Factors Associated with the Incidence of Ectopic Pregnancy in Women Undergoing Assisted Reproductive Treatment
Ectopic pregnancy (EP) is a significant complication in women undergoing assisted reproductive treatment (ART), particularly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). EP occurs when a fertilized embryo implants outside the uterine cavity, most commonly in the fallopian tube. This condition is associated with severe maternal morbidity and, in rare cases, mortality. The incidence of EP following ART is notably higher than in natural conceptions, ranging from 1.6% to 8.6%. Despite extensive research, the underlying causes of EP in ART remain incompletely understood. This study aimed to identify and analyze factors associated with the incidence of EP in women undergoing IVF/ICSI treatment.
The study was conducted as a retrospective analysis of 13,142 IVF/ICSI cycles that resulted in clinical pregnancies between January 1, 2013, and December 31, 2017, at the Assisted Reproduction Unit of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. The primary objective was to explore the relationship between various clinical factors and the incidence of EP. The factors examined included patient age, infertility diagnosis (tubal factor or non-tubal factor), type of infertility (primary or secondary), type of embryo transfer (fresh or frozen-thawed), stage of embryo transferred (cleavage-stage or blastocyst), number of embryos transferred (one, two, or three), previous history of EP, and endometrial combined thickness (ECT).
The study population was divided into two groups based on pregnancy outcome: the EP group and the non-EP group. The EP group included women diagnosed with EP or heterotopic pregnancy, while the non-EP group comprised women with intrauterine pregnancies. Statistical analyses were performed to compare these groups and identify factors significantly associated with EP. Categorical variables were analyzed using the Chi-squared test or Fisher’s exact test, while logistic regression analysis was used to determine the independent predictors of EP.
The overall incidence of EP in the study population was 2.12%, with heterotopic pregnancy accounting for 0.27% of cases. The analysis revealed several significant differences between the EP and non-EP groups. First, the percentage of patients with secondary infertility was significantly higher in the EP group (68.7%) compared to the non-EP group (53.3%). This finding suggests that women with secondary infertility may be at a higher risk of EP following ART. Additionally, the percentage of patients with tubal infertility was significantly higher in the EP group (89.2%) than in the non-EP group (63.6%). Tubal factor infertility, defined as the presence of tubal scarring, occlusion, hydrosalpinx, or previous salpingectomy, was identified as a strong independent predictor of EP in both univariate and multivariate analyses.
The stage of embryo transfer also played a significant role in the incidence of EP. The percentage of cycles involving the transfer of cleavage-stage embryos was significantly higher in the EP group (91.4%) compared to the non-EP group (84.4%). Conversely, blastocyst-stage embryo transfer was associated with a lower risk of EP. This finding aligns with previous studies suggesting that blastocyst transfer reduces the risk of EP compared to cleavage-stage embryo transfer. The speculated mechanism involves decreased uterine contractility during the late luteal phase and the larger size of blastocysts, which may reduce the likelihood of ectopic implantation.
The study also examined the impact of a previous history of EP on the risk of recurrence. Among patients with a history of one to four EPs, the percentage of cleavage-stage embryo transfers was significantly higher in the EP group (92.2%) compared to the non-EP group (77.6%). This suggests that patients with a history of EP may benefit from blastocyst transfer to reduce the risk of recurrence. However, in patients with no previous history of EP, the stage of embryo transfer did not significantly influence the incidence of EP.
Endometrial combined thickness (ECT) was another factor significantly associated with EP. Women with an ECT of less than 9 mm had a higher risk of EP compared to those with an ECT of 12 mm or greater. This finding is consistent with the hypothesis that endometrial receptivity plays a critical role in successful intrauterine implantation. A thinner endometrium may compromise receptivity, increasing the likelihood of ectopic implantation.
The type of embryo transfer (fresh vs. frozen-thawed) and the number of embryos transferred were also analyzed. The study found no significant difference in the incidence of EP between fresh and frozen-thawed embryo transfers. Similarly, the number of embryos transferred (one, two, or three) did not significantly influence the risk of EP. These findings contrast with some previous studies that reported an increased risk of EP with a higher number of embryos transferred. However, the study authors recommend transferring one or two embryos per cycle to minimize the risk of multiple pregnancies and other complications.
Multivariate logistic regression analysis identified tubal infertility, stage of embryo transfer (cleavage vs. blastocyst), previous history of EP, and ECT as independent predictors of EP. Tubal infertility had the strongest association with EP, with an adjusted odds ratio of 3.995. Blastocyst transfer was associated with a reduced risk of EP, particularly in patients with a history of EP. A thinner endometrium (ECT <9 mm) was also significantly associated with an increased risk of EP.
The study has several limitations. As a retrospective analysis, it is subject to potential recall bias. Additionally, the data were collected from a single center, which may limit the generalizability of the findings. The study also did not account for other potential confounding factors, such as the use of ultrasound guidance during embryo transfer or the specific techniques used for ovarian stimulation.
In conclusion, this study highlights the importance of tubal infertility as a key factor in the incidence of EP following ART. Secondary infertility, a history of previous EP, and a thinner endometrium are also associated with an increased risk of EP. Blastocyst transfer, particularly in patients with a history of EP, may reduce the risk of ectopic implantation. These findings underscore the need for individualized treatment strategies to minimize the risk of EP in women undergoing IVF/ICSI. Future research should focus on prospective studies with larger, more diverse populations to further elucidate the factors contributing to EP in ART.
doi.org/10.1097/CM9.0000000000001058
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