medicina

Review Heterotopic Quadruplet . Literature Review and Case Report

1 2 1,3, 3 3 Brîndus, a Cimpoca , Amira Moldoveanu , Nicolae Gică * , Corina Gică , Anca Marina Ciobanu , Anca Maria Panaitescu 1,3 and Dana Oprescu 1,2

1 Department of and Gynecology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; [email protected] (B.C.); [email protected] (A.M.P.); [email protected] (D.O.) 2 INSMC “Alessandrescu Rusescu”, 011062 Bucharest, Romania; [email protected] 3 Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, 011171 Bucharest, Romania; [email protected] (C.G.); [email protected] (A.M.C.) * Correspondence: [email protected]; Tel.: +40-727827815

Abstract: Heterotopic pregnancy is the condition where both intrauterine and are present. It rarely occurs after natural conception, but is more common with assisted reproductive techniques, when more than one embryo is transferred. Quadruplet heterotopic pregnancy is exceedingly rare. Methods: A literature review was conducted aiming to highlight the diagnosis difficulties and the management options in heterotopic quadruplet . Results: Nine relevant studies were identified by researching PubMed up to 2021 for “heterotopic quadruplet

 pregnancy”, “quadruplet intrauterine and ectopic pregnancy”, “synchronous intrauterine and ectopic  pregnancy”. Conclusions: In this paper, we present a case of heterotopic quadruplet pregnancy and

Citation: Cimpoca, B.; Moldoveanu, address the difficulty in diagnosing this condition and make formal recommendations. A.; Gic˘a,N.; Gic˘a,C.; Ciobanu, A.M.; Panaitescu, A.M.; Oprescu, D. Keywords: heterotopic quadruplet pregnancy; quadruplet intrauterine and ectopic pregnancy; Heterotopic Quadruplet Pregnancy. synchronous intrauterine and ectopic pregnancy Literature Review and Case Report. Medicina 2021, 57, 483. https:// doi.org/10.3390/medicina57050483 1. Introduction Academic Editors: Heterotopic pregnancy is the condition where both intrauterine and ectopic preg- Dan-Bogdan Navolan and Eliza nancies are present. It rarely occurs after natural conception, but is more common in IVF Claudia Filimon (in vitro fertilization), when more than one embryo is transferred [1]. Although ectopic pregnancy is not uncommon in women of reproductive age, heterotopic pregnancy is a rare Received: 13 April 2021 event, and the incidence varies from 1/8000 to 1/30,000 [2,3]. In general practice, ectopic Accepted: 8 May 2021 Published: 12 May 2021 pregnancy is rarely considered if intrauterine pregnancy is confirmed. The increased inci- dence of pelvic inflammatory disease, the wide use of ovarian stimulation with or without assisted reproductive techniques (ART) have contributed to the increasing incidence of Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in both, multiple gestations and heterotopic pregnancies over the last decades [4]. Quadruplet published maps and institutional affil- heterotopic pregnancy may occur when there is simultaneously a pair of intrauterine iations. and another pair of twins outside the uterine cavity. At times there is an intrauterine triplet pregnancy and a singleton ectopic gestation. The aim of this paper is to offer a narrative literature research regarding diagnosis and management options for heterotopic quadruplet pregnancy and to present a case managed in our units. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 2. Materials and Methods This article is an open access article distributed under the terms and A systematic research of the literature was conducted in the database of PubMed, conditions of the Creative Commons in order to select full-length articles published in peer-reviewed journals up to Febru- Attribution (CC BY) license (https:// ary 2021. The keywords included in the search strategy were: Heterotopic quadruplet creativecommons.org/licenses/by/ pregnancy, quadruplet intrauterine and ectopic pregnancy, synchronous intrauterine, and 4.0/). ectopic pregnancy.

Medicina 2021, 57, 483. https://doi.org/10.3390/medicina57050483 https://www.mdpi.com/journal/medicina Medicina 2021, 57, 483 2 of 6

3. Results We found a total number of 15 relevant articles, published between 1989 and 2021. We selected only full-text articles, with studies including a population of women aged 18 years and older, published in this period in the literature and only nine fulfilled the criteria of truly quadruplet heterotopic pregnancy (Table1).

Table 1. Characteristics of included-case reports.

Author Age (y) Past History GA(w) Method Intrauterine Ectopic Symptoms Intervention Obstetric Outcome -cornual pregnancy: US guided transvaginal Park HR Cornual Elective CS at 30 None NA NA Twins NA injection of KCl [5] and tubal 37 w twins -tubal pregnancy laparoscopy painless bilateral vaginal Chan interstitial Elective CS at 31 salpingec- 7 IVF Twins spotting Laparotomy [6] twins 38 w twins tomy 35 days after ET Medically -10 weeks: Tubal abdominal Tamhane managed TCTA pregnancy- laparotomy CS after PPROM at 34 32 10 ICSI Tubal pain, vaginal NA [7] ectopic triplets -12 weeks: ER triplets to w twins spotting pregnancy twins Term delivery singleton-agenesis of Ovulation Triplets Soares A Primary abdominal one distal phalanx of 31 9 induc- only 1 Tubal Laparotomy [8] infertility pain the hand and agenesis tion viable of distal phalanges of all toes Ovulation Omosh NA pregnancy Primary induc- abdominal RK 20 10 Triplets Tubal Laparotomy outcome; at 23 weeks infertility tion pain [9] all 3 viable + IUI -7 weeks: Laparoscopy Uysal F Primary abdominal Elective CS at 30 7 IUI Triplets Tubal -13 weeks: 1 [10] infertility pain 37 w twins spontaneous fetal loss abdominal pain, anemia, marked Sherer CS after PPROM at 32 Unremarkable 8 IVF Triplets Interstitial weakness, Laparoscopy DM [11] 33 w triplets and right shoulder pain Laparotomy and CS severe -abdominal: Multiple preeclamp- 3 Neonatal deaths, Aguemon malformation alive; + TCTA sia + 1 survivor CT 22 Unremarkable 34 Spontaneous Abdominal administration of triplets periumbili- Maternal heart failure- [12] methotrexate cal 6 months F/U stable -livebirth of TCTA pain triplets Lavanya Ovulation abdominal None viable intrauterine Primary R NA 12 induc- Twins Twins pain, vaginal None infertility [13] tion bleed + methotrexate Ovulation Laparotomy Primary induc- TCTA abdominal CS after PPROM at 35 Our case 35 10 tubal 12 weeks: Only 2 infertility tion triplets pain w twins alive + IVF NA—not available; US—ultrasound; CS—cesarean section; IVF—In vitro fertilization; ET—; ICSI intracytoplasmic sperm injection; TCTA—Trichorionic Triamniotic Triplets; ER—embryo reduction; PPROM—preterm premature rupture of membrane; IUI—intrauterine insemination; F/U—follow-up.

Almost all pregnancies included in the case reports were conceived with assisted reproductive techniques and only three out of nine had an unremarkable previous obstet- ric history. Heterotopic quadruplet pregnancy usually appears after ART and . The risk is 30–60 times higher after assisted reproduction when compared to spontaneous conception [14]. All cases included twin or triplet intrauterine pregnancy. The diagnosis was most of the time clinically guided, as severe pain was the predominant symptom. In eight out of nine cases, the diagnosis was made in the first trimester. Interest- Medicina 2021, 57, x FOR PEER REVIEW 3 of 6

Almost all pregnancies included in the case reports were conceived with assisted re- productive techniques and only three out of nine had an unremarkable previous obstetric history. Heterotopic quadruplet pregnancy usually appears after ART and ovulation in- duction. The risk is 30–60 times higher after assisted reproduction when compared to spontaneous conception [14]. All cases included twin or triplet intrauterine pregnancy. The diagnosis was most of the time clinically guided, as severe pain was the predominant symptom. In eight out of nine cases, the diagnosis was made in the first trimester. Inter- estingly, Aguemon CT et al. reported the case of a late diagnosis, the reason being that this was the case of an that developed until almost term [12]. There are several treatment options for ectopic pregnancy [15]. When there is a het- erotopic pregnancy diagnosed, local treatments are preferred. Local methotrexate injec- tion or local potassium chloride injection (KCl) are the topical medical treatments availa- ble. However, when heterotopic pregnancy is considered, methotrexate is not the elective choice due to the toxicity for the intrauterine pregnancy [16]. Therefore, KCl injected in the ectopic sac is recommended. In the searched literature, only one case managed the Medicina 2021, 57, 483 heterotopic pregnancy with local injections. Seven out of the3 ofnine 6 papers reviewed man- aged the cases surgically. The non-medical treatment consists of laparoscopy or laparot-

ingly,omy Aguemon aiming CT for et al.removal reported theof casethe of ectopic a late diagnosis, pregnancy, the reason leaving being that the this intrauterine gestation un- wastouched the case of[6]. an abdominal pregnancy that developed until almost term [12]. There are several treatment options for ectopic pregnancy [15]. When there is a hetero- topic pregnancy diagnosed, local treatments are preferred. Local methotrexate injection or4. local Case potassium Presentation chloride injection (KCl) are the topical medical treatments available. However,We when present heterotopic the pregnancy case of is a considered, 35-year methotrexate-old wom isa notn, thewith elective history choice of primary infertility but due to the toxicity for the intrauterine pregnancy [16]. Therefore, KCl injected in the ectopic sacotherwise is recommended. healthy. In the The searched patient literature, was only under one case the managed care of the reproductive heterotopic medicine services for pregnancymale factor with local infertility injections. Seven with out severe of the nine oligo papers-asteno reviewed-teratospermia. managed the cases The pregnancy was ob- surgically. The non-medical treatment consists of laparoscopy or laparotomy aiming for removaltained of after the ectopic an pregnancy,IVF treatment, leaving the with intrauterine an antagonist gestation untouched short [ 6protocol]. (recombinant FSH 200 UI/day for 10 days and gonadotrophin releasing hormone antagonist for 5 days). On the 4. Case Presentation dayWe of present oocyt thee retrieval case of a 35-year-old she had woman, 20 follicles with history above of primary 14 mm, infertility but only but 6 oocytes were obtained. otherwiseIntracytoplasmic healthy. The patient sperm was injection under the care (ICSI) of reproductive was performed medicine services using for the only 5 mature oocytes male(MII). factor On infertility the next with severeday, oligo-asteno-teratospermia.there were only four The normally pregnancy was fertilized obtained embryos (2PN). She had after an IVF treatment, with an antagonist short protocol (recombinant FSH 200 UI/day forda 10y 3 days embryo and gonadotrophin-transfer (ET) releasing of four hormone embryos antagonist (one for 5 8 days).-cell embryo On the day grade 1, one 8-cell embryo ofgrade oocyte 2 retrieval, and shetwo had 4- 20cell follicles embryos above 14 grade mm, but 2– only3). 6She oocytes had were luteal obtained. phase support with vaginal Intracytoplasmic sperm injection (ICSI) was performed using the only 5 mature oocytes (MII).micronized On the next progesterone day, there were only 40 four0 m normallyg twice fertilized daily. embryos Her first (2PN). β Shehcg had level was 601 mIU/mL and dayprogesterone 3 embryo-transfer 46 (ET).7 ng of/mL. four embryos After (one 48 8-cellh, the embryo βhcg grade level 1, onewas 8-cell 1383.2 embryo8 mIU/mL. She had the first grade 2, and two 4-cell embryos grade 2–3). She had luteal phase support with vaginal micronizedultrasound progesterone examination 400 mg twice 14 days daily. Herafter first theβhcg βhcg level dynamic, was 601 mIU/mL with and the visualization of a triplet progesteronepregnancy. 46.7 The ng/mL. follow After- 48up h, was the β hcgprogramed level was 1383.28 in 10 mIU/mL. days. She had the first ultrasoundIn early examination pregnancy, 14 days at after the the 9 weeksβhcg dynamic, of gestation, with the visualization after ET ofthe a ultrasound scan demon- triplet pregnancy. The follow-up was programed in 10 days. stratedIn early a pregnancy,triplet triamniotic at the 9 weeks viable of gestation, intrauterine after ET the ultrasound pregnancy scan demon-was diagnosed (Figure 1) along stratedwith aovarian triplet triamniotic hyperstimulation viable intrauterine syndrome. pregnancy was She diagnosed was (Figurehemodynamically1) along stable, however at with ovarian hyperstimulation syndrome. She was hemodynamically stable, however at 1010 weeks weeks gestational gestational age she complained age she ofcomplained lower abdominal ofpain. lower abdominal pain.

Figure 1. Transabdominal scan at 9 weeks of pregnancy confirms a trichorionic triamniotic (TCTA) pregnancy.Figure 1. Clear Transabdominal visualization of the two scan lambda at 9 signs weeks and thick of pregnancy intertwin membranes, confirms composed a trichorionic of triamniotic (TCTA) apregnancy. central layer of chorionicClear visualization tissue sandwiched of between the two two layers lambda of , signs therefore and thick multi-layered, intertwin membranes, composed more echogenic.

On physical examination, the patient’s vitals were stable, and there was tenderness in the left lower abdomen. Transabdominal ultrasound revealed free intraperitoneal fluid, raising the question of ruptured ectopic pregnancy. Hemoglobin abruptly decreased

Medicina 2021, 57, x FOR PEER REVIEW 4 of 6

of a central layer of chorionic tissue sandwiched between two layers of amnion, therefore multi- layered, more echogenic.

On physical examination, the patient’s vitals were stable, and there was tenderness Medicina 2021, 57, 483 in the left lower abdomen. Transabdominal ultrasound revealed free intraperitoneal fluid,4 of 6 raising the question of ruptured ectopic pregnancy. Hemoglobin abruptly decreased from 9.5 to 7.5 g/dL and she experienced dyspnea, therefore exploratory laparotomy was per- formedfrom 9.5 (Figure to 7.5 g/dL 2a,b) and and she revealed experienced intraperitoneal dyspnea, therefore blood accumul exploratoryation laparotomy (approximately was 150performed0 mL), dilated (Figure ruptured2a,b) and right revealed fallopian intraperitoneal tube measuring blood 10/4 accumulation cm and hyperstimulation (approximately aspect1500 mL), of the dilated right rupturedovary. Unilateral right fallopian salpingectomy tube measuring was performed 10/4 cm and and the hyperstimulation patient had an uneventfulaspect of the recovery right ovary. and was Unilateral discharged salpingectomy on day 3. was performed and the patient had an uneventful recovery and was discharged on day 3.

(a) (b)

Figure 2. Intraoperative aspects: ( (a)) D Directirect visualization of the ruptured fallopian tube during laparotomy laparotomy;; (b) unilateralunilateral salpingectomy was performed, and overall blood loss was 15001500 mL.mL.

TheThe post-surgical post-surgical evolution evolution was was uneventful, uneventful, the the mother mother continued continue progesteroned progesterone treat- treatmentment as per as per the the guidelines. guidelines At. At the the first first trimester trimester screening screeningand and earlyearly anomalyanomaly scan (12(12 weeks) weeks) only only two two of ofthe the TCTA TCTA fetuses were were alive alive and the and pregnancy the pregnancy evolved evolved as a DCDA as a twinDCDA pregnancy, twin pregnancy, with a low with risk a low for riskaneuploidies. for aneuploidies. Serial measurem Serial measurementsents for cervical for cervical length werelength arranged were arranged and the andpatient the was patient followed was followedup according up according to our local to protocol our local for protocol DCDA twins.for DCDA The rest twins. of the The pregnancy rest of the was pregnancy completely was uneventful completely. S uneventful.he delivered She via delivered cesarean sectionvia cesarean due to section the transverse due to the presentation transverse of presentation the fetus A of at the 35 weeks fetus A after at 35 a weeksspontaneous after a rupturespontaneous of the rupture membranes of the, two membranes, girls (2200 two and girls 2100 (2200 g, Apgar and 2100 9 and g, Apgar10 at 19 and and 5 10 min at), 1 withoutand 5 min), structural without defects. structural defects.

5.5. Discussion Discussion TheThe diagnosis diagnosis of of heterotopic heterotopic pregnancy is sometimes difficult difficult to make, but one might considerconsider it it when when there there is is acute acute abdominal abdominal pain pain and and hemorrhagic hemorrhagic shock, shock, in inthe the presence presence of anof anintrauterine intrauterine pregnancy, pregnancy, especially especially after after ART. ART. New New onset onset acute acute abdominal abdominal pain pain an andd hemorrhagichemorrhagic shock shock sings sings are are formal indications for laparoscopy or laparotomy in any pregnant patient. pregnant patient. Aiming to avoid the late diagnosis of a heterotopic pregnancy, and therefore rupture Aiming to avoid the late diagnosis of a heterotopic pregnancy, and therefore rupture of the tube and surgical repair, we propose a new approach. We recommend systematic of the tube and surgical repair, we propose a new approach. We recommend systematic transvaginal ultrasound assessment of the female pelvis after diagnosing an early intrauter- transvaginal ultrasound assessment of the female pelvis after diagnosing an early intrau- ine pregnancy for high risk patients (IVF procedures and ovarian stimulation). This should terine pregnancy for high risk patients (IVF procedures and ovarian stimulation). This be arranged particularly for the high-risk population for developing heterotopic pregnancy should be arranged particularly for the high-risk population for developing heterotopic with a systematic approach that must be followed at the early pregnancy (6–7 weeks of ges- pregnancy with a systematic approach that must be followed at the early pregnancy (6–7 tation) scan. After an intrauterine pregnancy is confirmed, the sonographer must visualize weeks of gestation) scan. After an intrauterine pregnancy is confirmed, the sonographer the bladder and the relationship between the cervix and the must be established. must visualize the bladder and the relationship between the cervix and the uterus must One must routinely visualize the ovaries and fallopian tubes. Should there be latero-uterine images, suspicious aspect of the fallopian tubes or considerable amount of free fluid in Douglas pouch, the possibility of heterotopic pregnancy should be raised. Eventually, a senior gynecologist (if available) can confirm the diagnosis and local transvaginal KCl injection in the ectopic pregnancy could be administered, aiming to avoid surgical treat- ment. Transvaginal ultrasonographically-guided injection of KCl (1 mL of 2 mEg/mL), using a 17-gauge needle is performed under general anesthesia, directly into the fetal Medicina 2021, 57, x FOR PEER REVIEW 5 of 6

be established. One must routinely visualize the ovaries and fallopian tubes. Should there be latero-uterine images, suspicious aspect of the fallopian tubes or considerable amount of free fluid in Douglas pouch, the possibility of heterotopic pregnancy should be raised. Eventually, a senior gynecologist (if available) can confirm the diagnosis and local trans- Medicina 2021, 57, 483 vaginal KCl injection in the ectopic pregnancy could be administered, aiming to avoid5 of 6 surgical treatment. Transvaginal ultrasonographically-guided injection of KCl (1 mL of 2 mEg/mL), using a 17-gauge needle is performed under general anesthesia, directly into the fetal thorax. The procedure aims to arrest the cardiac activity in the fetus [17]. An thorax. The procedure aims to arrest the cardiac activity in the fetus [17]. An overview of overview of the algorithm is pictured in Figure 3. Regarding the number of embryos trans- the algorithm is pictured in Figure3. Regarding the number of embryos transferred, the ferred, the ESHRE guideline recommends a single embryo transfer and this decision ESHRE guideline recommends a single embryo transfer and this decision should be made should be made by the quality of the embryo, the stage of development, maternal age, by the quality of the embryo, the stage of development, maternal age, ovarian response, ovarianand rankresponse of treatment,, and rank but of to treatment, transfer more but thanto transfer two embryos more than is discouraged two embryos [18]. is An dis- early couragedultrasonographic [18]. An early diagnosis ultrasonographic of multiple diagnosis pregnancies of multiple is mandatory, pregnancies in order is mandatory, to establish a in ordernormal to establish intrauterine a normal localization, intrauterine chronicity, localization, and to detect chronicity different, and abnormal to detect different major struc- abnormaltural defects. major structural In extremely defects. rare In cases, extremely the late rare splitting cases, ofthe the late embryonic splitting of mass the inembry- two can oniclead mass to in a conjoinedtwo can lead twin to pregnancy,a conjoined with twin itspregnancy, major complication with its major [19]. complication [19].

Figure 3. Flowchart on decision making after confirming an intrauterine pregnancy and assessment Figureof pelvic 3. Flowchart organs. on decision making after confirming an intrauterine pregnancy and assess- ment of pelvic organs. 6. Conclusions 6. ConclusionsWe acknowledge that the heterotopic pregnancy is a rare event, and therefore the learningWe acknowledge curve for anthat accurate the heterotopic diagnosis pregnancy can take a is long a rare time. event, We proposeand therefore a systematic the learningapproach curve of for the an pelvis accurate in high diagnosis risk patients, can take with a every long earlytime. pregnancy We propose ultrasound a systematic in order approachto identify of the the pelvis extremely in high rare risk cases patients of heterotopic, with every pregnancy. early pregnancy ultrasound in order to identify the extremely rare cases of heterotopic pregnancy. Author Contributions: Conceptualization, B.C. and D.O.; methodology, A.M.; software, A.M.C.; Authorvalidation, Contribution A.M.P.,s: andConceptualization, N.G.; formal analysis, B.C. and B.C.; D.O.; investigation, methodology, A.M. A.M.; and D.O.;software, resources, A.M.C.; C.G.; validationdata curation,, A.M.P. A.M.C.;, and N.G.; writing—original formal analysis, draft B.C.; preparation, investigation, B.C., A.M. A.M.P., and and D.O.; N.G.; resources, writing—review C.G.; dataand curation, editing, A.M.C.; B.C. and writing N.G.— visualization,original draft C.G.; preparation, supervision B.C A.M.P.;, A.M.P. project, and N.G.; administration, writing—review A.M.and andD.O. editing, All B authors.C. and haveN.G readvisualization, and agreed C.G.; to thesupervision published A.M.P.; version project of the adm manuscript.inistration, A.M. and D.O. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki Ethical review and approval was waived for this study, due to the type of the article “case report and literature review”. Informed Consent Statement: Written informed consent has been obtained from the patient to publish this paper. Medicina 2021, 57, 483 6 of 6

Data Availability Statement: The data presented in this study are available on reasonable request from the corresponding author on the condition of relevant approval from the originating institution. Conflicts of Interest: The authors declare no conflict of interest.

References 1. Luo, X.; Lim, C.E.; Huang, C.; Wu, J.; Wong, W.S.; Cheng, N.C. Heterotopic pregnancy following in vitro fertilization and embryo transfer: 12 cases report. Arch. Gynecol. Obstet. 2009, 280, 325–329. [CrossRef][PubMed] 2. Chin, H.Y.; Chen, F.P.; Wang, C.J.; Shui, L.T.; Liu, Y.H.; Soong, Y.K. Heterotopic pregnancy after in-vitro fertilization–embryo transfer. Int. J. Gynecol. Obstet. 2004, 86, 411–416. [CrossRef] 3. Reece, E.A.; Petrie, R.H.; Sirmans, M.F.; Finster, M.; Todd, W.D. Combined intrauterine and extrauterine gestations: A review. Am. J. Obstet. Gynecol. 1983, 146, 323–330. [CrossRef] 4. Refaat, B.; Dalton, E.; Ledger, W.L. Ectopic pregnancy secondary to in vitro fertilization-embryo transfer: Pathogenic mechanisms and management strategies. Reprod. Biol. Endocrinol. 2015, 13, 30. [CrossRef][PubMed] 5. Park, H.R.; Moon, M.J.; Ahn, E.H.; Baek, M.J.; Cho, H.D. Case report. Heterotopic quadruplet pregnancy: Conservative managment with ultrasonographically-guided KCl injection of cornual pregnancy and laparoscopic operation of tubal pregnancy. Fetal. Diagn. Ther. 2009, 26, 227–230. [CrossRef][PubMed] 6. Chan, Y.; Lee, J.N.; Yang, C.H.; Hsu, S.C.; Tsai, E.M. Case report. An unexpected quadruplet heterotopic pregnancy after bilateral salpingectomy and replacement of three embryos. Fertil. Steril. 2003, 80, 218–220. [CrossRef] 7. Tamhane, N.A.; Parikh, A.; Joshi, V.M. Heterotopic Quadruplet Pregnancy After ICSI Conception. J. Obstet. Gynaecol. India 2018, 68, 505–507. [CrossRef][PubMed] 8. Soares, A.; Duarte, C.; Oliveira, P.; Andrade, A.; Furtado, J. Heterotopic Quadruplet Gestation after Uncontrolled Ovulation Induction: A Case Report. J. Preg. Child. Health 2019, 6. [CrossRef] 9. Omosh, R.K.; Fayez, I.A.; Alfayez, N.D.; Karaki, M.M.A. Quadruplet Heterotopic Pregnancy: A Case Report. Jordan Int. Med. 2017, 63, 1–3. [CrossRef] 10. Uysal, F.; Uysal, A.; Oztekin, D.C.; Avcı, M.S. Heterotopic quadruplet pregnancy and successful twin outcome. Arch. Gynecol. Obstet. 2013, 288, 715–717. 11. Sherer, D.M.; Scibetta, J.J.; Sanko, S.R. Heterotopic quadruplet gestation with laparoscopic resection of ruptured and subsequent successful outcome of triplets. Am. J. Obstet. Gynecol. 1995, 172, 216–217. [CrossRef] 12. Aguemon, C.T.; Denakpo, J.; Hounkpatin, B.B.; Tossa, L.B.; Adisso, S.; Sacca, J.; de Souza, J. Heterotopic pregnancy in the University Clinic of Gynecology and Obstetrics of the National Hospital and University of Benin Hubert Maga Koutoukou: Report of a case of quadruple pregnancy; 3 fetal intrauterine and 1 abdominal fetal. Pan Afr. Med. J. 2015, 22, 394. 13. Lavanya, R.; Deepika, K.; Patil, K. Successful pregnancy following medical management of heterotopic pregnancy. J. Hum. Reprod. Sci. 2009, 2, 35–40. [CrossRef] 14. Habana, A.; Dokras, A.; Giraldo, J.L.; Jones, E.E. Cornual heterotpic pregnancy: Contemporary management options. Am. J. Obstet. Gynecol. 2000, 182, 1264–1270. [CrossRef][PubMed] 15. Siraj, S.H.M.; Wee-Stekly, W.W.; Chern, B.S.M. Heterotopic pregnancy in a natural conception cycle presenting as acute abdomen: A case report and literature review. Gynecol. Minim. Invasive Ther. 2014, 3, 100–102. [CrossRef] 16. Sentilhes, L.; Bouet, P.E.; Gromez, A.; Poilblanc, M.; Lefebvre-Lacoeuille, C.; Descamps, P. Successful expectant management for a cornual heterotopic pregnancy. Fertil. Steril. 2009, 91, 934.e11–934.e13. [CrossRef][PubMed] 17. Kwon, B.; Kang, S.; Lee, H.J.; Kim, M.; Lee, Y.H.; Im, J.; Moon, M.J.; Ahn, E.H.; Kim, Y.R. Non-surgical management and obstetric outcomes of heterotopic interstitial pregnancies. Minim. Invasive Ther. Allied Technol. 2020, 29, 375–379. [CrossRef][PubMed] 18. Guideline of the European Society of Human Reproduction and Embryology ESHRE. Guideline Group on Good Practice in IVF Labs. December 2015. Available online: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Revised-guidelines-for-good- practice-in-IVF-laboratories-(2015).aspx (accessed on 28 March 2021). 19. Gica, N.; Gana, N.; Mat, C.; Panaitescu, A.M.; Peltecu, G.; Vayna, A.M. Conjoined twins-early prenatal diagnosis. J. Obstet. Gynaecol. 2020, 40, 723–724. [CrossRef][PubMed]