In Vitro Fertilization-Embryo Transfer in Patients with Unexplained Recurrent Pregnancy Loss
Recurrent pregnancy loss (RPL) is defined as three consecutive spontaneous pregnancy losses (SPLs) before 20 weeks in the same couple under normal circumstances. However, after two SPLs, patients often seek clinical help, leading to the current international consensus that a history of two or more SPLs can be diagnosed as RPL. The causes of RPL are complex and can be broadly divided into maternal and fetal factors. Maternal factors include anatomical abnormalities in the genital tract, a hypercoagulable state, autoimmune diseases, parental chromosomal abnormalities, genetic susceptibility, etc. Fetal factors mainly include fetal chromosomal abnormalities. Approximately 50% of RPLs have no clear causes and are called unexplained recurrent pregnancy loss (URPL).
URPL patients often choose in vitro fertilization (IVF) due to secondary infertility, concern about declining fertility due to advanced age, and an urgent desire to achieve a live birth. Multiple SPLs are regarded as a pathological condition, with possible pathogenesis including low levels of serum folic acid due to mutations in folate metabolism-related genes, abnormal maturation and activation of peripheral blood lymphocyte subsets, and a lack of factors associated with placental vascularization and vascular endothelial cell function maintenance. However, treatments such as anticoagulation, lymphocyte immunotherapy, intravenous immunoglobulin therapy, and pre-implantation genetic testing for aneuploidy (PGT-A) have not been consistently effective and may increase the incidence of adverse reactions. The outcomes of URPL patients undergoing IVF without PGT-A remain unclear, and whether these patients have a poorer assisted reproductive technology prognosis is still unknown.
A retrospective cohort study was designed to address these questions, including 312 infertile patients with URPL treated from January 2012 to December 2015 at the Reproduction Center of Peking University Third Hospital. These patients were compared with those with tubal factor infertility (TFI) to analyze factors affecting clinical outcomes.
The clinical pregnancy rate and live birth rate (LBR) in fresh embryo transfer (ET) cycles were not significantly different between the URPL group and TFI group (35.18% vs. 34.52%, P = 0.877 for clinical pregnancy rate; 27.67% vs. 26.59%, P = 0.785 for LBR). However, the URPL group had a lower LBR in frozen-thawed ET cycles than the TFI group (23.56% vs. 33.56%, P = 0.047). The cumulative LBRs were not significantly different between the two groups (34.69% vs. 38.26%, P = 0.368).
Increased endometrial thickness (EMT) on the human chorionic gonadotropin (HCG) day (odds ratio [OR]: 0.848, 95% confidence interval [CI]: 0.748–0.962, P = 0.010) and the increased number of eggs retrieved (OR: 0.928, 95% CI: 0.887–0.970, P = 0.001) were protective factors for clinical pregnancy in stimulated cycles. The increased number of eggs retrieved (OR: 0.875, 95% CI: 0.846–0.906, P < 0.001), the increased two-pronucleus rate (OR: 0.151, 95% CI: 0.052–0.437, P < 0.001), and increased EMT (OR: 0.876, 95% CI: 0.770–0.997, P = 0.045) on ET day were protective factors for the cumulative live birth outcome.
The study found no significant differences in clinical outcomes between URPL and TFI patients after matching ages. A thicker endometrium and more retrieved oocytes increase the probability of pregnancy in fresh transfer cycles, but a better normal fertilization potential will increase the possibility of a live birth.
The study included 312 stimulation cycles for both URPL and TFI groups. The average ages of the women in the URPL and TFI groups were 35.60 ± 4.80 and 35.51 ± 4.69 years, respectively, with women >35 years accounting for 48.72% of the overall sample in both groups. Baseline characteristics showed no significant differences in age between the two groups, but differences in EMT on the HCG day and sperm density were statistically significant.
In fresh ET cycles, no significant differences were observed in the outcomes between the two groups. Binary logistic regression analysis identified increased EMT on HCG day and the number of eggs retrieved as protective factors for clinical pregnancy in fresh ET cycles. No factors affecting the LBR in fresh ET cycles were found among the included factors.
In frozen-thawed ET cycles, the URPL group had a lower LBR than the TFI group (23.56% vs. 33.56%, P = 0.047). After removing one case of induced labor in the second trimester due to fetal malformations in the URPL group, no significant differences in the outcomes of frozen-thawed ET cycles were identified between the two groups.
The cumulative pregnancy rate and LBR were calculated using the number of patients as the unit. No significant difference in the proportion of patients who did not reach an endpoint was found between the two groups, and both proportions were <6%. Most patients in both groups completed a full cycle, and no significant difference in the cumulative pregnancy rate or LBR was found between these patients.
Binary logistic regression analysis of the cumulative LBR showed that more eggs, a higher two-pronucleus rate, and thicker endometrium on transfer day were associated with an increased cumulative LBR. No risk factors that lowered the cumulative LBR were identified among the included factors.
The study concluded that after matching ages, no significant differences in clinical outcomes were found between URPL and TFI patients. A thicker endometrium and more retrieved oocytes increase the probability of pregnancy in fresh ET cycles, but a better normal fertilization potential will increase the possibility of a live birth.
The study was supported by a grant from the National Science and Technology Major Project of China (No. 2017ZX09304012-012). The authors declared no conflicts of interest.
doi.org/10.1097/CM9.0000000000001657
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