Bilateral tubal ectopic pregnancy following induction ovulation can be missed in emergent ultrasonography: Case report.

A 25-year-old primigravid, non-smoker woman was admitted to our hospital with a complaint of severe lower abdominal pain and vaginal bleeding. Her home pregnancy test was positive and she was not referred for vaginal ultrasound and other pregnancy care routines at our center or any other facilities. She was at 8 weeks and 3 days of pregnancy according to her last menstrual period. She had a history of 5 years of infertility due to her diagnosis of polycystic ovarian syndrome (PCOS). The patient underwent ovulation induction with human recombinant follicle stimulating hormone (rFSH) and letrozole for the past 6 months. On physical examination, she was pale and had a blood pressure of 100/60 mmHg and a pulse rate of 120 bpm. Her abdomen was distended with tenderness, especially on the right lower quadrant. A vaginal examination showed mild spotting and cervical excitation with a right adnexal mass. In her laboratory exams, serum hemoglobin level was 6.5 g/dl, and serum β-human chorionic gonadotropin (β –hCG) level was 6462 mIU/mL. After initial resuscitation with 2 L of Ringer's serum, the patient was sent for ultrasound imaging. The transvaginal ultrasound study demonstrated moderate hemoperitoneum, empty uterus with endometrial stripe of 22 mm, and right adnexal mass suggestive of ruptured ectopic pregnancy ( Fig. 1 ). There was nothing reported about the left adnexa as blood obscured the view. She was counseled about the diagnosis and salpingectomy was explained to her. After obtaining informed consent, an emergency laparotomy was performed. At laparotomy, a 700 ml clot was suctioned, the uterus was grossly normal, and the right ovary was enlarged so the right salpingectomy due to a ruptured ectopic mass with active bleeding was done. Surprisingly, while checking the other side, an intact second ectopic mass was noticed on the left fallopian tube ( Fig. 2 ). Because she asked to persevere fertility, the left salpingostomy was done. During the operation, 3 units of packed cell and 2 units of fresh frozen plasma were transfused. The rest of the abdominal cavity was normal. The postoperative period was uneventful and she was discharged after three days. On 48-hour-follow, β-hCG dropped to 883 mIU/mL and she was monitored until it became negative. Pathology findings confirmed bilateral ectopic pregnancies. Fig. 1 Transvaginal ultrasonographic image of the right ectopic pregnancy hematoma complex mass. Fig. 1 Fig. 2 Intact second ectopic mass on the left fallopian tube. Fig. 2 Transvaginal ultrasonographic image of the right ectopic pregnancy hematoma complex mass. Intact second ectopic mass on the left fallopian tube. This study has been reported in line with the SCARE 2023 criteria [ 7 ].

Niloofar Hoorshad. MD.: Conception and Design of the study, Writing the paper, Critical review Azadeh Tarafdari. MD.: Data collection and/or processing, Writing the paper Narges Zamani. M.D.: Critical review Shahrzad Sheikh Hasani. MD.: Writing the paper, Critical review Maryam Deldar Pasikhani.MD: Writing the paper, Data collection and/or processing

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval (IR.TUMS.IKHC.REC.1402.291) for this study was provided by the Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran on 23 February 2024.

This study was not funded nor granted.

Niloofar Hoorshad

Consequently, the occurrence of spontaneous BTP is infrequent and typically confirmed during surgical intervention. Despite its rarity, this condition can lead to maternal mortality in the first trimester. This underscores the importance of thorough and attentive assessment of both fallopian tubes during ultrasound examinations and surgical procedures to promptly detect the condition and implement interventions to prevent maternal mortality and morbidity.

BTP is rare, arising in approximately 1 per 200,000 pregnancies, and stands as a leading cause of maternal mortality in the first trimester [ 3 ]. While BTP has been documented since the 1940s, there has been an increase in the incidence of BTP secondary to the advancements in ARTs [ 8 ]. Table 1 summarizes the characteristics of previous cases of bilateral ectopic pregnancy. Table 1 Summary of previously reported cases of bilateral ectopic pregnancy. US: ultrasound, G: gravidity, P: parity, MVB: mild vaginal bleeding, MTX: methotrexate, PG: primigravid. Table 1 First author Year Age Gestational age Gravidity Previous history of infertility Risk factors Presentation US findings Treatment Eghbali et al. [ 9 ] 2023 34 6 weeks G2, P1 9 years None MVB 13 mm adnexal mass in the right and 21 mm in the left Laparoscopic bilateral salpingostomy Damiani et al. [ 5 ] 2020 33 7 weeks G2, P1 Not mentioned IVF MVB Mass of 17 × 17 mm in the right adnexa Laparoscopic bilateral salpingectomy Fukuda et al. [ 10 ] 2014 32 6 weeks G1, P1 Clomiphene citrate for ovulatory disturbance None Intermittent pain Left adnexal mass of 9 cm in diameter Laparoscopic left salpingectomy, and linear right salpingotomy Mansouri et al. [ 11 ] 2023 22 6 weeks G2 2.5 mg/day Letrozole administration for 10 days None MVB, abdominal pain and spotting Complex mass (50 ∗ 70 mm) in left adnexa, intact right tube Left laparoscopic salpingostomy for the first episode, and MTX therapy for the second episode Gerli et al. [ 12 ] 2016 32 5 weeks PG Clomiphene 50 mg twice a day for five days Smoking Abdominal pain A gestational sac with a yolk sac close to the right ovary. Normal left adnexa Right salpingectomy for the first episode and laparoscopic left salpingotomy for the second episode. Terzic et al. [ 13 ] 2013 30 3 weeks and 3 days PG Clomiphene citrate, 50 mg twice a day, for 5 days. None Abdominal pain, MVB A gestational sac with a diameter of 22 mm close to the right ovary. Right salpingectomy for the first episode. Laparoscopic left salpingectomy for the second episode. Pehlivanov et al. [ 14 ] 2012 32 3 weeks and 2 days PG Clomiphene citrate 100 mg/day for 5 days Not mentioned Abdominal pain, MVB bilateral adnexal hypogenic formations (59.0/61.0 mm and 62.0/67.0 mm). Laparotomy and bilateral salpingectomy Summary of previously reported cases of bilateral ectopic pregnancy. US: ultrasound, G: gravidity, P: parity, MVB: mild vaginal bleeding, MTX: methotrexate, PG: primigravid. The majority of individuals diagnosed with BTP typically manifest similar clinical symptoms to those with unilateral ectopic pregnancy. Common signs include amenorrhea, metrorrhagia, and abdominal pain, constituting a triad of symptoms. Serum β-hCG levels do not exhibit a correlation with bilateral disease. On the other hand, ultrasound imaging may fail to be effective in distinguishing BTP. The fact that the clinical presentation of BTP mirrors that of unilateral ectopic pregnancy emphasizes the importance of comprehensive ultrasound examination to assess both fallopian tubes [ 15 ]. Thus, the diagnosis of BTP is typically concluded at the time of surgery, as it is extremely difficult to identify abnormalities of the contralateral tube on ultrasound [ 2 ]. This is in part due to the rareness of the condition or obscured visibility from the presence of blood in the pelvis [ 2 ]. One literature review completed by Ramadan et al. discovered that only 7/45 (15.5 %) of BTP cases were diagnosed preoperatively with transvaginal ultrasound [ 2 ]. In our case, although right-sided EP was found, the contralateral adnexal evaluation was inconclusive as blood obscured the view. Studies have demonstrated that ovulation induction, especially with clomiphene citrate (CC), was an independent risk factor of ectopic pregnancy. In cases reviewed by Zhu et al., [ 16 ] two were reported after CC induction. However, protocols using gonadotropin-releasing hormone analogs (GnRHa) did not demonstrate any increased risk in this study. In our case, the patient was taking letrozole for induction ovulation and we hypothesized that it is the etiology of developing BTP in this patient. However, we are aware that the causal link between taking letrozole and developing BTP cannot be judged based on one case. Polycystic ovary syndrome (PCOS) is the leading cause of oligomenorrhoea and amenorrhea, affecting approximately 5 % to 20 % of women worldwide and often resulting in anovulatory infertility [ 17 ]. Aromatase inhibitors (AIs) were introduced for ovulation induction in 2001. Since then, clinical trials have produced varying conclusions regarding whether letrozole, an AI, is at least as effective as CC, a selective estrogen receptor modulator (SERM) [ 18 ]. Letrozole, a specific AI, was initially administered to women with PCOS who were resistant to CC. Letrozole could prevent the hypothalamic-pituitary axis from receiving estrogen-negative feedback by inhibiting estrogen biosynthesis, thus increasing FSH production and promoting follicle growth. Letrozole gradually replaced CC as the first-line ovulation induction agent administered to women with PCOS [ 19 ]. In a systematic review study, Franik et al. [ 20 ], included all RCTs of AIs, used alone or with other medical therapies, for ovulation induction in women of reproductive age with anovulatory PCOS to assess the effectiveness and safety of Letrozole compared to SERMs for infertile women with anovulatory PCOS, followed by timed intercourse or intrauterine insemination. They found that letrozole appears to improve live birth and pregnancy rates compared to SERMs when used for ovulation induction followed by intercourse. High-certainty evidence indicates that OHSS rates are similar between letrozole and SERMs. Additionally, there is high-certainty evidence of no difference in miscarriage and multiple pregnancy rates. On the other hand, letrozole has been proposed as a treatment of EP. The idea of using AIs in the treatment of EP is associated with the role of estrogens in the process of implantation and embryonic development [ 21 ]. Kochhar et al. [ 22 ], Mitwally et al. [ 23 ], and El-Sayed et al. [ 24 ], used letrozole with a specific regimen all of which implicated higher doses than what is used for ovulation induction. All these authors reported treatment was equivalent to methotrexate, with β-hCG level concentrations decreasing more rapidly in women treated with letrozole. Management of BTP depends on the extent of the damage to the fallopian tube and the desirability of future fertility. According to the American College of Obstetricians and Gynecologists (ACOG) practice bulletin No. 193, methotrexate is the treatment of choice for the medical management of ectopic pregnancy in those who do not have absolute contraindications. Our patient's elevated beta-hCG of >5000 and the hemodynamic instability are known relative contraindications to methotrexate administration [ 25 ]. Therefore, surgical intervention was pursued. There are no guidelines available on the management of BTP. Ultrasound typically diagnoses an ectopic pregnancy in one tube and the contralateral EP is found during abdominal surgery. Thus, we recommend that radiologists take an active role in history taking during ultrasound examination including previous history of gestation, ovulation induction, and medications prescribed. Moreover, it can be possible that a specific data sheet is designed to register important risk factors of developing EP, and in cases of high suspicion complementary ultrasonography examination of both sides is planned. On the other hand, to increase diagnostic accuracy of ultrasonography examination we suggest sweeping the bilateral adnexal areas for careful examination and combining transabdominal and transvaginal ultrasound images to reduce missed diagnoses. The decision to perform a salpingostomy versus salpingectomy is determined by the patient's desire for future fertility and the extent of fallopian tube damage [ 25 ]. This emphasizes the importance of maintaining a high level of suspicion at the time of surgical intervention and of visualizing the contralateral tube during abdominal surgery to avoid missing a potential second ectopic tubal pregnancy [ 11 , 26 ]. One cohort study found that salpingostomy is associated with higher rates of subsequent intrauterine pregnancy but also a higher risk of a repeated EP [ 27 ] when significant fallopian tube damage is visualized, salpingectomy is the preferred method of treatment, as seen in our patient. Although laparotomy is preferred for cases who are in hemorrhagic shock and hemodynamically unstable in case of a patient's stable condition laparoscopy might be a feasible option. Benz et al. [ 15 ], developed an interesting algorithm based on clinical symptoms, serial elevations of β-hCG, and transvaginal ultrasound findings. In this algorithm, patients are considered to be at high risk for BTP if they have a history of PID/Sexually transmitted infection, a history of ART, a history of previous EP, and history of tubal surgery. The treatment option mainly depended on the patient's hemodynamic status, signs of intraperitoneal bleeding, and symptoms of ongoing ruptured ectopic mass.

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Ectopic pregnancy (EP) refers to the occurrence of embryo implantation and development outside the endometrial cavity [ 1 ]. The frequency of ectopic pregnancies varies based on the implantation site: ampullary (70.0 %), isthmic (12.0 %), fimbrial (11.1 %), ovarian (3.2 %), interstitial (2.4 %), and abdominal (1.3 %) [ 1 ]. Bilateral tubal ectopic pregnancy (BTP) is the rarest manifestation of EP, with an incidence ranging from 1 in 725 to 1 in 1580 of all ectopic pregnancies, which is equivalent to 1 in every 200,000 live births [ 2 ]. Moreover, there is speculation that BTP is underestimated and increasing due to the expanding application of assisted reproductive technology (ART) [ 3 ]. While a history of prior ectopic pregnancies presents the strongest risk factor, other conditions that lead to significant tubal pathology elevate the risk of ectopic pregnancy such as pelvic bacterial infections, nonspecific salpingitis, and pelvic inflammatory disease (PID) [ 4 ]. Other risk factors for BTP encompass prior tubal surgery, tubal endometriosis, intrauterine device usage, in vitro fertilization, oral estrogen/progestin contraceptive usage, and smoking [ 5 ]. The precise mechanism underlying BTP remains elusive, with hypotheses positing transperitoneal migration of trophoblastic cells. Alternative theories suggest multiple ovulations, oocyte implantation on a site of tubal damage, or superfecundation - fertilization of an ovum in an already pregnant female [ 6 ]. Here we discuss a case of BTP in a 25-year-old woman presented with vaginal bleeding and abdominal pain.

All authors declare that there is no conflict of interest to disclose.