Use of Selective Serotonin-Reuptake Inhibitors During Pregnancy and the Risk of Clubfoot

Yazdy, Mahsa M.; Mitchell, Allen A.; Louik, Carol; Werler, Martha M.

doi:10.1097/ede.0000000000000157

Cited by 34 publications

(27 citation statements)

References 27 publications

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“…We analysed as prior hypotheses associations between SSRI prescription and 10 pre-specified anomalies identified from the literature as associated with SSRI exposure[31]: CHD, severe CHD, neural tube defects, ano-rectal atresia/stenosis, renal dysplasia, craniosynostosis, hypospadias, including 3 anomalies associated with vasoconstriction (limb reduction, abdominal wall defects (gastroschisis and omphalocele) [55,56], and talipes equinovarus[57]. e Abdominal wall defects (gastroschisis, Q792, omphalocele, Q793 and other wall defects, Q795) were combined to achieve sufficient numbers to report, considering their purported common aetiology (vasoconstriction of the omphalomesenteric artery) [58,59].…”

Section: Methodsmentioning

confidence: 99%

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

et al. 2016

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BackgroundHypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).Methods and FindingsThree population-based EUROCAT congenital anomaly registries- Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010)—were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06–2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03–1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99–1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12–1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.ConclusionThe additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

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Section: Methodsmentioning

confidence: 99%

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

et al. 2016

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“…; Yazdy et al. ). To begin to identify possible patterning roles for other neurotransmitter families, this study took advantage of compounds developed for neuropharmacological research, and an exploratory drug screen was conducted in the Xenopus laevis embryo, a popular vertebrate model for the study of well‐conserved developmental mechanisms (Kaltenbrun et al.…”

Section: Introductionmentioning

confidence: 97%

Neurotransmitter signaling pathways required for normal development inXenopus laevisembryos: a pharmacological survey screen

Sullivan

Levin

2016

Journal of Anatomy

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Neurotransmitters are not only involved in brain function but are also important signaling molecules for many diverse cell types. Neurotransmitters are widely conserved, from evolutionarily ancient organisms lacking nervous systems through man. Here, we report results from a loss- and gain-of-function survey, using pharmacologic modulators of several neurotransmitter pathways to examine possible roles in normal embryogenesis. Applying reagents targeting the glutamatergic, adrenergic, and dopaminergic pathways to embryos of Xenopus laevis from gastrulation to organogenesis stages, we observed and quantified numerous malformations including craniofacial defects, hyperpigmentation, muscle mispatterning, and miscoiling of the gut. These data implicate several key neurotransmitters in new embryonic patterning roles, reveal novel earlier stages for processes involved in eye development, suggest new targets for subsequent molecular-genetic investigation, and highlight the necessity for in-depth toxicology studies of psychoactive compounds to which human embryos might be exposed during pregnancy.

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“…A study performed in Massachusetts, New York, and North Carolina included a total of 622 clubfoot cases and 2002 nonmalformed controls born between 2006 and 2011 [62]. For the 2nd or 3rd lunar month of pregnancy, SSRI use for a period of > 30 days was higher in case mothers (5%) than control mothers (3%).…”

Section: S Gentilementioning

confidence: 98%

Early pregnancy exposure to selective serotonin reuptake inhibitors, risks of major structural malformations, and hypothesized teratogenic mechanisms

Gentile

2015

Expert Opinion on Drug Metabolism & Toxicology

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The only recurrent pattern of congenital anomalies associated with antenatal SSRI exposure is heart defects. SSRIs may alter the function of serotonin and related receptors which are involved in the development of the monoamine-dependent cardiac structures. Nevertheless, the magnitude of this increase and, thus, its clinical significance are unclear. Therefore, a cautious approach of using SSRI during pregnancy only in the case of major depressive episodes should be applied. However, this risk should be balanced against the risks associated with the worsening of depressive symptoms, and take into consideration the large number of studies that found no associations between transplacental SSRI exposure and cardiac anomalies. Prenatal ultrasonography and Doppler sonography to detect early cardiac defects are also advisable. Non-pharmacological approaches are preferred for less severe psychiatric disorders.

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Use of Selective Serotonin-Reuptake Inhibitors During Pregnancy and the Risk of Clubfoot

Cited by 34 publications

References 27 publications

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

Neurotransmitter signaling pathways required for normal development inXenopus laevisembryos: a pharmacological survey screen

Early pregnancy exposure to selective serotonin reuptake inhibitors, risks of major structural malformations, and hypothesized teratogenic mechanisms

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