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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 postmarketing setting. Regulatory guidance and legislation on medication use in pregnancy and breastfeeding were reviewed globally by the TransCelerate IGR PV Pregnancy and Breastfeeding Team. The International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards and Council for International Organizations of Medical Sciences guidelines served as benchmarks for national safety regulations and guidance. The landscape assessment identified a lack of harmonization of global regulations on research in pregnant and breastfeeding women and a lack of specific regulations on this topic in the majority of the territories included in the assessment. This article focuses on the ambiguities and lack of harmonization in global regulations on postmarketing 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 harmonization would facilitate more timely completion of postmarketing pregnancy safety studies that would ultimately generate the critical data needed to optimize benefit-risk decisions for women who may conceive, as well as pregnant and breastfeeding women.

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RESUMEN

Limited evidence related to the safety or efficacy of medicines in pregnancy and during breastfeeding is available to inform patients and healthcare professionals. Understanding the current regulatory landscape in the clinical trial and postmarketing settings is critical to facilitate the development of applicable processes and tools for studying medicine use during pregnancy and breastfeeding and comply with health authority expectations. This review summarizes key findings from a landscape assessment of regulations, guidelines, and guidance on the use of medicines in pregnancy and breastfeeding issued by health authorities in various territories (including the Americas, Europe, Africa, and Asia Pacific) and outlines relevant initiatives undertaken by health authorities, academic institutions, industry consortia, and public-private organizations. While global pharmacovigilance legislation regarding medication use during pregnancy and breastfeeding exists and continues to evolve, the landscape assessment revealed that there is a lack of global legislative harmonization in both the clinical trial and postmarketing surveillance settings and regulatory gaps still exist in many countries/regions. Despite ongoing efforts from health authorities and public and private organizations, intensive efforts for legislation harmonization and stakeholder collaboration are required to improve the current environment of medication safety in pregnancy and breastfeeding.

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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.

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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.

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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 METHODS: The 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. Duloxetine-exposed 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.