New research to be presented at the Annual Meeting of The European Association for the Study of Diabetes (EASD) in Milan, Italy (Sept 28 – Oct 2) and published in The Lancet Obstetrics, Gynaecology & Women's Health shows that, following a review and meta-analysis of available studies, use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) drugs for diabetes and weight management in women living with diabetes is not associated with adverse pregnancy outcomes in most cases.
But the international panel of authors – who include Professor Claire Meek, Leicester Diabetes Research Centre and Leicester NIHR Biomedical Research Centre, Leicester, UK – say more research to address this field is critical to address large evidence gaps and to keep pace with the huge and accelerating increase in women of reproductive age using these drugs. Prof Meek said: "Millions of women are now using GLP-1 receptor agonists, but there remain important unanswered questions about their impact on fertility, pregnancy, and maternal and child health. Women deserve clearer evidence to guide some of the most important healthcare decisions of their lives. As new weight loss medications enter clinical practice at pace, generating robust evidence for women before, during, and after pregnancy has never been more urgent."
The prevalence of diabetes in pregnancy, including type 1 diabetes (T1D), type 2 diabetes (T2D), and gestational diabetes mellitus (GDM), continues to rise globally, underscoring the need to optimise maternal metabolic health before conception – that is, make women as healthy as possible before they conceive, including improving their blood sugar status and weight loss if needed. GLP-1 RA-based therapies offer substantial benefits for weight reduction and blood sugar control and are increasingly prescribed to women of reproductive age. However, their safety and effectiveness before, during, and after pregnancy remain uncertain. To investigate the available evidence, the authors did a systematic review and used seven studies with more than 43,000 participants exposed to GLP-1 RAs in their meta-analysis. Among these studies, 6 of the 7 assessed exposure in the first trimester of pregnancy; 1 of the 7 assessed exposure at any point in the 12 months pre-pregnancy, which could include exposure in early pregnancy. The exact timings of exposure in terms of weeks of pregnancy were often not well documented.
The meta-analysis suggested no significant associations between GLP-1 RA exposure and risk of preterm birth, stillbirth or neonatal death, caesarean section, pregnancy hypertensive disorders or pre-eclampsia, or small-for-gestational age infant. Early pregnancy loss (<14-22 weeks), including miscarriage or termination, was 31% more common among exposed women (2 studies; n=41,046); however caution is warranted with this finding because deliberate termination or pregnancy loss through miscarriage was counted as the same outcome in the study representing 99% of the women involved; thus it was impossible to tell the difference between women who had had a miscarriage from those who had chosen to terminate their pregnancy. Evidence regarding miscarriage, pregnancy exposure to GLP-1 RA beyond the first trimester, and postpartum use of these drugs remains limited.
The authors say: "The first international consensus recommendations on the use of GLP-1 RAs across the reproductive journey in women with diabetes were developed by integrating a systematic review and meta-analysis of over 43,000 women exposed to GLP-1RA, expert consensus from 42 specialists with international representation, and input from 60 women with lived experience. Available evidence, predominantly in women with type 2 diabetes, suggests that there is no increase in congenital anomaly risk following first-trimester discontinuation of GLP-1RAs compared to no GLP1-RA exposure, but important uncertainties remain regarding pregnancy loss, pregnancy exposure beyond the first trimester and postpartum use. The consensus panel supported GLP-1RA use for preconception metabolic health optimisation where needed in women with type 2 diabetes and recognised potential benefits in women with type 1 diabetes and previous gestational diabetes, although direct evidence in these groups is limited.
"The consensus recommendations should be interpreted in the context of limited direct evidence, particularly for women with type 1 diabetes, previous gestational diabetes, pregnancy exposure beyond the first trimester and lactation. Substantial evidence gaps remain, highlighting an urgent need for prospective studies evaluating fertility, pregnancy, breastfeeding and long-term maternal and offspring outcomes
They add: "More evidence, especially on duration of exposure, route of administration and pregnancy outcomes is needed, with separate data also needed for the different GLP1-RA based therapies."
They highlight evidence regarding GLP-1RA use in the second and third trimesters remains extremely limited, and robust data on maternal, fetal and offspring outcomes are needed. Postpartum evidence was similarly sparse, comprising only one small, randomised trial in non-breastfeeding women and two pharmacokinetic lactation studies. Available data suggest that subcutaneously administered GLP-1RAs are undetectable or present at negligible concentrations in breast milk, but clinical safety data in breastfed infants remain insufficient, particularly for oral formulations containing absorption enhancers.
The conclude: "Overall, current evidence is insufficient to define the benefits and risks of GLP-1RA therapy across the reproductive life course. Large prospective studies are urgently required to evaluate maternal, fetal and infant outcomes, alongside longer-term metabolic and developmental consequences for both mother and child."
The full paper contains recommendations that the Expert Consensus Panel has made in light of its findings.
