Fluoxetine and Congenital Malformations: a Systematic Review and Meta-analysis of Cohort Studies

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2017 May 18

PMID 28513059

Citations 25

Authors

Shan-Yan Gao

Qi-Jun Wu

Tie-Ning Zhang

Zi-Qi Shen

Cai-Xia Liu

Xin Xu

Chao Ji

Yu-Hong Zhao

Affiliations

Soon will be listed here.

Abstract

Aims: To investigate the safety of fluoxetine use during pregnancy, and to better understand the relationship between maternal fluoxetine use during the first trimester and congenital malformations in infants.

Methods: PubMed and Web of Science databases were systematically searched from inception to 21 March 2016. Additional studies were identified in a manual search of the reference lists. Two reviewers independently extracted data. A third reviewer checked the data. Estimates were pooled using a random-effects model to calculate the summarized relative ratios (RR) and 95% confidence intervals (CI).

Results: Among 1918 initially identified articles, 16 cohort studies were included. The offspring of pregnant women exposed to fluoxetine during the first trimester had a statistically increased risk of major malformations (RR = 1.18, 95% CI = 1.08-1.29), cardiovascular malformations (RR = 1.36, 95% CI = 1.17-1.59), septal defects (RR = 1.38, 95% CI = 1.19-1.61), and non-septal defects (RR = 1.39, 95% CI = 1.12-1.73) with low heterogeneity in infants. There were no significant observations of other system-specific malformations in the nervous system, eye, urogenital system, digestive system, respiratory system, or musculoskeletal system, respectively. There was no indication of publication bias.

Conclusions: The results of this meta-analysis indicate maternal fluoxetine use is associated with a slightly increased risk of cardiovascular malformations in infants. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with fluoxetine during pregnancy.

Citing Articles

Gestational Diabetes Mellitus Does Not Change the Pharmacokinetics and Transplacental Distribution of Fluoxetine and Norfluoxetine Enantiomers.

Carvalho D, Nardotto G, Filgueira G, Duarte G, Cavalli R, Lanchote V Pharmaceutics. 2025; 17(1).

PMID: 39861684 PMC: 11768268. DOI: 10.3390/pharmaceutics17010035.

Cardiovascular Considerations in Antidepressant Use.

Taghavi Zanjani F, Nateghi S Avicenna J Med Biotechnol. 2023; 15(4):207-208.

PMID: 38078342 PMC: 10709754. DOI: 10.18502/ajmb.v15i4.13489.

Psychiatric Treatment in Pregnancy: A Narrative Review.

Gruszczynska-Sinczak I, Wachowska K, Blizniewska-Kowalska K, Galecki P J Clin Med. 2023; 12(14).

PMID: 37510861 PMC: 10380824. DOI: 10.3390/jcm12144746.

The molecular mechanisms in prenatal drug exposure-induced fetal programmed adult cardiovascular disease.

Wu T, Zhou K, Hua Y, Zhang W, Li Y Front Pharmacol. 2023; 14:1164487.

PMID: 37153765 PMC: 10157035. DOI: 10.3389/fphar.2023.1164487.

Benefits and Risks of Antidepressant Drugs During Pregnancy: A Systematic Review of Meta-analyses.

Desaunay P, Eude L, Dreyfus M, Alexandre C, Fedrizzi S, Alexandre J Paediatr Drugs. 2023; 25(3):247-265.

PMID: 36853497 DOI: 10.1007/s40272-023-00561-2.

References

Gong T, Wu Q, Wang Y, Ma X . Circulating adiponectin, leptin and adiponectin-leptin ratio and endometrial cancer risk: Evidence from a meta-analysis of epidemiologic studies. Int J Cancer. 2015; 137(8):1967-78. DOI: 10.1002/ijc.29561. View

Bennett H, Einarson A, Taddio A, Koren G, Einarson T . Prevalence of depression during pregnancy: systematic review. Obstet Gynecol. 2004; 103(4):698-709. DOI: 10.1097/01.AOG.0000116689.75396.5f. View

Shen Z, Gao S, Li S, Zhang T, Liu C, Lv H . Sertraline use in the first trimester and risk of congenital anomalies: a systemic review and meta-analysis of cohort studies. Br J Clin Pharmacol. 2016; 83(4):909-922. PMC: 5346877. DOI: 10.1111/bcp.13161. View

Einarson A, Choi J, Einarson T, Koren G . Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry. 2009; 54(4):242-6. DOI: 10.1177/070674370905400405. View

Southan C, Sharman J, Benson H, Faccenda E, Pawson A, Alexander S . The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res. 2015; 44(D1):D1054-68. PMC: 4702778. DOI: 10.1093/nar/gkv1037. View

Zhang T, Gao S, Shen Z, Li D, Liu C, Lv H . Use of selective serotonin-reuptake inhibitors in the first trimester and risk of cardiovascular-related malformations: a meta-analysis of cohort studies. Sci Rep. 2017; 7:43085. PMC: 5318893. DOI: 10.1038/srep43085. View

Jiao Y, Gong T, Wang Y, Wu Q . Comorbidity and survival among women with ovarian cancer: evidence from prospective studies. Sci Rep. 2015; 5:11720. PMC: 4484350. DOI: 10.1038/srep11720. View

Jiang L, Hou R, Gong T, Wu Q . Dietary fat intake and endometrial cancer risk: dose-response meta-analysis of epidemiological studies. Sci Rep. 2015; 5:16693. PMC: 4645223. DOI: 10.1038/srep16693. View

Luan N, Wu L, Gong T, Wang Y, Lin B, Wu Q . Nonlinear reduction in risk for colorectal cancer by oral contraceptive use: a meta-analysis of epidemiological studies. Cancer Causes Control. 2014; 26(1):65-78. DOI: 10.1007/s10552-014-0483-2. View

10.

Grigoriadis S, VonderPorten E, Mamisashvili L, Roerecke M, Rehm J, Dennis C . Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence. J Clin Psychiatry. 2013; 74(4):e293-308. DOI: 10.4088/JCP.12r07966. View

11.

Gentile S . Early pregnancy exposure to selective serotonin reuptake inhibitors, risks of major structural malformations, and hypothesized teratogenic mechanisms. Expert Opin Drug Metab Toxicol. 2015; 11(10):1585-97. DOI: 10.1517/17425255.2015.1063614. View

12.

Addis A, Koren G . Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies. Psychol Med. 2000; 30(1):89-94. DOI: 10.1017/s0033291799001270. View

13.

Hendrick V, Stowe Z, Altshuler L, Hwang S, Lee E, Haynes D . Placental passage of antidepressant medications. Am J Psychiatry. 2003; 160(5):993-6. DOI: 10.1176/appi.ajp.160.5.993. View

14.

Huybrechts K, Palmsten K, Avorn J, Cohen L, Holmes L, Franklin J . Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014; 370(25):2397-407. PMC: 4062924. DOI: 10.1056/NEJMoa1312828. View

15.

Chatillon O, Even C . [Antepartum depression: prevalence, diagnosis and treatment]. Encephale. 2010; 36(6):443-51. DOI: 10.1016/j.encep.2010.02.004. View

16.

OKeane V, Marsh M . Depression during pregnancy. BMJ. 2007; 334(7601):1003-5. PMC: 1867919. DOI: 10.1136/bmj.39189.662581.55. View

17.

Hansen D, Sondergaard J, Vach W, Gram L, Rosholm J, Mortensen P . Socio-economic inequalities in first-time use of antidepressants: a population-based study. Eur J Clin Pharmacol. 2004; 60(1):51-5. DOI: 10.1007/s00228-003-0723-y. View

18.

Hou R, Wu Q, Gong T, Jiang L . Dietary fat and fatty acid intake and epithelial ovarian cancer risk: evidence from epidemiological studies. Oncotarget. 2015; 6(40):43099-119. PMC: 4767494. DOI: 10.18632/oncotarget.5525. View

19.

Yavarone M, Shuey D, Tamir H, Sadler T, Lauder J . Serotonin and cardiac morphogenesis in the mouse embryo. Teratology. 1993; 47(6):573-84. DOI: 10.1002/tera.1420470609. View

20.

Furu K, Kieler H, Haglund B, Engeland A, Selmer R, Stephansson O . Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. BMJ. 2015; 350:h1798. PMC: 4410618. DOI: 10.1136/bmj.h1798. View