Carbimazole, methimazole and propylthiouracil: Use in women of childbearing age and exposed pregnancies in Germany

Background Hyperthyroidism during pregnancy is associated with maternal, obstetrical and fetal complications. Antithyroid drugs (ATD) including carbimazole (CMZ), methimazole (MMI) and propylthiouracil (PTU) are the main pharmacotherapy for hyperthyroidism. Exposure to CMZ and MMI during the first trimester was associated with birth defects, while PTU is assumed to be the safer alternative.

To calculate the prescription prevalences of ATD in women of childbearing age over time and to describe pregnancies occurring after or during ATD use.

Using the GePaRD database (claims data; 20% of the German population), we conducted year-wise cross-sectional studies for the period 2004-2020 to calculate prescription prevalences of CMZ, MMI and PTU in females aged 13-49 years. In longitudinal analyses, we included all women with any ATD dispensing between 2005 and 2020 aged 13- 49 years at the first dispensing. We identified pregnancies occurring in this cohort and described ATD use before and during pregnancy.

The age-standardized prescription prevalence of ATDs decreased by 32.1% between 2004 (2.71 per 1,000) and 2020 (1.84 per 1,000). This decrease was attributable to CMZ (2004: 1.40 per 1,000; 2020: 0.76 per 1,000; relative decrease: 45.7%) and MMI (2004: 1.25 per 1,000; 2020: 0.99 per 1,000; relative decrease: 20.8%). In the cohort including 9,723 women, 13,586 pregnancies were observed, of which 67% (n=9,140) occurred after ATD use. In 16.2% of the pregnancies (n=2,203), ATD use overlapped with pregnancy onset. The proportion exposed to CMZ/MMI at pregnancy onset decreased from 30.7% in 2005 to 10.9% in 2020. In 16.5% of pregnancies (n=2,243), ATD use was started during pregnancy.

The prescription prevalence of ATD overall and specifically of CMZ/MMI in girls and women of childbearing age decreased between 2005 and 2020 in Germany. The decrease in exposure to CMZ/MMI at pregnancy onset indicate that physicians became increasingly aware of the potential risks of CMZ/MMI to the unborn child. Competing Interest Statement The authors have declared no competing interest. Funding Statement The project was funded by the Federal Institute for Drugs and Medical Devices (BfArM), funding reference V-2020.7 / 1516 68605 / 2020-2022. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: According to the Ethics Committee of the University of Bremen studies based on the German Pharmacoepidemiological Research Database are exempt from institutional review board review. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability As we are not the owners of the data we are not legally entitled to grant access to the data of the German Pharmacoepidemiological Research Database. In accordance with German data protection regulations, access to the data is granted only to BIPS employees on the BIPS premises and in the context of approved research projects. Third parties may only access the data in cooperation with BIPS and after signing an agreement for guest researchers at BIPS.