Incretins are gut hormones that regulate blood glucose by stimulating insulin secretion in response to food intake. Incretin-based medications, including GLP-1 receptor agonists and DPP-4 inhibitors, have become widely used for managing type 2 diabetes. However, their role in pregnancy remains a critical concern for women of childbearing age. Current UK guidance advises against using incretin therapies during pregnancy due to insufficient safety data. Women taking these medications who are planning pregnancy or discover they are pregnant require prompt medication review and transition to pregnancy-safe alternatives such as insulin or metformin. Understanding the safety considerations and appropriate management strategies is essential for optimising maternal and fetal outcomes.

What Are Incretins and How Do They Work?

Incretins are naturally occurring hormones produced in the gastrointestinal tract that play a crucial role in regulating blood glucose levels. The two primary incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are released in response to food intake and work by stimulating insulin secretion from pancreatic beta cells when blood glucose levels rise.

The mechanism of action of incretins is glucose-dependent, meaning they only promote insulin release when blood sugar is elevated, which significantly reduces the risk of hypoglycaemia compared to some other diabetes medications. GLP-1 also suppresses glucagon secretion (a hormone that raises blood glucose), slows gastric emptying to moderate the rate of glucose absorption, and may reduce appetite through central nervous system effects.

In people with type 2 diabetes, the incretin effect is diminished, contributing to inadequate insulin secretion and poor glycaemic control. This observation led to the development of incretin-based therapies, which include GLP-1 receptor agonists (such as exenatide, liraglutide, semaglutide, dulaglutide, and tirzepatide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (such as sitagliptin, saxagliptin, linagliptin, and alogliptin). GLP-1 receptor agonists mimic the action of natural GLP-1, whilst DPP-4 inhibitors work by preventing the breakdown of endogenous incretins, thereby prolonging their activity. Tirzepatide is a dual GIP/GLP-1 receptor agonist licensed in the UK for type 2 diabetes.

These medications have become increasingly popular for managing type 2 diabetes due to their efficacy in lowering HbA1c. GLP-1 receptor agonists are associated with weight loss, and certain agents (including liraglutide, semaglutide subcutaneous, and dulaglutide) have demonstrated cardiovascular benefits in clinical trials. DPP-4 inhibitors are generally weight-neutral. However, the use of incretin-based therapies in specific populations, particularly pregnant women, requires careful consideration of both efficacy and safety, and these medications are not recommended during pregnancy.

Safety of Incretin-Based Medications in Pregnancy

The safety profile of incretin-based medications during pregnancy remains inadequately established, and current evidence is limited primarily to animal studies and small case series. The Summary of Product Characteristics (SmPC) for all GLP-1 receptor agonists, DPP-4 inhibitors, and tirzepatide advises against use during pregnancy due to insufficient human data.

Animal reproductive studies have shown varying results. Some GLP-1 receptor agonists have demonstrated skeletal abnormalities and growth restriction in animal offspring at doses exceeding human therapeutic levels, though the relevance to human pregnancy is uncertain. There is no definitive evidence of teratogenicity in humans, but the absence of robust clinical trial data means potential risks cannot be excluded.

Key safety considerations include:

• Placental transfer: It is unclear to what extent these medications cross the placental barrier

• Fetal development: Potential effects on fetal growth and organ development remain unknown

• Maternal outcomes: Impact on pregnancy-related complications has not been systematically studied

• Lactation: Limited data exist regarding excretion in breast milk; SmPCs generally advise against use whilst breastfeeding

Women of childbearing potential using incretin-based medications should employ effective contraception and discuss pregnancy planning with their healthcare team well in advance. Product-specific preconception advice is important: for example, the SmPC for semaglutide recommends discontinuation at least two months before a planned pregnancy due to its long half-life. Women should check the specific SmPC for their medication or consult their diabetes specialist for agent-specific guidance.

If a woman becomes pregnant whilst taking incretin-based medication, she should contact her GP or diabetes specialist immediately. The medication will typically be discontinued and alternative diabetes management strategies (such as insulin or metformin) implemented. Any inadvertent exposure during early pregnancy should be documented, and the woman should receive appropriate counselling and monitoring. The UK Teratology Information Service (UKTIS) can provide individualised risk assessment and advice following inadvertent exposure. Isolated exposure does not necessarily indicate harm to the developing fetus, but specialist review is essential.

If you suspect an adverse drug reaction related to incretin-based therapy or any other medication during pregnancy, report it via the MHRA Yellow Card Scheme at https://yellowcard.mhra.gov.uk or through the Yellow Card app.

Managing Diabetes in Pregnancy: Treatment Options

Diabetes management during pregnancy requires a fundamentally different therapeutic approach compared to non-pregnant adults, with the primary goal of maintaining tight glycaemic control to minimise maternal and fetal complications whilst ensuring medication safety. Pregnancy can involve either pre-existing diabetes (type 1 or type 2) or gestational diabetes mellitus (GDM), which develops during pregnancy.

Insulin therapy remains the gold-standard pharmacological treatment for diabetes in pregnancy. It does not cross the placental barrier, has decades of safety data, and can be precisely titrated to achieve target glucose levels. NICE recommends specific glycaemic targets for pregnant women with diabetes: fasting plasma glucose below 5.3 mmol/L and one-hour postprandial glucose below 7.8 mmol/L (or two-hour postprandial below 6.4 mmol/L). Multiple daily injection regimens or insulin pump therapy may be required to achieve these stringent targets.

Metformin is increasingly used as an alternative or adjunct to insulin, particularly for gestational diabetes and type 2 diabetes in pregnancy. Whilst metformin does cross the placenta, extensive observational data and randomised trials (such as the MiG trial) have demonstrated its safety and efficacy. NICE guidelines support metformin use in GDM when blood glucose targets are not met with dietary modifications alone, and it may be continued in women with pre-existing type 2 diabetes, though insulin is often added or substituted.

Glibenclamide (a sulfonylurea) may be considered for women with gestational diabetes if metformin is contraindicated or not tolerated and the woman declines insulin therapy, as supported by NICE guidance. However, glibenclamide is associated with an increased risk of neonatal hypoglycaemia and macrosomia, and women should be informed of these risks.

Self-monitoring of blood glucose (SMBG) is essential. NICE recommends that women test at least fasting and one-hour postprandial (or two-hour postprandial) glucose levels. Additional pre-meal, bedtime, or night-time checks may be advised depending on individual circumstances and treatment regimen.

Lifestyle modifications form the foundation of diabetes management in pregnancy:

• Dietary advice: Individualised nutritional counselling focusing on carbohydrate distribution and glycaemic index

• Physical activity: Regular moderate exercise as appropriate for pregnancy

• Weight management: Appropriate gestational weight gain based on pre-pregnancy BMI

Women with pre-existing diabetes should ideally achieve optimal glycaemic control (HbA1c below 48 mmol/mol) before conception and commence high-dose folic acid (5 mg daily) to reduce neural tube defect risk. Preconception care should also include retinopathy assessment and renal function review, with ongoing monitoring during pregnancy. Multidisciplinary care involving obstetricians, diabetes specialists, midwives, and dietitians is essential throughout pregnancy.

Urgent medical review is required if any of the following occur:

• Symptoms of diabetic ketoacidosis (DKA): persistent nausea or vomiting, abdominal pain, rapid breathing, ketonuria or ketonaemia

• Severe or recurrent hypoglycaemia

• Persistent vomiting with inability to retain fluids or food

• Reduced fetal movements

Women experiencing these symptoms should seek same-day assessment from their diabetes team or maternity unit.

Current UK Guidelines on Incretins and Pregnancy

UK regulatory and clinical guidance consistently advises against the use of incretin-based therapies during pregnancy. The Summary of Product Characteristics (SmPC) for all licensed GLP-1 receptor agonists (including semaglutide, liraglutide, dulaglutide, exenatide, and tirzepatide) and DPP-4 inhibitors (including sitagliptin, saxagliptin, linagliptin, and alogliptin) states that these medications should not be used during pregnancy due to insufficient data on safety and efficacy in this population.

NICE guidance on diabetes in pregnancy (NG3) does not recommend incretin-based medications as treatment options for any form of diabetes during pregnancy. The guideline emphasises insulin as the preferred pharmacological agent, with metformin as an acceptable alternative in specific circumstances, and glibenclamide as an option in gestational diabetes when metformin is unsuitable and insulin is declined. Women taking incretin therapies for type 2 diabetes should have their treatment reviewed and modified before conception or as soon as pregnancy is confirmed.

The Joint British Diabetes Societies (JBDS) guidance and the Royal College of Obstetricians and Gynaecologists (RCOG) support this position, recommending that women with diabetes planning pregnancy should transition to pregnancy-safe medications during the preconception period. The timing of discontinuation should follow product-specific SmPC advice: for example, semaglutide should be stopped at least two months before a planned pregnancy, whilst other agents may have different recommendations.

Practical recommendations for healthcare professionals include:

• Preconception counselling: Discuss pregnancy plans with all women of childbearing age taking incretin-based medications

• Contraception advice: Ensure effective contraception is in place for women not planning pregnancy

• Medication review: Switch to insulin ± metformin before conception when pregnancy is planned, following product-specific discontinuation timelines

• Unplanned pregnancy: Promptly discontinue incretin therapy and initiate appropriate alternatives if pregnancy occurs

• Documentation: Record any inadvertent exposure and arrange appropriate monitoring; consider referral to UKTIS for individualised risk assessment

• Breastfeeding: Incretin-based therapies are generally not recommended during breastfeeding per SmPCs; insulin and metformin are preferred options if pharmacological treatment is needed

Women should be reassured that with appropriate management using pregnancy-safe medications, excellent maternal and fetal outcomes can be achieved. The transition from incretin-based therapy to insulin may seem daunting, but comprehensive diabetes education and support can facilitate successful adaptation. Any woman with concerns about diabetes management in pregnancy should contact her GP or diabetes specialist team for individualised advice and care planning.

Frequently Asked Questions