Abstract
Objective
To study obstetric outcomes of a second pregnancy among women with a first ectopic pregnancy (EP) treated with methotrexate compared with laparoscopic salpingectomy.
Methods
A retrospective cohort study including all women with a first EP and a following pregnancy that concluded by delivery at ≥24 weeks of gestation between March 2011 and April 2021. Second pregnancy outcomes were compared between women treated with methotrexate and those treated with salpingectomy in their first pregnancy.
Results
Overall, 125 women were included, of which 64 (51.2%) were treated with methotrexate and 61 (48.8%) were treated with salpingectomy. In women treated with salpingectomy, the proportion of women conceiving by in vitro fertilization and those with measured gestational sac diameter or β‐subunit human chorionic gonadotropin was higher. The proportion of women conceiving by in vitro fertilization in their second pregnancy was higher in the salpingectomy group (55.2% versus 18.0%, P < 0.001). All maternal and neonatal outcomes were similar in both groups.
The rate of low birth weight < 2500 g was 7.8% in the methotrexate group versus 18% in the salpingectomy group (P = 0.111).
Conclusion
Maternal and neonatal outcomes of a second pregnancy among women treated for EP in their first pregnancy are similar in women treated by methotrexate and those treated by salpingectomy.
Keywords: extrauterine pregnancy, laparoscopy, maternal outcome, mode of delivery, neonatal outcome
Synopsis
The method of treatment for a first ectopic pregnancy is not associated with maternal and neonatal outcome in the following delivery.
1. INTRODUCTION
Ectopic pregnancy (EP) accounts for up to 2% of pregnancies. 1 In recent decades, earlier diagnosis of EP has been achieved by improved utilization of serial quantitative β‐subunit human chorionic gonadotropin (βhCG) hormone measurements coupled with early transvaginal ultrasound examination for early gestation localization. 2
The treatment of tubal EP has been widely studied, with laparoscopic surgery and methotrexate systemic treatment found to be generally of equal efficacy in select patients. 3 , 4 , 5
It is established that women with an EP have relatively compromised fertility when compared with women without an EP. 6 However, improved early diagnosis, prompt adequate treatment, and widely available assisted reproductive technologies may lead to improved delivery rates for women with a prior EP. 6 , 7
Literature regarding which management option for EP is better in terms of obstetric outcomes is limited. Studies related to obstetric outcomes of women with a prior EP mainly focus on comparing women with a prior EP with women with no history of EP. 6 , 7 , 8 , 9 In early EP among properly selected patients, methotrexate and laparoscopic surgery are both acceptable. 10 Therefore, data regarding obstetric outcomes of women with an EP treated with systemic methotrexate compared with women treated with laparoscopy is interesting and clinically important, as mechanical effects of the different treatments may be associated with pregnancy outcomes.
In light of the scarce literature, we aimed to compare obstetric outcomes of women with an EP treated by methotrexate with those treated with laparoscopic salpingectomy. We hypothesized that outcomes will be better in the methotrexate group compared with the laparoscopic salpingectomy group.
2. MATERIALS AND METHODS
2.1. Patients
We conducted a retrospective cohort study of women who gave birth in a tertiary obstetric center in Israel between March 2011 and April 2021. We included women in whom the first pregnancy was diagnosed as an EP and their following pregnancy concluded by delivery at 24 weeks of gestation or later. Sheba Medical Center's institutional review board approval (7145‐20‐SMC) was obtained for the study, and informed consent was waived.
The cohort included two groups: (1) women who had laparoscopic salpingectomy treatment of EP, and (2) those who were treated with methotrexate for EP. We excluded patients who were initially treated with methotrexate and subsequently underwent salpingectomy because of medical treatment failure or who turned symptomatic following methotrexate treatment necessitating salpingectomy. In addition, patients with miscarried intrauterine pregnancies or pregnancies terminated before 24 weeks of gestation in the second pregnancy were not included in the cohort. All women treated with methotrexate had all of the following criteria: no intrauterine pregnancy, hemodynamic stability, no abnormal liver or renal function tests, and no known allergy to methotrexate. Methotrexate treatment consisted of a single dose of intramuscular injection of 50 mg/m2. Laparoscopic salpingectomy was offered to women with severe symptoms or signs suggesting intra‐abdominal bleeding, acute abdomen, hemodynamic shock, presence of a fetal heartbeat, gestational mass diameter > 35 mm, and βhCG >5000 IU/L. We do not practice laparoscopic salpingotomy in our center.
2.2. Data collection
We manually reviewed all women admitted to labor at >24 weeks of gestation in their second pregnancy without a prior delivery and identified the cases with a first EP. Diagnosis of EP was confirmed by the pathologic report for women treated surgically and by ultrasound examinations 11 and βhCG measurements for women treated with methotrexate.
2.3. Variables of interest
We collected variables of the EP including mode of conception, gestational age at diagnosis, sonographic characteristics, and βhCG levels; variables of the second pregnancy including age, tobacco use, medical history, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), interval from EP to the second pregnancy delivery, and mode of conception; delivery characteristics including preterm birth at <37 weeks of gestation, intrapartum variables, and mode of delivery; and fetal and neonatal outcome including birth weight, APGAR scores, umbilical artery pH levels, and neonatal intensive care unit admission.
2.4. Statistical analysis
Statistical analysis was performed using SPSS for Windows version 25.0 (IBM). Normality of data was assessed by Kolmogorov–Smirnov test. Descriptive statistics were reported as median and interquartile range for continuous variables. The nominal variables were reported as absolute number and percentage. Continuous variables were compared by nonparametric tests. Qualitative data were compared using χ2 test or Fisher exact test when the expected frequency was <5. Statistical significance was defined at P < 0.05. Sample size calculation was not performed, as the cohort was limited to the cases included in our database.
3. RESULTS
Overall, we included 125 women in our study cohort. Of those, 64 (51.2%) were treated with methotrexate in the first EP group and 61 (48.8%) were treated by laparoscopic salpingectomy. Table 1 presents EP characteristics. In women treated with laparoscopic salpingectomy, the proportion of women conceiving by in vitro fertilization (IVF) was higher (41.7% versus 12.7%, P = 0.004). Gestational age at EP treatment was similar in both study groups and gestational sac diameter was higher in women treated by laparoscopy (19.0 millimeters versus 14.5 millimeters, P = 0.037). Median βhCG levels were higher in the laparoscopy‐treated group (3044 IU\L versus 1155 IU\L, P < 0.001).
TABLE 1.
Characteristics of EPs of women admitted for labor in their second pregnancy
| Characteristics | Methotrexate (n = 64) | Salpingectomy n = 61) | P value |
|---|---|---|---|
| Mode of conception at EP a | |||
| Spontaneous | 44 (80.0) | 26 (54.2) | 0.004 |
| Ovulation induction | 4 (7.3) | 2 (4.2) | |
| In vitro fertilization | 7 (12.7) | 20 (41.7) | |
| Gestational age at EP treatment (wk) | 6.5 (6.0–7.1) | 6.5 (5.6–7.5) | 0.768 |
| Gestational sac diameter at EP presentation (mm) | 14.5 (12.3–18.0) | 19.0 (15.0–25.0) | 0.037 |
| βhCG at admission at EP (IU/L) | 1155.0 (485.5–2348.5) | 3044.0 (1795.3–7691.8) | <0.001 |
Note: Continuous variables are expressed as median (interquartile range). Categorical variables are presented as proportions. Bold values indicate significance.
Abbreviations: βhCG, β‐subunit human chorionic gonadotropin; EP, ectopic pregnancy.
Missing cases.
Table 2 describes the following pregnancy characteristics after EP treatment. Age, BMI, and tobacco use rate were similar in both study groups. The proportion of women with prior abdominal surgery (excluding salpingectomy for EP) was higher in the laparoscopy group (27.1% versus 7.9%, P = 0.007). Median time from EP to current delivery was 543 days in the methotrexate group versus 452 days in the laparoscopy group (P = 0.070). The proportion of women conceiving by IVF was higher in the laparoscopy group (55.2% versus 18.0%, P < 0.001). Table 3 describes obstetric outcomes in the study groups. The rate of preterm delivery, use of epidural anesthesia, intrapartum fever, second stage duration, and mode of delivery were similar in both study groups. Neonatal outcomes are presented in Table 4. The rate of low birth weight < 2500 g was 7.8% in the methotrexate group versus 18% in the salpingectomy group (P = 0.111). All neonatal outcomes were similar in both groups.
TABLE 2.
Pregnancy characteristics of women with a prior EP
| Characteristics | Methotrexate (n = 64) | Salpingectomy (n = 61) | OR (95% CI) | P value |
|---|---|---|---|---|
| Age at admission to delivery (y) | 30.0 (28.0–33.0) | 32.0 (29.0–36.0) | 0.133 | |
| Smoking | 1 (1.6) | 3 (4.9) | 0.357 | |
| Prior pelvic inflammatory disease | 0 | 0 | 1.000 | |
| Prior abdominal surgery, excluding salpingectomy | 5 (7.9) | 16 (27.1) | 4.32 (1.47–12.70) | 0.007 |
| Endometriosis diagnosis | 1 (1.6) | 5 (8.2) | 0.109 | |
| Prepregnancy BMI (kg/m2) | 21.1 (19.8–23.5) | 21.4 (19.4–26.6) | 0.206 | |
| Predelivery BMI (kg/m2) | 26.6 (24.9–29.1) | 27.5 (24.7–30.6) | 0.275 | |
| Weight gain during pregnancy (kg) | 13.0 (10.0–16.0) | 12.0 (9.3–18.0) | 0.958 | |
| Time from EP to delivery at second pregnancy (d) | 542.9 (416.8–702.2) | 451.9 (297.5–668.5) | 0.070 | |
| Mode of conception at second pregnancy a | ||||
| Spontaneous | 49 (80.3) | 26 (44.8) | <0.001 | |
| Ovulation induction | 1 (1.6) | 0 (0) | ||
| In vitro fertilization | 11 (18.0) | 32 (55.2) | ||
| Multiple gestation at second pregnancy | 0 | 0 | 1.000 | |
| Glucose challenge test (mg/dl) | 110.5 (95.0–130.3) | 128.0 (98.3–155.3) | 0.052 | |
| Diabetes | 6 (9.4) | 11 (18.0) | 0.196 | |
| Hypertension | 4 (6.3) | 6 (9.8) | 0.524 | |
| Male fetus | 42 (65.6) | 34 (55.7) | 0.277 |
Note: Continuous variables are expressed as median (interquartile range). Categorical variables are presented as proportions.
Abbreviations: BMI, body mass index; CI, confidence interval; EP, ectopic pregnancy; OR, odds ratio.
Missing cases.
TABLE 3.
Delivery characteristics of women with a prior EP
| Characteristics | Methotrexate (n = 64) | Salpingectomy (n = 61) | P value |
|---|---|---|---|
| Amniotic fluid index before delivery (mm) | 130.0 (94.5–172.0) | 122.0 (102.5–153.8) | 0.693 |
| Hemoglobin before delivery | 12.5 (11.8–13.0) | 12.3 (11.7–12.9) | 0.376 |
| Preterm premature rupture of membranes | 5 (7.8) | 5 (8.2) | 1.000 |
| Gestational age at delivery (wk) | 39 ± 4 (38 ± 5–40 ± 3) | 39 ± 0 (37 ± 6–40 ± 1) | 0.115 |
| Delivery at <37 ± 0 weeks | 8 (12.5) | 9 (14.8) | 0.800 |
| Spontaneous onset of labor | 24 (37.5) | 21 (34.4) | 0.852 |
| Epidural anesthesia | 43 (67.2) | 40 (65.6) | 0.852 |
| Intrapartum fever a | 2 (3.3) | 2 (3.4) | 1.000 |
| Second stage duration (min) | 90.0 (56.5–128.0) | 122.0 (37.5–191.0) | 0.204 |
| Mode of delivery | |||
| Spontaneous vaginal | 36 (53.3) | 34 (55.7) | 0.624 |
| Vacuum extraction | 10 (15.6) | 7 (11.5) | |
| Forceps extraction | 1 (1.6) | 0 (0) | |
| Cesarean delivery | 17 (26.6) | 20 (32.8) | |
| Elective cesarean delivery | 4 (6.3) | 6 (9.8) | 0.464 |
| Emergent cesarean delivery | 13 (20.3) | 14 (23.0) | 0.720 |
| Cesarean delivery indication | |||
| Breech presentation | 1 (1.6) | 4 (6.6) | 0.005 |
| Dysfunctional labor | 0 (0) | 6 (9.8) | |
| Nonreassuring fetal heart rate | 10 (15.6) | 2 (3.3) | |
| Maternal request | 2 (3.1) | 5 (8.2) | |
| Placenta previa | 0 (0) | 2 (3.3) | |
| Other indications | 4 (6.3) | 1 (1.6) | |
| Duration of cesarean delivery (min) | 38.5 (34.3–79.3) | 41.0 (34.0–95.0) | 0.728 |
Note: Continuous variables are expressed as median (interquartile range). Categorical variables are presented as proportions. Bold values indicate significance.
Abbreviation: EP, ectopic pregnancy.
Missing cases.
TABLE 4.
Fetal and neonatal outcomes of women with a prior EP
| Characteristics | Methotrexate (n = 64) | Salpingectomy (n = 61) | P value |
|---|---|---|---|
| Birth weight (g) | 3135.0 (2762.5–3403.8) | 3045.0 (2705.0–3528.0) | 0.451 |
| Low birth weight, <2500 g | 5 (7.8) | 11 (18.0) | 0.111 |
| APGAR 5 minute <7 | 0 (0) | 2 (3.3) | 0.236 |
| Stillbirth | 0 (0) | 1 (2.1) | 0.466 |
| Umbilical artery arterial pH | 7.3 (7.2–7.3) | 7.3 (7.2–7.3) | 0.237 |
| Umbilical artery arterial base excess (mmol/L) | −5.5 (−8.0 to −4.1) | −4.7 (−7.0 to −2.9) | 0.256 |
| Neonatal intensive care unit admission | 5 (7.8) | 3 (4.9) | 0.718 |
Note: Continuous variables are expressed as median (interquartile range). Categorical variables are presented as proportions.
Abbreviation: EP, ectopic pregnancy.
4. DISCUSSION
In this study of obstetric outcomes of women treated for EP, maternal and neonatal outcomes in the second pregnancy were similar in women treated with methotrexate and those treated with laparoscopic salpingectomy.
Literature is scarce regarding the future birth outcomes of women with EP. Available data mostly focus on comparison of women with a history of EP with those without a prior EP. 7 , 8 , 9 Women with an EP are at higher risk of a subsequent EP, miscarriage, and stillbirth. 8 However, whether the treatment method of the EP has an association with following obstetric outcomes is less clear. In a large Scottish retrospective cohort study including 2969 women, EP was associated with a following increased risk for pre‐eclampsia, preterm delivery, and emergency cesarean delivery. 8 However, that study did not account for treatment methods for the EP.
It was previously suggested that the type of EP management may have a role in the risk of future adverse birth outcomes. 7 That study compared salpingectomy and salpingotomy and did not evaluate methotrexate treatment. Another study evaluated outcomes following methotrexate and salpingectomy treatment; however, no obstetrical outcomes were available for evaluation. 12
In our study, women treated with salpingectomy had a higher proportion of EPs achieved by IVF. This could be attributable to the preference of the treating physician to remove an inflicted fallopian tube in woman who will likely undergo subsequent IVF. Not surprisingly, women treated with laparoscopy more commonly conceived their following pregnancy by IVF. A further study should be performed to thoroughly evaluate the indications for IVF among women with prior EP treatment.
Median EP gestational sac measurement and βhCG serum levels were also higher in the salpingectomy group. This difference could also represent a selection preference to treat these women surgically, as it is well established that higher serum βhCG levels and gestational sac measurements are associated with methotrexate treatment failure. 13 , 14
Time from EP to live birth delivery in the second pregnancy was 91 days longer in the methotrexate group (P = 0.070). This corresponds with the general recommendation to postpone pregnancy following methotrexate systemic treatment to reduce potential risk of teratogenicity. 15
We found similar maternal and neonatal outcomes in our study. It should be acknowledged that the current study's sample size could account for the lack of difference between our study groups, as could be inferred by the more than doubled rate of low birth weight in the salpingectomy group compared with the methotrexate group (P = 0.111). Notwithstanding the sample size limitation, our results should be discussed in the context of patient counseling before recommending a route of treatment for women with an EP. Salpingectomy may potentially cause placental dysfunction, leading to hypertensive disorders of pregnancy or intrauterine growth restriction, as was previously presented. 7 However, whether the EP itself or the surgical treatment play a role in subsequent complications of pregnancy is yet to be elucidated.
Further studies should focus on pregnancy outcomes following medical and surgical treatment of EP, preferably in a multicenter setting and using a prospective method.
Our study has limitations. The most pronounced is the limited sample size, which might preclude reaching statistical significance and detect a difference between the study groups. The retrospective nature of the study carries inherent biases including information and selection bias for the treatment chosen to treat the primary EP. We could not rule out that selection bias in the treatment of primary EP might be associated with pregnancy outcomes. In addition, we could not account for women who had a prior EP and delivered in another hospital. Furthermore, we had limited information on women who underwent emergent surgery as a result of shock, which might potentially affect the outcomes. Of note, we excluded patients treated first by methotrexate and thereafter underwent salpingectomy. While baseline characteristics differ between the groups, the outcomes did not, excluding indications for cesarean delivery. Thus, we did not perform a multivariable regression analysis to account for potential confounders. Finally, we did not include gestations concluded before 24 weeks of gestation. This information might further shed light on outcomes of treatment methods and aid in management guidance.
The main strength of the current study is the inclusion of a distinct group of women (only gravida 2, parity 0), limiting the introduction of potential confounders for obstetric outcomes. The EP treatment methods and labor and delivery management add to the generalizability of our results. However, the mostly White population of our cohort limits the generalizability to countries with similar populations.
5. CONCLUSION
Maternal and neonatal outcomes of a second pregnancy among women treated for EP in their first pregnancy and delivered at ≥24 weeks of gestation are similar in women treated with methotrexate and those treated with laparoscopic salpingectomy. Future prospective studies are needed to further identify obstetric outcomes in larger cohorts.
AUTHOR CONTRIBUTIONS
G.L. and R.M. reviewed the literature, collected data, and wrote the paper. A.O., T.W., and Y.B. collected data. All authors read, revised, and approved the final manuscript.
FUNDING INFORMATION
None.
CONFLICTS OF INTEREST
The authors of this manuscript declare no conflicts of interest.
Levin G, Ohayon A, Weissbach T, Burke YZ, Meyer R. Ectopic first pregnancy treated by methotrexate versus salpingectomy–Maternal and perinatal outcomes in a subsequent pregnancy: A retrospective study. Int J Gynecol Obstet. 2023;160:823–828. doi: 10.1002/ijgo.14365
DATA AVAILABILITY STATEMENT
Research data are not shared.
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Data Availability Statement
Research data are not shared.