Predictors of small-for-gestational-age infants in gestational diabetes mellitus: the impact of metformin use

Archives of Gynecology and Obstetrics https://doi.org/10.1007/s00404-025-08029-z RESEARCH Predictors of small‑for‑gestational‑age infants in gestational diabetes mellitus: the impact of metformin use Sivan Farladansky‑Gershnabel1,2 · Dina Lidsky‑Sachs1,2 · Nur Abd El Qadir1,2 · Ronny Biton Ram1,2 · Tal Biron‑Shental1,2 · Michal Kovo1,2 · Dorit Ravid1,2 Received: 26 February 2025 / Accepted: 7 April 2025 © The Author(s) 2025 Abstract Introduction Gestational diabetes mellitus (GDM) affects 3%–25% of pregnancies worldwide, posing risks to maternal, fetal, and neonatal health. GDM is often associated with macrosomia and large-for-gestational-age (LGA) infants. However, the association between GDM and small-for-gestational-age (SGA) infants is less understood. This study aimed to identify predictors of SGA in women with GDM. Methods This retrospective study included GDM patients (GDMA1 and A2) admitted to the fetal–maternal unit between 2014 and 2023. The study population was divided into those who delivered an appropriate for gestational age (AGA) neonate and those who delivered an SGA neonate (defined as birthweight < 10th percentile. Women with pregestational diabetes mellitus were excluded. Obstetric and neonatal outcomes were compared between the groups. A subgroup analysis focused on GDMA2 patients, comparing maternal and neonatal outcomes and treatment regimens (insulin and metformin use). Results The study included 894 GDM patients. Compared to the AGA group (n = 712), the SGA group (n = 182) had lower maternal BMI (p = 0.02). Maternal age was comparable between groups. Rates of GDMA2 (30.2% vs. 23.4%, p = 0.07), and hypertensive disorders (7.1% vs. 5%, p = 0.21) did not differ significantly between the groups. The neonatal birthweight of the SGA infants was 2375 ± 432 g vs. 3021 ± 165 g in the AGA infants, (p = 0.005). The SGA group had a higher rate of CD due to NRFHR (27.4% vs. 18.4%, p < 0.01). Among GDMA2 patients (n = 222), more women in the SGA group (n = 55) were treated with metformin as compared to the AGA group (n = 167) (72.7% vs. 23.9%, p < 0.001). Multivariate regression analysis revealed that among GDMA2 patients metformin treatment was independently associated with SGA neonates OR 1.7, CI 1.18–1.35, p < 0.01). Conclusion Metformin use in GDMA2 pregnancies may be linked to SGA neonates. The impact of metformin on fetal growth highlights the need for careful monitoring and individualized treatment strategies in managing GDMA2. Keywords Metformin · GDM · GDMA2 · SGA What does this study add to the clinical work Metformin use in GDMA2 pregnancies was associated with a higher risk of delivering small for gestational age (SGA) infants compared to insulin therapy. These findings support a more individualized approach to pharmacologic management of GDM, particularly in patients with risk factors for fetal growth restriction. * Sivan Farladansky‑Gershnabel 1 Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel 2 Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel Vol.:(0123456789) Archives of Gynecology and Obstetrics Introduction Gestational diabetes mellitus (GDM) represents a significant health challenge, with prevalence rates ranging from 3 to 25%, depending on ethnic composition, diagnostic criteria employed, and underlying population character istics [1, 2]. This metabolic disorder, characterized by glucose intolerance first recognized during pregnancy, carries substantial risks for both maternal and fetal outcomes. Maternal complications include an elevated risk of hypertensive disorders, an increased likelihood of cesarean delivery (CD), and heightened susceptibility to subsequent type 2 diabetes mellitus (T2DM) [3, 4]. The primary fetal complication traditionally associated with GDM has been large-for-gestational-age (LGA) status, a consequence of fetal hyperinsulinemia triggered by maternal hyperglycemia. This condition predisposes infants to various complications, including macrosomia, shoulder dystocia, neonatal hypoglycemia, and long-term metabolic disorders [5]. However, emerging evidence suggests that GDM pregnancies may also result in smallfor-gestational-age (SGA) infants, defined as birthweight below the 10 th percentile for gestational age [6, 7]. SGA infants face their own set of challenges, including respiratory distress, hypoglycemia, neurodevelopmental impairments, and increased risk of metabolic syndrome later in life [8]. When dietary interventions prove insufficient for glycemic control (GDMA1), pharmacological management becomes necessary (GDMA2) [9]. Insulin therapy, traditionally considered the gold standard due to its safety profile and its inability to cross the placental barrier, is recommended as the first-line treatment by several professional organizations, including the American Diabetes Association (ADA) and the American College of Obstetricians and Gynecologists (ACOG) [10, 12]. Alternatively, metformin has gained recognition as a viable treatment option, endorsed by the Society of Maternal–Fetal Medicine (SMFM) as a first-line treatment and by the National Institute for Clinical Excellence (NICE) as an adjunct or alternative to insulin [13, 14]. While metformin offers advantages in terms of administration, cost, and reduction in maternal weight gain, neonatal birth weight, and macrosomia [15, 16], its ability to cross the placental barrier raises questions about potential fetal effects through direct or indirect pathways, independent of glycemic control [17]. The optimal degree of glycemic control in GDMA2 patients remains a subject of debate, particularly concerning SGA risk. While strict glycemic control effectively prevents macrosomia, excessively stringent glucose targets may compromise fetal nutrient availability and growth, potentially contributing to SGA development [18, 19]. This study sought to identify predictive factors associated with SGA births among pregnant women with GDM, addressing an important gap in current maternal–fetal medicine research. Methods Study design and population This retrospective cohort study was conducted using electronic health records from January 2014 to December 2023 of patients who were admitted during their pregnancy to the fetal–maternal unit at Meir Medical Center (MMC) and delivered at MMC. The main reasons for hospitalization included, among others, induction of labor, diabetes management, blood pressure stabilization, fetal monitoring, and observation. Included patients had GDM (A1 and A2) according to American Diabetes Association (ADA) guidelines [10], with a singleton pregnancy. Exclusion criteria included pre-existing diabetes, multiple gestations, and estimated fetal weight above the 90 th percentile. Patients with GDMA2 were managed with either insulin or metformin according to the American College of Obstetricians and Gynecologists (ACOG) guidelines [12] and standardized departmental protocols. The ch (...truncated)