Abstract

Purpose

In the first of two companion papers, we comprehensively reviewed the recent evidence in the primary literature, which addressed the increased prevalence of hypertensive disorders of pregnancy, late-onset or term preeclampsia, fetal overgrowth, postterm birth, and placenta accreta in women conceiving by in vitro fertilization. The preponderance of evidence implicated frozen embryo transfer cycles and, specifically, those employing programmed endometrial preparations, in the higher risk for these adverse maternal and neonatal pregnancy outcomes. Based upon this critical appraisal of the primary literature, we formulate potential etiologies and suggest strategies for prevention in the second article.

Methods

Comprehensive review of primary literature.

Results

Presupposing significant overlap of these apparently diverse pathological pregnancy outcomes within subjects who conceive by programmed autologous FET cycles, shared etiologies may be at play. One plausible but clearly provocative explanation is that aberrant decidualization arising from suboptimal endometrial preparation causes greater than normal trophoblast invasion and myometrial spiral artery remodeling. Thus, overly robust placentation produces larger placentas and fetuses that, in turn, lead to overcrowding of villi within the confines of the uterine cavity which encroach upon intervillous spaces precipitating placental ischemia, oxidative and syncytiotrophoblast stress, and, ultimately, late-onset or term preeclampsia. The absence of circulating corpus luteal factors like relaxin in most programmed cycles might further compromise decidualization and exacerbate the maternal endothelial response to deleterious circulating placental products like soluble fms-like tyrosine kinase-1 that mediate disease manifestations. An alternative, but not mutually exclusive, determinant might be a thinner endometrium frequently associated with programmed endometrial preparations, which could conspire with dysregulated decidualization to elicit greater than normal trophoblast invasion and myometrial spiral artery remodeling. In extreme cases, placenta accreta could conceivably arise. Though lower uterine artery resistance and pulsatility indices observed during early pregnancy in programmed embryo transfer cycles are consistent with this initiating event, quantitative analyses of trophoblast invasion and myometrial spiral artery remodeling required to validate the hypothesis have not yet been conducted.

Conclusions

Endometrial preparation that is not optimal, absent circulating corpus luteal factors, or a combination thereof are attractive etiologies; however, the requisite investigations to prove them have yet to be undertaken. Presuming that in ongoing RCTs, some or all adverse pregnancy outcomes associated with programmed autologous FET are circumvented or mitigated by employing natural or stimulated cycles instead, then for women who can conceive using these regimens, they would be preferable. For the 15% or so of women who require programmed FET, additional research as suggested in this review is needed to elucidate the responsible mechanisms and develop preventative strategies.

中文翻译：

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与程序化胚胎移植相关的病理性孕产妇和新生儿结局：潜在病因和预防策略

摘要

目的

在两篇配套论文的第一篇中，我们全面回顾了主要文献中的最新证据，这些证据涉及妊娠期高血压疾病、迟发型或足月先兆子痫、胎儿过度生长、过期产和植入性胎盘在怀孕妇女中的患病率增加。体外受精。大量证据表明冷冻胚胎移植周期，特别是那些采用程序化子宫内膜准备的周期，导致孕产妇和新生儿不良妊娠结局的风险较高。基于对主要文献的批判性评估，我们在第二篇文章中阐述了潜在的病因并提出了预防策略。

方法

原始文献的综合回顾。

结果

假设通过程序化自​​体 FET 周期受孕的受试者中这些明显不同的病理妊娠结局存在显着重叠，那么共同的病因可能在起作用。一种看似合理但明显具有启发性的解释是，由于子宫内膜准备不充分而引起的异常蜕膜化会导致比正常滋养细胞侵袭和子宫肌层螺旋动脉重塑更大的影响。因此，过于坚固的胎盘会产生较大的胎盘和胎儿，进而导致子宫腔内绒毛过度拥挤，侵犯绒毛间隙，从而引发胎盘缺血、氧化和合体滋养层应激，并最终导致晚发或足月先兆子痫。大多数程序化周期中缺乏循环黄体因子（如松弛素）可能会进一步损害蜕膜化，并加剧母体内皮细胞对有害循环胎盘产物（如介导疾病表现的可溶性 fms 样酪氨酸激酶 1）的反应。另一种但并非相互排斥的决定因素可能是较薄的子宫内膜，通常与程序性子宫内膜准备相关，这可能与失调的蜕膜化共同引发大于正常的滋养层侵袭和子宫肌层螺旋动脉重塑。在极端情况下，可能会出现植入性胎盘。尽管在程序化胚胎移植周期中妊娠早期观察到的较低子宫动脉阻力和搏动指数与这一起始事件一致，但尚未进行验证该假设所需的滋养层侵袭和子宫肌层螺旋动脉重塑的定量分析。

结论

子宫内膜准备不理想、缺乏循环黄体因子或其组合都是有吸引力的病因；然而，尚未进行必要的调查来证明这些情况。假设在正在进行的随机对照试验中，与程序化自体 FET 相关的一些或所有不良妊娠结局可以通过采用自然或刺激周期来规避或减轻，那么对于可以使用这些方案怀孕的女性来说，它们会更好。对于 15% 左右需要编程 FET 的女性，需要进行本综述中建议的额外研究，以阐明责任机制并制定预防策略。