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.

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.

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.

Abdominal pregnancy, Ectopic pregnancy, In vitro fertilization, IVF-ET

Ectopic pregnancy is the leading cause of maternal mor- bidity and mortality during the first trimester and the in- cidence increases dramatically with assisted reproductive technology (ART), occurring in approximately 1.5 –2.1% of patients undergoing IVF [1, 2]. The majority of ec- topic pregnancies from either IVF or spontaneous preg- nancy 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 –9]. How- ever, very little data exists regarding risk factors for abdominal ectopic pregnancy after IVF. * Correspondence: [email protected] Division of Reproductive Endocrinology & Infertility, Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yoder et al. Reproductive Biology and Endocrinology (2016) 14:69 DOI 10.1186/s12958-016-0201-x 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 pa- tients 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 sonohystero- gram. Her first IVF cycle with an elective single embryo transfer resulted in a negative pregnancy test. Her sec- ond IVF cycle used a GnRH antagonist stimulation protocol and she was triggered with Ovidrel on stimula- tion 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 approxi- mately 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 con- tinued 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 asso- ciated 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 coun- seled 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 diag- nostic laparoscopy for treatment of ectopic pregnancy after failure of methotrexate therapy. The patient contin- ued to be asymptomatic with no vaginal bleeding or ab- dominal 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 diffi- culty 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 ec- topic 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 ’,a n d ‘het- erotopic pregnancy ’. To the best of our knowledge, all reported cases and avail able data are summarized in Table 2.

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 fac- tor in 4 (14 %) cases, pelvic adhesive disease in 2 (7 %) cases, structural/DES exposure in 2 (7 %) cases, unex- plained in 4 (14 %) cases, and one case did not specify the cause. Overall, anatomic/structural factors accounted Table 1 Beta hCG level and timeline of events Day Beta HCG pg/mL Event −5 Oocyte retrieval, ICSI 0 Day 5 single embryo transfer 9 28.7 11 45.5 13 130 15 382 17 991 19 2020 28 12,400 Sac Check - No IUP or adnexal abnormalities 29 13,000 Methotrexate given 32 20,000 33 TVUS - Right adnexal mass with gestational sac and fetal cardiac activity 34 Diagnostic laparoscopy - Abdominal ectopic Yoder et al. Reproductive Biology and Endocrinology (2016) 14:69 Page 2 of 10 for 17 (61 %) of the cases. A history of ectopic preg- nancy was identified in 11 (39 %) cases. History of tubal surgery had been described in 14 (50 %) cases, 9 (32 %) of which were bilateral salpingectomy. Transfer of more than two embryos was reported in 15 (54 %) cases, two embryos were transferred in 7 (25 %) cases, while single embryo transfer was reported in only two (7 %) cases. No information about number of embryos transferred was available in 4 (14 %) cases. Fresh embryo transfer accounted for 20 (71 %) cases, frozen embryo transfer in 3 (11 %) cases, and 5 (18 %) cases did not specify fresh versus frozen embryo transfer. Heterotopic abdominal pregnancy occurred in 13 (46 %) cases, and 15 (54 %) were abdominal ectopic pregnancies. Notable cases in- clude 5 retroperitoneal ectopic pregnancies, an abdom- inal fetal demise at 28 weeks, and 4 cases of viable abdominal pregnancies at 30 weeks, 32 weeks (two cases), and 34 weeks gestation.

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 chal- lenge 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 preg- nancies after ART when compared to rates in spontan- eous 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 ab- dominal ectopic pregnancies after IVF, our systematic Fig. 1 Diagnostic laparoscopy demonstrating hemoperitoneum ( top image) and products of conception implanted in the posterior cul-de-sac (bottom image) Yoder et al. Reproductive Biology and Endocrinology (2016) 14:69 Page 3 of 10 Table 2 Abdominal ectopic case reports Author (year) Age/ Parity Infertility etiology Other pertinent history Priorectopic Stimulation Protocol Egg # ET no./ timing Fresh/ Frozen ET Max HCG level (mIU/ ml) Location (E/H) Stage at diagnosis Rupture? Intervention Outcome Oehniger (1988) [23] 35 yo G0P0 Endometriosis Laparotomy x 2, left salpingectomy, frozen pelvis; Right hydrosalpinx with partial obstruction No FSH/Pergonal (hMG/hCG), hCG trigger 44 42– 44 h Fresh NA Sigmoid mesentery (E) ~41 days PT No Exploratory Laparotomy Removal of pregnancy tissue by laparotomy Bassil (1991) [24] 33 yo NA Male factor NA NA Clomid/hMG, hCG trigger 64 NA Fresh NA Posterior uterus, broad ligament (H) 19 weeks gestation No Laparotomy, right adnexectomy Delivery of viable twins at 34 weeks Ferland (1991) [25] 32 yo G4P0030 DES exposure, secondary infertility Right salpingectomy, left hydrosalpinx Tubal ectopic Long protocol w/ GnRH agonist 73 Day 2E T Fresh 19,450 Retroperitoneal (E) 37 days PT Yes Laparotomy, left salpingectomy Ragni (1991) [26] 32 yo G1P0010 Pelvic adhesive disease Right adnexectomy, hysteropexy Tubal ectopic Long protocol w/ GnRH agonist 43 Day 2E T Fresh NA Right adnexa (H) 12 weeks gestation No Selective reduction of abdominal pregnancy, laparotomy Laparotomy for resorbing abdominal pregnancy, SAB of IUP at 16 weeks Balmaceda (1993) [ 27] 33 yo G3P1021 Tubal Right salpingectomy, left salpingostomy Tubal Ectopic x2 Short protocol, w/ GnRH agonist 15 4 Day 4E T Fresh 4651 Abdominal - broad ligament (E) 30 days PT No Laparoscopy, salpingectomy Laparoscopic removal of abdominal ectopic, left salpingectomy Fisch (1995) [28] 32 yo G2P0020 Tubal Bilateral salpingectomy Tubal ectopic x2 Long protocol w/ GnRH agonist 53 NA Fresh NA Ileum, left uterine cornua (H) 10 weeks gestation Yes Gastrostoscopy, sigmoidoscopy, Tc scan, angiography, D&C, tagged RBC scan, Laparotomy Laparotomy for abdominal ectopic, D&C for incomplete AB of IUP DelRosario (1996) [ 29] 33 yo G1P1001 Tubal Breast Cancer No NA NA 4 NA Frozen 563 Bladder (E) 75 days PT Yes Methotrexate, laparoscopy Laparoscopic removal of pregnancy tissue Yoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 4 of 10 Table 2 Abdominal ectopic case reports (Continued) Fisch (1996) [11] 38 yo G2P0020 Tubal Laparoscopic Salpingectomy x2, 8th IVF cycle Tubal ectopic x 2 Long protocol w/ GnRH agonist 14 4 Day 3E T Fresh 1730 Broad Ligament (E) 21 days PT Yes Exploratory Laparotomy Removal of pregnancy tissue by laparotomy Moonen- Delarue (1996) [30] 23 yo G2P0020 Pelvic adhesive disease Right salpingectomy Tubal and abdominal ectopic NA NA NA NA Fresh NA Abdominal - uterine fundus (E) 28 weeks Placental abruption Laparotomy Fetal demise of abdominal ectopic @ 28 weeks Pisarska (1998) [31] 35 yo G2P0020 Unexplained NA No Long protocol w/ GnRH agonist 96 NA Fresh 6004 Bladder serosa (H) 6 weeks gestation No Diagnostic laparoscopy Laparoscopic removal of ectopic pregnancy (bladder), term delivery of IUP Deshpande (1999) [ 32] 33 yo G1P0010 Endometriosis Endometriosis, left salpingectomy, Patent right tube No Long protocol w/ GNRH agonist 82 Day 3E T Fresh 55,560 Twin pregnancy in broad ligament (H) 7 weeks PT No Laparotomy Removal of twin ectopic pregnancy by laparotomy at 7 weeks Scheiber (1999) [33] 37 yo G3P0030 Tubal factor EndometriosisDOR Salpingostomy, donor oocytes Tubal ectopic NA NA 2 Day 3E T Frozen NA Abdominal (H) 8.5 weeks PT No KCl selective reduction of abdominal pregnancy Selective reduction of abdominal pregnancy, full term viable IUP Dmowski (2002) [34] 34 yo G0P0 Tubal Bilateral Salpingectomy No Long protocol w/ GnRH agonist 15 3 Day 3E T Fresh 38,635 Retroperitoneal pancreatic (E) 41 days PT Yes Laparotomy Retroperitoneal subpancreatic ectopic removed by laparotomy Jain (2002) [35] 29 yo G0P0 Unexplained NA No NA NA 2 NA NA NA Pouch of Douglas (H) 9 weeks PT NA Laparotomy at 4w weeks (no IUP seen), selective reduction of ectopic at 13 weeks Selective reduction of abdominal ectopic, removal by laparotomy, SAB of IUP Cormio (2003) [36] 30 yo G2P0020 Tubal Bilateral salpingectomy Tubal ectopic x2 Menotropins, hCG trigger 74 Day 3E T Fresh 256,400 Omentum, uterine fundus (H) 13 weeks gestation No Laparotomy Laparotomy for abdominal ectopic; Live IUP delivered at 36 weeks Reid (2003) [37] 28 yo G5P1041 Tubal bilateral salpingectomy Tubal ectopic x3 NA NA 3 NA NA 5500 Retroperitoneal, iliac bifurcation (E) 63 days PT NA Laparotomy Removal of ectopic via laparotomy Yoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 5 of 10 Table 2 Abdominal ectopic case reports (Continued) Kitade (2005) [38] 37 yo G0P0 Unexplained NA No Long protocol w/ GnRH agonist 12 3 Day 3E T Fresh 45,896 Splenic and Tubal (H) 34 days PT (tubal), 46 day PT (splenic) Tubal - No, Splenic - Yes 1) Laparoscopic salpingectomy 2) Exploratory laparotomy Removal of tubal ectopic by laparoscopy, removal of splenic ectopic by laparotomy (12 days later) Ali (2006) [39] 35 NA Tubal Pelvic adhesions No NA 11 1 NA Fresh 1524 Tube with Omental/ peritoneal trophoblastic tissue (H) 3 weeks PT - tubal ectopic; 5 weeks PT – omental tissue No Laparoscopic salpingectomy; Laparocopic removal of omental/ peritoneal trophoblastic tissue Removal of tubal and peritoneal/ omental pregnancy tissue by 2 laparoscopies Apantaku (2006) [40] 33 G3P1021 Tubal Bilateral salpingectomy Tubal ectopic x2 NA NA 2 NA Fresh NA Right adnexa (E) 6 weeks PT No Laparoscopy Laparoscopic removal of pregnancy tissue Knopman (2007) [41] 37 yo G4P0040 Unexplained NA No GnRH antagonist 92 Day 5E T Fresh 1023 Posterior cul-de- sac (H) 7 weeks, nonviable IUP; 9 weeks ectopic Yes Laparoscopy D&C for non- viable IUP; Laparoscopy for abdominal ectopic Shih (2007) [42] 33 yo G0P0 Male Factor Patent tubes No Long protocol w/ GnRH agonist 4N A NA Fresh 901 Cul-de-sac (E) 28 days PT No Laparoscopy converted to laparotomy Removal of pregnancy tissue by laparotomy Shojai (2007) [43] 35 yo G0P0 Structural, DES exposure NA No NA NA 3 NA NA NA Abdominal - uterine fundus (H) 21 weeks gestation No Laparotomy Delivery of viable twins at 32 weeks Iwama (2008) [44] 31 yo G1P0010 Tubal Right Salpingectomy for tubal ectopic after IVF, left salpingectomy for hydrosalpinx Tubal ectopic NA NA 3 Day 3E T Fresh 45, 369 Inferior Vena Cava/ Retroperitoneal (E) 32 days PT: PUL; 53 days PT: retroperitoneal ectopic Yes D&C, MTX, Diagnostic laparoscopy, repeat MTX, Exploratory laparotomy Ruptured retroperitoneal ectopic, removed by laparotomy Hyvarinen (2009) [ 45] NA NA NA NA NA NA NA NA NA NA NA Abdominal (E) 30 weeks gestation No Laparotomy Delivery of viable fetus at 30 weeks Zacche (2011) [46] 36 G1P1 Tubal Bilateral Salpingectomy, PID No NA NA 2 NA Fresh NA Abdominal (H) 32 weeks at Cesarean Delivery No Laparotomy, hysterectomy Viable twin pregnancies at 32 weeks; Hysterectomy Yoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 6 of 10 Table 2 Abdominal ectopic case reports (Continued) Angelova (2015) [47] 33 NA Male Factor Obturated left tube NA Short protocol, w/ GnRH antagonist NA 2 Day 3E T Fresh NA Abdominal - vesicouterine junction (E) 23 days PT No Laparoscopy Laparoscopic removal of pregnancy tissue Dalmia (2015) [48] 37 G1P0010 EndometriosisTubal factor Bilateral salpingectomy for hydrosalpinx NA NA NA NA NA NA 21,730 Left adnexa (E) 2 weeks PT No Mini- laparotomy Removal of ectopic via laparotomy Koyama (2015) [49] 32 G5P1 Male Factor NA No NA NA 1 NA Frozen 14,800 Retroperitoneal (E) 10 weeks gestation NA Laparoscopy Laparoscopic removal of pregnancy tissue Abbreviations: AB Abortion, D&C Dilation and curettage, DES Diethylstilbestrol, E Ectopic, FSH Follicle stimulating hormone, GnRH Gonadotropin-releasing hormone, H Heterotopic, hCG Human chorionic gonadotropin, hMG Human menopausal gonadotropin, HSG Hysterosalpingogram, IUP Intrauterine pregnancy, IVF In vitro fertilization, KCl Potassium chloride, MTX Methotrexate, NA Not available, PID Pelvic inflammatory disease, PT Post transfer, RBC Red blood cell, Tc Technetium, SAB Spontaneous abortion Yoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 7 of 10 review demonstrates several trends among reported cases. First, the majority of cases (61 %) report a history of anatomic/structural infertility etiology with history of tubal factor infertility (TFI) (46 %) being the most com- mon. This is consistent with TFI being a known risk fac- tor for ectopic pregnancy following IVF. One study that examined the risk factors for EP following IVF in 712 women reported an odds ratio (OR) of 3.99 (95 % CI: 1.23 to 12.98) for women with TFI compared to those with other infertility causes [12]. In a larger, more recent study of 553,577 ART cycles in the US, among all infer- tility diagnoses, TFI was the only one significantly asso- ciated with increased risk for ectopic pregnancy (adjusted relative risk (RR) 1.25, 95 % CI 1.16 –1.35) [13]. In addition, history of tubal ectopic pregnancy was par- ticularly common, being reported in 37 % of the abdom- inal ectopic cases. This also appears to be consistent with the general ART-associated EP literature. A retro- spective study that measured the risk of EP following IVF in 181 women with a previous ectopic demonstrated a 45-fold higher risk of recurrence when compared with 377 women with other causes of infertility. The authors reported that the prevalence of EP was 8.95 % compared with 0.75 % in the control group [14]. History of prior tubal surgery was also particularly common (50 %) among abdominal ectopic cases in our systematic review. A history of tubal/pelvic surgery is another major risk factor for the development of EP following IVF. Odds ratio for developing EP was 8.52 (95 % CI: 5.91 –12.27) for prior adnexal surgery, 11.02 (95 % CI: 5.49 –22.15) for a previous tubal infertility surgery, 5.16 (95 % CI: 1.25–21.21) for prior surgery for endometriosis and 17.70 (95 % CI: 8.11 –38.66) for a previous abdominal/ pelvic surgery [12, 15, 16]. Interestingly, bilateral salpin- gectomy was the most common tubal surgery reported in our case review. While the exact mechanism of ab- dominal ectopic after bilateral salpingectomy remains unclear, many authors have proposed that it may be due to the development of a micro-fistulous tract after sal- pingectomy. 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 sug- gestions have been made regarding optimal transfer lo- cation within the endometrium, ranging from 5 to 20 mm from the fundal surface, while others recom- mend “mid-cavity” location to avoid proximity to the fal- lopian tubes [17 –19]. Other trends identified in our systematic review in- clude >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 intrauter- ine pregnancy often leads to delayed diagnosis of ab- dominal 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 ab- dominal ectopic until beyond the 12th week of preg- nancy. Unfortunately, this type of delayed diagnosis has the potential to lead to significantly morbid outcomes. In our review, four cases of viable abdominal pregnan- cies were identified, which is an extremely rare outcome. Three of these cases were identified at 19 weeks or be- yond, and all three had attachment of the abdominal placenta to the peritoneal surface of the uterus without involvement of other abdominal organs. Placental at- tachment 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 fro- zen IVF cycles [1, 6]. A limitation of this review is the heterogeneity of re- ported cases and IVF practices which encompass several decades. Further research focusing on more homogenous population may help in better characterizing this rare IVF complication.

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 preg- nancy after IVF including tubal factor infertility, his- tory of tubal ectopic and tubal surgery, higher number of embryos transferred, and fresh embryo transfers. These are consistent with known risk fac- tors for ectopic pregnancy following IVF. Yoder et al. Reproductive Biology and Endocrinology (2016) 14:69 Page 8 of 10 Abbreviations AB: Abortion; ART: Assisted reproduction technologies; D&C: Dilation and curettage; DES: Diethylstilbestrol; E: Ectopic; FSH: Follicle stimulating hormone; GnRH: Gonadotropin-releasing hormone; H: Heterotopic; hCG: Human chorionic gonadotropin; hMG: Human menopausal gonadotropin; HSG: Hysterosalpingogram; IUP: Intrauterine pregnancy; IVF: In vitro fertilization; KCl: Potassium chloride; MTX: Methotrexate; NA: Not available; PID: Pelvic inflammatory disease; PT: Post transfer; RBC: Red blood cell; SAB: Spontaneous abortion; Tc: Technetium

None. Funding None. Availability of data and materials Not applicable. Authors’ contributions NY performed the systematic literature search, extracted and analyzed the data, and wrote the manuscript; RT conceived and designed the study, critically reviewed and revised the manuscript; JRM conceived the study, critically reviewed and revised the manuscript. All authors read and approved the final submission. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable. Ethics approval and consent to participate Since this study used only deidentified patient data, and published data from the literature, no approval from our institutional review board (IRB) was required. Received: 31 August 2016 Accepted: 6 October 2016

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Gynecol Minim Invasive Ther. doi:10.1016/j.gmit.2015.04.006. • We accept pre-submission inquiries  Our selector tool helps you to find the most relevant journal  We provide round the clock customer support  Convenient online submission  Thorough peer review  Inclusion in PubMed and all major indexing services  Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit Submit your next manuscript to BioMed Central and we will help you at every step: Yoder et al. Reproductive Biology and Endocrinology (2016) 14:69 Page 10 of 10