Exposure to <scp>GLP</scp>‐1 receptor agonists in early pregnancy did not increase the risk of congenital malformations

The incidence of obesity, gestational diabetes mellitus and type 2 diabetes mellitus among women of reproductive age has been rapidly increasing in recent years.1 As a result, there has been a significant rise in the development of drug therapies to treat obesity and type 2 diabetes mellitus. Notably, the promising results of glucagon like peptide-1 (GLP-1) receptor agonists have led to their increasing use in younger age groups.2 Initially, these medications were used as a second-line treatment for type 2 diabetes mellitus. With expanding evidence supporting their efficacy, there is likely to be more use of GLP-1 receptor agonists among women of reproductive age. Consequently, it is crucial to analyse the impact of these medications on pregnancy and offspring. A systematic review published in 2023 aimed to address this issue and included three case reports of pregnancies with early pregnancy GLP-1 receptor agonist use.3 All three cases resulted in full-term neonates without medical complications or malformations. However, larger studies on the influence of early pregnancy GLP-1 receptor agonist use on neonatal outcomes and malformations have been lacking. This review aimed to systematically analyse the evidence regarding GLP-1 receptor agonist use during early pregnancy and its impact on congenital malformations. For this brief review, PubMed and Scopus databases were searched on 19 May 2024, using the search phrase “GLP-1 and pregnancy”. The search results were uploaded to Covidence software for screening. Both retrospective and prospective cohort studies were included, and the risk of bias was assessed using the Cochrane Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool. The main outcome was the risk or odds of congenital malformations. The definition of congenital malformation in this review was the one the original studies had used. All review processes were performed by a single author (IK). A total of 359 studies were screened, with four undergoing further assessment, and ultimately, two were included in the synthesis.4, 5 The overall risk of bias was low in both included studies. The first study was a retrospective register-based study combining data from the Nordic countries, the United States and Israel.4 It included 938 pregnancies where GLP-1 receptor agonists were used. All participants had been diagnosed with type 2 diabetes mellitus prior to conception and used the medication during early pregnancy. This study compared GLP-1 receptor agonist use to insulin use, finding that the risk ratio (RR) for any major congenital malformation was 0.95 (CI 0.72–1.26), and for cardiac malformations, it was 0.68 (CI 0.42–1.12) (Table 1). Adjusted RR for major malformations 0.95 (CI 0.72–1.26) Adjusted RR for cardiac malformations 0.68 (CI 0.42–1.12) Compared to other diabetics adjusted OR 0.98 (CI 0.16–5.82) Compared to obese adjusted OR 0.54 (CI 0.11–2.75) The second included study was a prospectively collected cohort study from teratological databases in five primarily European countries.5 This study compared GLP-1 receptor agonist users to women using other antidiabetic drugs and to women with obesity. The adjusted odds ratios (OR) for congenital malformations were 0.98 (CI 0.16–5.82) compared to other diabetic medications, and 0.54 (CI 0.11–2.75) compared to women with obesity (Table 1). This review identified two register-based cohort studies that did not indicate an increased risk of congenital malformations following exposure to GLP-1 receptor agonists in the first trimester. These findings are significant given the increased early pregnancy exposure to GLP-1 receptor agonists.4 The main limitation of the included studies is their limited sample size. Given the rarity of congenital malformations, large cohorts are required to detect significant associations. Although the studies utilised a multinational register-based design, the confidence intervals for outcome estimates were wide, encompassing both potential increases and decreases in malformation risk. Both the included studies used relevant control groups, as the groups included other antidiabetic medication users or women with obesity, as these both are known to be associated with higher odds for congenital malformations than women without additional morbidities.6 This should be remembered when considering the generalisability of the results. The patients had already an increased baseline risk for congenital anomalies compared to healthy women. Furthermore, the geographic regions should be noted, as for example none of the studies included pregnancies from Australia, Asia, Africa or South America. It is essential to continue monitoring and gathering more data to confirm these initial findings and to detect any signals of rarer malformations. A further limitation was the brief report format, where only a single author performed all the phases of the review process, and the reporting is rather condensed. Overall, exposure to GLP-1 receptor agonists does not appear to increase the risk of congenital malformations, but the evidence is limited by the small number of studies and uncertainty in the outcome estimates. Ilari Kuitunen: Conceptualization; writing – original draft; writing – review and editing; methodology; visualization; formal analysis; data curation. None to report.