Obesity Reviews recently published a systematic review conducted by an international, multidisciplinary team of experts. The review was jointly authored by experts in endocrinology, obstetrics and gynecology, pharmacy, midwifery, and nutrition from multiple countries, and focused on the risks and benefits of GLP 1/GIP-class drugs among women of childbearing age (18–45 years) throughout the entire cycle—from preconception through pregnancy to the postpartum and breastfeeding periods—and formulated clinical consensus recommendations, while also identifying gaps in the existing evidence and outlining future research directions.
Research Background and Methods
Clinical Realities and Contradictions
Obesity significantly impairs women’s reproductive health: it increases the risk of polycystic ovary syndrome (PCOS), infertility, gestational diabetes (GDM), preeclampsia, macrosomia, cesarean section, and preterm birth. Globally, one in five pregnancies is complicated by obesity.
Intropins improve ovulation and endometrial receptivity and are widely used by women of childbearing age. Product labels explicitly contraindicate their use during pregnancy and lactation, primarily because animal studies suggest a potential teratogenic risk, although real-world exposure data in humans are insufficient. Current WHO guidelines cover only non-pregnant populations and lack specific guidance for the preconception and perinatal periods.
Intestinins vary greatly in half-life and protein binding, which determine the duration of drug clearance after discontinuation; while large molecular weight and high plasma protein binding theoretically reduce placental and breast milk penetration, comprehensive human evidence is lacking.
The Dual Effects of Intropin on Female Reproduction
Beneficial Mechanisms
Endocrine: Improves LH and estrogen levels; reduces insulin resistance;
Ovaries: Reduces the number of cystic follicles in polycystic ovaries; restores regular ovulation; increases the success rates of natural conception and in vitro fertilization (IVF);
Metabolic: Significantly reduces body fat and weight; improves endometrial receptivity and increases embryo implantation rates;
Potential Risks
Slows gastric emptying, reducing the absorption of oral contraceptives and diminishing their efficacy;
Appetite suppression may lead to insufficient intake of micronutrients.
Research Methods
Following the JBI scoping review methodology and the PRISMA ScR guidelines, an international multidisciplinary expert panel was formed to conduct a systematic search of multiple databases (12 databases, including Embase, Medline, and Cochrane, plus gray literature) by July 23, 2025.
Inclusion criteria: Women aged 18–45; who used exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, or tirzopentide; studies that included reproductive or pregnancy outcomes;
The studies covered 32 core research questions, of which only 18 (56.3%) had human evidence, while the remaining 14 lacked data. These were categorized into six major life-cycle dimensions: 1. Preconception / fertility; 2. Pregnancy (fetal risks); 3. Pregnancy (maternal risks); 4. Early postpartum period + breastfeeding; 5. Long-term maternal and infant outcomes; 6. Multidisciplinary collaborative management.
Key Findings from the Evidence
(I) Preconception Period (Pre-pregnancy / Fertility)
- Benefits for Fertility (primary evidence from obese women with PCOS)
Metformin, either alone or in combination, can restore menstrual cycles and increase ovulation frequency;
Intervention starting 12 weeks before conception significantly increases the natural conception rate: 29.2% in the exenatide group vs. 14.7% in the metformin group;
Benefits for assisted reproductive technology (ART): The pregnancy rate following embryo transfer with liraglutide plus metformin was 85.7%, significantly higher than the 28.6% rate with metformin alone;
Mechanism: Weight loss and improved insulin resistance are key; the drugs have no direct, independent endocrine-improving effects (hormonal improvements disappear after adjusting for BMI). - Drug Interactions with Contraceptives (Key Clinical Safety Considerations)
Exenatide: Delays gastric emptying and reduces the absorption of combined oral contraceptives; a minimum 1-hour interval is required between doses;
Dulaglutide, liraglutide, and semaglutide: Do not affect the plasma concentrations of oral contraceptives; no dosing interval is required;
Telapertide: Causes the strongest inhibition of gastric emptying, significantly reducing the bioavailability of oral contraceptives; guidelines explicitly warn against this. - Evidence Gaps
No studies provide guidance on managing adverse reactions during preconception;
No data are available to assess the effects of these drugs on key micronutrients for preconception, such as folic acid, vitamin B12, and fat-soluble vitamins;
No standard screening criteria exist to determine which obese women should be prioritized for incretin therapy.
(2) Pregnancy (Fetal Safety)
- Risk of Congenital Malformations (Key Conclusion):
In a total of over 1,500 cases from a cohort of unintended early-pregnancy exposures (most of whom discontinued the drug upon discovering the pregnancy), no increased risk of major congenital malformations (MCM) was observed in any human cohort:
Multinational pharmacovigilance data: GLP 1: 2.7% malformation rate in the exposure group versus 5.3% in the placebo group;
Multinational registries and retrospective cohorts (n=938, n=163): the risk of malformations was comparable to that in pregnant women with diabetes treated with insulin;
Only 16 cases of medication use throughout the entire pregnancy were reported, and none resulted in fetal malformations. - Placental Transfer: In vitro studies show extremely low placental penetration of exenatide; trace amounts of liraglutide were detected in umbilical cord blood samples; human placental penetration data for newer drugs (semaglutide, tirzopotide) are completely lacking.
- Conflicting data on fetal growth:
Some Danish cohorts suggest an increased risk of macrosomia in the exposed group; however, after propensity score matching, it was confirmed that the risk stemmed from underlying maternal obesity or diabetes rather than the drug itself. Animal studies suggest that GLP-1 activation may inhibit fetal growth, which is inconsistent with human observations.
(3) Pregnancy (Maternal Complications)
- Gestational diabetes, hypertension, preeclampsia: The evidence is inconsistent:
A large-scale matched cohort study in the U.S. found that pre-pregnancy GLP-1 receptor agonist users had a lower risk of GDM, preeclampsia, and preterm birth;
Another Massachusetts cohort study suggests that after discontinuation, there is an increased risk of excessive weight gain during pregnancy and preterm birth, which is presumed to be due to weight rebound following discontinuation;
General consensus: Confounding variables (baseline obesity, diabetes, socioeconomic status) are the root cause of these differences; the medication itself does not increase the risk of gestational hypertension. - Gestational Weight Gain (GWG): There is a lack of prospective human data; widespread weight regain after discontinuation (in the general population, 0.4 kg per month after discontinuation, with return to baseline weight within 1.7 years) may offset the benefits of pre-pregnancy weight loss.
- Evidence Gaps: There are no data to guide micronutrient supplementation during pregnancy or whether GDM screening criteria need to be adjusted.
(4) Lactation / Early Postpartum Period
- Very limited data on the safety of drug transfer into breast milk:
Small-scale lactation study of semaglutide (8 participants): The drug was not detected in breast milk, and no abnormalities in infant growth were observed;
Limited data on tirzoparide: The drug was not quantifiable in breast milk at doses of 2.5–5 mg;
Limitations: Small sample size; participants were predominantly women more than 6 months postpartum; no data on the safety of semaglutide in breast milk when administered orally with absorption-enhancing excipients. - Theoretical risk: The drug’s appetite-suppressing effect may lead to insufficient intake of maternal protein and micronutrients; combined with the high nutritional demands of breastfeeding, this poses a risk of hidden malnutrition;
- Postpartum weight loss benefits: Women with a history of GDM who use liraglutide have shown significant weight loss and improved HbA1c levels; however, there is no consensus on the optimal start time or whether breastfeeding should be considered.
(5) Long-term and Long-range Outcomes for Mothers and Infants
- Mother: After discontinuation of the drug, metabolic parameters (blood glucose, blood lipids, blood pressure) all rebounded to baseline levels within 1.4 years;
- Offspring: Only one animal study examined long-term postnatal metabolism; there are no long-term follow-up data from humans, and the risk of obesity and diabetes in offspring due to in utero exposure is unknown.
Expert Consensus: Clinical Practice Recommendations
- Contraceptive Management
All women of childbearing age taking this medication must use reliable contraception; use additional barrier contraception in cases of severe vomiting or diarrhea;
For users of telapodide: Switch to a non-oral contraceptive method, such as an intrauterine device (IUD), or use condoms in addition to the medication whenever the dose is increased or within 4 weeks of starting treatment;
No change in contraceptive method is required for semaglutide, liraglutide, dulaglutide, or exenatide. - Preconception and Discontinuation Counseling
Individualized preconception counseling: Inform patients of current safety data regarding unintended pregnancy, and follow the recommended washout period as per the prescribing information (there is no uniform evidence supporting a fixed 4–8-week washout period);
Discontinue medication immediately upon confirmation of pregnancy; continued use throughout pregnancy is permitted only in extremely rare cases after weighing the benefits and risks and is not recommended for routine use;
Post-discontinuation interventions: A high-protein, high-fiber diet and exercise program to mitigate rapid weight regain. - Nutritional Interventions (Focusing on Key Deficiencies, Derived by Analogy from Bariatric Surgery Patients)
Prioritize nutrient-dense diets to compensate for insufficient intake caused by reduced appetite;
Routinely supplement with folic acid and vitamin D; women planning pregnancy should additionally take a prenatal multivitamin; women not planning pregnancy should routinely take a multivitamin;
A high-fiber diet and adequate hydration help alleviate gastrointestinal side effects such as nausea and bloating. - Prenatal Monitoring Protocol
Discontinuation of medication after exposure in early pregnancy: Only standard obstetric fetal growth ultrasound is required, and the pregnancy drug exposure registry must be updated;
Continuous medication use / failure to discontinue medication in mid-to-late pregnancy: Add a series of fetal growth monitoring sessions in late pregnancy;
Strictly monitor weight gain during pregnancy; intensify fetal monitoring for those whose weight gain deviates from guideline ranges;
Conduct GDM screening according to national standards; early glucose screening may be added for those exposed during early pregnancy. - Medication Decisions During Lactation
Individualized risk-benefit assessment: The benefits of breastfeeding are clear, but evidence regarding the long-term safety of medications in breast milk is insufficient;
If medication is necessary during lactation: Closely monitor the infant’s growth and development, as well as the mother’s complete blood count and micronutrient levels, and promptly supplement any vitamin or mineral deficiencies. - Postpartum Medication
For women with a history of GDM, incretin mimetics can effectively promote weight loss and improve glucose tolerance;
The timing of initiation should be determined based on the duration of breastfeeding and plans for future pregnancies; there are currently no uniform standards. - Patient Selection
Priority should be given to women with PCOS, severe obesity, multiple metabolic complications, or those who need to meet BMI eligibility criteria for assisted reproductive technology. - Multidisciplinary Team
Women of childbearing age receiving medication require joint care from endocrinologists, obstetricians, and registered dietitians, with comprehensive follow-up throughout preconception, pregnancy, and the postpartum period.
Gaps in the Evidence and Future Directions
- Preconception Period
Surveys on contraceptive adherence and patient acceptance;
The impact of weight regain and blood glucose fluctuations after discontinuing medication on fertility;
The effect of novel incretins on improving fertility in obese women without PCOS;
Longitudinal studies on the impact of medications on the consumption of key nutrients such as folic acid, iron, and vitamins. - Pregnancy
Human trials on placental transmembrane transport of various drugs;
Dose- and gestational age-specific effects of drugs binding to placental GLP-1 receptors on fetal blood glucose and growth;
Stratified analysis of the association between drug dose and duration of exposure and miscarriage, preterm birth, macrosomia, and congenital anomalies. - Postpartum / Lactation
Quantitative detection of various incretins (including oral formulations) and excipients in breast milk;
Long-term follow-up of breast milk composition in medicated mothers and infant growth and development;
Optimal timing for initiating postpartum medication and its impact on duration of breastfeeding. - General Areas
Survey on training needs for healthcare professionals;
The effectiveness of multidisciplinary collaboration models in improving maternal and infant outcomes;
Qualitative studies incorporating patients’ real-life experiences (currently entirely lacking);
Long-term follow-up cohort study on childhood metabolism in children exposed in utero.
Conclusion
Current human evidence is reassuring: accidental exposure to incretins during early pregnancy does not increase the risk of fetal congenital malformations. Preconception medication use can improve ovulation and pregnancy rates in women with obesity or PCOS and reduce certain adverse pregnancy outcomes. The key unknown risks center on: the optimal washout period for long-acting medications before conception; the safety of medication use throughout pregnancy; the long-term effects of breast milk on infants during lactation; and micronutrient deficiencies resulting from appetite suppression. Clinical practice should adhere to the following core principles: use reliable contraception; discontinue medication immediately upon confirmation of pregnancy; monitor nutrition throughout pregnancy; conduct tiered fetal ultrasound follow-ups; and perform individualized assessments during lactation. There is an urgent need for prospective cohort studies, long-term mother-infant follow-ups, and specialized studies on nutritional interventions to fill the significant gaps in the evidence base and provide women of childbearing age with more precise and safe guidelines for medication use.
References:
Maslin K, Shawe J, Schoenmakers S, et al. Incretin‑Based Medications in Women and Reproduction: A Systematic Scoping Review and Consensus Guidelines for Clinical Practice [J]. Obesity Reviews, 2026, 0: e70203. DOI:10.1111/obr.70203.