The influence of embryo stage on obstetric complications and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: A systematic review and meta-analysis
Authors: Zhao Zhonghua , Chen Yan , Deng Hongxia , Huang Lu , Lu Danhua , Shen Xiaoyang , Xu Liangzhi 
Published: March 2023

Background
Recent literature has reported that the higher obstetric and perinatal complications in FET may be associated with endometrial preparation protocols. To date, the specific mechanism behind these higher complications is unknown and probably multifactorial. Multiple data indicate that blastocyst transfer led to a better live birth rate than cleavage-stage embryo transfer. Therefore, does the embryo stage at the time of transfer play a role in obstetric and perinatal complications in FET?
Methods
This is a systematic review with meta-analysis. The PubMed, MEDLINE, and EMBASE databases and the Cochrane Central Register of Controlled Trials (CCRT) were searched from 1983 to October 2022. Studies were included only if at least two cohorts underwent programmed-cycle FET versus natural FET cycles and if obstetric and/or perinatal outcomes following programmed cycle FET versus natural FET cycle were reported. The primary outcomes were hypertensive disorders of pregnancy (HDPs), gestational hypertension and preeclampsia (PE). The secondary outcomes were gestational diabetes mellitus (GDM), placenta previa, postpartum haemorrhage (PPH), placental abruption, preterm premature rupture of membranes (PPROM), large for gestational age (LGA), small for gestational age (SGA), macrosomia, and preterm delivery (PTD).
Results
The risk of HDP (14 studies, odds ratio (OR) 2.17; 95% confidence interval (CI) 1.95–2.41; P < 0.00001; I2 = 43%), gestational hypertension (11 studies, OR 1.38; 95% CI 1.15–1.66; P = 0.0006; I2 = 19%), PE (12 studies, OR 2.09; 95% CI 1.88–2.32; P < 0.00001; I2 = 0%), GDM (20 studies, OR 1.09; 95% CI 1.02–1.17; P = 0.02; I2 = 8%), LGA (18 studies, OR 1.11; 95% CI 1.07–1.15; P < 0.00001; I2 = 46%), macrosomia (12 studies, OR 1.15; 95% CI 1.07–1.24; P = 0.0002; I2 = 31%), PTD (22 studies, OR 1.21; 95% CI 1.15–1.27; P < 0.00001; I2 = 49%), placenta previa (17 studies, OR 1.2; 95% CI 1.02–1.41; P = 0.03; I2 = 11%), PPROM (9 studies, OR 1.19; 95% CI 1.02–1.39; P = 0.02; I2 = 40%), and PPH (12 studies, OR 2.27; 95% CI 2.02–2.55; P < 0.00001; I2 = 55%) were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer. Blastocyst transfer had a higher risk of HDP (6 studies, OR 2.48; 95% CI 2.12–2.91; P < 0.00001; I2 = 39%), gestational hypertension (5 studies, OR 1.87; 95% CI 1.27–2.75; P = 0.002; I2 = 25%), PE (6 studies, OR 2.23; 95% CI 1.93–2.56; P < 0.00001; I2 = 0%), GDM (10 studies, OR 1.13; 95% CI 1.04–1.23; P = 0.005; I2 = 39%), LGA (6 studies, OR 1.14; 95% CI 1.07–1.21; P < 0.0001; I2 = 9%), macrosomia (4 studies, OR 1.15; 95% CI 1.05–1.26; P < 0.002; I2 = 68%), PTD (9 studies, OR 1.43; 95% CI 1.31–1.57; P < 0.00001; I2 = 22%), PPH (6 studies, OR 1.92; 95% CI 1.46–2.51; P < 0.00001; I2 = 55%), and PPROM (4 studies, OR 1.45; 95% CI 1.14–1.83; P = 0.002; I2 = 46%) in programmed FET cycles than in natural FET cycles. Cleavage-stage embryo transfers revealed no difference in HDPs (1 study, OR 0.81; 95% CI 0.32–2.02; P = 0.65; I2 not applicable), gestational hypertension (2 studies, OR 0.85; 95% CI 0.48–1.51; P = 0.59; I2 = 0%), PE (1 study, OR 1.19; 95% CI 0.58–2.42; P = 0.64; I2 not applicable), GDM (3 study, OR 0.79; 95% CI 0.52–1.20; P = 0.27; I2 = 21%), LGA (1 study, OR 1.15; 95% CI 0.62–2.11; P = 0.66; I2 not applicable), macrosomia (1 study, OR 1.22; 95% CI 0.54–2.77; P = 0.64; I2 not applicable), PTD (2 studies, OR 1.05; 95% CI 0.74–1.49; P = 0.79; I2 = 0%), PPH (1 study, OR 1.49; 95% CI 0.85–2.62; P = 0.17; I2 not applicable), or PPROM (2 studies, OR 0.74; 95% CI 0.46–1.21; P = 0.23; I2 = 0%) between programmed FET cycles and natural FET cycles.
Conclusions
The risks of HDPs, gestational hypertension, PE, GDM, LGA, macrosomia, SGA, PTD, placenta previa, PPROM, and PPH were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer and blastocyst transfer, but the risks were not clear for cleavage-stage embryo transfer.