Prenatal SSRI Exposure and Its Impact on Neonatal Gastrointestinal and Urinary system: A Case-Control Study

Prenatal SSRI Exposure and Its Impact on Neonatal Gastrointestinal and Urinary system: A Case-Control Study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 29 January 2025 V1 Latest version Share on Prenatal SSRI Exposure and Its Impact on Neonatal Gastrointestinal and Urinary system: A Case-Control Study Authors : Ronella Marom 0000-0003-4019-7146 [email protected] , Laurence Mangel , Addy BrandStetter , Jacky Herzlich , Dror Mandel , and Yuval Bar -Yosef Authors Info & Affiliations https://doi.org/10.22541/au.173813773.36765188/v1 318 views 128 downloads Contents Abstract Participants and study design Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: Selective serotonin reuptake inhibitors (SSRIs) cross the placenta, and their use during pregnancy can impact neonatal outcomes. However, the effects of maternal SSRI treatment during pregnancy on neonatal urinary and gastrointestinal systems has not yet been investigated. Methods This retrospective case-control study compared neonates born to women who consumed SSRI drugs during pregnancy with the closest birth of healthy delivered newborn not exposed to SSRI in utero, matched for gestational age (GA) and weight for gestational age. The primary outcomes measured were the time to first void and the time to first stool. Results The cohort included 133 neonates in each group. Mothers in the SSRI-exposed group were older (34.5 vs 32.2 years, p<0.001) compared to those in the control group. The time to first stool was significantly shorter in neonates exposed to SSRIs compared to those who were not exposed (7.4 vs 8.6 hours, p=0.023), while the time to first void did not differ between the two groups. In regression analysis, the time to first stool was associated with the time to first void (β=0.138, p=0.032) and SSRI exposure (β=-1.561, p=0.030), but not with GA, gender, and maternal age. SSRI-exposed neonates had three times the rate of formula feeding compared to unexposed neonates (19.5% vs 6%, adjusted p=0.001). Conclusions Maternal SSRI use during pregnancy did not influence the timing of the first void but does impact gut motility. Introduction The use of antidepressant drugs during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), has increased over the past few years and is currently estimated at 2-6% of pregnant women [1-4]. These drugs might affect neonatal outcomes because they traverse the placenta. Around 30% of all infants exposed to an SSRI in utero will develop neurological, respiratory and gastrointestinal symptoms, as a consequence of either an abrupt discontinuation of drug exposure after birth, defined as poor neonatal adaptation syndrome (PNAS) [5,6], or a transient disturbance of the neonatal serotonergic system probably due to serotonergic overstimulation syndrome [7,8]. Various neonatal complications associated with maternal SSRI intake during pregnancy have been described, such as lower gestational age (GA), lower Apgar scores at 1- and 5-minute, and an increase in the risk of preterm delivery [9]. SSRIs work by targeting the serotonin transporter (SERT). Most of the serotonin is found in the gut and is produced by the enterochromaffin cells of the GI epithelium and the neurons of the enteric nervous system, while in the central nervous system it is produced by the serotonergic neurons [10]. \RL Beyond its well-known role in modulating neural activities and psychological processes [11], serotonin has significant and wide-ranging implications for gastrointestinal functions, including motility, sensory signaling, epithelial homeostasis, inflammation, and neurogenesis [12, 13]. Retrospective and prospective studies have shown that in utero exposure to SSRIs increased the likelihood of GI disturbances in childhood [14, 15]. Additionally, Eliezer et al. have reviewed the effects of behavioral pharmacotherapy such as SSRIs on bladder dysfunction in children with behavioral disorders [16]. There is limited data on the gastrointestinal and bladder impact of SSRIs in neonates. Therefore, we aimed to investigate the effect of in utero exposure to SSRIs on the urinary system and gut motility in neonates during and after delivery. The primary goals of this study were to assess whether maternal SSRI use during pregnancy affects the timing of the first void and the first stool. We propose that neonates exposed to SSRIs, but otherwise healthy, will experience delayed first voiding and increased gut motility. Methods Participants and study design In this retrospective study, we reviewed medical records of neonates admitted to the nursery department between January 2015 and May 2019. This tertiary referral hospital performed on average 12,000 deliveries per year. The study group included healthy singleton newborns admitted to the nursery, born at GA between 35+0 and 41+6 weeks, with a 5-minute Apgar score of ≥8, to mothers who had taken SSRI drugs as monotherapy during pregnancy. Were excluded any combination of SSRIs, multiple gestations, amniotic fluid deficiency in pregnancy, newborns with congenital malformations of the urinary system, congenital heart defects, and neonatal intensive care unit admissions. The control group was designed by including the closest birth of healthy delivered newborn not exposed to SSRI in utero, matched for GA and weight for gestational age (appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA)). The local institutional review board, the Helsinki committee, approved this study (0408-19-TLV) and waived the need for informed consent due to its retrospective character. The study was carried out in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Data collection Demographic and clinical data of the neonates included GA, gender, birth weight (BW), mode of delivery, morbidities, SGA, AGA and LGA (17), meconium-stained amniotic fluid (MSAF), crying and respiratory distress after birth, start of enteral feeding, feeding regimen at discharge, timing of first void, timing of first stool and Finnegan Neonatal Abstinence Scoring System. Maternal data included age, prenatal medication and medical conditions. Statistical analyses Categorical variables were described as frequency and percentage. Continuous variables were evaluated for normal distribution by Shapiro-Wilk tests, histograms and Q-Q plots. Normally distributed continuous variables were reported as means and standard deviations, while skewed variables were reported as medians and interquartile ranges. Chi-square tests or Fisher’s exact tests were applied to compare categorical variables. Independent T-test, Mann-Whitney U test or Kruskal-Wallis test was applied to compare continuous variables between the groups when appropriate. Stepwise linear regression analysis was computed to determine the correlation between the time to first stool and maternal use of SSRI during pregnancy while taking into account maternal variables such as maternal age, and neonatal variables such as BW, GA, gender and the time to first void. All statistical tests were two-sided and p<0.05 was considered statistically significant. The IBM SPSS software for windows, version 29, was used for all statistical analyses. Results A total of 266 neonates were included in the study. Table 1 shows the comparison of perinatal and neonatal data of 133 neonates exposed to SSRIs in utero with 133 neonates unexposed to SSRIs (control group). Mothers in the study group were in average significantly older than those in the control group (34.5 vs 32.2 years, respectively, p<0.001). As per the study design, there were no significant differences in GA and weight for gestational age between the groups. Enteral feeding was initiated at similar time point across the groups but there were significant variations in neonatal feeding practices (p=0.001). Unexposed neonates were more likely to be fed with mother’s own milk at discharge, almost doubling the rate compared to SSRIs-exposed neonates (29.3% vs 17.3%, respectively). Conversely, formula feeding was significantly more common in SSRIs-exposed neonates, with almost three times the rate compared to unexposed neonates (19.5% vs 6%, respectively, adjusted p=0.001). The timing of first void did not differ between the groups. However, the median time to first stool, was \RL shorter in neonates exposed to SSRIs compared to non-exposed (7.4 vs 8.6 hours, respectively, p=0.023). Although the rate of MSAF among neonates exposed to SSRI was higher than the one seen in unexposed neonates, it did not reach statistical significance. However, all neonates with MSAF, exposed as well as unexposed to SSRIs, had a shorter median time to first stool compared to those without MSAF (6.5 vs. 8.9 hours, p=0.001, and 5.5 vs. 8.3 hours, p=0.009, respectively). Neonates in the SSRI exposed group had clinically non-significant Finnegan scores ≤4. Timing of the first void (p=0.229), timing of the first stool (p=0.774), initiation of enteral feeding (p=0.366), and weight loss at discharge (p=0.341) were similar across the Finnegan scores as well as the rates of MSAF (p=0.053), respiratory distress (p=0.0609), and lack of crying at birth (p=0.603). In regression analysis, the time to first stool was associated with the time to first void (\RLβ=0.13\RL8, p=0.03\RL2) and SSRI exposure (\RLβ=-\RL1.561, p=0.0\RL30), but not with GA, gender, and maternal age. Although the model was significant (F=4.452, p=0.030), it explained only a small part of the variance in time to first stool (adjusted R 2 =0.025). Discussion We found that the timing of the first void was not affected by maternal SSRI use during pregnancy, which contrasts with our initial hypothesis based on studies in children and adults [16,18]. However, SSRI exposure during pregnancy did impact gastrointestinal movement in neonates, leading to a shorter time to the first stool. Another notable finding was the shorter time to the first stool observed in SSRI-exposed neonates, even among those who had already passed meconium during delivery. The increased rate of MSAF associated with maternal SSRI use has been reported in other studies [19, 20] and is already known to be linked to fetal distress [21]. Previous reports have shown a correlation between SSRI exposure and gastrointestinal symptoms in neonates as part of PNAS [4]. However, considering the reported effect of SSRIs on gut motility and the fact that our cohort had a Finnegan score ≤4, we suggest that the observed increase in motility might be linked to the broader impact of SSRIs on the gut. Overall, the intricate balance of serotonin and its regulation by SERT in the gut plays a critical role in modulating gastrointestinal motility, making both serotonin and SERT attractive targets for therapeutic interventions in gastrointestinal disorders [22].Top of Form Bottom of Form Prowse et al. found that SSRI exposure throughout the fetal and pre-weaning periods in rats impact the serotonergic signaling pathways involved in GI development and innervation with a significant increase in the frequency of contractions in SSRI-exposed rat offspring compared with control [23]. Several studies have described the potential link between SSRI exposure during fetal development and an increased risk of adverse neonatal outcomes [8, 20]. To our knowledge, this study is the first to assess the correlation between the time to first void and the time to first stool among neonates and maternal SSRI use during pregnancy. Additionally, we found that maternal preferences for neonatal feeding showed significant differences between the groups, with mothers in the study group being less likely to breastfeed compared to those in the control group. This observation can be related to previous reports on the impact of SSRIs on the lactation process. Holland et al. have observed a reduced milk supply in six nursing mothers treated with sertraline [24]. Marshall et al.’s study of 431 women demonstrated that those on SSRI were more likely to experience delayed secretory activation [25], probably due to modulation of secretory activation in the metabolism of the mammary glands that are influenced by serotonin. This study has several limitations. First, there was heterogeneity in the types of SSRIs the mothers had taken during pregnancy. Second, we lacked data on the duration of SSRI treatment during pregnancy and whether the treatment had been initiated and used before pregnancy. Conclusions In conclusion, maternal use of SSRIs during pregnancy impacts gut motility in neonates and nutrition preference. It is important for patients and clinicians to thoughtfully reflect on the potential risks of SSRI use in the neonatal period, and should be considered when evaluating potential gastrointestinal symptoms in the neonate. Further research is needed to assess the long-term effects of fetal SSRI exposure, even in the absence of PNAS. Statements and Declarations : Acknowledgements- We thank Esther Eshkol for editorial assistance. Statement of Ethics - The study was conducted in accordance with the Declaration of Helsinki, and approved by the Helsinki committee of the Tel Aviv Medical Center, approval number 0408-19-TLV. Patient consent was waived due to the retrospective nature of the study. Conflict of Interest Statement - The authors have no conflicts of interest to declare. Funding Sources- No funding. Author Contributions- RM and YBY conceived the original project, its scientific design, performed the initial data analysis and drafted the initial version of the manuscript. AB collected the data, assisted with data analysis and reviewed drafts of the manuscript. LM performed data analysis, drafted and revised the manuscript. YH and DM contributed to the first draft and reviewed the final version of the manuscript. All authors have read and agreed to the published version of the manuscript. Data Availability Statement All data generated or analyzed during this study are included in this article. For further inquiries, please contact the corresponding author. References 1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl JMed. 2011;365:1605–1611. 2. Ornoy A, Koren G. Selective serotonin reuptake inhibitors in human pregnancy: on the way to resolving the controversy. Semin Fetal Neonatal Med. 2014;19:188–194 3. National Board of Health and Welfare. The Swedish Medical Birth Register. Available at: http://www. socialstyrelsen. se/ register/halsodataregister / medicinskafodelseregistret. 2014. Accessed January 15, 2016. 4. Tran H, Robb AS. SSRI use during pregnancy. Seminars in perinatology. 2015;39: 545–547. 5. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134: e547–e561. 6. Kieviet N, Dolman KM, Honig A. The use of psychotropic medication during pregnancy: how about the newborn? Neuropsychiatr Dis Treat. 2013;9:1257-66. 7. Grigoriadis S, VonderPorten EH, Mamisashvili L, Eady A,Tomlinson G, Dennis CL,et al. The effect of prenatal antidepressant exposure on neonatal adaptation: a systematic review and meta-analysis. J Clin Psychiatry. 2013;74:e309-20. 8. Kieviet N, van Keulen V, van de Ven PM, Dolman KM, Deckers M, Honig A. Serotonin and poor neonatal adaptation after antidepressant exposure in utero. Act Neuropsychiatr. 2017;29:43-53. 9. Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry. 2013;70:436-43. YY, Akindele AO, Jalkh AP, et al. A Systematic Review on the Efficacy and Safety of Selective Serotonin Reuptake Inhibitors in Gastrointestinal Motility Disorders: More Control, Less Risk. Cureus. 2022;4;14:e27691. 11. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355-66. 12. Najjar SA, Hung LY, Margolis KG. Serotonergic Control of Gastrointestinal Development, Motility, and Inflammation. Compr Physiol. 2023;26; 13:4851-4868 13. Koopman N, Katsavelis D, Hove AST, Brul S, Jonge WJ, Seppen J. The Multifaceted Role of Serotonin in Intestinal Homeostasis. Int J Mol Sci. 2021 Aug 31;22:9487. 14. Nijenhuis CM, ter Horst PG, van Rein N, Wilffert B, de Jong-van den Berg LT. Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 2: Testing the hypotheses. Br J Clin Pharmacol. 2012;73:126-34. 15. Salisbury AL, Papandonatos GD, Stroud LR, Smith AK, Brennan PA. Prenatal antidepressant exposures and gastrointestinal complaints in childhood: A gut-brain axis connection? Dev Psychobiol. 2020;62:816-828. 16. Eliezer DD, Lam C, Smith A, Coomarasamy JM, Samnakay N, Starkey MR, Deshpande AV. Optimizing the management of children with concomitant bladder dysfunction and behavioral disorders. Eur Child Adolesc Psychiatry. 2023;32:1989-1999. 17. Dollberg S, Haklai Z, Mimouni FB, Gorfein I, Gordon ES. Birth weight standards in the live-born population in Israel. Isr Med Assoc J. 2005;7:311-4. 18. Movig KL, Leufkens HG, Belitser SV, Lenderink AW, Egberts AC. Selective serotonin reuptake inhibitor-induced urinary incontinence. Pharmacoepidemiology and drug safety. 2002;11: 271–279. 19. Leibovitch L, Rymer-Haskel N, Schushan-Eisen I, Kuint J, Strauss T, Maayan-Metzger. A Short-term neonatal outcome among term infants after in utero exposure to serotonin reuptake inhibitors. Neonatology. 2013;104:65-70 20. Levy M, Kovo M, Miremberg H, Anchel N, Herman HG, Bar J, Schreiber L, Weiner E. Maternal use of selective serotonin reuptake inhibitors (SSRI) during pregnancy-neonatal outcomes in correlation with placental histopathology. J Perinatol. 2020;40:1017-1024 21. Gallo DM, Romero R, Bosco M, Gotsch F, Jaiman S, Jung E, et al. Meconium-stained amniotic fluid. Am J Obstet Gynecol. 2023; 228:S1158-S1178. 22. Najjar SA, Hung LY, Margolis KG. Serotonergic Control of Gastrointestinal Development, Motility, and Inflammation. Compr Physiol.2023;13:4851-4868. 23. Prowse KL, Law H, Raez-Villanueva S, Markovic F, Wang M, Borojevic R, et al. Effects of in utero exposure to fluoxetine on the gastrointestinal tract of rat offspring. Am J Physiol Gastrointest Liver Physiol. 2023;325:G528-G538. 24. Holland D. An observation of the effect of sertraline on breast milk supply. Aust N Z J Psychiatry. 2000;34:1032. 25. Marshall AM, Nommsen-Rivers LA, Hernandez LL, Dewey KG, Chantry CJ, Gregerson KA, Horseman ND. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrinol Metab.2010; 95:837-46. Variable Exposed to SSRI (N=133) Unexposed to SSRI (N=133) p value Maternal age 34.\RL5±4.8 (21-48) 32.\RL2±4.8 (20-45) 0.99 Gestational age (week) 39 (38-39.5) 39 (38-39.5) >0.99 Birth weight (g) 3167.9±432.4 (2153-4380) 3189.4±416.5 (2175-4165) \RL 0.679 Female 76 (57.1) 68 (51.1) 0.\RL325 Delivery mode Vaginal Vacuum Caesarian section 95 (71.4) 11 (8.3) 27 (20.3) 92 (69.2) 10 (7.5) 31 (23.3) 0.\RL830 Anesthesia during delivery None Epidural + Spinal General 30 (22.6) 102 (76.7) 1 (0.8) 26 (19.5) 105 (78.9) 2 (1.5) 0.\RL738 Appropriate for gestational age Small for gestational age Large for gestational age 113 (85) 11 (8.3) 9 (6.8) 113 (85) 11 (8.3) 9 (6.8) >0.99 Meconium-Stained Amniotic Fluid \RL32 (2\RL4.1) 2\RL2 (1\RL6.5) \RL0.127 Timing of first voiding (h) 10 (6.\RL7-14.\RL3) \RL9.4 (6.\RL2-13.\RL3) 0.\RL460 First voiding above 24 hours \RL5 (3.8) \RL3 (2.\RL3) 0.\RL722 Timing of first stool (h) 7.4 (4.\RL6-11.5) \RL8.6 (6-12.8) 0.0\RL23 Start of enteral feeding (h) 8 (4.\RL3-1\RL0.8) 7\RL.2 (3.\RL3-10.3) 0.\RL319 Feeding regimen at discharge Mother Own Milk Formula Mixed 2\RL3 (1\RL7.3)\RL 26 (19.\RL5)\RL 84 (6\RL3.2) \RL 39 (2\RL9.3)\RL 8 (\RL6)\RL 86 (64.\RL7) 0.001 Weight loss at discharge (%) 5.\RL6±2.\RL1 (\RL1.4-12.9) 5.\RL7±1.\RL7 (\RL1-9.\RL5) 0.5\RL04 Not crying shortly after birth \RL9 (6.\RL8) \RL5 (3.8) 0.272 Respiratory distress \RL34 (2\RL5.6) 3\RL0 (2\RL2.6) 0.566 Spitting \RL53 (39.\RL8) \RL53 (3\RL9.8) >0.99 Finnegan Neonatal Abstinence Scoring System 0 1 2 3 4 43 (33.6) 75 (58.6) 4 (3.1) 4 (3.1) 2 (1.6) NA Data are expressed by median [IQR], mean ± SD (range) or n (%); In bold significant p. 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Keywords clinical pharmacology drug information drug utilization evidence-based medicine Authors Affiliations Ronella Marom 0000-0003-4019-7146 [email protected] Tel Aviv Sourasky Medical Center Ichilov View all articles by this author Laurence Mangel Tel Aviv Sourasky Medical Center Ichilov View all articles by this author Addy BrandStetter Tel Aviv Sourasky Medical Center Ichilov View all articles by this author Jacky Herzlich Tel Aviv Sourasky Medical Center Ichilov View all articles by this author Dror Mandel Tel Aviv Sourasky Medical Center Ichilov View all articles by this author Yuval Bar -Yosef Tel Aviv Sourasky Medical Center Ichilov View all articles by this author Metrics & Citations Metrics Article Usage 318 views 128 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ronella Marom, Laurence Mangel, Addy BrandStetter, et al. Prenatal SSRI Exposure and Its Impact on Neonatal Gastrointestinal and Urinary system: A Case-Control Study. 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