Description of the condition

Non‐tubal ectopic pregnancy is the implantation of an embryo at a site lying outside the uterine cavity or fallopian tubes. Sites include a caesarean scar, the cornua uteri, the ovary, the cervix, and the abdomen. There has been an increasing trend in the occurrence of these rare conditions, especially caesarean scar pregnancy (CSP), which poses a diagnostic and treatment challenge for clinicians (Ngu 2011; Petersen 2016). The incidence of non‐tubal ectopic pregnancy is estimated at 5.0% to 8.3% of all ectopic pregnancies, while the incidence of ectopic pregnancy is estimated at about 1% to 2% of all pregnancies (Bouyer 2002; Stucki 2008; Jurkovic 2011; Ngu 2011; Shan 2014; Yao 2005). Although relatively uncommon, these conditions are responsible for serious immediate and delayed complications (Bouyer 2002; Stucki 2008), with significant haemorrhages and a high rate of maternal fatality (Lewis 2007; Stucki 2008; Barnhart 2009; Orazulike 2013). Ectopic pregnancy makes up 80% of maternal deaths that occur in the first trimester, of which non‐tubal ectopic pregnancy deaths account for a higher rate than tubal pregnancy deaths (Stucki 2008; Jurkovic 2011). Thus, it is important to recognize that the implantation site of ectopic pregnancy affects the severity of the condition (Bouyer 2002; Kirk 2014), and early diagnosis and effective treatment are essential to reduce the immediate and delayed adverse effects, and to avoid significant maternal morbidity and mortality.

CSP has increased because of the increased rate of caesarean sections performed (Maymon 2004; Seow 2004; Shen 2012; Gibbons 2012), and may account for up to 6.1% of all ectopic pregnancies in women with a history of at least one caesarean section (Seow 2004). The criteria for ultrasonography diagnosis include: (i) no fetal parts observed in the uterine cavity or cervical canal; (ii) a gestational sac located in the anterior part of the isthmic portion separated from the endometrial cavity or fallopian tube; (iii) a gestational sac embedded within the myometrium and the fibrous tissue of the caesarean section scar with diminished healthy myometrium between the bladder and the sac; and (iv) high velocity with low impedance blood flow surrounding the gestation sac (Jurkovic 2003; Pascual 2007; Seow 2004). CSP typing according to direction of growth of the gestational sac and thickness of the myometrium between the bladder and gestational sac has been proposed, and three types (I, II, and III) were divided as different ultrasonic manifestations (Yuan 2010).

Ovarian pregnancy accounts for 1% to 6% of all ectopic pregnancies (Bouyer 2002; Comstock 2005; Tinelli 2008; Goyal 2014; Melcer 2015). Ovarian pregnancy is often confused with corpus luteum cysts. Ultrasonography examination is routinely required and laparoscopy often plays a key role in diagnosis, with confirmation by pathological examination of removed tissue. The criteria are as follows: (i) empty uterine cavity; (ii) tubes entirely intact, separated from the ovary; (iii) a gestational sac located at the normal position of the ovary; (iv) ovary and a gestational sac connected to the uterus by the ovarian ligament; and (v) trophoblastic tissue attached to the ovarian cortex in the tissue specimen (Nadarajah 2002; Comstock 2005). However, the new 'Green top' guideline summarizes that there are no agreed ultrasonography criteria for the diagnosis of ovarian pregnancy (Elson 2016).

Cornual pregnancy has a prevalence of 1.7% to 2.1% of all ectopic pregnancies (Stucki 2008; Shan 2014; Nadi 2017). The term cornual pregnancy is often used interchangeably in the literature with interstitial pregnancy, but it actually refers to a pregnancy located in the interstitial portion of a unicornuate or bicornuate uterus (Tulandi 2004; Chetty 2009). The diagnosis can be made by the following ultrasonography criteria: (i) a single interstitial portion of a fallopian tube in the main uterine body; (ii) a mobile gestational sac surrounded by myometrium but separated from the uterus; and (iii) a vascular pedicle adjoining the gestational sac to the unicornuate uterus (Jurkovic 2007; Levine 2007).

Cervical pregnancy is a rare form of ectopic pregnancy with an estimated frequency of less than 1% of all ectopic pregnancies (Chetty 2009; Faschingbauer 2011; Anev 2013). Cervical pregnancy can be diagnosed by the following ultrasonography presentations: (i) empty uterine cavity; (ii) dilated or barrel‐shaped cervix; (iii) a gestational sac within the mucosa located in the endocervical canal; and (iv) a sliding sac sign (Jurkovic 1996; Kirk 2014).

Abdominal pregnancy is one of the rarest forms of ectopic gestation and occurs in 0.3% to 1.4% of all ectopic pregnancies (Bouyer 2002; Molinaro 2007; Stucki 2008; Goyal 2014; Shan 2014). It refers to a gestational sac implanted in the omentum, abdominal vital organs, or large vessels, and is described as either primary or secondary. A primary abdominal pregnancy is due to a failure of the fimbria to pick up the ovulated follicle, while a secondary abdominal pregnancy is believed to follow early rupture or abortion of a tubal pregnancy or uterine perforation of a intrauterine pregnancy into the peritoneal cavity. The following criteria have been suggested to diagnose abdominal pregnancy: (i) empty uterine cavity; (ii) absence of a dilated fallopian tube and a complex adnexal mass; (iii) absence of myometrial tissue between the bladder and pregnancy; (iv) a gestational sac surrounded by intestinal tissue and separated by the peritoneum; and (v) a free mobility similar to fluctuation of the sac (Varma 2003; Gerli 2004; Onan 2005; Kirk 2014).

See Table 1.

Description of the intervention

The diagnosis of, and treatment for, non‐tubal ectopic pregnancy are challenging and frequently constitute a medical emergency. Thus, prompt and effective treatment is important to avoid potentially catastrophic consequences such as massive haemorrhaging, hysterectomy, and death. The improved ultrasonography technology widely used in early pregnancy assessment and high awareness of the possibility of ectopic pregnancy have contributed to earlier diagnosis of these pregnancies. This has led to advances in their management, aiming to limit morbidity and to preserve the uterus and subsequent fertility (Molinaro 2007). Treatments include surgery, medical treatment, and expectant management. Although many treatment options have been recommended, the optimal treatment is yet to be clarified.

Surgery is the primary treatment for most ovarian, cornual, and abdominal pregnancies (Ngu 2011; Shan 2014). Management of ovarian pregnancy usually requires ovariectomy or ovarian wedge resection. Ovarian wedge resection may be considered by women with future fertility in mind, whereas ovariectomy is limited to cases of advanced gestation (Einenkel 2000; Goyal 2014). cornual pregnancy has traditionally been treated using cornual resection or hysterectomy in the cases with severely damaged uteri (Molinaro 2007). The surgery can be completed through laparoscopy or laparotomy, but laparotomy may be required for women with uterine rupture and haemoperitoneum (Tulandi 2004). Surgical management with ligation of the placental blood supply and removal of some early abdominal pregnancies implanted on a less vascular surface can be managed by laparoscopy (Molinaro 2007); in advanced pregnancies, selective arterial embolization is necessary before surgery to avoid haemorrhage (Rahaman 2004). For cervical and caesarean scar pregnancies, laparotomy and hysterectomy may be required for more advanced pregnancies (Hsieh 1998; Jin 2004; Fuchs 2015; Alammari 2017). Surgery is often performed as a life‐saving emergency measure for women with massive active bleeding or failed conservative treatment.

Improvements in the early detection of these conditions, before rupture, have led to the utilization of possible conservative treatment options. For women who desire fertility preservation, conservative measures have become the first‐line approach. These options include administration (local or systemic) of various chemotherapeutic agents (including methotrexate (MTX), etoposide, actinomycin D, and cyclophosphamide) and endoscopic removal techniques (laparoscopy or hysteroscopy), alone or as adjuvant therapies, with or without haemostatic techniques (balloon tamponade, uterine artery ligation, cerclage, and cervical stay sutures). With cervical pregnancies before 12 weeks' gestation where the women have lower serum β‐human chorionic gonadotropin (β‐hCG) levels and no fetal cardiac activity, it may seem reasonable to administer conservative treatment (Molinaro 2007). Systemic MTX administration is a common approach to cervical pregnancy and has high efficacy, but it may be associated with increased risk of primary failure for pregnancies greater than nine weeks' gestation, with β‐hCG levels above 10,000 mlU/mL, crown–rump length greater than 10 mm, and fetal cardiac activity (Hung 1998). Suction curettage with balloon tamponade or uterine arterial embolization (UAE) may be a choice for first trimester cervical pregnancy (Fylstra 2014; Hu 2016). Local or systemic injection of chemotherapy has met with various degrees of success for treatment of CSP (Marchiole 2004; Graesslin 2005; Jabeen 2018). Advances in UAE have enabled a minimally invasive approach in these women (Yu 2009; Lian 2012; Shen 2012; Zhang 2012; Zhu 2016). Dilation and suction curettage can be used after chemotherapy but should not be the first‐line approach in cervical and CSP because of the risk of perforation and catastrophic haemorrhage (Lee 1999). Medical management with MTX has been reported for ovarian pregnancy but may not be practical (Molinaro 2007). Conservative measures may be attempted for selective cornual pregnancies but carry a high risk of initial failure (Bernstein 2001; Molinaro 2007). However, Horne and colleagues reported five successful cases with gefitinib plus MTX (Horne 2014). Systemic MTX chemotherapy and ultrasonography‐guided injection of potassium chloride for management of early abdominal pregnancies has been reported (Mitra 2003). 

Expectant management does not seem to be an appropriate choice for most cases and may be only suitable for women with declining β‐hCG levels and absence of fetal cardiac activity (Chetty 2009; Timor‐Tritsch 2015; Jabeen 2018). However, women should be closely monitored in case the lesion ruptures or the situation deteriorates.

How the intervention might work

Although surgery is not a routine method of diagnosis, due to improvements in the early ultrasonography diagnosis of these challenging pregnancies, it remains the main treatment option for ectopic pregnancy. Laparoscopy has been recommended in preference to laparotomy in clinically stable women because of shorter operating time, reduced recovery time, lower blood loss, and shorter duration of hospitalizations (Seinera 1997; Einenkel 2000; Shaw 2007). However, laparotomy is preferable to laparoscopy in women who have had heavy abdominal haemorrhaging and who have to undergo immediate haemostasis (Jurkovic 2011). Conservative surgery (preservation of uterus or ovary) to remove only the products of gestation or a part of the ovary is more desirable, especially for women who wish to preserve their fertility. Hysterectomy or ovariectomy is a radical modality used for urgent blood control or in women at an advanced gestational age and following misdiagnosis and failed conservative treatment or with severely damaged uteri (Ushakov 1997; Molinaro 2007; Chetty 2009).

Suction curettage can serve to extract the products of gestation and achieve haemostasis, used either as a single treatment or as an adjuvant therapy (Jurkovic 2003; Marchiole 2004).

Systemic and local administration of drugs is considered a safe and effective treatment. MTX is the most widely used chemotherapy drug, and, combined with folic acid, it is similar to treatment of gestational trophoblastic disease (Ory 1986; Sauer 1987; Liang 2010). 

UAE involves blocking the arteries using gelatin beads or other materials (Shen 2012). It has been used as an adjuvant therapy to prevent excessive haemorrhage before uterine surgery or curettage procedures (Frates 1994; Honey 1999; Trambert 2005). Bilateral uterine arterial chemoembolization (UACE) is a combination of arterial embolization and local administration of chemotherapy. During the procedure, MTX is delivered directly into the gestational foci via the bilateral uterine arteries, which provide the blood supply. Then occlusive agents are injected into the delivery catheter to block the blood vessels. The procedure uses both chemotherapy and tissue ischaemia and thus uses a higher concentration of MTX leading to more effective embryocide, with fewer systemic toxic effects and reduced haemorrhage. As a minimally invasive treatment, it has been considered as a conservative method for treating CSP (Zhang 2009; Liang 2010; Li 2011a; Litwicka 2011; Lian 2012; Shen 2012).

Why it is important to do this review

To date, there has been no systematic review presenting evidence from randomized controlled trials (RCTs) to show the optimal management of non‐tubal ectopic pregnancy. The optimal treatment, treatment success rate, and complications are largely unknown. In this review, we evaluated the clinical effectiveness and safety of surgery, medical treatment, and expectant management of non‐tubal ectopic pregnancy in terms of primary treatment success and preservation of the uterus and future fertility, and collated the best evidence on interventions for non‐tubal ectopic pregnancy.