(C) PLOS One [1]. This unaltered content originally appeared in journals.plosone.org. Licensed under Creative Commons Attribution (CC BY) license. url:https://journals.plos.org/plosone/s/licenses-and-copyright ------------ Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden ['Mikkel Zöllner Ankarfeldt', 'Copenhagen Phase Iv Unit', 'Department Of Clinical Pharmacology', 'Center For Clinical Research', 'Prevention', 'Copenhagen University Hospital Bispebjerg', 'Frederiksberg', 'Copenhagen', 'Janne Petersen', 'Section Of Biostatistics'] Date: 2022-01 Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy. Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates. A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MZA, JP, and EJS have performed other studies regarding antidepressants involving funding from Janssen Pharmaceutical via Phase4CPH. JP is also supervising a PhD student in the area of pregnancy outcomes and insulin funded by Novo Nordisk A/S. JTA, TF, and SMH have no relevant financial activities outside the submitted work in the past 36 months. HL and SPM are former employees of Eli Lilly and Company and are minor stockholders. Funding: The study was performed by the Copenhagen Phase 4 Unit (Phase4CPH), Department of Clinical Pharmacology and the Institute of Applied Economics and Health Research Aps (ApHER), and financed by Eli Lilly, the manufacturer of duloxetine. MZA and JP are employed at the Copenhagen Phase 4 Unit (Phase4CPH). JTA and EJS are employed at the Department of Clinical Pharmacology. HL and SPM are former employees of Eli Lilly and Company and thereby received a salary from the funder. HL is currently employed by Gilead Science Inc. and SPM is currently employed by Amgen Inc. TF is former employee of ApHER and is currently employed by Quantify Research. SMH is employed at ApHER. The funder had the opportunity to comment study design, data collection and analysis, where to publish and preparation of the manuscript, but MZA and EJS had the final decisions. Data Availability: Data from the Danish and Swedish registers are third party data, meaning that we as researchers do not hold the data, but have obtained data after application at relevant parties. The Danish data can be applied for at Statistics Denmark ( https://www.dst.dk/en/TilSalg/Forskningsservice ). The Swedish data can be applied for at Statistic Sweden ( https://www.scb.se/en/About-us/contact-us/ ) and Swedish National Board of Health and Welfare data ( https://www.socialstyrelsen.se/en/statistics-and-data/statistics/statistical-databases/ ). Copyright: © 2021 Ankarfeldt 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. The present study evaluates the association between duloxetine exposure during pregnancy and the risk of major and minor congenital malformation and stillbirths in a cohort based on all pregnancies in Sweden and Denmark between 2004 and 2016. Duloxetine (an SNRI) was approved in the United States and Europe in 2004. In Europe, the indication is for major depressive disorder, generalized anxiety disorder, stress urinary incontinence, and diabetic peripheral neuropathy. A common indication for women of childbearing age is for depressive disorder [ 15 ]. The safety of antidepressants during pregnancy, especially their teratogenic effect, has been uncertain [ 16 – 20 ]. However, studies that address potential confounding report no association between first trimester exposure to SSRIs and malformation [ 21 ] or stillbirth [ 22 , 23 ]. This is not necessarily applicable to SNRIs, since they affect also norepinephrine levels [ 24 ]. Studies on SNRIs suggest no increased risk of major malformation, based on postmarketing surveillance systems [ 25 – 27 ], small cohorts without a comparison group [ 28 , 29 ], or cohorts with a comparison group [ 30 – 32 ]. A recent review found no increased risk of major malformations but concluded that the evidence for duloxetine is limited [ 33 ]. A large cohort study is necessary to assess the risk of rare outcomes (e.g., malformations, stillbirth). Depression or depressive symptoms are common during pregnancy [ 1 – 4 ]. Despite a drop in recent years [ 5 ], the use of antidepressants among pregnant women has grown steadily [ 6 – 12 ]. Selective serotonin reuptake inhibitors (SSRIs) are the most common [ 9 , 12 , 13 ], followed by serotonin and norepinephrine reuptake inhibitors (SNRIs) [ 5 , 12 , 14 ]. Methods The present study is based on a safety study regarding duloxetine and pregnancy outcomes, with the protocol and the full study report available via the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP, EUPAS20253) [34]. Beside malformation and stillbirth, the protocol and full study include abortion, preterm birth, and being born small for gestational age (SGA) as outcomes. Results about abortion is published elsewhere [35], and results about preterm birth and SGA is under preparation for publication. The study is based on nationwide registers from Sweden and Denmark covering all registered births from 2004 to 2016, with 1-year follow-up data of congenital malformations. Registers were linked with unique personal identification numbers given to all Swedish and Danish citizens upon birth or immigration. The following Danish and Swedish nationwide registers were used. The prescription registers [36–38], containing electronically submitted information on prescriptions dispensed by pharmacies, classified according to the global ATC system. The patient registers [39,40] that include discharge diagnoses of all inpatients and outpatients in contact with a hospital. The medical birth registers [41–43] were all live births as well as stillbirths from varying gestational ages in the different countries are notified to the registers with information on the mother, the neonate, and the father as well. Registers holding information about education and household income [44–46] based on national statistics on education (highest obtained education) and annual tax reports. The study was approved by the Swedish regional ethics review board in Gothenburg (ref: 1040–17 and T782-18), the Swedish National Board of Health and Welfare (ref: 30714/2017), and in Denmark by the Data Protection Agency (j.nr. VD-2018-371, I-Suite nr. 6621). No approval from the Danish Research Ethics Committees for the Capital Region was needed since only national registers were used. Cohorts The cohort consisted of registered live and stillbirths from 2004 to 2016 of women with a valid personal identification number aged 18 and above. Exclusion criteria for the malformation analyses were the following: mothers migrating between 365 days prior to last menstrual period (LMP) until 365 days postdelivery, stillbirths, invalid personal identification number of offspring, births with a chromosomal abnormality diagnosis (ICD-10 codes Q87.1, Q87.4, Q9X), and mothers with a redeemed prescription for a teratogenic drug in the period from LMP to 90 days post LMP (warfarin [ATC: B01AA03], antineoplastic agents [ATC: L01], isotretinoin [ATC: D10AD04, D10BA01, D10AD54], misoprostol [ATC: A02BB01, G02AD06, M01AE56], lithium [ATC: N05AN01], and thalidomide [ATC: L04AX02]). Exclusion criteria for the stillbirth analyses were the following: mothers migrated between 90 days prior to LMP until delivery and gestational age shorter than 22 weeks or longer than 45 weeks. Exposure, comparison groups, and outcome Maternal exposure to medication was defined as a redeemed prescription at a pharmacy. The exposure time window for malformations was from LMP to 90 days after LMP, corresponding to the first trimester of the pregnancy. The exposure time window for stillbirth was from LMP to end of pregnancy. With maternal exposure, fetal exposure is assumed. Duloxetine exposure was defined as at least one redeemed prescription of duloxetine (ATC N06AX21) in the exposure time window. Four comparison groups were used, all with no redeemed prescription of duloxetine in the relevant exposure time window: (1) duloxetine nonexposed: no redeemed prescription of duloxetine in the exposure time window; (2) SSRI exposed: at least one redeemed prescription of an SSRI (ATC N06AB) in the exposure time window; (3) venlafaxine exposed: at least one redeemed prescription of venlafaxine (ATC N06AX16. Venlafaxine is an SNRI like duloxetine) in the exposure time window; and (4) duloxetine discontinuers: at least one redeemed prescription of duloxetine between 365 days prior to LMP to LMP and not during pregnancy. SSRI-exposed and venlafaxine-exposed women and duloxetine discontinuers were used as comparators to take confounding by indication and severity, and maybe even unmeasured confounding, into account, as they are expected to be similar to duloxetine-exposed women with regard to, e.g., the underlying psychological disease, comorbidity, and health behavior. The comparison groups were not mutually exclusive, and comparisons were analyzed separately with each comparison group. For both the malformation and the stillbirth analyses, an additional exclusion criterion was applied when comparing duloxetine-exposed women with duloxetine nonexposed, SSRI exposed, and venlafaxine exposed: women with duloxetine exposure from 90 days prior to LMP but no exposure from LMP to 90 days after LMP were excluded. This washout period was applied to avoid misclassification. Major and minor malformations were classified according to the EUROCAT classification of congenital malformations version 1.4 [47]. Diagnoses of the offspring were gathered from the national patient registers as either a primary or secondary diagnosis registered within 365 days after birth. Major malformations were defined as the following ICD-10 codes: Q-chapter, D215, D821, D1810, P350, P351, P371, except for the ICD-10 codes used to define minor malformations. Minor malformations were defined as the ICD-10 codes in Table A in S1 Tables. Also, analyses of major malformation subtypes were performed: abdominal wall; cardiac; digestive system; ear, face, and neck; eye; genital; limb; nervous system; orofacial clefts; respiratory system; urinary system; and other anomalies (Table B in S1 Tables). Information on stillbirth was gathered from the medical birth registers and was defined as no signs of life at birth after week 22 of pregnancy and from the patient register if abortions were registered after week 22 [48]. [END] [1] Url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003851 (C) Plos One. "Accelerating the publication of peer-reviewed science." Licensed under Creative Commons Attribution (CC BY 4.0) URL: https://creativecommons.org/licenses/by/4.0/ via Magical.Fish Gopher News Feeds: gopher://magical.fish/1/feeds/news/plosone/