Departments of Physiology and Aging and of Obstetrics and Gynecology, D.H. Barron Reproductive and Perinatal Biology Research Program, University of Florida College of Medicine, Gainesville, FL, USA.
Department of Obstetrics, Gynecology, and Reproductive Medicine, Division of Gynecologic Endocrinology and Reproductive Medicine, Hannover Medical School, Hannover, Germany.
J Assist Reprod Genet. 2024 Apr;41(4):843-859. doi: 10.1007/s10815-024-03042-8. Epub 2024 Mar 27.
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.
Comprehensive review of primary literature.
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.
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.
在两篇相关论文中的第一篇中，我们全面回顾了主要文献中的最新证据，这些证据涉及体外受精妊娠的孕妇中高血压疾病、晚期或足月子痫前期、胎儿过度生长、过期妊娠和胎盘植入的发生率增加。大量证据表明，冷冻胚胎移植周期，特别是采用程序化子宫内膜准备的周期，增加了这些不良母婴妊娠结局的风险。基于对主要文献的批判性评估，我们在第二篇文章中提出了潜在的病因，并提出了预防策略。
对主要文献进行全面回顾。
假设通过程序化自体 FET 周期受孕的患者中这些明显不同的病理性妊娠结局存在显著重叠，可能存在共同的病因。一种合理但显然具有挑衅性的解释是，来自子宫内膜准备不足的异常蜕膜化导致异常的滋养细胞侵袭和子宫螺旋动脉重塑。因此，过度活跃的胎盘形成会产生更大的胎盘和胎儿，进而导致绒毛在子宫腔内的空间拥挤，侵犯绒毛间空间，导致胎盘缺血、氧化和合体滋养层应激，最终导致晚期或足月子痫前期。大多数程序化周期中缺乏循环黄体生成素等因子，如松弛素，可能进一步损害蜕膜化，并加剧母体内皮对有害循环胎盘产物（如可溶性 fms 样酪氨酸激酶-1）的反应，这些产物介导疾病表现。另一个但不是相互排斥的决定因素可能是子宫内膜较薄，这与程序化子宫内膜准备经常相关，这可能与调节不良的蜕膜化一起引起异常的滋养细胞侵袭和子宫螺旋动脉重塑。在极端情况下，胎盘植入可能会发生。虽然在程序化胚胎移植周期中，妊娠早期观察到的子宫动脉阻力和搏动指数较低与这一启动事件一致，但尚未进行定量分析以验证滋养细胞侵袭和子宫螺旋动脉重塑的假说。
子宫内膜准备不理想、缺乏循环黄体生成素或两者兼而有之是很有吸引力的病因；然而，尚未进行证明这些病因所需的必要研究。假设在正在进行的 RCT 中，某些或所有与程序化自体 FET 相关的不良妊娠结局通过采用自然或刺激周期来避免或减轻，那么对于能够使用这些方案受孕的女性来说，这些方案将是首选。对于需要程序化 FET 的 15%左右的女性，需要进行本文中建议的额外研究，以阐明相关机制并制定预防策略。
