Surgical treatment
The traditional treatment for tubal pregnancy is laparotomy and salpingectomy. Laparoscopic approaches became more widely accepted after the development of video laparoscopy and the publication of the first series of successful use of laparoscopy for the treatment of EP in the 1980’s [
132]. Laparoscopic surgery is the preferred approach in haemodynamically stable patients and has largely replaced the need for laparotomy due to improved postoperative recovery time and reduced morbidity [
133,
134].
Laparotomy is the preferred technique when the patient is haemodynamically unstable, if the surgeon has not been trained in laparoscopy or if laparoscopic surgery equipment is not available [
133-
135]. There is no difference in subsequent reproductive outcome between these surgical approaches. However, there is a trend towards higher rates of persistent trophoblast associated with laparoscopic surgery for EP [
133-
136].
Salpingectomy is preferable for tubal pregnancy in patients with uncontrolled bleeding, extensive tubal damage or recurrent EP in the same tube. Salpingostomy is indicated where the patient is haemodynamically stable, wishes to conserve her fertility, if there is an unruptured EP < 5 cm in diameter and, especially, when the contralateral tube is absent or damaged [
134,
137].
Two RCTs have compared salpingectomy and salpingostomy and have recently been published (DEMETER and ESEP). Both reported on reproductive outcomes after treatment of EP by both techniques [
137,
138]. Subsequent fertility, recurrent EP and IUP rates were similar following both approaches. However, persistent trophoblastic tissues were more common with salpingostomy with a relative risk of 15 (95% CI: 2.0-113.4) for persistence [
137].
Hence, Mol et al. (2014) have suggested that salpingectomy should be the procedure of choice in women with tubal pregnancy and a healthy contralateral tube. These recommendations are also adapted by NICE in their guidelines for the management of EP [
139]. Furthermore, a study that investigated the preference of patients regarding the type of operation found out that the majority of women preferred salpingectomy to avoid the possibility of another EP. However, the risk of persistent trophoblast was acceptable for these women if compensated by a small increase in the chances of an IUP following surgery [
140].
Medical treatment
Medical management for EP requires effective early diagnosis as its success is inversely correlated with the level of serum hCG at diagnosis [
130,
141-
143]. Several agents can be used for the treatment of EP, including methotrexate (MTX), potassium chloride (KCl) and hyperosmolar glucose [
130,
144,
145]. The advantages of medical treatment are the avoidance of anaesthesia, surgery and its complications, preservation of tubal patency and function, and possibly cost effectiveness [
130,
145].
MTX, a cytotoxic drug that destroys rapidly dividing trophoblastic cells, is the most popular medical agent for the treatment of EP. MTX is a folic acid antagonist with metabolism and excretion in the liver and kidney, respectively [
146,
147]. MTX is given as single or multiple doses. The variable dose regimen, which consists of 4 injections, involves the addition of a reduced form of folate, citrovorum, to block the effect of MTX and to prevent adverse effects on other tissues [
130,
147]. Another treatment protocol with two doses of MTX and a schedule for follow-up for the patient similar to the ‘multiple doses’ regimen was first proposed in 2007. This protocol does not need the addition of citrovorum for the prevention of the drug side effects [
143].
The dose of MTX is calculated according to body surface area (50 mg/m
2) or body weight (1 mg/kg). For most women this will be between 75 and 90 mg [
146,
147]. MTX can be administered by intravenous or intramuscular injection, or by local injection under the guidance of either ultrasound or laparoscopy [
141,
147]. There is a significant risk of tubal rupture in unsuccessful cases following the use of MTX. Other side effects include abdominal pain due to tubal abortion, stomatitis and diarrhoea, hCG concentrations may rise for up to three days after MTX even in successful cases, and some may need a second dose of MTX [
130,
147].
Criteria for the use of MTX treatment in EP according to ACOG and NICE guidelines are listed in Table
2. Briefly, methotrexate can be used in haemodynamically stable patients with minimal or no symptoms and who have initial serum hCG concentrations < 5000 IU/L and EP size < 3.5 cm [
130,
139]. Patients should be advised to avoid sexual intercourse during treatment, becoming pregnant for 6 months post treatment and excessive exposure to sunlight and alcohol [
147].
Table 2
Criteria of methotrexate (MTX) treatment for ectopic pregnancy (EP)
Indications
| • Haemodynamically stable patients |
• Minimal or no symptoms |
• Serum hCG is < 5000 IU/L |
• Ectopic mass < 3.5 cm |
• No embryonic cardiac activity |
• Confirmed diagnosis of ectopic pregnancy |
• Able to comply with the follow-up |
Contraindications
| • Hemodynamically unstable |
• Suspected ruptured EP |
• Heterotopic pregnancy |
• Pregnancy of unknown location |
• Breastfeeding |
• Chronic liver disease |
• Renal disease |
• Active peptic ulcer or colitis |
• Active pulmonary disease |
• Immunodeficiency |
• Haematological disease |
• Sensitivity to MTX |
• Unable to comply with visits and follow-up |
The treatment with MTX continues until hCG falls by 15% from its peak concentration within two days for single dose regimen or between day 4 and 7 for the multiple dose/two dose regimens [
142,
143,
146,
147]. A serum hCG measurement is performed on day 4 and 7 and a further dose is given if levels have failed to fall by more than 15% in the multiple dose/two doses regimens [
142,
143]. Approximately 50% of the treated patients will not require the full 4 doses in the ‘multiple dose’ protocol [
130,
147].
Several studies have compared laparoscopic salpingostomy with MTX, finding MTX to be almost as effective as surgery in terms of success rates and future fertility outcomes [
135,
136,
138]. Tubal patency was documented by hysterosalpingography in 78% of cases and in 65% of patients who attempted to conceive again. Additionally, the incidence of recurrent EP was relatively low (12%) and was not significantly different from the observed rate (9%) with salpingostomy [
138].
A meta-analysis reported that the success rate of MTX treatment was 92.7% and 88.1% for ‘multi-dose’ and ‘single dose’, respectively. The failure rate of ‘single dose’ protocol was estimated to be about 3 times higher than the ‘multiple dose’ regimen and the possibility of tubal rupture cannot be excluded even with falling hCG levels [
148]. Signs of treatment failure or suspected rupture are indications to stop medical treatment and to shift to surgical management. Signs include haemodynamic instability, increasing abdominal pain regardless of trends in hCG levels, and rapidly increasing hCG concentrations (>53% over 2 days) after two doses or four doses in the ‘single’ and ‘multiple-dose’ regimens, respectively [
138,
143,
149-
151].
The use of MTX in women with a viable IUP is absolutely contraindicated as the drug would cause miscarriage or congenital malformations [
130,
152,
153]. Hence, women with a pregnancy of unknown location (PUL) or HP following IVF-ET should be managed by other means [
130].
Several other agents have been used for the medical treatment of EP. Sonographically guided local injection of KCl into the heart of the ectopic fetus can induce cardiac asystole with resolution of EP [
154,
155]. Hyperosmolar glucose can also be injected into the gestation sac causing local dehydration, necrosis of the trophoblastic tissue and resolution of EP [
156,
157]. These agents are not associated with fetal malformation but careful consideration should be given before use of hyperosmolar glucose since high doses could increase the risk of bleeding [
158].
Recently, two studies have shown that the combination of gefitinib, an orally active epidermal growth factor receptor inhibitor, in combination with a single dose of intramuscular MTX (50 mg/m
2) for the treatment of tubal (n = 12) and non-tubal (n = 8) EP was safe and associated with a faster time of EP resolution by 34% compared with MTX alone [
145,
159]. The new drug at a daily single dose of 250 mg for seven days was well tolerated by the patients with mild to moderate side effects (e.g. acne/rash and diarrhea) that are known to be associated with gefitinib [
145,
159]. However, gefitinib should only be used for a short and limited 7 days course and women with significant pulmonary comorbidities and Japanese ethnicity should be excluded to decrease/eliminate the risk of interstitial lung disease during the treatment of EP with gefitinib [
145,
159]. RCTs are still needed to confirm the aforementioned findings about the efficacy and safety of combining gefitinib with MTX for the treatment of EP [
160].
Expectant management
When serum hCG is below the discriminatory zone and there is no intra- or extrauterine pregnancy detected by TVS, the pregnancy can be described as being PUL [
121,
150]. Several studies have reported that 44-69% of PUL resolve spontaneously [
161,
162] and 8.7–42.8% of PUL will eventually be diagnosed as early EP which were too small to visualise on initial ultrasound scan [
112,
114,
163].
Expectant management is an option for clinically stable women with serum hCG levels below the discriminatory zone, minimal symptoms associated with either PUL or EP diagnosed on ultrasound [
161,
164,
165]. Recent results from an RCT study showed that there is no significant difference in the outcome between MTX and expectant management groups in suitable patients [
165]. Another Australian research group announced recently the initiation of a double-blinded multicentre RCT to compare between medical and expectant management for EP but the results has not been published yet [
166].
Patients with EP may have an initial 50-66% increase in β-hCG concentrations every two days [
112,
165], mimicking a viable IUP. However the eventual fate of EP is either spontaneous resolution or rupture. This is dependent on the activity of the invading trophoblast tissue, with less aggressive invasion of the trophoblast tissue being associated with spontaneous resolution and more aggressive invasion leading to tubal rupture [
167,
168]. If the serum hCG concentrations increase, intervention is essential or the patients may suffer ruptured EP. On the other hand, for patients at an early stage, with lower gestational age and declining β-hCG titres, the risk of rupture is small [
161,
165].
Regular follow-up is essential if expectant management is to be successful and clear information about the importance of compliance with follow-up should be given to the patient. Serial serum hCG concentrations should be followed until they reach < 15 IU/L. If symptoms and signs of EP develop, serum hCG concentrations rise above discriminatory zone or start to plateau, active intervention should be considered [
164,
165].
Management of heterotopic pregnancy
The clinical management of HP aims to remove the EP without disturbing the viable IUP. Currently, there is no general consensus on the treatment of HP and the majority of data about its clinical management derive from case reports. Surgical treatment by laparotomy or laparoscopy, injection of feticides with or without fetal reduction by embryo aspiration under ultrasound guidance and expectant management have all been used and reported to be successful in the elimination of the ectopic and preservation of ongoing IUP. The selection of treatment protocol depends on the gestational age at diagnosis, the clinical condition of the patient, the site of ectopic implantation and the experience of the treating physician. In a number of studies, the success rate for rescuing the viable IUP was about 66% with the remainder ending in early or late miscarriage [
108,
122,
169].
The treatment of HP with a tubal implantation can be performed by laparotomy or laparoscopy and the removal of EP is usually done by salpingectomy and occasionally by salpingostomy [
170-
174]. For interstitial HP, either medical treatment with local injection of a feticide/embryo reduction for small non-ruptured EP [
158,
175,
176] or cornual resection by laparoscopy or laparotomy in ruptured cases has been used with rescue of the IUP [
177-
180]. A few studies have also reported the use of expectant management for tubal and interstitial HP [
181,
182].
Currently, only 14 cases of caesarean scar HP are reported in the literature. The majority of cases were treated medically by local injection of feticides and/or embryo aspiration to rescue the viable IUP except for 2 cases that were treated by laparoscopic and hysteroscopic excision of the EP masses [
169,
183]. Caesarean scar pregnancy can lead to massive haemorrhage due to uterine rupture and laparotomy followed by wedge excision has been reported to be the preferred approach to completely remove the EP, repair the scar and prevention of recurrence [
169,
184,
185].
The majority of cases with cervical HP have been treated conservatively using embryo aspiration with or without local injection of a feticide to preserve the viable IUP [
186-
188]. Others have successfully used laparoscopy or hysteroscopy for the removal of cervical EP and preservation of the IUP [
189,
190]. Efficacious use of expectant management with continuous close monitoring by TVS was also reported in a few cases [
141,
188]. However, dilatation and curettage was also found to be necessary in some cases to prevent massive bleeding from cervical pregnancy [
141,
188].
Ovarian HPs have been managed by wedge resection using laparoscopy or by laparotomy in cases of massive bleeding [
191]. Other cases have resulted in salpingo-oophorectomy due to massive adhesions from a ruptured EP [
192]. Other ectopic sites within the abdominal cavity have also been reported and have been treated surgically due to bleeding.