PEDIATRICS Vol. 119 No. 1 January 2007, pp. 52-59 (doi:10.1542/peds.2006-2133)
ARTICLE |
Effects of Selective Serotonin Reuptake Inhibitors and Venlafaxine During Pregnancy in Term and Preterm Neonates
a Departments of Pharmacy (Centre IMAGe)
c Pediatrics
e Psychiatry
f Obstetrics
g Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada
b Faculties of Pharmacy
d Medicine, Université de Montréal, Montréal, Québec, Canada
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Our goals were to (a) describe neonatal behavioral signs in a group of newborns exposed in utero to selective serotonin reuptake inhibitors or venlafaxine at the time of delivery, (b) compare the rate of neonatal behavioral signs, prematurity, and admission to specialized neonatal care between a group of exposed and unexposed newborns, and (c) compare the effects in exposed preterm and term newborns.
PATIENTS AND METHODS. This was a retrospective cohort study including mothers taking selective serotonin reuptake inhibitors or venlafaxine during the third trimester and mothers who were not taking any antidepressants, psychotropic agents, or benzodiazepines at the time of delivery of their newborns. Neonatal behavioral signs included central nervous, respiratory, and digestive systems, as well as hypoglycemia and the need for phototherapy.
RESULTS. Seventy-six mothers taking antidepressants and 90 untreated mothers and their newborns were analyzed. Smoking, alcohol intake, and substance abuse were more frequent among treated mothers. In infants in the exposed group, signs involving the central nervous and the respiratory systems were often observed (63.2% and 40.8%, respectively). These signs appeared during the first day of life, with a median duration of 3 days for exposed newborns. The signs resolved in 75% of cases within 3 to 5 days for term and premature newborns, respectively. All exposed premature newborns presented behavioral manifestations compared with 69.1% of term exposed newborns. Median length of stay was almost 4 times longer for exposed premature newborns than for those who were unexposed (14.5 vs 3.7 days).
CONCLUSIONS. Neonatal behavioral signs were frequently found in exposed newborns, but symptoms were transient and self-limited. Premature infants could be more susceptible to the effects of selective serotonin reuptake inhibitors and venlafaxine.
Key Words: selective serotonin reuptake inhibitors • venlafaxine • pregnancy • neonates • prematurity
Abbreviations: SSRI—selective serotonin reuptake inhibitors • CHU—Centre Hospitalier Universitaire • OR—odds ratio • CI—confidence interval
Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are prescribed for pregnant women with depressive or anxiety disorders.1–3 Several studies show that these treatments late in pregnancy have potential effects on newborns, but they lack critical information about onset, duration, and severity of neonatal symptoms, all of which are essential for clinical management of mothers and their infants.4–16 Moreover, to our knowledge, these studies did not differentiate these effects between term and preterm newborns. Indeed, some authors excluded premature infants from their studies. We have hypothesized that premature infants would be more susceptible to complications after exposure to SSRIs and venlafaxine than term newborns.
Our goals for this study were to (a) describe neonatal behavioral signs in a group of newborns exposed in utero to SSRIs and to venlafaxine at the time of delivery, (b) compare the rate of neonatal behavioral signs, prematurity, and admission to specialized neonatal care between a group of newborns who were exposed to SSRIs and venlafaxine at delivery and an unexposed group of newborns, (c) compare the effects in exposed preterm and term newborns.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Design
We conducted a retrospective cohort study by using patients' charts from Centre Hospitalier Universitaire (CHU) Sainte-Justine in Montréal. This study was approved by the institutional ethics board of CHU Sainte-Justine, a tertiary mother-child center with an average of 3500 deliveries per year and level 1, 2, and 3 neonatal care units. The study population included women who delivered at CHU Sainte-Justine between January 1, 2002, and July 31, 2004, and their newborns. We studied 2 groups of women: those taking SSRIs or venlafaxine and a control group. This study was conducted before the Health Canada Advisory in August 2004 regarding the possible association between late exposure to SSRIs during pregnancy and adverse neonatal outcomes.17 Mothers using benzodiazepines, barbiturates, and any other antidepressant on a daily basis during pregnancy or at the time of delivery were excluded from exposed and unexposed groups. Other drugs for chronic diseases were permitted.
Study Groups
Exposed Group
We identified mothers taking SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline) or venlafaxine during the third trimester of pregnancy, or at least the 2 last weeks before delivery, through the pharmacy computerized system at CHU Sainte-Justine. Once identified, medical charts of mothers and infants were retrieved for review. At low doses, pharmacological effects of venlafaxine are similar to other SSRIs.
Unexposed Group
The unexposed group consisted of mothers who delivered at CHU Sainte-Justine during the study period. To have at least a 1:1 ratio of exposed to unexposed patients, we selected randomly 1 mother for every 25 deliveries through medical charts. No matching between exposed and unexposed subjects was performed. Charts of mothers and newborns were reviewed in a similar fashion to the exposed group.
Data Collection
Data collection was performed by a single investigator (Dr Agogué). Maternal demographics and medical and psychiatric diagnoses were obtained from prenatal clinical assessment in the medical charts. Neonatal data were retrieved from medical and nursing observation notes for the first week of life or until discharge.
Outcome Measures
Neonatal behavioral signs were defined as a composite of signs and symptoms involving central nervous, respiratory, and digestive systems, as well as hypoglycemia and the need for phototherapy. If at least 1 clinical manifestation involving any system cited above was observed during the study period (entered as yes/no in the daily data-collection sheet), it was considered that the infant had had a neonatal behavioral sign.
Infants were considered premature if they were born before 37 weeks of gestation according to ultrasound results and/or the first day of last menses. Levels 2 and 3 neonatal care were considered as specialized care units.
Statistical Analysis
Statistical analyses were performed by using SPSS (SPSS, Inc, Chicago, IL). In the case of twin pregnancies, 1 sibling was selected randomly to avoid variable pairing problems. 
2 and t test analyses were used to compare dichotomic and continuous variables, respectively, and the critical P value was set at .05. Means were used when distribution was normal, and results were presented with medians with ranges for asymmetrical distribution. Logistic regression analyses were first performed to examine the effect of late pregnancy exposure to SSRIs or venlafaxine on adverse neonatal effects, prematurity, and admission to specialized care. The following clinical factors were then added: prematurity, maternal age >35 years, smoking, illicit drug use, cesarean section, maternal hypertension, prolonged preterm rupture of membranes, history of prematurity, history of 
2 miscarriages, gestational diabetes, and small for gestational age. Nonsignificant covariates were eliminated in a stepwise manner. Results of logistic regression are presented as adjusted odds ratios and with 2-sided 95% confidence intervals (CIs).
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Seventy-six mothers who were taking SSRIs or venlafaxine at the time of delivery and their 79 infants (3 sets of twins) and 90 untreated mothers and their 91 infants (1 set of twins) met eligibility criteria and were considered for analysis.
Among exposed mothers, maternal psychiatric diagnoses were major depression (n = 31 [41%]), mixed disorders (n = 20 [26%]), other anxiety disorders (n = 12 [16%]), generalized anxiety disorders (n = 11 [14%]), and unknown (n = 2 [3%]). Forty-six (60.5%) were taking paroxetine (5–40 mg), 10 (13.2%) fluoxetine (10–40 mg), 9 (11.8%) venlafaxine (75–150 mg), 6 (8%) citalopram (10–30 mg), 3 (3.9%) sertraline (125–150 mg), and 2 (2.6%) fluvoxamine (50–150 mg). In the treated group, 2 women were taking lithium and 1 olanzapine. According to medical chart information, the mean duration of SSRIs use was 32 months (range:1–132 months) for the 61 mothers for whom the information was available.
Smoking, alcohol intake, and substance abuse were more frequent among exposed mothers (P < .01) compared with unexposed mothers (Table 1). Asthma, migraine, and cesarean sections were also statistically more frequent in exposed women (P < .01).
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First Outcome: Description of Neonatal Behavioral Signs
In our cohort of exposed infants, the median gestational age was lower when compared with unexposed infants, 38.3 weeks (interquartile range: 35.9–39.7 weeks) vs 39.7 weeks (interquartile range: 38.6–40.3 weeks) (P < .001). The signs most often observed involved the central nervous system (63.2%): tremors, shaking, agitation, spasms, hyper or hypotonia, irritability, and sleep disturbances (Table 2). Seizures were not observed. In our cohort, signs involving the respiratory system (40.8%) were indrawing, apnea/bradycardia, and tachypnea. Other differences observed in the exposed group were higher rates of vomiting, tachycardia, and jaundice. Medical interventions included supportive care, ventilatory support, and the use of prophylactic antibiotics; no term newborns needed to be intubated.
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All neonatal signs appeared during the first day of life. The median duration of neonatal behavioral signs was 3 days for newborns exposed to SSRIs or venlafaxine. In exposed infants, 75% of these signs resolved after the fifth day for premature newborns (third day for term newborns) compared with 3 days for unexposed premature infants (2 days for term unexposed newborns). The median length of stay was 3.9 days for exposed newborns (interquartile range: 2.8–7.1 days) vs 2.4 days for unexposed newborns (interquartile range: 2.1–2.8 days) (P < .001). When comparing premature newborns, exposed infants were hospitalized almost 4 times longer than unexposed infants, 14.5 days (interquartile range: 6.0–26.4 days) vs 3.7 days (interquartile range: 2.8–6.4 days) (P < .001). The infants were not readmitted at the CHU Sainte-Justine later, but we cannot assess with certainty whether they were admitted in another medical center.
In the exposed group, we found the following malformations: phenotypic dimorphisms (2), absence of septum pellicidum (1), sagittal craniosynostosis (1), pulmonary peripheral stenosis (1), and hypospadias (1); no newborn presented with persistent pulmonary hypertension. In the control group we noted the following: phenotypic dimorphisms (3), angioma (1), heart murmur (1), and cryptorchidia (1).
Second Outcome: Comparison Between Exposed and Unexposed Newborns
Neonatal Behavioral Signs
The results of the comparison between the 2 groups are presented in Table 2. In univariate analyses, we observed a higher rate of neonatal behavioral signs among infants exposed to SSRIs or venlafaxine (77.6% vs 41.1%; P < .001) compared with unexposed infants (Table 2). Adjusted odds ratios (OR) for the effect of late exposure to SSRIs or venlafaxine and prematurity on neonatal behavioral signs were 3.1 (1.3–7.1) and 8.0 (1.4–44.6), respectively (Table 3). Advanced maternal age and smoking were also significantly associated with an increased risk of neonatal behavioral signs (Table 3).
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Prematurity
The rate of prematurity was higher in the exposed group, 21 (27.6%) vs 8 (8.9%; P = .003). When adjusting for confounding variables, exposure to SSRIs or venlafaxine was not associated with an increased risk of prematurity (Table 3).
Admission to Specialized Care
Multivariate analyses indicated that prematurity was the only variable that increased the risk of admission to specialized care (Table 3). Length of stay in NICUs was 1.5 days (interquartile range: 1–6 days) vs 2.5 days (interquartile range: 1–4 days) for exposed and unexposed newborns, respectively (not significant). Moreover, the length of stay among infants who were admitted in NICUs did not differ significantly between exposed and unexposed newborns at delivery with a median of 1 day for both groups (interquartile range: 1–5 days).
Third Outcome: Comparison Between Exposed Premature and Term Newborns
Premature infants represented 28% of the exposed cohort and when excluding twin pregnancies, 6 (32%) presented with intrauterine growth retardation. Median gestational age for premature infants was 34 weeks (interquartile range: 32–34.7 weeks), median birth weight was 1794 g (range: 874–2865 g), and median Apgar score at 5 minutes was 8 (range: 4–10). Fifty-two percent of premature newborns were male. Cord pH was 7.3 ± 0.1. In the exposed group, all patients with malformations were born prematurely. We found evidence that all premature newborns (100%) exposed to SSRIs or venlafaxine presented behavioral manifestations compared with 69.1% of term exposed newborns (P = .002; Table 4). Median length of stay of exposed premature infants and term newborns was 14.5 days (interquartile range: 6.0–26.4 days) vs 3.6 days (interquartile range: 2.5–4.2 days; P < .001).
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The prevalence of depressive disorders during pregnancy has been estimated at 14%, and the incidence of anxiety disorders during pregnancy has been estimated as high as 21.9%.18–20 In our study, mothers were treated mainly for major depression and mixed disorders. SSRIs and venlafaxine are the treatments most often prescribed for these disorders, and continued treatment may be needed throughout pregnancy for maternal well-being. Because nontreatment or suboptimal treatment could affect antenatal and postnatal maternal well-being and early mother-infant interactions, it is recommended to optimize treatment during pregnancy instead of abruptly discontinue treatment.21 Several studies and case series associated these antidepressants used near term to neonatal complications.9–16,22–30
To ensure that mothers were really taking their medications, we used several methods of verification, including pharmacy and medical charts. In our cohort, paroxetine was used in the majority of the cases. During data analysis, we tried to analyze the effects of paroxetine on adverse pregnancy outcomes; however, we chose not to report it because the numbers were too small to be clinically significant. In our cohort, cigarette use, alcohol intake, and substance abuse were statistically more frequent among treated mothers; this finding is consistent with others studies.31–33
Despite all the literature on the topic, the decision to continue or to stop antidepressant treatment during pregnancy remains a current challenge for clinicians. In 2004, the US Food and Drug Administration and Health Canada cautioned health care professionals and patients about neonatal effects and late pregnancy exposure to SSRIs and related compounds.17,34 Some authors believe those recommendations were only partially evidence-based and may lead the depressed mother to be at a health risk, which was the reason why we chose all patients who were born before these advisories.14
Growing data indicate that these medications are not teratogenic6,25,35–38 except for paroxetine, which has recently been associated with a risk of cardiovascular birth defects.39 Glaxo Smith Kline39 and Kallen40 suggested a possible risk of cardiovascular malformations in neonates born from women taking paroxetine. In our cohort, we report 1 absence of septum pellicidum as previously described by Hendrick.13 We only found 1 patient with peripheral pulmonary stenosis after his mother took paroxetine for 1 year. Persistent pulmonary hypertension of the newborn was also associated with the maternal use of SSRIs in the second half of pregnancy,41,42 but clinically we did not find any persistent pulmonary hypertension of the newborn among our subjects. In our cohort, there were no neonatal deaths attributable to neonatal SSRI exposure. Indeed, rare reports of serious complications related to these treatments have been published.4,14
In recent years, several studies and case series have been published indicating that SSRIs and venlafaxine were associated with a variety of neonatal complications including neonatal behavioral signs, mainly respiratory and central nervous symptoms, prematurity, low birth weight, and increased admission to neonatal specialized care units.6,9,33 Recently, Levinson-Castiel23 found that 30% of exposed newborns presented neonatal behavioral signs; in our cohort, 77.6% of exposed newborns presented abnormal movements, hypo/hypertonia, insomnia, and dyspnea. The way we conducted our data collection could explain our higher rates of neonatal manifestations in exposed and unexposed groups compared with other studies. Our results are consistent with those observed by Sanz,28 who reported more neurologic symptoms. In our cohort of exposed newborns, we found a significant association with neonatal behavioral signs, the ORs were similar to those found by Lattimore43 (4.1 [95% CI: 1.2–19.9]) and by Moses-Kolko4 (3.0 [95% CI: 2.0–4.4]) in a literature review. In our study, no glycemic effects were found, unlike others.22,29
Most published studies lacked critical data regarding the onset, duration, and severity of neonatal symptoms, all of which are essential for clinical management of mothers and their infants. In our study, these signs were observed within the first 3 days of life and lasted up to 5 days after birth. Despite our higher incidence, symptoms were transient and self-limited, and symptomatic infants were managed with supportive care. Our results are similar to those found by Levinson-Castiel.23 Our study, like others, is not able to assess whether symptoms result either from SSRI withdrawal or from a type of serotoninergic syndrome.14
Several studies showed an association between the use of SSRIs during pregnancy and an increased rate of preterm birth.6,16,33 In our cohort, the rate of prematurity was higher in the exposed group, but when adjusted for different variables, the exposure to SSRIs or venlafaxine was not associated with an increased risk of prematurity. In our analysis, none of the known risk factors for prematurity, including smoking and maternal hypertension, could explain our higher rate of prematurity.
Premature infants show more lung and central nervous system immaturity, which predispose them to more respiratory problems, irritability, and convulsions. Despite our small sample size, we were able to assume that after exposure to SSRIs or venlafaxine, premature infants are more susceptible than term newborns to these complications. However, our study cannot determine whether these neonatal signs were related to SSRI exposure or to the vulnerability inherent to prematurity because we had only 8 unexposed premature infants. In our cohort, prematurity was the only variable that increased the risk of admission to a specialized care and not the exposure to SSRIs or venlafaxine. Indeed, in our exposed patients, adjusted ORs were 2.4 (95% CI: 0.9–6.3) and 2.4 (95% CI: 0.8–6.9) for prematurity and admission to specialized care unit similar to 1.9 (95% CI: 0.8–4.3) and 3.3 (95% CI: 1.5–7.5) found by Lattimore.43 In the literature, there are only case reports or short series of cases of neonatal behavioral signs associated with the use of SSRIs by pregnant women, but we did not find any series with premature infants. Our study specifically focused on the consequences of these treatments for exposed premature infants.30
Our study had some limitations: it was retrospective, which was our main problem; in fact, data were retrieved from medical files, and we were unable to characterize maternal psychiatric status or treatment intake data throughout pregnancy, which can affect neonatal outcome. Ideally, our control group should have included untreated mothers with depression to evaluate the effects of the illness on neonatal behavior. Our results could be influenced by detection bias, because we had a single investigator recording data. Moreover, staff's attitudes toward newborns born to mothers taking antidepressants could have lead to closer monitoring. Our assessment period was short, and the clinical implications of our study are limited to the first 7 days of life. Long-term effects of exposure to SSRIs or venlafaxine are beyond the scope of this article and cannot be evaluated by our data. Effects of antidepressants on the development of exposed children were not studied and need to be further addressed prospectively.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Neonatal behavioral signs are more frequently observed in newborns exposed to SSRIs or venlafaxine; however, symptoms are transient and self-limited. Premature infants are more susceptible to the effects of these antidepressants than term newborns.
When indicated, antidepressant treatment may be continued until the end of pregnancy to maintain optimal maternal mental health and function and to prevent maternal postnatal decompensation and disturbances of early mother-infant interactions. Pregnant women and clinicians should be aware of the potential adverse effects and the risks and benefits of treatment with SSRIs and venlafaxine, and the decision to continue with the treatment should be considered depending on the case.
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ACKNOWLEDGMENTS |
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Drs Ferreira and Bérard and Ms Martin are on the Research Chair on Medication, Pregnancy and Lactation of the Faculty of Pharmacy, Université de Montréal. Dr Bérard received a career award from the Canadian Institutes of Health Research and the Health Research Foundation.
We thank Jean-François Bussières for continuous support and Myles Lee Masley for manuscript review.
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FOOTNOTES |
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Accepted Sep 18, 2006.
Address correspondence to Ema Ferreira, BPharm, MSc, PharmD, FCSHP, Department of Pharmacy, CHU Sainte-Justine, 3175 Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5. E-mail: ema.ferreira{at}umontreal.ca
This work was presented in part at the clinical annual meeting for the Society of Obstetricians and Gynecologists of Canada; June 16–21, 2005; Québec City, Québec, Canada; the joint annual meeting of the Canadian Academy of Child and Adolescent Psychiatry and American Academy of Child and Adolescent Psychiatry; October 18–23, 2005; Toronto, Ontario, Canada; the annual meeting of the Canadian Paediatric Society, June 13–17, 2006; St-John's, Newfoundland, Canada; and the 4e colloque annuel du Réseau Mère-Enfant de la Francophonie; June 8-9, 2006; Paris, France.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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