Objective To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine. Design Cohort study nested in the Medicaid Analytic eXtract for 2004-13. Setting Publicly insured pregnancies in the United States. Participants Pregnant women 18 to 55 years of age and their liveborn infants. Interventions Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy. Main outcome measures Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage. Results Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses. Conclusions On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient. Trial registration EUPAS 15946.

Background Depression and antidepressant treatment are widespread among women of childbearing age. Objective This study evaluates the association between duloxetine exposure during pregnancy and spontaneous and elective abortions. Patients and MethodsThe nationwide, observational study based on register data from Denmark included women with a recorded pregnancy in the birth register or an abortion in the patient register between 2004 and 2016. Duloxetine-exposed women were compared with (1) duloxetine non-exposed, (2) selective serotonin reuptake inhibitor (SSRI)-exposed, (3) venlafaxine-exposed, and (4) women discontinuing duloxetine before pregnancy. Exposure status was based on records of redeemed prescriptions. Cox regression with adjustments and propensity score matching was applied. Results The data from 1,019,957 pregnancies were used, including 1,212 pregnancies exposed to duloxetine. Duloxetineexposed women had an increased hazard ratio (HR) for spontaneous abortions compared with SSRI-exposed women: propensity score matched HR 1.25 [95% confidence interval (CI), 1.00-1.57]. No increased hazard was observed for duloxetine-exposed women compared with duloxetine non-exposed: 1.08 (95% CI 0.89-1.31); venlafaxine-exposed: 1.08 (95% CI 0.82-1.41); and duloxetine discontinuers: 0.99 (95% CI 0.76-1.30). An increased HR of elective abortions was observed in duloxetine-exposed women compared to duloxetine non-exposed: 1.41 (95% CI 1.25-1.59); SSRI-exposed: 1.32 (95% CI 1.15-1.51); and duloxetine discontinuers: 1.46 (95% CI 1.23-1.75), but not to venlafaxine-exposed women: 1.09 (95% CI 0.93-1.27). Conclusion There was no increased risk of spontaneous or elective abortion associated with exposure to duloxetine. The increase risk observed for women exposed to duloxetine in comparison with SSRI-exposed for spontaneous and in comparison with all groups (except venlafaxine-exposed) for elective abortion suggested confounding.

Pregnancy is a unique physiological state that results in many changes in bodily function, including cellular, metabolic, and hormonal changes. These changes can have a significant impact on the way small‐molecule drugs and monoclonal antibodies (biologics) function and are metabolized, including efficacy, safety, potency, and adverse effects. In this article, we review the various physiologic changes that occur during pregnancy and their effects on drug and biologic metabolism, including changes in the coagulation, gastrointestinal, renal, endocrine, hepatic, respiratory, and cardiovascular systems. Additionally, we discuss how these changes can affect the processes of drug and biologic absorption, distribution, metabolism, and elimination (pharmacokinetics), and how drugs and biologics interact with biological systems, including mechanisms of drug action and effect (pharmacodynamics) during pregnancy, as well as the potential for drug‐induced toxicity and adverse effects in the mother and developing fetus. The article also examines the implications of these changes for the use of drugs and biologics during pregnancy, including consequences of suboptimal plasma drug concentrations, effect of pregnancy on the pharmacokinetics and pharmacodynamics of biologics, and the need for careful monitoring and individualized drug dosing. Overall, this article aims to provide a comprehensive understanding of the physiologic changes during pregnancy and their effects on drug and biologic metabolism to improve the safe and effective use of drugs.

Globally, more than 200 million women become pregnant each year, most of whom receive medications despite limited information on their safe use during pregnancy. The paucity of drug safety data on pregnant and breastfeeding women stems from the routine exclusion of this population from clinical trials due to scientific, ethical, regulatory and legal concerns. Consequently, at the time of initial drug approval, there may be scant safety data to inform the drug benefit-risk balance to the mother, foetus, or infant. Although momentum is growing to include this underrepresented population in clinical trials, most information on drug exposure outcomes comes from data collected in the post-marketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by TransCelerate IGR PV Pregnancy and Breastfeeding Team. ICH standards and CIOMS guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonisation of global regulations on research in pregnant and breastfeeding women. This editorial focuses on the ambiguities and lack of harmonisation in global regulations on post-marketing pregnancy and breastfeeding safety studies. There is currently no ICH standard to guide these types of safety studies and, in most regions reviewed, there are no clear regulations or guidance on when and how to conduct them. While a challenging undertaking, greater clarity and harmonisation would facilitate more timely completion of post-marketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for pregnant and breastfeeding women.

Background Depression or depressive symptoms are common among pregnant women. The use of antidepressants during pregnancy has grown steadily. The risk of offspring being born small for gestational age or prematurely when exposed to duloxetine during pregnancy is not established. Objective We aimed to investigate the association between duloxetine exposure during pregnancy and offspring being born small for gestational age or prematurely. Methods We conducted an observational study including live births in Sweden and Denmark (2004–2016). Duloxetine exposure during early (0–140 days) or late (141 to delivery) pregnancy compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, venlafaxine-exposed, and duloxetine discontinuers. Results In total, 2,083,467 pregnancies were identified, where 1589 and 450 were duloxetine exposed in early and late pregnancy, respectively. For small for gestational age, no increased risk was seen for duloxetine across comparators. In the early and late exposure windows, propensity score-matched odds ratios for small for gestational age ranged between 0.64 (95% confidence interval 0.44–0.95) and 1.48 (95% confidence interval 0.85–2.57). For preterm birth, the findings differed across comparators and exposure-time windows, but trended towards an increased risk for duloxetine-exposed when compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, and duloxetine discontinuers in both early exposure and late exposure. The odds ratios ranged between 1.17 and 2.04, of which some did not reach statistical significance. No clear association was observed when compared with venlafaxine exposed, 0.91 (95% confidence interval 0.73–1.14) for early exposure and 1.26 (95% confidence interval 0.86–1.86) for late exposure. Most preterm births (79.2%) occurred in weeks 33–36 of gestation. Conclusions Duloxetine exposure during pregnancy is unlikely to increase the risk of small for gestational age. Although not consequently statistically significant across comparisons, a trend towards an increased risk of preterm birth was observed for duloxetine exposed. Therefore, an increased risk of preterm birth cannot be excluded, especially for women exposed to duloxetine throughout pregnancy. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-022-00334-2.