The Risk of GLP ‐1 Receptor Agonist ( GLP ‐1 RA ) Exposure in Early Pregnancy. A Call to Action: Quantifying the Impact on Pregnancy Outcomes in the United Kingdom

Current guidelines universally advise against GLP-1 RA use during pregnancy 5, recommending a two-month ‘washout’ period due to the half-life of a once weekly administered drug. However, as access to GLP-1 RA for supporting weight loss is now being delivered overwhelmingly over the internet through private prescribing, any checks and contraception advice might be less robust than access through regular face-to-face health care. A ‘fertility paradox’ exists: by improving insulin sensitivity, promoting weight loss and restoring ovulation in conditions like PCOS 6, these medications actively increase the likelihood of conception 7, 8. While human observational data on lower-dose GLP-1 RA users in type 2 diabetes populations remain sparse and inconclusive, preclinical evidence is alarming. In some studies, small animals exposed to GLP-1 RAs in pregnancy show evidence of adverse outcomes in the offspring, including decreased foetal growth, skeletal and visceral anomalies and embryonic death 9. Furthermore, human data from bariatric surgery patients—who experience endogenous GLP-1 surges—correlate with small-for-gestational-age infants 10. Although there are no prospective studies in humans, reports have not shown a pattern of congenital anomalies in infants 11. A recent large, observational, population-based cohort study examined pregnancies affected by type 2 diabetes mellitus and compared outcomes from periconceptional exposure to GLP-1 RA (n = 160) and insulin (n = 3191) 12. The authors concluded there was not a significantly increased risk of major congenital malformations in patients taking GLP-1 RAs, although there was no information on maternal glycaemic control. Recent murine models provide a physiological mechanism, showing that GLP-1 activation significantly reduces placental capillary and foetal pancreatic development 13, so there are concerns that these infants might carry lifelong glycaemic control and cardiovascular legacy healthcare burdens, related to their early exposure in the womb. Given that over 45% of pregnancies are unplanned or not actively planned 14, the percentage of conceptions being terminated (a proxy for unplanned pregnancy) is increasing, and there is anecdotal evidence that a significant number of expectant mothers are reporting use of GLP-1 RA at conception in their 13-week review. This suggests that we are facing a significant cohort of infants with unintended first-trimester exposure. By aggregating the expected birth rate and GLP-1 RA use by age group and applying a range of assumptions for continuing growth rate in use of GLP-1 RA and level of contraceptive mitigation, we can provide an estimate of potential levels of impact of births in 2026. This indicates that, depending on the realised growth rate in the use of GLP-1 RA and the effectiveness of contraception mitigation, an estimated 12,000 to 84,000 (2.1%–14.5%) infants may be affected. Table S1 provides a sensitivity analysis of the outcomes to the two key assumptions of GLP-1 RA growth and contraceptive mitigation in relation to potential percentage of total births at risk for the total 580 000 expected births in 2026. The level of impact on birth outcomes will also depend on the levels of exposure, which are determined by the dose and timing relative to conception. The risks of discontinuation of GLP-1 RA treatment prior to conception in early pregnancy must also be considered, as described in a large recently published retrospective cohort study which reported that women exposed to GLP-1 RA treatment vs. women with no exposure had a higher risk of excess gestational weight gain (65% vs. 49%), greater mean birth weight percentile (58% vs. 55%), higher risk of preterm delivery (17% vs. 13%), of gestational diabetes (20% vs. 15%) and of hypertension in pregnancy (46% vs. 36%) 15. Thus, prior GLP-1 RA use with discontinuation for pregnancy was associated with undesired consequences. Regarding bariatric surgery, if this is carried out in the months and years before conception, this in itself is not a panacea. A 2019 meta-analysis concluded that bariatric surgery, especially gastric bypass prior to conception, was associated with increased risk of some adverse perinatal outcomes, such as increased perinatal mortality, increased likelihood of preterm birth and of admission of the newborn baby to a neonatal intensive care unit, together with a tendency for small gestational age babies 16. There was a recommendation that all women who have undergone bariatric surgery would benefit from preconception of pregnancy nutritional support and more intensive monitoring of foetal health than women who have not undergone this procedure. There will always be a trade-off between the risks of gestational complications in women who are overweight, potentially, with an associated degree of dysglycaemia, compared with the potential for any drug-related side effects. This does not just apply to GLP-1 receptor agonists, but to any agent which improves metabolic profile in pregnancy. Currently, where the balance sits is not something that can be estimated until we have sufficient data from women exposed to GLP-1 RAs in the early stages of pregnancy versus those women who have not taken such agents. Comparator Cohort: An unexposed comparator cohort will be selected from the same hospital records to allow comparison of birth outcomes, with matching criteria to be determined following assessment of the baseline characteristics of the exposed cohort. We must act promptly to capture data to establish both the actual prevalence in births of GLP-1 RA use at conception and follow those exposed pregnancies to identify the presence or lack of significant effects on birth outcomes. These results can then be part of the evidence used to develop the communication to both healthcare providers and GLP-1 RA potential users on the levels of precautions that might be most suitable. As technology and biology continue to entwine, we must ensure our pharmacological progress does not compromise the fundamental health of the next generation. We call upon all those interested in the health of our children, including pharmaceutical providers, the clinical community and regulatory bodies, to support this initiative to safeguard these potential future infants. The authors have nothing to report. The authors declare no conflicts of interest. The data that supports the findings of the study are available on reasonable request. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70791. Table S1: Projected Growth Rate of GLP-1 agonists versus % of total births at risk. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.