Original Article
Effect of Methotrexate or Salpingectomy for Ectopic Pregnancy on Subsequent In Vitro Fertilization–Embryo Transfer Outcomes Nigel Pereira, MD, Deanna Gerber, MD, Rachel S. Gerber, MD, Jovana P. Lekovich, MD, Rony T. Elias, MD, Steven D. Spandorfer, MD, and Zev Rosenwaks, MD* From the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, New York, NY (all authors).
ABSTRACT Objective: To investigate the effect of methotrexate (MTX) or salpingectomy for ectopic pregnancy on the outcomes of subsequent in vitro fertilization (IVF)–embryo transfer (ET) cycles. Design: Retrospective cohort study (Canadian Task Force Classification II-3). Setting: Academic center. Patients: All patients undergoing fresh IVF-ET between January 2004 and July 2013 after treatment of an ectopic pregnancy with MTX or salpingectomy in the preceding IVF-ET cycle were analyzed for potential inclusion. Intervention: MTX or laparoscopic salpingectomy for an ectopic pregnancy followed by a subsequent IVF-ET cycle. Measurements and Main Results: A total of 144 patients with sonographically confirmed ectopic pregnancies were identified during the study period. Of these, 107 (74.3%) patients were treated with MTX and 37 (25.7%) were treated with laparoscopic salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) patients in the salpingectomy group underwent a subsequent IVF-ET cycle. There were no significant differences in demographic data or baseline cycle characteristics between the 2 groups. No difference was observed in basal follicle-stimulating hormone (FSH) level before and after MTX or salpingectomy treatment. Indicators of ovarian responsiveness, including total days of stimulation, total dosage of gonadotropins, and number of mature oocytes before and after either treatment, were comparable in the 2 groups. The number of doses of MTX (1 vs . 1) did not correlate with changes in ovarian response. The pregnancy outcomes, specifically live birth, were equivalent in the 2 groups. Comparing post-MTX cycles and post-salpingectomy cycles, patients in the latter group required higher doses of gonadotropins (1705 IU vs 1221.5 IU; p , .01), although the number of mature oocytes remained similar in the 2 groups. Conclusion: Treatment of ectopic pregnancies with MTX or salpingectomy might not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. However, in our study cohort, patients treated with MTX, those s treated with laparoscopic salpingectomy required higher gonadotropin doses in a subsequent cycle to attain the same number of mature oocytes. Journal of Minimally Invasive Gynecology (2015) 22, 870–876 Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Ectopic pregnancy; In vitro fertilization; Methotrexate; Outcomes; Ovarian reserve; Salpingectomy
You can discuss this article with its authors and with other AAGL members at http:// www.AAGL.org/jmig-22-5-JMIG-D-15-00154
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
The authors declare no conflicts of interest. Corresponding author: Zev Rosenwaks, MD, Weill Cornell Medical Center, The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, 1305 York Ave, New York, NY 10021. E-mail: [email protected] Submitted March 6, 2015. Accepted for publication April 16, 2015. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2015.04.013
Ectopic pregnancy accounts for approximately 1% to 2% of all pregnancies in the United States [1,2]. In general, risk factors that alter fallopian tube structure or function, such as pelvic inflammatory disease, tubal surgery, and cigarette smoking, increase the risk of ectopic pregnancy [3]. Assisted reproductive techniques, especially in vitro fertilization (IVF), are also thought to increase the risk of ectopic pregnancy [1]. Methotrexate (MTX) and laparoscopic salpingectomy are the most common modalities for medical and
Pereira et al.
Effect of Methotrexate or Salpingectomy on Subsequent IVF Outcomes
surgical management, respectively, of ectopic pregnancies [4,5]. Recent years have seen increasing interest in investigating the effects of MTX and salpingectomy for ectopic pregnancy on ovarian reserve [4–6]. The potential impacts of MTX and salpingectomy on ovarian reserve and ovarian responsiveness are particularly important for patients contemplating subsequent fertility treatments, specifically IVF. To address these questions, we sought to investigate the effect of MTX and salpingectomy for ectopic pregnancy on the outcomes of subsequent IVF cycles at our center. Our investigation also included a subcomparison of IVF outcomes in patients receiving MTX therapy versus those undergoing salpingectomy.
Materials and Methods Cycle Inclusion Criteria The Weill Cornell Medical College Institutional Review Board approved our study protocol. Criteria for inclusion into the study were as follows: (1) The patient underwent a fresh IVF-ET cycle resulting in a sonographically confirmed ectopic pregnancy, (2) was treated with MTX or salpingectomy, and (3) underwent a subsequent fresh IVF-ET cycle within 12 months. Exclusion criteria included donor oocyte cycles, frozen-thawed embryo cycles, pregnancies of unknown location, and combined treatment with MTX and salpingectomy. An ectopic pregnancy was diagnosed in the setting of abnormally rising beta human chorionic gonadotropin (bhCG) levels using transvaginal ultrasonography; sonographic criteria included an extrauterine gestational sac, an adnexal mass with a hypoechoic ring around a gestational sac, and an adnexal mass separate from the ovary [1,7,8]. Patients diagnosed with an ectopic pregnancy ,3.5 cm and bhCG level ,5000 mIU/mL were treated with a 50-mg/m2 dose of MTX [2]. The dose was administered on day 0, after which serial bhCG levels were drawn on days 4 and 7 after treatment. If a 15% drop was noted in the bhCG level between days 4 and 7, treatment was considered successful, and weekly bhCG levels were drawn until negative. A second MTX dose was administered on day 7 if a 15% drop was not observed. All patients treated with MTX were advised to delay pregnancy for at least 3 months after achieving a nonpregnant bhCG level. Patients with an ectopic pregnancy .3.5 cm, fetal cardiac activity, bhCG level .5000 mIU/mL, or significant abdominal pain underwent diagnostic laparoscopy with total salpingectomy. The total salpingectomy was performed by cauterizing the mesosalpinx with a 5-mm LigaSure device (Covidien, Dublin, Ireland) along the entire length of the fallopian tube, beginning at the fimbriated end and running to the cornual end. Care was taken to cauterize the mesosalpinx as close as possible to the fallopian tube, to avoid inadvertent damage to the underlying vascular supply. The proximal end of the fallopian tube was then transected, and the specimen was removed with an endoscopic bag through a 12-mm port. The overall decision to proceed with MTX or laparoscopic salpingectomy was based on the patient’s reproductive history, clinical symptoms, and the attending physician’s discretion. Salpingostomies are not performed routinely at our center.
871
Clinical and Laboratory Protocols Ovarian stimulation, hCG trigger, oocyte retrieval, embryo culture, and ET were performed following standard protocols [9]. Patients were down-regulated in the preceding luteal phase using oral contraceptive pills (Ortho-Novum; Janssen Pharmaceuticals, Beerse, Belgium) or 0.1-mg estradiol (E2) patches (Climara; Bayer Healthcare Pharmaceuticals, Berlin, Germany). Ovarian stimulation was carried out to maximize follicular response while minimizing the risk of ovarian hyperstimulation syndrome. Patients were stimulated with gonadotropins, followed by pituitary suppression with a gonadotropinreleasing hormone antagonist (Ganirelix acetate 0.25 mg [Organon, Oss, The Netherlands] or Cetrotide 0.25 mg [EMD-Serono, Rockland, MA]) based on a flexible protocol as described previously [9]. Gonadotropin doses were based on patient age, weight, antral follicle count, and previous response to stimulation. hCG was used to trigger ovulation in the majority of cycles. Novarel (Ferring Pharmaceuticals, Parsippany, NJ) or Pregnyl (Schering-Plough, Kenilworth, NJ) was administered according to a sliding-scale dosage schedule (10 000 IU for E2 , 1500 pg/mL, 5000 IU for E2 1501–2500 pg/mL, 4000 IU for E2 2501–3000 pg/mL, and 3300 IU for E2 . 3001 pg/mL). In most cycles, the hCG trigger was given when the 2 lead follicles reached a mean diameter of R17 mm. Oocyte retrieval was performed using transvaginal ultrasound guidance under conscious sedation approximately 35 to 37 hours after hCG administration. Luteal support with 50 mg of intramuscular progesterone daily was started on the day after retrieval. IVF was carried out using conventional insemination or intracytoplasmic sperm injection based on the couple’s history. All embryos were cultured using an in-house culture media. Embryo transfers were performed with Wallace catheters (Smiths Medical, St Paul, MN) at approximately 1 cm less than the uterine depth identified at previous trial transfer. Ultrasound guidance was used only when the transfer was deemed difficult based on the previous trial transfer or history of a previous difficult embryo transfer.
Outcome Variables Demographic characteristics analyzed included age, gravidity, parity, body mass index (BMI; kg/m2), ethnicity, infertility diagnosis, and number of previous IVF attempts. IVF cycle characteristics included basal FSH level, basal endometrial stripe thickness (in millimeters), total days of stimulation, total dosage of gonadotropins administered (in international units), peak endometrial stripe thickness (in millimeters), number of oocytes retrieved, number of mature oocytes, number of embryos transferred, and number of surplus embryos cryopreserved. Any pregnancy loss after visualization of an intrauterine gestation was considered a spontaneous miscarriage. Any birth after 24 weeks gestational age was considered a live birth.
Statistical Analyses Categorical variables were expressed as number of cases (n) and percentage of occurrence (%). Continuous variables were checked for normality and expressed as mean 6 standard deviation (SD). The c2 test with Mantzel–Hansel correction and Fisher’s exact test were used for categorical variables. Paired and independent Student t tests were used for continuous variables as appropriate. IVF cycle characteristics before and after treatment with MTX or
872
salpingectomy were analyzed. In addition, the differences in IVF cycle characteristics were compared in the MTX group (D preMTX vs post-MTX) and the salpingectomy group (D presalpingectomy v. postsalpingectomy). Statistical significance was set at p , .05. Based on the study of McLaren et al [10] showing a 22.7% difference (10.1 vs 7.80) in number of oocytes retrieved after MTX therapy, a sample size of 26 patients was estimated assuming an a error of 5% and a power of 80%. All statistical analyses were performed using Stata version 13 (StataCorp, College Station, TX).
Results A total of 144 patients with sonographically confirmed ectopic pregnancy were identified during the study period. Of these, 107 patients (74.3%) were treated with MTX and 37 (25.7%) were treated with salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) in the salpingectomy group underwent a subsequent IVF-ET cycle. Figure 1 summarizes the process of selecting the study cohort. Table 1 compares the baseline demographic characteristics of the study population. There were no significant between-group differences in mean age, gravidity, parity, BMI, ethnicity, number of previous IVF attempts, or distribution of infertility diagnoses. Table 2 compares the characteristics of IVF-ET cycles in patients before and after MTX treatment, and presents the corresponding difference (D) in magnitude. There were no differences in ovarian reserve (as indicated by basal FSH level), in the total days of stimulation, or in the total dosage of gonadotropins. Although fewer oocytes were retrieved in the post-MTX group compared with the pre-MTX group (10.6 6 5.51 vs 12.4 6 5.77; p 5 .03), the number of mature oocytes was comparable in the 2 groups, indicating equivalent ovarian responsiveness. The number of surplus embryos cryopreserved was comparable in the 2 groups. Table 3 compares the baseline and IVF cycle characteristics in patients treated with 1 dose of MTX versus those treated with .1 dose of MTX. No difference in baseline characteristics was noted. As evident from the IVF cycle characteristics, the number of MTX doses (single vs double) did not correlate with changes in ovarian reserve or ovarian responsiveness. Table 4 compares the IVF-ET cycle characteristics of patients before and after salpingectomy and presents the corresponding difference (D) in magnitude. There were no statistically significant differences in basal FSH level, total
Fig. 1 Flow diagram showing selection of study cohort.
Journal of Minimally Invasive Gynecology, Vol 22, No 5, July/August 2015
Table 1 Baseline characteristics of the study cohort (n 5 110)
Parameter Age, yr, mean 6 SD Gravidity, mean 6 SD Parity, mean 6 SD BMI, kg/m2, mean 6 SD Ethnicity, n (%) African American Asian Caucasian Other Infertility diagnosis, n (%) Ovulatory Tubal Endometriosis Male factor Idiopathic Other Previous IVF attempts, mean 6 SD
Pre-MTX (n 5 88)
Presalpingectomy (n 5 22)
p value
37.1 6 4.01 1.12 6 0.63 0.66 6 0.34 23.2 6 4.23
36.4 6 3.03 1.10 6 0.41 0.71 6 0.38 24.0 6 3.65
.45 .89 .19 .55
5 (5.68) 8 (9.09) 71 (80.7) 4 (4.55)
1 (4.55) 2 (9.09) 18 (81.8) 1 (4.55)
.96
.75 29 (32.9) 11 (12.5) 7 (7.95) 22 (23.9) 5 (5.68) 14 (15.9) 2.09 6 0.39
7 (31.8) 3 (13.6) 2 (9.09) 4 (18.1) 1 (4.55) 4 (18.1) 2.05 6 0.58
.70
days of stimulation, number of mature oocytes retrieved, number of embryos transferred, and number of surplus embryos cryopreserved. The postsalpingectomy group required higher doses of gonadotropins (mean, 3126.4 6 1967.5 IU) compared with the presalpingectomy group (mean, 2421.4 6 1468.8 IU), although the difference (1705 IU) was not statistically significant. Table 5 provides a subcomparison of IVF outcomes in patients before and after MTX (D pre-MTX vs post- MTX) versus salpingectomy (D presalpingectomy vs postsalpingectomy). Patients treated with salpingectomy initiated a subsequent IVF cycle sooner than patients treated with MTX (mean, 165.7 6 46.1 days vs 204.7 6 64.3 days; p , .01). Furthermore, patients in the salpingectomy group required higher doses of gonadotropins compared with the MTX group (1705 IU vs 1221.5 IU; p , .01) in the IVF cycle after treatment, although the total days of stimulation and number of mature oocytes retrieved remained the same in both groups. The pregnancy outcomes of IVF-ET cycles after treatment were comparable in the 2 groups, with overall live birth rates of 32.9% in the MTX group and 36.3% in the salpingectomy group. Discussion Our study suggests that IVF cycle outcomes are not compromised by previous treatment of ectopic pregnancies with MTX or salpingectomy, and that neither modality’s use in the preceding cycle adversely affects ovarian reserve
Pereira et al.
Effect of Methotrexate or Salpingectomy on Subsequent IVF Outcomes
873
Table 2 Comparison of IVF cycle characteristics of patients pre-MTX and post-MTX treatment
Parameter
Pre-MTX (n 5 88)
Post-MTX (n 5 88)
p value
D pre-MTX vs post-MTX
Basal FSH level, mIU/mL, mean 6 SD Basal endometrial stripe, mm, mean 6 SD Total stimulation days, mean 6 SD Total gonadotropins, IU, mean 6 SD Peak endometrial stripe, mm, mean 6 SD Number of oocytes retrieved, mean 6 SD Number of mature oocytes, mean 6 SD Number of embryos transferred, mean 6 SD Surplus embryos cryopreserved, mean 6 SD IVF cycle outcome, n (%) Ectopic pregnancy rate Spontaneous miscarriage rate Live birth rate
4.98 6 2.19 3.86 6 0.71 9.55 6 1.99 3286.4 6 1748.3 9.91 6 2.53 12.4 6 5.77 9.75 6 4.45 2.92 6 1.24 0.98 6 0.42
4.87 6 2.97 4.05 6 0.87 9.76 6 2.33 3507.9 6 2090.1 10.4 6 2.15 10.6 6 5.51 8.89 6 4.67 2.95 6 1.38 1.06 6 0.52
.78 .11 .52 .45 .17 .03 .21 .88 .26
20.11 10.19 10.21 1221.5 10.49 21.8 20.86 10.03 10.08
d
d
88 (100) 0 (0) 0 (0)
or ovarian responsiveness in the subsequent cycle. However, we did find that patients treated with salpingectomy required higher doses of gonadotropins in a subsequent IVF-ET cycle compared with those treated with MTX to ultimately attain the same number of mature oocytes. Medical management of ectopic pregnancies with MTX has become increasingly popular [1,2]. MTX is a folate antagonist that targets rapidly dividing cells, most notably the trophoblast cells at the implantation site, by inhibiting the action of dihydrofolate reductase [1,2]. Because MTX can affect rapidly growing cells, there is concern that it may affect proliferating germinal cells in the ovary, thereby impacting folliculogenesis and ovarian reserve [4,5]. These concerns are particularly important in subfertile or infertile patients contemplating subsequent
0 (0) 9 (10.2) 29 (32.9)
fertility treatments. Despite these potential concerns, a majority of studies have shown that treatment of ectopic pregnancies with MTX does not affect ovarian reserve [11–13] or the chance of future conception [14–16]. Furthermore, in the IVF patient population, previous studies have found no difference in ovarian responsiveness or outcomes of IVF-ET cycles after treatment with MTX in a preceding cycle [17,18]. Although the aforementioned results were obtained from studies with relatively small sample sizes, a recent systematic review and meta-analysis by Ohannessian et al [6] confirmed these findings. The effect of MTX, if any, on ovarian reserve and responsiveness may be timedependent. For example, McLaren et al [10] showed that the oocyte yield was lower in patients who underwent
Table 3 Comparison of baseline and IVF cycle characteristics of patients with 1 vs. .1 dose of MTX (n 5 88) Parameter
1 MTX dose (n 5 71)
.1 MTX dose (n 5 17)
p value
Age, yr, mean 6 SD Gravidity, mean 6 SD Parity, mean 6 SD BMI, kg/m2, mean 6 SD Previous IVF attempts, mean 6 SD Basal FSH level, mIU/mL, mean 6 SD Basal endometrial stripe, mm, mean 6 SD Total stimulation days, mean 6 SD Total gonadotropins, IU, mean 6 SD Peak endometrial stripe, mm, mean 6 SD Number of oocytes retrieved, mean 6 SD Number of mature oocytes, mean 6 SD Number of embryos transferred, mean 6 SD Surplus embryos cryopreserved, mean 6 SD
37.2 6 3.87 1.09 6 0.78 0.67 6 0.37 22.8 6 5.31 2.20 6 0.69 5.06 6 2.38 4.14 6 0.78 9.99 6 2.05 3316.7 6 1743.9 10.5 6 2.20 11.1 6 5.79 9.37 6 4.46 2.97 6 1.29 1.02 6 0.41
36.9 6 4.76 1.22 6 0.73 0.70 6 0.32 23.8 6 4.67 1.97 6 0.83 4.77 6 2.74 4.03 6 0.82 9.78 6 1.78 3596.1 6 1830.1 10.3 6 1.69 9.46 6 5.51 7.89 6 4.67 3.05 6 1.06 1.09 6 0.44
.78 .53 .76 .48 .24 .66 .61 .70 .56 .73 .29 .23 .81 .53
874
Journal of Minimally Invasive Gynecology, Vol 22, No 5, July/August 2015
Table 4 Comparison of IVF cycle characteristics of patients presalpingectomy and postsalpingectomy (n 5 22)
Parameter Basal FSH level, mIU/mL, mean 6 SD Basal endometrial stripe, mm, mean 6 SD Total stimulation days, mean 6 SD Total gonadotropins, IU, mean 6 SD Peak endometrial stripe, mm, mean 6 SD Number of oocytes retrieved, mean 6 SD Number of mature oocytes, mean 6 SD Number of embryos transferred, mean 6 SD Surplus embryos cryopreserved, mean 6 SD IVF cycle outcome, n (%) Ectopic pregnancy rate Spontaneous miscarriage rate Live birth rate
Presalpingectomy (n 5 22)
Postsalpingectomy (n 5 22)
p value
D presalpingectomy vs postsalpingectomy
4.81 6 2.75 4.46 6 1.05 9.63 6 2.21 2421.4 6 1468.8 10.8 6 2.51 12.2 6 6.43 10.4 6 4.45 2.86 6 1.19 0.95 6 0.45
4.94 6 2.05 4.31 6 1.11 9.86 6 1.93 3126.4 6 1967.5 11.3 6 2.38 10.2 6 4.23 9.69 6 4.24 2.81 6 1.01 1.01 6 0.32
.62 .65 .32 .18 .28 .23 .41 .85 .83
10.13 20.15 10.23 1705 10.50 22 20.71 20.05 10.06
22 (100) 0 (0) 0 (0)
0 (0) 3 (13.6) 8 (36.3)
d
d
IVF-ET cycles within 180 days of MTX exposure compared with those who did so after 180 days. Consistent with the foregoing findings, the patients in our study cohort underwent IVF-ET cycles at a mean of 204.7 6 64.3 days after treatment with MTX and exhibited no differences in ovarian reserve, ovarian responsiveness, or outcomes in a subsequent cycle. Laparoscopic treatment of an ectopic pregnancy is a safe option that also allows for assessment of pelvic anatomy [2]. Although the ovarian blood supply is primarily from the ovarian artery, some of its supply may arise from the ascending branch of the uterine artery, which traverses the mesosalpinx [19]. Thus, there is a theoretical concern that
salpingectomy can reduce ovarian blood supply and thereby compromise ovarian reserve [20]. A review of the published literature regarding the impact of laparoscopic salpingectomy on ovarian reserve and responsiveness is inconclusive regarding this point. In their retrospective study of 193 women undergoing unilateral salpingectomy, bilateral salpingectomy, or no tubal surgery, Ye et al [20] found that salpingectomy was associated with decreased anti-M€ ullerian hormone (AMH) levels and increased FSH levels in women seeking in vitro fertilization treatment. Similarly, Gelbaya et al [21] showed that women undergoing salpingectomy for hydrosalpinges had higher basal FSH levels, lower antral follicle counts, and fewer oocytes retrieved compared with
Table 5 Comparison of IVF cycle characteristics of patients post-MTX and postsalpingectomy (n 5 110)
Parameter Days between treatment and IVF cycle, mean 6 SD Basal FSH level, mIU/mL, mean Basal endometrial stripe, mm, mean Total stimulation days, mean Total gonadotropins, IU, mean Peak endometrial stripe, mm, mean Number of oocytes retrieved, mean Number of mature oocytes, mean Number of embryos transferred, mean Surplus embryos cryopreserved, mean IVF cycle outcome, n (%) Ectopic pregnancy rate Spontaneous miscarriage rate Live birth rate
D pre-MTX vs post- MTX (n 5 88)
D presalpingectomy vs postsalpingectomy (n 5 22)
204.7 6 64.3
165.7 6 46.1
0.11 0.19 0.21 221.5 0.49 1.8 0.86 0.03 0.08
0.13 0.15 0.23 705 0.50 2 0.71 0.05 0.06
0 (0) 9 (10.2) 29 (32.9)
0 (0) 3 (13.6) 8 (36.3)
p value .01 .40 .10 .40 ,.01 .68 .40 .12 .99 .11 .21
Pereira et al.
Effect of Methotrexate or Salpingectomy on Subsequent IVF Outcomes
women who did not undergo surgery. In contrast, Xi et al [22] reported no differences in basal FSH level, E2 level, total ovarian stimulation days, and number of oocytes retrieved in IVF-ET cycles before and after salpingectomy. Using similar measurements, Wiser et al [4], Hill et al [5], Almog et al [23], Strandell et al [24], and Findley et al [25] also found that salpingectomy does not have a detrimental effect on markers of ovarian reserve or ovarian responsiveness during ovarian stimulation. Despite these conflicting results in ovarian reserve and responsiveness, none of the aforementioned studies showed that salpingectomy affects pregnancy outcomes in subsequent IVF-ET cycles. Although the overall results of our study are consistent with the existing medical literature, few studies to date have compared the before-and-after differences in ovarian reserve, responsiveness, and outcomes of MTX and salpingectomy. In their study of 36 patients treated with MTX and 22 patients treated with salpingectomy, Wiser et al [4] found no statistically significant differences in cycle characteristics or outcomes when comparing pretreatment and posttreatment cycles in both the MTX and salpingectomy group. In contrast to those results, we found that patients in the salpingectomy group required an additional 705 IU after treatment, as opposed to 221.5 IU after treatment in the MTX group; however, the overall days of stimulation and mature oocytes retrieved remained the same. Although it is difficult to ascertain whether these results have a physiological basis, the results may be attributed in part to the lower starting gonadotropin dose in the salpingectomy group compared with the MTX group (2421.4 6 1468.8 vs 3316.7 6 1743.9). Based on the study of McLaren et al [10], it can be postulated that the increase in gonadotropin doses in our study cohort also may be time-dependent. Despite gathering data from 22 993 IVF-ET cycles over a span of 9 years, our study has several limitations. First, only 144 ectopic pregnancies were considered, largely owing to the exclusion of ectopic pregnancies from donor oocyte cycles and frozen-thawed embryo cycles. Our sample size, specifically the salpingectomy group, may be underpowered, albeit slightly. We also excluded pregnancies of unknown location, although it is encouraging to note that our results are in line with those from the study by Hill et al [5] that included both pregnancies of unknown location and ultrasonogram-proven ectopic pregnancies. Second, AMH levels were not used as a marker for ovarian reserve. It has been argued that AMH levels better correlate with the number of early antral follicles compared with other hormonal markers [26], and are more specific than FSH levels for predicting oocyte yield and IVF response [27,28]. However, routine measurement of AMH levels was incorporated into our practice only after 2010. Even then, measuring AMH level is not repeated before initiating a new IVF cycle at our center. Nonetheless even studies that showed lower AMH levels after treatment with MTX or salpingectomy simultaneously showed no
875
difference in oocyte yield after treatment [4,5]. For women undergoing IVF, the quantitative ovarian response to gonadotropins and oocyte yield ultimately reflects ovarian reserve, and thus our overall results are reassuring. Finally, as with any retrospective study, larger prospective studies are needed to validate our findings, particularly as to whether increased doses of gonadotropins are required postsalpingectomy compared to post-MTX treatment. In conclusion, current evidence suggests that treatment of ectopic pregnancies with methotrexate or salpingectomy may not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. The live birth rates in our MTX group (32.9%) and salpingectomy group (36.3%) are slightly higher, but comparable to our center’s overall live birth rate (31.6%) of patients aged 35 to 37. The choice between MTX and salpingectomy, both acceptable management strategies for ectopic pregnancies, should be individualized according to the patient’s clinical symptoms, bhCG level, and reliability with follow-up [2].
References 1. Barnhart KT. Clinical practice: ectopic pregnancy. N Engl J Med. 2009; 361:379–387. 2. Bachman EA, Barnhart K. Medical management of ectopic pregnancy: a comparison of regimens. Clin Obstet Gynecol. 2012;55: 440–447. 3. Barnhart KT, Sammel MD, Gracia CR, Chittams J, Hummel AC, Shaunik A. Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies. Fertil Steril. 2006;86:36–43. 4. Wiser A, Gilbert A, Nahum R, et al. Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy in the subsequent IVF cycle. Reprod Biomed Online. 2013;26:449–453. 5. Hill MJ, Cooper JC, Levy G, et al. Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location. Fertil Steril. 2014;101: 413–419. 6. Ohannessian A, Loundou A, Courbiere B, Cravello L, Agostini A. Ovarian responsiveness in women receiving fertility treatment after methotrexate for ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod. 2014;29:1949–1956. 7. Condous G, Okaro E, Khalid A, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod. 2005;20:1404–1409. 8. Kirk E, Papageorghiou AT, Condous G, Tan L, Bora S, Bourne T. The diagnostic effectiveness of an initial transvaginal scan in detecting ectopic pregnancy. Hum Reprod. 2007;22:2824–2828. 9. Reichman DE, Chung P, Meyer L, Greenwood E, Davis O, Rosenwaks Z. Consecutive gonadotropin-releasing hormone-antagonist in vitro fertilization cycles: does the elapsed time interval between successive treatments affect outcomes? Fertil Steril. 2013;99: 1277–1282. 10. McLaren JF, Burney RO, Milki AA, Westphal LM, Dahan MH, Lathi RB. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil Steril. 2009; 92:515–519. 11. Oriol B, Barrio A, Pacheco A, Serna J, Zuzuarregui JL, GarciaVelasco JA. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril. 2008;90:1579–1582. 12. Uyar I, Yucel OU, Gezer C, et al. Effect of single-dose methotrexate on ovarian reserve in women with ectopic pregnancy. Fertil Steril. 2013; 100:1310–1313.
876 13. Xiao C, Dahan MH. The effect of methotrexate injection for treatment of an ectopic pregnancy on ovarian reserve [letter]. Fertil Steril. 2014; 101. e23. 14. Gervaise A, Masson L, de Tayrac R, Frydman R, Fernandez H. Reproductive outcome after methotrexate treatment of tubal pregnancies. Fertil Steril. 2004;82:304–308. 15. Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod. 2013;28:1247–1253. 16. Buster JE, Krotz S. Reproductive performance after ectopic pregnancy. Semin Reprod Med. 2007;25:131–133. 17. Boots CE, Gustofson RL, Feinberg EC. Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness? Fertil Steril. 2013;100:1590–1593. 18. Orvieto R, Kruchkovich J, Zohav E, Rabinson J, Anteby EY, Meltcer S. Does methotrexate treatment for ectopic pregnancy influence the patient’s performance during a subsequent in vitro fertilization/embryo transfer cycle? Fertil Steril. 2007;88:1685–1686. 19. Sezik M, Ozkaya O, Demir F, Sezik HT, Kaya H. Total salpingectomy during abdominal hysterectomy: effects on ovarian reserve and ovarian stromal blood flow. J Obstet Gynaecol Res. 2007;33:863–869. 20. Ye XP, Yang YZ, Sun XX. A retrospective analysis of the effect of salpingectomy on serum anti-M€ullerian hormone level and ovarian reserve. Am J Obstet Gynecol. 2015;212:53.e1–53.e10. 21. Gelbaya TA, Nardo LG, Fitzgerald CT, Horne G, Brison DR, Lieberman BA. Ovarian response to gonadotropins after laparoscopic
Journal of Minimally Invasive Gynecology, Vol 22, No 5, July/August 2015
22.
23.
24.
25.
26.
27.
28.
salpingectomy or the division of fallopian tubes for hydrosalpinges. Fertil Steril. 2006;85:1464–1468. Xi W, Gong F, Tang Y, Zhang H, Lu G. Ovarian response to gonadotropins after laparoscopic salpingectomy for ectopic pregnancy. Int J Gynaecol Obstet. 2012;116:93–96. Almog B, Wagman I, Bibi G, et al. Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal. Fertil Steril. 2011;95:2474–2476. Strandell A, Lindhard A, Waldenstr€om U, Thorburn J. Prophylactic salpingectomy does not impair the ovarian response in IVF treatment. Hum Reprod. 2001;16:1135–1139. Findley AD, Siedhoff MT, Hobbs KA, et al. Short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial. Fertil Steril. 2013;100: 1704–1708. Fanchin R, Schon€auer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-M€ullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod. 2003;18:323–327. Barad DH, Weghofer A, Gleicher N. Comparing anti-M€ullerian hormone (AMH) and follicle-stimulating hormone (FSH) as predictors of ovarian function. Fertil Steril. 2009;91(4 Suppl):1553–1555. Nardo LG, Gelbaya TA, Wilkinson H, et al. Circulating basal antiM€ullerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization. Fertil Steril. 2009;92:1586–1593.
Effect of Methotrexate or Salpingectomy for Ectopic Pregnancy on Subsequent In Vitro Fertilization–Embryo Transfer Outcomes Nigel Pereira, MD, Deanna Gerber, MD, Rachel S. Gerber, MD, Jovana P. Lekovich, MD, Rony T. Elias, MD, Steven D. Spandorfer, MD, and Zev Rosenwaks, MD* From the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, New York, NY (all authors).
ABSTRACT Objective: To investigate the effect of methotrexate (MTX) or salpingectomy for ectopic pregnancy on the outcomes of subsequent in vitro fertilization (IVF)–embryo transfer (ET) cycles. Design: Retrospective cohort study (Canadian Task Force Classification II-3). Setting: Academic center. Patients: All patients undergoing fresh IVF-ET between January 2004 and July 2013 after treatment of an ectopic pregnancy with MTX or salpingectomy in the preceding IVF-ET cycle were analyzed for potential inclusion. Intervention: MTX or laparoscopic salpingectomy for an ectopic pregnancy followed by a subsequent IVF-ET cycle. Measurements and Main Results: A total of 144 patients with sonographically confirmed ectopic pregnancies were identified during the study period. Of these, 107 (74.3%) patients were treated with MTX and 37 (25.7%) were treated with laparoscopic salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) patients in the salpingectomy group underwent a subsequent IVF-ET cycle. There were no significant differences in demographic data or baseline cycle characteristics between the 2 groups. No difference was observed in basal follicle-stimulating hormone (FSH) level before and after MTX or salpingectomy treatment. Indicators of ovarian responsiveness, including total days of stimulation, total dosage of gonadotropins, and number of mature oocytes before and after either treatment, were comparable in the 2 groups. The number of doses of MTX (1 vs . 1) did not correlate with changes in ovarian response. The pregnancy outcomes, specifically live birth, were equivalent in the 2 groups. Comparing post-MTX cycles and post-salpingectomy cycles, patients in the latter group required higher doses of gonadotropins (1705 IU vs 1221.5 IU; p , .01), although the number of mature oocytes remained similar in the 2 groups. Conclusion: Treatment of ectopic pregnancies with MTX or salpingectomy might not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. However, in our study cohort, patients treated with MTX, those s treated with laparoscopic salpingectomy required higher gonadotropin doses in a subsequent cycle to attain the same number of mature oocytes. Journal of Minimally Invasive Gynecology (2015) 22, 870–876 Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Ectopic pregnancy; In vitro fertilization; Methotrexate; Outcomes; Ovarian reserve; Salpingectomy
You can discuss this article with its authors and with other AAGL members at http:// www.AAGL.org/jmig-22-5-JMIG-D-15-00154
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
The authors declare no conflicts of interest. Corresponding author: Zev Rosenwaks, MD, Weill Cornell Medical Center, The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, 1305 York Ave, New York, NY 10021. E-mail: [email protected] Submitted March 6, 2015. Accepted for publication April 16, 2015. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2015.04.013
Ectopic pregnancy accounts for approximately 1% to 2% of all pregnancies in the United States [1,2]. In general, risk factors that alter fallopian tube structure or function, such as pelvic inflammatory disease, tubal surgery, and cigarette smoking, increase the risk of ectopic pregnancy [3]. Assisted reproductive techniques, especially in vitro fertilization (IVF), are also thought to increase the risk of ectopic pregnancy [1]. Methotrexate (MTX) and laparoscopic salpingectomy are the most common modalities for medical and
Pereira et al.
Effect of Methotrexate or Salpingectomy on Subsequent IVF Outcomes
surgical management, respectively, of ectopic pregnancies [4,5]. Recent years have seen increasing interest in investigating the effects of MTX and salpingectomy for ectopic pregnancy on ovarian reserve [4–6]. The potential impacts of MTX and salpingectomy on ovarian reserve and ovarian responsiveness are particularly important for patients contemplating subsequent fertility treatments, specifically IVF. To address these questions, we sought to investigate the effect of MTX and salpingectomy for ectopic pregnancy on the outcomes of subsequent IVF cycles at our center. Our investigation also included a subcomparison of IVF outcomes in patients receiving MTX therapy versus those undergoing salpingectomy.
Materials and Methods Cycle Inclusion Criteria The Weill Cornell Medical College Institutional Review Board approved our study protocol. Criteria for inclusion into the study were as follows: (1) The patient underwent a fresh IVF-ET cycle resulting in a sonographically confirmed ectopic pregnancy, (2) was treated with MTX or salpingectomy, and (3) underwent a subsequent fresh IVF-ET cycle within 12 months. Exclusion criteria included donor oocyte cycles, frozen-thawed embryo cycles, pregnancies of unknown location, and combined treatment with MTX and salpingectomy. An ectopic pregnancy was diagnosed in the setting of abnormally rising beta human chorionic gonadotropin (bhCG) levels using transvaginal ultrasonography; sonographic criteria included an extrauterine gestational sac, an adnexal mass with a hypoechoic ring around a gestational sac, and an adnexal mass separate from the ovary [1,7,8]. Patients diagnosed with an ectopic pregnancy ,3.5 cm and bhCG level ,5000 mIU/mL were treated with a 50-mg/m2 dose of MTX [2]. The dose was administered on day 0, after which serial bhCG levels were drawn on days 4 and 7 after treatment. If a 15% drop was noted in the bhCG level between days 4 and 7, treatment was considered successful, and weekly bhCG levels were drawn until negative. A second MTX dose was administered on day 7 if a 15% drop was not observed. All patients treated with MTX were advised to delay pregnancy for at least 3 months after achieving a nonpregnant bhCG level. Patients with an ectopic pregnancy .3.5 cm, fetal cardiac activity, bhCG level .5000 mIU/mL, or significant abdominal pain underwent diagnostic laparoscopy with total salpingectomy. The total salpingectomy was performed by cauterizing the mesosalpinx with a 5-mm LigaSure device (Covidien, Dublin, Ireland) along the entire length of the fallopian tube, beginning at the fimbriated end and running to the cornual end. Care was taken to cauterize the mesosalpinx as close as possible to the fallopian tube, to avoid inadvertent damage to the underlying vascular supply. The proximal end of the fallopian tube was then transected, and the specimen was removed with an endoscopic bag through a 12-mm port. The overall decision to proceed with MTX or laparoscopic salpingectomy was based on the patient’s reproductive history, clinical symptoms, and the attending physician’s discretion. Salpingostomies are not performed routinely at our center.
871
Clinical and Laboratory Protocols Ovarian stimulation, hCG trigger, oocyte retrieval, embryo culture, and ET were performed following standard protocols [9]. Patients were down-regulated in the preceding luteal phase using oral contraceptive pills (Ortho-Novum; Janssen Pharmaceuticals, Beerse, Belgium) or 0.1-mg estradiol (E2) patches (Climara; Bayer Healthcare Pharmaceuticals, Berlin, Germany). Ovarian stimulation was carried out to maximize follicular response while minimizing the risk of ovarian hyperstimulation syndrome. Patients were stimulated with gonadotropins, followed by pituitary suppression with a gonadotropinreleasing hormone antagonist (Ganirelix acetate 0.25 mg [Organon, Oss, The Netherlands] or Cetrotide 0.25 mg [EMD-Serono, Rockland, MA]) based on a flexible protocol as described previously [9]. Gonadotropin doses were based on patient age, weight, antral follicle count, and previous response to stimulation. hCG was used to trigger ovulation in the majority of cycles. Novarel (Ferring Pharmaceuticals, Parsippany, NJ) or Pregnyl (Schering-Plough, Kenilworth, NJ) was administered according to a sliding-scale dosage schedule (10 000 IU for E2 , 1500 pg/mL, 5000 IU for E2 1501–2500 pg/mL, 4000 IU for E2 2501–3000 pg/mL, and 3300 IU for E2 . 3001 pg/mL). In most cycles, the hCG trigger was given when the 2 lead follicles reached a mean diameter of R17 mm. Oocyte retrieval was performed using transvaginal ultrasound guidance under conscious sedation approximately 35 to 37 hours after hCG administration. Luteal support with 50 mg of intramuscular progesterone daily was started on the day after retrieval. IVF was carried out using conventional insemination or intracytoplasmic sperm injection based on the couple’s history. All embryos were cultured using an in-house culture media. Embryo transfers were performed with Wallace catheters (Smiths Medical, St Paul, MN) at approximately 1 cm less than the uterine depth identified at previous trial transfer. Ultrasound guidance was used only when the transfer was deemed difficult based on the previous trial transfer or history of a previous difficult embryo transfer.
Outcome Variables Demographic characteristics analyzed included age, gravidity, parity, body mass index (BMI; kg/m2), ethnicity, infertility diagnosis, and number of previous IVF attempts. IVF cycle characteristics included basal FSH level, basal endometrial stripe thickness (in millimeters), total days of stimulation, total dosage of gonadotropins administered (in international units), peak endometrial stripe thickness (in millimeters), number of oocytes retrieved, number of mature oocytes, number of embryos transferred, and number of surplus embryos cryopreserved. Any pregnancy loss after visualization of an intrauterine gestation was considered a spontaneous miscarriage. Any birth after 24 weeks gestational age was considered a live birth.
Statistical Analyses Categorical variables were expressed as number of cases (n) and percentage of occurrence (%). Continuous variables were checked for normality and expressed as mean 6 standard deviation (SD). The c2 test with Mantzel–Hansel correction and Fisher’s exact test were used for categorical variables. Paired and independent Student t tests were used for continuous variables as appropriate. IVF cycle characteristics before and after treatment with MTX or
872
salpingectomy were analyzed. In addition, the differences in IVF cycle characteristics were compared in the MTX group (D preMTX vs post-MTX) and the salpingectomy group (D presalpingectomy v. postsalpingectomy). Statistical significance was set at p , .05. Based on the study of McLaren et al [10] showing a 22.7% difference (10.1 vs 7.80) in number of oocytes retrieved after MTX therapy, a sample size of 26 patients was estimated assuming an a error of 5% and a power of 80%. All statistical analyses were performed using Stata version 13 (StataCorp, College Station, TX).
Results A total of 144 patients with sonographically confirmed ectopic pregnancy were identified during the study period. Of these, 107 patients (74.3%) were treated with MTX and 37 (25.7%) were treated with salpingectomy. Eighty-eight patients (82.2%) in the MTX group and 22 patients (59.4%) in the salpingectomy group underwent a subsequent IVF-ET cycle. Figure 1 summarizes the process of selecting the study cohort. Table 1 compares the baseline demographic characteristics of the study population. There were no significant between-group differences in mean age, gravidity, parity, BMI, ethnicity, number of previous IVF attempts, or distribution of infertility diagnoses. Table 2 compares the characteristics of IVF-ET cycles in patients before and after MTX treatment, and presents the corresponding difference (D) in magnitude. There were no differences in ovarian reserve (as indicated by basal FSH level), in the total days of stimulation, or in the total dosage of gonadotropins. Although fewer oocytes were retrieved in the post-MTX group compared with the pre-MTX group (10.6 6 5.51 vs 12.4 6 5.77; p 5 .03), the number of mature oocytes was comparable in the 2 groups, indicating equivalent ovarian responsiveness. The number of surplus embryos cryopreserved was comparable in the 2 groups. Table 3 compares the baseline and IVF cycle characteristics in patients treated with 1 dose of MTX versus those treated with .1 dose of MTX. No difference in baseline characteristics was noted. As evident from the IVF cycle characteristics, the number of MTX doses (single vs double) did not correlate with changes in ovarian reserve or ovarian responsiveness. Table 4 compares the IVF-ET cycle characteristics of patients before and after salpingectomy and presents the corresponding difference (D) in magnitude. There were no statistically significant differences in basal FSH level, total
Fig. 1 Flow diagram showing selection of study cohort.
Journal of Minimally Invasive Gynecology, Vol 22, No 5, July/August 2015
Table 1 Baseline characteristics of the study cohort (n 5 110)
Parameter Age, yr, mean 6 SD Gravidity, mean 6 SD Parity, mean 6 SD BMI, kg/m2, mean 6 SD Ethnicity, n (%) African American Asian Caucasian Other Infertility diagnosis, n (%) Ovulatory Tubal Endometriosis Male factor Idiopathic Other Previous IVF attempts, mean 6 SD
Pre-MTX (n 5 88)
Presalpingectomy (n 5 22)
p value
37.1 6 4.01 1.12 6 0.63 0.66 6 0.34 23.2 6 4.23
36.4 6 3.03 1.10 6 0.41 0.71 6 0.38 24.0 6 3.65
.45 .89 .19 .55
5 (5.68) 8 (9.09) 71 (80.7) 4 (4.55)
1 (4.55) 2 (9.09) 18 (81.8) 1 (4.55)
.96
.75 29 (32.9) 11 (12.5) 7 (7.95) 22 (23.9) 5 (5.68) 14 (15.9) 2.09 6 0.39
7 (31.8) 3 (13.6) 2 (9.09) 4 (18.1) 1 (4.55) 4 (18.1) 2.05 6 0.58
.70
days of stimulation, number of mature oocytes retrieved, number of embryos transferred, and number of surplus embryos cryopreserved. The postsalpingectomy group required higher doses of gonadotropins (mean, 3126.4 6 1967.5 IU) compared with the presalpingectomy group (mean, 2421.4 6 1468.8 IU), although the difference (1705 IU) was not statistically significant. Table 5 provides a subcomparison of IVF outcomes in patients before and after MTX (D pre-MTX vs post- MTX) versus salpingectomy (D presalpingectomy vs postsalpingectomy). Patients treated with salpingectomy initiated a subsequent IVF cycle sooner than patients treated with MTX (mean, 165.7 6 46.1 days vs 204.7 6 64.3 days; p , .01). Furthermore, patients in the salpingectomy group required higher doses of gonadotropins compared with the MTX group (1705 IU vs 1221.5 IU; p , .01) in the IVF cycle after treatment, although the total days of stimulation and number of mature oocytes retrieved remained the same in both groups. The pregnancy outcomes of IVF-ET cycles after treatment were comparable in the 2 groups, with overall live birth rates of 32.9% in the MTX group and 36.3% in the salpingectomy group. Discussion Our study suggests that IVF cycle outcomes are not compromised by previous treatment of ectopic pregnancies with MTX or salpingectomy, and that neither modality’s use in the preceding cycle adversely affects ovarian reserve
Pereira et al.
Effect of Methotrexate or Salpingectomy on Subsequent IVF Outcomes
873
Table 2 Comparison of IVF cycle characteristics of patients pre-MTX and post-MTX treatment
Parameter
Pre-MTX (n 5 88)
Post-MTX (n 5 88)
p value
D pre-MTX vs post-MTX
Basal FSH level, mIU/mL, mean 6 SD Basal endometrial stripe, mm, mean 6 SD Total stimulation days, mean 6 SD Total gonadotropins, IU, mean 6 SD Peak endometrial stripe, mm, mean 6 SD Number of oocytes retrieved, mean 6 SD Number of mature oocytes, mean 6 SD Number of embryos transferred, mean 6 SD Surplus embryos cryopreserved, mean 6 SD IVF cycle outcome, n (%) Ectopic pregnancy rate Spontaneous miscarriage rate Live birth rate
4.98 6 2.19 3.86 6 0.71 9.55 6 1.99 3286.4 6 1748.3 9.91 6 2.53 12.4 6 5.77 9.75 6 4.45 2.92 6 1.24 0.98 6 0.42
4.87 6 2.97 4.05 6 0.87 9.76 6 2.33 3507.9 6 2090.1 10.4 6 2.15 10.6 6 5.51 8.89 6 4.67 2.95 6 1.38 1.06 6 0.52
.78 .11 .52 .45 .17 .03 .21 .88 .26
20.11 10.19 10.21 1221.5 10.49 21.8 20.86 10.03 10.08
d
d
88 (100) 0 (0) 0 (0)
or ovarian responsiveness in the subsequent cycle. However, we did find that patients treated with salpingectomy required higher doses of gonadotropins in a subsequent IVF-ET cycle compared with those treated with MTX to ultimately attain the same number of mature oocytes. Medical management of ectopic pregnancies with MTX has become increasingly popular [1,2]. MTX is a folate antagonist that targets rapidly dividing cells, most notably the trophoblast cells at the implantation site, by inhibiting the action of dihydrofolate reductase [1,2]. Because MTX can affect rapidly growing cells, there is concern that it may affect proliferating germinal cells in the ovary, thereby impacting folliculogenesis and ovarian reserve [4,5]. These concerns are particularly important in subfertile or infertile patients contemplating subsequent
0 (0) 9 (10.2) 29 (32.9)
fertility treatments. Despite these potential concerns, a majority of studies have shown that treatment of ectopic pregnancies with MTX does not affect ovarian reserve [11–13] or the chance of future conception [14–16]. Furthermore, in the IVF patient population, previous studies have found no difference in ovarian responsiveness or outcomes of IVF-ET cycles after treatment with MTX in a preceding cycle [17,18]. Although the aforementioned results were obtained from studies with relatively small sample sizes, a recent systematic review and meta-analysis by Ohannessian et al [6] confirmed these findings. The effect of MTX, if any, on ovarian reserve and responsiveness may be timedependent. For example, McLaren et al [10] showed that the oocyte yield was lower in patients who underwent
Table 3 Comparison of baseline and IVF cycle characteristics of patients with 1 vs. .1 dose of MTX (n 5 88) Parameter
1 MTX dose (n 5 71)
.1 MTX dose (n 5 17)
p value
Age, yr, mean 6 SD Gravidity, mean 6 SD Parity, mean 6 SD BMI, kg/m2, mean 6 SD Previous IVF attempts, mean 6 SD Basal FSH level, mIU/mL, mean 6 SD Basal endometrial stripe, mm, mean 6 SD Total stimulation days, mean 6 SD Total gonadotropins, IU, mean 6 SD Peak endometrial stripe, mm, mean 6 SD Number of oocytes retrieved, mean 6 SD Number of mature oocytes, mean 6 SD Number of embryos transferred, mean 6 SD Surplus embryos cryopreserved, mean 6 SD
37.2 6 3.87 1.09 6 0.78 0.67 6 0.37 22.8 6 5.31 2.20 6 0.69 5.06 6 2.38 4.14 6 0.78 9.99 6 2.05 3316.7 6 1743.9 10.5 6 2.20 11.1 6 5.79 9.37 6 4.46 2.97 6 1.29 1.02 6 0.41
36.9 6 4.76 1.22 6 0.73 0.70 6 0.32 23.8 6 4.67 1.97 6 0.83 4.77 6 2.74 4.03 6 0.82 9.78 6 1.78 3596.1 6 1830.1 10.3 6 1.69 9.46 6 5.51 7.89 6 4.67 3.05 6 1.06 1.09 6 0.44
.78 .53 .76 .48 .24 .66 .61 .70 .56 .73 .29 .23 .81 .53
874
Journal of Minimally Invasive Gynecology, Vol 22, No 5, July/August 2015
Table 4 Comparison of IVF cycle characteristics of patients presalpingectomy and postsalpingectomy (n 5 22)
Parameter Basal FSH level, mIU/mL, mean 6 SD Basal endometrial stripe, mm, mean 6 SD Total stimulation days, mean 6 SD Total gonadotropins, IU, mean 6 SD Peak endometrial stripe, mm, mean 6 SD Number of oocytes retrieved, mean 6 SD Number of mature oocytes, mean 6 SD Number of embryos transferred, mean 6 SD Surplus embryos cryopreserved, mean 6 SD IVF cycle outcome, n (%) Ectopic pregnancy rate Spontaneous miscarriage rate Live birth rate
Presalpingectomy (n 5 22)
Postsalpingectomy (n 5 22)
p value
D presalpingectomy vs postsalpingectomy
4.81 6 2.75 4.46 6 1.05 9.63 6 2.21 2421.4 6 1468.8 10.8 6 2.51 12.2 6 6.43 10.4 6 4.45 2.86 6 1.19 0.95 6 0.45
4.94 6 2.05 4.31 6 1.11 9.86 6 1.93 3126.4 6 1967.5 11.3 6 2.38 10.2 6 4.23 9.69 6 4.24 2.81 6 1.01 1.01 6 0.32
.62 .65 .32 .18 .28 .23 .41 .85 .83
10.13 20.15 10.23 1705 10.50 22 20.71 20.05 10.06
22 (100) 0 (0) 0 (0)
0 (0) 3 (13.6) 8 (36.3)
d
d
IVF-ET cycles within 180 days of MTX exposure compared with those who did so after 180 days. Consistent with the foregoing findings, the patients in our study cohort underwent IVF-ET cycles at a mean of 204.7 6 64.3 days after treatment with MTX and exhibited no differences in ovarian reserve, ovarian responsiveness, or outcomes in a subsequent cycle. Laparoscopic treatment of an ectopic pregnancy is a safe option that also allows for assessment of pelvic anatomy [2]. Although the ovarian blood supply is primarily from the ovarian artery, some of its supply may arise from the ascending branch of the uterine artery, which traverses the mesosalpinx [19]. Thus, there is a theoretical concern that
salpingectomy can reduce ovarian blood supply and thereby compromise ovarian reserve [20]. A review of the published literature regarding the impact of laparoscopic salpingectomy on ovarian reserve and responsiveness is inconclusive regarding this point. In their retrospective study of 193 women undergoing unilateral salpingectomy, bilateral salpingectomy, or no tubal surgery, Ye et al [20] found that salpingectomy was associated with decreased anti-M€ ullerian hormone (AMH) levels and increased FSH levels in women seeking in vitro fertilization treatment. Similarly, Gelbaya et al [21] showed that women undergoing salpingectomy for hydrosalpinges had higher basal FSH levels, lower antral follicle counts, and fewer oocytes retrieved compared with
Table 5 Comparison of IVF cycle characteristics of patients post-MTX and postsalpingectomy (n 5 110)
Parameter Days between treatment and IVF cycle, mean 6 SD Basal FSH level, mIU/mL, mean Basal endometrial stripe, mm, mean Total stimulation days, mean Total gonadotropins, IU, mean Peak endometrial stripe, mm, mean Number of oocytes retrieved, mean Number of mature oocytes, mean Number of embryos transferred, mean Surplus embryos cryopreserved, mean IVF cycle outcome, n (%) Ectopic pregnancy rate Spontaneous miscarriage rate Live birth rate
D pre-MTX vs post- MTX (n 5 88)
D presalpingectomy vs postsalpingectomy (n 5 22)
204.7 6 64.3
165.7 6 46.1
0.11 0.19 0.21 221.5 0.49 1.8 0.86 0.03 0.08
0.13 0.15 0.23 705 0.50 2 0.71 0.05 0.06
0 (0) 9 (10.2) 29 (32.9)
0 (0) 3 (13.6) 8 (36.3)
p value .01 .40 .10 .40 ,.01 .68 .40 .12 .99 .11 .21
Pereira et al.
Effect of Methotrexate or Salpingectomy on Subsequent IVF Outcomes
women who did not undergo surgery. In contrast, Xi et al [22] reported no differences in basal FSH level, E2 level, total ovarian stimulation days, and number of oocytes retrieved in IVF-ET cycles before and after salpingectomy. Using similar measurements, Wiser et al [4], Hill et al [5], Almog et al [23], Strandell et al [24], and Findley et al [25] also found that salpingectomy does not have a detrimental effect on markers of ovarian reserve or ovarian responsiveness during ovarian stimulation. Despite these conflicting results in ovarian reserve and responsiveness, none of the aforementioned studies showed that salpingectomy affects pregnancy outcomes in subsequent IVF-ET cycles. Although the overall results of our study are consistent with the existing medical literature, few studies to date have compared the before-and-after differences in ovarian reserve, responsiveness, and outcomes of MTX and salpingectomy. In their study of 36 patients treated with MTX and 22 patients treated with salpingectomy, Wiser et al [4] found no statistically significant differences in cycle characteristics or outcomes when comparing pretreatment and posttreatment cycles in both the MTX and salpingectomy group. In contrast to those results, we found that patients in the salpingectomy group required an additional 705 IU after treatment, as opposed to 221.5 IU after treatment in the MTX group; however, the overall days of stimulation and mature oocytes retrieved remained the same. Although it is difficult to ascertain whether these results have a physiological basis, the results may be attributed in part to the lower starting gonadotropin dose in the salpingectomy group compared with the MTX group (2421.4 6 1468.8 vs 3316.7 6 1743.9). Based on the study of McLaren et al [10], it can be postulated that the increase in gonadotropin doses in our study cohort also may be time-dependent. Despite gathering data from 22 993 IVF-ET cycles over a span of 9 years, our study has several limitations. First, only 144 ectopic pregnancies were considered, largely owing to the exclusion of ectopic pregnancies from donor oocyte cycles and frozen-thawed embryo cycles. Our sample size, specifically the salpingectomy group, may be underpowered, albeit slightly. We also excluded pregnancies of unknown location, although it is encouraging to note that our results are in line with those from the study by Hill et al [5] that included both pregnancies of unknown location and ultrasonogram-proven ectopic pregnancies. Second, AMH levels were not used as a marker for ovarian reserve. It has been argued that AMH levels better correlate with the number of early antral follicles compared with other hormonal markers [26], and are more specific than FSH levels for predicting oocyte yield and IVF response [27,28]. However, routine measurement of AMH levels was incorporated into our practice only after 2010. Even then, measuring AMH level is not repeated before initiating a new IVF cycle at our center. Nonetheless even studies that showed lower AMH levels after treatment with MTX or salpingectomy simultaneously showed no
875
difference in oocyte yield after treatment [4,5]. For women undergoing IVF, the quantitative ovarian response to gonadotropins and oocyte yield ultimately reflects ovarian reserve, and thus our overall results are reassuring. Finally, as with any retrospective study, larger prospective studies are needed to validate our findings, particularly as to whether increased doses of gonadotropins are required postsalpingectomy compared to post-MTX treatment. In conclusion, current evidence suggests that treatment of ectopic pregnancies with methotrexate or salpingectomy may not adversely affect ovarian reserve, ovarian responsiveness, or subsequent IVF cycle outcomes. The live birth rates in our MTX group (32.9%) and salpingectomy group (36.3%) are slightly higher, but comparable to our center’s overall live birth rate (31.6%) of patients aged 35 to 37. The choice between MTX and salpingectomy, both acceptable management strategies for ectopic pregnancies, should be individualized according to the patient’s clinical symptoms, bhCG level, and reliability with follow-up [2].
References 1. Barnhart KT. Clinical practice: ectopic pregnancy. N Engl J Med. 2009; 361:379–387. 2. Bachman EA, Barnhart K. Medical management of ectopic pregnancy: a comparison of regimens. Clin Obstet Gynecol. 2012;55: 440–447. 3. Barnhart KT, Sammel MD, Gracia CR, Chittams J, Hummel AC, Shaunik A. Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies. Fertil Steril. 2006;86:36–43. 4. Wiser A, Gilbert A, Nahum R, et al. Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy in the subsequent IVF cycle. Reprod Biomed Online. 2013;26:449–453. 5. Hill MJ, Cooper JC, Levy G, et al. Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location. Fertil Steril. 2014;101: 413–419. 6. Ohannessian A, Loundou A, Courbiere B, Cravello L, Agostini A. Ovarian responsiveness in women receiving fertility treatment after methotrexate for ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod. 2014;29:1949–1956. 7. Condous G, Okaro E, Khalid A, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod. 2005;20:1404–1409. 8. Kirk E, Papageorghiou AT, Condous G, Tan L, Bora S, Bourne T. The diagnostic effectiveness of an initial transvaginal scan in detecting ectopic pregnancy. Hum Reprod. 2007;22:2824–2828. 9. Reichman DE, Chung P, Meyer L, Greenwood E, Davis O, Rosenwaks Z. Consecutive gonadotropin-releasing hormone-antagonist in vitro fertilization cycles: does the elapsed time interval between successive treatments affect outcomes? Fertil Steril. 2013;99: 1277–1282. 10. McLaren JF, Burney RO, Milki AA, Westphal LM, Dahan MH, Lathi RB. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil Steril. 2009; 92:515–519. 11. Oriol B, Barrio A, Pacheco A, Serna J, Zuzuarregui JL, GarciaVelasco JA. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril. 2008;90:1579–1582. 12. Uyar I, Yucel OU, Gezer C, et al. Effect of single-dose methotrexate on ovarian reserve in women with ectopic pregnancy. Fertil Steril. 2013; 100:1310–1313.
876 13. Xiao C, Dahan MH. The effect of methotrexate injection for treatment of an ectopic pregnancy on ovarian reserve [letter]. Fertil Steril. 2014; 101. e23. 14. Gervaise A, Masson L, de Tayrac R, Frydman R, Fernandez H. Reproductive outcome after methotrexate treatment of tubal pregnancies. Fertil Steril. 2004;82:304–308. 15. Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod. 2013;28:1247–1253. 16. Buster JE, Krotz S. Reproductive performance after ectopic pregnancy. Semin Reprod Med. 2007;25:131–133. 17. Boots CE, Gustofson RL, Feinberg EC. Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness? Fertil Steril. 2013;100:1590–1593. 18. Orvieto R, Kruchkovich J, Zohav E, Rabinson J, Anteby EY, Meltcer S. Does methotrexate treatment for ectopic pregnancy influence the patient’s performance during a subsequent in vitro fertilization/embryo transfer cycle? Fertil Steril. 2007;88:1685–1686. 19. Sezik M, Ozkaya O, Demir F, Sezik HT, Kaya H. Total salpingectomy during abdominal hysterectomy: effects on ovarian reserve and ovarian stromal blood flow. J Obstet Gynaecol Res. 2007;33:863–869. 20. Ye XP, Yang YZ, Sun XX. A retrospective analysis of the effect of salpingectomy on serum anti-M€ullerian hormone level and ovarian reserve. Am J Obstet Gynecol. 2015;212:53.e1–53.e10. 21. Gelbaya TA, Nardo LG, Fitzgerald CT, Horne G, Brison DR, Lieberman BA. Ovarian response to gonadotropins after laparoscopic
Journal of Minimally Invasive Gynecology, Vol 22, No 5, July/August 2015
22.
23.
24.
25.
26.
27.
28.
salpingectomy or the division of fallopian tubes for hydrosalpinges. Fertil Steril. 2006;85:1464–1468. Xi W, Gong F, Tang Y, Zhang H, Lu G. Ovarian response to gonadotropins after laparoscopic salpingectomy for ectopic pregnancy. Int J Gynaecol Obstet. 2012;116:93–96. Almog B, Wagman I, Bibi G, et al. Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal. Fertil Steril. 2011;95:2474–2476. Strandell A, Lindhard A, Waldenstr€om U, Thorburn J. Prophylactic salpingectomy does not impair the ovarian response in IVF treatment. Hum Reprod. 2001;16:1135–1139. Findley AD, Siedhoff MT, Hobbs KA, et al. Short-term effects of salpingectomy during laparoscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial. Fertil Steril. 2013;100: 1704–1708. Fanchin R, Schon€auer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-M€ullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod. 2003;18:323–327. Barad DH, Weghofer A, Gleicher N. Comparing anti-M€ullerian hormone (AMH) and follicle-stimulating hormone (FSH) as predictors of ovarian function. Fertil Steril. 2009;91(4 Suppl):1553–1555. Nardo LG, Gelbaya TA, Wilkinson H, et al. Circulating basal antiM€ullerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization. Fertil Steril. 2009;92:1586–1593.
