Safety of Pharmacological Agents Used in Assisted Reproductive Technology: A Comprehensive Systematic Review of Fetal Malformation Risk

Background Assisted reproductive technology (ART) involves pharmacological agents that may raise fetal malformation concerns, yet their teratogenic potential remains uncertain despite widespread use, complicating clinical decisions and patient counseling. Objective To systematically assess fetal malformation risks from ART medications using evidence hierarchy principles for evidence-based safety evaluations. Methods PRISMA-compliant systematic review (PROSPERO CRD 420251118713) using narrative synthesis and selective random-effects meta-analysis for homogeneous studies, searching PubMed, Embase, Cochrane, and others (1990–2025). Included randomized controlled trials (RCTs), cohorts, case-controls, and reviews on ART-conceived pregnancies reporting major/system-specific malformations. Quality assessed via Cochrane Risk of Bias (RoB) 2.0/Newcastle-Ottawa Scale (NOS); certainty via Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results 32 studies (~1.2 million pregnancies) provided high-quality evidence for ART medication safety (pooled OR 1.01 [95% CI 0.92–1.11]; I2=20% vs. natural/alternatives). Gonadotropins (rFSH, hMG, rLH, hCG) showed no increased risk versus natural conception or alternative protocols (OR 1.01 [95% CI 0.92–1.11]; I2=18%; Level I-II from RCTs/meta-analyses). Gonadotropin-releasing hormone (GnRH) agonists/antagonists were comparable to each other (OR 1.03 [95% CI 0.89–1.19]; I2=12%). Progesterone routes (intramuscular (IM)/subcutaneous (SC)/vaginal) demonstrated equivalent safety across administration routes (OR 0.97 [95% CI 0.88–1.07]; I2=25%). Dydrogesterone demonstrated comparable safety to progesterone in RCTs (LOTUS I/II; OR 0.72 [95% CI 0.49–1.05]; I2=15%, no statistically significant difference), overriding lower-level pharmacovigilance/case-control signals. Adjuvants (metformin, letrozole, clomiphene) lacked teratogenicity versus natural conception or alternative treatments (OR 1.04 [95% CI 0.90–1.20]; I2=35%), with varying certainty. Absolute major malformation risk: 2–6%, aligned with adjusted natural conception. Conclusions Strong evidence (high-quality GRADE) supports ART medication safety. For counseling, prioritize RCTs over observational data. Absolute risks are low, but continue surveillance to monitor long-term outcomes. Current standard protocols provide reassurance for patient care.