospective case–control study with 377 case infants (aOR 6.1; 95% CI 2.2–16.8). The authors speculated that the vasoconstrictive activity of serotonin and the inhibitory effect of SSRIs on nitric oxide synthesis could serve as the biological underlying mechanism [66]. Källén and Olausson found an adjusted risk ratio of 3.57 (95% CI 1.2–8.3) for PPHN with prolonged exposure to SSRIs [67]. These results were further confirmed in a more recent study based on accumulating data on the same registers, consisting of over 1 million births and 572 infants with PPHN diagnosis, with an aOR of 3.44 (95% CI 1.49–6.79) for prolonged exposure to SSRIs in utero [30]. Contrary to these findings, the prevalence of PPHN was not increased in 933 full-term infants exposed to SSRIs during the third trimester in a retrospective cohort study [68], nor were there any infants with PPHN diagnosis in a cohort of more than 800 exposed infants included in a retrospective cohort study based on medical records [31]. It has been postulated that PPHN could be a rare expression of the association between maternal use of SSRI and the well-established respiratory problems in the newborn [67]. Preliminary studies have suggested that polymorphisms in the promoter alleles of the serotonin transporter-gene [52] and in enzymes involved in catecholamine metabolism [63] may predispose to neonatal adverse effects, including respiratory distress. 6. Long-term neurodevelopment Major concerns of prenatal exposure to SSRI drugs include neonatal neurologic symptoms and possible adverse effects on the developing central nervous system. No conclusive clinical evidence of increased risk of adverse long-term effects exists at present. Two studies assessing neurodevelopment in pre-school and schoolage children and with partially overlapping study subjects did not find significant differences in global intelligence quotient (IQ) or language or behavioral development compared with non-exposed controls, or with children exposed to tricyclic antidepressants [69,70]. Furthermore, normal neurodevelopment was observed in a 1-year follow-up of 11 infants exposed to citalopram during pregnancy in a prospective, controlled study [71]. Longer term outcome was not, however, assessed. Prenatal SSRI exposure alters hypothalamic–pituitary–adrenal axis stress response patterns and reduces basal cortisol levels in cord blood [72]. Altered response to pain stimulus up to 2 month’s age has also been observed [73]. While the severe serotonergic or withdrawal symptoms in the neonate may contribute to adverse neurodevelopmental outcomes, serotonin itself is known to have a crucial role in neural development and maturation [74,75]. Experimental studies in mice have suggested that interference with serotonin reuptake during fetal life and exposure to SSRI drugs during the early postnatal period may result in permanent neurobehavioral changes [76,77]. Experimental data also suggest that the role of serotonin in the developing brain may differ from that in the adult brain and that the critical time window for these effects in human development may be the latter half of pregnancy [76]. These findings suggest that exposure to SSRI’s during pregnancy may be associated with neuropsychiatric outcomes that emerge following childhood [78,79]. 7. Breastfeeding Experimental studies have suggested that pharmacological inhibition of serotonin reuptake may alter mammary epithelial

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function and consequently affect milk production by delaying secretory activation [80]. An observational study by the same authors and in clinical setting suggested that initial milk secretion may be delayed in mothers using SSRI drugs but the study included only eight mothers on SSRI therapy [80]. As there are no other clinical studies supporting these findings, no definitive conclusions of the clinical relevance of these results can currently be made. All SSRIs are excreted in breast milk but most studies suggest that the amount ingested is generally low although individual variations may exist.

range as for citalopram even if the lower binding to plasma proteins could imply higher penetration of escitalopram to milk. None of these studies, including an observational study with 30 infants have revealed citalopram-associated adverse effects in breast-fed infants [101]. There is one case report reporting necrotizing enterocolitis in a 5-day-old breast-fed infant whose mother was using escitalopram during the entire pregnancy and continuing the medication after delivery [102]. However, based on the previous data indicating low exposure via mother’s milk, causality between drug ingestion via milk and the infant’s symptoms is highly unlikely.

7.1. Fluoxetine

7.3. Paroxetine

Fluoxetine and the active metabolite norfluoxetine are excreted in milk with a milk–plasma ratio close to 1 [81–85] or somewhat higher [86–88]. As the milk–plasma ratio does not directly predict infant exposure or correlate to risk for adverse effects, several studies have assessed the weight-adjusted relative infant dose (RID, indicating the percent of the weight adjusted maternal dose ingested by the infant), or directly analysed drug concentration in infant plasma. The RID for fluoxetine has in most studies been reported to be below or close to 10%, generally considered as the upper limit for relative safety [81–83,85,88]. Low or undetectable plasma concentrations of fluoxetine and norfluoxetine have been observed in some studies [82,84] whereas in some cases the concentrations have been relatively high or even at the level of therapeutic drug concentrations [83,86,89]. It is important to realize that in some cases the measurable drug concentrations in an infant may reflect placental transfer of the drug rather than drug exposure via milk, therefore timing of blood sampling is important to consider when interpreting study results [83–85]. The half life of fluoxetine is 4–6 days and for norfluoxetine up to several weeks, therefore it is possible that accumulation may occur in continuous exposure. Drug clearance is limited in neonates due to immature drug metabolism and decreased renal clearance and may predispose to adverse effects. Only a few reports have suggested adverse effects in infants exposed to fluoxetine via mother’s milk [89–91]. In one of these reports, therapeutic fluoxetine and norfluoxetine drug concentrations were measured in a 10-week-old infant with severe colic symptoms suggesting causality [89]. Furthermore, in a study measuring decrease in platelet 5-HT levels as an index of neuronal 5-HT transport blockade, and including eleven infants exposed to fluoxetine in utero and during breastfeeding, one exclusively breast-fed infant had a significant reduction in platelet 5-HT levels together with a measurable plasma fluoxetine concentration at the age of 6 weeks, raising some concern about possible pharmacological effects associated with drug exposure via mother’s milk [92]. However, due to the long half life of norfluoxetine this may still have reflected in utero drug exposure, and no decrease in platelet 5-HT levels or measurable fluoxetine concentrations was observed in any other infant in that study. Overall, the majority of studies including more than 70 infants have not observed clinical symptoms related to fluoxetine exposure via mother’s milk [91,93].

Paroxetine is excreted in milk in small amounts. Milk–plasma ratios below 1 or close to 1 have been reported in several studies and the weight-adjusted RID has been calculated as 1–3% [84,103–107]. Undetectable or low plasma paroxetine concentrations were observed in four studies including more than 50 infants [84,104,105,107] and no adverse effects have been reported.

7.2. Citalopram and escitalopram Citalopram is excreted in milk, with a milk–plasma ratio of 2–3 and the weight adjusted RID has been reported to vary between <1% and 9% [94–97,71,98]. Drug concentration in infant serum has been low or undetectable in several studies including nearly 30 breastfed infants [84,94,96,71,98]. Contrary to these findings, a higher concentration corresponding to >10% of maternal drug serum concentration was reported in a 5-week-old breast-fed infant [97]. According to one case report [99] and a study including eight breastfeeding women [100], infant exposure to escitalopram, the biologically active S-enantiomer of citalopram, was in the same

7.4. Sertraline Sertraline is excreted in milk with a milk–plasma ratio ranging from 1 to 4 and a weigh-adjusted relative infant dose of 2% has been calculated [84,91,108,109]. Drug concentrations in more than 20 infants have been low or undetectable [84,108–111]. Furthermore, no decrease in platelet serotonin levels was observed in 14 breastfed infants, confirming minimal exposure [112]. 7.5. Fluvoxamine Similarly to paroxetine, fluvoxamine concentrations in milk are typically equal or less than in maternal plasma [93,113,114]. However, these data are based on single case reports and case series, including overall less than 10 infants. The weight-adjusted RID has been estimated as 1–2%. Based on data of four infants, plasma levels have been undetectable [115,116]. By contrast, one case report described an 11 weeks old infant with fluvoxamine concentration nearly 50% of that of the mother but no adverse effects were reported [117]. 8. Discussion To summarize, no conclusive evidence exists of an increased overall risk for major malformations associated with SSRI use. Of the individual SSRIs, fluoxetine and paroxetine have provided quite conflicting results. Paroxetine – and possibly fluoxetine – use is obviously associated with a small increase in cardiovascular defects [30] and paroxetine possibly specifically with right outflow tract defects [28,35]. However, the indications for paroxetine use differ significantly from other SSRIs, paroxetine being used more often for anxiety-related disorders, and efforts to control for maternal illness or illness severity are challenging. No studies have considered the possible confounding created by the situation where the drug is used to relieve anxiety caused by a previous birth of an affected infant. Paroxetine has been reported to cause more severe neonatal adaptation problems than other SSRIs [55,56]. This could lead to more extensive examination of the newborns and consequently, to increased diagnosis of congenital heart defects. Women using antidepressants use also other psychotropic drugs, especially sedatives and hypnotics, but also neuroleptics and anticonvulsants [30]. Smoking is also significantly more common among pregnant women who use antidepressants [25,30]. While data on smoking have been considered in most studies, few studies have addressed the issue of using additional drugs. In the study by Reis and Källén, the authors analysed the material excluding

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women with exposure to possible teratogens or drugs used for chronic diseases which might affect pregnancy outcome but this changed only slightly the OR estimates [30]. Contrary to this, the use of SRIs – for which the vast majority were SSRIs – together with benzodiazepine use, was associated with a significant risk for congenital heart defects in a study based on population health register data and 359 exposed infants (regression adjusted Risk Difference 1.18 (95% CI 0.18–2.18), whereas no increased risk was observed in the cohort exposed to SRIs only (n = 2625) [32]. While the prospective cohort studies are limited in their power to detect rare outcomes due to insufficient numbers of exposed, register-based studies are subject to bias by non-compliance. Even if purchasing a drug from the pharmacy, the woman may discontinue the medication when suspecting that she is pregnant, and exposure may not take place during the most vulnerable period of organogenesis. However, this is mostly true for short-term medications, as drugs used for chronic illnesses are usually continued also during pregnancy [118,119]. Retrospective studies based on maternal interviews are useful when investigating rare outcomes, such as specific malformations, but are prone to recall bias if the interview is done as late as after delivery [120]. Furthermore, unfavourable pregnancy outcome may increase this bias in studies where the control cohort consists of non-malformed infants. A further problem is the classification of malformations to major or minor. While small muscular VSDs have closure rates approaching 90% by the first years of life and do not need surgical intervention or medication, VSDs are usually classified as major defects because the long-term outcome of such a defect is usually not known either due to the short follow-up period in prospective cohort studies or due to register data based on birth registers with no long-term information on outcome. The prevalence of noncomplex malformations, such as VSDs, varies due to differences in methods and activity of ascertainment, whereas the prevalence of more severe malformations does not tend to vary [121]. Because of the frequent occurrence of neonatal problems in SSRI-exposed neonates, these infants may be examined more thoroughly after birth than those not exposed, allowing less severe malformations – easily going undetected in the absence of symptoms – to be ascertained more frequently, as suggested by the study by Bar-Oz et al. [40]. Furthermore, only a few studies have included data on pregnancy terminations due to fetal malformation [25,36,39]. Several studies have excluded offspring with genetic malformations from analysis, however, it might be argued that this approach may overlook a possible susceptibility of genetically affected infants to certain malformations. 9. Conclusion Exposure to paroxetine or fluoxetine in early pregnancy may increase the risk for cardiac malformations but the risk is obviously small. The other SSRI drugs have not been consistently associated with increased malformation risk. Neonatal adaptation problems are common, and the risk for persistent pulmonary hypertension of the newborn may be elevated in neonates exposed in utero to SSRIs. Data on possible long-term effects on neurodevelopment in humans are yet scanty but animal studies have demonstrated permanent neurobehavioral changes after prenatal exposure. SSRIs should only be used during pregnancy when clearly indicated. SSRI drugs are usually compatible with breastfeeding. However, individual variations in drug metabolism and excretion exist, and are important to keep in mind if possible drug-related adverse effects in the nursing infant are suspected. Conflicts of interest The authors declare that there are no conflicts of interest.

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