Pregnancy outcomes following in vitro fertilization treatment in women with previous recurrent ectopic pregnancy.

Ectopic pregnancy (EP) which accounts for about 1–2% of all spontaneous pregnancies, is the most cause of maternal death during the first trimester of pregnancy [ 1 – 3 ]. With the wide application of assisted reproductive technologies (ART), the incidence of EP trends to increase, occurring in approximately 1.4–3.2% of pregnancies after IVF treatment [ 4 – 6 ]. Compared with patients with no history of EP, patients with a history of EP had a higher risk of recurrent EP after IVF treatment, which ranged from 0.6% to 8.9% in the published studies [ 7 – 9 ]. Previous studies assessing the pregnancy outcomes only focused on women with a previous single EP [ 7 – 10 ]. There are few data on pregnancy outcomes in women with previous recurrent EP who undergoing IVF treatment [ 11 – 14 ]. Moreover, most studies have focused on the risk factors for recurrent EP [ 11 – 13 ], or on optimizing treatment methods to preserve fertility [ 14 ]. Infertile patients, who have a history of recurrent EP, may be particularly worried about future reproductive outcomes including the pregnancy rate and the likelihood of EP after IVF treatment. However, there is little evidence available in the studies to guide physicians in counseling this specific group of women. The aim of this present study was to investigate the impact of a history of single EP and recurrent EP on pregnancy outcomes of subsequent IVF treatment. We also evaluated the effect of the different EP treatments on the incidence of EP.

The characteristics of patients are presented in Table 1 . No significant differences were observed in maternal age, BMI, basal serum FSH, LH and E2 levels, parity, and prevalence of the pelvic inflammatory disease among the groups. The average duration of infertility was significantly longer for women with SEP compared with women with previous REP or IUP (SEP vs. REP: 3.7 ± 3.1 vs.3.4 ± 2.9, P = 0.006; SEP vs. IUP: 3.7 ± 3.1 vs. 3.3 ± 2.7, P < 0.001). Women in IUP group had a significantly higher AFC than those with SEP and REP (IUP vs. SEP: 7.8 ± 4.0 vs. 8.2 ± 3.7, P < 0.001; IUP vs. REP: 8.2 ± 3.7 vs. 7.8 ± 4.2, P < 0.001). In addition, the percentage of tubal factor infertility was significantly higher in SEP and REP groups than in the control group. There was a greater proportion of couples with male factor infertility in the IUP group compared with couples in SEP and REP groups. The infertility factors of ovulatory disorder and endometriosis were similar among the three groups of patients. No statistically significant difference in the proportion of ovarian stimulation protocols among the three groups was observed. The duration of stimulation was significantly shorter in the REP group than in the IUP group (8.4 ± 2.6 vs. 8.7 ± 2.7, P = 0.030). Table 2 shows that women with previous REP had a lower median number of oocytes retrieved (7; range,1–34 vs 8; range, 1–36; P = 0.002) than those in the control group. The percentage of blastocyst transfer in the IUP group was significantly higher than that in the SEP group (32.2% vs. 26.3%, P = 0.004). There was a higher proportion of frozen-thawed cycles in the SEP group compared with those in the IUP group (72.6% vs. 68.0%, P = 0.024). The percentage of double embryo transfer in the IUP group was significantly lower than that in the SEP group (57.1% vs. 65.8%, P < 0.001). Note : Values as mean ± standard deviation or number (%). a We defined the statistical outcomes of SEP group versus REP group as P1; SEP group versus IUP group as P2; REP group versus IUP group as P3. Abbreviations: SEP, single ectopic pregnancy; REP, recurrent ectopic pregnancy; IUP, intrauterine pregnancy; BMI, body mass index; AFC, antral follicle count; PID, pelvic inflammatory disease. Note : Values as median (range) or number (%). a We defined the statistical outcomes of SEP group versus REP group as P1; SEP group versus IUP group as P2; REP group versus IUP group as P3. Abbreviations: SEP, single ectopic pregnancy; REP, recurrent ectopic pregnancy; IUP, intrauterine pregnancy; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection. Pregnancy outcomes of each cohort are summarized in Table 3 . The incidence of EP in the REP group after IVF treatment was significantly lower than those in the SEP group (2.4% vs. 6.8%, P = 0.011), and similar to those in the IUP group (2.4% vs. 2.1%, P = 0.830). There were no significant differences in the clinical pregnancy rate, miscarriage rate, and live birth rate among the three groups. Pregnancy outcomes of each cohort were stratified into the following categories according to maternal age: < 30 years, 30–35 years, and ≥ 35 years. In the subgroups of women aged 30–35 years and ≥ 35 years, women with previous SEP had significant higher rate of EP than those with previous IUP (6.4% vs. 1.1%, P = 0.002; 7.5% vs. 2.5%, P = 0.027, respectively). In the SEP group, 33 cases after embryo transfer had recurrent EP, including two patients with heterotopic pregnancy, 27 patients with tubal pregnancy, one patient with cornual pregnancy, and three patients with cesarean scar pregnancy. In the REP group, 3 cases with recurrent EP after IVF were tube EP, and 3 cases with tube stump. In the IUP group, ectopic pregnancy occurred in 14 cases after embryo transfer, including 12 cases of tubal pregnancy, one case of abdominal pregnancy, and one case of cesarean scar pregnancy. Note : Values as number (%). a We defined the statistical outcomes of SEP group versus REP group as P1; SEP group versus IUP group as P2; REP group versus IUP group as P3. Abbreviations: SEP, single ectopic pregnancy; REP, recurrent ectopic pregnancy; IUP, intrauterine pregnancy; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection. To evaluate the effect of different treatments of previous ectopic pregnancy on the recurrence risk of EP, the patients were categorized into two groups: the salpingectomy group and the salpingostomy group. In the group with a single history of EP, the incidence of recurrent EP was 6.2% for salpingectomy treatment and 8.4% for salpingostomy, and in the previous REP group, 2.3% for salpingectomy and 4.4% for salpingostomy. There was no statistically significant difference in the recurrent EP rate between the two groups. Detailed results are shown in Table 4 . Note : Values as number (%). a Seventy-six patients with clinical pregnancy were excluded because they had experienced both salpingectomy and salpingostomy treatments in their multiple EP conditions. Abbreviations: SEP, single ectopic pregnancy; REP, recurrent ectopic pregnancy; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection. The ORs with 95% CIs of live birth following REP versus the other two types of pregnancy histories are presented in Table 5 . Adjusting for female age, male factor, stimulation protocol, stage of embryos transferred, type of embryos transferred and the number of embryos transferred did not influence live birth rates for women with previous REP compared with women with previous SEP and those with IUP. As shown in Table 6 , after adjusting for maternal and treatment factors that might influence EP, the results indicate that the odds of EP were 82.2% lower (OR 0.178, 95% CI 0.042–0.762; P = 0.020) in women who had blastocyst transfer compared with cleavage embryo transfer in SEP group. The odds of EP were over six times (OR 6.260, 95% CI 1.255–31.220; P = 0.025) in women who underwent double embryo transfer as opposed to single embryo transfer in the IUP group. Abbreviations: SEP, single ectopic pregnancy; REP, recurrent ectopic pregnancy; IUP, intrauterine pregnancy; CI, confidence interval. $ Statistically significant (P = 0.020). *Statistically significant (P = 0.025). Abbreviations: SEP, single ectopic pregnancy; REP, recurrent ectopic pregnancy; IUP, intrauterine pregnancy; CI, confidence interval; REF, reference.

Women with previous recurrent EP had lower risks of EP after IVF treatment compared with women with one history of EP. Previous single EP significantly increased the risk of recurrent EP. No significant differences were observed in the clinical pregnancy rate, miscarriage rate, and live birth rate among the three groups. The salpingostomy and salpingectomy treatments of EP did not influence the incidence of recurrent EP after IVF. The results suggest that closer attention to the EP history of patients undergoing IVF is warranted.

We performed this retrospective cohort study and collected electronic records of women who underwent IVF/ICSI treatments at the Reproductive Medicine Center, Sir Run Run Shaw Hospital between January 2016 and May 2020. The study was approved by the Reproductive Medical Ethics Committee of Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University. The names of patients were not divulged, the requirement for informed consent was therefore waived. Inclusion criteria were infertility women with (1) a history or histories of tubal EP treated by surgery, or intrauterine pregnancy (control group) from a natural pregnancy before IVF treatment, (2) regular menstrual cycle (interval 21–35 days), and (3) undergoing the first fresh or frozen embryo transfer cycle. The exclusion criteria were as follows: (1) the previous EP resulted from ART (IVF/ICSI and related technology), (2) patients with conservative treatment of previous EP, (3) oocyte donor cycles, (4) the cycles of preimplantation genetic diagnosis and screening; and (5) the cycles involving incomplete records. The control group with intrauterine pregnancy was matched to the experimental group using the criteria: (1) age (± 1 year); (2) body mass index; (3) the level of basal serum FSH; (4) presence of male factor infertility; and/or (5) presence of endometriosis or pelvic inflammatory disease. We required exact matching for criteria 1–3, and we attempted to match criteria 4–5 as closely as possible. During the study period, a total of 457 women with a history of recurrent EP (REP group), 912 women with a history of single EP (SEP group), and 1169 women with a history of intrauterine pregnancy (IUP group) as control group were analyzed. To evaluate the effect of the different EP treatments on the incidence of recurrent EP, we further divided into two groups: salpingostomy and salpingectomy treatments. We collected baseline characteristics including maternal age, body mass index, infertility duration, basal serum FSH, LH, and E2 levels, antral follicle count (AFC), cause of infertility, stimulation protocol, duration of stimulation, parity, preexisting condition of pelvic inflammatory disease, methods of EP treatments (salpingectomy or salpingostomy). The evaluated parameters of IVF cycles included the number of oocytes retrieved, methods of fertilization, the normal fertilization rate, stage of embryos transferred, type of embryo transfer, and the number of embryos transferred. As previously described [ 6 ], controlled ovarian hyperstimulation (COH) was performed to maximize follicular response while minimizing the risk of ovarian hyperstimulation syndrome. The dose of gonadotropin (Gonal-F, Serono Laboratories, Aubonne, Switzerland; or Puregon, N.V. Organon, Oss, the Netherlands) was individually adjusted according to female age, weight, day 3 serum FSH value, and antral follicle count. Human chorionic gonadotropin (hCG) (6500–10,000 IU; Serono Laboratories, Modugno, Italy) was administered in patients when three or more follicles reached 16–18 mm or more. Transvaginal ultrasonography-guided oocyte retrieval was performed 35 to 37 hours after the administration of hCG. Conventional IVF or intracytoplasmic sperm injection (ICSI) was used for fertilization. Embryos were cultured individually in sequential media in microdrops under mineral oil. Embryonic development was assessed on day 3, day 5, or day 6 after oocyte retrieval. The fresh embryo transfer took place on day 3, day 5, or day 6 under ultrasound guidance. If the whole embryos were frozen, the thawed embryo transfer occurred in natural cycles or hormone replacement treatment cycles. The number of transferred embryos or blastocysts was based on the Fourth Session of the Committee of Chinese Society of Reproductive Medicine (CSRM) guideline [ 15 ]. Regardless of maternal age and number of transfer cycles, no more than two embryos transferred is recommended. Single ET is suggested when the patient is young and had more than one good-quality embryo. The embryo(s) was/were transferred using a soft catheter (Sydney®, Cook, Melbourne, Australia) under transabdominal ultrasound guidance. Before ET, patients were asked to keep filling of the bladder to facilitate an ultrasound view of the uterine cavity. The catheter was loaded with embryo(s) in a volume of about 10 μl of transfer medium. The embryo(s) was/were replaced approximately 1–1.5 cm from the uterine fundus under ultrasound visualization. After transfer, the catheter was immediately and carefully checked for retained embryos. The definition of EP referred to a pregnancy when the fertilized ovum implants outside the uterine cavity. Heterotopic pregnancy was defined by the co-occurrence of ectopic pregnancy and intrauterine pregnancy. In this study, heterotopic pregnancy was also grouped into EP. Clinical pregnancy was defined as visualization of the gestational sac with fetal heartbeat by transvaginal ultrasound 35 days after embryo transfer. Live birth referred to the delivery of one or more live infants. The miscarriage was defined as spontaneous abortion or intrauterine demise before 24 weeks of gestational age. The EP and miscarriage rates were calculated as per the number of clinical pregnancies. The statistical analysis was conducted in Statistical Package for Social Sciences version 20.0 (SPSS, Chicago, IL, USA). For continuous variables, we presented mean and standard deviation (SD) for symmetrical distribution or median and range (minimum-maximum values) for asymmetrical distributions. The variables were compared with one way ANOVA test or the nonparametric Kruskal-Wallis test depending on whether the data showed a normal distribution. Categorical variables were compared with Pearson’s Chi-squared or Fisher’s exact test based on sample size. Binary logistic regression was used to identify the odds ratio (OR) and 95% confidence interval (CI) for factors independently related to reproductive outcomes. Variables that are believed to influence both histories of ectopic pregnancy and pregnancy outcome were considered potential confounders [ 5 , 9 , 10 ]. These variables included female age, infertility duration, antral follicle count, cause of infertility, stimulation protocols, duration of stimulation, the number of oocytes retrieved, fertilization rate, stage of embryos transferred, type of embryos transferred, and the number of embryos transferred. The result was considered significant if the P-value was <0.05.

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