Singleton term pregnancies resulting from frozen-thawed embryo transfer in hormone replacement cycles increase the risk of aberrant placentation, including velamentous umbilical cord insertion

Archives of Gynecology and Obstetrics https://doi.org/10.1007/s00404-025-07935-6 MATERNAL-FETAL MEDICINE Singleton term pregnancies resulting from frozen‑thawed embryo transfer in hormone replacement cycles increase the risk of aberrant placentation, including velamentous umbilical cord insertion Satoshi Furuya1,2 · Takashi Yamaguchi2 · Ikuno Ishikawa2 · Makoto Ishikawa2 · Rintaro Kawanami1 · Sayuri Kasano1 · Yuka Shirai1 · Hiroya Yagi1 · Keisuke Kurose1 · Kiyoshi Kubonoya1 Received: 7 August 2024 / Accepted: 2 January 2025 © The Author(s) 2025 Abstract Purpose The number of frozen-thawed embryo transfers (FETs) has recently increased, and FET must be completed in the ovulatory (NC-FET) or programmed hormone replacement cycle (HRC-FET). However, the relationship between FET and abnormal placentation is unclear. This study aimed to determine whether the two distinct endometrial preparation protocols affect the incidence of several pathologic conditions caused by abnormal placentation, such as placenta with velamentous umbilical cord insertion (VCI), hypertensive disorders of pregnancy (HDP), and placenta accreta spectrum (PAS). Methods For this retrospective cohort study, the medical records of 1,161 singleton term FET-conceived and -delivered cases were reviewed from January 2016 to July 2024. The study population was categorized into HRC-FET (Group A: n = 846) and NC-FET (Group B: n = 315) cases. After adjusting for confounding factors, the odds ratios (ORs) of the investigated targeted variables in Group A compared to Group B were calculated using multivariate logistic regression. Results The incidence of VCI and PAS in Groups A and B was 7.0% and 2.5% for VCI and 5.1% and 1.0% for PAS, respectively, with a significant difference (P < 0.01). The adjusted ORs for VCI, PAS, and HDP in Group A compared to those in Group B were 3.07 (P < 0.01), 5.73 (P < 0.01), and 1.24 (P = 0.42), respectively. Conclusion Pregnancies achieved through HRC-FET have higher risks of developing abnormal placentation (i.e., VCI and PAS) than those achieved through NC-FET. These pregnancies are high risk and should be managed carefully for a healthy perinatal course. Keywords Assisted reproductive technology · Endometrial preparation protocol · Placenta accreta spectrum · Hypertensive disorders of pregnancy · Obstetric outcomes What does this study add to the clinical work * Satoshi Furuya 1 Kubonoya Women’s Hospital, 2‑2‑12 Chuou, Kashiwa City, Chiba 277‑0023, Japan 2 Kubonoya IVF Clinic, 2‑5‑14 Kashiwa, Kashiwa City, Chiba 277‑0005, Japan Pregnancies achieved through frozen–thawed embryo transfer (FET) in the hormone replacement cycle have a higher risk of developing abnormal placenta, including velamentous umbilical cord insertion and placenta accreta spectrum, than do pregnancies achieved in the ovulatory cycle. Therefore, the advantages and disadvantages of FET in the alternative endometrial preparation regimen of hormone replacement or the ovulatory cycle should be re-evaluated to ensure safety during the perinatal period. Vol.:(0123456789) Archives of Gynecology and Obstetrics Introduction Methods The transition from slow-freezing techniques to vitrification for embryo and oocyte preservation has marked the advent of a new era in assisted reproductive technology (ART). The primary benefits of vitrification are improved gamete and embryo survival rates, cumulative pregnancy rates, and ART safety through single embryo transfer to avoid multiple gestation [1]. Recently, many completed oocyte retrieval cycles used a “freeze-all” strategy using vitrification to eliminate ovarian hyperstimulation syndrome. These cycles were followed by frozen–thawed embryo transfer (FET). In Japan, over 90% of newborns conceived through ART in 2021 were born following FET [2], and approximately 80% of all egg retrieval cycles started in 2022 in the U.S. used embryo cryopreservation for subsequent FET [3]. Therefore, reappraising the value of FET as a central component in contemporary ART treatment is crucial. FET is a beneficial technique for most patients treated with ART [4]. Pregnancies resulting from FET have advantages over fresh embryo transfer, such as lower risks of preterm birth and small for gestational age (SGA) infants, lower incidence of placenta previa and abruption, and lower perinatal mortality [5–8]. However, FET can also lead to a higher incidence of large for gestational age (LGA) infants, increased risks of hypertensive disorders of pregnancy (HDP), and placenta accreta spectrum (PAS) [5–11]. The pathophysiology of HDP and PAS is examined from the perspective of microscopic abnormal placentation resulting from FET [12–14]. Pregnancies achieved by ART have more macroscopic (morphological) abnormal placentation than unassisted natural pregnancies, typified by a placenta with velamentous umbilical cord insertion (VCI). Additionally, FET is not directly associated with the increased incidence of VCI compared to fresh embryo transfer [15]. However, the relationship between FET and macroscopic abnormal placentation is unclear [16, 17]. Two endometrial preparation protocols exist for the FET cycle: FET in the ovulatory cycle (NC-FET) and the programmed hormone replacement cycle (HRC-FET). Although NC-FET has a higher chance of clinical pregnancy and live birth than HRC-FET [18, 19], HRC-FET is more widely and readily applied than NC-FET because of its convenience for patients and practitioners [20, 21]. Thus, we hypothesized that the difference in endometrial preparation methods in the FET cycle would affect the etiopathogenesis of abnormal placentation such as VCI, HDP, and PAS. This study aimed to determine whether NC-FET and HRC-FET affect the incidence of VCI, HDP, and PAS and to assess the effects of each protocol on prenatal/neonatal outcomes. Study design and ethical approval This observational retrospective cohort study was conducted over 8 years from January 2016 to July 2024, in accordance with Japanese laws and STROBE guidelines. Obtaining informed consent from the patients was waived because this study had an observational retrospective cohort design. The study protocols conformed to the provisions of the Declaration of Helsinki (revised in Tokyo, 2004). The study was approved by the Kubonoya Women’s Hospital Ethics Committee and Review Board, which approved the use of an electronic medical record database for this clinical study (approval no. 2024–1). Setting, participants, and inclusion and exclusion criteria A total of 11,354 consecutive singleton labor and delivery cases managed at Kubonoya Women’s Hospital in Chiba, Japan, were analyzed from the hospital’s obstetric database. From these, only cases conceived via FET (n = 1225) were extracted. All FET cases were referred from other fertility treatment clinics, where the endometrial preparation method for each FET cycle was arbitrarily determined. Detailed ART information, including indications of ART treatment, f (...truncated)