Neonatal Risks of Singleton Live Births Following Embryo Transfer in Fresh and Frozen Cycles between Mild Ovarian Stimulation with Clomiphene Citrate and Conventional IVF Protocols: A Real-World Retrospective Study

Abstract Background: Evaluating the efficacy and safety of ovarian stimulation protocols is beneficial for infertile patients undergoing in vitro fertilization (IVF). The mild ovarian stimulation-IVF (m-IVF) protocol using clomiphene citrate is considered to have better neonatal outcomes in fresh cycles; however, few studies have evaluated the neonatal outcomes in frozen-thawed embryo transfer (FET) cycles. Therefore, we aimed to compare the neonatal risks following fresh embryo transfer (ET) and FET between m-IVF and conventional IVF protocols. Methods: The baseline characteristics, treatment, and clinical outcomes of the cohorts from January, 2013 to December, 2020 were compared using propensity score matching analysis. All singleton pregnancies and live births from m-IVF (n = 129 in fresh ET, n = 522 in FET) and long gonadotropin-releasing hormone agonist (GnRH-a; n = 301 in fresh ET, n = 1057 in FET) protocol cycles were analyzed to compare the primary outcomes, including mean birth weight (BW), small for gestational age (SGA), and large for gestational age (LGA). Logistic regression was used to calculate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for SGA and LGA. Results: The mean BW of m-IVF infants was slightly higher than that of conventional IVF infants with fresh ET (P > 0.05). In the FET group, the incidence of SGA (7.85 vs. 4.64%) and LGA (13.79 vs. 18.83%) was significantly different between the m-IVF and long GnRH-a groups (P < 0.05). Further analysis revealed that the occurrence of SGA was related to the stage of embryo transfer (aOR = 0.67, 95% CI = 0.46–0.98) and female infants (aOR = 2.02, 95% CI = 1.38–2.96), and the occurrence of LGA was related to maternal body mass index (BMI; aOR = 1.68, 95% CI = 1.30–2.17 for ≥24 kg/m2), blastocyst transfer (aOR = 1.44, 95% CI = 1.09–1.90), male infants (aOR = 1.84, 95% CI = 1.42–2.38), and FET (aOR = 1.69, 95% CI = 1.12–2.53). Conclusions: SGA was associated with cleavage embryo transfer and female infants, but not with ovarian stimulation protocols. Similarly, LGA was associated with maternal BMI, blastocyst transfer, male infants, and FET, but not with the ovarian stimulation protocols.