The Fertility Clinic, Skive Regional Hospital, Skive, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Hum Reprod. 2023 Dec 4;38(12):2373-2381. doi: 10.1093/humrep/dead218.
How common is bleeding in early pregnancy after Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) and does bleeding affect the reproductive outcome?
A total of 47% of HRT-FET patients experience bleeding before the eighth week of gestation, however, bleeding does not affect the reproductive outcome.
Bleeding occurs in 20% of spontaneously conceived pregnancies, although most will proceed to term. However, our knowledge regarding bleeding in early pregnancy after HRT-FET and the reproductive outcome is sparse.
STUDY DESIGN, SIZE, DURATION: We performed a systematic review of the existing literature on early pregnancy bleeding after assisted reproductive technology (ART) to evaluate the bleeding prevalence and resulting reproductive outcome in this population. A random-effects proportional meta-analysis was conducted. Subsequently, we performed a prospective cohort study including 320 pregnant patients undergoing HRT-FET and a secondary analysis of the cohort study was performed to evaluate bleeding prevalence and reproductive outcome. The trial was conducted from January 2020 to November 2022 in a public fertility clinic.
PARTICIPANTS/MATERIALS, SETTING, METHODS: A systematic literature search was performed, using MESH terms and included studies with data from ART patients and with early pregnancy bleeding as a separate outcome. The cohort study included patients with autologous vitrified blastocyst transfer treated in an HRT-FET protocol. In the event of a positive HCG-test, an early pregnancy scan was performed around 8 weeks of gestation. During this visit, patients answered a questionnaire regarding bleeding or spotting and its duration after the positive pregnancy test. The information was verified through medical files, and these were used to obtain information on reproductive outcomes.
The review revealed a total of 12 studies of interest. The studies reported a prevalence of early pregnancy bleeding ranging from 2.1% to 36.2%. The random effects proportional meta-analysis resulted in a pooled effect estimate of the prevalence of early pregnancy bleeding in the ART population of 18.1% (95% CI (10.5; 27.1)). Four of the included studies included data on miscarriage rate following an episode of bleeding. All four studies showed a significantly increased risk of miscarriage in patients with early pregnancy bleeding as compared to patients with no history of bleeding. No studies investigated bleeding after HRT-FET specifically. In our HRT-FET cohort study, we found that a total of 47% (149/320) of patients with a positive pregnancy test experienced bleeding before 8 weeks of gestation. Generally, the bleeding was described as spotting with a median of 2 days (range 0.5-16 days). Out of 149 patients with one or several bleeding episodes, a total of 106 patients (71%) had an ongoing pregnancy at 12 weeks of gestation. In comparison, 171 patients reported no bleeding episodes and a total of 115 (67%) of these patients had an ongoing pregnancy at 12 weeks of gestation. This difference was not significant (P = 0.45). Furthermore there was no difference in the live birth rate between the two groups (P = 0.29).
LIMITATIONS, REASONS FOR CAUTION: Most studies included in the review were older and not all studies specified the type of ART. Moreover, the studies were of moderate methodological quality. The patients in the cohort study were treated in a personalized HRT-FET protocol using a rectal supplementary rescue regimen if serum progesterone levels were <35 nmol/l at embryo transfer. The results may not be applicable to other FET protocols, and the present data were based on self-reported symptoms. The systematic review revealed an increased risk of miscarriage following an episode of early pregnancy bleeding. However our cohort study found no such association. This discrepancy can partly be due to the fact, that the four studies in the review only included episodes of heavy bleeding. Also, none of the four studies included data on HRT-FET cycles making them unfit for direct comparison.
Episodes of early bleeding during pregnancy are associated with distress for the pregnant woman, especially in a cohort of infertile patients. Our cohort study showed that at least minor bleeding seems to be a common adverse event of early pregnancy after HRT-FET. From the systematic review, it seems that this prevalence is higher than what has previously been described in relation to other types of ART. However, minor bleeding during early pregnancy after HRT-FET does not seem to affect the reproductive outcome. Knowledge regarding the frequent occurrence of bleeding during early pregnancy after HRT-FET and the fact that this should not be used as a prognostic parameter will help the clinician in counselling patients.
STUDY FUNDING/COMPETING INTEREST(S): Gedeon Richter Nordic supported this investigator-initiated study with an unrestricted grant as well as study medication (Cyclogest). B.A. has received an unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. P.H. received honoraria for lectures from Merck, Gedeon Richter, Institut Biochimique SA (IBSA), and Besins as well as unrestricted research grants from Merck, Gedeon Richter, and Institut Biochimique SA (IBSA). The other authors have no conflict of interest to declare.
EudraCT no.: 2019-001539-29.
激素替代疗法（HRT）冷冻胚胎移植（FET）后早期妊娠出血的发生率是多少，出血是否会影响生殖结局？
47%的 HRT-FET 患者在妊娠 8 周前出现出血，但出血不会影响生殖结局。
虽然大多数自发性妊娠会继续进行，但仍有 20%的妊娠会出现出血。然而，我们对 HRT-FET 后早期妊娠出血和生殖结局的了解还很匮乏。
研究设计、规模、持续时间：我们对辅助生殖技术（ART）中早期妊娠出血的现有文献进行了系统回顾，以评估该人群的出血发生率和生殖结局。我们进行了随机效应比例荟萃分析。随后，我们进行了一项包括 320 名接受 HRT-FET 的妊娠患者的前瞻性队列研究，并对该队列研究进行了二次分析，以评估出血发生率和生殖结局。该试验于 2020 年 1 月至 2022 年 11 月在一家公立生育诊所进行。
参与者/材料、设置、方法：我们使用 MESH 术语进行了系统文献搜索，包括来自 ART 患者的数据和作为单独结局的早期妊娠出血的研究。该队列研究包括接受 HRT-FET 方案治疗的自体冷冻囊胚转移患者。在 HCG 检测阳性后，进行了一次早期妊娠扫描，妊娠 8 周左右进行。在此就诊期间，患者回答了一份关于出血或点滴出血及其在阳性妊娠试验后持续时间的问卷。通过医疗档案核实了这些信息，这些档案用于获取生殖结局的信息。
综述共发现 12 项相关研究。这些研究报告的早期妊娠出血发生率从 2.1%到 36.2%不等。随机效应比例荟萃分析得出的 ART 人群中早期妊娠出血发生率的汇总效应估计值为 18.1%（95%CI（10.5；27.1））。其中 4 项研究包括出血后流产率的数据。这 4 项研究均显示，与无出血史的患者相比，有出血史的患者流产风险显著增加。没有研究专门调查 HRT-FET 后的出血情况。在我们的 HRT-FET 队列研究中，我们发现 320 名接受 HCG 检测阳性的患者中，有 47%（149/320）在妊娠 8 周前出现出血。一般来说，出血被描述为点状出血，中位数为 2 天（范围 0.5-16 天）。在 149 名出现一次或多次出血的患者中，共有 106 名（71%）在 12 周时妊娠仍在继续。相比之下，171 名患者报告没有出血，其中共有 115 名（67%）在 12 周时妊娠仍在继续。这一差异无统计学意义（P=0.45）。此外，两组的活产率无差异（P=0.29）。
局限性、谨慎的原因：综述中纳入的大多数研究较为陈旧，并非所有研究都明确了 ART 的类型。此外，这些研究的方法学质量中等。该队列研究中的患者接受了个性化的 HRT-FET 方案治疗，如果胚胎移植时血清孕酮水平<35 nmol/l，则使用直肠补充救援方案。结果可能不适用于其他 FET 方案，目前的数据基于自我报告的症状。综述显示，早期妊娠出血后流产风险增加，但我们的队列研究并未发现这种关联。这种差异可能部分归因于综述中的四项研究仅包括大量出血的病例。此外，这四项研究均未包括 HRT-FET 周期的数据，因此不适合直接比较。
妊娠早期的出血事件会给孕妇带来困扰，尤其是在不孕患者的队列中。我们的队列研究表明，至少轻微的出血似乎是 HRT-FET 后早期妊娠的常见不良事件。从系统综述来看，这种发生率似乎高于以前在其他类型的 ART 中描述的发生率。然而，HRT-FET 后早期妊娠的轻微出血似乎不会影响生殖结局。对 HRT-FET 后早期妊娠出血频繁发生的认识，以及这种情况不应作为预后参数的事实，将有助于临床医生为患者提供咨询。
研究经费/利益冲突：Gedeon Richter Nordic 为这项由研究者发起的研究提供了资金支持，包括一项无限制赠款和研究药物（Cyclogest）。B.A. 从 Gedeon Richter Nordic 和 Merck 获得了无限制的赠款以及演讲费，来自 Gedeon Richter、Merck、IBSA 和 Marckyrl Pharma 的演讲费。P.H. 获得了 Merck、Gedeon Richter、Institut Biochimique SA（IBSA）和 Besins 的演讲费以及 Merck、Gedeon Richter 和 Institut Biochimique SA（IBSA）的无限制研究赠款。其他作者没有利益冲突需要声明。
EudraCT 编号：2019-001539-29。
