Early pregnancy bleeding after assisted reproductive technology: a systematic review and secondary data analysis from 320 patients undergoing hormone replacement therapy frozen embryo transfer

Study question: How common is bleeding in early pregnancy after Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) and does bleeding affect the reproductive outcome?

Summary answer: A total of 47% of HRT-FET patients experience bleeding before the eighth week of gestation, however, bleeding does not affect the reproductive outcome.

What is known already: 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.

Main results and the role of chance: 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.

Wider implications of the findings: 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.

Trial registration number: EudraCT no.: 2019-001539-29.