Heterotopic pregnancy

Heterotopic pregnancy is defined as the presence of multiple gestations, with one present in the uterine cavity and the other outside the uterus [1]. The most common ectopic site is the fallopian tube and uncommon implantation sites include  the cervix, ovary, caesarean section scar, or even the abdomen [2]. Some cases of triplet or quadruplet of heterotopic pregnancy have been reported [3], [4].

The incidence of heterotopic pregnancy is around 1/30,000 in spontaneous pregnancies. Among pregnancies resulting from assisted reproduction techniques, the incidence is greater, ranging from 1/100 to 1/3,900 [2].

Risk factors for heterotopic pregnancy are divided into two categories: use of ART and damage of the fallopian tubes. The rates are 30 - 60 times higher after assisted reproduction as compared to spontaneous conception. The most important risk factor for heterotopic pregnancy is ART involving induction of ovulation and the risk is exacerbated by the number of embryos transferred. Tubal pathologies (infection, tubal surgery, previous ectopic pregnancy, sterilization) are the single most crucial risk factor for heterotopic pregnancy. Other factors are exogenous hormones, ovarian factors, zygote abnormalities, endometriosis, unilateral salpingectomy, and pelvic abnormalities [5].

Recurrence of heterotopic pregnancy is very rare.

An early and accurate diagnosis of heterotopic pregnancy is difficult and challenging because the presence of an intrauterine pregnancy often leads to the mistaken exclusion of a concomitant ectopic pregnancy. In addition, an ectopic pregnancy may also be missed or misdiagnosed as a haemorrhagic corpus luteum cyst.

The clinical presentations of heterotopic pregnancy are variable and not specific. Four common presenting signs and symptoms were defined in the literature: abdominal pain, adnexal mass, peritoneal irritation and an enlarged uterus. Some patients have mild symptoms mimicing other early pregnant complications such as lower abdominal pain or vaginal bleeding, while about 50% heterotopic pregnant patients can be totally asymptomatic [6]. If the ectopic pregnancy has ruptured, the patient may present  in an emergent and life-threatening condition with severe abdominal pain, rebound tenderness, hypovolemic shock and at risk of  loss of life. Therefore, the early and accurate diagnosis of heterotopic pregnancy is critical.

Human beta chorionic gonadotropin (β hCG) levels cannot establish the diagnosis of heterotopic pregnancy. Similarly, serial β hCG measurements are not valuable for predicting the progress of ectopic pregnancy due to the co-existence of the intrauterine pregnancy.

Transvaginal sonographic (TVS) examination plays an important role in the diagnosis of heterotopic pregnancy. The typical image of a heterotopic pregnancy is the presence of an intrauterine gestation sac coexisting with an ectopic pregnancy containing an embryo or a yolk sac. The most common ectopic site is the fallopian tube both in spontaneous and ART heterotopic pregnancies [2], [5]. Cervix, Ovaries, pelvis, and abdomen are much rarer sites.  It is estimated that about 58.93% to 73.75% cases of heterotopic pregnancy are not confirmed before surgery [6], [7]. Diagnosis of heterotopic pregnancy is more challenging in patients without risk factors. Despite its low sensitivity (33%) in the detection of heterotopic pregnancy, transvaginal ultrasound is the gold standard for diagnosis [2], [7].

To prevent unwanted complications of heterotopic pregnancy, an early transvaginal sonographic examination is recommended in early pregnancy, especially those patients with assisted reproductive technologies. If transvaginal ultrasound is indeterminate, MRI of the pelvis may be used to assist the diagnosis in such cases. Structures located in the adnexal region that are similar to the gestational sac, or even cystic formations, may be identified on MRI [8].

The main symptoms of heterotopic pregnancy are abdominal pain, adnexal mass, peritoneal irritation and an enlarged uterus, which can mimic other gynaecological causes (miscarriage, intrauterine pregnancy with haemorrhagic corpus luteum, adnexal torsion…) and non-gynaecological ones (appendicitis, cholecystitis, bowel obstruction) [9]. The most important different diagnosis of heterotopic pregnancy is to distinguish a tubal ectopic pregnancy from a hemorrhagic corpus luteum cyst. The most sensitive and specific ultrasonographic image for unruptured tubal ectopic pregnancies is “tubal ring sign”, that is an adnexal mass with a concentric echogenic rim of tissue surrounding a hypoechoic empty center. However, even with TVS, the adnexal sac can be mistaken for a hemorrhagic corpus luteum or ovarian cyst, especially in hyperstimulated ovaries. Therefore, in patients with a documented intrauterine pregnancy, conceived via ART,  who present with persistent pain and free fluid in the pelvis, a deligient search for a concomitant ectopic pregnancy should performed.

Ectopic pregnancy is still the leading cause of hemorrhage-related maternal mortality in the first trimester. Early diagnosis is a crucial step in preventing unexpected complications. Despite advances in diagnostic modalities, pre-rupture diagnosis remains challenging because heterotopic pregnancies may be obscured in the presence of intrauterine pregnancies and the differential diagnosis between an ectopic pregnancy and a hemorrhagic corpus luteum can be difficult. Soriano et al [10] estimated that 70% of heterotopic pregnancies occurred between 5 and 8 weeks of gestation, 20% occurred between 9 and 10 weeks, and 10% occurred after 11 weeks. Therefore, it is recommended to perform high-resolution transvaginal ultrasonography with close attention to the adnexa to rule out a  possible early diagnosis of a co-existent ectopic pregnancy in patients with high risk factors.

Unlike those patients with ectopic pregnancy only, the main concern in treating heterotopic pregnancy is the effect of treatment on the intrauterine pregnancy, especially in patients who conceived via ART and have a strong desire to preserve the viable intrauterine pregnancy [5], [6]. The key goal of treatment is to conserve the viable intrauterine pregnancy and to resolve the ectopic pregnancy. Treatment of the ectopic pregnancy should be tailored to the site of the implantation and should use the least invasive therapy in order to preserve the viable intrauterine pregnancy. There are three options for treating heterotopic pregnancy: (1) expectant management, (2) transabdominal sonographic guided transvaginal aspiration of ectopic gestational sac and (3) surgical treatment.

•  In unstable hemodynamic situations or in the presence of clinical signs indicating rupture of ectopic pregnancy, treatment must be initiated rapidly to prevent maternal and fetal complications. The concurrent diagnosis and treatment of heterotopic pregnancy is achieved with surgical intervention either by laparoscopy or laparotomy. Salpingectomy is the standard surgical approach of a coexistent tubal pregnancy and should be the first line of patients in this group. Laparoscopy may be a preferred operative approach but depends on the availability of necessary surgical equipment and the skill of surgeons. In some emergency situations such as hypovolemic shock or when significant hemoperitoneum is suspected, laparotomy is recommended.
•  In stable hemodynamic situations or with asymptomatic patients, expectant management can be an option. This method will not be considered if patients have any signs indicating rupture of ectopic pregnancy or have evidence of a viable ectopic pregnancy such as the detection of a yolk sac or fetal cardiac activity. The main advantage of expectant management is that it avoids all potential complications related to the surgery and/or transabdominal ultrasound-guided transvaginal aspiration of ectopic gestational sac. For patient choosing expectant management, serial ultrasonographic surveillance and close observation are essential. One study of  20 patients managed expectantly reported  that  6 patients in the group converted to surgical management and 4 patients suffered rupture of the ectopic pregnancy [6]. Detailed counselling of patients regardign all the potential risks of expectant management is imperative and patients should be advised to present to hospital immediately if they have any signs of potential ruptured ectopic pregnancy.
• If the patient is hemodynamically stable, transabdominal, sonographically-guided transvaginal aspiration of ectopic gestational sac,  with or without embryo reduction, can be another option. The difficulty of this treatment depends on the location of the ectopic gestational sac. It should be attempted only when the ectopic gestational sac is clearly visualized. Both potassium chloride and hyperosmolar glucose can be used as agents for embryo reduction while methotrexate (MTX) should be avoided because of its teratogenic effects on the viable intrauterine pregnancy. Since rupture of the ectopic pregnancy after this procedure have been reported, repeated ultrasound and close observation are strongly advised till the ectopic gestational sac becomes stable. A literature review of 11 cases of heterotopic pregnancy treated with potassium chloride (KCL) injection reported that six patients (55%) failed this therapy and required surgical intervention [11]. Compared with surgery, transabdominal sonographically- guided transvaginal aspiration of ectopic gestational sac with or without embryo reduction would be preferred in heterotopic pregnancies  with caesarean  scar and cervical ectopics.

Heterotopic pregnancy is associated with a considerable risk of maternal morbidity and mortality because ruptured ectopic pregnancy is a life-threatening complication. When ruptured, ectopic pregnancy is a true medical emergency. It is the leading cause of maternal mortality in the first trimester and accounts for 10%–15% of all maternal deaths [12]. It is known that in surgically managed heterotopic pregnancies  about two-thirds of intrauterine pregnancies result in live delivery, while the other third end in abortion [8].  Yiki Guan et at [13] reviewed clinical outcomes of patients with heterotopic pregnancy and surgical treatment between January 2010 and December 2015. In this study the live birth rate was 82.4%, and the miscarriage rate was 17.86%. Ko Jennifer et at [14] reported a live birth rate of 80% in 10 patients with heterotopic pregnancy between 2000 and 2011.

The incidence of heterotopic pregnancy has risen dramatically with the widespread application of assisted reproductive technology. The diagnosis and management of heterotopic pregnancy remain challenging. Diagnosis is often delayed or missed therefore heterotopic pregnancy can lead to severe complications including fetal loss, maternal hypovolemic shock, or death. The goal of management of heterotopic pregnancy is to terminate the ectopic pregnancy while minimizing the threat to intrauterine pregnancy. Physicians managing this condition need to take into account several factors such as the patient’s desire to have a baby, the clinical symptoms, and the size and location of the ectopic pregnancy in order to choose the optimal treatment method.

1. Govindarajan MJ, Rajan R. Heterotopic pregnancy in natural conception. J Hum Reprod Sci. 2008;1:37–8. 

2.  Molinaro TA, Barnhart KT, Levine D, et al. Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy. UpToDate, 26 October 2015.

3. Guimarães, A. C., Reis, L. D. D. O., Leite, F. C., Reis, C. F. D. D., Costa, A. P., & Araujo, W. J. B. D. (2019). Spontaneous Heterotopic Triplet Pregnancy with a Two Viable Intrauterine Embryos and an Ectopic One with Right Tubal Rupture. Revista Brasileira de Ginecologia e Obstetrícia, 41, 268-272.

4. Tamhane, N. A., Parikh, A., & Joshi, V. M. (2018). Heterotopic Quadruplet Pregnancy After ICSI Conception. The Journal of Obstetrics and Gynecology of India, 68(6), 505-507.

5. Luo X, Lim CE, Huang C, Wu J, Wong WS, Cheng NC: Heterotopic pregnancy following in vitro fertilization and embryo transfer: 12 cases report. Arch Gynecol Obstet. 2009, 280:325-29. 10.1007/s00404-008-0910-2

6. Li, J. B., Kong, L. Z., Yang, J. B., Niu, G., Fan, L., Huang, J. Z., & Chen, S. Q. (2016). Management of heterotopic pregnancy: experience from 1 tertiary medical center. Medicine, 95(5).

7. Soares, C., Maçães, A., Veiga, M. N., & Osório, M. (2020). Early diagnosis of spontaneous heterotopic pregnancy successfully treated with laparoscopic surgery. BMJ Case Reports, 13(11).

8. Sun, S. Y., Araujo Júnior, E., Elito Júnior, J., Rolo, L. C., Campanharo, F. F., Sarmento, S. G. P., ... & Moron, A. F. (2012). Diagnosis of heterotopic pregnancy using ultrasound and magnetic resonance imaging in the first trimester of pregnancy: a case report. Case reports in radiology, 2012.

9. Ramalho I, Ferreira I, Marques JP, et al. Live birth after treatment of a spontaneous ovarian heterotopic pregnancy: a case report. Case Rep Womens Health 2019

10. Soriano D, Vicus D, Schonman R, et al. Long-term outcome after laparoscopic treatment of heterotopic pregnancy: 19 cases. J Minim Invasive Gynecol. 2010;17:321–324.

11. Goldstein, J. S., Ratts, V. S., Philpott, T., & Dahan, M. H. (2006). Risk of surgery after use of potassium chloride for treatment of tubal heterotopic pregnancy. Obstetrics & Gynecology, 107(2), 506-508.

12. Sara HG, Uzelac PS. Early pregnancy risks. In: DeCherney AH, Nathan L, Goodwin MT, Laufer N, editors. Current Diagnosis and Treatment: Obstetrics and Gynecology. 10th ed. Columbus (OH): McGraw-Hill; 2007. pp. 259–272

13. Guan, Y., & Ma, C. (2017). Clinical outcomes of patients with heterotopic pregnancy after surgical treatment. Journal of minimally invasive gynecology, 24(7), 1111-1115.

14. Ko JK, Cheung VY. A 12-year experience of the management and outcome of heterotopic pregnancy at Queen Mary Hospital, Hong Kong, China. Int J Gynaecol Obstet. 2012;119:194–195.

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