Two case reports of triple ectopic: Literature review of incidence, risk factors and management of recurrent ectopic pregnancy

Abstract

Ectopic pregnancy is a gynaecological emergency. While its identification and management are monumental, it also impacts the patient’s future fertility. Ectopic pregnancy is one of the leading causes for maternal deaths in the first trimester. The rate of ectopic pregnancy in the United Kingdom is reported to be 11 per 1000 pregnancies, with a maternal mortality of 0.2 per 1000 estimated ectopic pregnancies and two-thirds of these deaths are associated with substandard care. Literature is replete with risk factors leading to ectopic pregnancy, such as tubal disease, previous pelvic surgery, tubal surgery, assisted reproduction, smoking and so on. The paper employs case scenarios of recurrent ectopic pregnancies in two patients with triple recurrent ecotpic pregnacies. It discusses the risk factors and preventive measures to avoid multiple recurrences.

Introduction

Ectopic pregnancy (EP) is a gynaecological emergency with implications on future fertility. We present two patients with occurrence of three recurrent ectopic pregnancies (REPs) in each. This is followed by a literature review of risk factors of incidence of REPs and to address preventive measures to avoid multiple recurrences.

Case reports

Case report 1

The first patient is a 32-year-old housewife (G6, P1+4) with a history of three ectopic pregnancies. She has had six pregnancies; the first pregnancy resulted in ventouse delivery of a female infant at term. She then had three consecutive ectopic pregnancies and two first-trimester miscarriages. She attained menarche at age 17 and had a regular menstrual cycle of 4/30 days with no history of dysmenorrhea, inter-menstrual or post-coital bleeds. She was up-to-date with her cervical screening with normal cytology. She has denied any history of sexually transmitted infections (STIs). However, previous laparoscopic examinations revealed features consistent with pelvic infection (pelvic and peri-hepatic adhesion consistent with Fitz-Hugh–Curtis syndrome). She was not on any contraceptive and was a non-smoker with allergies to penicillin.

First EP

This occurred at age 22 when she was gravida 2 para 1 (3-year-old baby). She presented with a triad of 7-week amenorrhoea, abdominal pain and 16 days of vaginal bleeding with clots. The β-hCG (human chorionic gonadotropin) was 734iu/L, and she was haemodynamically stable. The abdomen was tender, with minimal vaginal bleeding, closed cervix and reflex excitation tenderness was elicited. A transvaginal ultrasound scan demonstrated a right adnexal irregular complex mixed echo mass measuring 66 × 88 × 88 mm and significant free fluid in the Pouch of Douglas (POD). Within 24 hours of admission, she began to show signs of a rupture, including tachycardia and hypotension. Haemoperitoneum (500ml), a right spontaneous tubal miscarriage and bilateral tubal adhesion were noted at laparoscopy. Peritoneal lavage was performed, and the tubal abortus was retrieved and sent for histology. A right tubal EP diagnosis with spontaneous tubal miscarriage and pelvic inflammatory disease (PID) was made. Histology confirmed products of conception from the fimbrial end of the right fallopian tube. She required two units of blood transfusion and postoperative antibiotics. Serum β-hCG on the fifth postoperative day was 36 IU/L. Five months later, a planned interval laparoscopy, adhesiolysis, salpingolysis, and methylene blue tubal insufflation revealed peri-hepatic violin string adhesions, minimal para-tubal adhesions and minimal adhesions in POD. Adhesiolysis resulted in a normal uterus, ovaries, and free and bilaterally patent fallopian tubes on methylene blue insufflation

Second EP

Her subsequent pregnancy was at age 26 (G4 para 1) in her fifth pregnancy, having had one miscarriage at 6 weeks’ gestation. She presented with left-sided abdominal pain, mild vaginal bleeding and collapse. Given previous EP, tubal surgery and PID, EP was suspected. Clinically, there was guarding and rebound tenderness, and pelvic assessment revealed minimal vaginal bleeding, bulky uterus, closed cervical os, and left adnexal and excitation tenderness. The urine pregnancy test was positive, and the serum β-hCG was 1588 IU/L (result obtained after her emergency operation). The ultrasound scan showed no evidence of intrauterine pregnancy (IUP), no free fluid in the POD or adnexal masses. However based on a thickened endometrium and guided by high suspicion due to the previous history of ectopic and PID, the patient was taken for diagnostic laparoscopy (see Figures 1 and 2). Laparoscopy revealed a left ampullary EP (see Figure 3) with a normal right tube and normal ovaries. Laparoscopic left salpingectomy was performed, and the postoperative period was uneventful. EP was confirmed on histology. She was counselled for recurrence risk and advised about self-referral to the early pregnancy assessment unit (EPAU) in her subsequent pregnancy.

Figure 1.

Thickened endometrium, no intrauterine pregnancy.

Figure 2.

No free fluid in POD.

Figure 3.

Left ampullary ectopic pregnancy.

Third EP

Six months later, she presented to the EPAU for an early ultrasound scan assessment because of a history of asymptomatic amenorrhoea and serum β-hCG of 1359 IU/L. Transvaginal scan (TVS) showed no evidence of IUP and endometrial thickness (ET) of 11 mm, and she was managed expectantly. The β-hCG was 2424 IU/L after 48 hours, representing a rise of 56%. She later became symptomatic at home with vaginal bleeding and abdominal pain. A repeat TVS was inconclusive. Laparoscopy showed an unruptured right tubal EP (see Figure 4), some haemoperitoneum, Fitz-Hugh–Curtis syndrome and an absent left fallopian tube. She underwent laparoscopic salpingectomy.

Figure 4.

Right unruptured tubal ectopic pregnancy.

Case report 2

In our second case, we present a 27-year-old lady. She is G3, P0 with history of three previous miscarriages and investigations for primary sub-fertility. She also had a past medical history of having an intrauterine contraceptive device and PID with numerous antibiotic therapies. She had three previous laparoscopies and adhesiolysis for chronic PID. She was allergic to plaster.

First EP

She presented with her first EP when she had a 3-day history of brownish vaginal discharge and lower abdominal pain. She was unsure of her dates but thought it was less than 4 weeks and had a negative urine pregnancy test, but a faintly positive test on admission. Clinically, the abdomen was tender in the right iliac fossa. Brownish vaginal discharge and closed cervical os were revealed at a vaginal examination. There was bilateral reflex cervical excitation tenderness. The ultrasound scan showed a bulky uterus, thickened endometrium and no evidence of in utero pregnancy. At laparoscopy, a haemoperitoneum and a right tubal mass measuring 3 × 2 cm with bilateral florid tubo-ovarian adhesive complex was revealed. At laparotomy, the right tube was incised, the pregnancy was evacuated and haemostasis was achieved with diathermy and the tube was closed with continuous nylon suture (open salpingostomy). EP was confirmed in histology.

Second EP

Five months later, at age 28+, she presented with amenorrhoea, jelly-like, brownish vaginal discharge and abdominal discomfort. Her periods were irregular lasting 2–3 days and occurring every 4–6 weeks. There was accompanied dyspareunia and she was not on any contraception. A home pregnancy test was negative. An abdominopelvic examination was unremarkable as well as a pelvic ultrasound scan. She was discharged home for a follow-up. She returned 13 days later to the hospital with suprapubic pain, brownish vaginal discharge and a positive pregnancy test. On examination, the abdomen was tender with guarding and rebound phenomena in the upper right abdomen. An ultrasound showed no evidence of IUP but a right adnexal mass. She underwent a laparoscopy and laparotomy and right salpingectomy. At operation, there was 100 mL of haemoperitoneum and a right tubal EP, measuring 6 × 3 cm and the left tube was normal. The histology confirmed ectopic.

Third EP

This occurred at age 33, now gravida 8, para 2, with two ectopic pregnancies and four miscarriages. The main complaint at the EPAU was a slight left iliac fossa (LIF) discomfort, no bleeding, a regular cycle following 6 weeks of amenorrhoea and a positive urine pregnancy test. She was managed expectantly initially. The ultrasound scan showed no IUP and an ET of 13.2 mm and serum β-hCGs were 443 IU/L, 539 IU/L, 731 IU/L on admission and at 48 and 96 hours, respectively. On review in the EPAU on the fifth day, she had brownish vaginal discharge and bleeding and increased lower abdominal pain, especially in the LIF and β-hCG of 731 IU/L. Due to high clinical suspicion, patient symptoms and sub-optimal HCG rise, she underwent a laparoscopy. A left cornual ectopic 3 × 3 cm was noted and a resection was performed at laparotomy. She was discharged home on the second day of the operation. She returned about 4 years later with history of further pain and underwent adhesiolysis secondary to multiple laparoscopic surgeries.

A summary of both case reports with age at presentation, order of presentation, site of ectopic and intervention is provided in Table 1.

Table 1.

Summary of ectopic pregnancy event and intervention in both case reports.

Events	Case 1			Case 2
	Age in years	Intervention	Intervals	Age in years	Intervention	Intervals
First	22	Right laparoscopic milking		27	Laparoscopy and laparotomy and right salpingotomy
Second	26	Left laparoscopic salipingectomy	4 years	28	Laparoscopy, laparotomy and right salpingectomy	6 months
Third	27	Right laparoscopic salpingectomy	6 months	33	Laparoscopy, laparotomy and left cornual resection	5 years
Risk factors		Evidence of PID at the first laparoscopy			Primary infertility, previous use of IUCD, chronic PID, laparoscopic adhesiolysis, smoker

PID: pelvic inflammatory disease; IUCD: intrauterine contraceptive device.

Discussion and literature review

Incidence of EP and REP

The rate of EP in the United Kingdom is reported to be 11 per 1000 pregnancies,^1,2 with a maternal mortality of 0.2 per 1000 estimated ectopic pregnancies.^3,4 Incidence of REP varies from 10% to 27%^5,6 representing a 5- to 15-fold increase in the general population. ⁵ The recurrence rate of ectopic is represented in Table 2. The trend of EP in our unit is given in Table 3. Most (93%) of the ectopic pregnancies occur in the fallopian tube, and only 10% account for occurrence in non-tubal sites such as adnexa, ovary, intramural or cornual. Of these, 70% are in the ampulla, 12% in the isthmus and 11% in the fimbriae. ² Non-tubal ectopic pregnancies are often referred to as unusual site ectopic pregnancies (see Table 4). They occur in about 7% pregnancies and account for significantly higher morbidity and mortality as they are more difficult to diagnose and tend to present later than tubal pregnancies.

Table 2.

Incidence of ectopic and recurrent ectopic pregnancy.^7–10

No previous EP	1%–3%
Recurrence of EP after one previous EP	10-15%
Recurrence of EP after two previous EPs	27%
Recurrence of EP following one salpingotomy for EP on ipsilateral tube	15.4% 10 (15% persistent EP)

EP: ectopic pregnancy.

Table 3.

Trend of ectopic pregnancy in Diana Princess of Wales Hospital. ¹

Triennium	Total ectopic pregnancies		Ectopic: delivery ratio	Ectopic pregnancies per 1000 pregnancies (rate)	No of deaths from ectopic pregnancies	Death rate /1000 estimated ectopic pregnancies
	Unit	UK	Unit	UK	UK	UK
1994–1996	46	33,550	1:130	11.5	12	0.358
1997–1999	38	31,946	1:173	11.1	13	0.407
2000–2002	55	30,100	1:109	11.0	11	0.365
2003–2005	57	32,100	1:117	11.1	10	0.312
2006–2008	56	35,496	1:132	11.3	6	0.169
2009–2011	72	37,650	1:526	11.0	2014 Cemace has early pregnancy mortality. Individual rate of mortality from ectopic pregnancy is not available

Unit: Northern Lincolnshire and Goole Hospitals, NHS Foundation Trust, Diana, Princess of Wales Hospital, Grimsby, UK.

Table 4.

Non-tubal ectopic pregnancy (adapted from Bolaji et al. ² ).

Term	Definitions	Incidence	Importance
Interstitial pregnancy a	The implantation of the conceptus within the interstitial portion of the fallopian tube which is surrounded by the muscular wall of the uterus 11	2% to 6% of all ectopic pregnancies	Account for almost a fifth of all deaths caused by ectopic pregnancies due to haemorrhage 12
Cornual pregnancy	The implantation of a blastocyst within the cornua of a bicornuate or septate uterus	Less than 1% of all ectopic pregnancies 13	Rupture of cornual pregnancy may happen at later gestations and therefore results in catastrophic haemorrhage
Cervical pregnancy a	The implantation of the conceptus within the cervix, below the level of internal os	Less than 1% of all ectopic pregnancies	Could be difficult to distinguish from cervical phase of miscarriage
Caesarean section scar ectopic	Implantation into myometrium of a deficient uterine caesarean section scar	1: 1800–2200 pregnancies 14	Those that progress into the third trimester are likely to be complicated by placenta previa/accrete 15
Ovarian pregnancy	Means implantation on the surface or inside the ovary	Around 0.5%–6.0% of all ectopic pregnancies 16	They are notoriously difficult to diagnose by ultrasound
Abdominal pregnancy	The implantation of the conceptus within the peritoneal cavity excluding the uterus, ovaries or fallopian tubes	Around 1% of ectopic pregnancies	Could be either primary, that is, pouch of douglas, bowel or omentum, or secondary, that is, originating as tubal pregnancies which then reimplant inside the abdomen 17

^aCervical and interstitial pregnancies are the most common form of ectopic pregnancies following artificial reproductive technology treatment.

Clinical presentation

The classic triad of symptoms are abdominal pain, amenorrhea and vaginal bleeding, which occur in only 50% of patients with index and REP. ⁶ In clinical presentation, the first case displayed the classic symptoms of EP, which are also the same for REP. Similar case reports of REP in patients from India and Iran supported this presentation.^6,18 However, in our case reports, the second case presented with brownish vaginal discharge as opposed to vaginal bleeding, which must be noted to avoid its exclusion from clinical diagnostic criteria. Hence, (lower) abdominal pain and delayed menstrual bleeding should be the two most important features to make a differential diagnosis of an index or REP.

There is a tendency for REP to more likely present at an earlier gestation, with a lower β-hCG level and less haemoperitoneum. The earlier gestation presentation is attributable to the robust safety netting and patient education on the risk of recurrence. Therefore, offering ultrasound at very early gestation could be a confounding factor. ⁷

Risk factors

The main risk factors for EP are tubal damage by pelvic infection or surgery, smoking, assisted reproduction^3,4,19 and other reproductive tract procedures that is use of intrauterine device (IUD) at conception. ⁴ Although identified risk factors for REP are previous occurrence of EP and abnormal anatomy of fallopian tube other definitive causes and risk factors remain unclear. ⁶ Understanding the risk factors of REP will help caregivers with the opportunity to counsel and evaluate patients and offer management options accordingly.

As per some case–control and cohort studies, Table 5 demonstrates a list of the summary of the risk factors for primary EP (PEP) versus risk factors for REP in Table 6. In theory, all risk factors for PEP should account for recurrence as well. A conspicuous risk factor noted in REP was history of previous tubal surgery or previous pelvic surgery. ⁵ One study proposed that history of PID was seen in both REP and PEP but, significant number of patients with REP had pelvic and peritubal adhesions. ¹⁹ They have inferred that this may suggest a substantial element of under diagnosis and treatment of PID. Hence, effective treatment of PID has its implications of PEP and thereby REP. In a case–control study that assessed subsequent REP pregnancies, patients who had two previous ectopic pregnancies by natural conception and treated with salpingectomy or salpingostomy were found to have a 10-fold increased risk of further REP as compared to those with one prior. ¹⁹ The same study findings revealed that compared to the patients in the PEP group, REP patients had significantly lower education (p = 0.001), higher proportion of previous infertility (p < 0.001) and significantly higher occurrences of pelvic and peritubal adhesions (p < 0.05). Further multiple regression analysis showed that lower educational background, nulliparity, history of salpingotomy were significant risk factors for REP. ⁵

Table 5.

Risk factors for primary ectopic.^3,4

Maternal age > 35

Smoking

Tubal damage by pelvic infection and pelvic surgery 3

Tubal ligation 3

History of sub-fertility 3

Assisted reproduction

History of exposure to diethylstilbestrol 3

Black ethinicity 3

Table 6.

Risk factors for recurrent ectopic pregnancy.^5,19–24

Low annual income 5 Lower educational background 19

Lack of contraception 19

Consanguinity20,23

Higher gravidity, previous miscarriage, higher number of previous abortions, previous dilatation and curettage, previous evacuation of retained products of conception3,5,20,21

Nulliparity, history of infertility or tubal infertility 19

Previous adnexal surgery or salpingotomy for previous EP 21

Pelvic adhesions noted at the time of primary ectopic management5,19

Tubal damage by pelvic infection, for example, Chlamydia trachomatis and salpingitis, pelvic surgery5,21,24

Previous medical management (e.g. methotrexate treatment) for previous EP 22

Late diagnosis of previous EP and developing complications 22

EP: ectopic pregnancy.

Management of REP

Management options for REP are like that of PEP. The choice could invariably depend on the management method employed in managing primary ectopic and the patient’s choice. Options include expectant, medical and surgical management, such as salpingostomy, fimbrial milking and salpingectomy. A retrospective cohort study showed a higher incidence of REP with medical management than with interventional management. ²² Among the surgical management, REP is more prevalent in the salpingostomy group than the salpingectomy group. ²⁵ In a 5-year follow-up cohort study, salpingectomy when compared to salpingostomy, and laparoscopy when compared with laparotomy, were found to be associated with a lower risk of REP. ²³ An extensive systematic review of randomised controlled trials (RCTs) has shown no significant difference in fertility prospective in salpingostomy compared with salpingectomy. ²⁵ Where the contralateral tube is appearing healthy, salpingectomy is favoured over salpingostomy.^3,25

Medical management with systemic methotrexate (MTX) represents an option for REP. However, there have been reports from a logistic regression analysis of study data of many patients with ectopic pregnancies treated with single-dose MTX. REP was the only independent variable found to be associated with treatment failure. Therefore, it is advisable to consider surgical options for managing REP ²⁴ where feasible unless the risks of surgery are higher than medical management. The site of the ectopic, gestation at identification, patient symptoms and co-morbidities significantly impacts the clinical decisions followed by patient choice. As such, there is no delineated mode of management of REP, and patient risk factors, choice and clinical feasibility should guide clinicians. ¹⁶

Managing cornual ectopic

In total, 2%–4% of EPs are cornual, while less-common forms include cervical, ovarian and peritoneal. Cornual pregnancy refers to the implantation and development of a gestational sac in one of the upper and lateral portions of the uterus. Conversely, an interstitial pregnancy is a gestational sac that implants within the proximal, intramural portion of the fallopian tube that is enveloped by the myometrium. Diagnosis is often difficult because the implantation site is still intrauterine in the cornua or intrauterine portion of the fallopian tube. ²⁶ Invasion through the uterine wall makes this pregnancy challenging to differentiate from an IUP on ultrasound. Because of their anatomical position, vascularity, risk of bleeding and incomplete resection, they are not always manageable surgically. Options around medical or surgical management are decisions made in light of gestation of diagnosis, HCG level and patient co-morbidities for surgery. Traditional cornual resection by laparotomy was an option. More conservative methods, such as cornuostomy by laparoscopy or laparotomy approach, are being performed with success ²⁶ with or without injecting vasopressin to reduce blood loss. Medical management methods with an option of injecting intra-amniotic injection of potassium chloride (KCl) and then intra-placental injection of MTX had good success.^27,28 Systemic MTX injection is another most common conservative treatment for managing early EP with a success rate of 91% and up to 66.7% in cornual ectopic.^29,27

Recurrence in cornual ectopic are extremely rare and their exact figures are unknown. ²⁹ The main etiological factor for recurrence is tubal disease and others are assisted conception and non-invasive management of cornual pregnancy. ²⁹ However there has been case report of recurrence of interstitial ectopic following surgical management of cornual ectopic. Most conservative surgical and medical management techniques do not remove the interstitial portion of fallopian tubes. It is advisable to be cognisant of persistent trophoblastic tissue and recurrence in future pregnancies. ²⁹

Managing ipsilateral tubal ectopic

Ipsilateral ectopic occurs after total salpingectomy or adnexectomy and can occur in either the isthmic part of the tube (stump ectopic) or the interstitial part of the tube. Isthmic EP is a gynaecological emergency, with mortality rates around 2.0%–2.5% in contrast to other ectopic pregnancies where mortality rates are around 0.14%. ³⁰ Ipsilateral tubal stump ectopic pregnancies give appearances similar to cornual ectopic. Various hypotheses have been postulated for ipsilateral ectopic pregnancies. These include transperitoneal migration of spermatozoa or embryo through the patent tube to the side of the damaged tube, the oocyte from the normal ovary may be fertilised normally in the patent tube and then later implant in the stump via intrauterine migration. It is also possible that despite the surgical excision of the tube following salpingectomy, there is some degree of patency in the remaining interstitial part. ³¹ There have been studies that endo-loop ligation is as good as electrosurgery for haemostasis, and it prevents visceral injury related to the use of diathermy.^32,33 It also enables reduced operating times and reduced postoperative pain. However, there are case-reports that endo-loop usage can lead to residual tubal stump due to technical difficulties. ³³ It has also been suggested that the use of electrosurgery to excise the proximal tube, followed by endo-loop for total salpingectomy to reduce the risk of recurrence of ectopic in tubal stump. ³³ The residual portion of the tube can be minimised by fulguration of the remnant stump.

Conclusion

REP has a significant impact on the reproductive health of patients. With a 10%–20% recurrence rate, once a patient has a history of EP, identifying any risk factors for future REP should be considered. This should start with the management of PE. Robust measures for identifying PID signs and prompt treatment with a test of cure and contact tracing should be the doctrine. Considering adhesiolysis, checking for tubal patency is an employable measure before planning future conception.

Ultrasound at very early gestation to locate the pregnancy is prudent. In cases of REP, medical management seems less effective. While medical management of cornual EP had a good success rate, the risk of failed treatment requiring repeat injections and increased risk of uterine rupture because of the eccentric location should be anticipated, and the patient counselled accordingly. Also, the need for repeated attendance for blood tests and patient compliance to this is a significant hurdle in the successful management of ectopic pregnancies. Gestation at which the EP has been identified has a momentous role to play as much as patient choice. All surgical management of ectopic pregnancies should justify a salpingectomy over salpingostomy unless the contralateral tube appears diseased.^3,13 Nevertheless the risk of recurrence is still high. At salpingectomy, care should be taken to ensure no residual tubal stump is left to avoid an ipsilateral tubal stump ectopic.