USE OF GLP-1 RECEPTOR AGONISTS IN PREGNANCY

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are licensed as second-line treatment options for type 2 diabetes mellitus (where metformin is inappropriate), for use in combination with diet and exercise for weight management in people with obesity, or those who are overweight with at least one weight-related co-morbidity. Currently available GLP-1 RAs in the UK include dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide. Tirzepatide is a long-acting dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist.

Obesity is associated with increased risks of adverse pregnancy and fetal outcomes, and all women are encouraged to eat a balanced healthy diet and be physically active (moderate- intensity). Dieting through calorie deficit, and/or anti-obesity or weight loss medications are not recommended in pregnancy.

Maternal hyperglycaemia in pregnancy is associated with increased risks of adverse pregnancy and fetal outcomes. As such, it is important that the maternal blood glucose is tightly controlled around the time of conception and during pregnancy. National Institute for Health and Care Excellence (NICE) recommendations suggest metformin (alone or in combination with insulin) for the management of pre-existing or gestational diabetes. For more information, please see the metformin monograph.

Safety data relating to GLP-1 RAs includes more than 47,000 exposed pregnancies. However, many of the available studies are methodologically limited, and in most cases treatment was discontinued in early to mid-pregnancy. As such, limited conclusions can be drawn regarding the safety of longer-term GLP-1 RA use in pregnancy. Given their high molecular masses, placental transfer of GLP-1 RAs is not expected.

The available data do not indicate increased risks of miscarriage, malformation, intrauterine death/stillbirth, low infant birth weight, macrosomia, or preterm delivery following exposure to GLP-1 RAs in early to mid-pregnancy. Although uncontrolled case reports have described fetal macrosomia and neonatal complications, including jaundice, sepsis, hypoglycaemia, and respiratory distress syndrome, these outcomes are considered unlikely to be causally related to GLP-1 RA use. Furthermore, a small number of controlled studies do not demonstrate clear increased risks of jaundice, hypoglycaemia, or respiratory distress syndrome among GLP-1 RA-exposed neonates, a small number of whom were exposed in late pregnancy. Two case reports describe normal infant growth and development up to 12 and 14 months post-delivery. No studies have been located which have investigated the risk of neurodevelopmental impairment or childhood cancer following GLP-1 RA use in pregnancy.

Inadvertent exposure to GLP-1 RAs at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, where exposure occurs close to delivery, there is a theoretical risk of neonatal hypoglycaemia; therefore, neonatal monitoring recommended. Other risk factors which could independently increase the risk of adverse pregnancy outcomes may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.