Study on diagnosis and management strategies on heterotopic pregnancy: a retrospective study

Abstract

Heterotopic pregnancy (HP) is a rare but potentially life-threatening event with a high risk of maternal death, which also jeopardise the coexisting intrauterine pregnancy (IUP), thus an early accurate diagnosis and prompt treatment can decrease adverse complications. We aimed to explore the early predictors for pregnancy outcomes of HP. We reviewed patients with HP following assisted reproductive technology in our institution between January 2013 and December 2020. The relationships between pregnancy outcomes and clinical features were analysed by logistic regression. We found that 29 patients (72.5%) of HP were accurately diagnosed by transvaginal ultrasonography (TVS). Eighteen patients in the surgery group had live births, three of whom delivered preterm. Additionally, the miscarriage rate was lower for patients with IUP cardiac activity than those without (16.7% vs. 90.0%, p < .001). Further by logistic regression analysis, an IUP with cardiac activity at HP diagnosis was identified as favourable independent predictor of live birth (p < .001). Therefore, early diagnosis and prompt surgical intervention are recommended to prevent the development of HP.

Impact of statement

• What is already known on this subject? Heterotopic pregnancy (HP) has long been thought to be a rare but potentially life-threatening event with a high risk of complications. The early diagnosis of HP is challenging due to the co-existence of a viable intrauterine pregnancy (IUP) and the absence of typical clinical symptoms.

• What do the results of this study add? This stduy showed that symptoms combined with routine transvaginal ultrasonography (TVS) scans reduce the rates of misdiagnosis of HP and prompt surgical intervention after diagnosis may minimise the incidence of miscarriage of the IUP.

• What are the implications of these findings for clinical practice and/or further research? An IUP with cardiac activity at HP diagnosis is a predictor of a favourable prognosis of HP, and laparoscopy under general anaesthesia is effective and safe during the first trimester of pregnancy. Awareness, assessment and early interventions in view of symptoms combined with routine TVS is recommended to reduce the risk of miscarriage and ensure a favourable live birth rate.

Keywords:

• Diagnosis
• treatment
• heterotopic pregnancy
• pregnancy outcome
• embryo transfer

Introduction

Heterotopic pregnancy (HP) refers to the simultaneous presence of the intrauterine pregnancy (IUP) and ectopic pregnancy (EP) in an individual (Talbot et al. 2011). The incidence of HP is known to be less than one in 30,000 in spontaneous conceptions and has been reported at the rate of 0.09–1% in gestations after ovarian induction or assisted reproductive technology (ART) (Marcus et al. 1995, Guan and Ma 2017). Heterotopic pregnancy is a rare but potentially life-threatening event with a high risk of tubal rupture, intraperitoneal haemorrhage and maternal death, which also jeopardises IUP, thus an early accurate diagnosis and prompt treatment can decrease complications (Li et al. 2016).

The early diagnosis of HP is challenging due to the co-existence of a viable IUP and the absence of typical clinical symptoms (Chen and Chen 2014). Serial β-human chorionic gonadotropin (β-hCG) level and β-hCG rise are helpful to discriminate between EP and one normal IUP, but it is useless to predict HP (Cookingham et al. 2015). Transvaginal ultrasonography (TVS) is critical for the diagnosis of HP with high sensitivity (87–99%) and specificity (94–99.9%) (Kirk et al. 2014). However, EP lesion might be too small to identify at early stage or be easily neglected by an inexperienced ultrasonologist who found a visible intrauterine gestational sac, may lead to increase the difficulties in early-stage HP diagnosis. Therefore, it is worthy to be familiar with clinical symptoms, ultrasound features and previous pelvic history of HP after ART.

The aim treatment of HP is to remove the EP mass while maintaining normal IUP as much as possible, so as to decrease risk of adverse pregnancy outcomes. Treatment strategies include surgical management, expectant management and ultrasound-guided gestational sac aspiration with or without embryo-killing drugs (Lv et al. 2020). However, HP remains a diagnostic and therapeutic challenge due to limited treatment experience and without sufficient evidence-based data of good perinatal outcome of IUP. The objective of this study was to summarise the clinical characteristics of HP, analyse the influence of different treatment strategies on IUP and evaluate the potential risk factors that predict HP, and thus to explore the standard therapeutic schedule for such a rare event and ensure better perinatal outcome of IUP.

Materials and methods

Participants

We retrospectively included 40 patients diagnosed with HP in Fujian Maternity and Child Health Hospital between January 2013 and December 2020. Data including patient characteristics, clinical pregnancy details, treatment strategies of EP, as well as perinatal pregnancy outcomes of IUP were prospectively collected from our database for analysis. The women who did not undergo the first TVS examination in our institution, who did not provide complete information, or those with chromosomal and anatomical foetal abnormalities were excluded. This study was approved by the institutional research ethics committee, and owing to the retrospective nature of the study, the requirement of informed consent was waived.

HP was diagnosed mainly based on TVS examination (first TVS), the serum β-HCG level and the history clinical manifestations used as a reference. Biochemical pregnancy was defined as a transient rise in β-hCG that subsequently declined, without evidence of a gestational sac in utero. IUP was defined as a yolk sac and/or foetal pole in an intrauterine sac, regardless of cardiac activity detecting by TVS. The diagnosis of tubal HP (excluded interstitial) was suspected when an IUP was accompanied with a gestational sac with or without cardiac activity, an empty extrauterine sac with a hyperechoic ring or a heterogeneous adnexal mass in an extrauterine sac (Condous et al. 2005). The differential diagnosis of cornual pregnancy and tubal interstitial pregnancy was based on as follows: the gestational sac location, inner/lateral side of the uterine horn, complete muscular layer around, connecting with the endometrial line, and inside/outside the ligament during the operation.

When a suspiciously HP was diagnosed, patients were managed different treatment modalities (expectantly or surgically) depending on their clinical symptoms and findings by repeated TVS. Patients with interstitial/cornual HP received cornual resection by experienced senior surgeons to remove the ectopic mass and those with tubal HP received laparotomic or laparoscopic salpingectomy by similarly competent surgeons. After the patient discharged, patient clinical manifestations, treatment protocol of HP, related complications after surgical treatment as well as clinical pregnancy details were summarised. The endpoint of the follow-up was the completion or termination of the respective pregnancy. Each patient received a telephone follow-up interview to inquire about her clinical outcomes, which included miscarriage rate, rate of live birth, unviable premature delivery, term delivery rate and foetal development, etc.

Statistical analysis

The statistical analyses were carried out in SPSS software (ver. 21.0) (SPSS Inc., Chicago, IL). Continuous variables that followed normal distributions were expressed as the mean ± standard deviation and categorical variables were shown as percentage or raw numbers. Measurement data were compared using Student’s t-test, if homogeneity test of variances was not significant, otherwise, Mann–Whitney’s U-test was chosen. Enumeration data were compared using Chi-square test and Fisher’s exact test. Multiple linear regression analysis was performed to explore independent predictors for gestational age at diagnosis and to identify the independent impact factors of clinical outcomes in patients with HP. A value of p <  .05 was considered statistically significant.

Results

The clinical characteristics of HP are listed in Table 1. The mean age of the 40 patients was 30.4 ± 4.9 (range 21–45) years, the mean body mass index (BMI) was 21.7 ± 2.7 (range 17.3–29.6) kg/m². Concerning the surgical history, 12 (30.0%) patients underwent uni/bilateral tuboplasty to treat fallopian tube obstruction, and seven (17.5%) patients had bilateral salpingectomy/tubal ligation because of severe hydrosalpinx. Five (12.5%) patients had received unilateral salpingectomy due to tubal EP, and 16 patients had no history of tubal surgery. Fifteen (37.5%) patients had a history of primary infertility, and 25 patients reported a history of pregnancy. All patients had two embryos transferred. Of these women, 15 patients had pregnancies via fresh non-donor embryo transfer cycles, and 25 patients conceived after frozen-thawed embryo transfer.

Table 1. General characteristics and diagnostic information.

Variables	No. (%) of patients
Age, mean ± SD (range), years	30.4 ± 4.9 (21–45)
BMI, mean ± SD (range), kg/m^2	21.7 ± 2.7 (17.3–29.6)
History of abortion, n (%)
0	15 (37.5)
1–2	12 (30.0)
≥3	13 (32.5)
History of tubal surgery, n (%)
Salpingotomy	0
Uni/bilateral tuboplasty	12 (30.0)
Unilateral salpingectomy	5 (12.5)
Bilateral salpingectomy/tubal ligation	7 (17.5)
No	16 (40.0)
Previous PID history	8 (20.0)
Type of infertility, n (%)
Primary	15 (37.5)
Secondary	25 (62.5)
Method of pregnancy, n (%)
Frozen-thawed embryo	15 (37.5)
Fresh non-donor embryo	25 (62.5)
Clinical manifestations, n (%)
Asymptomatic	7 (17.5)
Abdominal pain	9 (22.5)
Vaginal bleeding	12 (30.0)
Abdominal pain and vaginal bleeding	9 (22.5)
Rectal tenesmus	3 (7.5)
Location of EP, n
Tubal (right vs. left)	27 (13 vs. 14)
Interstitial (right vs. left)	7 (5 vs. 2)
Cornual (right vs. left)	6 (3 vs. 3)
Gestational age at symptom onset, mean ± SD (range), days	44.8 ± 8.6 (27–68)
Gestational age on first TVS, mean ± SD (range), days	46.3 ± 7.6 (29–68)
Gestational age at diagnosis, mean ± SD (range), days	49.4 ± 7.6 (29–68)
First TVS suspected HP, n (%)
Yes	29 (72.5)
No	11 (27.5)
Diameters of gestational mass, mean ± SD (range), mm	24.1 ± 11.5 (11.3–56.3)

SD: standard deviation; BMI: body mass index; PID: pelvic inflammatory disease; EP: ectopic pregnancy; TVS: transvaginal sonography; HP: heterotopic pregnancy; IUP: intrauterine pregnancy.

The most frequent manifestations before diagnosis were vaginal bleeding (12/40, 30.0%), nine patients (22.5%) had abdominal pain, nine patients (22.5%) had both abdominal pain and vaginal bleeding, but seven patients (17.5%) had no symptoms and were found by routine ultrasound examination (listed on Table 1). We reviewed previous abortion, previous EP and pelvic surgery history in HP, 62.5% (25/40) of HP had more than once abortion before; and 12.5% (5/40) of HP had EP before. The distribution of ectopic embryos location is shown in Table 1, most of ectopic lesion in HP occurred at fallopian tubes, taking up 67.5% (27/40); 17.5% (7/40) of ectopic lesion occurred at interstitial fallopian and 15.0% (6/40) occurred at cornual. Sites of EPs were confirmed at surgery, nine patients were diagnosed with rupture of EP, two of them had hypovolemic shock, but no maternal death was reported.

Thirty-five patients (83.3%) had symptoms appearing before first TVS, and the other five patients after TVS, the mean gestational age at symptom onset was 44.8 ± 8.6 (range, 27–68) days. The gestational age at the time of diagnosis was 49.4 ± 7.6 (range, 29–68) days. The time of diagnosis by TVS ranged from 15 and 54 days after ET, and the mean gestational age on first TVS was 46.3 ± 7.6 (range, 29–68) days. The mean gestational mass diameter of the EP was 24.1 ± 11.5 (range, 11.3–56.3) mm. Twenty-nine (85.5%) patients had suspected HP when they received first TVS. Among these cases, 23 patients (57.5%) presented with inhomogeneous masses, three patients (7.5%) had extrauterine empty gestational sacs, three patients (7.5%) had gestational sacs with yolk, and 11 patients (27.5%) had feta poles with cardiac activity. Moreover, patients who found no sign of ectopic embryos on first TVS had received repeated TVS before they were admitted to inpatient department. Hence, the sensitivity of TVS for detecting HP was 72.5% (29/40).

In order to monitor the changing situation of HP, patients were admitted to receive repeated TVS. The last TVS before surgery showed that 30 patients (75.0%) were detected the foetal cardiac activity in intrauterine conception (Table 2). Eleven patients (27.5%) received expectant management, 29 patients (72.5%) underwent surgery management, including laparotomy (13/29, 44.8%) or laparoscopy (16/29, 55.2%) without anaesthetic complications, and no patients received ultrasound-guided embryo aspiration. The mean gestational age at surgery day was 51.0 ± 8.6 (range 33–67) days. In the expectant group, no patients suffered rupture of EP and three miscarriages occurred during the period of strict observation. In the surgical group, nine patients had EP ruptures, three of whom required blood transfusions. The total miscarriage rate in the surgical group was 37.9% (11/29). Furthermore, there was no significant difference between expectant management and surgical groups in the live birth rate (p = .169).

Table 2. Surgical information and clinical outcomes.

Variables	No. (%) of patients
Management of HP, n (%)
Expectant management	11 (27.5)
Surgical management	29 (72.5)
Embryo aspiration management	0
TVS before surgery
IUP, n (%)
Gestational sac	10 (25.0)
Foetal cardiac activity	30 (75.0)
HP, n (%)
Inhomogeneous/hyperechoic mass	23 (57.5)
Gestational sac	6 (15.0)
Foetal cardiac activity	11 (27.5)
Gestational age at surgery day, mean ± SD (range), days	51.0 ± 8.6 (33–67)
Clinical outcomes, n (%)
Term delivery	22 (55.0)
Preterm delivery	4 (10.0)
Abortion	14 (35.0)
Mode of delivery, n (%)
Vaginal delivery	5 (19.2)
Cesarean section	21 (80.8)

IUP: intrauterine pregnancy.

Transvaginal ultrasonography at HP diagnosis revealed that a gestational sac of an IUP without foetal cardiac activity was found in 10 patients (10/40, 25.0%), while with foetal cardiac activity was found in 30 patients (30/40, 75.0%). Moreover, both three patients (3/10, 30.0%) with empty gestational sac and four patients (4/10, 40.0%) with yolk sac for the IUP were ended in early miscarriage. The miscarriage rate of the co-existing IUP was 16.7% (5/30) for patients with IUP cardiac activity at HP diagnosis, and 90.0% (9/10) for patients without IUP cardiac activity; a significant correlation was identified (χ² = 18.857, p < .001) (Supplementary Table 1). Further logistic regression models indicated that patients following an IUP with foetal cardiac activity at HP diagnosis were identified as an favourable independent factor of live birth (p < .001) (Table 3). However, the rate of miscarriage exhibited no significant association with other factors, such as patients’ age, first TVS-suspected HP, gestational age at diagnosis, HP positions, ectopic gestational mass diameter, EP foetal heartbeat and pelvic haemorrhage volume (Table 3).

Table 3. Uni- and multi-variable logistic regressions of predictive factors associated with pregnancy outcomes in HP patients.

Variables	N	Pregnancy outcomes		Univariate analyses		Multivariate analyses
		Live birth	Miscarriage	p	Regression coefficient (SE)	p	95% CI
Age (years)
<34	29	20	9	.406	0.144 (0.172)	.846	–0.286 to 0.347
≥34	11	6	5
Method of IVF-ET, n (%)
Frozen-thawed embryo	15	12	3	.130	0.240 (0.155)	.412	–0.175 to 0.416
Fresh non-donor embryo	25	14	11
Gestational age at diagnosis, days
<52	24	15	9	.694	–0.062 (0.158)	.870	–0.288 to 0.338
≥52	16	11	5
Suspected HP at the initial TVS, n
Yes	29	20	9	.406	0.144 (0.172)	.805	–0.470 to 0.368
No	11	6	5
Gestational mass diameter (mm)
<30	30	21	9	.262	0.200 (0.176)	.151	–0.084 to 0.520
≥30	10	5	5
EP foetal heartbeat
Yes	11	7	4	.914	–0.019 (0.173)	.267	–0.600 to 0.173
No	29	19	10
IUP foetal heartbeat
Yes	30	25	5	<.001	0.733 (0.133)	<.001	0.474–1.119
No	10	1	9
HP positions
Adnexal regions	27	18	9	.758	0.051 (0.165)	.655	–0.390 to 0.249
Other regions	13	8	5
Pelvic haemorrhage volume, n
<400 ml	32	22	10	.540	–0.107 (0.172)	.669	–0.504 to 0.328
≥400 ml	8	4	4
Ruptured EP, n
Yes	9	5	4	.333	0.188 (0.191)	.499	–0.645 to 1.294
No	31	21	10
Treatment modality, n
Surgical managements	29	18	11	.512	–0.122 (0.184)	.634	–0.646 to 1.043
Other managements	11	8	3

Discussion

The accurate diagnosis of HP is usually challenging and difficult because of the rarity of HP. Despite use of improved ART and increased medical knowledge, the early diagnosis of HP remains challenging and elusive to practitioners due to the coexistence of a viable IUP and the absence of typical clinical symptoms (Talbot et al. 2011). The suspicious symptoms of HP are supposed as abdominal pain, irregular vaginal bleeding, adnexal mass and an enlarged uterus; however, these symptoms are non-specific, which can also be observed in IUP or EPs, suggesting they may difficultly provide clues to accurate diagnosis of HP. A study showed that vaginal bleeding and/or abdominal pain were independent predictors of early pregnancy failure after ART, the specificity and sensitivity of these symptoms for HP were 73.4% and 72.2%, respectively (Cookingham et al. 2015). We found that patients with symptoms were diagnosed early than those without symptoms, which was comparable to that of previous reports (Hassiakos et al. 2002, Yu et al. 2016); this evidence suggested that patients afflicted with HP could be diagnosed at an early stage if they had symptoms appearing before the scheduled first TVS.

Despite most of HP are asymptomatic (50%) (Lyu et al. 2017), some efficient methods may help in the diagnosis of HP, notably TVS and β-hCG levels. As the IUP can cause the β-hCG level to increase appropriately, therefore, continuous detection of the β-hCG concentration is often difficult to interpret. Transvaginal ultrasonography plays an important role in the diagnosis of HP due to its assessment capability of the whole pelvis; however, atypical symptoms and ultrasonic diagnosis level can lead to a low sensitivity. It has been reported that six patients were diagnosed as HP after three weeks of missed abortion (Jeon et al. 2016). In view of this, patients were counselled on repeat routine TVS scans after ART procedures, especially in asymptomatic women with an suspiciously diagnosis of HP. For the purposes of the prognosis of HP, we incorporated analysis of potential variables and explored the predictive factors of pregnancy outcomes. In this study, the total live birth rate was 65.0%, which was comparable to the results of previous reports (Shang et al. 2019). Our result suggested that gestational age at diagnosis was seven weeks, the abnormal embryo without cardiac activity of IUP during this period indicated that the poor quality of the embryo which may cause early abortion. Therefore, routine TVS scans at gestational age six to eight weeks should be performed, and a normal embryo with foetal cardiac activity in IUP at diagnosis gestational age may have a favourable prognosis for patients with HP.

Many studies demonstrated that fallopian tube disease and pelvic adhesion factors increase the risk of HP after ART (Xiao et al. 2018, Goldberg et al. 2019, Pi et al. 2020). Fallopian tube lesion was demonstrated as the most well-defined risk factor predisposing to the occurrence of HP (Audebert et al. 2014), especially after salpingoplasty, and the level of risk depends on the extent of anatomic alteration and the degree of damage (Rana et al. 2013). Moreover, tubal pregnancy history is an acknowledged risk factor for subsequent HP (Jeon et al. 2016), we found 60.0% of the patients with HP had a history of tubal surgery. As hydrosalpinx impairs tubal function, such as the ciliary movement and the motility of normal rhythmic contraction, the history of hydrosalpinx might be a risk factor in the HP (Liu et al. 2015). In addition, the widespread use of ART is associated with a dramatically increased incidence of HP (Nargund et al. 2013). Therefore, timely treatment of hydrosalpinx before ART could reduce the incidence of HP and improve the outcome of ART treatment (Blazar et al. 1997). Heterotopic pregnancy rarely occurs in women without high-risk factors or spontaneous conceptions, other possible risk factors include age ≤35 years, smoking history and use of intrauterine device (Arsala and Danso 2014, Diagnosis and Management of Ectopic Pregnancy 2016). Thus, we can conclude that the vast majority of patients with HP are women with a history of pelvic surgery or tubal inflammation after ART, improvement of clinicians’ vigilance to those with high-risk factors is particularly important for the early diagnosis of HP.

Patients with HP after tubal ligation or bilateral salpingectomy were represented by several case reports; this reminds clinicians of the possibility of such rare and potentially fatal presentations after ART even in these patients, since early diagnosis and prompt treatment can yield a favourable prognosis. The most common location of EP is the fallopian tube. We compared the risk factors, treatment and pregnancy outcomes between HP-interstitial and HP-tube (except interstitial) pregnancies. In the HP-tube group, previous tubal surgery was lower than in the HP-interstitial group. Although there was still no general consensus on the best optimal treatment for tubal interstitial pregnancy (Jeon et al. 2016), we were more inclined to recommend surgical procedure in our centre. The rate of live birth was higher in the HP-tube group, whereas previous study indicated that miscarriage rate had marginal significance between two groups based on the site of the HP (Warda et al. 2014).

It was difficult to define the optimal management for the rarity of HP. The individualised treatment plan of HP should be formulated according to clinical symptoms, the location of EP, mass size, hemodynamic situation and the preservation or development of IUP. Aim of HP treatment is to eliminate EP effectively and safely if the IUP is not preserved, maintain IUP with minimal manipulation of the uterus if the IUP was to be preserved; this makes the treatment of HP very limited and challenging (Barrenetxea et al. 2007). Expectant management is suitable for asymptomatic patients with a stable hemodynamic situation; however, it is not applicable to patients with a viable EP or unstable hemodynamic situation. We strictly observed any signs of EP rupture in expectant management group, such as the unstable hemodynamic presentations and progression of abdominal pain. Among them, three patients finally had received surgery because of abrupt change of their clinical feature (signs of internal haemorrhage or sudden abdominal pain). The expectant management may fail at any time due to the risks of continued growth and rupture of the EP mass, thus, we speculate that surgical procedure may be a priority for the management of HP.

The preferred treatment modality of HP to preserve the IUP is not yet established. Now, it is widely agreed that the IUP prognosis after surgery procedure for HP as favourable, but what are the risk factors for miscarriage and what are the favourable factors to improve the live birth rate after surgery management are not elucidated. Studies have demonstrated that laparoscopy is effective and safe during the first trimester of pregnancy (Maruotti et al. 2010), which has the advantages of less postoperative pain, better operative field exposure and minimal manipulation (Kim et al. 2016). In this study, patients underwent surgery without any congenital abnormalities or deleterious anaesthetic complications. However, there was no significant difference in the live birth rate between two groups. So far, the optimal management for HP women remains unpredictable and lack of data confirmation, more prospective studies are required to be performed in the future. Hence, positive individualised interventions should be taken to avoid the need for emergency surgery after the diagnosis of HP and ensure maternal safety to obtain good perinatal outcome.

The strength of our study is that we showed that an IUP with cardiac activity at HP diagnosis might be taken as predictors for a favourable prognosis of HP. Our study also has several limitations. First, the data were collected from our hospital retrospectively, it may lead to false-negative results because of inevitable selection bias and the limited sample size. Multi-centre studies with larger samples are needed to validate or refute our findings. Furthermore, the findings in this study may not be applicable to general female population as their risk factors may be different and diverse compared to those seeking ART services.

Conclusions

In summary, we proposed that an IUP with cardiac activity at HP diagnosis is a good predictor of favourable prognosis in HP. Symptoms combined with routine TVS scans could reduce misdiagnosis of HP. Prompt surgical intervention after diagnosis may minimise the incidence of abortion of IUP and improve its prognosis. We hope to raise awareness and improve the management process for such a rare event to reduce the risk of miscarriage and ensure a favourable live birth rate by suggesting routine TVS at 6–8 weeks in cases of ART with embryo transfer.

Author contributions

YZ: project development, data collection and manuscript writing. XC: project development and manuscript editing. YL: data collection. CL: data collection. XX: data collection. All authors contributed to the article and approved the submitted version.

Ethical approval

This study was approved by the Ethics Committee of the Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University (no. 2021KLRD09014).

Consent form

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Acknowledgements

The authors acknowledge all of the people who have contributed to this paper in some manner and the participants who participated in this study.

Disclosure statement

The authors declare that they have no competing interests.

Data availability statement

The patients’ clinical data that support the findings of this study are not publicly available due to privacy or ethical restrictions.

Additional information

Funding

This research was supported by the Startup Fund for Scientific Research, Fujian Medical University (Grant Number: 2020QH1196) and Sponsored by Fujian Provincial Health Technology Project (Grant Number: 2020QNB012).