human psychopharmacology Hum. Psychopharmacol Clin Exp 2015; 30: 143–151 Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2473
REVIEW ARTICLE
The safety of serotonin–noradrenaline reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a comprehensive review Cesario Bellantuono1, Marianna Vargas1, Gabriele Mandarelli2, Bernardo Nardi1 and Maria Giulia Martini1* 1
Psychiatric Unit and DEGRA Center, United Hospitals of Ancona and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy 2 Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sant’Andrea Hospital, University of Rome Sapienza, Roma, Italy
Objective The present study provides a comprehensive review of the existing literature on the safety of serotonin–noradrenaline reuptake inhibitors (SNRIs) in pregnancy and lactation. Methods Studies published in English, reporting the use of SNRIs in pregnant and/or breastfeeding women, were identified by searching MEDLINE/Pubmed, PsycINFO, and EMBASE. Results Twenty-nine studies were included in the review. Altogether, the initial evidence coming from the reviewed studies suggests a lack of association between SNRIs and an increased risk of major congenital malformations. Conversely, exposure to SNRIs seems to be significantly associated with an increased risk of some perinatal complications. No neonatal adverse events emerged, so far, in the few studies concerning the safety of SNRIs during breastfeeding. Conclusions Available data suggest that venlafaxine is relatively safe during pregnancy, in particular as far as major malformations are concerned, whereas considering the small number of studies published, no definitive conclusions can be drawn on its safety during breastfeeding. Because of the few studies so far published, the safety of duloxetine during pregnancy and breastfeeding remains to be well established. Copyright © 2015 John Wiley & Sons, Ltd. key words—SNRI; major malformations; perinatal complications; pregnancy; breastfeeding
INTRODUCTION Major depressive disorder (MDD) is a major health burden in pregnancy and postpartum, with an estimated prevalence rate between 8% and 12% (Borri et al., 2008; Byers et al., 2010; Balestrieri et al., 2012). Antidepressant drugs (ADs) are considered a first-line therapeutic strategy in women affected by severe MDD as well as anxiety disorders in pregnancy and puerperium (NICE, 2007; ACOG, 2008; SIGN, 2012). Because pregnant women are excluded from randomized clinical trials involving the use of ADs, data concerning the safety of ADs in pregnancy are fairly limited and are derived mostly from noncontrolled clinical trials and case reports. A number of *Correspondence to: M. G. Martini, Psychiatric Unit and DEGRA Center, United Hospital of Ancona and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Via Conca, 71, 60020 Ancona, Italy. Tel: +39 071 5963313; Fax: +39 071 5963313. E-mail: [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
studies have clearly shown that untreated severe MDD can lead to harmful prenatal health behaviors, such as inadequate nutrition, poor prenatal medical care, smoking, alcohol/drug use, and risk of suicide (Hallberg and Sjöblom, 2005). Untreated MDD has also been associated with several gestational adverse events and can significantly increase the risk of postpartum depression (Alder et al., 2007; Grigoriadis et al., 2013a). Among ADs, selective serotonin reuptake inhibitors (SSRIs) have been the most frequently prescribed drugs during pregnancy in the last decade (Jimenez-Solem et al. 2013). Consistent evidence indicates that SSRIs are associated with a risk of inducing major congenital malformations (MMs) which is comparable to the risk of MMs reported in the general population (1–3%) (Ross et al., 2013). Nonetheless, some studies have shown a small increase of relative risk of cardiovascular malformations in women treated with some SSRIs, such as paroxetine, sertraline, and fluoxetine, during Received 17 April 2014 Accepted 12 February 2015
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early pregnancy (Wurst et al., 2010; Bakker et al., 2010, Malm et al., 2011), even though recent systematic reviews and meta-analyses did not report such association (Gentile and Bellantuono, 2009; Einarson and Koren, 2010; Huybrechts et al., 2014a; Huybrechts et al., 2014b). Despite the good safety profile of SSRIs in early pregnancy, some concerns have been raised for newborns exposed to such drugs in late pregnancy, as some gestational and perinatal complications (PCs) have been reported in a number of studies and metaanalyses (Gentile, 2010; El Marroun et al., 2012; Grigoriadis et al., 2013b). Exposure to ADs in late pregnancy has also been associated, in nearly 20% of newborns, with a risk of postnatal adaptation syndrome (PNAS), which includes respiratory distress, cyanosis, apnea, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotonia or hypertonia, persistent crying, jitteriness, and hyper-reflexia (Pearlstein, 2013; Andrade, 2014). Although an FDA alert in 2004 warned that some infants exposed to SSRIs in late pregnancy may develop complications requiring tube feeding, respiratory support, and prolonged hospitalization, the symptoms of PNAS are usually mild and resolve spontaneously in most newborns (Grigoriadis et al., 2013b). To date, limited data are available on the safety of ADs classified as serotonin–noradrenaline reuptake inhibitors (SNRIs or “Dual action ADs”), such as venlafaxine (VEN), duloxetine (DUL), and milnacipran (MNL), in pregnancy and breastfeeding, even though these drugs have been approved for the treatment of MDD and generalized anxiety disorder (GAD) (Cipriani et al., 2009; Kasper and Pail, 2010) and, apart from MNL, are nowadays widely prescribed in women affected by mood and/or anxiety disorders. The aim of this paper is to review the results of the studies focusing on the safety of SNRIs in newborns exposed to such drugs during early and late pregnancy and in breastfeeding. METHODS We searched medical literature published in English reporting data on the safety of VEN and DUL in pregnancy and lactation. Studies were identified searching MEDLINE/Pubmed, PsycINFO, and EMBASE. However, we did not take into account books, chapters in books, conference proceedings, working papers, and other unpublished works. We searched the following set of keywords: (“Venlafaxine” OR “Duloxetine” OR “Milnacipran” OR “serotonin-noradrenaline reuptake inhibitor”) AND Copyright © 2015 John Wiley & Sons, Ltd.
ET AL.
(“pregnancy” OR “perinatal” OR “lactation” OR “breastfeeding”). Titles and abstracts were checked independently by two of the authors (MGM, MV) in order to identify studies reporting data on the risk of MMs, spontaneous abortion (SA), and PCs. The included articles’ references were further analyzed in order to include additional eligible studies. We considered only peerreviewed articles published in English. Data obtained from the reviewers were compared and discrepancies were settled through discussion. The initial literature search identified 72 and 18 studies concerning the safety of DUL and VEN in pregnancy, respectively. Twenty-one and four studies presented data on the safety of VEN and DUL during lactation, respectively; the final sample included 18 and seven studies suitable for assessing the safety of VEN and DUL, respectively. We considered seven studies on VEN and two on DUL reporting data during breastfeeding. No studies were found concerning the use of MLN both in pregnancy and during breastfeeding. We excluded from this review all the studies for which information on maternal and neonatal major outcomes were not reported. RESULTS The main results of the studies investigating the safety of VEN and DUL in pregnancy are summarized in Tables 1 and 2. Data concerning women exposed to SNRIs both in early and late pregnancy have been presented separately, focusing on the major perinatal outcomes such as MMs, SA, and PCs. VENLAFAXINE IN PREGNANCY Early pregnancy (0–28 weeks, I and II trimesters) Major malformations. Five studies (Einarson et al., 2001; Lennestal and Kallen, 2007; Einarson et al., 2009; Lind et al. 2013; Polen et al., 2013) focused on the association between MMs and VEN exposure. Einarson et al., (2009) analyzed pregnancy outcomes of 928 women exposed to ADs during the first trimester of pregnancy. Of these, 154 were treated with VEN; although two newborns out of 154 presented MMs (hypospadias and club foot), no increased risk for MMs was observed above the baseline. These findings are consistent with those of a previous study in which VEN was taken in 70% of the sample (501 women) and comparisons were made with all deliveries in the Swedish Medical Birth Registry. No increased risk for stillbirth or MMs was reported (Lennestal and Kallen, 2007). Similar results were found in an early study including 150 pregnant women exposed to Hum. Psychopharmacol Clin Exp 2015; 30: 143–151 DOI: 10.1002/hup
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snris in pregnancy and breastfeeding Table 1.
Studies on the safety of venlafaxine in pregnancy Authors
Study design
No. of newborns
Time of exposure
1 Calderon-Margalit et al. (2009) 2 Einarson et al. (2009) 3 Rampono et al. (2009) 4 Lennestal et al. (2007)
Cohort prospective
Not reported
Cohort prospective
I trimester
Cohort prospective
Daily dosage (mg/day)
9
Not reported
154
Not reported
Not reported
11
150–300
Cohort prospective
I–II trimesters
505
Not reported
5 Loughhead et al. (2006) 6 Einarson et al. (2001) 7 Kjaersgaard et al. (2013) 8 Lind et al. (2013)
Cohort prospective Cohort prospective
Mean duration of exposure: 36.1 weeks I–II–III trimesters
Case–control
Not reported
Case–control
Not reported
9 Polen et al. (2013)
Case–control
10 Nakhai-Pour et al. (2010) 11 Hoppenbrouwers et al. (2010) 12 Treichel, et al. (2009) 13 Koren et al. (2006) 14 Pakalapati et al. (2006) 15 Rampono et al. (2004) 16 Yaris et al. (2004) 17 De Moor et al. (2003) 18 Hendrick et al. (2001)
3
Mean dose: 200
150
37.5–300
Not reported
Not reported
Main results Preterm delivery reported in four women (OR 3.78; CI: 0.81–17.6) Hypospadias (one newborn); club foot (one newborn) Withdrawal symptoms in one newborn Risk of MMs; SNRI/NRI versus control group (OR 0.85 95% CI: 0.58–1.24); rate of MMs, 17/505 (3.3%) Preterm delivery reported in three women Rates of SA: 12% (OR 2.2; CI: 0.20–24.89); no increased risk of MMs Risks of SA (RR 1.80; 95% CI: 1.19–2.72)
9
Not reported
I trimester
91
Not reported
Case–control
Not reported
33
75–225
Case-report
Not reported
1
75
Neonatal seizures
Case-report
I–II–III trimesters
75
Neonatal necrotizing enterocolitis
Case-report Case-report
I–II–III trimesters I–II trimesters
1 2
375 150–225
Case-report
III trimester
1
150
Case-report Case-report
I–II trimesters Not reported
Case-report
I–II–III trimesters
2 twins
10 1
75–225 300
1
150
Increased risk of hypospadias (OR 2.4; 95% CI: 1.0–6.00) Increased risk of MMs: anencephaly (OR 6.3; CI: 1.5–20.2), atrial septal defect secundum (OR 3.1; CI: 1.3–7.4), coarctation of aorta (OR 4.1; CI: 1.3–11.5), cleft palate (OR 3.3; CI: 1.1–8.8), gastroschisis (OR 5.7; CI: 1.8–15.9) Risks of SA (OR 2.11; CI: 1.34–3.30)
Withdrawal symptoms Neonatal seizures No adverse events reported Preterm delivery reported in one newborn Withdrawal symptoms No adverse events reported
SA, spontaneous abortion; MMs, major congenital malformations; PCs, perinatal complications.
Table 2.
Studies on the safety of duloxetine in pregnancy
Authors 1 Einarson et al. (2012) 2 Hoog et al. (2013) 3 Kjaersgaard et al. (2013) 4 Bellantuono et al. (2013) 5 Eyal and Yaeger (2008) 6 Briggs et al. (2009) 7 Boyce et al. (2011)
Study design
Time of exposure
Prospective I trimester, 206; III trimester, study 2; I–II–III trimesters, 51 Cohort study Not reported Case–control Not reported
No. of newborns 259
Daily dosage (mg/day)
Main results
Not reported MMs (1.8%): clubfoot, kidney agenesis, hydronephrosis
400
Not reported SA in 41 women; PCs in 25 newborns; preterm delivery in 19 women Not reported Not reported Risks of SA: (RR 3.12; 95% CI: 1.55–6.31)
Case-report
I–II–III trimesters
1
60
No adverse events reported
Case-report
I–II–III trimesters
1
90
Case-report
II–III trimesters
1
60
PCs: jitteriness, poor muscle tone, weak cry, respiratory distress, low Apgar score, and seizures No adverse events reported
Case report
I–II–III trimesters
1
60
No adverse events reported
SA, spontaneous abortion; MMs, major congenital malformations; PCs, perinatal complications.
Copyright © 2015 John Wiley & Sons, Ltd.
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VEN; in two newborns, hypospadias and neural tube defects with clubfoot were reported. No differences between VEN and the two comparison groups emerged in the endpoints investigated (Einarson et al., 2001). However, these results were not confirmed in two more recent studies. Lind et al. (2013) using data from the National Birth Defects Prevention investigated the associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants; 1697 infants with hypospadias have been identified, and among these, nine have been exposed to VEN during pregnancy. Among the ADs prescribed, only for VEN, an increase of relative risk of hypospadias emerged (OR 2.4; 95% CI: 1.0–6.0). An increased risk of MMs after VEN exposure was also found in another case-control study (Polen et al., 2013); among the 27 045 participants, 0.17% (14/8002) of control mothers and 0.40% (77/ 19 043) of case mothers reported any use of VEN in early pregnancy (dosage not reported); statistically significant associations were found for anencephaly (adjusted OR 6.3; CI: 1.5–20.2), atrial septal defect secundum (OR 3.1; CI: 1.3–7.4), coarctation of aorta (OR 4.1; CI: 1.3–11.5), cleft palate (OR 3.3; CI: 1.1–8.8) and gastroschisis (OR 5.7; CI: 1.8–15.9). Spontaneous abortion. Three studies focused on the associations between risk of SA and VEN exposure during early pregnancy. The first study investigated the risk of SA associated with different ADs during pregnancy, including VEN. The use of VEN alone, occurring in 33 women, was found to be associated with an increased risk of SA in comparison with a control group (OR 2.66; 95% CI: 1.81–3.90). In addition, a dose of VEN more than 150 mg/day was associated with an increased risk of SA, consistent with a possible dose-dependent effect (Nakhai-Pour et al., 2010). Likewise, the second study conducted by Kjaersgaard et al. (2013) according to a case-control design, found an association between both VEN and DUL and a small increased risk of SA (RR 1.80; 95% CI: 1.19–2.72 and RR 3.12; 95% CI: 1.55–6.31, respectively). No higher risk of SA or intrauterine death was observed by Yaris et al., (2004) in 10 women who took VEN during early pregnancy (75–225 mg daily) as compared with the unexposed group.
ET AL.
(O-desmethylvenlafaxine) were 0.72 and 1.08, respectively. Withdrawal symptoms were present in one out of 11 infants exposed to VEN. Likewise, in seven newborns exposed to VEN during the third trimester of pregnancy, five presented with symptoms including tachypnea, respiratory depression, tremors, and agitation; all symptoms however resolved spontaneously. Symptoms appeared as the concentration in the blood of VEN declined, suggesting a “discontinuation syndrome” as a possible explanation (Boucher et al., 2009). Koren et al., (2006) and De Moor et al., (2003) described two cases of neonatal withdrawal syndrome due to VEN exposure, characterized by lethargy, jitteriness, rapid breathing, poor feeding, and dehydration. Symptoms subsided gradually and spontaneously in a week; dosages in the two cases were 375 and 300 mg/day, respectively. Conversely, different results were reported in other two studies. Rampono et al., (2004) analyzed maternal concentrations in cord and maternal serum in 11 women; among these, no withdrawal symptoms were observed in the only newborn treated with VEN (150 mg/day) during the third trimester. No adverse events were also observed by Hendrick et al., (2001) in a newborn whose mother was treated with VEN (150 mg/day) throughout pregnancy. Preterm delivery. Two studies considered the risk of preterm delivery in relation to maternal use of different psychotropic medications, including VEN (Calderon-Margalit et al., 2009). The authors reported a small but statistically significant increased risk of preterm delivery in four out of nine pregnant women exposed to VEN in comparison to the unexposed group (OR 7.72; 95% CI: 2.06–29.0); however, dosage and time of exposure were not reported. In addition, Loughhead et al., (2006) conducted a prospective study to determine the concentrations of different ADs in amniotic fluid of 28 women during pregnancy. A preterm delivery was reported in one out of three women who received VEN at a daily dose of 200 mg.
Late pregnancy (29–40 weeks, III trimester)
Neonatal seizures. Hoppenbrouwers et al., (2010) and Pakalapati et al., (2006) reported three cases (one and two cases, respectively) of infants exposed to VEN throughout pregnancy who developed neonatal seizures; dosage ranged from 75 to 225 mg/day.
Perinatal complications. Withdrawal symptoms. Rampono et al., (2009) investigated the placental transfer and the neurobehavioral effect in neonates exposed to SSRIs (n = 56) and VEN (n = 11). Median cord/maternal ratio values for VEN and ODV
Necrotizing enterocolitis. A case of necrotizing enterocolitis was described by Treichel et al. (2009) in a set of twins exposed to VEN (75 mg daily) throughout pregnancy.
Copyright © 2015 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2015; 30: 143–151 DOI: 10.1002/hup
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snris in pregnancy and breastfeeding
DULOXETINE IN PREGNANCY
Late pregnancy
Early pregnancy (0–28 weeks, I and II trimesters)
Risk of perinatal complications. Withdrawal symptoms. Eyal and Yaeger (2008) described a woman exposed to DUL throughout pregnancy at the dose of 90 mg/day whose infant developed a neonatal “behavioural syndrome,” characterized by jitteriness, poor muscle tone, weak cry, respiratory distress, low Apgar score, and seizures. The authors suggested a discontinuation syndrome as possible explanation. On the contrary, Boyce et al., (2011) reported a case of a pregnant woman exposed to DUL in the second half of pregnancy at the daily dose of 60 mg, whose newborn did not present any adverse effects.
Risk of major congenital malformations. We found four studies focusing on DUL exposure during early pregnancy. A recent study reported data on pregnancy outcomes of women exposed to DUL, obtained from the Lilly Safety System (LSS) and the FDA Adverse events reporting system and including MMs, SA, PCs, pre/post-term deliveries, and ectopic pregnancies. Four hundred pregnancies were identified from LSS database: 90 pregnancy outcomes were considered “abnormal”, consisting mainly in SA (n = 41), PCs (n = 25), or preterm births (n = 19). In women with abnormal pregnancy outcomes, concomitant medications use and a history of organic illness were more frequently reported as compared with women who had a normal pregnancy. The authors concluded that “frequency of abnormal outcomes reported in DUL pregnancy cases is generally consistent with the historic control rates in the general population” (Hoog et al., 2013). Similar findings were reported by Einarson et al. (2012) on the use of DUL in 256 pregnant women; among these, the majority (n = 206) took DUL in the first trimester, two during the second and third trimesters, and the others throughout the pregnancy. The rate of MMs (1.8% consisting in clubfoot, kidney agenesis, and hydronephrosis) was within the baseline rate in the general population. Analogue results were found by Briggs et al. (2009) and Bellantuono et al. (2013) who reported two cases of pregnant women exposed to DUL throughout pregnancy at the daily dose of 60 mg; both women gave birth to healthy newborns. Assessments at 3, 6, and 9 months of age were also performed in the study by Bellantuono et al., (2013), where no adverse events were observed in the newborn during the follow-up.
Table 3.
Study design
1 Newport et al. (2009) 2 Berle et al. (2004) 3 Ilett et al. (2002)
5 6 7
The main findings emerging from the studies published on the safety of VEN during breastfeeding are summarized in Table 3. No neonatal short-term adverse effects during breastfeeding have been reported in the seven studies exploring the safety of VEN during lactation. Newport et al., (2009) analyzed 13 newborns exposed to VEN during breastfeeding (6.4 to 60 weeks); relative infant dose (RID), calculated as the product of estimated milk production rate and average concentrations of VEN in the milk, normalized to body weight, was 8.1%; no adverse reactions were observed in any of the breastfed infants. Berle et al., (2004) performed an open-label study in 25 nursing women treated with ADs to quantify the plasma drug concentration in breastfed newborns, to identify possible adverse events, and to correlate these variables to maternal and infant drug metabolismrelevant genotypes and milk triglyceride content. Among these women, three took VEN with a dosage between 75 and 225 mg/day. The milk/maternal serum drug concentration was 2.4 (range 2.00–3.2), RID was
Studies on the safety of venlafaxine in breastfeeding Authors
4
VENLAFAXINE DURING BREASTFEEDING
Time of exposure
Cohort prospective 6.4 to 60 weeks Cohort prospective 8 to 30 weeks Cohort prospective Mean time of exposure: 7 months Ilett et al. (1998) Cohort prospective Mean time of exposure: 0.5, 5, 0.23 months Misri et al. (2006) Case-report Not reported Koren et al. (2006) Case-report Not reported Hendrick et al. (2001) Case-report 6 months
No. of newborns Daily dosage (mg/day)
Main results
13 3 7
37.5–300 75–225 225–300
RID, 8.1%; no adverse events reported RID, 5.2%; no adverse events reported No adverse events reported
3
Not reported
No adverse events reported
2 1 1
75 and 225 376 150
No adverse events reported No adverse events reported No adverse events reported
RID, relative infant dose.
Copyright © 2015 John Wiley & Sons, Ltd.
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5.2. Detectable concentrations of the drug were found in the breast milk, but no adverse events were reported in the infants. Ilett et al., (2002) studied the transfer of VEN in human breast milk in six women and its safety in their seven infants. Dosages varied from 225 to 300 mg/day. Mean total drug exposure in percent of weight-adjusted dose of the mother was 6.4%; no adverse events were observed in the infants. The excretion of VEN in breast milk was examined in a previous study in which VEN and ODV were detected in breast milk (RID: 7.6%) (Ilett et al., 1998). Misri et al., (2006) reported two cases treated with quetiapine during lactation, which included two women taking additionally VEN (75 and 225 mg/day, respectively). The two babies scored as being within normal limits on the Bayley Scales of Infant Development. Likewise, other two case-reports did not report any adverse effects in breastfed infants whose mother took 375 and 150 mg/day, respectively (Hendrick et al., 2001; Koren et al., 2006); in the latter case, no PCs or health problems were reported in the infant during the first year of follow-up.
clinical indications to be drawn on their safety profile in the newborns exposed. With regard to the use of VEN during pregnancy, the occurrence of MMs has been reported in five studies. In three of these (Einarson et al., 2001; Lennestal and Kallen, 2007; Einarson et al., 2009), the rate of MMs ranged from 1.3% to 3.4%, which is within the range of MMs reported in the general population. In two more recent case-control studies (Polen et al., 2013 and Lind et al., 2013), a small increase in the relative risk of MMs was found, even though the authors did not exclude that these findings could have been affected by residual confounding factors, which they were not able to account for, particularly the severity of maternal depression. It should be considered, in fact, that severe depression itself has been found to be associated with adverse pregnancy outcomes (Grote et al., 2010); consequently, it cannot be excluded that in these studies, women treated with VEN had a more severe depressive illness (Schueler et al., 2011). Conflicting results also emerged for the risk of SA. While Nakhai-Pour et al. (2010) and Kjaersgaard et al. (2013) observed an increased risk of SA in women treated with VEN, another study did not found such association (Einarson et al., 2001). When considering these contradictory results, it should be noted that even the risk of SSRIs in inducing SA still remains to be established (Santone et al., 2009). The risk of PCs in newborns exposed to VEN during late pregnancy has been reported in 10 studies. Withdrawal symptoms were the most frequently reported adverse event; most of the newborns, however, had a spontaneous recovery, and in all cases, the symptoms resolved with an appropriate treatment. In those cases in which the PCs were characterized by neonatal seizures, newborns were successfully treated with phenobarbitone. In the case reported by Hoppenbrouwers et al., (2010), neonatal epileptiform activity was documented through electroencephalography, but missing follow-up after discharge did not provide long-term information. Data from the seven studies on the neonatal safety of VEN during breastfeeding could be considered
DULOXETINE DURING BREASTFEEDING In the two aforementioned case-reports (Briggs et al., 2009; Boyce et al., 2011), no adverse reactions were registered in the breastfed infants; in both cases, the dose was 60 mg/day, and the RID was 0.81% (Table 4). Recently, it has been reported that the infant exposure to DUL in breast milk is
REVIEW ARTICLE
The safety of serotonin–noradrenaline reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a comprehensive review Cesario Bellantuono1, Marianna Vargas1, Gabriele Mandarelli2, Bernardo Nardi1 and Maria Giulia Martini1* 1
Psychiatric Unit and DEGRA Center, United Hospitals of Ancona and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy 2 Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sant’Andrea Hospital, University of Rome Sapienza, Roma, Italy
Objective The present study provides a comprehensive review of the existing literature on the safety of serotonin–noradrenaline reuptake inhibitors (SNRIs) in pregnancy and lactation. Methods Studies published in English, reporting the use of SNRIs in pregnant and/or breastfeeding women, were identified by searching MEDLINE/Pubmed, PsycINFO, and EMBASE. Results Twenty-nine studies were included in the review. Altogether, the initial evidence coming from the reviewed studies suggests a lack of association between SNRIs and an increased risk of major congenital malformations. Conversely, exposure to SNRIs seems to be significantly associated with an increased risk of some perinatal complications. No neonatal adverse events emerged, so far, in the few studies concerning the safety of SNRIs during breastfeeding. Conclusions Available data suggest that venlafaxine is relatively safe during pregnancy, in particular as far as major malformations are concerned, whereas considering the small number of studies published, no definitive conclusions can be drawn on its safety during breastfeeding. Because of the few studies so far published, the safety of duloxetine during pregnancy and breastfeeding remains to be well established. Copyright © 2015 John Wiley & Sons, Ltd. key words—SNRI; major malformations; perinatal complications; pregnancy; breastfeeding
INTRODUCTION Major depressive disorder (MDD) is a major health burden in pregnancy and postpartum, with an estimated prevalence rate between 8% and 12% (Borri et al., 2008; Byers et al., 2010; Balestrieri et al., 2012). Antidepressant drugs (ADs) are considered a first-line therapeutic strategy in women affected by severe MDD as well as anxiety disorders in pregnancy and puerperium (NICE, 2007; ACOG, 2008; SIGN, 2012). Because pregnant women are excluded from randomized clinical trials involving the use of ADs, data concerning the safety of ADs in pregnancy are fairly limited and are derived mostly from noncontrolled clinical trials and case reports. A number of *Correspondence to: M. G. Martini, Psychiatric Unit and DEGRA Center, United Hospital of Ancona and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Via Conca, 71, 60020 Ancona, Italy. Tel: +39 071 5963313; Fax: +39 071 5963313. E-mail: [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
studies have clearly shown that untreated severe MDD can lead to harmful prenatal health behaviors, such as inadequate nutrition, poor prenatal medical care, smoking, alcohol/drug use, and risk of suicide (Hallberg and Sjöblom, 2005). Untreated MDD has also been associated with several gestational adverse events and can significantly increase the risk of postpartum depression (Alder et al., 2007; Grigoriadis et al., 2013a). Among ADs, selective serotonin reuptake inhibitors (SSRIs) have been the most frequently prescribed drugs during pregnancy in the last decade (Jimenez-Solem et al. 2013). Consistent evidence indicates that SSRIs are associated with a risk of inducing major congenital malformations (MMs) which is comparable to the risk of MMs reported in the general population (1–3%) (Ross et al., 2013). Nonetheless, some studies have shown a small increase of relative risk of cardiovascular malformations in women treated with some SSRIs, such as paroxetine, sertraline, and fluoxetine, during Received 17 April 2014 Accepted 12 February 2015
144
c. bellantuono
early pregnancy (Wurst et al., 2010; Bakker et al., 2010, Malm et al., 2011), even though recent systematic reviews and meta-analyses did not report such association (Gentile and Bellantuono, 2009; Einarson and Koren, 2010; Huybrechts et al., 2014a; Huybrechts et al., 2014b). Despite the good safety profile of SSRIs in early pregnancy, some concerns have been raised for newborns exposed to such drugs in late pregnancy, as some gestational and perinatal complications (PCs) have been reported in a number of studies and metaanalyses (Gentile, 2010; El Marroun et al., 2012; Grigoriadis et al., 2013b). Exposure to ADs in late pregnancy has also been associated, in nearly 20% of newborns, with a risk of postnatal adaptation syndrome (PNAS), which includes respiratory distress, cyanosis, apnea, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotonia or hypertonia, persistent crying, jitteriness, and hyper-reflexia (Pearlstein, 2013; Andrade, 2014). Although an FDA alert in 2004 warned that some infants exposed to SSRIs in late pregnancy may develop complications requiring tube feeding, respiratory support, and prolonged hospitalization, the symptoms of PNAS are usually mild and resolve spontaneously in most newborns (Grigoriadis et al., 2013b). To date, limited data are available on the safety of ADs classified as serotonin–noradrenaline reuptake inhibitors (SNRIs or “Dual action ADs”), such as venlafaxine (VEN), duloxetine (DUL), and milnacipran (MNL), in pregnancy and breastfeeding, even though these drugs have been approved for the treatment of MDD and generalized anxiety disorder (GAD) (Cipriani et al., 2009; Kasper and Pail, 2010) and, apart from MNL, are nowadays widely prescribed in women affected by mood and/or anxiety disorders. The aim of this paper is to review the results of the studies focusing on the safety of SNRIs in newborns exposed to such drugs during early and late pregnancy and in breastfeeding. METHODS We searched medical literature published in English reporting data on the safety of VEN and DUL in pregnancy and lactation. Studies were identified searching MEDLINE/Pubmed, PsycINFO, and EMBASE. However, we did not take into account books, chapters in books, conference proceedings, working papers, and other unpublished works. We searched the following set of keywords: (“Venlafaxine” OR “Duloxetine” OR “Milnacipran” OR “serotonin-noradrenaline reuptake inhibitor”) AND Copyright © 2015 John Wiley & Sons, Ltd.
ET AL.
(“pregnancy” OR “perinatal” OR “lactation” OR “breastfeeding”). Titles and abstracts were checked independently by two of the authors (MGM, MV) in order to identify studies reporting data on the risk of MMs, spontaneous abortion (SA), and PCs. The included articles’ references were further analyzed in order to include additional eligible studies. We considered only peerreviewed articles published in English. Data obtained from the reviewers were compared and discrepancies were settled through discussion. The initial literature search identified 72 and 18 studies concerning the safety of DUL and VEN in pregnancy, respectively. Twenty-one and four studies presented data on the safety of VEN and DUL during lactation, respectively; the final sample included 18 and seven studies suitable for assessing the safety of VEN and DUL, respectively. We considered seven studies on VEN and two on DUL reporting data during breastfeeding. No studies were found concerning the use of MLN both in pregnancy and during breastfeeding. We excluded from this review all the studies for which information on maternal and neonatal major outcomes were not reported. RESULTS The main results of the studies investigating the safety of VEN and DUL in pregnancy are summarized in Tables 1 and 2. Data concerning women exposed to SNRIs both in early and late pregnancy have been presented separately, focusing on the major perinatal outcomes such as MMs, SA, and PCs. VENLAFAXINE IN PREGNANCY Early pregnancy (0–28 weeks, I and II trimesters) Major malformations. Five studies (Einarson et al., 2001; Lennestal and Kallen, 2007; Einarson et al., 2009; Lind et al. 2013; Polen et al., 2013) focused on the association between MMs and VEN exposure. Einarson et al., (2009) analyzed pregnancy outcomes of 928 women exposed to ADs during the first trimester of pregnancy. Of these, 154 were treated with VEN; although two newborns out of 154 presented MMs (hypospadias and club foot), no increased risk for MMs was observed above the baseline. These findings are consistent with those of a previous study in which VEN was taken in 70% of the sample (501 women) and comparisons were made with all deliveries in the Swedish Medical Birth Registry. No increased risk for stillbirth or MMs was reported (Lennestal and Kallen, 2007). Similar results were found in an early study including 150 pregnant women exposed to Hum. Psychopharmacol Clin Exp 2015; 30: 143–151 DOI: 10.1002/hup
145
snris in pregnancy and breastfeeding Table 1.
Studies on the safety of venlafaxine in pregnancy Authors
Study design
No. of newborns
Time of exposure
1 Calderon-Margalit et al. (2009) 2 Einarson et al. (2009) 3 Rampono et al. (2009) 4 Lennestal et al. (2007)
Cohort prospective
Not reported
Cohort prospective
I trimester
Cohort prospective
Daily dosage (mg/day)
9
Not reported
154
Not reported
Not reported
11
150–300
Cohort prospective
I–II trimesters
505
Not reported
5 Loughhead et al. (2006) 6 Einarson et al. (2001) 7 Kjaersgaard et al. (2013) 8 Lind et al. (2013)
Cohort prospective Cohort prospective
Mean duration of exposure: 36.1 weeks I–II–III trimesters
Case–control
Not reported
Case–control
Not reported
9 Polen et al. (2013)
Case–control
10 Nakhai-Pour et al. (2010) 11 Hoppenbrouwers et al. (2010) 12 Treichel, et al. (2009) 13 Koren et al. (2006) 14 Pakalapati et al. (2006) 15 Rampono et al. (2004) 16 Yaris et al. (2004) 17 De Moor et al. (2003) 18 Hendrick et al. (2001)
3
Mean dose: 200
150
37.5–300
Not reported
Not reported
Main results Preterm delivery reported in four women (OR 3.78; CI: 0.81–17.6) Hypospadias (one newborn); club foot (one newborn) Withdrawal symptoms in one newborn Risk of MMs; SNRI/NRI versus control group (OR 0.85 95% CI: 0.58–1.24); rate of MMs, 17/505 (3.3%) Preterm delivery reported in three women Rates of SA: 12% (OR 2.2; CI: 0.20–24.89); no increased risk of MMs Risks of SA (RR 1.80; 95% CI: 1.19–2.72)
9
Not reported
I trimester
91
Not reported
Case–control
Not reported
33
75–225
Case-report
Not reported
1
75
Neonatal seizures
Case-report
I–II–III trimesters
75
Neonatal necrotizing enterocolitis
Case-report Case-report
I–II–III trimesters I–II trimesters
1 2
375 150–225
Case-report
III trimester
1
150
Case-report Case-report
I–II trimesters Not reported
Case-report
I–II–III trimesters
2 twins
10 1
75–225 300
1
150
Increased risk of hypospadias (OR 2.4; 95% CI: 1.0–6.00) Increased risk of MMs: anencephaly (OR 6.3; CI: 1.5–20.2), atrial septal defect secundum (OR 3.1; CI: 1.3–7.4), coarctation of aorta (OR 4.1; CI: 1.3–11.5), cleft palate (OR 3.3; CI: 1.1–8.8), gastroschisis (OR 5.7; CI: 1.8–15.9) Risks of SA (OR 2.11; CI: 1.34–3.30)
Withdrawal symptoms Neonatal seizures No adverse events reported Preterm delivery reported in one newborn Withdrawal symptoms No adverse events reported
SA, spontaneous abortion; MMs, major congenital malformations; PCs, perinatal complications.
Table 2.
Studies on the safety of duloxetine in pregnancy
Authors 1 Einarson et al. (2012) 2 Hoog et al. (2013) 3 Kjaersgaard et al. (2013) 4 Bellantuono et al. (2013) 5 Eyal and Yaeger (2008) 6 Briggs et al. (2009) 7 Boyce et al. (2011)
Study design
Time of exposure
Prospective I trimester, 206; III trimester, study 2; I–II–III trimesters, 51 Cohort study Not reported Case–control Not reported
No. of newborns 259
Daily dosage (mg/day)
Main results
Not reported MMs (1.8%): clubfoot, kidney agenesis, hydronephrosis
400
Not reported SA in 41 women; PCs in 25 newborns; preterm delivery in 19 women Not reported Not reported Risks of SA: (RR 3.12; 95% CI: 1.55–6.31)
Case-report
I–II–III trimesters
1
60
No adverse events reported
Case-report
I–II–III trimesters
1
90
Case-report
II–III trimesters
1
60
PCs: jitteriness, poor muscle tone, weak cry, respiratory distress, low Apgar score, and seizures No adverse events reported
Case report
I–II–III trimesters
1
60
No adverse events reported
SA, spontaneous abortion; MMs, major congenital malformations; PCs, perinatal complications.
Copyright © 2015 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2015; 30: 143–151 DOI: 10.1002/hup
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c. bellantuono
VEN; in two newborns, hypospadias and neural tube defects with clubfoot were reported. No differences between VEN and the two comparison groups emerged in the endpoints investigated (Einarson et al., 2001). However, these results were not confirmed in two more recent studies. Lind et al. (2013) using data from the National Birth Defects Prevention investigated the associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants; 1697 infants with hypospadias have been identified, and among these, nine have been exposed to VEN during pregnancy. Among the ADs prescribed, only for VEN, an increase of relative risk of hypospadias emerged (OR 2.4; 95% CI: 1.0–6.0). An increased risk of MMs after VEN exposure was also found in another case-control study (Polen et al., 2013); among the 27 045 participants, 0.17% (14/8002) of control mothers and 0.40% (77/ 19 043) of case mothers reported any use of VEN in early pregnancy (dosage not reported); statistically significant associations were found for anencephaly (adjusted OR 6.3; CI: 1.5–20.2), atrial septal defect secundum (OR 3.1; CI: 1.3–7.4), coarctation of aorta (OR 4.1; CI: 1.3–11.5), cleft palate (OR 3.3; CI: 1.1–8.8) and gastroschisis (OR 5.7; CI: 1.8–15.9). Spontaneous abortion. Three studies focused on the associations between risk of SA and VEN exposure during early pregnancy. The first study investigated the risk of SA associated with different ADs during pregnancy, including VEN. The use of VEN alone, occurring in 33 women, was found to be associated with an increased risk of SA in comparison with a control group (OR 2.66; 95% CI: 1.81–3.90). In addition, a dose of VEN more than 150 mg/day was associated with an increased risk of SA, consistent with a possible dose-dependent effect (Nakhai-Pour et al., 2010). Likewise, the second study conducted by Kjaersgaard et al. (2013) according to a case-control design, found an association between both VEN and DUL and a small increased risk of SA (RR 1.80; 95% CI: 1.19–2.72 and RR 3.12; 95% CI: 1.55–6.31, respectively). No higher risk of SA or intrauterine death was observed by Yaris et al., (2004) in 10 women who took VEN during early pregnancy (75–225 mg daily) as compared with the unexposed group.
ET AL.
(O-desmethylvenlafaxine) were 0.72 and 1.08, respectively. Withdrawal symptoms were present in one out of 11 infants exposed to VEN. Likewise, in seven newborns exposed to VEN during the third trimester of pregnancy, five presented with symptoms including tachypnea, respiratory depression, tremors, and agitation; all symptoms however resolved spontaneously. Symptoms appeared as the concentration in the blood of VEN declined, suggesting a “discontinuation syndrome” as a possible explanation (Boucher et al., 2009). Koren et al., (2006) and De Moor et al., (2003) described two cases of neonatal withdrawal syndrome due to VEN exposure, characterized by lethargy, jitteriness, rapid breathing, poor feeding, and dehydration. Symptoms subsided gradually and spontaneously in a week; dosages in the two cases were 375 and 300 mg/day, respectively. Conversely, different results were reported in other two studies. Rampono et al., (2004) analyzed maternal concentrations in cord and maternal serum in 11 women; among these, no withdrawal symptoms were observed in the only newborn treated with VEN (150 mg/day) during the third trimester. No adverse events were also observed by Hendrick et al., (2001) in a newborn whose mother was treated with VEN (150 mg/day) throughout pregnancy. Preterm delivery. Two studies considered the risk of preterm delivery in relation to maternal use of different psychotropic medications, including VEN (Calderon-Margalit et al., 2009). The authors reported a small but statistically significant increased risk of preterm delivery in four out of nine pregnant women exposed to VEN in comparison to the unexposed group (OR 7.72; 95% CI: 2.06–29.0); however, dosage and time of exposure were not reported. In addition, Loughhead et al., (2006) conducted a prospective study to determine the concentrations of different ADs in amniotic fluid of 28 women during pregnancy. A preterm delivery was reported in one out of three women who received VEN at a daily dose of 200 mg.
Late pregnancy (29–40 weeks, III trimester)
Neonatal seizures. Hoppenbrouwers et al., (2010) and Pakalapati et al., (2006) reported three cases (one and two cases, respectively) of infants exposed to VEN throughout pregnancy who developed neonatal seizures; dosage ranged from 75 to 225 mg/day.
Perinatal complications. Withdrawal symptoms. Rampono et al., (2009) investigated the placental transfer and the neurobehavioral effect in neonates exposed to SSRIs (n = 56) and VEN (n = 11). Median cord/maternal ratio values for VEN and ODV
Necrotizing enterocolitis. A case of necrotizing enterocolitis was described by Treichel et al. (2009) in a set of twins exposed to VEN (75 mg daily) throughout pregnancy.
Copyright © 2015 John Wiley & Sons, Ltd.
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snris in pregnancy and breastfeeding
DULOXETINE IN PREGNANCY
Late pregnancy
Early pregnancy (0–28 weeks, I and II trimesters)
Risk of perinatal complications. Withdrawal symptoms. Eyal and Yaeger (2008) described a woman exposed to DUL throughout pregnancy at the dose of 90 mg/day whose infant developed a neonatal “behavioural syndrome,” characterized by jitteriness, poor muscle tone, weak cry, respiratory distress, low Apgar score, and seizures. The authors suggested a discontinuation syndrome as possible explanation. On the contrary, Boyce et al., (2011) reported a case of a pregnant woman exposed to DUL in the second half of pregnancy at the daily dose of 60 mg, whose newborn did not present any adverse effects.
Risk of major congenital malformations. We found four studies focusing on DUL exposure during early pregnancy. A recent study reported data on pregnancy outcomes of women exposed to DUL, obtained from the Lilly Safety System (LSS) and the FDA Adverse events reporting system and including MMs, SA, PCs, pre/post-term deliveries, and ectopic pregnancies. Four hundred pregnancies were identified from LSS database: 90 pregnancy outcomes were considered “abnormal”, consisting mainly in SA (n = 41), PCs (n = 25), or preterm births (n = 19). In women with abnormal pregnancy outcomes, concomitant medications use and a history of organic illness were more frequently reported as compared with women who had a normal pregnancy. The authors concluded that “frequency of abnormal outcomes reported in DUL pregnancy cases is generally consistent with the historic control rates in the general population” (Hoog et al., 2013). Similar findings were reported by Einarson et al. (2012) on the use of DUL in 256 pregnant women; among these, the majority (n = 206) took DUL in the first trimester, two during the second and third trimesters, and the others throughout the pregnancy. The rate of MMs (1.8% consisting in clubfoot, kidney agenesis, and hydronephrosis) was within the baseline rate in the general population. Analogue results were found by Briggs et al. (2009) and Bellantuono et al. (2013) who reported two cases of pregnant women exposed to DUL throughout pregnancy at the daily dose of 60 mg; both women gave birth to healthy newborns. Assessments at 3, 6, and 9 months of age were also performed in the study by Bellantuono et al., (2013), where no adverse events were observed in the newborn during the follow-up.
Table 3.
Study design
1 Newport et al. (2009) 2 Berle et al. (2004) 3 Ilett et al. (2002)
5 6 7
The main findings emerging from the studies published on the safety of VEN during breastfeeding are summarized in Table 3. No neonatal short-term adverse effects during breastfeeding have been reported in the seven studies exploring the safety of VEN during lactation. Newport et al., (2009) analyzed 13 newborns exposed to VEN during breastfeeding (6.4 to 60 weeks); relative infant dose (RID), calculated as the product of estimated milk production rate and average concentrations of VEN in the milk, normalized to body weight, was 8.1%; no adverse reactions were observed in any of the breastfed infants. Berle et al., (2004) performed an open-label study in 25 nursing women treated with ADs to quantify the plasma drug concentration in breastfed newborns, to identify possible adverse events, and to correlate these variables to maternal and infant drug metabolismrelevant genotypes and milk triglyceride content. Among these women, three took VEN with a dosage between 75 and 225 mg/day. The milk/maternal serum drug concentration was 2.4 (range 2.00–3.2), RID was
Studies on the safety of venlafaxine in breastfeeding Authors
4
VENLAFAXINE DURING BREASTFEEDING
Time of exposure
Cohort prospective 6.4 to 60 weeks Cohort prospective 8 to 30 weeks Cohort prospective Mean time of exposure: 7 months Ilett et al. (1998) Cohort prospective Mean time of exposure: 0.5, 5, 0.23 months Misri et al. (2006) Case-report Not reported Koren et al. (2006) Case-report Not reported Hendrick et al. (2001) Case-report 6 months
No. of newborns Daily dosage (mg/day)
Main results
13 3 7
37.5–300 75–225 225–300
RID, 8.1%; no adverse events reported RID, 5.2%; no adverse events reported No adverse events reported
3
Not reported
No adverse events reported
2 1 1
75 and 225 376 150
No adverse events reported No adverse events reported No adverse events reported
RID, relative infant dose.
Copyright © 2015 John Wiley & Sons, Ltd.
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c. bellantuono
5.2. Detectable concentrations of the drug were found in the breast milk, but no adverse events were reported in the infants. Ilett et al., (2002) studied the transfer of VEN in human breast milk in six women and its safety in their seven infants. Dosages varied from 225 to 300 mg/day. Mean total drug exposure in percent of weight-adjusted dose of the mother was 6.4%; no adverse events were observed in the infants. The excretion of VEN in breast milk was examined in a previous study in which VEN and ODV were detected in breast milk (RID: 7.6%) (Ilett et al., 1998). Misri et al., (2006) reported two cases treated with quetiapine during lactation, which included two women taking additionally VEN (75 and 225 mg/day, respectively). The two babies scored as being within normal limits on the Bayley Scales of Infant Development. Likewise, other two case-reports did not report any adverse effects in breastfed infants whose mother took 375 and 150 mg/day, respectively (Hendrick et al., 2001; Koren et al., 2006); in the latter case, no PCs or health problems were reported in the infant during the first year of follow-up.
clinical indications to be drawn on their safety profile in the newborns exposed. With regard to the use of VEN during pregnancy, the occurrence of MMs has been reported in five studies. In three of these (Einarson et al., 2001; Lennestal and Kallen, 2007; Einarson et al., 2009), the rate of MMs ranged from 1.3% to 3.4%, which is within the range of MMs reported in the general population. In two more recent case-control studies (Polen et al., 2013 and Lind et al., 2013), a small increase in the relative risk of MMs was found, even though the authors did not exclude that these findings could have been affected by residual confounding factors, which they were not able to account for, particularly the severity of maternal depression. It should be considered, in fact, that severe depression itself has been found to be associated with adverse pregnancy outcomes (Grote et al., 2010); consequently, it cannot be excluded that in these studies, women treated with VEN had a more severe depressive illness (Schueler et al., 2011). Conflicting results also emerged for the risk of SA. While Nakhai-Pour et al. (2010) and Kjaersgaard et al. (2013) observed an increased risk of SA in women treated with VEN, another study did not found such association (Einarson et al., 2001). When considering these contradictory results, it should be noted that even the risk of SSRIs in inducing SA still remains to be established (Santone et al., 2009). The risk of PCs in newborns exposed to VEN during late pregnancy has been reported in 10 studies. Withdrawal symptoms were the most frequently reported adverse event; most of the newborns, however, had a spontaneous recovery, and in all cases, the symptoms resolved with an appropriate treatment. In those cases in which the PCs were characterized by neonatal seizures, newborns were successfully treated with phenobarbitone. In the case reported by Hoppenbrouwers et al., (2010), neonatal epileptiform activity was documented through electroencephalography, but missing follow-up after discharge did not provide long-term information. Data from the seven studies on the neonatal safety of VEN during breastfeeding could be considered
DULOXETINE DURING BREASTFEEDING In the two aforementioned case-reports (Briggs et al., 2009; Boyce et al., 2011), no adverse reactions were registered in the breastfed infants; in both cases, the dose was 60 mg/day, and the RID was 0.81% (Table 4). Recently, it has been reported that the infant exposure to DUL in breast milk is
