Selective serotonin reuptake inhibitors and adverse pregnancy outcomes

doi:10.1016/j.ajog.2006.02.019

American Journal of Obstetrics and Gynecology

Volume 194, Issue 4, April 2006, Pages 961-966

https://doi.org/10.1016/j.ajog.2006.02.019 Get rights and content

Objective

The purpose of this study was to assess the safety of the use of selective serotonin reuptake inhibitors in pregnancy.

Study design

We carried out a retrospective cohort study of 972 pregnant women who had been given at least 1 selective serotonin reuptake inhibitor prescription in the year before delivery and 3878 pregnant women who did not receive selective serotonin reuptake inhibitors and who were matched by the year of the infant's birth, the type of institute at birth, and the mother's postal code from 1990 to 2000 in the Canadian province of Saskatchewan.

Results

The risks of low birth weight (adjusted odds ratio, 1.58; 95% CI, 1.19, 2.11), preterm birth (adjusted odds ratio, 1.57; 95% CI, 1.28, 1.92), fetal death (adjusted odds ratio, 2.23; 95% CI, 1.01, 4.93), and seizures (adjusted odds ratio, 3.87; 95% CI, 1.00, 14.99) were increased in infants who were born to mothers who had received selective serotonin reuptake inhibitor therapy.

Conclusion

The use of selective serotonin reuptake inhibitors in pregnancy may increase the risks of low birth weight, preterm birth, fetal death, and seizures.

Section snippets

Study population

We conducted a retrospective cohort study, using the linked maternal/infant/prescription records from the Canadian province of Saskatchewan. The Saskatchewan Health databases include prescription information on most residents (>90%) of the province of Saskatchewan.¹⁸ We first identified all live births and stillbirths in Saskatchewan to Saskatchewan residents between January 1, 1990, and December 31, 2000 (SSRIs were introduced into the Saskatchewan Formulary in 1989). These data were then

Results

A total of 972 pregnant women with at least 1 SSRI prescription being dispensed in 1 year before delivery were identified from the 1990 to 2000 Saskatchewan linked mother/infant database. From the remainder of the maternal/infant database, 3878 pregnant women (10 subjects less than planned because not enough nonexposed women could be identified from the database according to the matching conditions) who had not received SSRIs in 1 year before delivery were selected.

Exposed women were older,

Comment

Our population-based study found that the risks of low birth weight, preterm birth, fetal death, and seizures were increased in infants who were born to mothers who had received prescription SSRIs than in infants who were born to mothers without such exposure. On the other hand, no association between prenatal SSRIs and birth defects and adverse maternal outcomes was observed. Our data also described the patterns of SSRI use by categories of SSRIs in routine practice, which provide useful

Acknowledgments

We thank Drs Sarah MacDonald and Dean Fergusson for critical appraisal of an earlier version of the manuscript.

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Systematic review and meta-analysis of risk of gestational diabetes in women with preconception mental disorders
2022, Journal of Psychiatric Research
There is a well-established bidirectional association between Type 2 diabetes and mental disorder and emerging evidence for an increased risk of perinatal mental disorder in women with gestational diabetes (GDM). However, the relation between mental disorder prior to pregnancy and subsequent risk of GDM remains relatively unexplored. This is a systematic review and meta-analysis of the risk of GDM in women with a range of preconception mental disorders. Peer-reviewed literature measuring odds of GDM and preconception mood, anxiety, psychotic and eating disorders was systematically reviewed. Risk of bias was assessed using a checklist. Two independent reviewers were involved. 22 observational studies met inclusion criteria; most were retrospective cohorts from English speaking, high income countries. 14 studies were at high risk of bias. There was evidence for an increased risk of GDM in women with schizophrenia (pooled OR 2.44; 95% CI 1.17,5.1; 5 studies) and a reduced risk of GDM in women with anorexia nervosa (pooled OR 0.63; 95% CI 0.49,0.80; 5 studies). There was some limited evidence of an increased risk in women with bipolar disorder. There was no evidence for an association with preconception depression or bulimia nervosa on meta-analysis. There were insufficient studies on anxiety disorders for meta-analysis. This review indicates that there is not a significant risk of GDM associated with many preconception mental disorders but women with psychotic disorders represent a group uniquely vulnerable to GDM. Early detection and management of GDM could improve physical and mental health outcomes for these women and their children.
Gestational exposure to antidepressants and risk of seizure in offspring: A systematic review and meta-analysis
2021, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
249 articles were identified for full-text review, 233 of which were excluded as they were reviews, editorial letters, commentaries, or did not investigate the association between gestational use of antidepressants and seizures in offspring. 16 studies (Bellissima et al., 2020; Boucher et al., 2008; Cantarutti et al., 2017; Davis et al., 2007; Galbally et al., 2009; Hayes et al., 2012; Kallen, 2004; Leibovitch et al., 2013; Lennestal and Kallen, 2007; Levinson-Castiel et al., 2006; Mao et al., 2016; Oberlander et al., 2006, 2008; Simon et al., 2002; Warburton et al., 2010; Wen et al., 2006) were included in the review and 13 with unique data sources were included in the meta-analyses. All of the studies were published after 2000.
In spite of the preliminary evidence suggesting a link between gestational use of antidepressant and neurodevelopmental disorders in their offspring, the association between maternal use of antidepressants during pregnancy and the risk of neurologically-related adverse outcomes such as neonatal seizure is still unclear. This study summarises the available evidence on the association between gestational exposure to any antidepressants and the risk of seizure in neonates and children. We found that gestational antidepressant exposure is associated with a 2.3-fold higher incidence of seizure in offspring. Although a causal relationship cannot be confirmed in view of other potential confounders, our findings warrant future research on related clinical aspects, and possibly more careful monitoring of foetal neurodevelopment in pregnant women taking antidepressants during pregnancy. However, this does not suggest the abrupt withdrawal of antidepressants during pregnancy for all cases at risk of seizure in offspring as this must be balanced with the risk of negative consequences caused by untreated maternal depression, and decision-making should be individualised for each patient.
Exposure of pregnant rats to stress and/or sertraline: Side effects on maternal health and neurobehavioral development of male offspring
2021, Life Sciences
Sertraline (SE) is one of the most prescribed medications for treating gestational depression, anxiety and stress. However, little is known about its effects on nervous-system development in offspring. Therefore, this study investigated the somatic, reflex and neurobehavioral development of rats exposed to SE during pregnancy, associated or not with stress.
Pregnant Wistar rats were assigned to the following groups (n = 10-8 rats/group): CO - control animals administered filtered water by gavage; SE - animals administered 20 mg/kg SE by gavage; ST - animals subjected to restraining stress and administered filtered water; ST/SE - animals subjected to restraining stress and administered 20 mg/kg SE. The treatment was administered between gestational days (GD) 13 to 20. Somatic and reflex developments were investigated in the male offspring from postnatal day (PND) 1 to 21. The elevated plus maze was performed on PND 25 and 80. The open field and light/dark box test were performed on PND 90 and 100, respectively.
Body weight reduction and vaginal bleeding were observed in pregnant rats exposed to SE. The male offspring of the SE group showed delay in incisor eruption, fur development and negative geotaxis. In addition, the SE group was less exploratory (anxious personality) compared to the CO and ST groups.
The results obtained in the present study demonstrate that sertraline not only impairs maternal health, but also, associated or not with stress, can compromise the somatic, reflex and neurobehavioral development of male rats.
Maternal use of antidepressants during pregnancy and risks for adverse perinatal outcomes: a meta-analysis
2020, Journal of Psychosomatic Research
Objective: To perform an updated and comprehensive meta-analysis on the risks of adverse perinatal outcomes in children whose mothers received antidepressants during pregnancy.
Methods: A systematic literature search of several databases was conducted through December 2018 to identify relevant studies. Risk estimates and their corresponding 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Subgroup and sensitivity analyses were performed to explore the source of heterogeneity and test the robustness.
Results: Forty-eight cohort and 6 case-control studies were included. In cohort studies, children whose mothers received antidepressants during pregnancy had higher risks of preterm birth (RR = 1.62, 95% CI: 1.37, 1.90), low birth weight (RR = 1.37, 95% CI: 1.04, 1.80), and admissions to neonatal intensive care unit (RR = 1.60, 95% CI: 1.38, 1.85) when compared with children born by depressed but untreated pregnant women. The risks of spontaneous abortions (RR = 1.49, 95% CI: 1.29, 1.73), large for gestational age (RR = 1.11, 95% CI: 1.03, 1.20), stillbirths (RR = 1.16, 95% CI: 1.02, 1.32), low Apgar score at 5 min (RR = 1.91, 95% CI: 1.42, 2.56), and neonatal convulsions (RR = 1.97, 95% CI: 1.56, 2.48) increased in children whose mothers received antidepressants during pregnancy when compared with children born by healthy pregnant women.
Conclusion: Compared with children whose mothers did not receive antidepressants during pregnancy, children whose mothers received antidepressants during pregnancy had increased risks of adverse perinatal outcomes. Further research on the dose of antidepressants is needed.
Association Between Gestational Diabetes and Mental Illness
2020, Canadian Journal of Diabetes
The rates of both gestational diabetes mellitus (GDM) and mental illness in pregnancy are rising. There is an association between type 2 diabetes and major depressive disorder, anxiety and schizophrenia, thus there is a need for greater understanding of the relationship between GDM and mental illness. This review suggests that there is a bidirectional and complex relationship between antenatal depression, gestational diabetes and postpartum depression. The combined effect of both a history of depression and gestational diabetes significantly increases the risk of postpartum depression. There is an association between severe mental illness and GDM; however, it is strongly mediated by antipsychotic medications and psychosocial factors, in addition to the disease itself. Medication has a major role in treating mental illness during pregnancy and is not directly linked with GDM in either depression or psychosis. Health-care providers should be mindful of the association between GDM and mental illness to appropriately screen and treat both disorders.
Les taux de diabète sucré gestationnel (DSG) et du trouble de santé mentale durant la grossesse augmentent. Il existe un lien entre le diabète de type 2 et la dépression majeure, l’anxiété et la schizophrénie. Par conséquent, il est nécessaire d’avoir une meilleure compréhension de la relation entre le DSG et le trouble de santé mentale. La présente revue suggère qu’il existe une relation bidirectionnelle et complexe entre la dépression anténatale, le diabète gestationnel et la dépression post-partum. L’effet combiné des antécédents de dépression et de diabète gestationnel augmente significativement le risque de dépression post-partum. Il existe un lien entre le trouble de santé mentale grave et le DSG. Toutefois; ce lien est fortement influencé par les médicaments antipsychotiques et les facteurs psychosociaux, outre la maladie elle-même. Les médicaments jouent un rôle majeur dans le traitement du trouble de santé mentale durant la grossesse et ne sont pas directement associés au DSG ni lors de dépression ni lors de psychose. Les prestataires de soins de santé devraient être conscients du lien qui existe entre le DSG et le trouble de santé mentale pour dépister et traiter de façon appropriée ces 2 troubles.
Serotonin and serotonin reuptake inhibitors alter placental aromatase
2019, Journal of Steroid Biochemistry and Molecular Biology
Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT_2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.

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Supported by a grant from The Hospital for Sick Kids Foundation (grant #XG-02-098) and by a research and development Research Allowance from The Canadian Institutes for Health Research (S.W.W.).

Based in part on nonidentifiable data provided by the Saskatchewan Department of Health. The interpretation and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health.

Presented at the 26th Annual Meeting of the Society for Maternal Fetal Medicine, January 30 - February 4, 2006, Miami, FL.

^†: Deceased.

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Selections from the 26th Annual Meeting of the Society for Maternal-Fetal Medicine, January 30-February 4th, 2006, Miami, FloridaSelective serotonin reuptake inhibitors and adverse pregnancy outcomes

Objective

Study design

Results

Conclusion

Section snippets

Study population

Results

Comment

Acknowledgments

J Pediatr

Am J Obstet Gynecol

J Clin Epidemiol

Prospective study of postpartum depression: prevalence, course, and predictive factors

J Abnorm Psychol

Preface and guidelines for prescribing drugs to pregnant women

Amitriptyline for in patients and SSRIs for outpatients with depression? Systematic review and meta-regression analysis

Pharmacopsychiatry

Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials

BMJ

Goodman and Gilman's: the pharmacological basis of therapeutics

Is maternal use of selective serotonin reuptake inhibitors in the third trimester of pregnancy harmful to neonates?

CMAJ

Birth outcomes in pregnant women taking fluoxetine

N Engl J Med

Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors

Acta Paediatr

Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis

Lancet

Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior

Pediatrics

Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations

Arch Gen Psychiatr

Selections from the 26th Annual Meeting of the Society for Maternal-Fetal Medicine, January 30-February 4th, 2006, Miami, Florida
Selective serotonin reuptake inhibitors and adverse pregnancy outcomes