Limited evidence related to the safety or efficacy of medicines in pregnancy is available to inform patients and healthcare professionals on the benefit/risk balance to the mother and fetus. While the majority of pregnant individuals take at least one medication during their pregnancy, only a few medications were developed to be used by pregnant people [2, 3]. Moreover, less than 25% of the medications available on the market present concrete information regarding risks during pregnancy in the product label. There is a dire need to understand and overcome the scientific, legislative, legal, and ethical challenges preventing the development of safe and effective medicinal products for use during pregnancy and while breastfeeding.

As a first step toward meeting this challenge, this regulatory landscape assessment, developed by experts in pharmacovigilance and/or maternal and fetal health, focused on regulatory challenges and represents an overview of current safety legislation for pregnancy and breastfeeding [13]. Based on information that was available as of March 2022, globally, pharmacovigilance legislation regarding medication use during pregnancy and breastfeeding exists (e.g., ICH guidelines, CIOMS recommendations, national legislations) and continues to evolve. For example, the ICH E21 Working Group on Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials was formed in Q4 2022 and the EMA GVP Chapter P.III pregnancy legislation is expected to be launched in Q3 2023 [6, 55].

However, despite ongoing efforts from health authorities and public and private organizations (e.g., EU IMI ConcePTION, US PRGLAC, national and global teratology centers), the landscape assessment revealed that there is currently a lack of global legislative harmonization in both the clinical trial and postmarketing surveillance settings [13]. While ICH/CIOMS regulations include general provisions on safety in pregnancy and breastfeeding, more details would be required to support development in this area [16,17,18, 20,21,22,23,24,25, 32, 36].

Additionally, while several health authorities have made immense progress by providing detailed recommendations in their respective territories (Tables 3, 7, 9 and 10), regulatory gaps still exist in many countries/regions that were included in the landscape assessment (Fig. 1) [6, 19, 26,27,28,29,30,31, 33,34,35,36,37,38,39,40,41,42]. In particular, significant regulatory gaps exist in the clinical trials setting [e.g., lack of regulations or granularity in the regulations for pregnancy or lactation studies (Tables 2 and 4)], whereas postmarketing surveillance legislation is generally further developed (Tables 5, 6, 8, and 10). In some instances, local regulations are more specific regarding signal management than ICH guidelines [e.g., focus on fetotoxicity in Australia, Saudi Arabia, and Switzerland (Tables 8 and 9)] [33,34,35].

Of note, no end-to-end product development guideline exists for medications to be used by pregnant women. Moreover, where national legislation on related topics exists, global inconsistencies among national requirements in the clinical trials setting were observed. For example, requirements for enrolling pregnant or nursing women into clinical trials vary; in India, Peru, and Russia, enrolling pregnant women into clinical trials is only permitted if the medication is designed specifically for use in this population, while in Canada, EU, Switzerland, and the US, enrollment is permitted after careful benefit/risk assessment, including the mother and the fetus (Table 2). In the postmarketing surveillance setting, requirements for post-authorization study design differ between the EU and US (Table 7). Recommendations for case collection after exposure to medication during breastfeeding or related to longer term follow-up vary as well. These aspects lead to a lack of clarity, uncertainty, establishment of complex pharmacovigilance processes, and delays when it comes to the much-needed product development for this population.

There is an acute need to harmonize global legislation for medication safety in pregnancy and breastfeeding and to provide end-to-end product development guidance for medications to be used in this population. While no investigational plan has been proposed or is required by health authorities in this area, discussions to develop a “maternal” or an “obstetric” investigational plan are currently ongoing in several territories. In 2021, the International Coalition of Medicines Regulatory Authorities (ICMRA) workshop (attended by the EMA and US Food and Drug Administration [FDA] representatives) called for the development of a maternal investigational plan, to be proposed by sponsors, outlining how these populations will be studied in the product development [48]. Similarly, discussions regarding an obstetric investigational plan, based on learnings from the successful pediatric investigational plans, are occurring in the UK [49].

Based on findings of the landscape assessment, the TransCelerate Pharmacovigilance Pregnancy and Breastfeeding Topic Team has developed a openly available toolkit (called `Points to Consider Concerning the Use of Medicines in Pregnancy throughout the Product Lifecycle`) that aims to provide a holistic view of pregnancy considerations across the lifespan of the drug and aid researchers to optimize their compliance with regulatory authority expectations [56].