BACKGROUND Reported increases in maternal and perinatal morbidity (including macrosomia, large for gestational age (LGA), cesarean section, hemorrhage and hypertensive disorders of pregnancy) following frozen embryo transfer (FET) cycles may be associated with the lack of a corpus luteum seen in programmed FET. Given the growing number of studies comparing outcomes between natural FET and programmed FET cycles, a meta-analysis would prove useful to detect the presence of abnormalities in fetal birth weight in patients undergoing natural and programmed FET cycles. OBJECTIVE AND RATIONALE The aim of this study was to provide a systematic review and meta-analysis of the effects of natural versus programmed methods of endometrial preparation for FET cycles on fetal weight and the risks of LGA and macrosomia. SEARCH METHODS A literature search using MEDLINE, SCOPUS, EMBASE and clinicaltrials.gov was conducted for published research comparing neonatal outcomes in natural FET and programmed FET cycles. Primary outcomes of interest were fetal weight, macrosomia and LGA. Studies were included if the following criteria were met: study contained cohorts of NFET and programmed FET with outcome data of birth weight, large for gestational data and/or macrosomia. The data are presented as average weight and odds ratio (OR) with 95% confidence interval (CI) with fixed- or random-effects meta-analysis between cohorts of NFET and programmed FET cycles. Bias was assessed using Newcastle-Ottawa quality assessment scale for the 14 included studies. Multiple subgroup analyses were performed to assess for effect of the true natural cycle (defined as no ovulation trigger medication use) and the day of embryo transfer on fetal weight parameters compared with programmed cycle FET. OUTCOMES A total of 879 studies were identified, with 15 meeting inclusion the criteria. The studies varied with respect to country of origin, definition of natural cycle FET and type of progesterone supplementation used. The included studies had similar gestational ages at the time of birth. Programmed FET cycles resulted in a higher fetal weight compared with natural FET cycles (mean difference 47.38 gp = 0.04). Programmed FET cycles were also at higher risk for macrosomia (OR 1.15, 95% CI 1.06–1.26) and LGA (OR 1.10, 95% CI 1.02–1.19) compared with natural FET cycles. Subgroup analyses demonstrated that programmed FET cycles resulted in a higher fetal weight compared with true natural FET (mean difference 62.18 gp = 0.0001) cycles. Cleavage stage embryo transfers had an increased risk of LGA (OR 1.27, 95% CI 1.00–1.62) and an increased risk of macrosomia (OR 1.25, 95% CI 1.08–1.44) in programmed FET cycles compared with natural FET cycles. Blastocyst transfer in programmed FET cycles resulted in no difference in risk of macrosomia but an increased risk of LGA (OR 1.13, 95% CI 1.06–1.21) compared with natural FET cycles. WIDER IMPLICATIONS Programmed endometrial preparation for FET cycles had a significant effect, causing increased fetal birth weight and increased risks of LGA and macrosomia. The numbers of studies in the subgroup analyses were too low to determine reliable results. Further prospective randomized trials are needed to determine whether the changes seen in the observational trials are indeed accurate.

中文翻译：

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不同冷冻胚胎移植方案对胎儿体重异常的影响：系统评价和荟萃分析

背景 据报道，冷冻胚胎移植 (FET) 周期后孕产妇和围产期发病率（包括巨大儿、大于胎龄 (LGA)、剖宫产、出血和妊娠期高血压疾病）的增加可能与在编程的 FET。鉴于越来越多的研究比较了自然 FET 和程序 FET 周期之间的结果，荟萃分析将被证明有助于检测接受自然和程序 FET 周期的患者是否存在胎儿出生体重异常。目的和基本原理 本研究的目的是对 FET 周期的自然子宫内膜制备方法与程序化子宫内膜制备方法对胎儿体重以及 LGA 和巨大儿风险的影响进行系统回顾和荟萃分析。搜索方法 使用 MEDLINE、SCOPUS、EMBASE 和 Clinicaltrials.gov 对已发表的研究进行文献搜索，比较自然 FET 和程序 FET 周期中的新生儿结局。感兴趣的主要结果是胎儿体重、巨大儿和 LGA。如果满足以下标准，则纳入研究：研究包含 NFET 队列和程序化 FET，其结果数据为出生体重、妊娠数据和/或巨大儿。数据以具有 95% 置信区间 (CI) 的平均体重和优势比 (OR) 呈现，并在 NFET 和程序 FET 周期组之间进行固定或随机效应荟萃分析。使用纽卡斯尔-渥太华质量评估量表评估 14 项纳入研究的偏倚。进行了多个亚组分析，以评估与程序化周期 FET 相比，真正的自然周期（定义为不使用促排卵药物）和胚胎移植日期对胎儿体重参数的影响。结果 共确定了 879 项研究，其中 15 项符合纳入标准。这些研究因原产国、自然循环 FET 的定义和使用的孕酮补充剂类型而异。纳入的研究在出生时具有相似的胎龄。与自然 FET 周期相比，程序 FET 周期导致胎儿体重增加（平均差异 47.38 gp = 0.04）。与自然 FET 周期相比，程序化 FET 周期对于巨大儿（OR 1.15, 95% CI 1.06–1.26）和 LGA（OR 1.10, 95% CI 1.02–1.19）的风险也更高。亚组分析表明，与真正的天然 FET（平均差 62.18 gp = 0.0001）周期相比，程序 FET 周期导致胎儿体重增加。与自然 FET 周期相比，在程序 FET 周期中，卵裂期胚胎移植的 LGA 风险增加（OR 1.27, 95% CI 1.00-1.62）和巨大儿风险增加（OR 1.25, 95% CI 1.08-1.44）。与自然 FET 周期相比，程序化 FET 周期中的囊胚移植导致巨大儿风险没有差异，但 LGA 风险增加（OR 1.13，95% CI 1.06-1.21）。更广泛的影响 FET 周期的程序化子宫内膜制备具有显着效果，导致胎儿出生体重增加以及 LGA 和巨大儿的风险增加。亚组分析中的研究数量太少，无法确定可靠的结果。