Antidepressivo Sereupin: va sospeso in gravidanza? Lo psichiatra dice sì, il ginecologo dice no

Elisa Valmori

Buongiorno signora, come si suol dire “calma e gesso!” Mi sento di rassicurarla completamente sul fatto che il Sereupin (ossia la paroxetina, principio attivo di Sereupin) è un farmaco non solo privo di rischi malformativi sul feto ma anche con minimi effetti collaterali sul versante materno, tanto che è tra i farmaci di scelta sia in gravidanza sia in allattamento per trattare patologie di tipo ansioso e/o depressivo. Capisco di darle un’informazione in contrasto con quella espressa dal collega curante psichiatra. Per completezza allego alla mia risposta alcuni articoli tratti dal database americano Reprotox di cui mi avvalgo per le mie consulenze. Alcuni ritengono che la Paroxetina possa indurre malformazioni cardiache nei feti ma questo (fortunatamente) non è vero. In ogni caso, nulla vieta di effettuare controlli ecografici approfonditi per essere certi che il piccolo stia bene da tutti i punti di vista, per esempio effettuando un’ecografia denominata traslucenza nucale verso la fine del primo trimestre. Oppure un altro esame denominato ecocardiografia fetale, qualora il ginecologo curante lo ritenga opportuno. Insomma, mi sembra davvero drastico l’approccio del curante psichiatra intenzionato a sospendere del tutto una terapia che per giunta è attualmente ad un dosaggio davvero contenuto e mi auguro che i miei colleghi possano trovare utili le informazioni che le allego. Eventualmente, si potrebbe decidere di proseguire il suo trattamento con Sertralina invece di paroxetina, a patto di utilizzare un dosaggio adeguato a contenere i sintomi ansiosi e/o depressivi. In gravidanza i farmaci vengono eliminati con notevole rapidità quindi è opportuno non essere troppo “tirchi” nei dosaggi, se non vogliamo che la mamma viva la cosiddetta “dolce attesa” come un incubo. Mi piace ripetere che il bambino sta bene se sta bene la sua mamma e che in gravidanza, specie se la prima, i cambiamenti cui si va incontro sono tali e tanti che è prudente mantenere un sottofondo di terapia, riservandosi la possibilità di sospenderla non certo prima ma casomai dopo il parto, ad allattamento bene avviato…quindi senza alcuna fretta. Spero di averla rincuorata, le ricordo l’assunzione di acido folico 1 compressa da 400 microgrammi al giorno, per tutto il tempo di ricerca della gravidanza e almeno il primo trimestre della stessa, se possibile lontano da the e latticini. La saluto cordialmente.

Allegati: 1) PAROXETINE Agent Number 3590 CAS Number 61869-08-7 Last Updated 10/24/2020 Agent Summary Quick take: Paroxetine has been associated with cardiovascular abnormalities in some epidemiology studies but not others. Experimental animal studies do not suggest an increased risk of congenital anomalies. Use of paroxetine late in pregnancy can be associated with a mild transient neonatal syndrome of central nervous system, motor, respiratory, and gastrointestinal signs. Long-term neurodevelopmental studies suggested that antenatal exposure to fluoxetine, sertraline, or paroxetine does not adversely affect outcome, unlike maternal depression. (*Note: Anthony Scialli, M.D., Director of the Reproductive Toxicology Center, has been a consultant for GlaxoSmithKline and has testified in paroxetine litigation. Shari I. Lusskin, MD, a contributor to this summary, has been a consultant to Pfizer regarding sertraline litigation and to Forest regarding escitalopram litigation). ________________________________________ Paroxetine is a serotonin reuptake inhibitor used in the treatment of depression and anxiety disorders. Other names include Paxil, Aropax, and Seroxat. Paroxetine is marketed as Brisdelle for menopausal hot flashes. Dosage increase during pregnancy may be necessary to maintain a therapeutic level (120,124, 125). Experimental animal studies Animal pregnancy testing has been performed in rats and rabbits (1). Rabbits given up to 6 mg/kg/day showed no increase in congenital abnormalities in the offspring. In rats, up to 50 mg/kg/day was given without an increase in offspring anomalies; however, there was a decrease in fertility and in viable pregnancies in rats given 13 mg/kg/day or more. According to the product labeling, paroxetine did not produce adverse effects on the offspring of pregnant rats and rabbits treated with 50 and 6 times the recommended human dose on a mg/kg basis (10 and 2 times the dose on a mg/square meter basis). Adverse fertility effects were noted in mating rats given 15 times the human dose on a mg/kg basis (4.4 times on a mg/square meter basis), with atrophy of the seminiferous tubules in males. One study in rats found that administration of paroxetine 10 mg/kg/day during the last week of gestation decreased the length of gestation, birth weight, and neonatal survival (57). A study in pregnant mice used a dietary paroxetine dose level of 30 mg/kg/day to produce serum drug concentrations at the upper limit of those achieved clinically (6). There was a decrease in male pup weight that did not persist after 5 days of age. There were no facial abnormalities and no abnormalities of pup development except a delay in incisor eruption. Reproductive capability of the offspring was unaffected by paroxetine exposure. Mouse offspring exposed in utero to paroxetine at a maternal dietary dose of 30 mg/kg/day were not different from controls on cognitive or behavioral testing except for an increase in vocalizations in response to separation from the mother (7,40). Reproductive function in the offspring was also normal. Clinical trial reports A one-year postmarketing survey conducted in England identified 63 pregnancies that included first trimester exposure to paroxetine (2). Among the outcomes of these pregnancies there were nine spontaneous abortions, 12 elective terminations, and nine unknown outcomes. Of three sets of twins, one twin was stillborn. There were no congenital anomalies in the liveborn infants. Another series reported three pregnancies exposed to paroxetine, all of which resulted in normal infants (4). Serotonin reuptake inhibitors as a group Serotonin reuptake inhibitors share some pharmacologic features but are also different in some regards. Studying pregnancies exposed to these medications as a group is not likely to be informative about individual medications in the group, but such studies have been published. We have collected the studies on serotonin reuptake inhibitors as a group in summary #4481. Examples of studies that include paroxetine exposures are references 5,31-33,41,60, 74,80, 89-91. Studies specifically on paroxetine during pregnancy A pregnancy registry for psychiatric medications, including this one, has been organized at the Massachusetts General Hospital. Contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Placental passage of paroxetine has been shown at term with cord blood concentrations about half or less of maternal blood concentrations (48,49). A report on 463 paroxetine-exposed pregnancies identified by teratogen information services stated that there was an increase in cardiovascular malformations; however, after adjustment for potential confounders, a statistically significant increase in risk was not identified (adjusted OR 2.66; 95% CI 0.80-8.90) (12). An abstract from a Canadian teratology information service pooled outcomes in 1013 infants from 8 information services worldwide (58). The incidence of congenital heart disease was 0.7%, which was identical to the incidence in a comparison group constructed by the Canadian service . A subsequent publication from the Canadian service identified 5 malformed infants among 148 pregnancies exposed to paroxetine (68). The malformations were pulmonary hypoplasia, ventricular septal defect, clinodactyly, cleft lip and palate, and omphalocele. A case-control study from the CDC National Birth Defects Prevention Study (NBDPS) reported that any serotonin reuptake inhibitor exposure increased the risk for anencephaly (OR 2.4, 95% CI 1.1-5.1), craniosynostosis (OR 2.5; CI 1.5-4.0), and omphalocele (OR 2.8; CI 1.3-5.7) (27). Paroxetine use was associated with anencephaly (OR 3.2, 95% CI 1.1-9.3), right ventricular outflow obstruction (OR 2.5, 95% CI 1.0-6.0), omphalocele (OR 8.1, 95% CI 3.1-20.8), and gastroschisis (OR 2.9, 95% CI 1.0-8.4). The authors pointed out that the study was limited by the use of multiple comparisons, giving rise to the possibility of chance associations. In addition, the number of affected children in each malformation group was small, ranging from 5 to 7. No association between paroxetine and cardiac septal defects was identified. Gastroschisis was not associated with paroxetine exposure (121). A case-control study from the Slone Epidemiology Birth Defects study (55) used maternal report of medication exposure during pregnancy to evaluate possible associations with malformations in the offspring. The study included 9849 infants with malformations and 5860 control infants. There was an association between paroxetine use and right ventricular outflow defects (OR 3.3, 95% CI 1.3-8.8) but not other cardiac abnormalities. Paroxetine use was also associated with parent-diagnosed clubfoot (OR 5.8, 95% CI 2.6-12.8), undescended testes (OR 2.8, 95% CI 1.0-7.8), and neural tube defects (OR 3.3, 95% CI 1.1-10.4). The authors did not adjust for multiple testing, raising the likelihood of chance associations. A subsequent study from the Sloan Epidemiology Center did not confirm a statistically significant increased risk for orthopedist-diagnosed clubfoot with presumed paroxetine exposure during the second or third lunar month of pregnancy, adjusting for maternal smoking, alcohol use, and body mass index (adjusted odds ratio 9.2, 95% CI 0.7-484.6) (112). An unpublished case-control study using an insurance data base and medical record review identified a possible association between prescription of paroxetine in the first trimester and congenital heart disease in offspring (28). This study was performed as part of an evaluation by the manufacturer of pregnancy effects of bupropion (#1238). In the evaluation of bupropion, other antidepressant medications were used as a comparator group and were examined individually. There were 14 children with cardiovascular defects among 704 pregnancies with first trimester prescription of paroxetine (prevalence 2%), giving an odds ratio (95% CI) of 2.08 (1.09-3.96) using other antidepressant pregnancies as a reference group. Of the 14 children with cardiac defects, 9 included ventricular septal defect. When this study was subsequently published, there was an association between paroxetine prescription during the first trimester of pregnancy and congenital malformation in the offspring (adjusted odds ratio 1.89, 95% CI 1.20-2.98) (59). The adjusted odds ratio for cardiovascular malformations was 1.46 (95% CI 0.74-2.88), which is not a statistically significant increase. A study from 5 HMOs using insurance records identified 182 infants whose mothers received a paroxetine prescription during the first trimester of pregnancy (60). Four of these children had a cardiovascular malformation (include 1 septal defect) compared to 1184 of 49,654 children not exposed to paroxetine. There was no significant difference between these rates. A letter-to-the-editor (30) used the Swedish Medical Birth Register to investigate a possible association between paroxetine and congenital heart disease. The association for paroxetine was statistically significant with an odds ratio of 2.22 (95% CI 1.39-3.55). Antidepressants as a group and other individual antidepressants were not associated with congenital heart disease, with the exception of clomipramine (#1262), for which the odds ratio was 1.87 (95% CI 1.16-2.99). Ventricular and atrial septal defects showed the strongest associations among the individual malformations. These results were subsequently published after the inclusion of additional subjects (42). The odds ratio for total malformations and paroxetine was 1.03 (95% CI 0.76-1.38), the odds ratio for cardiac malformations was 1.63 (95% CI 1.05-2.53), and the risk estimate for atrial or ventricular septal defect was 1.81 (95% CI 0.96-3.09). When obese women and women using neuroleptics, sedatives, hypnotics, folic acid, NSAIDs, or anticonvulsants were excluded, the odds ratio for any cardiac defect (based on 12 cases) was 2.93 (95% CI 1.52-5.13), and the odds ratio for atrial or ventricular septal defect (based on 7 cases) was 3.23 (95% CI 1.30-6.65). When the results of the Swedish Medical Birth Registry were updated in 2010, there was no increase in the risk of what the authors called relatively severe malformations, presumably excluding minor muscular VSDs (105). The odds ratio for any cardiovascular defect was 1.66 (95% CI 1.09-2.53), and the odds ratio for hypospadias was 2.45 (95% CI 1.12-4.64). In a 2013 update, again there was no association of paroxetine with relatively severe malformations (106). The odds ratio for any cardiovascular malformation was 1.63 (95% CI 1.17-2.27). Septum defects accounted for 24 of the 34 paroxetine-exposed children with cardiovascular defects. The hypospadias risk estimate was no longer statistically significant in the 2013 update. An abstract from a Canadian group reported results from a population-based registry linked to administrative data bases. Among 24 infants with cardiac anomalies, there was no statistically significant association with recorded maternal paroxetine usage (44). A full publication from this group (45) reported that although the OR was not significantly elevated for paroxetine exposure, when restricted to doses of >25 mg/day, the OR was 3.07 (95% CI 1.00-9.42) based on 5 exposed cases. A 2017 study from this group using insurance data bases in Quebec compared offspring of women with an antidepressant prescription during the first trimester of pregnancy with offspring of women with a prescription during the year prior to pregnancy but not during the first trimester of pregnancy (115). There was no association of major congenital malformations overall and paroxetine, and there were no associations of paroxetine with malformations of individual organ systems except for cardiac malformations, adjusted OR 1.45, 95% CI 1.12-1.88. An association with septal defects was marked as statistically significant, although the 95% CI included 1.00 (adjusted OR 1.39, 95% CI 1.00-1.93). A supplemental table showed the 99% CI of the risk estimate for cardiac malformations and paroxetine to include 1.00 (0.87-2.03), suggesting a possible influence of multiple comparisons on the finding. A study from a German teratology information service, presented in abstract (38) reported 119 paroxetine-exposed pregnancies, of which 18 were electively terminated and 13 spontaneously aborted. Among the remaining 88 pregnancies, there were 3 children with congenital malformations including 1 each with club feet, a large flame nevus, and spastic torticollis. The authors did not find the overall rate of spontaneous abortion or congenital malformations different from that in a comparison group. An abstract from French teratology information services reported an association between pregnancy use of paroxetine and spontaneous abortion (RR 2.6, 95% CI 1.8-4.3). The relative risk for congenital malformations was 1.4 (95% CI 0.6-3.3). There were 683 paroxetine-exposed pregnancies in this sample. Three children each in the paroxetine-exposed and control group had cardiac malformations (46). A case-control study conducted in Quebec examined spontaneous abortion in women who had filled at least one prescription for an antidepressant during pregnancy (79). The study authors concluded that there was an increased risk of miscarriage associated with paroxetine alone (OR 1.75, 95% CI 1.31-2.34). Limitations included the inability to confirm antidepressant exposure, lack of adjustment for tobacco, alcohol, and illicit drug use, and inadequate adjustment for the severity of maternal mental illness. A study from the Denmark Medical Birth Registry from 1997-2010 concluded there was no significant difference in the risk of miscarriage with exposure to paroxetine during the first 35 days of pregnancy (hazard ratio 1.27; 95% CI 1.14-1.42) versus discontinuing paroxetine 3-12 months before pregnancy (hazard ratio 1.20; 95% CI 1.05-1.37) when compared to unexposed women (104). Retrospective review of an obstetrical data base at Mayo Clinic identified 119 women believed to be exposed to paroxetine during pregnancy, 111 of whom may have been exposed during the first trimester (69). There were no diagnoses of ventricular septal defect among the offspring. It is not clear in this study how outcome information was obtained. Examination of outcome information for 24,406 pregnancies in the data base without exposure to paroxetine gave a prevalence of ventricular septal defect diagnosis of 0.1%. A registry-linkage study from Denmark reported no significant association between paroxetine use during pregnancy and total congenital malformations (OR 1.41, 95% CI 0.79-2.51), heart defects (OR 0.88, 95% CI 0.22-3.55), or septal defects (OR 0.76, 95% CI 0.11-5.43) (71). There were 299 paroxetine-exposed pregnancies in this study, 3 of which gave rise to children with heart defects. In contrast, a subsequent publication using the same registry (and perhaps including some of the same patients) did not find a statistically significant association between paroxetine and any malformation, non-cardiac malformations, cardiac malformations, or cardiac septal defects (73). Another publication from the Danish medical birth registry showed no increase in total cardiovascular, total septal, or ventricular septal defects, but reported an increase in atrial septal defects with exposure to paroxetine (OR 3.51, 95% CI 1.57-7.87) (99). This study reported increases in total cardiovascular and septal defects associated with use of some serotonin reuptake inhibitors during pregnancy in women who took medication during pregnancy or in women who only took medication before and after pregnancy but not during pregnancy, suggesting confounding by indication. A data base linkage study from Western Australia did not show a statistically significant increase in heart defects among the offspring of women taking paroxetine during pregnancy), although there was an increase in anomalies of the pulmonary artery (75,76). There was no increase in total birth defects or other individual birth defects. This study was unable to adjust for use of ethanol or illicit drugs. Birth weight and gestational age were reduced in paroxetine-exposed pregnancies and in pregnancies exposed to other serotonin reuptake inhibitors, suggesting a possible effect of the underlying illness. A study from Finland used a prescription data base to identify early pregnancy exposures to paroxetine and registers of births and congenital malformations to identify pregnancy outcomes (77). Paroxetine prescription was associated with an increase in right ventricular outflow tract defects in the offspring based on 3 exposed cases (adjusted odds ratio 4.68, 95% confidence interval 1.48-14.74). There was no significant association between paroxetine prescription and atrial or ventricular septal defects, other heart defects, or other categories of malformations. A case-control study was conducted in the Netherlands using a population-based birth defects registry (81). Using data collected between 1997 and 2006, 678 fetuses and children with isolated cardiac defects were compared with 615 controls (fetuses and children who had a genetic defect but no heart defects). Based on three exposed cases, the adjusted odds ratio for having an atrial septal defect was increased if the mother had filled a prescription for paroxetine between one month prior to pregnancy and the end of the first trimester (adjusted OR 5.7; 95% CI, 1.4-23.7). No association was found between heart malformations as a group and presumed paroxetine exposure, based on 10 exposed cases (AOR 1.5; 95% CI 0.5-4.0). A study in Norway did not find an association between use of paroxetine during pregnancy and total malformations, major malformations, or cardiovascular malformations in the child (98). Exposure was ascertained based on maternal questionnaires during the prenatal period. The study was limited by a low participation rate. A 2014 cohort study using prospectively recorded information from a British general practitioner data base found an association between paroxetine use during the first trimester and congenital heart defects when pregnancies in non-depressed women were used as the control (adjusted OR 1.78, 95% confidence interval 1.09-2.88) (102). When women with untreated depression were used as controls, the risk estimate decreased and was no longer statistically significant (adjusted OR 1.67, 95% confidence interval 1.00-2.80, P = 0.051). The authors noted that some chance associations would be expected based on the large number of comparisons in the study. No association was found with abnormalities of other organ systems using either a depressed or non-depressed control group. A study using US Medicaid claims data did not find an increase in any cardiac malformation, right ventricular outflow tract obstruction, or ventricular septal defect associated with prescription of paroxetine during the first trimester of pregnancy after adjustment for maternal illness (103). In a population-based case-control study from Denmark, Finland, Iceland, Norway, and Sweden using nationwide health registers and prescription databases, there were 2879 live born infants with presumed first trimester exposure to paroxetine (118). There were no statistically significant increases in the risk estimates for all major malformations combined, any cardiac defects, or atrial and ventricular septal defects. There were statistically significant increases in the risk estimates for conotruncal and major arch anomalies (adjusted odds ratio 2.27, 95% CI 1.01-5.07) and right ventricular outflow tract obstruction (adjusted odds ratio 2.54, 95% CI 1.31-4.90). The study did not adjust for confounding by indication and no adjustment was made for multiple comparisons. In a sibling-controlled analysis that combined exposures to all serotonin reuptake inhibitors, there were no statistically significant increases in the risk estimates for all malformations combined, any cardiac malformation, or right ventricular outflow tract obstructions, lending support to the theory that the increased point estimates for certain malformations might be due to confounding by indication or other confounding. A case-control study from the U.S. National Birth Defects Prevention Study of births from 1997-2009 examined rates of congenital malformations that had been reported previously in the literature in association with serotonin reuptake inhibitor exposure using maternal recall to ascertain exposure (119). There were 165 cases and controls with presumed first trimester exposure to paroxetine. Using a special analysis to look for consistency with prior reports, the authors found no statistically significant increases in the risk estimates for cleft palate or hypospadias, defects previously reported in association with paroxetine. They reported statistically significant increased risk estimates for anencephaly (posterior odds ratio 3.2, 95% CI 1.6-6.2), atrial septal defects (posterior odds ratio 1.8, 95% CI 1.1-3.0), right ventricular outflow tract obstruction (posterior odds ratio 2.4, 95% CI 1.4-3.9), gastroschisis (posterior odds ratio 2.5, 95% CI 1.2-4.8), and omphalocele (posterior odds ratio 3.5, 95% CI 1.3-8.0). The group of studies used for the prior risk estimates was incomplete. The authors did not include the studies by Jimenez-Solem et al. 2012 (99) or Huybrechts et al. 2014 (103), neither of which found a significant association between serotonin reuptake inhibitor exposure and various malformations when adjusting for indication. Paroxetine exposure during the first trimester compared to any antidepressant outside of the first trimester was associated with anomalous pulmonary venous return, aOR 4.29, 95% CI 1.13-16.32, anencephaly and cranioarachischisis, aOR 3.76, 95% CI 1.06-13.33, and gastroschisis, aOR 2.30, 95% CI 1.03-5.14 (123). The findings were adjusted for maternal education but not other potential confounding factors. A congenital anomaly registry compared rates of serotonin reuptake inhibitor exposure between cases with congenital heart defects or other malformations previously reported in association with exposure and controls who had other types of malformations (111). For presumed paroxetine exposure, the study failed to confirm prior associations with eye defects, gastroschisis, or hypospadias but reported an association with clubfoot (adjusted odds ratio 2.99, 95% CI 1.44-6.21). The study reported an increased risk estimate for septal defects as a group (adjusted odds ratio 1.92, 95% CI 1.09-3.37), ventricular septal defects (adjusted odds ratio 1.91, 95% CI 1.03-3.98), and ventricular septal defects without severe congenital heart defects (adjusted odds ratio 2.12, 95% CI 1.15-3.92). There were no adjustments for psychiatric disorders, additional medication exposures, or lifestyle factors. Linkages of congenital malformation registries in Wales, Norway, and Denmark and prescription data bases were used to evaluate associations with serotonin reuptake inhibitors combined; data for individual agents were presented in an appendix (113). For paroxetine, there was an increase in congenital heart defects, odds ratio 1.76, 95% CI 1.09-2.85, but no increase in severe congenital heart defects. There was an increase in ventricular septal defect, OR 2.61, 95% CI 1.47-4.62. These findings are consistent with biased ascertainment of transient ventricular septal defects. There were no increases in total anomalies or hypospadias with inadequate numbers of exposed cases to evaluate neural tube defects, anorectal atresia/stenosis, abdominal wall defects, renal dysplasia, limb reduction, or orofacial clefts. In 2007, an American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin advised that pregnant women and women planning pregnancy avoid use of paroxetine when possible but also noted that treatment decisions should be individualized to minimize the risk of relapse of depression (39). Two years later, a joint task force of ACOG and the American Psychiatric Association published an evaluation of antidepressant use during pregnancy in which the lack of consistency of the paroxetine studies was noted (72). The task force noted that media stories about possible risks of paroxetine use during gestation might prompt some women to avoid this medication. It was noted that the risk of relapse should be clearly discussed with women for whom paroxetine was proven to be uniquely effective in their treatment before substituting an alternative agent. An administrative data base study reported that women with a diagnostic code for pregnancy induced hypertension were more likely to have filled a prescription for paroxetine during pregnancy, aOR 1.81, 95% CI 1.02-3.23 (97). The study adjusted for the presence of depression or anxiety but not for disease severity. Use of tobacco, ethanol, or illicit drugs was not assessed. There was no association between prescription of paroxetine and a diagnosis of preeclampsia in a different insurance data base study (127). Meta-analyses A 2006 meta-analysis on serotonin reuptake inhibitors and pregnancy (43) reported a summary OR for major malformations of 1.39 (95% CI 0.91-2.15) and a summary OR for cardiovascular malformations of 1.19 (95% CI 0.53-2.68). The summary OR for spontaneous abortion was 1.7 (95% CI 1.28-2.24). Individual medications were not separately analyzed. A meta-analysis in 2007 evaluated 7 eligible studies and identified a summary odds ratio of 1.72 (95% CI 1.22-2.42) for cardiovascular malformation and first-trimester paroxetine exposure (61). This study also found that women taking antidepressants were more likely than women not taking antidepressants to have diagnostic imaging during pregnancy and that their children were more likely to have echocardiograms during the first year of life, raising the possibility that exposed children with transient septal defects were more likely to have those defects diagnosed than unexposed children. This paper also found that paroxetine was more likely than other antidepressant medications to be prescribed for anxiety and panic disorder. The same investigators subsequently published a calculation based on reports on 1174 infants from 8 teratology information services showing no increase in cardiovascular malformations in paroxetine-exposed infants compared to controls (62). When subjects from published data bases were also considered, the rate of cardiovascular malformations was 1.2%, which is comparable to the general population background rate for this group of anomalies. A subsequent meta-analysis from this group, which included unpublished data, did not identify a statistically significant association between paroxetine exposure during pregnancy and congenital cardiac malformations (67). A meta-analysis sponsored by GlaxoSmithKline, which marketed Paxil, identified a summary odds ratio for congenital defects at 1.24 (95% CI 1.08-1.43) and for heart defects 1.46 (95% confidence interval 1.17-1.82) (70). The meta-analyses used somewhat different methods and neither meta-analysis included all available studies. A meta-analysis in 2013 included 11 studies and reported a risk estimate for heart defects of 1.25, 95% confidence interval 1.01-1.54 (100). An additional meta-analysis in 2013 of 19 studies found a small increased risk for cardiovascular malformations (RR = 1.36; 95% CI, 1.08-1.71; P = 0.008) and septal heart defects (RR = 1.40; 95% CI, 1.10-1.77; P = .005) but no association with total congenital malformations (RR = 0.93; 95% CI, 0.85-1.02; P = 0.113) or major malformations (RR = 1.07; 95% CI, 0.99-1.17; P = 0.095) (101). A 2014 systematic review and meta-analysis that was conducted for the Agency for Healthcare Research and Quality on the use of antidepressant drugs during pregnancy and postpartum examined reports published between 1946 and July 2013 (107). Using data from 11 studies that reported on presumed paroxetine exposure during pregnancy, the pooled adjusted odds ratio for major malformations was 1.17 (95% confidence interval 1.02-1.35) with a combined sample size of 4,192,613. The studies included in the analysis adjusted for at least two of four key confounding factors: race, parity, age, and potentially toxic exposures including smoking, alcohol, and others. After limiting the analysis to the 6 studies that adjusted for at least three of four key confounding factors, the pooled adjusted odds ratio was 1.20 (95% confidence interval 1.03-1.41). A second analysis was conducted to examine the risk of cardiac malformations following presumed intrauterine paroxetine exposure. A pooled analysis of data from 6 studies yielded an adjusted odds ratio for cardiac malformations of 1.49 (95% confidence interval 1.20-1.85). In a sensitivity analysis limited to the 5 studies that used additional methods to identify serious cardiac malformations, the pooled odds ratio was 1.45 (95% confidence interval 1.13-1.85). A meta-analysis of 4 prospective cohort studies reported data for individual serotonin reuptake inhibitors from 3 of the studies (110). The authors concluded that there was no increased risk estimate for cardiovascular defects in association with presumed paroxetine exposure (adjusted odds ratio 0.97, 95% confidence interval 0.75-1.19). While the results were consistent with one prior meta-analysis, the findings are limited by the inclusion of only 3 studies. A 2016 meta-analysis reported an increase in major malformations and in cardiac malformations associated with paroxetine use during the first trimester (111). The findings lost statistical significance when the control group included women on other serotonin reuptake inhibitors or other anti-depressant medications, consistent with confounding by indication. The authors discounted that lack of statistical significance by indicating that all risk estimates were above unity. Neonatal and childhood effects of pregnancy exposure to paroxetine Adverse effects in neonates exposed to paroxetine and other serotonin reuptake inhibitors prenatally have been described in a variety of reports, including individual cases, prospective studies, and a data mining investigation of the large WHO data base of adverse drug reactions (11,13,15,17-24,26, 34, 35,47,88,108). The adverse effects reported included respiratory distress and persistent pulmonary hypertension (34,66), jitteriness, irritability, vomiting, and convulsions. In most cases, the symptoms were mild and disappeared by 2 weeks of age with no treatment or with only supportive care (26). One series identified four neonates who also developed necrotizing enterocolitis, although all the infants in this report were also prenatally exposed to other drugs (15). Respiratory distress and other abnormalities of neonatal adaptation were described more frequently in infants exposed to paroxetine than with other serotonergic antidepressants, although the actual relative frequency is not known (e.g.13,22,25). It is possible that these symptoms gave rise to more diagnostic cardiovascular studies in paroxetine-exposed children, increasing the likelihood that a cardiac malformation would be identified. In an unblinded cohort study in which mother-infant pairs exposed to serotonergic antidepressants in the third trimester were admitted for observation after delivery, there were 49 infants exposed to paroxetine monotherapy among whom 34 had signs of poor neonatal adaptation (108). Poor neonatal adaptation was defined as a Finnegan score of at least 4 on one occasion in the 72-hour observation period. There was no relationship to dose. An unspecified number of children were breastfed. Exclusive formula feeding was associated with a 3-fold higher rate of poor neonatal adaptation compared to partial or complete breastfeeding. It was concluded that neonates exposed prenatally to serotonin reuptake inhibitors can be evaluated for signs of adverse effects, but the incidence and severity of these effects do not appear to be so frequent or severe that women should avoid using these medications if they are otherwise indicated (25,109). Some commentators suggested that paroxetine has a particular receptor profile that includes noradrenergic and muscarinic blockade, giving rise to adverse neonatal effects (25). There is an ongoing debate about whether the adverse effects seen in some neonates are due to withdrawal or, toxicity, or should be considered more broadly as “side effects.” (16,25). The risk of developing neonatal behavioral symptoms might be mediated by infant serotonin transporter promoter genotype (56). Persistent Pulmonary Hypertension of the Newborn In July, 2006, the FDA issued a public health advisory about a possible link between in-utero exposure to serotonin reuptake inhibitors and PPHN (92). On 12/14/11 the FDA issued an FDA Drug Safety Communication that retracted the warning (93). The FDA stated that “The initial Public Health Advisory in July 2006 on this potential risk was based on a single published study. Since then, there have been conflicting findings from new studies evaluating this potential risk, making it unclear whether use of SSRIs during pregnancy can cause PPHN. FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.” For a discussion of the studies (including 66, 69, 94-96) please see summary #4481. Neurodevelopment Neurodevelopmental outcome data were collected from an ongoing cohort study at the University of British Columbia, comparing serotonin reuptake inhibitor-exposed mother-infant pairs with healthy, unmedicated control pairs (22,36,37,54). Diminished pain response was demonstrated in 38 newborn infants with prolonged prenatal exposure either to serotonin reuptake inhibitors alone (N=22: fluoxetine, paroxetine, or sertraline) or to serotonin reuptake inhibitors plus clonazepam #1384 (N=16) compared with 23 unmedicated controls (22). There were 11 infants exposed to paroxetine alone and 14 to paroxetine plus clonazepam. None of the babies required admission to a special care nursery or the neonatal intensive care unit. Neurodevelopmental outcome of children exposed at least during the third trimester to a serotonin reuptake inhibitor (paroxetine, fluoxetine, or sertraline) or to paroxetine plus clonazepam was prospectively studied in 46 mother-child pairs and 23 healthy, unmedicated control pairs (36) While transient neonatal symptoms (mostly respiratory) occurred in 30% of the exposed group compared to 9% of the control group, there were no differences in developmental outcomes between the symptomatic or asymptomatic infants or between the exposed or unexposed infants at 2 and 8 months. Some of the infants were also exposed postnatally through breastfeeding. A follow-up study evaluated internalizing and externalizing behaviors at age 4-5 years in the same cohorts (37, 54). All of the mothers remained on medication, but due to attrition, the study groups were reduced to 22 exposed and 14 unexposed mother-child pairs. The rates of internalizing behaviors (emotional reactivity, withdrawal, irritability, depression, or anxiety) and externalizing behaviors were no different between the groups when using parent, teacher, or clinician ratings. The degree of current maternal depression was negatively associated with parental ratings, suggesting that parental mood affects child development independent of antenatal medication exposure. A case control study in 2011 using medical records from a health maintenance organization reported an association between a prescription for serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine) and a diagnostic code for autism spectrum disorder in the offspring (78). The findings were not statistically significant when adjusted for demographic factors including maternal mental illness except with respect to first trimester exposure (adjusted odds ratio 3.5, 95% confidence interval 1.5-7.9). The study neglected to adjust for paternal psychiatric disease or exposure to tobacco, ethanol, or illicit drugs, and the study neglected to show an analysis that excluded families with other affected children, a known risk for autism spectrum disorder. A record-linkage study comparing pregnancies with a paroxetine prescription with pregnancies with a maternal mental illness diagnosis but no antidepressant prescription did not find an association with autism spectrum disorder in the child (117). For a discussion of other studies on autism outcomes, please refer to summary #4481. Reproductive effects Sexual dysfunction (including decreased desire, decreased arousal, and delayed orgasm or anorgasmia) has been reported with all serotonergic antidepressants including paroxetine (82). Paroxetine has been used to treat premature ejaculation (116). Galactorrhea, both with and without hyperprolactinemia, has been reported with paroxetine exposure (83-86). The only symptom of hyperprolactinemia in men can be decreased libido (87). Thirty-five normal volunteers treated with paroxetine for 5 weeks had increases in a sperm assay for DNA fragmentation without a change in standard semen analysis end points (63). There was also a decrease in serum testosterone and estradiol and worsening of erectile and ejactulatory function. DNA fragmentation in sperm might impair fertility, particularly for assisted reproductive techniques (64). However, not all studies have found a clear correlation between the degree of DNA fragmentation in sperm and successful outcomes in intracytoplasmic sperm injection (ICSI #4219) (65). The authors of the study suggested that alterations in sperm transport rather than sperm production might be responsible for the observed changes in DNA fragmentation. They did not comment on possible differences between the pre-paroxetine and on-paroxetine samples in the length of time the sperm were present in the genital duct system prior to sample collection. Men given paroxetine had a decrease in ejaculatory function, and the increase in DNA fragmentation might have reflected aging of sperm in the genital tract. Lactation Paroxetine is excreted in human milk (3,8-10,14,29,50-52). The mean dose of paroxetine received by the infants was estimated at 1.13% (range 0.5 to 1.7) of the weight-adjusted maternal dose, with a milk:plasma ratio of about 0.2 (10). 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Acta Paediatr. 2015;104(4):384-91. doi:10.1111/apa.12921. 109. Grigoriadis S, Vonderporten EH, Mamisashvili L, Eady A, Tomlinson G, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Ross LE. The effect of prenatal antidepressant exposure on neonatal adaptation: a systematic review and meta-analysis. J Clin Psychiatry. 2013;74(4):e309-20. doi:10.4088/JCP.12r07967. 110. Wang S, Yang L, Wang L, Gao L, Xu B, Xiong Y. Selective Serotonin Reuptake Inhibitors (SSRIs) and the Risk of Congenital Heart Defects: A Meta-Analysis of Prospective Cohort Studies. Journal of the American Heart Association. 2015;4(5). doi:10.1161/jaha.114.001681. 111. Berard A, Iessa N, Chaabane S, Muanda FT, Boukris T, Zhao J-P. The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis. Br J Clin Pharmacol 2016; doi: 10.1111/bcp.12849. 112. Yazdy MM, Mitchell AA, Louik C, Werler MM. Use of selective serotonin reuptake inhibitors during pregnancy and the risk of clubfoot. Epidemiology 2014;25(6):859-865. 113. Jordan S, Morris JK, Davies I, Tucker D, Thayer DS, Luteijn JM, Morgan M, Garne E, Hansen AV, Klungsoyr K, Engeland A, Boyle B, Dolk H. Selective serotonin reuptake inhibitor (SSRI) in pregnancy and congenital anomalies: Analysis of linked databases in Wales, Norway and Funen, Denmark. PLOS One 2016; DOI:10.1371/journal.pone.0165122 114. Uguz F, Arpaci N. Short-Term Safety of Paroxetine and Sertraline in Breastfed Infants: A Retrospective Cohort Study from a University Hospital. Breastfeed Med. 2016;11:487-9. doi:10.1089/bfm.2016.0095. 115. Berard A, Zhao J-P, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: An updated analysis of the Quebec Pregnancy Cohort. BMJ Open 2017;7:e013372. doi:10.1136/bmjopen-2016-013372 116. Salem AM, Kamel II, Rashed LA, GamelEl Din SF. Effects of paroxetine on intravaginal ejaculatory latency time in Egyptian patients with lifelong premature ejaculation as a function of serotonin transporter polymorphism. Int J Impotence Res 2017;29:7-11. 117. Rai D, Lee BK, Dalman C, Newschaffer C, Lewis G. Magnusson C. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ 2017;358:j2811. http://dx.doi.org/10.1136/bmj.j2811. 118. Furu K, Kieler H, Haglund B, Engeland A, Selmer R, Stephansson O, Valdimarsdottir UA, Zoega H, Artama M, Gissler M, Malm H, Norgaard M. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. Bmj. 2015;350:h1798. doi:10.1136/bmj.h1798. 119. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA. Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. Bmj. 2015;351:h3190. doi:10.1136/bmj.h3190. 120. Westin AA, Brekke M, Molden E, Skogvoll E, Spigset O. Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition. PLoS One. 2017;12(7):e0181082. doi:10.1371/journal.pone.0181082. 121. Werler MM, Guery E, Waller DK, Parker SE. Gastroschisis and cumulative stressor exposures. Epidemiology. 2018. doi:10.1097/ede.0000000000000860. 122. Uguz F.Short-term safety of paroxetine plus low-dose mirtazapine during lactation. Breastfeed Med. 2019;14(2):131-2. doi:10.1089/bfm.2018.0197. 123. Anderson KN, Lind JN, Simeone RM, Bobo WV, Mitchell AA, Riehle-Colarusso T, Polen KN, Reefhuis J. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA psychiatry. 2020. doi:10.1001/jamapsychiatry.2020.2453. 124. Schoretsanitis G, Spigset O, Stingl JC, Deligiannidis KM, Paulzen M, Westin AA.The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis. Expert opinion on drug metabolism & toxicology. 2020;16(5):431-40. doi:10.1080/17425255.2020.1750598. 125. Javelot H, Fichter A, Meyer G, Michel B, Hingray C.A case of paroxetine-induced antidepressant discontinuation syndrome related to pregnancy: time to redefine the syndrome? Psychiatry Res. 2020;291:113259. doi:10.1016/j.psychres.2020.113259. 126. Palmsten K, Huybrechts KF, Michels KB, Williams PL, Mogun H, Setoguchi S, Hernandez-Diaz S. Antidepressant use and risk for preeclampsia. Epidemiology 2013;24(5):682-691. /ars 2)SEROTONIN REUPTAKE INHIBITORS Agent Number 4481 CAS Number NONE Last Updated 05/20/2018 Agent Summary Quick take: This summary presents information from studies performed on serotonin reuptake inhibitors as a group. More definitive information may be obtained from the individual agent summaries. (Note: Anthony Scialli, M.D., Director of the Reproductive Toxicology Center, has been a consultant for GlaxoSmithKline and has testified in paroxetine litigation. Shari I. Lusskin, MD, Director of Psychopharmacologic Agents for Reprotox has been a consultant for Pfizer and has testified in sertraline litigation and is a consultant to Forest Laboratories regarding escitalopram litigation.) ________________________________________ Serotonin reuptake inhibitors (SRIs, also called SSRIs) include citalopram #4062, escitalopram #4062, fluoxetine #1898, fluvoxamine #3718, paroxetine #3590, and sertraline #3390. Although these agents share some pharmacologic features, they are also different in some regards. Studying pregnancies exposed to these medications as a group is not likely to be informative about individual medications in the group, but such studies have been performed and are presented here. For additional information, please consult the individual summaries. Pregnancy Registry A pregnancy registry for psychiatric medications, including serotonin reuptake inhibitors, has been organized at the Massachusetts General Hospital. Contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Congenital anomalies A study reported pregnancy outcome in women who were followed prospectively after contacting a teratology information service regarding use of serotonin reuptake inhibitors (1). The incidence of malformations in children born to women taking serotonin reuptake inhibitors was comparable to that found in unexposed control subjects. The mothers were the source of information on pregnancy outcome, and the individual medications were not considered separately, limiting the interpretation of the study. A retrospective population-based study from the Finnish Medical Birth Register found no increase in malformations among 1782 women who filled a prescription for one or more serotonin reuptake inhibitors immediately before or during pregnancy compared with matched controls who had no prescription drug purchases of any kind (3). There were 229 women who filled serotonin reuptake inhibitor prescriptions throughout pregnancy. The serotonin reuptake inhibitors were citalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine. An update from the same register, which included births and terminations from 1996-2006, confirmed the finding of no increased risk of major congenital anomalies as a group in the offspring of women who filled prescriptions for serotonin reuptake inhibitors in the first trimester (N=6976) (59). Fetal alcohol spectrum disorders were 10 times more prevalent in the serotonin reuptake inhibitor group compared to women who did not fill prescriptions for serotonin reuptake inhibitors. A population-based cohort study from the Danish National Birth Registry found that for any serotonin reuptake inhibitor prescription filled from 30 days prior to conception until the end of the first trimester, the odds ratio for cardiovascular malformations was 1.4 (95% CI 1.1-1.8) (2,9). When restricted to prescriptions filled during the second or third month after conception, the odds ratio for malformations was 1.84 (95% CI 1.25-2.71). The results were initially presented in an abstract (2). When the full article appeared, the adjusted relative risk for any congenital malformation with early pregnancy exposure was 1.34 (95% CI 1.0-1.79) and 1.84 (95% CI 1.25-1.71) when restricted to prescriptions filled during the second or third month after conception (9). The authors did not report relative risks for cardiovascular malformations in either group. Another study based on the Danish Medical Birth Registry found that offspring of women filling a prescription for a serotonin reuptake inhibitor during the first trimester of pregnancy had an increase in congenital heart defects and some subtypes of heart defects (42). The increase in defects was statistically similar to an increase seen in women who filled a prescription for serotonin reuptake inhibitors three or more months before a pregnancy but not during a pregnancy. The authors indicated that these findings suggest that the disease state might be a marker of increased risk as opposed to the medication exposure. A similar increase in defects was not seen when tricyclic or other non-serotonin reuptake inhibitor antidepressants were considered. A study using the same registry reported that hydrocephalus was increased among children whose mothers used serotonin reuptake inhibitors in the first trimester, relative risk 2.7, 95% CI 1.5-4.6, based on 13 affected children in the exposed group (72). The authors noted that they could not adjust for alcohol use, maternal nutrition, or other lifestyle factors. Maternal smoking, body mass index, and use of illicit drugs also did not appear to have been considered, and the use of multiple comparisons increased the likelihood of chance associations. A 2014 Danish study based on the EUROCAT register, including all registered pregnancies (72,290) in Funen, Denmark from 1995-2008, found an increased risk of severe congenital heart disease in children of women who used selective serotonin-reuptake inhibitors in the first trimester, aOR 4.03 (95% CI 1.75-9.26) (74). No increased risk of septal defects from early pregnancy exposure was detected (74). In an Israeli study, all newborn infants found to have a heart murmur were examined by a cardiologist and underwent echocardiography (5). The relative risk of congenital heart disease in those infants exposed to serotonin reuptake inhibitors was 2.17 (95% confidence interval 1.07-4.39) based on 8 children with abnormal echocardiograms. Six of the 8 abnormalities were mild ventricular septal defects. There was no adjustment for possible confounders. The Norwegian Mother and Child Cohort Study assessed infant outcome following in-utero serotonin reuptake inhibitor exposure after adjusting for maternal depression and found no increased risk of congenital malformations in general or cardiac malformations in particular (49). A retrospective cohort study of 972 women who filled at least one prescription for a serotonin reuptake inhibitor in the twelve months prior to delivery found no increase in the risk of birth defects (4). A data base linkage study that adjusted for propensity score, which gave an approximation of the severity of maternal illness, found no association between a prescription for a serotonin reuptake inhibitor during pregnancy and cardiac malformations in the offspring (55). The study included more than 3000 pregnancies with first-trimester exposure to a serotonin reuptake inhibitor. A prospective cohort study from the Swedish Medical Birth Register that included births through 2011 found no statistically significant association between exposure to serotonin reuptake inhibitors as a group and any relatively severe malformations, cardiac defects, or cardiac septal defects (58). Another study from the same register found no increased risk of malformations in the offspring of women who used serotonin reuptake inhibitors in combination with benzodiazepines (N=406) (60). A study of singleton pregnancies found no increase in risk of total malformations, cardiac malformations, stillbirth, or infant mortality within 30 days of birth (106). A study using US Medicaid claims data did not find an increase in any cardiac malformation, right ventricular outflow tract obstruction, or ventricular septal defect associated with prescription of a serotonin reuptake inhibitor during the first trimester of pregnancy after adjustment for maternal illness (66). A US study reported a higher than expected rate of radiologically diagnosed Chiari I malformation in a group of 33 toddlers who had been exposed during pregnancy to serotonin reuptake inhibitors when compared to a control group of 66 children who had not been exposed to serotonin reuptake inhibitors or maternal depression (OR 10.32, 95% CI 2.04-102.46) (65). The control group was drawn from a larger cohort of 109 unexposed children and was matched to the exposed group using propensity scores for maternal age, ethnicity, education, and household income, gender, twin status, and date of birth (65). In a secondary analysis of unexposed children, there were no significant differences in the prevalence of Chiari I malformation when comparing unexposed children whose mothers had a history of depression but were not taking serotonin reuptake inhibitors or other antidepressants during pregnancy (N=30) with a matched control group of unexposed children whose mothers had no history of depression (N=60) (OR 1.44, 95% CI 0.23-7.85). There was some overlap between the children used as controls for each of the analyses. The serotonin reuptake inhibitors used in the exposed group were sertraline (N=25), fluoxetine (N=4), citalopram (N=3), paroxetine (N=2, 1 subject also exposed to fluoxetine). There was no adjustment for a family history of malformations, and brain imaging was not performed on the parents or siblings of the study children. The authors acknowledged the methodologic limitations of the study and recommended that clinical practice not be altered based on their preliminary findings. A study from the United Kingdom using linked maternal-child primary care databases found no statistically significant risk for overall major malformations or any individual class of malformations when comparing offspring exposed during the first trimester to selective serotonin reuptake inhibitors as a group (N=7683) to those exposed to unmedicated maternal depression (N=13,432) or to those not exposed to depression, antidepressants, or other major psychotropic medications (N=325,294) (67). A population-based case-control study of clubfoot suggested an increased risk with SSRI use for a greater than 30 day period in lunar months 2 and 3 after adjustment for maternal smoking and body mass index (OR 1.8; 95% CI 1.1-2.8) (73). No increased risk was found for short duration use and/or outside the given window of time. For individual agents, the risk estimate was elevated for escitalopram (OR 2.9, 95% CI 1.1-7.2). In a population-based case-control study from Denmark, Finland, Iceland, Norway, and Sweden using nationwide health registers and prescription databases, there were 36,772 live born infants with presumed first trimester exposure to any serotonin reuptake inhibitor (77). There were increased risk estimates for all major malformations combined (aOR 1.13, 95% CI 1.06-1.20), any cardiac defect (aOR 1.15, 95% CI 1.05-1.26); right ventricular outflow tract obstructions (aOR 1.48, 95% CI 1.15-1.89), atrial and ventricular septal defects (aOR 1.17, 95% CI 1.05-1.31), clubfoot (aOR 1.34, 95% CI 1.05-1.71), and omphalocele (aOR 2.11, 95% CI 1.01-4.39). The study did not adjust for indication or multiple testing. In a sibling-controlled analysis that combined exposures to all serotonin reuptake inhibitors, there were no statistically significant increases in the risk estimates for all malformations combined, any cardiac malformation, or right ventricular outflow tract obstruction, lending support to the theory that the increased point estimates for certain malformations are due to confounding by indication or other factors. Data for individual serotonin reuptake inhibitors and specific malformations are presented in the individual summaries. The EUROCAT database compared prevalence of serotonin reuptake inhibitor exposure between cases with congenital heart defects or other malformations previously reported in association with SSRI exposure and controls that had other types of malformations (78). For presumed exposure to any serotonin reuptake inhibitor, the study failed to confirm prior associations with anencephaly, craniosynostosis, or limb reduction defects. The study confirmed previously reported increased risk estimates for clubfoot (aOR 2.41, 95% CI 1.59-3.65) and renal dysplasia (aOR 3.01, 95% CI 1.61-5.61). The study also found increased risk estimates for congenital heart defects combined (aOR 1.41, 95% CI 1.07-1.86), severe congenital heart defects combined (aOR 1.56, 95% CI 1.02-2.39), and atrial septal defects (aOR 1.71, 95% CI 1.09-2.68) but did not confirm an association with septal defects as a group. The study reported increased risk estimates for tetralogy of Fallot (aOR 3.16, 95% CI 1.52-6.58) and Ebstein anomaly (Aor 8.23, 95% CI 2.92-23.16), neither of which had been previously reported in association with any SSRI. The risk estimates were increased for anorectal atresia and stenosis (aOR 2.46, 95% CI 1.06-5.68) and gastroschisis (aOR 2.42, 95% CI 1.10-5.29) both of which had been previously reported with individual serotonin reuptake inhibitors but not all serotonin reuptake inhibitors combined. There were no adjustments for psychiatric disorders, additional medication exposures, or lifestyle factors. A prescription database study in the United Kingdom found no association between cardiac malformations as a group in live born singletons and filling by the mother of at least 2 prescriptions during the first trimester either for serotonin reuptake inhibitors as a group or for other antidepressants as a group (97). Comparison groups included women who filled prescriptions for serotonin reuptake inhibitors 2-6 months prior to pregnancy but not during pregnancy or women who did not fill a prescription for an antidepressant for at least 6 months before and during pregnancy. A case-control study of conotruncal heart defects and combined left and right ventricular outflow tract obstruction defects evaluated 872 polymorphisms for 60 genes involved in folate, homocysteine, glutathione/transulfuration, or DNA repair pathways (100). There was an association between four of the polymorphisms and use of a serotonin reuptake inhibitor among mothers of children with the combined categories of heart defects and for three of the polymorphisms among children with one of these heart defects. When restricted to category of defect, there were no associations identified for conotruncal heart defects, and only one polymorphism was associated with the combined category of left and right ventricular outflow tract defects. These associations may have arisen by chance given the large number of comparisons. The authors noted that because women were questioned about medication exposures 12-24 months after delivery, recall bias might have played a role. The authors also noted that some of the polymorphisms may be associated with maternal depression, which was not adjusted in this study. A study using insurance data bases in Quebec compared offspring of women with an antidepressant prescription during the first trimester of pregnancy with offspring of women with a prescription during the year prior to pregnancy but not during the first trimester of pregnancy (101). There was no association of major congenital malformations overall and serotonin reuptake inhibitors as a group. This study included analyses on individual agents, which are presented in the individual summaries on those agents. A 2006 meta-analysis on serotonin reuptake inhibitors and pregnancy reported a summary odds ratio for major malformations of 1.39 (95% CI 0.91-2.15) and a summary odds ratio for cardiovascular malformations of 1.19 (95% CI 0.53-2.68) (7). The summary odds ratio for spontaneous abortion was 1.7 (95% CI 1.28-2.24). Individual medications were not analyzed separately. A 2013 meta-analysis reported no association between serotonin reuptake inhibitor use during pregnancy and major malformations and an association with cardiac malformations (risk ratio 1.36, 95% CI 1.08-1.71) and septal defects (risk ratio 1.40, 95% CI 1.10-1.77) (70). Only papers published through 2010 were included. A 2015 meta-analysis of 4 prospective cohort studies reported that there was no increased risk estimate for presumed exposure to serotonin reuptake inhibitors combined and congenital cardiac defects combined, pooled adjusted odds ratio 1.06, 95 % CI 0.94-1.18 (79). The finding was limited by the inclusion of only 4 studies. Other outcomes Adverse effects in neonates exposed to serotonin reuptake inhibitors prenatally were described in a variety of reports, including individual cases, prospective studies, and a data mining investigation of the large WHO data base of adverse drug reactions (14-29,88, 98). The adverse effects reported included respiratory distress and persistent pulmonary hypertension (26,30), jitteriness, irritability, vomiting, and convulsions. In most cases, the symptoms were mild and disappeared by 2 weeks of age with no treatment or with only supportive care (25). One small series identified four neonates who also developed necrotizing enterocolitis, although all the infants in this report were also prenatally exposed to other drugs (16). An unblinded cohort study conducted to determine risk factors for poor neonatal adaptation reported on 247 infants exposed to serotonergic antidepressants in the third trimester who were admitted for observation after delivery (90). Poor neonatal adaptation was defined as a Finnegan score of at least 4 on one occasion during the 72-hour observation period. An unspecified number of these infants were also exposed through breastfeeding. There were 187 infants with exposure to a serotonin reuptake inhibitor (sertraline N=68; citalopram N=51; paroxetine N=49; fluoxetine N=15; fluvoxamine N=4). For all serotonin reuptake inhibitors combined, there were 127 infants who had poor neonatal adaptation, but only 5 required a NICU admission for this reason. Breastfeeding, either partial or exclusive, was associated with a significantly lower risk than exclusive formula feeding. Study limitations included the unblinded design and reliance on maternal self-report for drug, alcohol, and tobacco use and for the severity of anxiety/depression. Another study associated serotonin reuptake inhibitor exposure during pregnancy with poorer self-regulation and higher levels of arousal in infants during the first month of life (98) There was no association with admission to a neonatal intensive care unit. Neonates exposed prenatally to serotonin reuptake inhibitors can be evaluated for signs of adverse effects, but the incidence and severity of these effects do not appear to be so frequent or severe that women should avoid using these medications if they are otherwise indicated (31,91). The risk of developing neonatal behavioral symptoms might be mediated by infant serotonin transporter promoter genotype (32). A report from the Danish Medical Birth Registry that included pregnancy outcomes from 1997-2008 found an increased risk of miscarriage among women who filled prescriptions for antidepressants as a group or serotonin reuptake inhibitors as a group, but the differences from the unexposed controls were no longer statistically significant when adjusted for an outpatient or inpatient diagnosis of depression (61). Another study from the Danish Medical Birth Register that included births from 1997-2007 found no increased risk for stillbirth among the offspring of women who filled a prescription for any serotonin reuptake inhibitor in 1, 2, or 3 trimesters (62). The results were adjusted for maternal age, parity, prior history of stillbirths, and smoking. The study also found no increased risk of neonatal mortality. Another paper from the Danish Medical Birth Register study including births from 1997-2010 noted slightly increased risks of miscarriage among women exposed to serotonin reuptake inhibitors during the first 35 days of pregnancy, with 12.6% miscarriages among exposed women compared with 11.1% among unexposed women (hazard ratio 1.27, 95% CI 1.22-1.33) (75). Among women who discontinued serotonin reuptake inhibitors 3-12 months before pregnancy, the risk of miscarriage was also increased compared with unexposed women (hazard ratio 1.24, 95% CI 1.18-1.30). The study authors noted that the increased risks were similar for women who stopped treatment before pregnancy and those who were treated during early pregnancy. The authors suggested that these data supported the recommendation that women not stop serotonin reuptake inhibitor treatment during pregnancy. The authors also noted that no increased hazard was observed among women who took high dose therapy vs. low dose therapy, and they suggested that there was no causal relationship between serotonin reuptake inhibitors and miscarriage. A study using Danish pregnancy registers from 1996 to 2009 found that exposure to selective serotonin reuptake inhibitors during or before pregnancy was more likely than unexposed pregnancies to result in a first trimester miscarriage (76). No association was made between serotonin reuptake inhibitor use and second trimester miscarriage. Pregnancies exposed to these agents without maternal depression or anxiety were less likely to result in first trimester miscarriage than unexposed pregnancies with a depression or anxiety diagnosis. The study authors found that use of this agent during pregnancy reflected an unhealthier lifestyle and mental health profile, which might have been a confounding factor in the miscarriage results. An increased risk for preterm birth (OR 1.4; 95% CI 1.1-1.8) was reported from a population-based cohort study from the Danish National Birth Registry when presented in abstract (2). When the full paper came out, no risk estimates for preterm birth were reported (9). A study from Denmark used questionnaires sent to health care providers to gather information on medication use and diagnoses during pregnancy (11). Exposure to serotonin reuptake inhibitors was associated with a decrease in birth weight and gestational age, although the effects were attenuated after adjusting for psychiatric diagnosis. The psychiatric illness comparator group included 4622 women most of whom had no diagnosis indicated. A diagnosis of depression was reported in only 86 of these women, raising the possibility of inadequate adjustment for maternal depression. Although cigarette and ethanol use were included in the questionnaire, use of illicit drugs was not mentioned. In the Finnish Medical Birth Register study, third trimester prescription purchases of serotonin reuptake inhibitors were associated with an increased risk of neonate treatment in a special care or neonatal intensive care unit (OR 1.6; CI 1.1-2.2); however, this risk also was associated independently with maternal smoking (OR 1.7; CI 1.2-2.3), which was twice as common in the serotonin reuptake inhibitor cohort as in the controls (3). Other limitations included not being able to confirm and quantify actual drug exposure and nicotine exposure or adjust for alcohol or illicit drug use, nonprescription drug use, or maternal mental health. Another study from the Finnish Medical Birth Register showed no difference in the risk of gestational hypertension comparing pregnancies with exposure to serotonin reuptake inhibitors, pregnancies in women with a psychiatric diagnosis but no exposure to serotonin reuptake inhibitors, and a matched group of women without a psychiatric diagnosis or serotonin reuptake inhibitor exposure (94). The risk of cesarean section was higher in the serotonin reuptake inhibitor group and the psychiatric diagnosis group compared to the unexposed group, but serotonin reuptake inhibitor exposure was associated with a lower cesarean section rate than that in women with a psychiatric diagnosis but no exposure to serotonin reuptake inhibitors. There was no difference between groups in hemorrhage during or after delivery. The prevalence of 5 minute Apgar <7 and of neonatal breathing difficulties was higher in infants exposed to serotonin reuptake inhibitors. Overall, the results demonstrate that certain pregnancy outcomes may be worse in women with a psychiatric diagnosis whether or not treated with a serotonin reuptake inhibitor. A US case-cohort study found that SSRI use during pregnancy was not associated with hypertensive disorders of pregnancy (107). A study from 5 US health maintenance organizations used insurance data to evaluate adverse outcome in women exposed to serotonin reuptake inhibitors and tricyclic antidepressants (6). Women who were prescribed any antidepressant were more likely than women not prescribed an antidepressant to deliver preterm. There was no increase in congenital malformations, but there was an increase in neonatal diagnoses (respiratory distress, disorders of temperature regulation, convulsions). Neonatal complications, described as a neonatal adaptation syndrome, were associated with serotonin reuptake inhibitor exposure during pregnancy in a 2013 meta-analysis (71). A Canadian retrospective cohort study of 972 women who filled at least one prescription for a serotonin reuptake inhibitor in the 12 months prior to delivery found increased risks of low birth weight, preterm birth, fetal death, and seizures (4). This study did not validate medication exposure periconceptionally or adjust for maternal disease or for use of tobacco, ethanol, or illicit drugs. A case-control study conducted in Canada assessed the risk of smallness for gestational age (SGA) in women filling prescription for an antidepressant medication during pregnancy (8). The authors did not find an increased relative risk for SGA associated with exposure in any trimester to monotherapy with serotonin reuptake inhibitors. Limitations included inadequate adjustment for tobacco use and maternal illness severity. A Canadian study comparing infants exposed during the third trimester to serotonin reuptake inhibitors (N=40) with unexposed infants (N=25) found some statistically significant differences in neonatal blood cortisol concentrations, neonatal blood corticosteroid binding globulin concentrations, and infant salivary cortisol concentrations at 3 months, which were modulated by mode of delivery but not by maternal depression (53). The authors noted that further study was needed to clarify the impact of prenatal serotonin reuptake inhibitor exposure on the developing hypothalamic-pituitary axis. A study conducted in Spain examined the relationship between serotonin reuptake inhibitor exposure in pregnancy and the risk of adverse obstetrical outcomes (10). Eighty-four women who took serotonin reuptake inhibitors for anxiety or depression during all or part of pregnancy were followed prospectively and compared to a control group of 168 women recruited 2-3 days after delivery. Control women denied a history of anxiety or depression during pregnancy, a history of a “severe and/or recurrent mental disorder;” and exposure to any psychotropic drugs during pregnancy other than benzodiazepines. Gestational age was lower for the serotonin reuptake inhibitor-exposed group compared to the control group (38.8 vs. 39.4 weeks). The risk of delivery between 32 and 37 weeks was increased in the exposed group (OR 3.44, 95% CI 1.30-9.11) after adjustment for smoking, a history of elective or spontaneous abortions, and a history of preterm birth. More women (44.4%) in the exposed group had preterm premature rupture of membranes compared to women in the control group (16.1%). A study using prescription and diagnosis data from the Tennessee Medicaid program on 228,876 singleton pregnancies found that filling 1 or more prescriptions in the second trimester for either a serotonin reuptake inhibitor or a non-serotonin reuptake inhibitor antidepressant was associated with a statistically significant reduction in gestational age proportional to the number of prescriptions filled (43). For 3 or more prescriptions, gestation was shortened by 6.6 (95% CI, 4.6-8.6) days. The odds ratios for neonatal convulsions were described as increased if 2 or more serotonin reuptake inhibitor prescriptions were filled in the third trimester; the odds ratio was 2.8 (95% CI, 1.4-5.5) for 2 prescriptions and 4.9 (95% CI, 2.6-9.5) when 3 or more were filled, but the 95% confidence intervals were widely overlapping. No such relationship was found for non-serotonin reuptake inhibitor antidepressant prescriptions. The results were adjusted for a history of preterm birth, sex of the newborn, episode onset, duration of pharmacotherapy, diagnosis, illness severity, and tobacco use. Limitations of this study included the inability to confirm medication exposure (including to other psychotropic medications) and inadequate adjustment for alcohol, illicit drug, and tobacco use. A prospective observational study in the United States of mother-infant pairs who were recruited during pregnancy found no differences in head circumference, weight, or length at birth or during the first year of life between infants exposed during gestation to serotonin reuptake inhibitors (N=46), infants exposed to maternal depression (N=31), and a control group not exposed to serotonin reuptake inhibitors or depression (N=97) (47). Most of the serotonin reuptake inhibitor group had been exposed throughout pregnancy. The rates of preterm birth were higher in the serotonin reuptake inhibitor group (N=9, 19.1%) compared to the healthy control group (N=5, 5%). This study used urine toxicology screens to exclude women with illicit substance use at the time of enrollment but relied on maternal self-report for alcohol and tobacco use. A prospective population-based study conducted in the Netherlands compared the infant outcomes of 99 women who took serotonin reuptake inhibitors at least in the first trimester with 370 women who had moderate to high depression scale scores but no serotonin reuptake inhibitor prescription and a group of 7027 women who had negative or low depression scores and no serotonin reuptake inhibitor prescription (50). After adjusting for various potential confounders, serotonin-reuptake inhibitor-exposed infants had a reduced rate of head growth but not body growth and an increased risk of preterm birth compared to the non-depressed control group, while the infants of depressed women not on serotonin reuptake inhibitors had reduced rates of both head and body growth. The clinical significance of these findings is unknown. The Norwegian Mother and Child Cohort Study assessed infant outcome following in-utero serotonin reuptake inhibitor exposure after adjusting for maternal depression and found no increased risk of preterm birth or low birth weight (49). This study compared the offspring of 572 women who used serotonin reuptake inhibitors during pregnancy, 1358 women who terminated serotonin reuptake inhibitor use within 6 months of pregnancy, and 61,648 women who did not use antidepressants during pregnancy or during the 6 months prior to pregnancy. Maternal depression was assessed by self-report on a standardized rating scale during the second and third trimesters. A Swedish Medical Birth Register study compared babies born between 2006 and 2008 who were prescribed a serotonin reuptake inhibitor during the second or third trimester with or without other psychotropic medications and a control group of infants not exposed to psychotropic medications (51). The study reported increased risk estimates for preterm birth and some neonatal complications following prescription of a serotonin reuptake inhibitor with or without other medications, but the number of different medication combinations limits interpretation of the results. The rate of NICU admission was increased for any serotonin reuptake inhibitor exposure during pregnancy after adjustment for some maternal and fetal factors (106). Exposed infants had higher rates of late preterm birth. They also had higher rates of hypoglycemia, feeding difficulties, CNS symptoms, and respiratory symptoms. A record-linkage study from Western Australia found an association between a prescription during pregnancy for a serotonin reuptake inhibitor and infant death (OR 1.8, 95% CI 1.2-2.6) and hospital admission of the infant in the first 2 years of life (OR 1.4, 95% CI 1.3-1.6) (44). Infant death was not associated with the individual medications (citalopram, paroxetine, sertraline, fluoxetine, escitalopram, or fluvoxamine). The most common diagnostic codes associated with the infant deaths were maternal complications and prematurity/low birth weight. The leading diagnosis for the infant admissions after the birth admission was bronchiolitis, even among infants whose mothers did not smoke. The authors suggested that their findings may have been due to maternal depression or an environmental exposure such as smoking. Hospital admission of young children was common in Western Australia, affecting almost 43% of children exposed to serotonin reuptake inhibitors and 34% of children not exposed to serotonin reuptake inhibitors. A retrospective cohort study in Australia using data from the Women’s and Children’s Health Network and prescription databases compared the offspring of women who had filled a prescription for a serotonin reuptake inhibitor in pregnancy (N= 221) with the offspring of a heterogeneous group of women with a psychiatric diagnosis but no prescription in pregnancy for a serotonin reuptake inhibitor (N=1566) and a control group with no psychiatric diagnoses and no serotonin reuptake inhibitor prescription (N=32,004) (52). Increased risks for preterm delivery, admission to neonatal intensive care or special care units, and hospital stays greater than 3 days were found for infants exposed to serotonin reuptake inhibitors compared to those whose mothers had a psychiatric diagnosis but no serotonin reuptake inhibitor prescription and compared to the healthy controls. The mothers of infants exposed to serotonin reuptake inhibitors were more likely to be older, to use alcohol, tobacco, and illicit drugs, and to have a prescription for anxiolytics. Among other limitations, the study did not adjust for mode of delivery. The authors noted that confounding by indication and severity of maternal mental illness might have affected the results. A Swedish Medical Birth Register study found an increased risk for preterm birth but not smallness for gestational age following first trimester exposure to serotonin reuptake inhibitors, aOR 1.33, 95% CI 1.16-1.53 (111). No differences in the rates of stillbirth, neonatal death, or infant mortality were found between serotonin reuptake inhibitor-exposed and unexposed infants in a Nordic population-based cohort study that examined over 1.6 million singleton births between 1996 and 2007 (48). Prescriptions filled were used as a proxy for serotonin reuptake inhibitor exposure. Logistic regression was used to adjust for potential confounders including a history of psychiatric hospitalization. The study populations were drawn from Denmark, Finland, Iceland, Norway, and Sweden. No association was found in the Nowegian Mother Baby Cohort Study between severe late onset pre-eclampsia and serotonin reuptake inhibitor exposure up to 34 weeks gestation after adjustment for depression or anxiety (114). Postpartum hemorrhage The Norwegian Mother and Child Cohort study did not identify an increase in postpartum hemorrhage in women exposed to serotonin reuptake inhibitors or other antidepressants, evaluated separately (84). A Canadian data base linkage study did not find an association between prescription fills for serotonin reuptake inhibitors compared to fills for other antidepressants among women with claims that included postpartum hemorrhage (85). Use of other antidepressants might not have been an appropriate comparison group if other drugs also had effects on platelet serotonin. Another Canadian study of live births from 2002-2011 found that there was no increase in the risk of postpartum hemorrhage following serotonin reuptake inhibitor exposure at any time from mid-pregnancy to delivery (95). In contrast, there was a statistically significant increase in the risk among women who filled prescriptions for a serotonin-norepinephrine reuptake inhibitor (primarily venlafaxine/desvenlafaxine #3791) in the last month of pregnancy. A US Medicaid-based study identified a statistically significant association with late pregnancy use of serotonin reuptake inhibitors and non-serotonin reuptake inhibitor antidepressants, analyzed separately, with adjusted risk estimates of about 1.4 compared to unmedicated patients (86). A health administrative data base study from Australia also showed a statistically significant increase in risk (adjusted relative risk 1.52, 95% CI 1.25-1.86) for postpartum hemorrhage among women treated with any antidepressant compared to unmedicated women (87). There was no increase in risk for women with a diagnosis of depression who did not receive antidepressants. Persistent Pulmonary Hypertension of the Newborn There were two studies reporting an increase in persistent pulmonary hypertension of the newborn (PPHN) with late (26) or early (30) exposure to serotonin reuptake inhibitors. Three other studies failed to confirm an association (33-35). In July, 2006, the FDA issued a public health advisory about a possible link between in-utero exposure to serotonin reuptake inhibitors and PPHN (36). In December, 2011, the FDA issued an FDA Drug Safety Communication that retracted the warning (37). The FDA stated that “The initial Public Health Advisory in July 2006 on this potential risk was based on a single published study. Since then, there have been conflicting findings from new studies evaluating this potential risk, making it unclear whether use of SSRIs during pregnancy can cause PPHN. FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.” Since the appearance of this FDA statement, a multinational record-linkage study reported an increase in PPHN in offspring born to women who had filled a prescription for a serotonin reuptake inhibitor in late pregnancy with an adjusted odds ratio of 2.1 (95% CI 1.5-3.0) (38). A 2012 literature review of this topic concluded the absolute risk could not be determined but it was probably less than 1% and not large enough to support discontinuation or lowering the dose of the antidepressant (45). Another review also stressed the importance of balancing the risks of untreated mental illness against a possible small risk of persistent pulmonary hypertension of the newborn (57). A meta-analysis of 7 studies published through 2012 concluded that third trimester exposure to SSRIs as a group was associated with PPHN (OR 2.50, 95% CI 1.32-4.73; P=0.005) while first trimester exposure was not (OR 1.23, 95% CI 0.58-2.60; P=0.58) (68). Among the confounding factors that were not adjusted were preterm birth, cesarean section, and maternal body mass index. A study using US Medicaid claims data reported a small increased risk estimate for primary PPHN in term infants without cardiac malformation, lung hypoplasia, or diaphragmatic hernia whose mother had filled at least one prescription for an SSRI in the 90 days prior to delivery after adjustment for maternal illness (aOR 1.28, 95% CI 1.10-1.64 (80). Women with a diagnosis of depression who filled prescriptions for serotonin reuptake inhibitors were more likely than women who did not to have chronic illnesses, to smoke, to be obese, and to have greater healthcare utilization. When the study results were added to the meta-analysis of studies published through 2012 (68), the pooled odds ratio for primary PPHN decreased to 2.03, 95% CI 1.21-3.41. The authors concluded that while exposure to serotonin reuptake inhibitors might increase the risk of primary PPHN, the risk was lower than previously estimated, and the absolute risk was small. In a 2016 paper from the Swedish Medical Birth Register, the rate of persistent pulmonary hypertension of the newborn was increased in preterm and term infants exposed during pregnancy to serotonin reuptake inhibitors (106). For term babies only, the rate of PPHN was higher with exposure in the 3rd trimester compared to exposure in the 1st or 2nd trimester only. The mortality rate with PPHN was 3%. The authors noted that this rate was lower than previously reported, that the absolute risk of PPHN was low, and that the number needed to harm was 285. The authors suggested that confounding by maternal indication might have been present. Autistic Spectrum Disorders Comparison of 208 Swedish preschool children with a diagnosis of autism spectrum disorder (ASD) and controls showed an association of ASD and parental identification of exposure to serotonin reuptake inhibitors during pregnancy, OR 4.5, 95% CI 2.19-9.05 (102). There also was an association with use of other psychoactive drugs, consistent with the identification of psychiatric disorders more commonly among parents of autistic children than normal children. A US case control study using medical records from a health maintenance organization reported an association between a prescription for serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine) and a diagnostic code for autism spectrum disorder in the offspring (41). The findings were not statistically significant when adjusted for demographic factors including maternal mental illness except with respect to first trimester exposure (adjusted odds ratio 3.5, 95% CI 1.5-7.9). The study did not adjust for paternal psychiatric disease or exposure to tobacco, ethanol, or illicit drugs, and the study did not show an analysis that excluded families with other affected children, a known risk for autism spectrum disorder. Actual ingestion of medications was not assessed. A Swedish nested case-control study conducted on children diagnosed with an autism spectrum disorder with or without intellectual disability found a correlation between maternal self-report (at the first antenatal visit) of antidepressant use (either serotonin reuptake inhibitors or tricyclic antidepressants) and a diagnosis of autism spectrum disorder without intellectual disability in the offspring (56). The adjusted odds ratio was 2.54 (95% CI 1.37-4.68). The sample was restricted to children who were between 0 and 17 years old between 2001 and 2007. The authors attempted to adjust for maternal and paternal psychiatric history by using diagnostic codes recorded in administrative registers. There was a correlation with maternal but not paternal depression, but this correlation appeared to be due mostly to those cases with antidepressant exposure. Of the case mothers, 1.3% reported antidepressant use compared to 0.6% of the control mothers. The authors noted that if a causal relationship existed, it would account for only 0.6% of the cases of autism spectrum disorder without intellectual disability. Methodologic limitations, including the inability to fully adjust for parental psychopathology and lifestyle factors including tobacco, illicit drug, and alcohol use, limit the strength of the conclusions. A study of Danish children born from 1996-2006 found no statistically significant increased risk of autism spectrum disorders among the offspring of mothers who filled a serotonin reuptake inhibitor prescription during pregnancy, adjusted for maternal diagnosis of an affective disorder and for having an affected unexposed sibling (63). Other authors reached a similar conclusion in a record linkage study from the same time period in Denmark (64). A third Danish study using prescription databases concluded that the risk for an autism spectrum disorder was increased after controlling for a history of maternal depression or other serotonin reuptake inhibitor indications, the sex of the child, and parental age, but not for having an affected sibling (81). In a US case-control study, maternal self-report of serotonin reuptake inhibitor use in pregnancy was associated with an increased risk estimate for an autism spectrum disorder in boys, adjusted odds ratio 2.91, 95% CI 1.07-7.93 (82). The results were no longer statistically significant when adjusted for a maternal history of anxiety or mood disorder. Another study used electronic medical records to identify children with an ASD diagnosis and three control children without a diagnosis of ASD, ADHD, or intellectual disability matched on year of birth, birth hospital, sex, insurance, ethnicity, and preterm/term status (103). There was no association of maternal prescription of serotonin reuptake inhibitors during pregnancy and childhood ASD after adjustment for maternal illness. A pharmacy data base study reported an increase in autism among offspring of women filling prescriptions in the second or third trimesters but not the first trimester, hazard ratio 2.17, 95% confidence interval 1.20-3.93 (92). The first trimester is when autism is believed to originate. The association between exposure to antidepressants as a group and a neurologist or psychiatrist diagnosis of autism in the child was not statistically significant, hazard ratio 1.65, 95% confidence interval 0.98-2.22. The authors attributed the lack of statistical significance to the smaller sample in the more restricted analysis. In the larger sample, other factors that were independently associated with an autism diagnosis in children were male sex, calendar year, maternal age of 25 or more, living alone, receipt of social assistance, chronic or gestational diabetes, and chronic or gestational hypertension. The authors were unable to consider maternal smoking, illicit drug use, or family history of autism, which were potential mediators of risk. Adjustment was made for use of some other medications but not for anticonvulsant drugs. A Finnish record-linkage study identified an association between maternal prescription of a serotonin reuptake inhibitor during pregnancy and anxiety, ADHD, and ASD diagnoses in their offspring compared to the offspring of unexposed women but not compared to women with unmedicated psychiatric disorders or women who discontinued serotonin reuptake inhibitors prior to pregnancy (104). A prospective study compared neurobehavioral outcomes in children from 2.5-5.5 years old who were exposed in utero to serotonin or serotonin-norepinephrine reuptake inhibitors (N=102) to a group that was not exposed to maternal depression or medication (N=76) and found that antidepressant exposure was associated with a decrease in a clinician-rated expressive language scale and with positive ratings by parent and caregiver report on a subscale for pervasive developmental disorder behaviors (93). The study did not provide clinician-confirmed diagnoses of child neurobehavioral disorders or adjust for paternal or other caregiver mental health or cognitive function among other potential confounds. A study using the Stockholm youth cohort and record-linkage to identify presumed exposure during pregnancy to antidepressants reported an association with autism spectrum disorder, adjusted odds ratio 1.68, 95% CI 1.23-2.30, that was attributable to autism spectrum disorder without intellectual disability (108). The comparison group included women with a psychiatric disorder but no antidepressant prescription during pregnancy. When a sibling matched analysis was performed, the association was no longer statistically significant. The association between antidepressants and autism spectrum disorder remained statistically significant when restricted to any serotonin reuptake inhibitor and when restricted to any non-serotonin reuptake inhibitor. The authors noted that confounding by indication might have influenced the results if the association were based on the severity of the maternal depression. A Swedish Medical Birth Register study found no association between exposure to any serotonin reuptake inhibitor or other antidepressants and a diagnosis of autism spectrum disorders at age 7-8 years of age after adjustment for maternal and paternal psychiatric diagnoses (109). Another study from the Register found no association between IQ < 70 and exposure to serotonin reuptake inhibitors or other antidepressants (110). A third Swedish Medical Birth Register study found that, after adjustment for maternal and paternal health and for discordant siblings, there were no increased risk for autism spectrum disorders or attention deficit hyperactivity disorder following first trimester exposure to serotonin reuptake inhibitors or to any antidepressants (111). A Canadian study found no increased risk for autism spectrum disorders and exposure to serotonin reuptake inhibitors as a group after adjustment for maternal illness severity using propensity scoring (112). The results were similarly negative when a sibling-controlled analysis was performed. In a secondary analysis, presented in the supplementary tables, second and third but not first trimester use of serotonin reuptake inhibitors was associated with an increased risk for autism spectrum disorders in the subset of women with mood or anxiety disorders, a finding that the authors concluded was likely due to residual confounding. Meta analyses have identified associations between serotonin reuptake inhibitor exposure during pregnancy and autism (83,96,105,117,118), although another meta-analysis did not (119). All of the analyses are limited by combining different drugs based on a presumed common mechanism of action and all are subject to the limitations of the underlying studies. Other Neurodevelopmental Outcomes MRI of neonates exposed antenatally to unspecified serotonin reuptake inhibitors showed an increased volume of the right insular cortex and amygdala and increased white matter connectivity between these regions compared to unexposed neonates and offspring of women with untreated depression (116). There was no adjustment for maternal illness severity or brain region size in parents, and there was no assessment of possible adversity associated with the reported changes. Neurodevelopmental outcome was studied prospectively in children exposed at least during the third trimester to a serotonin reuptake inhibitor (paroxetine, fluoxetine, or sertraline) or to paroxetine plus clonazepam #1384 in 46 mother-child pairs and 23 healthy, unmedicated control dyads (22). While transient neonatal symptoms (mostly respiratory) occurred in 30% of the exposed group compared to 9% of the control group, there were no differences in developmental outcomes between the symptomatic or asymptomatic infants or between the exposed or unexposed infants at 2 and 8 months. Some of the infants were also exposed postnatally through breastfeeding. A follow-up study evaluated internalizing and externalizing behaviors at age 4-5 years in the same cohort (39,40). All of the mothers remained on medication, but due to attrition, the study groups were reduced to 22 exposed and 14 unexposed mother-child pairs. The rates of internalizing behaviors (emotional reactivity, withdrawal, irritability, depression, or anxiety) and externalizing behaviors were no different between the groups when using parent, teacher, or clinician ratings. The degree of current maternal depression correlated significantly and negatively with parental ratings, suggesting that parental mood affects child development or maternal perception of development independent of antenatal medication exposure. Diminished pain response was demonstrated in 38 newborn infants with prolonged prenatal exposure either to serotonin reuptake inhibitors alone (N=22: fluoxetine, paroxetine, or sertraline) or to serotonin reuptake inhibitors plus clonazepam (N=16) compared with 23 unmedicated controls (54). A study from the Danish National Birth Cohort reported small but statistically significant delays in sitting and walking in children exposed to serotonin reuptake inhibitors in the second and third trimester of pregnancy compared to unmedicated depressed women (12). Data were based on maternal responses to questionnaires on four interview dates during and after pregnancy and were adjusted for self-reported use of ethanol and tobacco. Information on exposure to illicit drugs was not reported. The authors adjusted for the presence and severity of psychiatric symptoms in women but acknowledged that there may have been differences in disease severity between medicated and unmedicated depressed women. By 19 months of age, there were no statistically significant differences between groups in maternal reports of childhood developmental milestones except for a small increase in attention problems in children exposed to serotonin reuptake inhibitors in late pregnancy. At 3 years of age, there was an association between use of serotonin reuptake inhibitors during pregnancy and delayed motor development that was not explained by maternal illness, but the authors commented that the extent of the delay was not clinically important (88). At 7 years of age, children exposed to serotonin reuptake inhibitors during pregnancy did not demonstrate an increase in behavioral problems as assessed by an instrument using parent report (89). A study conducted by a Canadian teratology information service compared behavioral and intellectual outcomes of children exposed in utero to serotonin reuptake inhibitors (N=62: citalopram 15, fluoxetine 15, fluvoxamine 1, paroxetine 20, and sertraline 20) or venlafaxine (N=62) to a healthy control group (N=62; mothers had no teratogenic exposures, took no psychotropic medications, and had no history of depression) and to an illness-matched control group of mothers who had discontinued antidepressants prior to pregnancy (N= 54) (46). Child IQ was assessed between 3 and 6-11/12 years of age by clinicians, but only maternal reports were used to determine behavioral problems. The venlafaxine group and the serotonin reuptake inhibitor group had significantly lower full-scale IQs and verbal IQs than the healthy group, and the serotonin reuptake inhibitor group also had lower performance IQs. There were no significant differences between the untreated depressed group and the other three groups. Although mothers with a history of depression, particularly those who were depressed at the time of the child’s assessment, rated their children as having more internalizing and externalizing behavioral problems, only one subscale score (total problems on the Conners Parent Rating Scale) was significantly different from the healthy control group. No correlations were found between dose or duration of antidepressant therapy during pregnancy and intellectual or behavioral outcomes. The investigators concluded that differences between the exposed and the control groups were likely due to confounding rather than to medication exposure. The study did not adjust for paternal IQ or psychiatric illness. Other limitations include using maternal self-report for alcohol, tobacco, and illicit drug use, for illness severity, and for child behavior. A small prospective study in the Netherlands compared early neurobehavioral outcomes for infants exposed in utero at least during the first trimester to a serotonin reuptake inhibitor or to venlafaxine (N=66) with a control group that was not exposed to a serotonin reuptake inhibitor or venlafaxine (n=44) (69). Pregnant women were self-referred to the study. The infants were evaluated for general movements in the first week after delivery and again at 3-4 months of age. In the first week of life, after adjusting for maternal depression scores in the 3rd trimester, the exposed group was more likely to have abnormal general movements (aOR 4.1, 95% CI 1.6-10.5, P=0.003). After adjusting for maternal anxiety in the 3rd trimester, the OR was 4.2 (95% CI 1.6-10.9, P=0.003). At 3-4 months of age, after adjusting for maternal and paternal depression (or anxiety) scores, exposed infants were more likely than unexposed to have monotonous movements (aOR 6.4, 95% CI 2.1-19.2, P=0.001, and OR 5.8, 95% confidence interval 1.9-17.7, P=0.002, respectively). A Finnish Medical Birth Register study found that full-term singleton offspring whose mothers filled at least two prescriptions for a serotonin reuptake inhibitors during pregnancy were more likely to have a speech/language disorder diagnosed between birth and 14 years than offspring exposed to antenatal depression only; both groups had a statistically significant increased risk compared to the control group of infants not exposed to maternal depression or serotonin reuptake inhibitorss (99). There were no differences in the rates of scholastic or motor disorders. The study did not examine the persistence of diagnoses made in early childhood, did not adjust for parental IQ or speech/language pathology, and did not provide data on individual medications. In a Dutch study comparing offspring exposed in utero either to serotonin reuptake inhibitors or to untreated maternal depression, there were no differences observed at age 4 in executive function, at age 5 in non-verbal intelligence, or at age 7 in neuropsychological function after adjustment for maternal depression in pregnancy and postpartum (115). Reproduction Sexual dysfunction including decreased desire, decreased arousal, and delayed orgasm or anorgasmia has been reported with all serotonergic antidepressants (13). In a retrospective study conducted at an infertility treatment center, exposure to serotonin reuptake inhibitors as a group during controlled ovarian hyperstimulation and egg retrieval was not associated with risk for aneuploidy (113). According to self-report, 176 patients were exposed to serotonin reuptake inhibitors, and 743 embryos were analyzed. In a subanalysis of thawed single embryo transfers (N=2132) of which 97 were exposed to an serotonin reuptake inhibitor before and/or during transfer continuing up to 12-14 weeks of pregnancy, there were no differences in the rates of implantation, clinical pregnancy, or multiple pregnancy. Final pregnancy outcomes were not reported. Selected References 1. Kulin NA, Pastuszak A, Sage SR et al: Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors. JAMA 279:609-10, 1998. 2. Wogelius P; Norgaard M; Munk EM; Mortensen PB; Lipworth L; Sorensen HT. Maternal Use of Selective Serotonin Reuptake Inhibitors and Risk of Adverse Pregnancy Outcomes. Pharmacoepidemiology and Drug Safety 2005;14(Suppl 2):S72-S73. 3. Malm H, Klaukka T, Neuvonen PJ: Risks associated with selective serotonin reuptake inhibitors in pregnancy. 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