Delayed Detection of Spontaneous Bilateral Tubal Ectopic Pregnancies After Methotrexate Treatment

Delayed Detection of Spontaneous Bilateral Tubal Ectopic Pregnancies After Methotrexate Treatment

The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2017 Ó 2017 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter http://dx.do...

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The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2017 Ó 2017 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2017.06.011

Clinical Communications: OB/GYN DELAYED DETECTION OF SPONTANEOUS BILATERAL TUBAL ECTOPIC PREGNANCIES AFTER METHOTREXATE TREATMENT Nicole E. Brown, PA-C,* Shereen A. Singer, MD,† and Joe Suyama, MD* *Emergency Department, Magee Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania and †Department of Obstetrics and Gynecology, Magee Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Corresponding Address: Nicole E. Brown, PA-C, Emergency Department, Magee Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213

, Abstract—Background: Bilateral tubal ectopic pregnancies are a rare subset of ectopic pregnancy that can pose a diagnostic dilemma for clinicians. There is no distinct clinical presentation for bilateral tubal ectopic pregnancies, although they are typically associated with assistive reproductive techniques. In addition, there is no single diagnostic feature to help clinicians delineate bilateral tubal ectopic pregnancies from other types of ectopic pregnancy prior to passing the discriminatory zone (such as heterotopic pregnancy or twin ectopic [two gestational sacs in one tube]). Diagnosis is typically made via direct visualization intraoperatively and therefore treatment is usually surgical. Case Report: We present a case of spontaneous bilateral tubal ectopic pregnancies diagnosed 7 days apart via transvaginal ultrasound. The patient presented to the emergency department with pelvic pain on the contralateral side of her previously diagnosed ectopic pregnancy and vaginal spotting. Bilateral adnexal masses were visualized on ultrasound and her serum beta–human chorionic gonadotropin level had a 5.9% decline from day 4 to day 7 after methotrexate administration 7 days prior; gynecology was consulted. The patient was successfully treated with an additional dose of intramuscular methotrexate without any complications. Why Should an Emergency Physician Be Aware of This?: The implications of this case suggest that diagnosis of bilateral tubal ectopic pregnancies requires clinicians to have a high level of suspicion in any pregnant female with a suspected or known ectopic pregnancy who presents

with pelvic pain regardless of prior diagnosis or treatment. Ó 2017 Elsevier Inc. All rights reserved. , Keywords—bilateral; ectopic; nancy; spontaneous; tubal

methotrexate;

preg-

INTRODUCTION Ectopic pregnancy accounts for 1.4% of all pregnancies (1). Even though rare, ectopic pregnancies are the leading cause of maternal death in the first trimester, with an incidence of death of 1 per 1000 pregnancies, necessitating prompt identification and intervention (1–3). Risk factors for ectopic pregnancy include a history of ectopic pregnancy, history of a sexually transmitted infection (particularly Chlamydia trachomatis) or pelvic inflammatory disease, tobacco use, prior tubal or pelvic surgery, use of infertility treatments, and in utero exposure to diethylstilbestrol (3,4). In addition, although rates of pregnancy are significantly decreased when an intrauterine contraceptive device is in place, if a pregnancy does occur it is more likely to result in an ectopic pregnancy compared to women not using any form of contraception (5). However, the majority of those diagnosed with an ectopic pregnancy have no identifiable risk factors (3). Bilateral tubal ectopic pregnancies have an estimated incidence of 1 in 750 to 1 in 1580 ectopic pregnancies

Reprints are not available from the authors.

RECEIVED: 20 July 2016; FINAL SUBMISSION RECEIVED: 1 February 2017; ACCEPTED: 28 June 2017 1

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and are typically the result of assisted reproductive techniques (2,6). Spontaneous bilateral tubal ectopic pregnancies are the rarest form of ectopic (heterotopic and twin ectopic [two gestational sacs in one tube] are more common) and are considered spontaneous when no fertility treatments are involved (2,7). Diagnosis typically happens at time of surgery with direct visualization (7,8). The most common treatment is bilateral salpingectomy (9). There are few reported cases of preoperative diagnosis of bilateral tubal ectopic pregnancies with most literature reporting no prior cases (2,10,11). There have been no reports of successful treatment of bilateral tubal ectopic pregnancies with methotrexate (7). This case report describes an instance of spontaneous bilateral tubal ectopic pregnancies diagnosed via ultrasound and treated with methotrexate. CASE REPORT A 32-year-old G5P1031 (gravida: 5 pregnancies including current pregnancy, para: 1 full-term delivery, 0 preterm deliveries, 3 abortions [2 spontaneous abortions and 1 prior ectopic pregnancy treated with methotrexate, side unknown], and 1 living child) with a right ectopic pregnancy diagnosed 7 days prior presented to the emergency department with vaginal bleeding and pelvic cramping. At time of diagnosis of right ectopic pregnancy, the patient had a serum beta–human chorionic gonadotropin (b-hCG) level of 2484 mIU/mL without an intrauterine pregnancy visualized on ultrasound and a visible 13  9  10 mm right adnexal mass with architectural pattern consistent with ectopic pregnancy. The patient’s only risk factor for ectopic pregnancy was her history of previous ectopic pregnancy. After consultation with gynecology, the patient received intramuscular methotrexate (single dose regimen of 50 mg/m2) and was scheduled for outpatient follow-up and b-hCG level on day 4 after methotrexate administration (level was 2526 mIU/mL on day 4). The patient stated after she received the methotrexate she had intermittent cramping that was initially moderate and located diffusely to the pelvic region, however, 48 h prior to arrival at the emergency department pain shifted to the left side of the pelvis and became more intense. Patient also noted interval resolution of vaginal bleeding after methotrexate administration; however, on the day of presentation to the emergency department she had onset of vaginal spotting. The patient’s temperature was 36.1 C (96.9 F), her heart rate was 76 beats/min, her blood pressure was 113/72 mmHg, her respiration rate was 16 breaths/min, and her O2 saturation was 100% on room air. Her abdominal examination revealed bilateral lower quadrant tenderness to palpation mostly in the pelvic region

without guarding, rigidity, or rebound tenderness. Pelvic examination was deferred given known tubal ectopic pregnancy on right. She had a b-hCG level of 2377 mIU/mL, indicating a 5.9% decline from day 4 to day 7 after methotrexate administration. Repeat pelvic ultrasound demonstrated the previously visualized adnexal mass on the right measuring 21  13  14 mm, consistent with patient’s previously diagnosed ectopic pregnancy (Figure 1). In addition, the ultrasound demonstrated a new left adnexal mass measuring 20  16  14 mm with architectural pattern consistent with an ectopic gestation (Figure 2). Gynecology was consulted for management recommendations. Ultimately, the patient received an additional dose of intramuscular methotrexate (50 mg/m2) in light of the patient’s clinical and hemodynamic stability. In addition, the patient highly desired medical management as opposed to surgical management with possible resulting sterility. The patient’s b-hCG level was followed until complete resolution without further incident. DISCUSSION A suspicion of ectopic pregnancy is based on the presence of abdominal or pelvic pain and vaginal bleeding in a female patient with a history of amenorrhea and a positive urine or serum pregnancy test (12). Although risk factors strengthen the likelihood of the diagnosis, the lack of risk factors should not prompt a clinician to rule out the condition because >50% of patients with an ectopic pregnancy have no risk factors (3). The diagnosis of ectopic pregnancy is based on quantitative serum b-hCG measurement and transvaginal ultrasonography, although it is sometimes diagnosed intraoperatively if the patient is hemodynamically unstable or has hemoperitoneum. Typically, evidence of an intrauterine gestation will be visualized on a transvaginal ultrasound when the b-hCG level is between 1500 and 2000 mIU/mL; this is classically referred to as the ‘‘discriminatory zone’’ (3). If the b-hCG level is >2000 mIU/mL and there is no evidence of an intrauterine gestation, this raises concern for ectopic pregnancy (3). The caveat to this scenario is with a gestation containing multiple pregnancies (i.e., twins, triplets) where the b-hCG level may be >2000 mIU/mL before there is evidence of an intrauterine gestation on transvaginal ultrasound (3,13). For this reason, it has been suggested that the level of the discriminatory zone be increased to at least 3000 mIU/mL to account for the possibility of multiple gestations and avoid inappropriate administration of methotrexate to a potentially viable pregnancy (13). When the b-hCG level is <1500 mIU/mL and there is no evidence of an intrauterine gestation on ultrasound, there are several outcomes. If b-hCG is <1500 mIU/mL and transvaginal ultrasound

Spontaneous Bilateral Tubal Ectopic Pregnancies After Methotrexate

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Figure 1. Right adnexal mass. Ultrasound image of previously visualized right adnexal mass at return emergency visit—mass measured 21  13  14 mm.

shows findings consistent with an ectopic pregnancy (absence of intrauterine gestational sac and yolk sac, presence of complex adnexal mass, or pseudosac within the endometrial cavity) then consultation with gynecology is warranted to determine whether expectant management with repeat b-hCG level in 48 h versus treatment (medically or surgically) is indicated (1). For those whose b-hCG level is <1500 mIU/mL with no evidence of intraor extrauterine pregnancy on transvaginal ultrasound

(also referred to as ‘‘pregnancy of unknown location’’), repeat b-hCG level in 48 h with close follow-up is typical (4). Although a rise of b-hCG level of <53% at 48 h is highly indicative of an abnormal pregnancy per the American Congress of Obstetricians and Gynecologists (ACOG) guidelines, it does not delineate between an ectopic pregnancy or a failing intrauterine gestation; therefore, ultrasound findings and clinical judgement play a significant role in the management of patients

Figure 2. Left adnexal mass. Ultrasound image of left adnexal mass measuring 20  16  14 mm found at the return visit seven days after initial treatment with methotrexate.

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with a possible ectopic pregnancy (3). However, the presence of a complex adnexal mass with a fetal pole and cardiac activity, regardless of b-hCG level, is diagnostic of an ectopic pregnancy and treatment is indicated (1). According to the ACOG guidelines on medical management of tubal ectopic pregnancy, patients qualify for treatment of a tubal ectopic pregnancy with methotrexate when the patient is hemodynamically stable without evidence of rupture (3). Single- and multidose methotrexate regimens are outlined in the guidelines, but single-dose regimens are more likely to be successful in patients whose b-hCG level is <5000 mIU/mL. After administration of methotrexate (considered day 1), the patient’s b-hCG level is repeated on day 4 and day 7 (3). Expected response to methotrexate treatment is a minimum of a 15% decrease in b-hCG level at day 7 follow-up when compared to day 4 levels (3). In this patient’s case, the b-hCG level declined by 5.9% from day 4 to day 7 after methotrexate administration, indicating an inadequate response to methotrexate, although this was likely compounded by the second ectopic pregnancy. Surgical treatment is indicated for any patient who is clinically or hemodynamically unstable or prefers surgical management (4). Detection of a second tubal ectopic pregnancy typically does not occur until the patient is symptomatic, as was demonstrated in this case where the patient presented 7 days after initial diagnosis and treatment with methotrexate (2). In addition, there is no distinct difference in the presentation of bilateral tubal ectopic pregnancy in comparison to a single tubal ectopic pregnancy (2,7). In this case, the patient had onset of pain on the contralateral side from her initially diagnosed ectopic pregnancy, which raised concerns for referred pain secondary to ruptured ectopic pregnancy. However, the ultrasound demonstrated a second adnexal mass consistent with tubal ectopic pregnancy, explaining the new location of pain. It has been suggested that early detection of continually rising b-hCG levels after surgical management could help to detect a bilateral tubal ectopic pregnancy; however, the application to this case is unclear because rising b-hCG levels could simply indicate incomplete treatment with methotrexate and would not necessarily indicate bilateral tubal ectopic pregnancies in a patient being managed medically (2). Although no specific diagnostic criteria exist for bilateral tubal ectopic pregnancies, it is typically defined by the presence of chorionic villi in each fallopian tube or the presence of cardiac activity within bilateral adnexal masses visualized on pelvic ultrasound (2,10,11). However, the most common way to diagnose bilateral tubal ectopic pregnancies is visually in the operating room with subsequent evaluation of obtained surgical specimens by a pathologist (7). Based on these

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definitions, the patient in this case cannot be definitively diagnosed with bilateral tubal ectopic pregnancies; however, the clinical picture and imaging was highly suspicious. Because of the rarity of the condition, there are no specific ACOG guidelines for treatment of bilateral tubal ectopic pregnancies. The majority of previously reported cases of bilateral tubal ectopic pregnancies were diagnosed at the time of surgery, and there are no prior reported cases where methotrexate was successfully used for management of this condition (11). However, in this case, gynecology felt that because the patient was hemodynamically stable, had no evidence of rupture, and the patient desired conservative management with methotrexate that the guidelines could be extrapolated and used in this case to help guide care. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? As seen in this case report, the diagnosis of bilateral tubal ectopic pregnancies may not occur at the time of initial diagnosis. As such, it is imperative for clinicians to consider the possibility of bilateral tubal ectopic pregnancies in any female who presents with continued or worsening abdominal pain and persistent or abnormally elevated b-hCG level despite prior medical or surgical management of an ectopic pregnancy. In addition, the use of methotrexate in this patient demonstrates that despite the likely presence of bilateral tubal ectopic pregnancies (which we are unable to confirm because the patient did not undergo surgical management and no cardiac activity was visualized on ultrasound) medical management is an option in conjunction with gynecology consultation if the patient’s clinical picture is appropriate (based on b-hCG level and trend, size of ectopic pregnancy, patient preference, no contraindications to methotrexate administration) and there is low suspicion of ruptured ectopic pregnancy (3,8). REFERENCES 1. Yamane D, Stella M, Goralnick E. Twin ectopic pregnancy. J Emerg Med 2015;48:e139–40. 2. Ryan MT, Saldana B. Bilateral tubal ectopic pregnancy: a tale of caution. Acad Emerg Med 2000;7:1160–3. 3. American Congress of Obstetricians and Gynecologists. ACOG Practice Bulletin: medical management of ectopic pregnancy. Obstet Gynecol 2008;111:1479–85. 4. Sivalingam VN, Duncan WC, Kirk E, Shephard LA, Horne AW. Diagnosis and management of ectopic pregnancy. J Fam Plann Reprod Health Care 2011;37:231–40. 5. Marion LL, Meeks GR. Ectopic pregnancy: history, incidence, epidemiology, and risk factors. Clin Obstet Gynecol 2012;55: 376–86. 6. Brady J, Wilson M. Spontaneous bilateral tubal ectopic pregnancy. J R Soc Med 2005;98:120–1. 7. Andrews J, Farrell S. Spontaneous bilateral tubal pregnancies: a case report. J Obstet Gynaecol Can 2008;30:51–4.

Spontaneous Bilateral Tubal Ectopic Pregnancies After Methotrexate 8. Basly M, Achour R, Ben Aissa I, Ben Abdala A, Ben Jemaa S, Chibani M, Rachdi R. Extra-uterine twin pregnancy. Case report of spontaneous bilateral tubal ectopic pregnancy. Int J Gynaecol Obstet 2012;16. 9. Greenberg JA. Bilateral ectopic pregnancy. Rev Obstet Gynecol 2008;1:48. 10. Mandal RD, Ghosh S, Mitra S, Basak A, Naskar P, Seth K, Halder A. Bilateral tubal pregnancy: a diagnostic dilemma. Open J Obstet Gynecol 2013;3:639–41.

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11. Sentilhes L, Bouet PE, Jalle T, Boussion F, LefebvreLacoeuille C, Descamps P. Ultrasound diagnosis of spontaneous bilateral tubal pregnancy. Aust N Z J Obstet Gynaecol 2009;49: 695–701. 12. Tay JI, Moore J, Walker JJ. Ectopic pregnancy. West J Med 2000; 173:131–4. 13. Doubilet PM, Benson CB, Bourne T, Blaivas M. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med 2013;369:1443–51.