{"paper_id":"f4918504-8e45-47d5-904b-15a2adcf1bcb","body_text":"R E V I E W Open Access\nAbdominal ectopic pregnancy after in vitro\nfertilization and single embryo transfer:\na case report and systematic review\nNicole Yoder, Reshef Tal * and J. Ryan Martin\nAbstract\nBackground: Ectopic pregnancy is the leading cause of maternal morbidity and mortality during the first trimester\nand the incidence increases dramatically with assisted-reproductive technology (ART), occurring in approximately 1.\n5–2.1 % of patients undergoing in-vitro fertilization (IVF). Abdominal ectopic pregnancy is a rare yet clinically\nsignificant form of ectopic pregnancy due to potentially high maternal morbidity. While risk factors for ectopic\npregnancy after IVF have been studied, very little is known about risk factors specific for abdominal ectopic\npregnancy. We present a case of a 30 year-old woman who had an abdominal ectopic pregnancy following\nIVF and elective single embryo transfer, which was diagnosed and managed by laparoscopy. We performed a\nsystematic literature search to identify case reports of abdominal or heterotopic abdominal ectopic pregnancies\nafter IVF. A total of 28 cases were identified.\nResults: Patients’ ages ranged from 23 to 38 (Mean 33.2, S.D. = 3.2). Infertility causes included tubal factor (46 %),\nendometriosis (14 %), male factor (14 %), pelvic adhesive disease (7 %), structural/DES exposure (7 %), and\nunexplained infertility (14 %). A history of ectopic pregnancy was identified in 39 % of cases. A history of tubal\nsurgery was identified in 50 % of cases, 32 % cases having had bilateral salpingectomy. Transfer of two embryos\nor more (79 %) and fresh embryo transfer (71 %) were reported in the majority of cases. Heterotopic abdominal\npregnancy occurred in 46 % of cases while 54 % were abdominal ectopic pregnancies.\nConclusions: Our systematic review has revealed several trends in reported cases of abdominal ectopic pregnancy\nafter IVF including tubal factor infertility, history of tubal ectopic and tubal surgery, higher number of embryos\ntransferred, and fresh embryo transfers. These are consistent with known risk factors for ectopic pregnancy\nfollowing IVF. Further research focusing on more homogenous population may help in better characterizing this\nrare IVF complication and its risks.\nKeywords: Abdominal pregnancy, Ectopic pregnancy, In vitro fertilization, IVF-ET\nBackground\nEctopic pregnancy is the leading cause of maternal mor-\nbidity and mortality during the first trimester and the in-\ncidence increases dramatically with assisted reproductive\ntechnology (ART), occurring in approximately 1.5 –2.1%\nof patients undergoing IVF [1, 2]. The majority of ec-\ntopic pregnancies from either IVF or spontaneous preg-\nnancy occur within the fallopian tubes, but implantation\nmay occur in other locations such as the cervix, ovary,\nor abdomen [3]. Abdominal ectopic pregnancies are a\nvery rare form of ectopic pregnancy, yet are clinically\nsignificant due to their potential for high morbidity and\noften atypical presentation [4].\nRecent studies have attempted to identify risk factors\nfor ectopic pregnancy after IVF. Suggested risk factors\ninclude infertility due to tubal factor, endometriosis,\ntransfer at blastocyst stage, higher number of embryos\ntransferred, decreased endometrial thickness, variation\nin culture media, and fresh embryo transfer [5 –9]. How-\never, very little data exists regarding risk factors for\nabdominal ectopic pregnancy after IVF.\n* Correspondence: reshef.tal@yale.edu\nDivision of Reproductive Endocrinology & Infertility, Department of\nObstetrics, Gynecology, & Reproductive Sciences, Yale University School of\nMedicine, 333 Cedar Street, New Haven, CT 06510, USA\n© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nYoder et al. Reproductive Biology and Endocrinology  (2016) 14:69 \nDOI 10.1186/s12958-016-0201-x\n\nIn this case study, we report an abdominal ectopic\npregnancy after IVF with fresh single embryo transfer.\nWe also performed a systematic review of the literature\nfor known cases of abdominal ectopic pregnancy after\nIVF and provide detailed characterization of these pa-\ntients and risk factors for this rare complication.\nCase description\nThe patient was a 30-year-old G2P0010 who presented\nto our fertility center seeking fertility treatment. She had\na medical history of polycystic ovarian syndrome (PCOS)\nand her partner had a diagnosis of male factor infertility.\nShe had no prior surgical history, no known allergies,\nand medications included prenatal vitamins. She denied\nany history of sexually transmitted infections and had a\nnormal hysterosalpingogram and saline sonohystero-\ngram. Her first IVF cycle with an elective single embryo\ntransfer resulted in a negative pregnancy test. Her sec-\nond IVF cycle used a GnRH antagonist stimulation\nprotocol and she was triggered with Ovidrel on stimula-\ntion day 12. Twenty-two oocytes were retrieved. On day\nfive a single fresh blastocyst was transferred using a pass\nthrough technique under ultrasound guidance. A stiff\nouter sheath was introduced through the cervix and past\nthe internal os. A soft tipped catheter containing the\nembryo was advanced through the outer sheath and the\nembryo was expelled into the uterine cavity approxi-\nmately 1.5 cm from the uterine fundus with good\nvisualization. Beta hCG was positive on post-transfer day\n9 and serial beta hCG values were monitored and con-\ntinued to rise appropriately (Table 1). On day 28 after\nembryo transfer, the patient underwent a transvaginal\nultrasound (TVUS) in the office that did not identify an\nintrauterine pregnancy (IUP) or any abnormal adnexal\nstructures. She was asymptomatic with no vaginal\nbleeding or abdominal pain. The patient was sent for a\nmore comprehensive ultrasound evaluation at the asso-\nciated Maternal Fetal Medicine unit and another beta\nhCG value was obtained. Repeat scan similarly failed to\nidentify an IUP or visualize an ectopic pregnancy. The\nbeta hCG was 12,400 pg/mL. Given the high beta hCG\nvalue in the absence of an IUP , the patient was coun-\nseled and advised to take methotrexate treatment for\npresumed ectopic pregnancy of unknown location. One\nday later (day 29), she received an intramuscular dose of\n83 mg (50 mg/m 2 body surface area) methotrexate with\nplans to follow up with repeat beta hCG and TVUS.\nFour days after methotrexate administration, repeat\nbeta hCG level continued to rise (20,000 pg/mL) and an\nultrasound performed 1 day later demonstrated a right\nadnexal mass with a yolk sac, fetal pole, and fetal cardiac\nactivity. The decision was made to proceed with diag-\nnostic laparoscopy for treatment of ectopic pregnancy\nafter failure of methotrexate therapy. The patient contin-\nued to be asymptomatic with no vaginal bleeding or ab-\ndominal pain. Diagnostic laparoscopy was performed on\nday 34 post-embryo transfer. The operative findings\nwere significant for minimal hemoperitoneum (<50 mL)\nand products of conception were noted to be implanted\non the peritoneum of the posterior cul-de-sac medial to\nthe left uterosacral ligament (Fig. 1). The products of\nconception were removed using graspers without diffi-\nculty and hemostasis was obtained with electrocautery\nand surgicel. All other pelvic organs including uterus\nand bilateral ovaries and tubes appeared grossly normal\nin appearance.\nSystematic review of the literature\nA systematic literature review was performed with the\naim of identifying all other case reports of abdominal ec-\ntopic pregnancies after IVF. The literature search was\nperformed using PubMed, Google Scholar, and EMBASE\nwithout language restriction encompassing publications\nuntil July 2016. Search terms used included ‘IVF’, ‘ectopic\npregnancy ’, ‘abdominal ectopic pregnancy ’,a n d ‘het-\nerotopic pregnancy ’. To the best of our knowledge,\nall reported cases and avail able data are summarized\nin Table 2.\nResults\nA total of 28 cases of abdominal ectopic pregnancy after\nIVF were identified. The age of patients ranged from 23\nto 38 yo (Mean = 33.2 S.D. = 3.2), with no age reported\nin 1 case. Infertility causes included tubal factor in 13\n(46 %) cases, endometriosis in 4 (14 %) cases, male fac-\ntor in 4 (14 %) cases, pelvic adhesive disease in 2 (7 %)\ncases, structural/DES exposure in 2 (7 %) cases, unex-\nplained in 4 (14 %) cases, and one case did not specify\nthe cause. Overall, anatomic/structural factors accounted\nTable 1 Beta hCG level and timeline of events\nDay Beta HCG pg/mL Event\n−5 Oocyte retrieval, ICSI\n0 Day 5 single embryo transfer\n9 28.7\n11 45.5\n13 130\n15 382\n17 991\n19 2020\n28 12,400 Sac Check - No IUP or adnexal abnormalities\n29 13,000 Methotrexate given\n32 20,000\n33 TVUS - Right adnexal mass with gestational sac\nand fetal cardiac activity\n34 Diagnostic laparoscopy - Abdominal ectopic\nYoder et al. Reproductive Biology and Endocrinology  (2016) 14:69 Page 2 of 10\n\nfor 17 (61 %) of the cases. A history of ectopic preg-\nnancy was identified in 11 (39 %) cases. History of tubal\nsurgery had been described in 14 (50 %) cases, 9 (32 %)\nof which were bilateral salpingectomy. Transfer of more\nthan two embryos was reported in 15 (54 %) cases, two\nembryos were transferred in 7 (25 %) cases, while single\nembryo transfer was reported in only two (7 %) cases.\nNo information about number of embryos transferred\nwas available in 4 (14 %) cases. Fresh embryo transfer\naccounted for 20 (71 %) cases, frozen embryo transfer in\n3 (11 %) cases, and 5 (18 %) cases did not specify fresh\nversus frozen embryo transfer. Heterotopic abdominal\npregnancy occurred in 13 (46 %) cases, and 15 (54 %)\nwere abdominal ectopic pregnancies. Notable cases in-\nclude 5 retroperitoneal ectopic pregnancies, an abdom-\ninal fetal demise at 28 weeks, and 4 cases of viable\nabdominal pregnancies at 30 weeks, 32 weeks (two\ncases), and 34 weeks gestation.\nDiscussion\nAbdominal ectopic pregnancies comprise less than 1 %\nof all ectopic pregnancies, yet have a maternal mortality\nrate eight times greater than tubal ectopic pregnancies\n[10]. For this reason, early recognition and treatment is\ncrucial in the setting of abdominal ectopic pregnancy.\nThe case presented demonstrates the diagnostic chal-\nlenge of abdominal ectopic, as the patient ’s beta hCG\nvalues followed a normal rise and the patient remained\nasymptomatic up to the point of diagnostic laparoscopy.\nTransvaginal ultrasound did not visualize the ectopic\npregnancy until the beta hCG value was 20,000 pg/mL,\nwhich is far beyond the usual discriminatory zone. This\natypical presentation of an ectopic pregnancy highlights\nthe need to consider abdominal ectopic pregnancy in\nthe differential of any pregnancy of unknown location\nafter IVF, especially in the setting of non-diagnostic\ntransvaginal ultrasound.\nThere appears to be an increased rate of ectopic preg-\nnancies after ART when compared to rates in spontan-\neous pregnancy [11]. As the number of IVF procedures\nperformed continues to rise, the incidence of ectopic\nand abdominal ectopic pregnancy will likely also rise.\nWhile there are still relatively few reported cases of ab-\ndominal ectopic pregnancies after IVF, our systematic\nFig. 1 Diagnostic laparoscopy demonstrating hemoperitoneum ( top image) and products of conception implanted in the posterior cul-de-sac\n(bottom image)\nYoder et al. Reproductive Biology and Endocrinology  (2016) 14:69 Page 3 of 10\n\nTable 2 Abdominal ectopic case reports\nAuthor\n(year)\nAge/\nParity\nInfertility\netiology\nOther pertinent\nhistory\nPriorectopic Stimulation\nProtocol\nEgg\n#\nET\nno./\ntiming\nFresh/\nFrozen\nET\nMax\nHCG\nlevel\n(mIU/\nml)\nLocation (E/H) Stage at\ndiagnosis\nRupture? Intervention Outcome\nOehniger\n(1988)\n[23]\n35 yo\nG0P0\nEndometriosis Laparotomy x\n2, left\nsalpingectomy,\nfrozen pelvis;\nRight\nhydrosalpinx\nwith partial\nobstruction\nNo FSH/Pergonal\n(hMG/hCG),\nhCG trigger\n44\n42–\n44 h\nFresh NA Sigmoid\nmesentery (E)\n~41 days PT No Exploratory\nLaparotomy\nRemoval of\npregnancy\ntissue by\nlaparotomy\nBassil\n(1991)\n[24]\n33 yo\nNA\nMale factor NA NA Clomid/hMG,\nhCG trigger\n64\nNA\nFresh NA Posterior uterus,\nbroad ligament\n(H)\n19 weeks\ngestation\nNo Laparotomy,\nright\nadnexectomy\nDelivery of\nviable twins\nat 34 weeks\nFerland\n(1991)\n[25]\n32 yo\nG4P0030\nDES\nexposure,\nsecondary\ninfertility\nRight\nsalpingectomy,\nleft hydrosalpinx\nTubal\nectopic\nLong\nprotocol w/\nGnRH agonist\n73\nDay\n2E T\nFresh 19,450 Retroperitoneal\n(E)\n37 days PT Yes Laparotomy, left\nsalpingectomy\nRagni\n(1991)\n[26]\n32 yo\nG1P0010\nPelvic\nadhesive\ndisease\nRight\nadnexectomy,\nhysteropexy\nTubal\nectopic\nLong\nprotocol w/\nGnRH agonist\n43\nDay\n2E T\nFresh NA Right adnexa\n(H)\n12 weeks\ngestation\nNo Selective\nreduction of\nabdominal\npregnancy,\nlaparotomy\nLaparotomy\nfor resorbing\nabdominal\npregnancy,\nSAB of IUP at\n16 weeks\nBalmaceda\n(1993) [ 27]\n33 yo\nG3P1021\nTubal Right\nsalpingectomy,\nleft\nsalpingostomy\nTubal\nEctopic x2\nShort\nprotocol, w/\nGnRH agonist\n15 4\nDay\n4E T\nFresh 4651 Abdominal -\nbroad ligament\n(E)\n30 days PT No Laparoscopy,\nsalpingectomy\nLaparoscopic\nremoval of\nabdominal\nectopic, left\nsalpingectomy\nFisch\n(1995)\n[28]\n32 yo\nG2P0020\nTubal Bilateral\nsalpingectomy\nTubal\nectopic x2\nLong\nprotocol w/\nGnRH agonist\n53\nNA\nFresh NA Ileum, left\nuterine cornua\n(H)\n10 weeks\ngestation\nYes Gastrostoscopy,\nsigmoidoscopy,\nTc scan,\nangiography,\nD&C, tagged\nRBC scan,\nLaparotomy\nLaparotomy\nfor abdominal\nectopic, D&C\nfor incomplete\nAB of IUP\nDelRosario\n(1996) [ 29]\n33 yo\nG1P1001\nTubal Breast Cancer No NA NA 4\nNA\nFrozen 563 Bladder (E) 75 days PT Yes Methotrexate,\nlaparoscopy\nLaparoscopic\nremoval of\npregnancy\ntissue\nYoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 4 of 10\n\nTable 2 Abdominal ectopic case reports (Continued)\nFisch\n(1996)\n[11]\n38 yo\nG2P0020\nTubal Laparoscopic\nSalpingectomy x2,\n8th IVF cycle\nTubal\nectopic x 2\nLong\nprotocol w/\nGnRH agonist\n14 4\nDay\n3E T\nFresh 1730 Broad Ligament\n(E)\n21 days PT Yes Exploratory\nLaparotomy\nRemoval of\npregnancy\ntissue by\nlaparotomy\nMoonen-\nDelarue\n(1996)\n[30]\n23 yo\nG2P0020\nPelvic\nadhesive\ndisease\nRight\nsalpingectomy\nTubal and\nabdominal\nectopic\nNA NA NA\nNA\nFresh NA Abdominal -\nuterine fundus\n(E)\n28 weeks Placental\nabruption\nLaparotomy Fetal demise\nof abdominal\nectopic @\n28 weeks\nPisarska\n(1998)\n[31]\n35 yo\nG2P0020\nUnexplained NA No Long\nprotocol w/\nGnRH agonist\n96\nNA\nFresh 6004 Bladder serosa\n(H)\n6 weeks\ngestation\nNo Diagnostic\nlaparoscopy\nLaparoscopic\nremoval of\nectopic\npregnancy\n(bladder), term\ndelivery of IUP\nDeshpande\n(1999) [ 32]\n33 yo\nG1P0010\nEndometriosis Endometriosis,\nleft\nsalpingectomy,\nPatent right\ntube\nNo Long\nprotocol w/\nGNRH\nagonist\n82\nDay\n3E T\nFresh 55,560 Twin pregnancy\nin broad\nligament (H)\n7 weeks PT No Laparotomy Removal of\ntwin ectopic\npregnancy by\nlaparotomy at\n7 weeks\nScheiber\n(1999)\n[33]\n37 yo\nG3P0030\nTubal factor\nEndometriosisDOR\nSalpingostomy,\ndonor oocytes\nTubal\nectopic\nNA NA 2\nDay\n3E T\nFrozen NA Abdominal (H) 8.5 weeks PT No KCl selective\nreduction of\nabdominal\npregnancy\nSelective\nreduction of\nabdominal\npregnancy, full\nterm viable IUP\nDmowski\n(2002)\n[34]\n34 yo\nG0P0\nTubal Bilateral\nSalpingectomy\nNo Long\nprotocol w/\nGnRH agonist\n15 3\nDay\n3E T\nFresh 38,635 Retroperitoneal\npancreatic (E)\n41 days PT Yes Laparotomy Retroperitoneal\nsubpancreatic\nectopic\nremoved by\nlaparotomy\nJain\n(2002)\n[35]\n29 yo\nG0P0\nUnexplained NA No NA NA 2\nNA\nNA NA Pouch of\nDouglas (H)\n9 weeks PT NA Laparotomy at\n4w weeks (no\nIUP seen),\nselective\nreduction of\nectopic at\n13 weeks\nSelective\nreduction of\nabdominal\nectopic,\nremoval by\nlaparotomy,\nSAB of IUP\nCormio\n(2003)\n[36]\n30 yo\nG2P0020\nTubal Bilateral\nsalpingectomy\nTubal\nectopic x2\nMenotropins,\nhCG trigger\n74\nDay\n3E T\nFresh 256,400 Omentum,\nuterine fundus\n(H)\n13 weeks\ngestation\nNo Laparotomy Laparotomy\nfor abdominal\nectopic; Live\nIUP delivered\nat 36 weeks\nReid\n(2003)\n[37]\n28 yo\nG5P1041\nTubal bilateral\nsalpingectomy\nTubal\nectopic x3\nNA NA 3\nNA\nNA 5500 Retroperitoneal,\niliac bifurcation\n(E)\n63 days PT NA Laparotomy Removal of\nectopic via\nlaparotomy\nYoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 5 of 10\n\nTable 2 Abdominal ectopic case reports (Continued)\nKitade\n(2005)\n[38]\n37 yo\nG0P0\nUnexplained NA No Long\nprotocol w/\nGnRH agonist\n12 3\nDay\n3E T\nFresh 45,896 Splenic and\nTubal (H)\n34 days PT\n(tubal), 46 day\nPT (splenic)\nTubal -\nNo,\nSplenic -\nYes\n1) Laparoscopic\nsalpingectomy\n2) Exploratory\nlaparotomy\nRemoval of\ntubal ectopic\nby laparoscopy,\nremoval of\nsplenic ectopic\nby laparotomy\n(12 days later)\nAli\n(2006)\n[39]\n35\nNA\nTubal Pelvic adhesions No NA 11 1\nNA\nFresh 1524 Tube with\nOmental/\nperitoneal\ntrophoblastic\ntissue (H)\n3 weeks PT -\ntubal ectopic;\n5 weeks PT –\nomental tissue\nNo Laparoscopic\nsalpingectomy;\nLaparocopic\nremoval of\nomental/\nperitoneal\ntrophoblastic\ntissue\nRemoval of\ntubal and\nperitoneal/\nomental\npregnancy\ntissue by 2\nlaparoscopies\nApantaku\n(2006)\n[40]\n33\nG3P1021\nTubal Bilateral\nsalpingectomy\nTubal\nectopic x2\nNA NA 2\nNA\nFresh NA Right adnexa (E) 6 weeks PT No Laparoscopy Laparoscopic\nremoval of\npregnancy\ntissue\nKnopman\n(2007)\n[41]\n37 yo\nG4P0040\nUnexplained NA No GnRH\nantagonist\n92\nDay\n5E T\nFresh 1023 Posterior cul-de-\nsac (H)\n7 weeks,\nnonviable IUP;\n9 weeks\nectopic\nYes Laparoscopy D&C for non-\nviable IUP;\nLaparoscopy\nfor abdominal\nectopic\nShih\n(2007)\n[42]\n33 yo\nG0P0\nMale Factor Patent tubes No Long\nprotocol w/\nGnRH agonist\n4N A\nNA\nFresh 901 Cul-de-sac\n(E)\n28 days PT No Laparoscopy\nconverted to\nlaparotomy\nRemoval of\npregnancy\ntissue by\nlaparotomy\nShojai\n(2007)\n[43]\n35 yo\nG0P0\nStructural, DES\nexposure\nNA No NA NA 3\nNA\nNA NA Abdominal -\nuterine fundus\n(H)\n21 weeks\ngestation\nNo Laparotomy Delivery of\nviable twins\nat 32 weeks\nIwama\n(2008)\n[44]\n31 yo\nG1P0010\nTubal Right\nSalpingectomy\nfor tubal ectopic\nafter IVF, left\nsalpingectomy\nfor hydrosalpinx\nTubal\nectopic\nNA NA 3\nDay\n3E T\nFresh 45, 369 Inferior Vena\nCava/\nRetroperitoneal\n(E)\n32 days PT:\nPUL; 53 days\nPT:\nretroperitoneal\nectopic\nYes D&C, MTX,\nDiagnostic\nlaparoscopy,\nrepeat MTX,\nExploratory\nlaparotomy\nRuptured\nretroperitoneal\nectopic,\nremoved by\nlaparotomy\nHyvarinen\n(2009) [ 45]\nNA\nNA\nNA NA NA NA NA NA\nNA\nNA NA Abdominal (E) 30 weeks\ngestation\nNo Laparotomy Delivery of\nviable fetus\nat 30 weeks\nZacche\n(2011)\n[46]\n36\nG1P1\nTubal Bilateral\nSalpingectomy,\nPID\nNo NA NA 2\nNA\nFresh NA Abdominal (H) 32 weeks at\nCesarean\nDelivery\nNo Laparotomy,\nhysterectomy\nViable twin\npregnancies\nat 32 weeks;\nHysterectomy\nYoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 6 of 10\n\nTable 2 Abdominal ectopic case reports (Continued)\nAngelova\n(2015)\n[47]\n33\nNA\nMale Factor Obturated\nleft tube\nNA Short\nprotocol, w/\nGnRH\nantagonist\nNA 2\nDay\n3E T\nFresh NA Abdominal -\nvesicouterine\njunction (E)\n23 days PT No Laparoscopy Laparoscopic\nremoval of\npregnancy\ntissue\nDalmia\n(2015)\n[48]\n37\nG1P0010\nEndometriosisTubal\nfactor\nBilateral\nsalpingectomy\nfor hydrosalpinx\nNA NA NA NA\nNA\nNA 21,730 Left adnexa (E) 2 weeks PT No Mini-\nlaparotomy\nRemoval of\nectopic via\nlaparotomy\nKoyama\n(2015)\n[49]\n32\nG5P1\nMale Factor NA No NA NA 1\nNA\nFrozen 14,800 Retroperitoneal\n(E)\n10 weeks\ngestation\nNA Laparoscopy Laparoscopic\nremoval of\npregnancy\ntissue\nAbbreviations: 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,\nhMG 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\nPost transfer, RBC Red blood cell, Tc Technetium, SAB Spontaneous abortion\nYoderet al. Reproductive Biology and Endocrinology (2016) 14:69 Page 7 of 10\n\nreview demonstrates several trends among reported\ncases. First, the majority of cases (61 %) report a history\nof anatomic/structural infertility etiology with history of\ntubal factor infertility (TFI) (46 %) being the most com-\nmon. This is consistent with TFI being a known risk fac-\ntor for ectopic pregnancy following IVF. One study that\nexamined the risk factors for EP following IVF in 712\nwomen reported an odds ratio (OR) of 3.99 (95 % CI:\n1.23 to 12.98) for women with TFI compared to those\nwith other infertility causes [12]. In a larger, more recent\nstudy of 553,577 ART cycles in the US, among all infer-\ntility diagnoses, TFI was the only one significantly asso-\nciated with increased risk for ectopic pregnancy\n(adjusted relative risk (RR) 1.25, 95 % CI 1.16 –1.35) [13].\nIn addition, history of tubal ectopic pregnancy was par-\nticularly common, being reported in 37 % of the abdom-\ninal ectopic cases. This also appears to be consistent\nwith the general ART-associated EP literature. A retro-\nspective study that measured the risk of EP following\nIVF in 181 women with a previous ectopic demonstrated\na 45-fold higher risk of recurrence when compared with\n377 women with other causes of infertility. The authors\nreported that the prevalence of EP was 8.95 % compared\nwith 0.75 % in the control group [14]. History of prior\ntubal surgery was also particularly common (50 %)\namong abdominal ectopic cases in our systematic review.\nA history of tubal/pelvic surgery is another major risk\nfactor for the development of EP following IVF. Odds\nratio for developing EP was 8.52 (95 % CI: 5.91 –12.27)\nfor prior adnexal surgery, 11.02 (95 % CI: 5.49 –22.15)\nfor a previous tubal infertility surgery, 5.16 (95 % CI:\n1.25–21.21) for prior surgery for endometriosis and\n17.70 (95 % CI: 8.11 –38.66) for a previous abdominal/\npelvic surgery [12, 15, 16]. Interestingly, bilateral salpin-\ngectomy was the most common tubal surgery reported\nin our case review. While the exact mechanism of ab-\ndominal ectopic after bilateral salpingectomy remains\nunclear, many authors have proposed that it may be due\nto the development of a micro-fistulous tract after sal-\npingectomy. Uterine perforation during embryo transfer\nhas also been suggested as a mechanism for abdominal\nectopic pregnancy, and embryo transfer technique has\nbeen related to overall EP risk after IVF. Aspects of the\ntransfer that may increase risk of EP include large\nvolume of transfer media, induction of abnormal uterine\ncontractions, and location of embryo transfer in relation\nto the uterine fundus [9]. These factors have all been\nassociated with retrograde flow of both transfer media\nand the embryo toward the fallopian tubes. Many sug-\ngestions have been made regarding optimal transfer lo-\ncation within the endometrium, ranging from 5 to\n20 mm from the fundal surface, while others recom-\nmend “mid-cavity” location to avoid proximity to the fal-\nlopian tubes [17 –19].\nOther trends identified in our systematic review in-\nclude >1 embryo transferred (reported in 79 % of cases)\nand a large number of heterotopic abdominal pregnancy\n(reported in 46 % of cases). Multiple embryo transfer\nhas always been associated with increased risk of EP\nwith transfer of two or less embryos carrying lower risk\nthan after three or more embryos [20]. In the setting of\nmultiple embryo transfers, identification of an intrauter-\nine pregnancy often leads to delayed diagnosis of ab-\ndominal pregnancy in the absence of clinical symptoms.\nAmong the heterotopic cases, 4 reported a 2 week delay\nin diagnosis of the abdominal ectopic from the time of\nsuspected ectopic, and 5 cases did not identify the ab-\ndominal ectopic until beyond the 12th week of preg-\nnancy. Unfortunately, this type of delayed diagnosis has\nthe potential to lead to significantly morbid outcomes.\nIn our review, four cases of viable abdominal pregnan-\ncies were identified, which is an extremely rare outcome.\nThree of these cases were identified at 19 weeks or be-\nyond, and all three had attachment of the abdominal\nplacenta to the peritoneal surface of the uterus without\ninvolvement of other abdominal organs. Placental at-\ntachment to the uterus has previously been associated\nwith viability of abdominal pregnancies [21], and with a\nrelatively lower risk of bleeding and lower likelihood of\nfetal growth retardation [22].\nFinally, abdominal ectopic pregnancies were far more\ncommon in fresh embryo transfer (71 % of cases) than\nfrozen embryo transfer (11 % of cases). This may be due\nto the fact that frozen embryo transfer has become\nwidely used only recently, and we may begin to see\nhigher frequency with frozen embryo transfers over time.\nHowever, several recent studies indicate that ectopic\npregnancy rates are higher for fresh as compared to fro-\nzen IVF cycles [1, 6].\nA limitation of this review is the heterogeneity of re-\nported cases and IVF practices which encompass several\ndecades. Further research focusing on more homogenous\npopulation may help in better characterizing this rare IVF\ncomplication.\nConclusions\nIn conclusion, ectopic pregnancy, including abdominal\nectopic, is a known risk of IVF. The case reported\nhighlights the diagnostic challenges behind this rare\nform of ectopic pregnancy, and the need to keep it in\nthe differential in atypical ectopic presentations. Our\nsystematic literature review has revealed several\ntrends in reported cases of abdominal ectopic preg-\nnancy after IVF including tubal factor infertility, his-\ntory of tubal ectopic and tubal surgery, higher\nnumber of embryos transferred, and fresh embryo\ntransfers. These are consistent with known risk fac-\ntors for ectopic pregnancy following IVF.\nYoder et al. Reproductive Biology and Endocrinology  (2016) 14:69 Page 8 of 10\n\nAbbreviations\nAB: Abortion; ART: Assisted reproduction technologies; D&C: Dilation and\ncurettage; DES: Diethylstilbestrol; E: Ectopic; FSH: Follicle stimulating\nhormone; GnRH: Gonadotropin-releasing hormone; H: Heterotopic;\nhCG: Human chorionic gonadotropin; hMG: Human menopausal\ngonadotropin; HSG: Hysterosalpingogram; IUP: Intrauterine pregnancy; IVF: In\nvitro fertilization; KCl: Potassium chloride; MTX: Methotrexate; NA: Not\navailable; PID: Pelvic inflammatory disease; PT: Post transfer; RBC: Red blood\ncell; SAB: Spontaneous abortion; Tc: Technetium\nAcknowledgements\nNone.\nFunding\nNone.\nAvailability of data and materials\nNot applicable.\nAuthors’ contributions\nNY performed the systematic literature search, extracted and analyzed the\ndata, and wrote the manuscript; RT conceived and designed the study,\ncritically reviewed and revised the manuscript; JRM conceived the study,\ncritically reviewed and revised the manuscript. All authors read and\napproved the final submission.\nCompeting interests\nThe authors declare that they have no competing interests.\nConsent for publication\nNot applicable.\nEthics approval and consent to participate\nSince this study used only deidentified patient data, and published data\nfrom the literature, no approval from our institutional review board (IRB)\nwas required.\nReceived: 31 August 2016 Accepted: 6 October 2016\nReferences\n1. Londra L, Moreau C, Strobino D, Garcia J, Zacur H, Zhao Y. Ectopic\npregnancy after in vitro fertilization: differences between fresh and frozen-\nthawed cycles. Fertil Steril. 2015;104(1):110 –8.\n2. Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds MA, Wright VC.\nEctopic pregnancy risk with assisted reproductive technology procedures.\nObstet Gynecol. 2006;107(3):595 –604.\n3. Bouyer J, Coste J, Fernandez H, Pouly JL, Job-Spira N. Sites of ectopic\npregnancy: a 10 year population-based study of 1800 cases. Hum Reprod.\n2002;17(12):3224–30.\n4. Alto WA. Abdominal pregnancy. Am Fam Physician. 1990;41(1):209 –14.\n5. Zhang Y-L, Sun J, Su Y-C, Guo Y-H, Sun Y-P. Study on the incidence and\ninfluences on ectopic pregnancy from embryo transfer of fresh cycles and\nfrozen-thawed cycles. Zhonghua Fu Chan Ke Za Zhi. 2012;47(9):655 –8.\n6. Huang B, Hu D, Qian K, et al. Is frozen embryo transfer cycle associated with\na significantly lower incidence of ectopic pregnancy? An analysis of more\nthan 30,000 cycles. Fertil Steril. 2014;102(5):1345 –9.\n7. Decleer W, Osmanagaoglu K, Meganck G, Devroey P. Slightly lower\nincidence of ectopic pregnancies in frozen embryo transfer cycles versus\nfresh in vitro fertilization-embryo transfer cycles: a retrospective cohort\nstudy. Fertil Steril. 2014;101(1):162 –5.\n8. Rombauts L, McMaster R, Motteram C, Fernando S. Risk of ectopic\npregnancy is linked to endometrial thickness in a retrospective cohort study\nof 8120 assisted reproduction technology cycles. Hum Reprod. 2015. doi:10.\n1093/humrep/dev249.\n9. Refaat B, Dalton E, Ledger WL. Ectopic pregnancy secondary to in vitro\nfertilisation-embryo transfer: pathogenic mechanisms and management\nstrategies. Reprod Biol Endocrinol. 2015;13:30.\n10. Atrash HK, Friede A, Hogue CJ. Abdominal pregnancy in the United States:\nfrequency and maternal mortality. Obstet Gynecol. 1987;69(3 Pt 1):333 –7.\n11. Fisch B, Peled Y, Kaplan B, Zehavi S, Neri A. Abdominal pregnancy following\nin vitro fertilization in a patient with previous bilateral salpingectomy.\nObstet Gynecol. 1996;88(4 Pt 2):642 –3.\n12. Malak M, Tawfeeq T, Holzer H, Tulandi T. Risk factors for ectopic pregnancy\nafter in vitro fertilization treatment. J Obstet Gynaecol Can. 2011;33(6):617 –9.\n13. Perkins KM, Boulet SL, Kissin DM, Jamieson DJ, National ART Surveillance\n(NASS) Group. Risk of ectopic pregnancy associated with assisted\nreproductive technology in the United States, 2001 –2011. Obstet Gynecol.\n2015;125(1):70–8.\n14. Weigert M, Gruber D, Pernicka E, Bauer P, Feichtinger W. Previous tubal\nectopic pregnancy raises the incidence of repeated ectopic pregnancies in\nin vitro fertilization-embryo transfer patients. J Assist Reprod Genet. 2009;\n26(1):13–7.\n15. Parashi S, Moukhah S, Ashrafi M. Main risk factors for ectopic pregnancy:\na case-control study in a sample of Iranian women. Int J Fertil Steril.\n2014;8(2):147–54.\n16. Li C, Meng C-X, Zhao W-H, Lu H-Q, Shi W, Zhang J. Risk factors for ectopic\npregnancy in women with planned pregnancy: a case-control study. Eur J\nObstet Gynecol Reprod Biol. 2014;181:176 –82.\n17. Rovei V, et al. IVF outcome is optimized when embryos are replaced\nbetween 5 and 15 mm from the fundal endometrial surface: a prospective\nanalysis on 1184 IVF cycles. Reprod Biol Endocrinol. 2013;11:114.\n18. Nazari A, Askari HA, Check JH, O ’Shaughnessy A. Embryo transfer\ntechnique as a cause of ectopic pregnancy in in vitro fertilization. Fertil\nSteril. 1993;60:919 –21.\n19. Coroleu B, et al. The influence of the depth of embryo replacement into the\nuterine cavity on implantation rates after IVF: a controlled, ultrasound –\nguided study. Hum Reprod. 2002;17:341 –6.\n20. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of\nembryos for transfer following in vitro fertilisation or intra-cytoplasmic\nsperm injection. Cochrane Database Syst Rev. 2013;7:CD003416.\n21. Dubinsky TJ, Guerra F, Gormaz G, Maklad N. Fetal survival in abdominal\npregnancy: a review of 11 cases. J Clin Ultrasound. 1996;24:513 –7.\n22. Huang K, Song L, Wang L, Gao Z, Meng Y, Lu Y. Advanced abdominal\npregnancy: an increasingly challenging clinical concern for obstetricians. Int\nJ Clin Exp Pathol. 2014;7(9):5461 –72.\n23. Oehninger S, Kreiner D, Bass MJ, Rosenwaks Z. Abdominal pregnancy\nafter in vitro fertilization and embryo transfer. Obstet Gynecol.\n1988;72(3 Pt 2):499 –502.\n24. Bassil S, Pouly JL, Canis M, et al. Advanced heterotopic pregnancy after in-\nvitro fertilization and embryo transfer, with survival of both the babies and\nthe mother. Hum Reprod. 1991;6(7):1008 –10.\n25. Ferland RJ, Chadwick DA, O ’Brien JA, Granai 3rd CO. An ectopic pregnancy\nin the upper retroperitoneum following in vitro fertilization and embryo\ntransfer. Obstet Gynecol. 1991;78(3 Pt 2):544 –6.\n26. Ragni G, Lombroso Finzi GC, Olivares MD, Crosignani PG. Twin in vitro\nfertilization (IVF) pregnancies: spontaneous intrauterine abortion after\nselective second-trimester termination of ectopic intraabdominal\npregnancy. J In Vitro Fert Embryo Transf. 1991;8(4):236 –7.\n27. Balmaceda JP, Bernardini L, Asch RH, Stone SC. Early primary abdominal\npregnancy after in vitro fertilization and embryo transfer. J Assist Reprod\nGenet. 1993;10(4):317 –20.\n28. Fisch B, Powsner E, Heller L, et al. Heterotopic abdominal pregnancy\nfollowing in-vitro fertilization/embryo transfer presenting as massive lower\ngastrointestinal bleeding. Hum Reprod. 1995;10(3):681 –2.\n29. delRosario R, el-Roeiy A. Abdominal pregnancy on the bladder wall\nfollowing embryo transfer with cryopreserved-thawed embryos: a case\nreport. Fertil Steril. 1996;66(5):839 –41.\n30. Moonen-Delarue MW, Haest JW. Ectopic pregnancy three times in line of\nwhich two advanced abdominal pregnancies. Eur J Obstet Gynecol Reprod\nBiol. 1996;66(1):87–8.\n31. Pisarska MD, Casson PR, Moise Jr KJ, DiMaio DJ, Buster JE, Carson SA.\nHeterotopic abdominal pregnancy treated at laparoscopy. Fertil Steril.\n1998;70(1):159–60.\n32. Deshpande N, Mathers A, Acharya U. Broad ligament twin pregnancy\nfollowing in-vitro fertilization. Hum Reprod. 1999;14(3):852 –4.\n33. Scheiber MD, Cedars MI. Case Report: Successful non-surgical management\nof a heterotopic abdominal pregnancy following embryo transfer with\ncryopreserved–thawed embryos. Hum Reprod. 1999;14(5):1375 –7.\n34. Dmowski WP, Rana N, Ding J, Wu WT. Retroperitoneal subpancreatic\nectopic pregnancy following in vitro fertilization in a patient with previous\nYoder et al. Reproductive Biology and Endocrinology  (2016) 14:69 Page 9 of 10\n\nbilateral salpingectomy: how did it get there? J Assist Reprod Genet.\n2002;19(2):90–3.\n35. Jain S, Justus K, Bober S. Selective transvaginal embryo reduction in\nheterotopic pregnancy located intra-abdominally. J Obstet Gynaecol.\n2002;22(3):330.\n36. Cormio G, Santamato S, Putignano G, Bettocchi S, Pascazio F. Concomitant\nabdominal and intrauterine pregnancy after in vitro fertilization in a woman\nwith bilateral salpingectomy. A case report. J Reprod Med. 2003;48(9):747 –9.\n37. Reid F, Steel M. An exceptionally rare ectopic pregnancy. BJOG. 2003;\n110(2):222 –3.\n38. Kitade M, Takeuchi H, Kikuchi I, Shimanuki H, Kumakiri J, Kinoshita K. A case\nof simultaneous tubal-splenic pregnancy after assisted reproductive\ntechnology. Fertil Steril. 2005;83(4):1042.\n39. Ali CR, Fitzgerald C. Omental and peritoneal secondary trophoblastic\nimplantation - an unusual complication after IVF. Reprod Biomed Online.\n2006;12(6):776–8.\n40. Apantaku O, Rana P, Inglis T. Broad ligament ectopic pregnancy following\nin-vitro fertilisation in a patient with previous bilateral salpingectomy. J\nObstet Gynaecol. 2006;26(5):474.\n41. Knopman JM, Talebian S, Keegan DA, Grifo JA. Heterotopic abdominal\npregnancy following two-blastocyst embryo transfer. Fertil Steril. 2007;88(5):\n1437. e13-e15.\n42. Shih C-C, Lee RK-K, Hwu Y-M. Cul-de-sac pregnancy following in vitro\nfertilization and embryo transfer. Taiwan J Obstet Gynecol. 2007;46(2):171 –3.\n43. Shojai R, Chaumoitre K, Chau C, Panuel M, Boubli L, d ’Ercole C. Advanced\ncombined abdominal and intrauterine pregnancy: a case report. Fetal Diagn\nTher. 2007;22(2):128 –30.\n44. Iwama H, Tsutsumi S, Igarashi H, Takahashi K, Nakahara K, Kurachi H. A case\nof retroperitoneal ectopic pregnancy following IVF-ET in a patient with\nprevious bilateral salpingectomy. Am J Perinatol. 2008;25(1):33 –6.\n45. Hyvärinen M, Raudaskoski T, Tekay A, Herva R. Abdominal pregnancy.\nDuodecim. 2009;125(22):2448 –51.\n46. Zacchè MM, Zacchè G, Gaetti L, Vignali M, Busacca M. Combined\nintrauterine and abdominal pregnancy following ICSI with delivery of two\nhealthy viable fetuses: a case report. Eur J Obstet Gynecol Reprod Biol. 2011;\n154(2):232–3.\n47. Angelova MA, Kovachev EG, Kozovski I, Kornovski YD, Kisyov SV, Ivanova VR.\nA case of secondary abdominal pregnancy after In Vitro Fertilization Pre-\nEmbryo Transfer (IVF-ET). Open Access Maced J Med Sci. 2015;3(3):426 –8.\n48. Dalmia R, Murthy J, Orakwue C. A case of abdominal pregnancy following\nin vitro fertilization in a patient with previous bilateral salpingectomy.\nIJMPCR. 2015;2(1):18 –21.\n49. Koyama S, Yoshino A, Okuno K, et al. A case of abdominal pregnancy\nfollowing in vitro fertilization and embryo transfer treated with laparoscopic\nsurgery. Gynecol Minim Invasive Ther. doi:10.1016/j.gmit.2015.04.006.\n•  We accept pre-submission inquiries \n  Our selector tool helps you to find the most relevant journal\n  We provide round the clock customer support \n  Convenient online submission\n  Thorough peer review\n  Inclusion in PubMed and all major indexing services \n  Maximum visibility for your research\nSubmit your manuscript at\nwww.biomedcentral.com/submit\nSubmit your next manuscript to BioMed Central \nand we will help you at every step:\nYoder et al. Reproductive Biology and Endocrinology  (2016) 14:69 Page 10 of 10","source_license":"CC0","license_restricted":false}