Adverse side effects of maternal levothyroxine consumption in pregnant women with subclinical hypothyroidism: a systematic review study

Introduction: Subclinical hypothyroidism (SCH) during pregnancy is a prevalent endocrine disorder, often managed with levothyroxine therapy. Although levothyroxine (LT4) is widely prescribed to mitigate potential risks associated with SCH, concerns persist regarding its safety profile and possible adverse effects on pregnancy outcomes. This systematic review evaluates the current evidence on the adverse maternal, fetal, and neonatal outcomes linked to levothyroxine use in pregnant women diagnosed with SCH. Materials and Methods: This systematic review was conducted on original research studies published between 2015 and 2025 that evaluated the adverse effects of levothyroxine use in pregnant women with SCH. Comprehensive searches were performed across PubMed, Web of Science, Scopus, Embase, Cochrane Library, and Google Scholar. Data extraction was independently performed by two reviewers using a standardized checklist, with a third reviewer resolving any discrepancies. Results: The systematic review encompassed 12 studies totaling 1,952,592 participants (20,010 treated with LT4; 1,932,582 untreated). Preterm labor was the most frequent adverse outcome (reported in six studies), followed by gestational diabetes (three studies). Small-for-gestational-age (SGA) infants, low birth weight (LBW), and preeclampsia each appeared in two studies. Other effects, seizures in children, inadequate gestational weight gain, infant death, premature rupture of membranes, fetal macrosomia, and postpartum hemorrhage, were each noted once. Two studies found no adverse effects. Conclusion: This review study highlights preterm labor as the most common adverse outcome of LT4 use in pregnancy, followed by gestational diabetes. Repeated observations of SGA infants, LBW, and preeclampsia further highlight risks to fetal growth and maternal health. Less common but serious complications, such as seizures, inadequate weight gain, infant death, premature membrane rupture, fetal macrosomia, and postpartum hemorrhage, were each noted once, while two studies found no adverse effects, indicating that risk may depend on study factors, patient populations. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (ID: CRD420251105434) and Research Registry (UIN: reviewregistry2025) websites.