Periodic Reporting for period 1 - InPreSS (International Pregnancy Safety Study) Reporting period: 2020-09-01 to 2022-02-28 Summary of the context and overall objectives of the project The majority of pregnant women take prescribed medication. However, for many medications there is limited knowledge of the efficacy and safety for both the woman and fetus. Pregnant women are largely excluded from clinical trials and post-marketing surveillance has been scarce and inadequate thus far. Therefore, we must rely on studies based on observational data to provide evidence for health professionals and pregnant women to make informed decisions on their treatments.Among women of childbearing age, diabetes mellitus has become an increasingly important public health problem in the last decades. Consequently, diabetes is now one of the most common disorders complicating pregnancy. Poorly controlled pre-gestational diabetes has been associated with significant maternal, fetal, and neonatal morbidity and mortality. Therefore, there is an increasing demand for safe and effective antidiabetic medication (ADM) for use in pregnancy.Therefore, the overall objectives of this fellowship are to assess the safety of the medications used to treat type 2 diabetes by investigating the risk of malformations in infants prenatally exposed to metformin and to newer 2nd line non-insulin antidiabetic medications including sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and other blood glucose lowering drugs. This objective will be achieved by using data from US insurance claims databases and the Nordic population health registers within the International Pregnancy Safety Study consortium (InPreSS). Combined, these sources include data for an unprecedented 5 million pregnant women. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Work towards these objectives thus far has focused on investigating the appropriate methodological approach for multinational observational studies using data from healthcare utilization databases such as the US insurance claims database and Nordic population health registers. The main focus of these investigations is how to appropriately design the studies examining the safety of antidiabetic medication use in pregnancy to ensure that the amount of bias, inherent in observational studies, is reduced. The main results point to the importance of choosing a comparison group of pregnant women with similar clinical characteristics to the target group of pregnant women using the drug of interest. This is particularly important in type 2 diabetes because commonly used analytic methods (such as propensity score matching) do not overcome the issue of confounding by indication (where the severity of type 2 diabetes affects both which medication a pregnant women will take as well as the risk of malformations in their infants). The results from these preliminary investigations have influenced the design of the studies addressing the objectives above. Analyses are ongoing and results are pending. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Research into the risk and benefits of prescribed drug use during pregnancy is complex and multifaceted but exceedingly important for maternal and child wellbeing. By the end of this project, evidence derived from the largest cohort of pregnancies studied thus far on the safety of antidiabetic medication use in pregnancy will be shared. These results can be used in the risk/benefit decisions pregnant women with the type 2 diabetes and their clinicians must make when deciding which medications use during pregnancy.