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Introduction and background

Ectopic pregnancy is defined as the presence of an embryo outside of the uterus. Heterotopic pregnancy (HP) is characterized by the simultaneous coexistence of an intrauterine and extrauterine pregnancy. In more complex cases, the uterus may implant one or more fetuses, while the remaining embryos may be present in different implantation sites [1, 2]. The word “heterotopic” originates from the Greek phrase “eteros topos,” which means sited in “another place” and in obstetrical terms, in a wrong place outside the uterus.

Heterotopic triplet pregnancy (HTP) predisposes the existence of three embryos and could present as a single or twin intrauterine gestation, with the rest of the embryos/embryo being ectopic. HTP is still considered exceptionally rare, especially in spontaneous pregnancies, but is increasing steadily in recent years with the increased use of assisted reproductive techniques (ART) in infertile couples [2]. In ascending order, the ectopic implantation site could be the cervix, the cornua, the salpinx, the ovary, and the abdomen. The literature has not yet mentioned any cases of heterotopic triplet abdominal pregnancy.

Until 1984, previous articles used the term "combined" ectopic or "combined" heterotopic pregnancy to describe the presence of three embryos [3,4]. The phrase “heterotopic triplet pregnancy” was first mentioned by Goldman in 1991 [5], and with the increased number of similar cases, it was actually established by most of the authors in the title of their manuscript, especially after 1998 [6-9].

The aim of this systematic review is to analyze all the reported cases of heterotopic triplet pregnancies following ovulation induction and ART published in the English literature. This review seeks to collect comprehensive data on factors such as maternal age, medical history, the type of ART used, and pregnancy outcomes. The goal is to raise awareness concerning the challenges of diagnosing and managing heterotopic triplet pregnancies, which are still rare but increasing steadily due to the growing use of ART, and also provide useful messages to clinicians.

Review

Materials and methods

Defining the Research Question (PICO Framework)

We defined the research question through the PICO framework as follows: Population (P): patients diagnosed with heterotopic triplet pregnancies, particularly those who have undergone ART or related treatments; Intervention (I): the primary interventions are ART such as in vitro fertilization (IVF), ovulation induction, or embryo transfer; Comparison (C): case reports often do not include a comparison group, but potential comparisons could be with spontaneous pregnancies or different ART procedures; Outcome (O): outcomes will focus on pregnancy results, maternal complications (e.g., hemorrhage, ectopic rupture), and fetal outcomes (e.g., live birth, premature delivery, neonatal health). Table 1 illustrates the PICO framework.

Table 1

PICO framework.

PICOS ElementDefinitionStudy-specific information
P-PopulationThe target group under investigationPatients diagnosed with heterotopic triplet pregnancy, specifically those after ART.
I-InterventionThe primary treatment or procedure appliedAssisted reproductive techniques (ART), including In vitro fertilization (IVF)-Ovulation induction-Embryo transfer.
C-ComparisonA group or standard for comparison (if applicable)Not explicitly applicable; comparison is implied between spontaneous vs. ART-conceived pregnancies or alternative ART protocols.
O-OutcomesKey results or consequences1. Maternal complications: hemorrhage, hemoperitoneum, ectopic rupture. 2. Obstetric outcomes: -Pregnancy viability, fetal survival, delivery mode, preterm birth, neonatal health.

Search Strategy

For comprehensive coverage, a systematic search was conducted using the databases PubMed, EMBASE, Scopus, Google Scholar, and Cochrane Library. A combination of Medical Subject Headings (MeSH) terms and keywords were employed, with Boolean operators (AND, OR) used to refine and combine relevant concepts. The search terms were structured around the population, intervention, and outcomes. Population-related search terms included “Heterotopic pregnancy”, “Triplet pregnancy”, “Ectopic pregnancy”, “Multiple pregnancy”, and the MeSH term “Pregnancy, Heterotopic”. Intervention-related terms encompassed “Assisted reproductive techniques”, “Ovulation induction”, “In vitro fertilization (IVF)”, and “Embryo transfer”. Outcome-related terms included “Pregnancy outcome”, “Maternal complications”, “Obstetric outcomes”, and “Fetal outcome”. Additionally, the search strategy incorporated terms specific to case reports, such as “case report” and “case series”, applying relevant filters where available. For instance, in PubMed, the search strategy combined population, intervention, and outcome terms as follows: (“Heterotopic pregnancy” OR “Ectopic pregnancy” OR “Triplet pregnancy” OR “Multiple pregnancy”) AND (“Assisted reproductive techniques” OR “In vitro fertilization” OR “IVF” OR “Embryo transfer”) AND (“Pregnancy outcome” OR “Maternal complications” OR “Obstetric outcomes” OR “Fetal outcome”) AND (“case report” OR “case series”). This systematic approach ensured the comprehensive identification of relevant case reports and clinical outcomes related to heterotopic and multiple pregnancies in the context of assisted reproductive technologies.

Inclusion/Exclusion Criteria

The inclusion and exclusion criteria for this review were clearly defined to ensure the selection of relevant studies. The inclusion criteria comprised case reports published in English, focusing on heterotopic triplet pregnancies following ART or IVF, and articles published within a specified date range. The exclusion criteria involved studies that were not case reports, such as reviews and clinical trials, as well as those that did not specifically address heterotopic triplet pregnancies. Additionally, editorials, opinion pieces, and other non-clinical articles were excluded. These criteria were applied to maintain a focused analysis on clinically relevant case reports related to heterotopic triplet pregnancies in the context of ART or IVF.

PRISMA Process

The PRISMA process for this systematic review on heterotopic triplet pregnancy after ART involved the following steps:

Identification: A total of 150 studies were identified, and the search was limited to case reports and clinical studies published in English up to December 2023.

Screening: After removing 30 duplicates, the titles and abstracts of 120 studies were reviewed based on predefined inclusion and exclusion criteria. Studies were included if they focused on heterotopic triplet pregnancies following ART, were published in peer-reviewed journals, and reported patient outcomes. Exclusion criteria resulted in the removal of 40 studies, which included reviews, editorials, clinical trials without a focus on heterotopic triplet pregnancies, and studies not in English.

Eligibility: Full-text articles for 80 studies were assessed for eligibility. During this phase, studies that did not specifically address heterotopic triplet pregnancies in ART cases or lacked clinical relevance were excluded. This assessment led to the exclusion of 23 studies, leaving 57 studies for further evaluation.

Inclusion: Ultimately, 57 case reports and clinical studies met the inclusion criteria and were incorporated into the systematic review. A PRISMA flowchart was created to visually represent the number of studies at each stage of the process (Figure 1).

These 57 studies provided comprehensive data on heterotopic triplet pregnancies and associated ART interventions (Figure 1).

Figure 1

Flowdiagram of the study selection process.

Quality Assessment

The quality assessment of the selected studies followed a structured framework to ensure the rigor and reliability of findings. Critical appraisal tools, such as the critical appraisal skills program (CASP) checklist for case reports, were used to evaluate essential elements, including patient demographics, ART intervention details, and outcomes. Methodological soundness, data completeness, and outcome relevance were key criteria. A Risk of Bias assessment categorized studies based on the potential for selection or reporting bias and conflicts of interest (Appendix A). Consistency and completeness of data, such as maternal age, ART procedures, and complications, further informed quality judgments, with missing data lowering the study’s rating. Lastly, outcome validity was scrutinized, emphasizing accurate diagnosis and management of heterotopic triplet pregnancies, ensuring the final review was based on high-quality, unbiased studies.

Data Extraction

The following data were extracted from the selected articles: a) Patient Demographics: Age, medical history, gravida/para status; b) Intervention Details: Type of ART (e.g., IVF, ovulation induction), medication used, number of embryos transferred, and stage of cells and c) Outcomes: Maternal outcomes (complications, surgical interventions), fetal outcomes (live birth, premature delivery, neonatal health).

Results

We identified 57 articles of heterotopic triplets after assisted reproductive techniques and recorded the year, maternal age, gravida/para, medical history, medication used and mode of conception, number of embryos and stage of cells transferred, number of embryos in utero and ectopic embryos, time of diagnosis after ovulation induction or embryo transfer, symptoms, rupture of the ectopic pregnancy with hemoperitoneum, complications in pregnancy, obstetric outcome, weeks of delivery, birth-weight status and sex of the infants.

The maternal age ranged from 24-year-old as the youngest to 47-year-old as the oldest, with a mean age of 32.36±4.84 years. From the medical history, we noted that the infertility etiology is multifactorial in most cases. The predominant infertility reason is the tubal factor, single (salpingectomy salpingostomy, tuboplasty, hydrosalpinx, ectopic, occlusion) or mostly combined with other causes, found in 23/57 (40.35%), [2-4, 8-27], followed by male infertility single or combined in 8/57 (14%), [18, 28-34]. Endometriosis is reported in 3/57 cases (5.26%) [27,35,36]. Diethyl Stilbestrol Syndrome was noted in 2/57 (3.50%) cases, which were reported mainly in the first cases [5,35]. There was a single case in 1/57 (1.75%) with pituitary adenoma [37], while in 6/57 (10.5%), the medical history and the cause/causes of infertility are not stated [6,38-42] (Table 2).

Table 2

Summary of the studies findings.

G/P: gravida/para;  DES: diethylstilbestrol syndrome; PID: pelvic inflammatory disease; PCOS: polycystic ovary syndrome; Lap: laparoscopy; NS: not stated; IVF: in vitro fertilization; ET: embryo transfer; ICSI: intra cytoplasmatic sperm injection; FSH: follicle stimulating hormone; LH: luteinizing hormone; HCG: human chorionic gonadotropin; HMG: human menopausal gonadotropin; GnRH: gonadotropin releasing hormone; MESA: microepididymal sperm aspiration; MTX: methotrexate; KCL: potassium chloride; D/C: dilation/curettage; MC: monochorionic twins; DC: dichorionic twins; PROM: premature rupture of membranes; TPL: threatened preterm labor; OHSS: ovarian hyperstimulation syndrome; SCEP: cesarean scar ectopic pregnancy; F: female, M: male; C/S: cesarean section.

NAuthorsYearAgeG/PMedical history/infertilityMedicationConceptionNo EmbryosStage(cells) US-(Sacs in utero)EctopicDiagnosisSymptomsTreatmentComplications/pregnancyObstetric outcomeDelivery (weeks)Birth weight/Status
1Payne S et al. [43]197127G1 P1Involuntary infertilityPrednisone 2.5mg/4dtp + Clomiphene 50mg (4th-8th)Ovulation induction – spontaneousNSNS2Right cornual48 daysAbdominal painLaparotomy-salpingectomyPremature laborCS35Twins-healthy 2400gr/2120gr
2Walker TA et al. [44]197233-InfertilityClomiphene Citrate 50mg (4th-8th)Ovulation induction – spontaneousNSNS2Right salpinx8 weeksSevere pain/pre-shock statusLaparotomy-salpingectomy/appendectomyNoVaginal delivery37Twins-healthy 2570gr/2260gr
3Sondheimer SJ et al. [35]198528G0 P0Primary infertility-endometriosis-DES (T-shaped uterus)GonadotropinIVF-ET55, 3, 2, 12Left salpinx41 daysLow abdominal painLap-salpingectomyCerclage-premature laborCS33NS
4Yovich JL et al. [3]198534-PID-bilateral hydrosalpinges-myomectomyClomiphene 100mg (2th-6th)+HMG+HCGIVF-ET542Left salpix8 weeksLeft pelvic painLap/converted to laparotomy-salpingectomyDemise 2nd twinNormal follow at 30 weeks-NS
5Porter R et al. [4]198633G2 P2Tubal factorClomiphene 100mg (3th-7th)+HMG 150IU (7-11)IVF-ET62,41Right Twin tubal6 weeksSevere abdominal painLaparotomy-salpingectomyNoVaginal delivery37Healthy infant/3040gr
6Hanf V et al. [10]199030G1Tubal factor-bilateral hydrosalpinxHMG+HCGIVF-ET441Bilateral tubal37 daysSevere abdominal pain-vaginal bleedingLap-salpingectomy bilateralNoCS38Healthy
7Goldman JA et al. [ 5]199128G1 P0Diethyl stilbestrol syndromeFSH+HMGIVF-ET441Right twin tubal6 weeksRight pelvic pain/vaginal bleedingLaparotomyPremature laborVaginal delivery30Healthy infant/2600 gr
8Chen SU et al. [11]199232G0 P0Primary infertility/bilateral tuboplasty-fibrioplastyFSH+HMG+HCGIVF-ET62 to 42Right salpinx10 weeksSevere low abdominal painLaparotomy-repair of ruptureAbortion-D/C---
9Smith S et al. [12]199327G0 P0Pelvic adhesions/bilateral hydrosalpinxGnRH agonist+HMG+HCGIVF-ET4Pronuclear2Right salpinx32 daysSevere low abdominal painLaparotomy-removalPremature laborPremature labor/CS24Expired
10Bassil S et al. [28]199531G0 P0Male infertilityFSH+HMG+HCGIVF-ET3NSNoneRight cornual triplets35 daysNo symptomsLaparotomy-excision/horn reconstructionExcision/corual pregnancy---
11Berliner I et al. [6]199829G1 P0NS75IU LH+FSHHomologous intrauterine inseminationNSNS2Left salpnix5 weeksPelvic painLap-salpingotomyNoVaginal delivery37Twins-healthy 2722gr/2863gr
12Inion I et al. [7]199830G0 P2PCOS/Ovulation Induction-Right ovarian torsion/laparotomy-2nd ovarian torsion/laparoscopyNSIVF-Intrauterine insemination (donor)282Right adnexa47 daysRight abdominal painLaparotomy-adnexectomyDemise 2nd twinVaginal deliveryNSHealthy
13Barnett A et al. [13]199932G0 P0Primary infertility/tubal damageNSIVF3NS2Right salpinx9 weeksRight abdominal painLaparotomy-salpingectomy+appendectomyNoCS37Twins-healthy 2080gr/2700gr
14Nair P et al. [8]199934G2 P1Lap left salpingostomy (hydrosalpinx)GnRH analogs+gonadotropinIVF/ET3NS2Left salpinx34 daysVaginal discharge/suprapubic tendernessLaparotomy-left partial salpingectomyNoCS38Twins-healthy
15Ludwig M et al. [9]199925G0 P0Primary infertility/tubal damage-PCOS/laparoscopy-ovarian abscessHMG Long protocolIVF-ET3NS2Right salpinx48 daysAbdominal pain-OHSSLap-bilateral calpingectomyNoNSNSNS
16Oliveira FG et al. [29]200231G0 P0Male factor-oligoasthenospermiaNSIVF-ICSI3NS2Left Adnexa38 daysSevere abdominal painLap-salpingectomyNoNS38Twins -healthy
17Pan HS et al. [36]200238G3 P1Endometriosis-pelvic adhesions-cervical strictureHMG+FSH+HCGIVF-ET(tubal due to cervical stenosis)42,3,41Bilateral tubal5 weeksAbdominal pain-vaginal bleedingLaparotomy-bilateral salpingectomyNoVaginalNSHealthy Infant
18Nikolaou DS et al. [14]200231G1 P0PCOS/laparoscopic drilling/laparotomy-Left oophorectomy+partial salpingectomyFSH+HCGIVF-ET2NS2Left interstitial28 daysIntermittent iliac fossa discomfortLaparotomy-left tube incised and evacuatedPremature labor-MC twinsVaginal33Twins –healthy 1400gr/1400gr
19Hoopmann M. [30]200339G0 P0Laparotomies (Crohn’s disease)-male InfertilityNSIVF-ICSINSNS1Bilateral tubal6+6 weeksNo symptomsLap-bilateral linear salpingostomyEmpty sac syndrome---
20Sayin NC et al. [45]200325G3 P0InfertilityClomiphene citrate 100mg/day 5-9Ovulation induction - SpontaneousNSNS2Left Salpinx8 weeksAcute abdomenLaparotomy-left salpingectomyPremature labor-MC twinsCS35Twins –healthy 2350gr/1900gr
21Strelec M et al. [15]200428G2 P0Infertility/tubal factor-Ectopic-right salpingectomyHMG+HCGIVF-ET3NS2NS10+1 weeksSevere pain-hypotensive/tachycardicLap-salpingectomyPROMCS29NS
22Bhat SM et al. [16]200431G1 P1Secondary infertility-Ectopic-left salpingostomy-right adnexectomyGnRH antagonist+FSH+HCGIVF-ET4NS2Right cornual12 weeksAbominal pain-collapsusLaparotomy-repair of uterine cornual ruptureNoCS36Twins –healthy 2500gr/2800gr
23Childs AJ et al. [38]200530G4 P2NSGonadotropinsUterine inseminationNSNS2Left Salpinx11 weeksAbdominal painLap-SalpingectomyMissed abortion 2nd twin (9weeks)NSNSNS
24Cirillo D et al. [39]200628G0 P0NSGonadotropinsNatural conceptionNSNS2Right Ovary8 weeksAbdominal pain-vaginal bleeding/OHSSLap-Partial right ovarian resectionPremature laborCS32Twins –healthy 1800gr/1950gr
25Muller Vranjes A et al. [46]200634G0 P0Infertility (5 years)/1 miscarriage/embolization for uterine myomaClomiphene citrate (2X50 mg), day 3-8Not statedNSNS2Right Salpinx10 weeksHemorrhagic shockLap-right salpingectomyNSNSNSNS
26Dundar O et al. [31]200635G0P0Male infertilityClomiphene citrateUterine inseminationNSNS2Right adnexa10 weeksAcute abdominal painLaparotomy-right salpingectomyMC-monoamniotic twinsFollow up-16 weeks--
27Gupta A et al. [37]200634G0P0Pituitary adenoma2.5 mg Bromocriptine X3 per daySpontaneous conceptionNSNS1Bilateral tubal9 weeksShockLaparotomy-left salpingectomy/right linear salpingotomyDemise of intrauterine fetus/9 weeks/DC---
28Divry V et al. [17]200732G0 P0Primary infertility (12 years)/tubal factor-bilateral salpingectomyNSIVF-ET382Right cornual6 weeksNo symptomsLap/converted to laparotomy-excision (cornual)NSCS31Twins –healthy 1360gr/1590gr
29Berkes E et al. [18]200826G1 P0Secondary infertility/right salpingectomy-male factor (asthenoteratoazospermia)GnRH agonist+HMG+1.25mg bromocryptineIVF-ICSI3NS0Left isthmic+Twin tubal33 daysAbdominal painMTX 50/100/100mg im-laparotomy/left interstitial salpingectomyEmpty uterus---
30Kasum M et al. [19]200932G0 P0Primary infertility/distal occlusion of left tube-reconstructive surgery  of the right tube/Left salpingectomy (ectopic)NSIVF-ETNSNS1Bilateral tubalNSAbdominal painLap-left salpingectomy                                                 -Vaginal40Healthy infant
31Bugatto F et al. [2]201028NSTubal factor (2 years)-Left tubal occlusionGonadotropin+HCGIVF-ETNSNS2Left salpinx12+4 weeksLeft iliac painLaparotomy/left salpingectomyTPL (admission/cervical incompetence)CS31+2Twins-healthy 1650gr/1800gr
32Timor-Tritsch I et al [20]201029G5P0Two miscarriages/Right ectopic-salpingectomy/bilateral ovarian ectopic-resection and left salpingectomyNSIVF-ET2NS1Right cornual MC Twin pregnancyNSNS-No symptoms (?)Vaginal needle KCL injection/laparotomy-cornual resectionNoCS37NS
33Tomic V et al. [21]201131NSPrimary infertility (tubal occlusion)GnRH+r-FSH+HCGIVF-ET3GI, GII2Right salpinx7 weeksAbdominal pain/OHSSLap/converted to laparotomy-right salpingectomyNoCS37Twins-healthy 2450gr/2840gr
34Litwicka K et al. [32]201131G1 P1Secondary infertility/Male infertility (azoopsermia)/previous CSGnRH antaonist+r-FSHIVF-ICSI3NS1Two sacs - isthmic6 weeksNo symptoms   Vaginal needle (20G) injection KCL(2ml)+MTX 15 mgContractions 28-34 weeksEmergency CS/ hemorrhage36Miller syndrome
35Okamura Y et al. [22]201131G2 P0Infertility (6 years)/left pyosalpinx-right tubal obstruction-left salpingectomyNSIVF-ET3NS2Left tubal isthmic8 weeksPre-shock statusLap-left isthmic excisionFetal demise 2nd twin/8 weeksElective CS37Healthy infant-2828 gr
36Bornstein E et al. [23]201129G5 P4Lap right salpingectomy/2 miscarriages/2 bilateral ectopic ovarian pregnancies/Left salpingectomyNSIVF-ET2NS1Right cornual MC Twin pregnancy8 weeksNo symptomsVaginal needle  KCL-Bleeding-Laparotomy-Cornual evacuation/repairNoElective CS37NS
37Gozukucuk M et al. [24]201129G1P0Right tubal ectopic-salpingectomy/unexplained infertilityNSIVF-ETNSNS1Twin cervicalNSNo symptomsDilatation and curettageEmpty sac syndrome---
38Osmanagaoglou M et al. [40]201147NSNSLeuprolide acetate 500 μg+225 IU r FSH+HCGIVF-ET3NS2Left salpinx9 weeksAbdominal painLap-Left salpingectomyNoNS35Twins-healthy 2206/2426gr
39Herrera E et al. [33]201134NSPrimary infertility/male actor-azoospermiaNSIVF-ET (blastocyst transfer)NSNS2Left cornual9 weeksAbdominal painLaparotomy-Left salpingectomy-NSNSNS
40Lin CK et al. [25]201332G2 P1Secondary infertility (10 years)/tubal factor200IU FSH+150IU HMG+HCGMESA+ICSI5NS2Cervix15 weeksNoSac needle aspitation+KCL 10ml KCLSevere preeclampsia-Uterine atony/hysterectomyCS-Hysterectomy27Twins DC-1000gr/705gr
41Delrieu et al. [26]201336G3P3Tubal ligation-unsuccessful tubal reanastomosisGnRH agonist+HCGIVF+ET4NS1Left salpinx+cervix38 daysAbdominal painLap-left salpingectomy/cervical mass excisionNoNSNSNS
42Fukuda T et al. [47]201432G1 P0History of ovulatory disturbanceGnRH agonist+225IU HMG+150IU r FSH+HCGIVF-ET3Day 33Cervix8+3 weeksNo symptomsSac needle aspitation (19G)Premature laborEmergency CS25Twins DC-660gr/620gr
43Felekis T et al. [1]201432G2 P0Idiopathic infertility( 3years)Clomiphene citrate (100mg for 5 days)+HCGUterine InseminationNSNS1Bilateral tubal9 weeksAbdominal pain/vaginal bleedingLap-left salpingectomy-right salpingostomyNoVaginal39Healthy infant
44Buca DI et al. [48]201537G0 P0Idiopathic infertility (5 years)NSIVF-ETNSNS2Right salpinx9+4 weeksAbdominal pain/nausea/vomitingLaparotomy-Right salpingectomyTPL (contractions/admission)Elective CS36+2Twins –healthy 2460gr/2600gr
45Kasap B et al. [49]201532G1P0Unexplained infertility (4 years)NSICSI-ET3GI1Bilateral tubal21 daysNo symptomsLap-Bilateral slapingectomySpontaneous abortion---
46Nitke S et al. [50]200745G0 P0Primary infertility (5 years)Donor eggsIVF-ET4NS12 sacs - cervix7 weeksNo symptomsUterine arteries catheterized/84 mg MTX/Uterine embolizationShrinkage of two cervical sacs/uterine sac---
47Hsieh BC et al. [51]200438G4 P2Secondary infertility/ two CSGnRH analogs+HCGIVF-ET3NS2CSEP21 daysNo symptomsVaginal needle aspiration of the sacPremature laborNS32NS
48Gaudier FL et al. [52]199531G0 P0Primary infertility (7 years)NSIVF-ETNSNS2Right interstitial15 weeks(MRI)Acute abdominal painLaparotomyContractions-20 weeksPremature labor/CS34Twins-healthy 2100gr/1500gr
49Al Mulla A et al [53]201838-Primary infertility-four unsuccessful ICSINSIVF-ET3Blastocyst 3CC2Right salpinx11 weeksSchockLap-right salpingectomyPremature laborCS34Twins DC-healthy 2460gr/2600gr
50Vitner D et al. [54]201147G0 P0Egg donationControlled minimal ovarian stimulationIVF-ICSINSNS2Right salpinx9+5 weeksSevere abdominal painLaparotomy-right salpingectomyNo-TermTwins DC- healthy
51Mustafa KB et al. [55]201637G2 P0Idiopathic infertility (6 years)Gonadotropins+metformin+HCGNatural conception21,21Bilateral tubal8 weeksAbdominal pain vaginal spotting/OHSSLap-bilateral salpingectomySpontaneous abortion---
52Jonler M et al. [56]199531G0 P0Primary infertility (7 years)NSIVF-ETNSNS1Bilateral tubal6+3 weeksNo symptomsLap-bilateral salpingotomyAbortion-D/C---
53Riestenberg CK et al. [57]201724G0 P0PCOSNSIVF-ETNSNS1Bilateral tubal25 daysAbdominal pain- spottingLap-right salpingostomy/Left salpingectomySpontaneous abortion-D/C---
54Korkontzelos I et al. [34]201938G4 P0Male factor (oligoasthenospermia)NSIVF-ICSI342Left salpinx8+2 weeksAbdominal pain/OHSSLaparotomy-left salpingectomyDemise 2nd twin-TPL-cerclageElective CS36+1Healthy infant -1980gr
55Bhattacharya R et al. [41]202033G2P0NSNSIVF-ETNSNS2NS11 weeksAbdominal painLaparotomy-Left salpingectomyDC twins-fetal demise---
56Morong J et al. [42]202131G3 P2NSClomiphene Citrate 50 mg for 5 daysNatural conceptionNSNS2Left Salpinx10+1 weeks-Severe abdominal pain/vaginal bleedingLap-left salpingectomyTPLElective CS36+5Twins-healthy
57Bhoi NR et al. [27]202335G0P0Hydrosalpinx-bilateral endometrioma-subserous fibroidGoserelin acetateIVF-ICSI2Grade 12Left adnexa7 weeksNoLap-cornual resectionNoElective CS36Twins MC-healthy 2200gr/200gr

All the heterotopic pregnancies in the manuscript are presented after the use of ovulation induction drugs. In 18/57 (31.5%) cases the medication used is not stated. Clomiphene citrate in a dosage of 50 or 100 mg, single or in association with other drugs, was used in 9/57 (15.7%) [3,4,31,42-47], with natural conception occurring in 4/57 (7%) women [42-45]. In vitro fertilization (IVF) and embryo transfer (ET) was used in most of the cases, 34/57 (59.6%), while IVF plus intracytoplasmatic sperm injection (ICSI) was used in 8/57 (14%) cases, [27,29,30,32-34,48], including one patient with additional use of bromocriptine [18]. Intrauterine insemination, a less expensive method, was also used in a percentage of 6/57 (10.52%) cases [6,7,31,38,47,49] (Table 2).

The method of embryo transfer is not mentioned in most of the articles. From this study, we noticed that in the first early cases, the oocytes were transferred laparoscopically, while after 1993, in all the reported cases, the intervention was performed vaginally. It was also considered useful to state the number of embryos transferred and the stage of cells. Until 1993, the number of embryos transferred was four up to six. From 1993 until today, the number of embryos decreased between two and three, with only a few exceptions [16,25,33,36,50]. In 22/57 (38.6%) the number of embryos transferred is not stated (Table 2).

In cases where a single intrauterine pregnancy is noted, the distribution of ectopic twins was: twin bilateral tubal gestation in 11/57 (19.3%), twin pregnancy in a single tube in 2/57 (3.5%), and three corneal-isthmic twin pregnancies, 3/57 (5.2%). Cornual-interstitial-isthmic pregnancy with a single embryo was noted in 6/57 (10.5%), an empty uterus and cornual triplets in 1/57 (1.7%), one or more cervical embryos in 5/57 (8.7%), cesarean scar ectopic pregnancy in 1/57 (1.7%) and one ovarian ectopic pregnancy (1.7%). The right adnexal ectopic side is predominant and presented in 21/57 (36.8%), followed by the left side in 15/57 (26.3%) and bilateral tubal in 9/57 cases (15.7%). The earliest diagnosis was made after 21 days/3 weeks [51] and the latest in two patients at 15 weeks of gestation [33,52]. One of these two patients presented was referred for a suspected fetal anomaly, and the diagnosis of HTP was confirmed after a magnetic resonance imaging (MRI) (Table 2) [52].

A variety of symptoms was present, starting from intermittent iliac fossa discomfort. Abdominal pain, mild or severe (acute abdomen) with or without vaginal bleeding, was the main symptom in 41/57 (71.9%) patients, with the rest 16/57 (28%) being asymptomatic. Intra-abdominal hemoperitoneum was present in 30/57 (52.6%) patients (250 ml-2500 ml). In the remaining 25/57 (43.8%) of the cases, the ectopic was not ruptured, while in two cases, it was not stated. It has to be noted that, in 7/57 (12.28%) women, the admission was made in a pre-shock/hypotension-tachycardia or in a collapse/shock status (Table 2) [15,16,22,37,44,53].

Treatment options were mostly determined by the clinical status of the presenting patient, the site of the ectopic gestation, the existence of hemoperitoneum or bleeding, and the woman’s preferences. In total, 29/57 (50.8%) cases were treated by laparotomy, including three cases that started laparoscopically and were converted to laparotomy. Furthermore, two cases started with vaginal needle injection of potassium chloride (KCL) with or without methotrexate (MTX), [20, 40] and one case of initial intramuscular (im) injection of MTX which ended also in laparotomy [18]. In total initial treatment by vaginal approach (aspiration or injection of KCL) was performed in 6/57 (10.5%) patients [20,23,26,32,33,51]. Laparoscopically, they were treated in 22/57 (38.6%) cases. There was also a single case of 1/57 (1.7%) treated with dilation and curettage of an intrauterine and twin cervical pregnancy [54] and one case treated with an injection of MTX and uterine artery embolization [50]. As mentioned before, seven patients were admitted in a shock status. Furthermore, another eight patients were admitted with severe abdominal pain, as stated by the authors, reaching a total of 15/57 (26.3%) patients admitted in a serious condition. Nine out of these fifteen patients (60%) were treated by laparotomy, and interestingly, the rest, 6/15 (40%) by laparoscopy. There were also five cases where ovarian hyperstimulation syndrome (OHSS) was officially diagnosed with or without hemoperitoneum [9,21,34,39,55], and 3/5 (60%) of those patients were treated laparoscopically [9, 39], and 2/5 patients (40%) by laparotomy (Table 2) [21,34,55].

Complications in pregnancy and obstetric outcomes were recorded in most of the cases, 54/57 (94.7%). In 20/57 (35%), no symptoms occurred, and where stated, the patient had a successful outcome. Spontaneous abortion or empty sac syndrome was present in 9/57 (15.7%), followed by dilatation and curettage when necessary [11, 18, 30, 37, 48, 54-57]. Contractions threatened preterm labor, premature rupture of membranes, and premature labor (24-36 weeks) were noted in 13/57 (22.8%) women. One case suffered from severe preeclampsia at 27 weeks and ended with a cesarean section followed by uterine atony and hysterectomy (Table 2) [33].

Twenty-five women delivered by cesarean section, and nine vaginally. There were 5/57 (8.7%) twin intrauterine pregnancies with the fetal demise of the second twin [3,7,22,34,38], and three of them had a favorable outcome, while in two cases, the fetal demise of both dichorionic twins was noted. Four cases had very early premature labor (<29 weeks) [12, 15, 26, 33]. Out of these cases, one infant was delivered at 24 weeks and expired, two dichorionic twin cases were delivered at 27 and 25 weeks, and the last case was delivered at 29 weeks of gestation. In those last three cases, the neonatal status after birth and the follow-up is not mentioned. In 11/57 (19.3%) cases, the pregnancy ended in abortion or empty sac syndrome treated mostly by dilation and curettage, while in 18/57 (31.5%) cases, obstetrical follow-up and the outcome was not specified. Data also missed the sex of the newborns, but we recorded the birth of 19 female and 16 male infants. In total, out of all these 57 single or twin intrauterine gestations, 49 healthy infants were delivered, and one term neonate was diagnosed with Miller syndrome (Table 2) [32].

It was difficult to identify the surgical treatment modality that could be considered most appropriate and that also resulted in a successful obstetrical outcome. It has to be noted that many cases were complex, multifactorial, heterogeneous and received combined therapy intra-abdominal/operative, intra-cervical by needle injection and aspiration accompanied by conservative treatment with KCL and/or MTX. Thus, we decided to consider only cases that were delivered after 30 weeks and had a favorable outcome, while unreported neonatal status or severely complicated cases were excluded. Out of these 28 cases, nineteen (67.8%) were treated by laparotomy and nine (32.2%) by laparoscopy.

Discussion

Historically, the first reported naturally occurring heterotopic pregnancy was described by Duverney in 1708 after an autopsy of a patient who died from a ruptured ectopic pregnancy but simultaneously had an intrauterine pregnancy [58]. The first successful birth after in vitro fertilization process occurred in 1978 by Patric Steptoe and Robert Edwards [59]. However, their first attempt in 1976, where a human embryo was introduced into the uterus, ended up in an ectopic tubal pregnancy removed at 13 weeks of gestation. In 1971, Payne et al. [43] reported the first heterotopic triplet (twin intrauterine and right tubal) pregnancy in the English literature after ovulation induction with clomiphene citrate and corticosteroids. The first HTP resulting from in vitro fertilization and embryo transfer was reported by Sondheimer et al. [35]. 

Tal et al. [58] reviewed 139 cases of heterotopic pregnancies from 1971 up to 1993, independent of the number of embryos. Since then, HP has been increased but there was also a notable increase in “multiple”, or “combined” (triplet-quadruplet-quintuplet-sextuplet) heterotopic gestations. Concerning specifically heterotopic triplets, it is impressive that in a period of 21 years (1971-1992), only eight cases are recorded, while from 1993 until now, another forty-nine new cases of heterotopic triplets were added.

In spontaneous pregnancies, the incidence of HP is 1/30000. In pregnancies resulting from ART, the incidence is increasing dramatically from 1/100 up to 1/3600. Overall, the incidence of HP is estimated to be approximately 1/7000 to 1/15000 live births [1]. Patients treated with ovulation induction have a ratio of 33/10000, while after IVF, the risk is increased, approaching a ratio of 100/10000 [2]. This major difference in the statistics is attributed to the broad use of assisted reproductive techniques, basically ovarian stimulation, intrauterine insemination, transfer of many embryos in utero, the quality of the embryos, the hormonal milieu at the moment of transfer, transfer near the uterine horn, the amount of fluid used as media for the embryos, excessive pressure on the syringe and deep insertion of the catheter. Additional factors are considered: the frequent use of intrauterine devices (IUDs) and the higher incidence of pelvic inflammatory disease or endometriosis resulting in tubal damage or tubal malformation [1, 2].

Buggato et al. [2] published a review article, including also a case report of a twin intrauterine and a left ectopic pregnancy. To his knowledge, only 14 cases of HTPs, with two embryos being in utero and one extrauterine, were reported. In our review, we recorded in total 36/57 cases of a twin intrauterine and one ectopic fetus, reaching 63% and becoming the most common sub-category of HTP.

The diagnosis of HTP is challenging and difficult. Serial β-HCG levels are not helpful due to the presence of a concomitant intrauterine pregnancy. Transvaginal ultrasound (TVS) remains the preferred imaging method for diagnosing both tubal and non-tubal heterotopic pregnancies. Despite the widespread use of high-resolution vaginal sonography in clinical settings, its sensitivity for detecting heterotopic pregnancies remains low, as the condition is frequently missed or overlooked [14]. False assurance could be obtained by the ultrasonographic visualization of an intrauterine pregnancy, the absence of clinical symptoms, the presence of enlarged ovaries with multiple leutal cysts, or the presence of ovarian hyperstimulation syndrome with intra-abdominal free fluid.

In 1993, Fernandez et al. [60] stated that only 10% of all heterotopic pregnancies are diagnosed preoperatively. In heterotopic pregnancies, the most frequent implantation site is in the fallopian tube and most commonly in its ampullary segment. Kemp et al. [61] noticed that only 6-16% of ectopic tubal pregnancies show fetal heartbeat. However, increased vascularization within the structure visualized by color Doppler indicates ongoing ectopic pregnancy. Furthermore, a definite diagnosis could be made only when extrauterine fetal cardiac activity is seen on an ultrasound or in the operating theatre. Li et al., in a retrospective study, set certain sonographic criteria for the diagnosis of HP using TVS even if a visible intrauterine gestational sac is observed: (i) an inhomogenous adnexal mass, (ii) an empty extrauterine gestational sac seen as a hyperechoic ring, (iii) a yolk sac and/or a fetal pole with or without cardiac activity in an extra-uterine sac [62]. The sensitivity and specificity of TVS for the detection of HP in this study were reported to be 92.4% and 100%, respectively. In his relatively recent review, Bugatto et al. reported that in heterotopic pregnancies an accurate or suspected diagnosis was made only in 57% of the patients and most of them (60%) were diagnosed before 10 weeks of gestation, however a timely surgical treatment does not appear to improve the prognosis [2].

The diagnosis of HTP is becoming more complicated in cases of ruptured heterotopic pregnancies associated with ovarian hyperstimulation syndrome (OHSS). Both conditions can be linked to hypotension, tachycardia, abdominal pain, and the presence of free fluid in the abdominal cavity, along with a concurrent intrauterine pregnancy. A ruptured corpus luteum may also be misdiagnosed as HP, as both conditions can display the "ring of fire" sign on ultrasound. In contrast, women with OHSS typically present with normal hemoglobin levels, elevated hematocrit, and enlarged ovaries [14,21]. In our review, many cases mentioned enlarged ovaries with multiple luteal cysts, but only five cases of HTP accompanied by OHSS syndrome (9%) were officially recorded, and in those cases, late diagnosis occurred (Table 4).

The management of heterotopic triplet pregnancy focuses on removing the ectopic pregnancy while preserving the viable intrauterine embryo(s). Currently, there is no standardized treatment for HTP, and available data are based solely on case reports. Treatment strategies depend on factors such as gestational age at diagnosis, uterine size, the patient's clinical status, the location of the ectopic implantation, and the treating physician's expertise. Generally, heterotopic tubal pregnancy can be managed either conservatively or surgically. In cases of rupture or when the patient is hemodynamically unstable, laparotomy and removal of the ectopic sac is the traditionally preferred approach. Laparoscopy has also become the preferred method for final diagnostic confirmation in cases of dilemmas and has been increasingly used in the last years [29]. Laparoscopic injection of KCL or MTX into the tube has also been performed [63]. However, a review by Goldstein et al. [64] revealed that 55% of tubal heterotopic pregnancies treated with KCL injection required subsequent salpingectomy. Generally, salpingectomy is preferred in cases of uncontrolled bleeding or significant tubal damage. Salpingostomy, on the other hand, is indicated for stable patients with an unruptured ectopic sac smaller than 5 cm, especially if the contralateral tube is absent or damaged and the patient has a strong desire to preserve fertility [65, 66]. Αρχή φόρμαςDuring the operation, special attention should be provided for manipulations that will not disturb the uterus, leading to postoperative contractions also respecting the ovarian or collateral blood supply [2].

Conservative treatment requires early diagnosis and should be performed in specific cases. The medication could be injected locally using a laparoscopic or transvaginal approach. Agents like methotrexate, potassium chloride, and hyperosmolar glucose could be used in nonviable pregnancies. The use of MTX in the presence of a viable pregnancy is contraindicated, as it can lead to miscarriage or congenital malformations. Instead, sonographically guided local injection of KCL into the heart of the ectopic fetus can induce cardiac asystole. Hyperosmolar glucose may also be injected into the gestational sac, causing local dehydration, necrosis, and resolution of the trophoblastic tissue. Cornual and interstitial pregnancies can be managed by surgical excision or ultrasound-guided aspiration with KCL injection. Cervical heterotopic pregnancy may be treated through ultrasound-guided aspiration with cervical sutures, intra-cardiac KCL injection, vacuum aspiration following ligation of the descending cervical branches of the uterine arteries, electrodesiccation, or hysteroscopic resection. For ovarian ectopic pregnancy, laparoscopic wedge resection or ipsilateral oophorectomy is the preferred treatment [25, 67]. In cases of single-twin fetal demise, chorionicity, and gestational age at the time of demise are the key factors influencing the survival of the second twin. The perinatal survival rate is reported to be 83% for monochorionic twins and 100% for dichorionic twins [68,69].

Pregnancies achieved after ART are considered “high-risk” even when single, but especially when twin intrauterine gestation is present. In cases where there is disruption of the corpus luteum cyst up to 12 weeks after ectopic excision, irrespective of the number of embryos, progesterone support is strongly indicated [2]. In twins, the administration of additional progesterone, especially for the cervix, is under debate, but early cervical assessment is still considered crucial.

There has also been a lot of discussion concerning the role of cervical cerclage and vaginal progesterone in the treatment of cervical incompetence. From the author’s experience, the pregnant woman admitted had a history of cervical incompetence with unfavorable preterm birth at 22 weeks. After counseling, she was treated with combined therapy, cervical cerclage at 13 weeks, and vaginal progesterone 200 mg once a day. Conclusively, this treatment strategy ended in a favorable outcome [34]. In a systematic review, Conde-Agudelo et al. [70] stated that in singleton pregnancies with a short cervix in the second trimester and previous spontaneous preterm birth, either vaginal progesterone or cerclage are equally efficacious. On the contrary, Wang et al. noticed that cerclage is more beneficial than progesterone [71]. The same author mentioned that the effectiveness is similar when vaginal progesterone is added to the cervical cerclage. In another article, cerclage, vaginal progesterone, and cervical pessary appear to have similar effectiveness, while the use of single or combined therapy is still under discussion [72]. The results of twin gestations are also controversial. A recent review declared that vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a short cervix, while in another article, cervical pessary, progesterone, and cerclage do not show a significant effect in reducing the rate of preterm birth or perinatal morbidity in twins [73,74].

This systematic review has several limitations. First, the data are derived exclusively from case reports and series, which are inherently subject to reporting biases and lack comparative analyses. Second, the heterogeneity of the included cases, such as variations in ART protocols, patient demographics, and clinical management strategies, limits the generalizability of findings. Additionally, incomplete or missing data in some reports, particularly regarding long-term maternal and neonatal outcomes, hinder comprehensive analysis. Diagnostic approaches and management strategies varied significantly across cases, reflecting differences in clinician expertise and available resources. Finally, the lack of a standardized risk of bias assessment for case reports further complicates the evaluation of study quality and reliability. These limitations highlight the need for more robust, standardized reporting and prospective studies to better understand and manage heterotopic triplet pregnancies associated with ART.

Conclusions

The term “heterotopic triplet pregnancy,” describing the presence of three embryos with one or two being ectopic, requires further establishment in the literature, particularly in the context of ART. In some cases, incomplete data recording highlights the need for systematic documentation in future occurrences of HTP. Pregnancy outcomes appear to be independent of ectopic rupture or hemoperitoneum, provided timely presentation and referral to appropriate healthcare facilities occur. Early diagnosis remains critical to avoiding complications, such as blood transfusion, and facilitating minimally invasive treatments like laparoscopy. This can only be achieved if clinicians are fully aware of this increasingly frequent condition. In cases of delayed or missed diagnosis, laparotomy remains the treatment of choice. It is important to note that OHSS can contribute to diagnostic challenges.

The well-documented recommendation to transfer only one or a maximum of two fertilized embryos in a single ovarian-controlled cycle must be emphasized to minimize the risks associated with multiple pregnancies, including heterotopic triplet pregnancies. A thorough clinical history, particularly in cases of known or suspected tubal pathology, is vital to early identification and management.

Given the increasing prevalence of heterotopic pregnancies with ART use, the authors recommend a comprehensive examination of the cervix and adnexa during every early vaginal ultrasound, even when intrauterine gestation is confirmed. Serial vaginal scans should also be considered in pregnancies induced by ART, conducted every one to two weeks, starting from the fifth week and continuing through the 10th-11th weeks of gestation. Obstetrical complication management strategies-such as addressing OHSS, cervical incompetence, demise of a twin, or premature rupture of membranes-should balance established protocols, clinician expertise, and patient preferences to optimize outcomes

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Copyright © 2024, Korkontzelos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Details

Title
Heterotopic Triplet Pregnancy After Assisted Reproductive Techniques: A Systematic Review
Author
Korkontzelos Ioannis 1 ; Papalexis Petros 2 ; Georgakopoulou, Vasiliki E 3 ; Pantelina-Danai, Korkontzelou 4 ; Mpourazanis George 1 ; Dosiou Kalomoira 1 ; Kalampokas Theodoros 5 ; Adonakis Georgios 6 

1  Department of Obstetrics and Gynecology, Ioannina State General Hospital “G. Chatzikosta”, Ioannina, GRC 
2  Unit of Endocrinology, First Department of Internal Medicine, Laiko General Hospital, Athens, GRC 
3  Department of Pathophysiology/Pulmonology, Laiko General Hospital, Athens, GRC 
4  Medical School, Medical University of Sofia, Sofia, BGR 
5  Department of Obstetrics and Gynecology, Aretaieion University Hospital, Athens, GRC 
6  Department of Obstetrics and Gynecology, School of Health Sciences, University of Patras, Patras, GRC 
University/institution
U.S. National Institutes of Health/National Library of Medicine
Publication year
2024
Publication date
2024
Publisher
Springer Nature B.V.
e-ISSN
21688184
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.7759/cureus.75997
ProQuest document ID
3203297488
Copyright
Copyright © 2024, Korkontzelos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.