International Pregnancy Safety Study

Project Information

InPreSS

Grant agreement ID: 844728

DOI

10.3030/844728

Project closed

EC signature date 22 October 2019

Start date 1 September 2020

End date 4 March 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 219 875,52

EU contribution

€ 219 875,52

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 2 - InPreSS (International Pregnancy Safety Study)

Reporting period: 2022-03-01 to 2023-02-28

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, type 2 diabetes is now one of the most common disorders complicating pregnancy. Poorly controlled type 2 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 objective of this fellowship was to assess the safety of the medications used to treat type 2 diabetes by investigating the risk of major 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, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. This objective was achieved by using data from US insurance claims databases, health care data from Israel, and the Nordic population health registers within the International Pregnancy Safety Study consortium (InPreSS). Combined, these sources include data for an unprecedented number of pregnant women for use in these high-quality pharmacoepidemiological observational research studies.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The focus of this project was to investigate the appropriate methodological approach studying antidiabetic medication for treatment of type 2 diabetes in pregnant women using observational healthcare data. These studies aimed to assess how well certain methodologies reduce the bias caused by confounding by indication, that is how to reduce the effect of the underlying type 2 diabetes severity so that we can properly evaluate the effect of the medication. Results from these studies highlighted 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 since the commonly used analytic methods tested (such as propensity score matching) did not overcome the issue of confounding by indication and create balance in measures of glycemic control. These results were used to design the safety studies where malformation risk was assessed in pregnant women with type 2 diabetes using metformin or the 2nd-line non-insulin antidiabetic drugs. Results from the safety studies show that there is no increased risk for malformations in infants prenatally exposed to 1) metformin and 2) sulfonylureas, DPP-4 inhibitors, GLP-1 analogues, and SGLT2 inhibitors compared to insulin, above the risk inherent to being born to a mother with pregestational type 2 diabetes.
Of the 7 methodological and outcomes studies included in this project, 3 have been published in high ranking peer-reviewed medical journals, and the remainder have or will soon be submitted for peer-review and subsequent publication.
The 3 published studies are available open-access on the journal websites and in the repository Zenodo.

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. When it comes to studying the safety of antidiabetic medication use for the treatment of type 2 diabetes during pregnancy, there are significant methodological challenges due to the risks to the mother and infant presented by the underlying glycemic control. The studies in this project were conducted using observational health care data of large cohorts of pregnant women and developed state of the art methodological approaches which will guide future research in this field.
Additionally, the results of this project provide evidence on the safety of antidiabetic medication use in pregnancy. These findings can be used in the risk/benefit decisions pregnant women with the type 2 diabetes and their clinicians must make when deciding on the best treatment strategy before and during pregnancy.

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