Abdominal ectopic pregnancy after in vitro fertilization and single embryo transfer: a case report and systematic review

Background Ectopic pregnancy is the leading cause of maternal morbidity and mortality during the first trimester and the incidence increases dramatically with assisted-reproductive technology (ART), occurring in approximately 1.5–2.1 % of patients undergoing in-vitro fertilization (IVF). Abdominal ectopic pregnancy is a rare yet clinically significant form of ectopic pregnancy due to potentially high maternal morbidity. While risk factors for ectopic pregnancy after IVF have been studied, very little is known about risk factors specific for abdominal ectopic pregnancy. We present a case of a 30 year-old woman who had an abdominal ectopic pregnancy following IVF and elective single embryo transfer, which was diagnosed and managed by laparoscopy. We performed a systematic literature search to identify case reports of abdominal or heterotopic abdominal ectopic pregnancies after IVF. A total of 28 cases were identified. Results Patients’ ages ranged from 23 to 38 (Mean 33.2, S.D. = 3.2). Infertility causes included tubal factor (46 %), endometriosis (14 %), male factor (14 %), pelvic adhesive disease (7 %), structural/DES exposure (7 %), and unexplained infertility (14 %). A history of ectopic pregnancy was identified in 39 % of cases. A history of tubal surgery was identified in 50 % of cases, 32 % cases having had bilateral salpingectomy. Transfer of two embryos or more (79 %) and fresh embryo transfer (71 %) were reported in the majority of cases. Heterotopic abdominal pregnancy occurred in 46 % of cases while 54 % were abdominal ectopic pregnancies. Conclusions Our systematic review has revealed several trends in reported cases of abdominal ectopic pregnancy after IVF including tubal factor infertility, history of tubal ectopic and tubal surgery, higher number of embryos transferred, and fresh embryo transfers. These are consistent with known risk factors for ectopic pregnancy following IVF. Further research focusing on more homogenous population may help in better characterizing this rare IVF complication and its risks.


Background
Ectopic pregnancy is the leading cause of maternal morbidity and mortality during the first trimester and the incidence increases dramatically with assisted reproductive technology (ART), occurring in approximately 1.5-2.1% of patients undergoing IVF [1,2]. The majority of ectopic pregnancies from either IVF or spontaneous pregnancy occur within the fallopian tubes, but implantation may occur in other locations such as the cervix, ovary, or abdomen [3]. Abdominal ectopic pregnancies are a very rare form of ectopic pregnancy, yet are clinically significant due to their potential for high morbidity and often atypical presentation [4].
Recent studies have attempted to identify risk factors for ectopic pregnancy after IVF. Suggested risk factors include infertility due to tubal factor, endometriosis, transfer at blastocyst stage, higher number of embryos transferred, decreased endometrial thickness, variation in culture media, and fresh embryo transfer [5][6][7][8][9]. However, very little data exists regarding risk factors for abdominal ectopic pregnancy after IVF.
In this case study, we report an abdominal ectopic pregnancy after IVF with fresh single embryo transfer. We also performed a systematic review of the literature for known cases of abdominal ectopic pregnancy after IVF and provide detailed characterization of these patients and risk factors for this rare complication.

Case description
The patient was a 30-year-old G2P0010 who presented to our fertility center seeking fertility treatment. She had a medical history of polycystic ovarian syndrome (PCOS) and her partner had a diagnosis of male factor infertility. She had no prior surgical history, no known allergies, and medications included prenatal vitamins. She denied any history of sexually transmitted infections and had a normal hysterosalpingogram and saline sonohysterogram. Her first IVF cycle with an elective single embryo transfer resulted in a negative pregnancy test. Her second IVF cycle used a GnRH antagonist stimulation protocol and she was triggered with Ovidrel on stimulation day 12. Twenty-two oocytes were retrieved. On day five a single fresh blastocyst was transferred using a pass through technique under ultrasound guidance. A stiff outer sheath was introduced through the cervix and past the internal os. A soft tipped catheter containing the embryo was advanced through the outer sheath and the embryo was expelled into the uterine cavity approximately 1.5 cm from the uterine fundus with good visualization. Beta hCG was positive on post-transfer day 9 and serial beta hCG values were monitored and continued to rise appropriately (Table 1). On day 28 after embryo transfer, the patient underwent a transvaginal ultrasound (TVUS) in the office that did not identify an intrauterine pregnancy (IUP) or any abnormal adnexal structures. She was asymptomatic with no vaginal bleeding or abdominal pain. The patient was sent for a more comprehensive ultrasound evaluation at the associated Maternal Fetal Medicine unit and another beta hCG value was obtained. Repeat scan similarly failed to identify an IUP or visualize an ectopic pregnancy. The beta hCG was 12,400 pg/mL. Given the high beta hCG value in the absence of an IUP, the patient was counseled and advised to take methotrexate treatment for presumed ectopic pregnancy of unknown location. One day later (day 29), she received an intramuscular dose of 83 mg (50 mg/m 2 body surface area) methotrexate with plans to follow up with repeat beta hCG and TVUS.
Four days after methotrexate administration, repeat beta hCG level continued to rise (20,000 pg/mL) and an ultrasound performed 1 day later demonstrated a right adnexal mass with a yolk sac, fetal pole, and fetal cardiac activity. The decision was made to proceed with diagnostic laparoscopy for treatment of ectopic pregnancy after failure of methotrexate therapy. The patient continued to be asymptomatic with no vaginal bleeding or abdominal pain. Diagnostic laparoscopy was performed on day 34 post-embryo transfer. The operative findings were significant for minimal hemoperitoneum (<50 mL) and products of conception were noted to be implanted on the peritoneum of the posterior cul-de-sac medial to the left uterosacral ligament (Fig. 1). The products of conception were removed using graspers without difficulty and hemostasis was obtained with electrocautery and surgicel. All other pelvic organs including uterus and bilateral ovaries and tubes appeared grossly normal in appearance.

Systematic review of the literature
A systematic literature review was performed with the aim of identifying all other case reports of abdominal ectopic pregnancies after IVF. The literature search was performed using PubMed, Google Scholar, and EMBASE without language restriction encompassing publications until July 2016. Search terms used included 'IVF' , 'ectopic pregnancy' , 'abdominal ectopic pregnancy' , and 'heterotopic pregnancy'. To the best of our knowledge, all reported cases and available data are summarized in Table 2.

Results
A total of 28 cases of abdominal ectopic pregnancy after IVF were identified. The age of patients ranged from 23 to 38 yo (Mean = 33.2 S.D. = 3.2), with no age reported in 1 case. Infertility causes included tubal factor in 13 (46 %) cases, endometriosis in 4 (14 %) cases, male factor in 4 (14 %) cases, pelvic adhesive disease in 2 (7 %) cases, structural/DES exposure in 2 (7 %) cases, unexplained in 4 (14 %) cases, and one case did not specify the cause. Overall, anatomic/structural factors accounted

Discussion
Abdominal ectopic pregnancies comprise less than 1 % of all ectopic pregnancies, yet have a maternal mortality rate eight times greater than tubal ectopic pregnancies [10]. For this reason, early recognition and treatment is crucial in the setting of abdominal ectopic pregnancy. The case presented demonstrates the diagnostic challenge of abdominal ectopic, as the patient's beta hCG values followed a normal rise and the patient remained asymptomatic up to the point of diagnostic laparoscopy. Transvaginal ultrasound did not visualize the ectopic pregnancy until the beta hCG value was 20,000 pg/mL, which is far beyond the usual discriminatory zone. This atypical presentation of an ectopic pregnancy highlights the need to consider abdominal ectopic pregnancy in the differential of any pregnancy of unknown location after IVF, especially in the setting of non-diagnostic transvaginal ultrasound. There appears to be an increased rate of ectopic pregnancies after ART when compared to rates in spontaneous pregnancy [11]. As the number of IVF procedures performed continues to rise, the incidence of ectopic and abdominal ectopic pregnancy will likely also rise. While there are still relatively few reported cases of abdominal ectopic pregnancies after IVF, our systematic      [12,15,16]. Interestingly, bilateral salpingectomy was the most common tubal surgery reported in our case review. While the exact mechanism of abdominal ectopic after bilateral salpingectomy remains unclear, many authors have proposed that it may be due to the development of a micro-fistulous tract after salpingectomy. Uterine perforation during embryo transfer has also been suggested as a mechanism for abdominal ectopic pregnancy, and embryo transfer technique has been related to overall EP risk after IVF. Aspects of the transfer that may increase risk of EP include large volume of transfer media, induction of abnormal uterine contractions, and location of embryo transfer in relation to the uterine fundus [9]. These factors have all been associated with retrograde flow of both transfer media and the embryo toward the fallopian tubes. Many suggestions have been made regarding optimal transfer location within the endometrium, ranging from 5 to 20 mm from the fundal surface, while others recommend "mid-cavity" location to avoid proximity to the fallopian tubes [17][18][19].
Other trends identified in our systematic review include >1 embryo transferred (reported in 79 % of cases) and a large number of heterotopic abdominal pregnancy (reported in 46 % of cases). Multiple embryo transfer has always been associated with increased risk of EP with transfer of two or less embryos carrying lower risk than after three or more embryos [20]. In the setting of multiple embryo transfers, identification of an intrauterine pregnancy often leads to delayed diagnosis of abdominal pregnancy in the absence of clinical symptoms. Among the heterotopic cases, 4 reported a 2 week delay in diagnosis of the abdominal ectopic from the time of suspected ectopic, and 5 cases did not identify the abdominal ectopic until beyond the 12th week of pregnancy. Unfortunately, this type of delayed diagnosis has the potential to lead to significantly morbid outcomes. In our review, four cases of viable abdominal pregnancies were identified, which is an extremely rare outcome. Three of these cases were identified at 19 weeks or beyond, and all three had attachment of the abdominal placenta to the peritoneal surface of the uterus without involvement of other abdominal organs. Placental attachment to the uterus has previously been associated with viability of abdominal pregnancies [21], and with a relatively lower risk of bleeding and lower likelihood of fetal growth retardation [22].
Finally, abdominal ectopic pregnancies were far more common in fresh embryo transfer (71 % of cases) than frozen embryo transfer (11 % of cases). This may be due to the fact that frozen embryo transfer has become widely used only recently, and we may begin to see higher frequency with frozen embryo transfers over time. However, several recent studies indicate that ectopic pregnancy rates are higher for fresh as compared to frozen IVF cycles [1,6].
A limitation of this review is the heterogeneity of reported cases and IVF practices which encompass several decades. Further research focusing on more homogenous population may help in better characterizing this rare IVF complication.

Conclusions
In conclusion, ectopic pregnancy, including abdominal ectopic, is a known risk of IVF. The case reported highlights the diagnostic challenges behind this rare form of ectopic pregnancy, and the need to keep it in the differential in atypical ectopic presentations. Our systematic literature review has revealed several trends in reported cases of abdominal ectopic pregnancy after IVF including tubal factor infertility, history of tubal ectopic and tubal surgery, higher number of embryos transferred, and fresh embryo transfers. These are consistent with known risk factors for ectopic pregnancy following IVF.