Heterotopic Triplet Pregnancy After Assisted Reproductive Techniques: A Systematic Review

Abstract

The literature has not yet mentioned any cases of heterotopic triplet abdominal pregnancy. [...]1984, previous articles used the term "combined" ectopic or "combined" heterotopic pregnancy to describe the presence of three embryos [3,4]. 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. 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). [...]outcome validity was scrutinized, emphasizing accurate diagnosis and management of heterotopic triplet pregnancies, ensuring the final review was based on high-quality, unbiased studies.

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 Element	Definition	Study-specific information
P-Population	The target group under investigation	Patients diagnosed with heterotopic triplet pregnancy, specifically those after ART.
I-Intervention	The primary treatment or procedure applied	Assisted reproductive techniques (ART), including In vitro fertilization (IVF)-Ovulation induction-Embryo transfer.
C-Comparison	A group or standard for comparison (if applicable)	Not explicitly applicable; comparison is implied between spontaneous vs. ART-conceived pregnancies or alternative ART protocols.
O-Outcomes	Key results or consequences	1. 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.

N

Authors

Year

Age

G/P

Medical history/infertility

Medication

Conception

No Embryos

Stage(cells)

US-(Sacs in utero)

Ectopic

Diagnosis

Symptoms

Treatment

Complications/pregnancy

Obstetric outcome

Delivery (weeks)

Birth weight/Status

1

Payne S et al. [43]

1971

27

G1 P1

Involuntary infertility

Prednisone 2.5mg/4dtp + Clomiphene 50mg (4th-8th)

Ovulation induction – spontaneous

NS

NS

2

Right cornual

48 days

Abdominal pain

Laparotomy-salpingectomy

Premature labor

CS

35

Twins-healthy 2400gr/2120gr

2

Walker TA et al. [44]

1972

33

-

Infertility

Clomiphene Citrate 50mg (4th-8th)

Ovulation induction – spontaneous

NS

NS

2

Right salpinx

8 weeks

Severe pain/pre-shock status

Laparotomy-salpingectomy/appendectomy

No

Vaginal delivery

37

Twins-healthy 2570gr/2260gr

3

Sondheimer SJ et al. [35]

1985

28

G0 P0

Primary infertility-endometriosis-DES (T-shaped uterus)

Gonadotropin

IVF-ET

5

5, 3, 2, 1

2

Left salpinx

41 days

Low abdominal pain

Lap-salpingectomy

Cerclage-premature labor

CS

33

NS

4

Yovich JL et al. [3]

1985

34

-

PID-bilateral hydrosalpinges-myomectomy

Clomiphene 100mg (2th-6th)+HMG+HCG

IVF-ET

5

4

2

Left salpix

8 weeks

Left pelvic pain

Lap/converted to laparotomy-salpingectomy

Demise 2nd twin

Normal follow at 30 weeks

-

NS

5

Porter R et al. [4]

1986

33

G2 P2

Tubal factor

Clomiphene 100mg (3th-7th)+HMG 150IU (7-11)

IVF-ET

6

2,4

1

Right Twin tubal

6 weeks

Severe abdominal pain

Laparotomy-salpingectomy

No

Vaginal delivery

37

Healthy infant/3040gr

6

Hanf V et al. [10]

1990

30

G1

Tubal factor-bilateral hydrosalpinx

HMG+HCG

IVF-ET

4

4

1

Bilateral tubal

37 days

Severe abdominal pain-vaginal bleeding

Lap-salpingectomy bilateral

No

CS

38

Healthy

7

Goldman JA et al. [ 5]

1991

28

G1 P0

Diethyl stilbestrol syndrome

FSH+HMG

IVF-ET

4

4

1

Right twin tubal

6 weeks

Right pelvic pain/vaginal bleeding

Laparotomy

Premature labor

Vaginal delivery

30

Healthy infant/2600 gr

8

Chen SU et al. [11]

1992

32

G0 P0

Primary infertility/bilateral tuboplasty-fibrioplasty

FSH+HMG+HCG

IVF-ET

6

2 to 4

2

Right salpinx

10 weeks

Severe low abdominal pain

Laparotomy-repair of rupture

Abortion-D/C

-

-

-

9

Smith S et al. [12]

1993

27

G0 P0

Pelvic adhesions/bilateral hydrosalpinx

GnRH agonist+HMG+HCG

IVF-ET

4

Pronuclear

2

Right salpinx

32 days

Severe low abdominal pain

Laparotomy-removal

Premature labor

Premature labor/CS

24

Expired

10

Bassil S et al. [28]

1995

31

G0 P0

Male infertility

FSH+HMG+HCG

IVF-ET

3

NS

None

Right cornual triplets

35 days

No symptoms

Laparotomy-excision/horn reconstruction

Excision/corual pregnancy

-

-

-

11

Berliner I et al. [6]

1998

29

G1 P0

NS

75IU LH+FSH

Homologous intrauterine insemination

NS

NS

2

Left salpnix

5 weeks

Pelvic pain

Lap-salpingotomy

No

Vaginal delivery

37

Twins-healthy 2722gr/2863gr

12

Inion I et al. [7]

1998

30

G0 P2

PCOS/Ovulation Induction-Right ovarian torsion/laparotomy-2nd ovarian torsion/laparoscopy

NS

IVF-Intrauterine insemination (donor)

2

8

2

Right adnexa

47 days

Right abdominal pain

Laparotomy-adnexectomy

Demise 2nd twin

Vaginal delivery

NS

Healthy

13

Barnett A et al. [13]

1999

32

G0 P0

Primary infertility/tubal damage

NS

IVF

3

NS

2

Right salpinx

9 weeks

Right abdominal pain

Laparotomy-salpingectomy+appendectomy

No

CS

37

Twins-healthy 2080gr/2700gr

14

Nair P et al. [8]

1999

34

G2 P1

Lap left salpingostomy (hydrosalpinx)

GnRH analogs+gonadotropin

IVF/ET

3

NS

2

Left salpinx

34 days

Vaginal discharge/suprapubic tenderness

Laparotomy-left partial salpingectomy

No

CS

38

Twins-healthy

15

Ludwig M et al. [9]

1999

25

G0 P0

Primary infertility/tubal damage-PCOS/laparoscopy-ovarian abscess

HMG Long protocol

IVF-ET

3

NS

2

Right salpinx

48 days

Abdominal pain-OHSS

Lap-bilateral calpingectomy

No

NS

NS

NS

16

Oliveira FG et al. [29]

2002

31

G0 P0

Male factor-oligoasthenospermia

NS

IVF-ICSI

3

NS

2

Left Adnexa

38 days

Severe abdominal pain

Lap-salpingectomy

No

NS

38

Twins -healthy

17

Pan HS et al. [36]

2002

38

G3 P1

Endometriosis-pelvic adhesions-cervical stricture

HMG+FSH+HCG

IVF-ET(tubal due to cervical stenosis)

4

2,3,4

1

Bilateral tubal

5 weeks

Abdominal pain-vaginal bleeding

Laparotomy-bilateral salpingectomy

No

Vaginal

NS

Healthy Infant

18

Nikolaou DS et al. [14]

2002

31

G1 P0

PCOS/laparoscopic drilling/laparotomy-Left oophorectomy+partial salpingectomy

FSH+HCG

IVF-ET

2

NS

2

Left interstitial

28 days

Intermittent iliac fossa discomfort

Laparotomy-left tube incised and evacuated

Premature labor-MC twins

Vaginal

33

Twins –healthy 1400gr/1400gr

19

Hoopmann M. [30]

2003

39

G0 P0

Laparotomies (Crohn’s disease)-male Infertility

NS

IVF-ICSI

NS

NS

1

Bilateral tubal

6+6 weeks

No symptoms

Lap-bilateral linear salpingostomy

Empty sac syndrome

-

-

-

20

Sayin NC et al. [45]

2003

25

G3 P0

Infertility

Clomiphene citrate 100mg/day 5-9

Ovulation induction - Spontaneous

NS

NS

2

Left Salpinx

8 weeks

Acute abdomen

Laparotomy-left salpingectomy

Premature labor-MC twins

CS

35

Twins –healthy 2350gr/1900gr

21

Strelec M et al. [15]

2004

28

G2 P0

Infertility/tubal factor-Ectopic-right salpingectomy

HMG+HCG

IVF-ET

3

NS

2

NS

10+1 weeks

Severe pain-hypotensive/tachycardic

Lap-salpingectomy

PROM

CS

29

NS

22

Bhat SM et al. [16]

2004

31

G1 P1

Secondary infertility-Ectopic-left salpingostomy-right adnexectomy

GnRH antagonist+FSH+HCG

IVF-ET

4

NS

2

Right cornual

12 weeks

Abominal pain-collapsus

Laparotomy-repair of uterine cornual rupture

No

CS

36

Twins –healthy 2500gr/2800gr

23

Childs AJ et al. [38]

2005

30

G4 P2

NS

Gonadotropins

Uterine insemination

NS

NS

2

Left Salpinx

11 weeks

Abdominal pain

Lap-Salpingectomy

Missed abortion 2nd twin (9weeks)

NS

NS

NS

24

Cirillo D et al. [39]

2006

28

G0 P0

NS

Gonadotropins

Natural conception

NS

NS

2

Right Ovary

8 weeks

Abdominal pain-vaginal bleeding/OHSS

Lap-Partial right ovarian resection

Premature labor

CS

32

Twins –healthy 1800gr/1950gr

25

Muller Vranjes A et al. [46]

2006

34

G0 P0

Infertility (5 years)/1 miscarriage/embolization for uterine myoma

Clomiphene citrate (2X50 mg), day 3-8

Not stated

NS

NS

2

Right Salpinx

10 weeks

Hemorrhagic shock

Lap-right salpingectomy

NS

NS

NS

NS

26

Dundar O et al. [31]

2006

35

G0P0

Male infertility

Clomiphene citrate

Uterine insemination

NS

NS

2

Right adnexa

10 weeks

Acute abdominal pain

Laparotomy-right salpingectomy

MC-monoamniotic twins

Follow up-16 weeks

-

-

27

Gupta A et al. [37]

2006

34

G0P0

Pituitary adenoma

2.5 mg Bromocriptine X3 per day

Spontaneous conception

NS

NS

1

Bilateral tubal

9 weeks

Shock

Laparotomy-left salpingectomy/right linear salpingotomy

Demise of intrauterine fetus/9 weeks/DC

-

-

-

28

Divry V et al. [17]

2007

32

G0 P0

Primary infertility (12 years)/tubal factor-bilateral salpingectomy

NS

IVF-ET

3

8

2

Right cornual

6 weeks

No symptoms

Lap/converted to laparotomy-excision (cornual)

NS

CS

31

Twins –healthy 1360gr/1590gr

29

Berkes E et al. [18]

2008

26

G1 P0

Secondary infertility/right salpingectomy-male factor (asthenoteratoazospermia)

GnRH agonist+HMG+1.25mg bromocryptine

IVF-ICSI

3

NS

0

Left isthmic+Twin tubal

33 days

Abdominal pain

MTX 50/100/100mg im-laparotomy/left interstitial salpingectomy

Empty uterus

-

-

-

30

Kasum M et al. [19]

2009

32

G0 P0

Primary infertility/distal occlusion of left tube-reconstructive surgery  of the right tube/Left salpingectomy (ectopic)

NS

IVF-ET

NS

NS

1

Bilateral tubal

NS

Abdominal pain

Lap-left salpingectomy

-

Vaginal

40

Healthy infant

31

Bugatto F et al. [2]

2010

28

NS

Tubal factor (2 years)-Left tubal occlusion

Gonadotropin+HCG

IVF-ET

NS

NS

2

Left salpinx

12+4 weeks

Left iliac pain

Laparotomy/left salpingectomy

TPL (admission/cervical incompetence)

CS

31+2

Twins-healthy 1650gr/1800gr

32

Timor-Tritsch I et al [20]

2010

29

G5P0

Two miscarriages/Right ectopic-salpingectomy/bilateral ovarian ectopic-resection and left salpingectomy

NS

IVF-ET

2

NS

1

Right cornual MC Twin pregnancy

NS

NS-No symptoms (?)

Vaginal needle KCL injection/laparotomy-cornual resection

No

CS

37

NS

33

Tomic V et al. [21]

2011

31

NS

Primary infertility (tubal occlusion)

GnRH+r-FSH+HCG

IVF-ET

3

GI, GII

2

Right salpinx

7 weeks

Abdominal pain/OHSS

Lap/converted to laparotomy-right salpingectomy

No

CS

37

Twins-healthy 2450gr/2840gr

34

Litwicka K et al. [32]

2011

31

G1 P1

Secondary infertility/Male infertility (azoopsermia)/previous CS

GnRH antaonist+r-FSH

IVF-ICSI

3

NS

1

Two sacs - isthmic

6 weeks

No symptoms

Vaginal needle (20G) injection KCL(2ml)+MTX 15 mg

Contractions 28-34 weeks

Emergency CS/ hemorrhage

36

Miller syndrome

35

Okamura Y et al. [22]

2011

31

G2 P0

Infertility (6 years)/left pyosalpinx-right tubal obstruction-left salpingectomy

NS

IVF-ET

3

NS

2

Left tubal isthmic

8 weeks

Pre-shock status

Lap-left isthmic excision

Fetal demise 2nd twin/8 weeks

Elective CS

37

Healthy infant-2828 gr

36

Bornstein E et al. [23]

2011

29

G5 P4

Lap right salpingectomy/2 miscarriages/2 bilateral ectopic ovarian pregnancies/Left salpingectomy

NS

IVF-ET

2

NS

1

Right cornual MC Twin pregnancy

8 weeks

No symptoms

Vaginal needle  KCL-Bleeding-Laparotomy-Cornual evacuation/repair

No

Elective CS

37

NS

37

Gozukucuk M et al. [24]

2011

29

G1P0

Right tubal ectopic-salpingectomy/unexplained infertility

NS

IVF-ET

NS

NS

1

Twin cervical

NS

No symptoms

Dilatation and curettage

Empty sac syndrome

-

-

-

38

Osmanagaoglou M et al. [40]

2011

47

NS

NS

Leuprolide acetate 500 μg+225 IU r FSH+HCG

IVF-ET

3

NS

2

Left salpinx

9 weeks

Abdominal pain

Lap-Left salpingectomy

No

NS

35

Twins-healthy 2206/2426gr

39

Herrera E et al. [33]

2011

34

NS

Primary infertility/male actor-azoospermia

NS

IVF-ET (blastocyst transfer)

NS

NS

2

Left cornual

9 weeks

Abdominal pain

Laparotomy-Left salpingectomy

-

NS

NS

NS

40

Lin CK et al. [25]

2013

32

G2 P1

Secondary infertility (10 years)/tubal factor

200IU FSH+150IU HMG+HCG

MESA+ICSI

5

NS

2

Cervix

15 weeks

No

Sac needle aspitation+KCL 10ml KCL

Severe preeclampsia-Uterine atony/hysterectomy

CS-Hysterectomy

27

Twins DC-1000gr/705gr

41

Delrieu et al. [26]

2013

36

G3P3

Tubal ligation-unsuccessful tubal reanastomosis

GnRH agonist+HCG

IVF+ET

4

NS

1

Left salpinx+cervix

38 days

Abdominal pain

Lap-left salpingectomy/cervical mass excision

No

NS

NS

NS

42

Fukuda T et al. [47]

2014

32

G1 P0

History of ovulatory disturbance

GnRH agonist+225IU HMG+150IU r FSH+HCG

IVF-ET

3

Day 3

3

Cervix

8+3 weeks

No symptoms

Sac needle aspitation (19G)

Premature labor

Emergency CS

25

Twins DC-660gr/620gr

43

Felekis T et al. [1]

2014

32

G2 P0

Idiopathic infertility( 3years)

Clomiphene citrate (100mg for 5 days)+HCG

Uterine Insemination

NS

NS

1

Bilateral tubal

9 weeks

Abdominal pain/vaginal bleeding

Lap-left salpingectomy-right salpingostomy

No

Vaginal

39

Healthy infant

44

Buca DI et al. [48]

2015

37

G0 P0

Idiopathic infertility (5 years)

NS

IVF-ET

NS

NS

2

Right salpinx

9+4 weeks

Abdominal pain/nausea/vomiting

Laparotomy-Right salpingectomy

TPL (contractions/admission)

Elective CS

36+2

Twins –healthy 2460gr/2600gr

45

Kasap B et al. [49]

2015

32

G1P0

Unexplained infertility (4 years)

NS

ICSI-ET

3

GI

1

Bilateral tubal

21 days

No symptoms

Lap-Bilateral slapingectomy

Spontaneous abortion

-

-

-

46

Nitke S et al. [50]

2007

45

G0 P0

Primary infertility (5 years)

Donor eggs

IVF-ET

4

NS

1

2 sacs - cervix

7 weeks

No symptoms

Uterine arteries catheterized/84 mg MTX/Uterine embolization

Shrinkage of two cervical sacs/uterine sac

-

-

-

47

Hsieh BC et al. [51]

2004

38

G4 P2

Secondary infertility/ two CS

GnRH analogs+HCG

IVF-ET

3

NS

2

CSEP

21 days

No symptoms

Vaginal needle aspiration of the sac

Premature labor

NS

32

NS

48

Gaudier FL et al. [52]

1995

31

G0 P0

Primary infertility (7 years)

NS

IVF-ET

NS

NS

2

Right interstitial

15 weeks(MRI)

Acute abdominal pain

Laparotomy

Contractions-20 weeks

Premature labor/CS

34

Twins-healthy 2100gr/1500gr

49

Al Mulla A et al [53]

2018

38

-

Primary infertility-four unsuccessful ICSI

NS

IVF-ET

3

Blastocyst 3CC

2

Right salpinx

11 weeks

Schock

Lap-right salpingectomy

Premature labor

CS

34

Twins DC-healthy 2460gr/2600gr

50

Vitner D et al. [54]

2011

47

G0 P0

Egg donation

Controlled minimal ovarian stimulation

IVF-ICSI

NS

NS

2

Right salpinx

9+5 weeks

Severe abdominal pain

Laparotomy-right salpingectomy

No

-

Term

Twins DC- healthy

51

Mustafa KB et al. [55]

2016

37

G2 P0

Idiopathic infertility (6 years)

Gonadotropins+metformin+HCG

Natural conception

2

1,2

1

Bilateral tubal

8 weeks

Abdominal pain vaginal spotting/OHSS

Lap-bilateral salpingectomy

Spontaneous abortion

-

-

-

52

Jonler M et al. [56]

1995

31

G0 P0

Primary infertility (7 years)

NS

IVF-ET

NS

NS

1

Bilateral tubal

6+3 weeks

No symptoms

Lap-bilateral salpingotomy

Abortion-D/C

-

-

-

53

Riestenberg CK et al. [57]

2017

24

G0 P0

PCOS

NS

IVF-ET

NS

NS

1

Bilateral tubal

25 days

Abdominal pain- spotting

Lap-right salpingostomy/Left salpingectomy

Spontaneous abortion-D/C

-

-

-

54

Korkontzelos I et al. [34]

2019

38

G4 P0

Male factor (oligoasthenospermia)

NS

IVF-ICSI

3

4

2

Left salpinx

8+2 weeks

Abdominal pain/OHSS

Laparotomy-left salpingectomy

Demise 2nd twin-TPL-cerclage

Elective CS

36+1

Healthy infant -1980gr

55

Bhattacharya R et al. [41]

2020

33

G2P0

NS

NS

IVF-ET

NS

NS

2

NS

11 weeks

Abdominal pain

Laparotomy-Left salpingectomy

DC twins-fetal demise

-

-

-

56

Morong J et al. [42]

2021

31

G3 P2

NS

Clomiphene Citrate 50 mg for 5 days

Natural conception

NS

NS

2

Left Salpinx

10+1 weeks-

Severe abdominal pain/vaginal bleeding

Lap-left salpingectomy

TPL

Elective CS

36+5

Twins-healthy

57

Bhoi NR et al. [27]

2023

35

G0P0

Hydrosalpinx-bilateral endometrioma-subserous fibroid

Goserelin acetate

IVF-ICSI

2

Grade 1

2

Left adnexa

7 weeks

No

Lap-cornual resection

No

Elective CS

36

Twins 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