GLP-1 receptor agonists and preconception planning: bridging the gap between obesity treatment and reproductive safety, a narrative review

Abstract

Background:

Obesity and associated metabolic disorders such as type 2 diabetes mellitus and polycystic ovary syndrome are rising globally, contributing to infertility and adverse pregnancy outcomes. This review synthesizes current evidence on pharmacokinetics, safety in preconception and early pregnancy, and clinical management strategies for glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in women of reproductive age. Ethical and health system considerations are also explored to inform clinical practice and highlight future research priorities.

Methods:

A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar identified 132 articles. After screening and full-text review, 9 studies met the inclusion criteria for synthesis.

Results:

Semaglutide (~7 days) and tirzepatide (~5 days) have long half-lives, requiring discontinuation at least 35 days and 25–35 days, respectively, before conception, while liraglutide requires ≥3 days. Human data show no significant increase in congenital anomalies with inadvertent early exposure, although evidence is limited and observational. Alternatives such as metformin, lifestyle modification, and bariatric surgery remain safer options.

Conclusion:

GLP-1 RAs may aid preconception metabolic optimization; however, evidence remains limited and largely observational. Preconception discontinuation timed to each agent’s half-life is prudent to minimize potential fetal exposure. Prospective studies and pregnancy registries are needed to confirm reproductive safety and refine guidance.

Introduction

Obesity prevalence has nearly tripled since 1975, with more than 650 million adults affected worldwide. Women of reproductive age are disproportionately impacted, and obesity is strongly associated with infertility, pregnancy complications, and adverse neonatal outcomes, often mediated by metabolic disorders such as type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome (PCOS)^[1,2,3,4]. In South Asia, rapid urbanization, dietary transitions, and genetic predispositions have driven a surge in obesity and T2DM. In Pakistan, nearly one in five reproductive-age women experiences obesity-related metabolic dysfunction, contributing to infertility, gestational diabetes, and adverse perinatal outcomes^[3,4].

HIGHLIGHTS

• Glucagon-like peptide-1 receptor agonists are effective for managing obesity and polycystic ovary syndrome in reproductive-age women.

• Due to long half-lives, agents like semaglutide and tirzepatide must be discontinued at least 35 days before conception.

• Limited human data suggest no increased risk of major birth defects with early accidental exposure.

• Metformin and lifestyle modifications are the preferred safer alternatives during preconception planning.

• There is an urgent need for clear clinical guidelines and further research to ensure maternal-fetal safety in this growing patient population.

Conventional treatment strategies have had limited success in addressing the metabolic and hormonal disturbances that impair fertility. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as highly effective therapies for weight reduction and glycemic control, and they show promise in improving fertility outcomes in women with obesity and PCOS^[5,6]. Despite these benefits, their use in women planning pregnancy is complicated by uncertainty regarding reproductive safety, the optimal timing of discontinuation, and the most effective alternatives to maintain metabolic health after withdrawal^[7,8].

Given the increasing use of GLP-1 RAs among women of childbearing potential and the lack of standardized guidance, this review synthesizes current evidence on their pharmacokinetics, safety in preconception and early pregnancy, and clinical management strategies. In accordance with the TITAN Guidelines 2025 for ethical use of Artificial Intelligence (AI) in healthcare research, we ensure transparency in methodology and reporting^[9]. Therefore, this review aims to synthesize current evidence on the use of GLP-1 RAs in women planning pregnancy, evaluate emerging safety data, and discuss practical clinical approaches for managing these patients. Ethical and health system considerations are also explored to inform clinical practice and highlight future research priorities.

Methodology

This narrative review was conducted using structured and transparent methods adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, while recognizing that a narrative review does not strictly follow systematic review methodology^[10].

Search strategy

A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar was conducted for studies published up to May 2025, identifying 132 articles. Screening followed PRISMA guidelines (titles/abstracts, then full text) to ensure transparency and reproducibility. The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to “GLP-1 receptor agonists,” “pregnancy,” “preconception,” “obesity,” “polycystic ovary syndrome,” and “reproductive safety,” with Boolean operators (“AND,” “OR”) to maximize retrieval. The full search string was: (“GLP-1 receptor agonist” OR “glucagon-like peptide-1 receptor agonist” OR “semaglutide” OR “liraglutide” OR “tirzepatide”) AND (“pregnancy” OR “preconception” OR “fertility” OR “reproductive health”) AND (“safety” OR “exposure” OR “discontinuation” OR “outcomes”).

Inclusion and exclusion criteria

Studies were eligible if they: (1) reported on the use of GLP-1 RAs in women planning pregnancy, during preconception, or in early pregnancy; (2) provided data on safety, pharmacokinetics, clinical management, or reproductive outcomes; (3) included randomized controlled trials, cohort studies, case-control studies, case series, systematic reviews, meta-analyses, or expert consensus statements; and (4) were published in English. Exclusion criteria included: (1) animal-only studies without translational relevance; (2) non-English publications; and (3) commentaries or editorials without supporting evidence.

Study selection and data extraction

Two independent reviewers screened titles and abstracts using predefined inclusion criteria. Full-text articles were retrieved for studies deemed potentially eligible, and discrepancies were resolved by discussion or consensus with a third reviewer.

Quality assessment

No formal quality scoring tool (e.g., NOS or GRADE) was applied, given the heterogeneity of included study designs. However, each study was qualitatively assessed for methodological soundness, clinical relevance, exposure clarity, and outcome reporting. Only studies judged to be of sufficient rigor were included in the final synthesis.

Data synthesis

Due to heterogeneity in study designs and reported outcomes, a qualitative synthesis was undertaken. Evidence was organized thematically into pharmacokinetics and discontinuation timing, safety of GLP-1 RA exposure in pregnancy, alternative metabolic management strategies, and ethical/clinical considerations.

Search results

A total of 132 relevant articles were identified across PubMed, Google Scholar, Web of Science, and Scopus. After screening titles and abstracts, 48 were retrieved for full-text review. Nine studies met the eligibility criteria and were included in the final synthesis. These studies focused on women planning pregnancy or inadvertently exposed to GLP-1 RAs during early gestation (Table 1).

Table 1.

Summary of included studies

Study (year)	Population	GLP-1 RA studied	Key findings
Drummond et al (2025)[11]	Women with T2DM and/or PCOS; case reports and small cohorts (semaglutide, liraglutide); no direct pregnancy data for tirzepatide	Semaglutide, tirzepatide, liraglutide	Semaglutide: no major congenital anomalies; one case with maternal weight gain, macrosomia, and neonatal hypoglycemia; cohort data show anomaly rates similar to diabetic/obese controls. Tirzepatide: no human data; animal studies show fetal growth restriction and anomalies; long half-life (~5 days) → discontinue ≥25–35 days before conception. Liraglutide: case reports show no major anomalies; one case of transient neonatal hypoglycemia; safe washout ≥3 days before conception. Overall, evidence is cautiously reassuring for semaglutide and liraglutide, but tirzepatide should be avoided until human data are available.
Kolding et al (2025)[12]	104 422 singleton pregnancies in Central Denmark Region; 32 exposed to semaglutide during first trimester (27 Ozempic, 5 Wegovy; many with insulin co-treatment)	Semaglutide	No increased risk of major malformations compared to insulin-exposed or unexposed pregnancies. However, semaglutide exposure was linked to higher risks of preterm birth, large-for-gestational-age (LGA), neonatal hypoglycemia, and jaundice compared to unexposed pregnancies, but outcomes were similar to those in insulin-treated pregnancies. Findings limited by small sample size (n = 32) and confounding from maternal age, BMI, and insulin co-use.
Dao et al (2024)[7]	Pregnant women with accidental exposure	Semaglutide	No significant ↑ difference in major birth defects.
Sharpe et al (2019)[13]	Women exposed in early pregnancy	Various GLP-1 RAs	No link to teratogenicity; fetal monitoring recommended.
Mahapatra et al (2022)[14]	Healthy adults	Semaglutide	Half-life ~7 days; informs discontinuation guidance.
Price and Nankervis (2025)[15]	Women planning pregnancy	GLP-1 RAs (class)	Discontinue ≥5 half-lives preconception.
Saadati et al (2025)[16]	Women with PCOS	GLP-1 RAs vs Metformin	Metformin safe in pregnancy; GLP-1 RA safety less established.
Tang et al (2022)[17]	Adults with T2DM	Tirzepatide	Effective, long half-life (~5 days).
Moran et al (2019)[18]	Women with metabolic syndrome	Lifestyle interventions	Beneficial but often insufficient alone.

CA, congenital anomaly; GLP-1 RA, glucagon-like peptide-1 receptor agonist; PCOS, polycystic ovary syndrome; T2DM, type 2 diabetes mellitus.

Pharmacokinetics and discontinuation timing

Analysis of pharmacokinetic data highlighted significant variability in half-lives across GLP-1 RAs. Semaglutide (~7 days) and tirzepatide (~5 days) demonstrate prolonged half-lives that allow once-weekly dosing but necessitate discontinuation at least 35 and 25–35 days before conception. Liraglutide, with a much shorter half-life (~13 hours), requires daily dosing and may be discontinued 3 days before conception^{[11,17,19–21]}.

Pharmacological guidance recommends discontinuing therapy after at least 5 half-lives to minimize fetal exposure. In clinical practice, many providers adopt a 4- to 6-week washout interval. Tirzepatide, a dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist, has superior metabolic effects compared to GLP-1 RAs (glucagon-like peptide-1 receptor agonist) alone. Still, its unique receptor profile means extrapolation of safety data from other agents should be done with caution (Table 2).

Table 2.

Pharmacokinetics and discontinuation recommendations for GLP-1 RAs

Agent	Half-life	Dosing	Suggested discontinuation interval	Notes
Semaglutide[22,23]	~7 days	Weekly	≥35 days	Long half-life, longer washout needed.
Liraglutide[24,25]	~13 hours	Daily	≥3 days	Shorter half-life, feasible short washout.
Tirzepatide[26,27]	~5 days	Weekly	≥25–35 days	Dual GLP-1/GIP agonist; extrapolation caution.

GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucagon-like peptide-1 receptor agonist.

Safety of GLP-1 RAs during pregnancy

Animal studies consistently demonstrate teratogenic risks at supratherapeutic doses, including skeletal anomalies and fetal growth restriction^[28]. Human evidence, although limited, is more reassuring.

The largest prospective cohort by Dao et al (2024) included 168 pregnancies and found no increased risk of congenital anomalies (CA) or pregnancy loss following first-trimester exposure. Morton and He (2025) described a small retrospective cohort of 13 women exposed to semaglutide; no major anomalies were detected, although one cardiac anomaly and one case of fetal growth restriction occurred. Kuitunen (2024) systematically reviewed two register-based cohorts encompassing 938 pregnancies and similarly found no association between GLP-1 RA exposure and CA, though sample sizes were small and confidence intervals wide.

These findings are further supported by retrospective data from Sharpe et al (2019) and several case series, which consistently reported no significant increase in miscarriage, preterm birth, or CA. Collectively, human data suggest that inadvertent early pregnancy exposure does not significantly increase teratogenic risk. However, small sample sizes, retrospective designs, and lack of long-term child follow-up limit certainty (Table 3)

Table 3.

Alternatives for preconception metabolic management

Therapy	Mechanism	Safety in pregnancy	Benefits	Limitations
Metformin	Insulin sensitizer	Established safety	Improves ovulation and glycemic control	GI(Gastro Intestinal) side effects
Lifestyle (diet + exercise)	Lifestyle modification	Safe	Weight reduction and insulin sensitivity	Variable adherence
SGLT2 inhibitors	Glycosuria induction	Not established	Glycemic control and weight loss	Contraindicated in pregnancy
Bariatric surgery	Surgical weight loss	Safe after stabilization	Sustained weight loss and fertility benefit	Requires delay before conception; multidisciplinary care

Placental transfer and mechanistic insights

Direct human data on placental transfer is unavailable. Given their large molecular size (3–4 kDa), GLP-1 RAs are unlikely to cross the placenta via passive diffusion. Animal studies demonstrate minimal fetal exposure, with adverse effects primarily linked to maternal weight loss and reduced food intake rather than direct drug transfer^[11,28,29].

Experimental models suggest that GLP-1 receptor activation may modulate the hypothalamic–pituitary–gonadal axis by influencing GnRH activity and gonadotropin release. This may restore ovulatory function in PCOS but could also disrupt luteal function upon abrupt withdrawal. While biologically plausible, these mechanisms remain unproven in humans.

Alternatives to GLP-1 RAs in preconception management

When GLP-1 RAs are discontinued, metformin remains the most established alternative, improving insulin sensitivity and ovulatory function with a strong safety record^[30,31]. Lifestyle modification through diet and exercise is safe but often insufficient alone, particularly in women with severe metabolic disease. SGLT2 inhibitors may benefit glycemic control preconceptionally but are contraindicated during pregnancy due to unestablished safety^[11]. Bariatric surgery is effective for sustained weight loss and fertility improvement, though it requires careful timing and multidisciplinary management before conception (Tables 4 and 5).

Table 4.

Human studies on GLP-1 RA exposure in preconception/early pregnancy (detailed design and outcomes)

Study (year)	Country	Design	Sample size	Agent(s)	Exposure timing	Primary outcomes	Secondary outcomes	Key findings	Limitations
Dao et al (2024)[7]	Multinational	Prospective cohort	168	Lira, Sema, Dula, Exe	1st trimester (median 5 weeks exposure)	No ↑ birth defects	No ↑ miscarriage, preterm	Early exposure not associated with anomalies	Limited sample; no long-term follow-up
Morton and He (2025)[32]	Australia	Retrospective cohort	13 (12 T2DM, 1 obesity)	Semaglutide	1st trimester	1 CA (cardiac)	1 FGR, 1 pre-eclampsia	No major anomalies overall	Very small sample; retrospective
Kuitunen (2024)[33]	Finland	Systematic review (2 cohorts)	938	Sema, Dula, Exe, Lira	Preconception –1st trimester	No ↑ CA	No major adverse outcomes	Early exposure not associated with risk	Wide CIs; limited studies
Price and Nankervis (2025)[15]	Australia	Narrative review	NA	Lira, Sema, Exe, Dula	Preconception	No ↑ malformations	No ↑ miscarriage/preterm	Reassuring safety profile	Based on limited studies

CA, congenital anomaly; Dula, dulaglutide; Exe, exenatide; FGR, fetal growth restriction; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Lira, liraglutide; Sema, semaglutide; NA, not applicable.

Table 5.

Human studies on pregnancy outcomes with GLP-1 RA exposure

Study (year)	Country	Design	Population	Agent(s)	Exposure timing	Exposed (n)	Comparator	Main outcomes
Dao et al (2024)[7]	Multicentre (6 TIS databases)	Prospective cohort	Pregnant women with early exposure	Sema (64%), Lira (28%), others (8%)	Conception– ≤12 weeks	168	Matched controls	No ↑ congenital anomalies; miscarriage comparable
Sharpe et al (2019)[13]	UK	Retrospective cohort	Women exposed during early pregnancy	Various GLP-1 RAs	1st trimester	62	Background population	No ↑ miscarriage, preterm birth, or anomalies
Brydon et al (2000)[34]	USA, Europe	Case series	Women with T2DM or obesity	Lira, Exe	Early pregnancy	3–15 per series	None	Mostly healthy outcomes; insufficient to rule out rare events

GLP-1 RA, glucagon-like peptide-1 receptor agonist.

Ethical, clinical, and health system considerations

The reviewed literature emphasizes the ethical dilemmas of balancing maternal metabolic benefits against uncertain fetal risks. Shared decision-making, transparent counseling, and multidisciplinary approaches were consistently recommended. Health system challenges, particularly in low-resource settings, include limited access to alternative therapies, lack of standardized guidelines, and sociocultural barriers to contraceptive use and pregnancy planning.^[11] Policymakers must prioritize equitable access to affordable pharmacotherapies, structured lifestyle programs, and bariatric services, alongside the development of adaptable clinical guidelines.

Comparative appraisal of human evidence

Human evidence on GLP-1 RA exposure in early pregnancy remains limited. Current data suggest no significant increase in CA or pregnancy loss; however, most findings derive from small observational studies, case series, or registries with inherent design limitations. Importantly, no studies have yet addressed long-term neurodevelopmental outcomes in exposed offspring, a critical gap given the rising use of these agents among reproductive-age women.

Prospective cohorts, such as Dao et al, improve validity through standardized definitions, but remain underpowered to detect rare anomalies. Retrospective cohorts provide real-world insights but are limited by confounding, misclassification of exposure timing, and incomplete reporting of early pregnancy losses. Small case series add clinical detail but lack comparators, while registry-based datasets improve sample size and generalizability but often exclude standardized neurodevelopmental outcomes. Collectively, the evidence is cautiously reassuring for major anomalies but insufficient to exclude uncommon risks or provide agent-specific safety estimates.

Practical roadmap and regional gaps

At present, no formal clinical algorithm exists in Saudi Arabia or other regional settings to guide GLP-1 RA management in women planning pregnancy. In practice, clinicians must rely on pharmacokinetic principles and emerging safety data. A pragmatic approach is to discontinue semaglutide (≥35 days) or tirzepatide (25–35 days) before conception and liraglutide ≥3 days prior, transition to safer alternatives such as metformin, and recommend enhanced fetal monitoring in cases of inadvertent exposure. Figure 1 provides a proposed clinical roadmap synthesizing these steps.

Figure 1.

Proposed clinical roadmap for glucagon-like peptide-1 receptor agonist management in women planning pregnancy. A pragmatic approach is illustrated, emphasizing discontinuation timing based on pharmacokinetics, transition to safer alternatives, and enhanced monitoring in cases of inadvertent exposure.

The absence of regional guidelines underscores an urgent need for context-specific recommendations. In South Asia and the Middle East, barriers such as affordability, limited access to structured lifestyle programs, and low uptake of preconception counseling compound the challenge. Tailored guidance developed by local professional societies is essential to improve equity and clinical outcomes.

Despite emerging evidence, several gaps remain. Longitudinal studies assessing neurodevelopmental and metabolic outcomes in offspring are urgently needed. Prospective research should clarify the optimal discontinuation window, balancing maternal stability with fetal safety. Comparative effectiveness studies evaluating transition strategies such as metformin and bariatric surgery would further guide clinical practice. Expansion of pregnancy registries is essential to strengthen the safety evidence base.

Strengths and limitations of current evidence

This review synthesizes multidisciplinary perspectives on GLP-1 RA use in preconception care. Strengths include comprehensive coverage of pharmacokinetics, safety, mechanistic insights, and health system considerations. A key limitation of this review is the absence of a formal risk of bias or quality grading tool, which is typically not required for narrative reviews. Instead, we qualitatively assessed the methodological strengths and weaknesses of the included studies and highlighted these in the synthesis. Future systematic reviews will be needed once larger, higher-quality studies become available. Limitations include reliance on small observational studies, lack of randomized controlled trials, heterogeneity across populations, and potential publication bias. Current recommendations remain provisional and should be individualized to the patient context.

Conclusion

GLP-1 RAs provide significant metabolic benefits but raise important considerations when used around conception. Current evidence suggests no consistent increase in CA or major adverse pregnancy outcomes with inadvertent early exposure, although the available data remain limited and largely observational. Accordingly, these findings should be interpreted with caution. Discontinuation before conception, guided by each drug’s pharmacokinetic profile, remains prudent to minimize potential fetal exposure: approximately ≥35 days for semaglutide (t½ ≈ 7 days), 25–35 days for tirzepatide (t½ ≈ 5 days), and ≥3 days for liraglutide (t½ ≈ 13 h). Alternatives such as metformin, lifestyle modification, and bariatric intervention should be prioritized in preconception care. Given the limited evidence base, these recommendations should be regarded as cautious clinical guidance rather than firm directives. Future prospective studies and pregnancy registries are needed to strengthen the evidence and inform standardized, region-specific practice.

Ethical approval

Ethical approval was not required as no human or animal subjects were involved. This is a narrative review based on previously published studies.

Consent

Informed consent was not required for this narrative review, as no individual patient data or case reports were included.

Sources of funding

None to declare.

Author contributions

A.S.A.: study conception, design, data extraction, analysis, and manuscript writing.

Conflicts of interest disclosure

The author declares there is no conflict of interest to declare.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Abdulrahman Saad Alfaiz.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The data is available from the corresponding author upon reasonable request.