https://orcid.org/0000-0002-7992-3005
Figures
Abstract
Background
The association of maternal exposure to selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) with the risk of system-specific congenital malformations in offspring remains unclear. We conducted a meta-analysis to examine this association and the risk difference between these two types of inhibitors.
Methods
A literature search was performed from January 2000 to May 2023 using PubMed and Web of Science databases. Cohort and case-control studies that assess the association of maternal exposure to SSRIs or SNRIs with the risk of congenital abnormalities were eligible for the study.
Results
Twenty-one cohort studies and seven case-control studies were included in the meta-analysis. Compared to non-exposure, maternal exposure to SNRIs is associated with a higher risk of congenital cardiovascular abnormalities (pooled OR: 1.64 with 95% CI: 1.36, 1.97), anomalies of the kidney and urinary tract (pooled OR: 1.63 with 95% CI: 1.21, 2.20), malformations of nervous system (pooled OR: 2.28 with 95% CI: 1.50, 3.45), anomalies of digestive system (pooled OR: 2.05 with 95% CI: 1.60, 2.64) and abdominal birth defects (pooled OR: 2.91 with 95%CI: 1.98, 4.28), while maternal exposure to SSRIs is associated with a higher risk of congenital cardiovascular abnormalities (pooled OR: 1.25 with 95%CI: 1.20, 1.30), anomalies of the kidney and urinary tract (pooled OR: 1.14 with 95%CI: 1.02, 1.27), anomalies of digestive system (pooled OR: 1.11 with 95%CI: 1.01, 1.21), abdominal birth defects (pooled OR: 1.33 with 95%CI: 1.16, 1.53) and musculoskeletal malformations (pooled OR: 1.44 with 95%CI: 1.32, 1.56).
Citation: Huang W, Page RL, Morris T, Ayres S, Ferdinand AO, Sinha S (2023) Maternal exposure to SSRIs or SNRIs and the risk of congenital abnormalities in offspring: A systematic review and meta-analysis. PLoS ONE 18(11): e0294996. https://doi.org/10.1371/journal.pone.0294996
Editor: Carmen Concerto, University of Catania Libraries and Documentation Centre: Universita degli Studi di Catania, ITALY
Received: August 21, 2023; Accepted: November 13, 2023; Published: November 29, 2023
Copyright: © 2023 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting information files.
Funding: This work was funded by an internal grant from Texas A&M University Division of Research and was awarded to the following authors: RP, TM, SA, AF, SS. The Grant number is 290414-00001. The URL for the funder is https://vpr.tamu.edu/find-funding/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Across the nation, birth defects are the leading cause of infant death, accounting for 20 percent of all infant deaths [1], so preventing birth defects is an important social goal. Yet, the etiology of birth defects is complex, which means that there are many pathways for improvement. One important focus is on the effect of SSRIs and SNRIs, used to treat depression, when taken during pregnancy. Depression is a common mood disorder. Since the start of the COVID-19 pandemic, more people, especially women, have suffered from depression and sought therapy for it [2]. In the United States, depression affects 10% to 20% of women during pregnancy, the postpartum period, or both [3], with higher rates reported among pregnant individuals during the COVID-19 pandemic [4]. Antidepressants are evidence-based treatments for depression during pregnancy. However, antidepressants’ adverse associations with fetal and infant health, including the possibility of congenital disabilities following exposure during pregnancy, remains a source of concern [5]. To provide evidence-based guidance for therapeutic management during pregnancy, it is necessary to investigate the relationships between antidepressant use during pregnancy and congenital abnormalities.
Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants prescribed during pregnancy, followed by serotonin and norepinephrine reuptake inhibitors (SNRIs) [6]. The chemical serotonin is responsible for regulating mood, sleep, bone health, wound healing, sexual drive and many more physiological and psychological activities. SSRIs treat depression by blocking the reuptake of serotonin by neurons and increasing levels of serotonin in brain, which makes more serotonin available to improve transmission of messages between neurons [7]. The chemical norepinephrine is responsible for maintaining blood pressure, increasing attention and regulating sleep-wake cycle, mood and memory. SNRIs help relieve depression by blocking the reuptake of both serotonin and norepinephrine in brain and affecting neurotransmitters used to communicate between brain cells, which ultimately affects changes in brain chemistry and communication in brain nerve cell circuitry known to regulate mood [8].
Serotonin is not only responsible for psychological activities and processes. Studies also suggest that serotonin plays an important role in fertility and normal embryonic development as different serotonin receptor subtypes can be found in human oocytes and granulosa cells that leads to the production of progesterone and estrogen [9, 10]. Norepinephrine plays an important role in arousal, attention, cognitive function and the body’s reaction to an emergency situation. Norepinephrine also plays a critical role in glycogenolysis and gluconeogenesis (while reducing glucose clearance) and inducing ketogenesis and lipolysis [11, 12]. These all may have detrimental effects on embryonic development. Over the past few decades, there has been a rise in women’s use of antidepressants during pregnancy. The most frequently prescribed antidepressants during pregnancy are selective serotonin reuptake inhibitors (SSRIs), with an estimated global prevalence of 3% and a North American prevalence of 5.5% [6]. For serotonin and norepinephrine reuptake inhibitors (SNRIs), the second most frequently prescribed antidepressants during pregnancy, the international prevalence estimate is 0.73% [6]. Therefore, studies estimating the risk of these antidepressants to the fetus are critical for providing evidence-based clinical guidelines for health care practitioners.
In the overarching goal of understanding the role of SSRI and SNRI on congenital development, many studies have analyzed the association of maternal exposure to SSRIs with adverse neonatal or pregnancy outcomes [13, 14]. In contrast, studies on the association of maternal exposusre to SNRIs with neonatal or pregnancy outcomes are limited [5] or do not separate the risk assessment of SNRIs from SSRIs [15]. Previous studies have indicated the differences in the risk of adverse clinical outcomes associated with SNRIs compared to SSRIs for cerebrovascular, cardiovascular, and mortality events [16] and the risk of fractures among 50 years or older adults [17]. But such a comparison has not been reported in congenital disabilities (commonly known as birth defects). Gao et al. [18] conducted a meta-analysis on the association of maternal exposure to SSRIs with the risks of 29 categories of congenital malformations. Still, there is no such meta-analysis on SNRIs. De Vries et al. [5] conducted a meta-analysis on the association of maternal antidepression exposure (SSRIs or SNRIs) with the risks of congenital heart defects without studying the differential effects of SSRIs and SNRIs. Ours is the first meta-analysis to examine the association of maternal exposure to SNRIs with system-specific malformations in offspring and the first to explore the difference between SNRIs and SSRIs in terms of the risk of congenital abnormalities in offspring.
Methods
Literature search, inclusion criteria and quality assessment
Two independent authors conducted a literature search examining articles published between January 2000 to May 2023 using the PubMed and the Web of Science databases. Medical Subject Heading (MeSH) terms, Key words and Boolean operators were used to form the search strategy S1 Appendix. Cohort studies and case-control studies that were published in English were included. Case reports, reviews, conference abstracts and basic science research were excluded. Eligible studies included (a) SSRIs or SNRIs as the exposure of interest, (b) congenital malformation as the outcome of interest, and (c) provided raw counts to calculate the crude odds ratio (cOR) and confidence intervals (CIs). Nine system-specific congenital malformations were analyzed separately, including cardiovascular abnormalities; kidney and urinary tract anomalies; nervous system malformations; digestive system anomalies; abdominal birth defects; musculoskeletal malformations; eye, ear, face and neck malformations; genital organs malformations; respiratory system malformations. Additionally, overall malformations that included any of the nine malformations were also analyzed. Newcastle-Ottawa Scale [19] was used to assess study quality. A study was judged on three broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of either the exposure or outcome of interest for case-control or cohort studies, respectively. A study was categorized as high quality if scored ≥ 8 points, fair quality if scored 6–7 points, and poor quality if scored <6 points.
Statistical analysis
STATA/MP 17.0 (Stata Corp. 2021, LLC) was used for data analyses. Pooled risk estimates with 95% confidence intervals (CIs) were obtained using a fixed effect model. When significant heterogeneity was present, we used a random effect model to estimate [20]. We used the I2 statistic to measure the heterogeneity among studies, and results were considered as heterogeneous for I2 >50% and the corresponding P <0.05 [21]. The statistic I2 can be seen as a relative measure of heterogeneity to the total variability. We also provided the τ2 estimate which is an absolute measure of between-study variability. The funnel plot and Egger’s regression tests assessed small-study effects, such as publication bias [22]. The funnel plot is a scatter plot of log (odds ratio) against the standard error for different studies. In the ideal case, the points should be equally distributed around the logarithm of the pooled odds ratio line. In contrast, an asymmetrical distribution of the points around that line indicates a possible publication bias. Besides this visual procedure, Egger’s test objectively identifies the publication bias. The trim-and-fill analyses were used to adjust for the potential publication bias [23] when the bias may exist, and pooled risk estimates with 95% confidence intervals (CIs) were recalculated after the trim-and-fill analyses.
Results
Characteristics of included studies
The literature search identified 2046 records from the two databases. After we screened the titles and abstracts based on the inclusion criteria, 2013 records were excluded for duplicates, conference abstract, case report, bench research, non-relevant to the study topic, etc. After the full text review of 33 studies to assess for eligibility, 5 studies, which did not specify categories of congenital malformations, were further excluded. In the end, we included 7 case-control studies and 21 cohort studies in the final analysis Fig 1. Of the 28, 14 studies were conducted in European countries, 9 studies were conducted in the US, 2 studies were conducted in Japan, 1 study was conducted in Canada, 1 study was conducted in Israel, and 1 study was conducted in European countries and Israel Table 1. All the 28 included studies were assessed as high-quality studies except for one fair quality study. These studies reported the associations of maternal exposure to SSRI or SNRI with specific congenital malformations in offspring. All the congenital malformations cases were clinically diagnosed and classified based on ICD-9 codes to identify the congenital malformations by organ system. Most studies were judged as high-quality studies with high Newcastle-Ottawa scores, which indicated relatively low risk of bias within these studies, see S1 and S2 Tables.
Risk of congenital cardiovascular abnormalities
Twenty studies assessed maternal exposure to SSRIs and the risk of cardiovascular anomalies in offspring, and nine studies assessed maternal exposure to SNRIs and the risk of cardiovascular malformations in offspring. These studies reported common congenital cardiovascular anomalies: tetralogy of Fallot, transposition of the great arteries, ventricular/atrial septal defect, left/right ventricular outflow tract obstruction, etc.
Compared to the offspring of women not exposed to SSRIs or SNRIs, the offspring of women exposed to SSRIs or SNRIs were at higher risk of congenital cardiovascular abnormalities. The pooled OR was 1.25 (95% CI: 1.20, 1.30) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.52 (95% CI: 0.19, 1.44) to 4.81 (95% CI: 1.73, 13.37) Fig 2. The pooled OR was 1.72 (95% CI: 1.53, 1.93) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 1.23 (95% CI: 0.90, 1.68) to 5.25 (95% CI: 0.72, 38.48) Fig 3. No significant heterogeneity was detected in either group at the 5% level of significance (I2 = 0.0%, P = 0.523; I2 = 35.1%, P = 0.076). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = -0.03, 95% CI: -0.52, 0.47; P = 0.913) Fig 4. However, for those women exposed to SNRIs, there was a publication bias as indicated by the funnel plot and Egger’s test (Coefficient = 1.73, 95% CI: 0.93, 2.52; P <0.001). When we used the trim and fill method to adjust for the potential publication bias, the recalculated pooled odds ratio of the association of maternal SNRIs exposure with cardiovascular malformations in offspring was 1.64 (95% CI: 1.36, 1.97) Fig 5.
A: Funnel plot before trim-and-fill methods. B: Funnel plot after trim-and-fill methods.
Risk of congenital anomalies of the kidney and urinary tract
Eight studies assessed maternal exposure to SSRIs and the risk of congenital anomalies of the kidney and urinary tract in offspring, and five studies assessed maternal exposure to SNRIs and the risk of congenital anomalies of the kidney and urinary tract in offspring. These studies reported birth defects involving hypospadias, renal agenesis/dysplasia and renal-collecting-system defects.
Compared to the offspring of women not exposed to SSRIs or SNRIs, the offspring of women exposed to SSRIs or SNRIs were at higher risk of kidney and urinary tract anomalies. The pooled OR was 1.14 (95% CI: 1.02, 1.27) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.37 (95% CI: 0.17, 0.80) to 3.16 (95% CI: 1.05, 9.56) Fig 6. The pooled OR was 1.72 (95% CI: 1.25, 2.35) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 1.27 (95% CI: 0.60, 2.67) to 2.55 (95% CI: 1.03, 6.34) Fig 7. No significant heterogeneity was detected in either group (I2 = 16.8%, P = 0.233; I2 = 0.0%, P = 0.851). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = -0.65, 95% CI: -1.67, 0.36; P = 0.194) Fig 8. However, for those women exposed to SNRIs, there was a publication bias as indicated by the funnel plot and Egger’s test (Coefficient = 5.03, 95% CI: 0.94, 9.13; P = 0.027). When we used the trim and fill method to adjust for the potential publication bias, the recalculated pooled odds ratio of the association of maternal SNRIs exposure with the kidney and urinary tract anomalies in offspring was 1.63 (95% CI: 1.21, 2.20) Fig 9.
A: Funnel plot before trim-and-fill methods. B: Funnel plot after trim-and-fill methods.
Risk of congenital malformations of the nervous system
Eight studies assessed maternal exposure to SSRIs and the risk of congenital anomalies of the nervous system in offspring, and three studies assessed maternal exposure to SNRIs and the risk of congenital anomalies of the nervous system in offspring. These studies reported several common congenital anomalies of the nervous system, including neural tube defects, spina bifida, anencephaly, hydrocephalus, Dandy–Walker malformation, cerebellar hypoplasia and holoprosencephaly.
Compared to the offspring of women not exposed to SNRIs, the offspring of women exposed to SNRIs were at higher risk of nervous system malformations. However, no association was observed in SSRIs group. The pooled OR was 1.07 (95% CI: 0.93, 1.23) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.57 (95% CI: 0.23, 1.39) to 3.63 (95% CI: 0.51, 25.78) Fig 10. The pooled OR was 2.28 (95% CI: 1.50, 3.45) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 1.64 (95% CI: 0.53, 5.08) to 5.61 (95% CI: 1.84, 17.11) Fig 11. No significant heterogeneity was detected in either group (I2 = 31.8%, P = 0.091; I2 = 0.0%, P = 0.562). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = 0.85, 95% CI: -0.53, 2.22; P = 0.212). For those women exposed to SNRIs, no publication bias was detected either based on the funnel plot and Egger’s test (Coefficient = 0.73, 95% CI: -5.62, 7.07; P = 0.740) Fig 12.
A: Funnel plot for SSRIs. B: Funnel plot for SNRIs.
Risk of congenital anomalies of the digestive system
Nine studies assessed maternal exposure to SSRIs and the risk of congenital digestive malformations in offspring, and three studies assessed maternal exposure to SNRIs and the risk of congenital digestive malformations in offspring. These studies reported the congenital anomalies of the tubular gastrointestinal tract such as esophageal atresia, intestinal atresia, anorectal atresia and Hirschsprung’s Disease, as well as cleft lip with or without cleft palate.
Compared to the offspring of women not exposed to SSRIs or SNRIs, the offspring of women exposed to SSRIs or SNRIs were at higher risk of digestive system anomalies. The pooled OR was 1.11 (95% CI: 1.01, 1.21) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.29 (95% CI: 0.04, 2.15) to 2.81 (95% CI: 1.33, 5.92) Fig 13. The pooled OR was 2.05 (95% CI: 1.60, 2.64) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 0.78 (95% CI: 0.19, 3.11) to 3.58 (95% CI: 1.44, 8.89) Fig 14. No significant heterogeneity was detected in either group (I2 = 0.0%, P = 0.614; I2 = 0.0%, P = 0.428). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = 0.42, 95% CI: -0.19, 1.03; P = 0.176). For those women exposed to SNRIs, no publication bias was detected either based on the funnel plot and Egger’s test (Coefficient = -0.29, 95% CI: -3.60, 3.02; P = 0.818) Fig 15.
A: Funnel plot for SSRIs. B: Funnel plot for SNRIs.
Risk of abdominal birth defects
Seven studies assessed maternal exposure to SSRIs and the risk of congenital abdominal birth defects in offspring, and four studies assessed maternal exposure to SNRIs and the risk of congenital abdominal birth defects in offspring. These studies reported three types of birth defects that affect the abdomen: diaphragmatic hernia (organs protrude into the chest cavity), omphalocele (organs protrude through the navel) and gastroschisis (organs protrude through the abdominal wall).
Compared to the offspring of women not exposed to SSRIs or SNRIs, the offspring of women exposed to SSRIs or SNRIs were at higher risk of abdominal birth defects. The pooled OR was 1.33 (95% CI: 1.16, 1.53) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.86 (95% CI: 0.27, 2.74) to 3.32 (95% CI: 1.55, 7.08) Fig 16. The pooled OR was 2.91 (95% CI: 1.98, 4.28) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 1.93 (95% CI: 0.44, 8.50) to 5.17 (95% CI: 1.29, 20.76) Fig 17. No significant heterogeneity was detected in either group (I2 = 18.1%, P = 0.233; I2 = 0.0%, P = 0.920). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = 0.53, 95% CI: -0.88, 1.95; P = 0.437). For those women exposed to SNRIs, no publication bias was detected either based on the funnel plot and Egger’s test (Coefficient = 0.414, 95% CI: -2.40, 3.23; P = 0.704) Fig 18.
A: Funnel plot for SSRIs. B: Funnel plot for SNRIs.
Risk of musculoskeletal congenital malformations
Eleven studies assessed maternal exposure to SSRIs and the risk of musculoskeletal congenital malformations in offspring, and three studies assessed maternal exposure to SNRIs and the risk of musculoskeletal congenital malformations in offspring. These studies reported musculoskeletal congenital malformations: craniosynostosis, limb-reduction defects, clubfoot and talipes equinovarus.
Compared to the offspring of women not exposed to SSRIs, the offspring of women exposed to SSRIs were at higher risk of musculoskeletal congenital malformations. However, no association was observed in SNRIs group. The pooled OR was 1.44 (95% CI: 1.32, 1.56) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.37 (95% CI: 0.09, 1.50) to 4.44 (95% CI: 1.10, 18.01), and modest heterogeneity was detected (I2 = 43.1%, P = 0.003) Fig 19. The pooled OR was 1.01 (95% CI: 0.73, 1.40) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 0.81 (95% CI: 0.54, 1.23) to 2.03 (95% CI: 0.58, 7.07), and no significant heterogeneity was detected (I2 = 14.5%, P = 0.322) Fig 20. For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = -0.28, 95% CI: -1.16, 0.60; P = 0.522) Fig 21. For those women exposed to SNRIs, publication bias may exist as indicated by the funnel plot and Egger’s test (Coefficient = 2.05, 95% CI: 1.00, 3.09; P = 0.008). When we used the trim and fill method to adjust for the potential publication bias, the recalculated pooled odds ratio of association of maternal SNRIs exposure with musculoskeletal congenital malformations in offspring was 0.90 (95% CI: 0.60, 1.36) Fig 22.
A: Funnel plot before trim-and-fill methods. B: Funnel plot after trim-and-fill methods.
Risk of congenital malformations of eye, ear, face and neck
Six studies assessed maternal exposure to SSRIs and the risk of congenital malformations of eye, ear, face and neck in offspring, and two studies assessed maternal exposure to SNRIs and the risk of congenital malformations of eye, ear, face and neck in offspring. These studies reported several congenital malformations such as anotia, microtia, cataracts, glaucoma and anterior chamber defects.
No association was observed between maternal exposure to SSRIs or SNRIs and congenital malformations of eye, ear, face and neck in offspring. The pooled OR was 1.00 (95% CI: 0.80, 1.26) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.47 (95% CI: 0.07, 3.39) to 3.13 (95% CI: 1.36, 7.19) Fig 23. The pooled OR was 1.44 (95% CI: 0.82, 2.55) for those women exposed to SNRIs during pregnancy, with the reported ORs ranging from 1.22 (95% CI: 0.16, 9.27) to 1.68 (95% CI: 0.75, 3.74) Fig 24. No significant heterogeneity was detected in either group (I2 = 26.0%, P = 0.182; I2 = 0.0%, P = 0.885). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = -0.67, 95% CI: -2.54, 1.20; P = 0.447). For those women exposed to SNRIs, no publication bias was detected either based on the funnel plot and Egger’s test (Coefficient = -0.41, 95% CI: -10.16, 9.35; P = 0.689) Fig 25.
A: Funnel plot for SSRIs. B: Funnel plot for SNRIs.
Risk of congenital malformations of genital organs
Four studies assessed maternal exposure to SSRIs exposure and the risk of congenital malformations of genital organs in offspring, and two studies assessed maternal exposure to SNRIs and the risk of congenital malformations of genital organs in offspring. One study reported undescended testis, and the remaining studies did not specify the categories of congenital malformations of genital organs.
No association was observed between maternal exposure to SSRIs or SNRIs and congenital malformations of genital organs in offspring. The pooled OR was 0.84 (95% CI: 0.65, 1.07) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.72 (95% CI: 0.39, 1.35) to 2.25 (95% CI: 0.51, 9.86) Fig 26. The pooled OR was 1.01 (95% CI: 0.48, 2.13) for those women exposed to SNRIs during pregnancy, with the reported ORs from two studies: 0.91 (95% CI: 0.41, 2.04) and 2.98 (95% CI: 0.41, 21.78) Fig 27. No significant heterogeneity was detected in either group (I2 = 0.0%, P = 0.606; I2 = 15.9%, P = 0.275). For those women exposed to SSRIs, no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = 1.72, 95% CI: -0.23, 3.68; P = 0.071) Fig 28. For those women exposed to SNRIs, publication bias may exist as indicated by the funnel plot. When we used the trim and fill method to adjust for the potential publication bias, the recalculated pooled odds ratio of the association of maternal SNRIs exposure with malformations of genital organs in offspring was 0.91 (95% CI: 0.46, 1.84) Fig 29.
A: Funnel plot before trim-and-fill methods. B: Funnel plot after trim-and-fill methods.
Risk of congenital malformations of the respiratory system
Three studies assessed maternal exposure to SSRIs and the risk of congenital malformations of the respiratory system in offspring, and one study assessed the maternal exposure to SNRIs and the risk of congenital malformations of the respiratory system in offspring. One study reported choanal atresia, and the remaining studies did not specify the categories of congenital malformations of the respiratory system.
No association was observed between maternal exposure to SSRIs or SNRIs and congenital malformations of the respiratory system in offspring. The pooled OR was 1.22 (95%CI: 0.80, 1.84) for those women exposed to SSRIs during pregnancy, with the reported ORs ranging from 0.75 (95%CI: 0.36, 1.55) to 1.75 (95%CI: 0.85, 3.59). No significant heterogeneity was detected (I2 = 41.7%, P = 0.180), and no publication bias was detected as indicated by the funnel plot and Egger’s test (Coefficient = -64.74, 95% CI: -789.10, 659.61; P = 0.460) Fig 30. Only one study reported the maternal SNRIs exposure and the risk of congenital malformations of the respiratory system in offspring with OR of 1.51 (95% CI: 0.49, 4.70).
A: Forrest plot. B: Funnel plot.
Overall malformation risk
We analyzed 14 studies on SSRIs that reported the case number of major malformation, and 8 studies on SNRIs that reported the case number of major malformation. Major malformation refers to the occurrence of at least one of the nine malformations we have listed previously. Of the total of 22 studies, 17 studies are from Table 1, and the remaining five studies did not classify malformations and were not included in our previous analyses [52–56].
Compared to the offspring of women not exposed to SSRIs, the offspring of women exposed to SSRIs had a higher overall malformation rate. Similarly, the offspring of women exposed to SNRIs had a higher overall malformation rate when compared to the offspring of women not exposed to SNRIs. The pooled OR between major malformation and exposure to SSRIs was 1.17 (95% CI: 1.13, 1.21), with the reported ORs ranging from 0.90 (95% CI: 0.66, 1.23) to 1.49 (95% CI: 1.22, 1.81), and no significant heterogeneity was detected (I2 = 35.4%, P = 0.093) Fig 31. The pooled OR between major malformation and exposure to SNRIs was 1.27 (95% CI: 1.15, 1.40), with the reported ORs ranging from 1.05 (95% CI: 0.35, 3.11) to 2.32 (95% CI: 1.31, 4.10), and no significant heterogeneity was detected (I2 = 49.2%, P = 0.055) Fig 32. No publication bias was detected for women exposed to SSRIs, as indicated by the funnel plot and Egger’s test (Coefficient = -0.05, 95% CI: -1.39, 1.29; P = 0.934). For those women exposed to SNRIs, no publication bias was detected either based on the funnel plot and Egger’s test (Coefficient = 0.95, 95% CI: -1.43, 3.33; P = 0.366) Fig 33.
A: Funnel plot for SSRIs. B: Funnel plot for SNRIs.
Discussion
To our knowledge, this is the first meta-analysis to examine the association of maternal exposure to SNRIs during pregnancy with system-specific malformations in offspring and the first to examine the difference in this association compared to SSRIs. We found that maternal exposure to SNRIs may be associated with a higher risk of congenital cardiovascular abnormalities, anomalies of the kidney and urinary tract, malformations of nervous system, anomalies of the digestive system and abdominal birth defects in offspring, but such association was not observed for other types of congenital abnormalities such as congenital musculoskeletal malformations, malformations of genital organs, malformations of the respiratory system, and malformations of eye, ear, face and neck. On the other hand, we found that maternal exposure to SSRIs during pregnancy may be associated with higher risk of congenital cardiovascular abnormalities, anomalies of the kidney and urinary tract, anomalies of the digestive system, abdominal birth defects and musculoskeletal malformations in offspring, but such association was not observed for congenital malformations of the nervous system, malformations of genital organs, malformations of the respiratory system, and malformations of eye, ear, face and neck. Regarding the overall malformation risk, offspring exposed to SSRIs or SNRIs also had a higher risk of congenital malformations than non-exposed offspring. Moreover, maternal exposure to SNRIs may have a larger teratogenic risk in offspring compared to maternal exposure to SSRIs for the congenital malformations associated with both exposures, including congenital cardiovascular abnormalities, anomalies of the digestive system and abdominal birth defects. However, when it came to the overall malformation risk, this risk difference was less prominent.
This meta-analysis supports the hypothesis that maternal exposure to antidepressants (SSRIs or SSNIs) during pregnancy has a negative influence on fetal development, even if research on the association of exposure to these medications with congenital abnormalities in offspring has produced inconsistent results [25, 26]. Our findings are consistent with previous meta-analyses studies: maternal exposure to SSRIs is associated with a higher risk of congenital cardiovascular abnormalities in offspring, although this teratogenic effect is not substantial [18, 57, 58]. Many previous studies have demonstrated adverse cardiac effects in animal models with disrupted serotonin signaling, from either serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor exposure during development [59–62]. Furthermore, this association has been demonstrated at the level of gene expression in human placental tissues [63]. Of note, we did not include studies on Paroxetine in the meta-analysis because in 2005 the FDA issued a Public Health Advisory and reclassified Paroxetine as pregnancy-category D which means that there is evidence of risk to the fetus with the use of this medication, and it is not recommended for use during pregnancy by the American College of Obstetricians and Gynecologists (ACOG). If the studies on Paroxetine were included in the meta-analysis, the pooled ORs would most likely increase because many studies have reported a substantial association of maternal exposure to Paroxetine during pregnancy with the higher risk of congenital abnormalities in offspring [64, 65].
In addition to cardiovascular malformations, we also found that maternal exposure to SSRI or SSNI was associated with a higher risk of congenital anomalies of the kidney and urinary tract, malformations of the nervous system, anomalies of the digestive system and musculoskeletal malformations in offspring. Although there are few meta-analyses of these associations [5, 18], the biological mechanisms supporting these associations have been demonstrated in animal models [66]. Some research has demonstrated the potential mechanisms through which maternal exposure to SSRIs had a negative effect on skeletal abnormalities in offspring such as affecting cell cycle [67] and affecting osteoblast maturation [68]. Previous study has demonstrated that prenatal exposure to Venlafaxine induced oxidative stress which caused apoptotic neurodegeneration in striatum and hippocampus of developing fetal brain [69]. Maternal exposure to Desvenlafaxine was demonstrated to increase the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and S100b in the fetal brain, altering brain development of albino rats [70]. Prowse et al. [71] found that maternal exposure to SSRIs had structural consequences on the developing enteric nervous system (ENS) in the exposed offspring of Wistar rats, influencing the development of the gastrointestinal tract of the offspring. The influence of maternal exposure to SSRIs on kidney development in rat neonates was demonstrated in a study: Ghavamabadi et al. [72] found that maternal exposure to Fluoxetine is associated with the neonatal kidney developmental deficiency by reducing the gene expression of BMP7 and WNT4 in the kidney.
There have been studies of the difference in the risk of adverse clinical outcomes between SSRIs and SNRIs [16, 17], and we found that this risk difference may also exist in congenital abnormalities in exposed offspring. In this meta-analysis, we found that the offspring of women exposed to SNRIs had a higher risk of congenital cardiovascular abnormalities, anomalies of the digestive system and abdominal birth defects, compared to the offspring of women exposed to SSRIs Table 2. This risk difference may also exist in congenital anomalies of the kidney and urinary tract, although the results showed that the difference was not statistically significant. In addition, according to data on congenital malformations published by the Centers for Disease Control and Prevention (CDC), the cardiovascular abnormalities accounted for half of the ten congenital abnormalities with the highest prevalence, followed by the anomalies of the digestive system Table 2. Our study found that the risk of congenital cardiovascular abnormalities and anomalies of the digestive system differed between SSRIs and SNRIs, so it is critical to distinguish their differences in teratogenic effects to guide clinical management. SSRIs block the reuptake of serotonin, while SNRIs block the reuptake of both serotonin and norepinephrine. Perhaps this difference in the blocking of neurotransmitters’ reuptake leads to the differences in their pharmacological effects, which causes the difference in the risk of adverse clinical outcomes. We did not find the potential biological mechanisms to explain these results based on current literature but hope our findings can spark new ideas for future scientific research. In addition, we did not examine this risk difference among individual medications, but we cannot rule out the possibility of this difference among individual antidepressants, even though they were classified as SSRIs and SNRIs. Similarly, such differences may also exist among individual congenital abnormalities even if they were categorized based on organ organization and function. Further population-based studies or animal research are needed to answer these questions.
Given the adverse effects of antidepressants on the health of offspring, we advocate that health providers consider non-pharmacological treatment in clinical practice to help women with depression during pregnancy. For example, randomized clinical trials have provided strong evidence that mindfulness-based cognitive therapy (MBCT) [73] and brief interpersonal therapy [74] can enhance psychological well-being in pregnant women. In addition, more than 20 states currently ban or restrict abortion procedures in early pregnancy, which has reduced the rate of women terminating pregnancies for medical reasons. A recent Stanford Medicine’s study suggested that abortion bans will increase the number of newborns with serious heart defects [75]. Considering the poor prognosis and difficult life faced by newborns born with congenital malformations, prevention of congenital malformations is of great importance and non-pharmaceutical options should be considered when treating depression during pregnancy.
A major strength of the study was the large sample size and inclusion of multicenter studies from the United States, Europe, Canada, Japan, and Israel, which could provide sufficient statistical power to detect even small effects. However, there are a number of limitations. First, we were unable to conduct subgroup analyses on the timing of maternal antidepressants exposure (i.e. first, second, or third trimester) as a small number of studies were stratified by gestational age. However, previous studies found that maternal exposure to SSRIs or SNRIs during the first trimester of pregnancy had significant teratogenic effects on offspring [24, 56]. Second, besides the well-established effects of smoking [76], alcohol consumption [77], and maternal age [78] on congenital malformations, we were unable to adjust the effects for these potential confounders as different sets of covariates were used in various studies and unavailability of individual-level data. Third, we used I2 to identify heterogeneity and also estimated τ2 and its 95% CI to shed light on the between-study variability [20]. Most groups had estimated τ2 values zero or close to zero, and nearly all groups’ 95% confidence intervals included zero, see S4 Table, demonstrating the validity of the pooled analysis. Fourth, publication bias may affect research results. We detected publication bias for the association of maternal exposure to SNRIs with congenital cardiovascular abnormalities and anomalies of the kidney and urinary tract in offspring. However, when we used the trim and fill method to adjust for the potential publication bias, the recalculated pooled ORs just slightly decreased, and the conclusion remained unchanged. Aside from the publication bias, the asymmetry of the funnel plot may result from true heterogeneity, data irregularities, artefacts or chance [22]. Even in the absence of publication bias, asymmetry is common in funnel plots when the number of studies is small [79]. Nevertheless, the majority of included studies were assessed to be of high quality, which may suggest a low risk of methodological bias and increase the reliability of the pooled results.
Conclusion
These meta-analysis findings have important implications for clinicians who prescribe antidepressant medications to their pregnant patients. Teratogenic effects of certain medications are well-documented, however clinicians must consider risk-benefit ratios and patient history when making prescribing decisions.
Supporting information
S1 Table. Quality assessment of cohort studies in the meta-analysis.
https://doi.org/10.1371/journal.pone.0294996.s002
(DOCX)
S2 Table. Quality assessment of case-control studies in the meta-analysis.
https://doi.org/10.1371/journal.pone.0294996.s003
(DOCX)
S3 Table. PRISMA for systematic reviews and meta-analyses checklist.
https://doi.org/10.1371/journal.pone.0294996.s004
(DOCX)
S4 Table. Analysis of absolute between-study variability.
https://doi.org/10.1371/journal.pone.0294996.s005
(DOCX)
Acknowledgments
We thank all members of the multidisciplinary research team for their support of this work.
References
- 1. Ely DM, Driscoll AK. Infant mortality in the United States, 2020: data from the period linked birth/infant death file. National Vital Statistics Reports: From the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System. 2022;71(5):1–18. pmid:36190428
- 2. Bryson A, Blanchflower D. COVID and Mental Health in America. PLoS One. 2022;17(7). pmid:35867704
- 3. Van Niel MS, Payne JL. Perinatal depression: A review. Cleveland Clinic journal of medicine. 2020;87(5):273–277. pmid:32357982
- 4. Tomfohr-Madsen LM, Racine N, Giesbrecht GF, Lebel C, Madigan S. Depression and anxiety in pregnancy during COVID-19: A rapid review and meta-analysis. Psychiatry research. 2021;300:113912. pmid:33836471
- 5. De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A systematic review and meta-analysis considering the risk for congenital heart defects of antidepressant classes and individual antidepressants. Drug Safety. 2021;44:291–312. pmid:33354752
- 6. Molenaar NM, Bais B, Lambregtse-van den Berg MP, Mulder CL, Howell EA, Fox NS, et al. The international prevalence of antidepressant use before, during, and after pregnancy: A systematic review and meta-analysis of timing, type of prescriptions and geographical variability. Journal of affective disorders. 2020;264:82–89. pmid:31846905
- 7. Nutt DJ, Forshall S, Bell C, Rich A, Sandford J, Nash J, et al. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. European neuropsychopharmacology. 1999;9:S81–S86. pmid:10523062
- 8. Cashman JR, Ghirmai S. Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression. Bioorganic & medicinal chemistry. 2009;17(19):6890–6897. pmid:19740668
- 9. Graveleau C, Paust HJ, Schmidt-Grimminger D, Mukhopadhyay AK. Presence of a 5-HT7 receptor positively coupled to adenylate cyclase activation in human granulosa-lutein cells. The Journal of Clinical Endocrinology & Metabolism. 2000;85(3):1277–1286. pmid:10720076
- 10. Koppan M, Bodis J, Verzar Z, Tinneberg HR, Torok A. Serotonin may alter the pattern of gonadotropin-induced progesterone release of human granulosa cells in superfusion system. Endocrine. 2004;24:155–159. pmid:15347842
- 11. Terbeck S, Savulescu J, Chesterman LP, Cowen PJ. Noradrenaline effects on social behaviour, intergroup relations, and moral decisions. Neuroscience & Biobehavioral Reviews. 2016;66:54–60. pmid:27126289
- 12. O’Donnell J, Zeppenfeld D, McConnell E, Pena S, Nedergaard M. Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochemical research. 2012;37:2496–2512. pmid:22717696
- 13. Vlenterie R, van Gelder MM, Anderson HR, Andersson L, Broekman BF, Dubnov-Raz G, et al. Associations between maternal depression, antidepressant use during pregnancy, and adverse pregnancy outcomes: an individual participant data meta-analysis. Obstetrics & Gynecology. 2021;138(4):633–646. pmid:34623076
- 14. Kautzky A, Slamanig R, Unger A, Höflich A. Neonatal outcome and adaption after in utero exposure to antidepressants: A systematic review and meta-analysis. Acta Psychiatrica Scandinavica. 2022;145(1):6–28. pmid:34486740
- 15. Selmer R, Haglund B, Furu K, Andersen M, Nørgaard M, Zoëga H, et al. Individual-based versus aggregate meta-analysis in multi-database studies of pregnancy outcomes: the Nordic example of selective serotonin reuptake inhibitors and venlafaxine in pregnancy. Pharmacoepidemiology and Drug Safety. 2016;25(10):1160–1169. pmid:27193296
- 16. Leong C, Alessi-Severini S, Enns MW, Nie Y, Sareen J, Bolton J, et al. Cerebrovascular, cardiovascular, and mortality events in new users of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors: a propensity score-matched population-based study. Journal of clinical psychopharmacology. 2017;37(3):332–340. pmid:28383363
- 17. Lanteigne A, Sheu Yh, Stürmer T, Pate V, Azrael D, Swanson SA, et al. Serotonin–norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor use and risk of fractures: a new-user cohort study among US adults aged 50 years and older. CNS drugs. 2015;29:245–252. pmid:25708711
- 18. Gao SY, Wu QJ, Sun C, Zhang TN, Shen ZQ, Liu CX, et al. Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births. BMC medicine. 2018;16(1):1–14. pmid:30415641
- 19.
Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. 2012. Ottawa Hospital Research Institute. L’Hopital d’Ottawa Institut de Recherche, Ottawa, Ontario, Canada. 2014;.
- 20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled clinical trials. 1986;7(3):177–188. pmid:3802833
- 21. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002;21(11):1539–1558. pmid:12111919
- 22. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj. 1997;315(7109):629–634. pmid:9310563
- 23. Duval S, Tweedie R. Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–463. pmid:10877304
- 24. Ankarfeldt MZ, Petersen J, Andersen JT, Li H, Motsko SP, Fast T, et al. Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden. PLoS Medicine. 2021;18(11):e1003851. pmid:34807906
- 25. Kolding L, Ehrenstein V, Pedersen L, Sandager P, Petersen O, Uldbjerg N, et al. Antidepressant use in pregnancy and severe cardiac malformations: danish register-based study. BJOG: An International Journal of Obstetrics & Gynaecology. 2021;128(12):1949–1957. pmid:34036715
- 26. Anderson KN, Lind JN, Simeone RM, Bobo WV, Mitchell AA, Riehle-Colarusso T, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA psychiatry. 2020;77(12):1246–1255. pmid:32777011
- 27. Huybrechts KF, Bateman BT, Pawar A, Bessette LG, Mogun H, Levin R, et al. Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study. bmj. 2020;368. pmid:32075794
- 28. Yamamoto-Sasaki M, Yoshida S, Takeuchi M, Tanaka-Mizuno S, Kawakami K. Association between antidepressant use during pregnancy and congenital anomalies in children: A retrospective cohort study based on Japanese claims data. Congenital Anomalies. 2020;60(6):180–188. pmid:32673440
- 29. Werler MM, Guéry E, Waller DK, Parker SE. Gastroschisis and cumulative stressor exposures. Epidemiology. 2018;29(5):721–728. pmid:29863532
- 30. Nielsen SW, Ljungdalh PM, Nielsen J, Nørgård BM, Qvist N. Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung’s disease in newborns–a nationwide cohort study. Orphanet journal of rare diseases. 2017;12:1–7. pmid:28633635
- 31. Nishigori H, Obara T, Nishigori T, Mizuno S, Metoki H, Hoshiai T, et al. Selective serotonin reuptake inhibitors and risk of major congenital anomalies for pregnancies in Japan: A nationwide birth cohort study of the Japan Environment and Children’s Study. Congenital Anomalies. 2017;57(3):72–78. pmid:27878857
- 32. Petersen I, Evans SJ, Gilbert R, Marston L, Nazareth I. Selective serotonin reuptake inhibitors and congenital heart anomalies: comparative cohort studies of women treated before and during pregnancy and their children. The Journal of clinical psychiatry. 2016;77(1):19174. pmid:26845280
- 33. Jordan S, Morris JK, Davies GI, Tucker D, Thayer DS, Luteijn JM, et al. Selective serotonin reuptake inhibitor (SSRI) antidepressants in pregnancy and congenital anomalies: analysis of linked databases in Wales, Norway and Funen, Denmark. PLoS One. 2016;11(12):e0165122. pmid:27906972
- 34. Bérard A, Zhao JP, Sheehy O. Sertraline use during pregnancy and the risk of major malformations. American journal of obstetrics and gynecology. 2015;212(6):795–e1. pmid:25637841
- 35. Furu K, Kieler H, Haglund B, Engeland A, Selmer R, Stephansson O, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. bmj. 2015;350. pmid:25888213
- 36. Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, et al. Antidepressant use in pregnancy and the risk of cardiac defects. New England Journal of Medicine. 2014;370(25):2397–2407. pmid:24941178
- 37. Ban L, Gibson JE, West J, Fiaschi L, Sokal R, Smeeth L, et al. Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study. BJOG: An International Journal of Obstetrics & Gynaecology. 2014;121(12):1471–1481. pmid:24612301
- 38. Knudsen TM, Hansen AV, Garne E, Andersen AMN. Increased risk of severe congenital heart defects in offspring exposed to selective serotonin-reuptake inhibitors in early pregnancy–an epidemiological study using validated EUROCAT data. BMC Pregnancy and Childbirth. 2014;14:1–8. pmid:25258023
- 39. Yazdy MM, Mitchell AA, Louik C, Werler MM. Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot. Epidemiology (Cambridge, Mass). 2014;25(6):859. pmid:25171134
- 40. Vasilakis-Scaramozza C, Aschengrau A, Cabral H, Jick SS. Antidepressant use during early pregnancy and the risk of congenital anomalies. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2013;33(7):693–700. pmid:23744675
- 41. Margulis AV, Abou-Ali A, Strazzeri MM, Ding Y, Kuyateh F, Frimpong EY, et al. Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in CPRD. Pharmacoepidemiology and drug safety. 2013;22(9):942–951. pmid:23733623
- 42. Lind J, Tinker S, Broussard C, Reefhuis J, Carmichael S, Honein M, et al. National Birth Defects Prevention Study. Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997–2007. Pharmacoepidemiol Drug Saf. 2013;22:783–793.
- 43. Polen K, Rasmussen S, Riehle-Colarusso T, Reefhuis J. National Birth Defects Prevention Study. Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997-2007. Birth Defects Res A Clin Mol Teratol. 2013;97(1):28–35. pmid:23281074
- 44. Nordeng H, Van Gelder MM, Spigset O, Koren G, Einarson A, Eberhard-Gran M. Pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian Mother and Child Cohort Study. Journal of clinical psychopharmacology. 2012;32(2):186–194. pmid:22367660
- 45. Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstetrics & Gynecology. 2011;118(1):111–120. pmid:21646927
- 46. Kornum JB, Nielsen RB, Pedersen L, Mortensen PB, Nørgaard M. Use of selective serotonin-reuptake inhibitors during early pregnancy and risk of congenital malformations: updated analysis. Clinical Epidemiology. 2010; p. 29–36. pmid:20865100
- 47. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. Bmj. 2009;339. pmid:19776103
- 48. Merlob P, Birk E, Sirota L, Linder N, Berant M, Stahl B, et al. Are selective serotonin reuptake inhibitors cardiac teratogens? Echocardiographic screening of newborns with persistent heart murmur. Birth Defects Research Part A: Clinical and Molecular Teratology. 2009;85(10):837–841. pmid:19691085
- 49. Diav-Citrin O, Shechtman S, Weinbaum D, Wajnberg R, Avgil M, Di Gianantonio E, et al. Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study. British journal of clinical pharmacology. 2008;66(5):695–705. pmid:18754846
- 50. Alwan S. Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356:2684–92. pmid:17596602
- 51. Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. New England Journal of Medicine. 2007;356(26):2675–2683. pmid:17596601
- 52. Wogelius P, Nørgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB, et al. Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology. 2006;17(6):701–704. pmid:17028507
- 53. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A, Koren G. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. American journal of obstetrics and gynecology. 2005;193(6):2004–2009. pmid:16325604
- 54. Richardson J, Martin F, Dunstan H, Greenall A, Stephens S, Yates L, et al. Pregnancy outcomes following maternal venlafaxine use: A prospective observational comparative cohort study. Reproductive Toxicology. 2019;84:108–113. pmid:30639403
- 55. Einarson A, Fatoye B, Sarkar M, Lavigne SV, Brochu J, Chambers C, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. American Journal of Psychiatry. 2001;158(10):1728–1730. pmid:11579012
- 56. Bérard A, Zhao JP, 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(1):e013372. pmid:28082367
- 57. Myles N, Newall H, Ward H, Large M. Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations. Australian & New Zealand Journal of Psychiatry. 2013;47(11):1002–1012. pmid:23761574
- 58. Grigoriadis S, VonderPorten EH, Mamisashvili L, Tomlinson G, Dennis CL, Koren G, et al. Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis. Bmj. 2014;348. pmid:24429387
- 59. Laurent L, Huang C, Ernest SR, Berard A, Vaillancourt C, Hales BF. In utero exposure to venlafaxine, a serotonin–norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat. Birth Defects Research Part A: Clinical and Molecular Teratology. 2016;106(12):1044–1055. pmid:27384265
- 60. Haskell SE, Lo C, Kent ME, Eggleston TM, Volk KA, Reinking BE, et al. Cardiac outcomes after perinatal sertraline exposure in mice. Journal of cardiovascular pharmacology. 2017;70(2):119. pmid:28459713
- 61. Haskell SE, Hermann GM, Reinking BE, Volk KA, Peotta VA, Zhu V, et al. Sertraline exposure leads to small left heart syndrome in adult mice. Pediatric research. 2013;73(3):286–293. pmid:23232669
- 62. Noorlander CW, Ververs FF, Nikkels PG, van Echteld CJ, Visser GH, Smidt MP. Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities. PloS one. 2008;3(7):e2782. pmid:18716672
- 63. Olivier JD, Åkerud H, Skalkidou A, Kaihola H, Sundström-Poromaa I. The effects of antenatal depression and antidepressant treatment on placental gene expression. Frontiers in cellular neuroscience. 2015;8:465. pmid:25628539
- 64. Bar-Oz B, Einarson T, Einarson A, Boskovic R, O’Brien L, Malm H, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clinical therapeutics. 2007;29(5):918–926. pmid:17697910
- 65. Bérard A, Iessa N, Chaabane S, Muanda FT, Boukhris T, Zhao JP. The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: a systematic review and meta-analysis. British journal of clinical pharmacology. 2016;81(4):589–604. pmid:26613360
- 66. Cray JJ, Weinberg SM, Parsons TE, Howie RN, Elsalanty M, Yu JC. Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice. Birth Defects Research Part A: Clinical and Molecular Teratology. 2014;100(12):912–923. pmid:25308507
- 67. Durham E, Jen S, Wang L, Nasworthy J, Elsalanty M, Weinberg S, et al. Effects of citalopram on sutural and calvarial cell processes. PLoS One. 2015;10(10):e0139719. pmid:26431045
- 68. Fraher D, Hodge J, Collier F, McMillan J, Kennedy R, Ellis M, et al. Citalopram and sertraline exposure compromises embryonic bone development. Molecular psychiatry. 2016;21(5):656–664. pmid:26347317
- 69. Singh K, Sharma P, Singh M. Prenatal Venlafaxine Exposure–Induced Neurocytoarchitectural and Neuroapoptotic Degeneration in Striatum and Hippocampus of Developing Fetal Brain, Manifesting Long-term Neurocognitive Impairments in Rat Offspring. Neurotoxicity Research. 2022;40(5):1174–1190. pmid:35819590
- 70. Ahmed SH, El Ghareeb AEWA, El-Rahman HAA, Almaaty AHA. Impact of maternal desvenlafaxine exposure on brain development in pregnant albino rats and their fetuses. Journal of Biochemical and Molecular Toxicology. 2022;36(7):e23062. pmid:35363936
- 71.
Prowse K. INFLUENCE OF MATERNAL SELECTIVE SEROTONIN REUPTAKE INHIBITOR EXPOSURE ON THE DEVELOPMENT OF THE GASTROINTESTINAL TRACT OF THE OFFSPRING; 2019.
- 72. Ghavamabadi RT, Taghipour Z, Hassanipour M, Khademi M, Shariati M. Effect of maternal fluoxetine exposure on lung, heart, and kidney development in rat neonates. Iranian Journal of Basic Medical Sciences. 2018;21(4):417. pmid:29796227
- 73. Zemestani M, Fazeli Nikoo Z. Effectiveness of mindfulness-based cognitive therapy for comorbid depression and anxiety in pregnancy: a randomized controlled trial. Archives of women’s mental health. 2020;23:207–214. pmid:30982086
- 74. Hankin BL, Demers CH, Hennessey EMP, Perzow SE, Curran MC, Gallop RJ, et al. Effect of Brief Interpersonal Therapy on Depression During Pregnancy: A Randomized Clinical Trial. JAMA psychiatry. 2023;80(6):539–547. pmid:37074698
- 75. Miller HE, Fraz F, Zhang J, Henkel A, Leonard SA, Maskatia SA, et al. Abortion Bans and Resource Utilization for Congenital Heart Disease: A Decision Analysis. Obstetrics & Gynecology. 2022; p. 10–1097.
- 76. Bolin EH, Gokun Y, Romitti PA, Tinker SC, Summers AD, Roberson PK, et al. Maternal Smoking and Congenital Heart Defects, National Birth Defects Prevention Study, 1997-2011. The Journal of pediatrics. 2022;240:79–86. pmid:34508749
- 77. Fisher SC, Howley MM, Romitti PA, Desrosiers TA, Jabs EW, Browne ML, et al. Maternal periconceptional alcohol consumption and gastroschisis in the National Birth Defects Prevention Study, 1997–2011. Paediatric and perinatal epidemiology. 2022;36(6):782–791. pmid:35437856
- 78. Mamasoula C, Bigirumurame T, Chadwick T, Addor MC, Cavero-Carbonell C, Dias CM, et al. Maternal age and the prevalence of congenital heart defects in Europe, 1995–2015: A register-based study. Birth Defects Research. 2023;115(6):583–594. pmid:36734416
- 79. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. Journal of clinical epidemiology. 2005;58(9):894–901. pmid:16085192