Ectopic pregnancy is defined as a pregnancy that has implanted at a site outside of the endometrial cavity. In 95% of cases, this will be in the fallopian tube (Elson et al, 2016). It was first described indirectly by Abulcasis in the late first century, but successful treatment was not documented until the late 1800s (Lurie, 1992). Its incidence in the UK has remained fairly stable over the last few decades at 11 in 1000 pregnancies (Rajkhowa et al, 2000); however, the incidence increases up to 3% in women presenting to early pregnancy units (Mavrelos et al, 2013). This increase highlights the importance and role of the early pregnancy unit and those working within it.
Ectopic pregnancy remains one of the main direct causes of maternal death. At a rate of 0.25 per 100 000 maternities, this is akin to eclampsia and pre-eclampsia (MBRRACE-UK, 2015). In lower resource countries, the mortality rate is up to ten times higher (Goyaux et al, 2003). It is therefore crucial that ectopic pregnancy is diagnosed and well managed, in order to avoid poor outcomes. The role of the midwife is important in this context, as they are often the first health professional to make contact with a woman when she is pregnant. An understanding of ectopic pregnancy is therefore essential for the midwife to help avoid morbidity and mortality.
Risk factors
There are many well recognised risk factors for ectopic pregnancies, which are described below. Nevertheless, it is important to remember that up to one-third of women with an ectopic pregnancy will not have an identifiable risk factor, so this should not be the focus of an encounter if there is a suspected ectopic pregnancy. The presence of a risk factor however, should raise the suspicion of an ectopic pregnancy for the clinician involved. Many women will ask what has caused them to have an ectopic pregnancy, and so being aware of the risk factors below will help explain causation. It may also present a public health opportunity to help promote lifestyle changes, such as smoking cessation, as this is a well known risk factor for ectopic pregnancy.
The highest risks associated with ectopic pregnancy include a previous ectopic pregnancy, tubal blockage and/or damage, and a history of infertility (Moini et al, 2014). Kashanian et al (2016) have shown that smoking increases risk five-fold. This is followed by previous chlamydia trachomatis infection, which accounts for a three-fold increased risk (Li et al, 2015).
Overall, having an intrauterine device reduces the risk of pregnancy, but if a patient is found to be pregnant with a device in situ, they are more likely to have an ectopic pregnancy. This is because the coil functions by preventing pregnancy from implantation in the endometrial cavity, but does not stop a pregnancy implanting in the fallopian tube. If a woman has a positive pregnancy test with a coil in situ, the chance of this being an ectopic pregnancy is up to 50% (Black et al, 2016).
In vitro fertilisation
Li et al (2015) have shown that in vitro fertilisation (IVF) carried out as a result of disease within the fallopian tubes carries a nine-fold increased risk of an ectopic pregnancy. If IVF is necessary for fertility problems other than diseased fallopian tubes, the risk is still increased but to a lesser degree. This becomes important at an initial booking visit by the midwife. Any mention of pain should raise the alarm of a possible ectopic pregnancy, particularly in circumstances of IVF. Perkins et al (2015) looked at a decade of IVF pregnancies in the USA and found the ectopic pregnancy rate ranged from 1.0% for fresh donor cycles, increasing to 2.0% for fresh, non-donor cycles (Li et al, 2015). Li et al (2015), however, found that this rate rose to 2.2% when two embryos were transferred, and to 2.5% (95% CI 2.42.6) with three embryos (Li et al, 2015). Similar rates of ectopic pregnancies with assisted reproductive technologies have been shown in the UK (Santos Ribeiro et al, 2016).
Other, less well associated risk factors include previous spontaneous miscarriages, a partner who smokes, multiparity, and increasing maternal age (Moini et al, 2014). These are all important to be aware of, not only for initial booking appointments in pregnancy, but also postnatally. Public health opportunities by midwives to offer smoking cessation advice and encouragement to both a woman and her partner are vitally important.
Scans for ectopic pregnancy
There is no screening for ectopic pregnancies in the general population. With rates of 12% of ectopic pregnancy among pregnant women, few of whom have risk factors, this may be questioned. In much of western Europe, early ultrasound scans are performed as routine. In the UK, however, early pregnancy units are already operating at maximum capacity, with demand increasing thanks to the increased accuracy of pregnancy tests. Not all units have managed to provide a seven-day service as recommended by the National Institute for Health and Care Excellence (NICE) (2013). Staffing numbers mean that placing further demands with screening is not possible, and there have been no studies on low-risk populations to know whether this would be of benefit.
Presentation
A triad of vaginal bleeding, pain and amenorrhoea may be the classical presentation, but one must be wary of atypical presentations. NICE guidance (2013) advises that women should be offered a pregnancy test even when symptoms are non-specific. These may include gastrointestinal or urinary symptoms in women of childbearing age. National investigations into maternal deaths have highlighted being wary of diarrhoea as a symptom in the presentation of ectopic pregnancy (MBRAACE-UK, 2015). Ayim et al (2016) have shown that the ectopic pregnancy rate is only 1.5% if there is no pelvic pain, no diarrhoea and the duration of bleeding is less than or equal to 3 days, although this increases to 5% in the presence of one risk factor, 8% with two risk factors and 9% with three risk factors (Ayim et al, 2016). This same group have also demonstrated that duration of bleeding was an independent risk factor. For every day of bleeding, the risk of an ectopic pregnancy increased by 20% (Ayim et al, 2016).
‘It is crucial that ectopic pregnancy is diagnosed and well managed. The role of the midwife is important, as they are often the first health professional to make contact with a woman when she is pregnant. An understanding of ectopic pregnancy is therefore essential’
NICE recommends that early pregnancy units are open seven days a week (NICE, 2013). Having access to early pregnancy units means that presentation with acute collapse is uncommon, as the majority of women present before ending up in extremis. It also means that women who have had a previous ectopic pregnancy will know where to access help for follow-up and any subsequent pregnancies. The psychological impact following an ectopic pregnancy should not be underestimated and the early pregnancy unit is a bastion of expertise in supporting these patients.
If a women presents at her booking appointment with symptoms of pain and or bleeding, an urgent referral to the early pregnancy unit should be sought. If pain is present and the early pregnancy unit cannot be contacted, they should be referred to the on-call gynaecology team and triaged through accident and emergency (A&E).
Diagnosis
Transvaginal ultrasound scan has now superseded surgery as the gold standard for diagnosis (Elson et al, 2016). Diagnosing a tubal ectopic pregnancy by transvaginal ultrasound scan is done in two steps. Firstly, an intrauterine pregnancy is excluded by the absence of a gestation sac in the uterine cavity. Secondly, an extrauterine ectopic pregnancy is demonstrated, either as an inhomogenous mass or as a developing gestation sac with or without a yolk sac or fetal pole separate to the ovary. The fetal pole may even exhibit cardiac activity. The majority of ectopic pregnancies will be present as an inhomogenous mass (Figure 1), while 20% will have a hyperechoic ring, and 13% are viable, having a gestational sac and a fetal pole that may exhibit cardiac activity (Winder et al, 2011).
Most ectopic pregnancies will be detected on the first transvaginal ultrasound scan, which has been shown to demonstrate 99% sensitivity (Condous et al, 2005, Kirk et al, 2007). An ectopic pregnancy may be too small to be seen at the first ultrasound scan, and it is only on a subsequent ultrasound scan that it would become visible.
The appearance of the endometrium can also help guide the diagnostician during the transvaginal ultrasound scan. When there is the presence of a triple line of the endometrium, this carries a 10% sensitivity and a 40% positive predictive value for an ectopic pregnancy (Wachsberg, 1998). Rombauts et al (2015) have shown that the risk of an ectopic pregnancy is increased four-fold when the endometrial thickness is less than 9 mm, compared to 12 mm or more. A common pitfall is to assume that a ‘pseudosac’ is actually an early gestation sac. Therefore, unless there is the characteristic echogenic ring around an anechoic collection of fluid that is eccentrically placed, high suspicion of an ectopic pregnancy should remain. In addition, the presence of echogenic fluid in the recto-uterine pouch (also known as the pouch of Douglas) represents haemoperitoneum, and can raise suspicions of an ectopic pregnancy. This is seen in up to 56% of ectopic pregnancies (Fleischer et al, 1990; Nyberg et al, 1991). The absence of blood certainly does not exclude an ectopic pregnancy. Anechoic fluid in the recto-uterine pouch is of uncertain significance and therefore cannot help with the diagnosis.
Human chorionic gonadotrophin
Human chorionic gonadotrophin (HCG) is produced from developing placental tissue. In a normal pregnancy, it would be expected to nearly double every 48 hours up to 1200 IU/L, making it detectable from as early as 1 week after conception (Surampudi et al, 2016). The higher the level, the more trophoblastic activity it represents, whether the pregnancy is ectopic or normal. A diagnosis of ectopic pregnancy cannot be made with a single blood HCG level (van Mello et al, 2012), but HCG levels have been advocated to raise clinical suspicion of an ectopic or failing pregnancy, based on a 48-hour interval when the initial ultrasound scan was a pregnancy of unknown location. Although one-quarter of ectopic pregnancies will exhibit a normal rise in HCG over 48 hours (Surampudi et al, 2016), a suboptimal rise of <63% is thought to be suspicious for an ectopic or failing pregnancy (NICE, 2013). Plateauing levels are seen in 1 in 5 cases, while a quarter will have a decrease of >15% (Surampudi et al, 2016).
The gold standard
Historically, the gold standard for diagnosis was at the time of surgery, with histological confirmation following removal of the ectopic pregnancy either by salpingectomy or salpingotomy. Good practice would dictate that is performed by a histopathologist after surgical removal. However, this can be done macroscopically at the time of surgery when a tubal ectopic pregnancy is visualised. If the ectopic pregnancy is too small, this can be missed at the time of the initial surgery. Negative laparoscopy rates varies from 1–6% (Muhammad et al, 2016; Berry et al, 2016). With the increased availability of early pregnancy units, high sensitivity of ultrasound scans and conservative management of ectopic pregnancies, surgery is no longer seen as the diagnostic gold standard.
Management
With more midwives working in early pregnancy units, it is important to be aware of the options available to manage tubal ectopic pregnancies. This can be split into three categories: expectant or conservative, medical, and surgical. A survey of early pregnancy units in the UK revealed that, in 2014, the majority (62%) of cases were still being managed surgically. A further 31% were being managed medically and 6% received expectant management alone (Odejinmi et al, 2015).
Conservative management
A recent conference on fertility highlighted that, in one London unit, expectant management has now reached 30% (Muhammad et al, 2016). Expectant management is suitable for women that have no or minimal pain, low or declining HCG levels, and who are able to attend for follow-up, according to the Royal College of Obstetricians and Gynaecologists (RCOG) (2016). Not only does this avoid surgery, but also the need for chemotherapeutic agent methotrexate, while the patient still manages to conserve the affected fallopian tube. Similar rates of success have been shown when compared to medical management, numbered at around 76% (Muhammad et al, 2016), but this could even reach 100% in well-selected cases (Craig et al, 2012). Success has been shown to directly correlate with HCG levels: the higher the level, the less likely conservative management is to be successful. If initial HCG is less than 1000 IU/L, success rates of up to 90% can be expected (Shalev et al, 1995; Cohen et al, 1999).
Medical management: Methotrexate
Medical management of tubal ectopic pregnancy is advocated for similar indications to expectant, but higher HCG levels of up to 5000 IU/L are tolerated. A single injection of methotrexate can be given systemically or directly via ultrasound (there is not enough evidence to advocate one route over the other). Multiple injections can also be given as necessary. Follow-up is required, with HCG levels recorded initially and on days 4 and 7. It is expected that the HCG level would fall by more than 15% between days 4 to 7 (RCOG, 2016). Certain caveats to in order to undergo methotrexate treatment use are required: the woman must live locally and be able to attend for follow-up, and should be advised not to try to conceive for 3 months after first dose. A woman's liver function should be normal in order to undergo this treatment, and she should not take alcohol or folic acid supplements (RCOG, 2016). Methotrexate is a chemotherapeutic agent and as such carries some adverse effects that women must be warned of—commonly, flatulence, bloating and stomatitis. More rarely, patients may experience pneumonitis, bone marrow suppression, pulmonary fibrosis, liver cirrhosis, renal failure and gastric ulceration (Joint Formulary Committee, 2016).
Women should be told that follow-up may last for weeks, depending on initial HCG levels. HCG levels of <3000 IU/L correlate with a mean of 26 days follow-up, compared to 42 days when the HCG is >3000 IU/L (Richardson, 2012). The serum hormone level may also help gauge the likelihood of a repeat methotrexate injection: when levels are <3000 IU/L, 10% of women will require a further dose, which doubles to almost 22% if levels are >3000 IU/L (Richardson, 2012). These trends also apply to whether subsequent surgery is required: a 4.5% likelihood with the lower titres, compared to 15% if higher (Richardson, 2012). Success rates have been shown of up to 91% (Lipscomb et al, 2009).
Capmas and Fernandez (2015) have examined an epidermal growth factor receptor inhibitor combined with methotrexate to see if its efficacy can be improved. Initial results are promising but more robust randomised control trials are awaited.
Case study
Mary was a 22 year-old woman who was referred to the early pregnancy unit via accident and emergency (A&E) at 6+6 weeks' gestation in her first pregnancy. She had abdominal pain and a positive pregnancy test. The HCG level was found to be 1858 IU/L. A transvaginal ultrasound scan was performed, which demonstrated an inhomogenous mass in her right tube with some evidence of haemoperitoneum (Figure 1). Mary was therefore advised by the early pregnancy unit to undergo a laparoscopic right-sided salpingectomy as an emergency procedure, which was done the same day. The procedure was uneventful and she went home the next day with follow-up by the early pregnancy unit.
A follow-up consultation took place the following week with the early pregnancy unit nurse. The diagnosis and management of Mary's case were reviewed, which proved important as the emergency situation had made it difficult for Mary to take on board exactly what had happened and the future implications. The consultation gave Mary the opportunity for clarification and to ask further questions. A patient information leaflet on ectopic pregnancies by the Royal College of Obstetricians and Gynaecologists was provided. Mary was also advised to inform the early pregnancy unit the next time she had a positive pregnancy test. This will enable her to receive help and support, as well as a timely diagnosis in the event of a subsequent ectopic pregnancy.
Surgical management
The majority of women are still managed surgically. This remains the first-line management for those women that are symptomatic with pain or for those who choose it. The surgical options are either a salpingectomy to remove the affected fallopian tube and ectopic pregnancy, or a salpingotomy, where a hole is made in the tube to remove the ectopic pregnancy while conserving the affected fallopian tube.
If the contralateral tube is normal, salpingectomy for the affected tube with the ectopic pregnancy is advised (Mol et al, 2014). However, if it appears abnormal or if the woman has had a previous ectopic pregnancy, salpingotomy is advised based on improved future pregnancy rates (75% versus 40%) (Mol et al, 2014). A disadvantage of salpingotomy over salpingectomy is the small risk of persistent trophoblastic tissue, and the need for a longer follow-up period to monitor HCG levels until they return to normal. If this does not occur, a salpingectomy may then become necessary.
Laparoscopy is generally the accepted method in a haemodynamically stable patient. Even when faced with haemoperitoneum (>800mls), laparoscopy has been shown to be safe, with shorter operating times (50 versus 60 minutes) and blood loss (1000 mls versus 1500 mls) compared to laparotomy (Cohen et al, 2013). No difference was seen when comparing need for blood products, length of stay or perioperative complications (Cohen et al, 2013).
Psychological treatment
The psychological impact for women who undergo treatment for ectopic pregnancy should not be underestimated. More often that not, women find out that they are pregnant, and are then told that it is an ectopic pregnancy, resulting in a grief reaction (Purandare et al, 2012). This is why written information, follow-up and knowing where to access counselling is so crucial for these women. Self-help groups and the Ectopic Trust can also provide help. Follow-up should be planned with the local early pregnancy unit and referred by the team looking after the woman. Ensuring that a woman does not get lost to follow-up may be a key role for a midwife, and due to the increased risk of an ectopic pregnancy in any subsequent pregnancies, this is an important safety net for women.
Long term implications
One of the first questions women ask after being diagnosed with an ectopic pregnancy is whether it will it affect their future fertility. The majority of women will go on to conceive after an ectopic pregnancy, with ongoing pregnancy rates of 56% after a salpingectomy and 61% after a salpingotomy in the 6 months following surgery (Mol et al, 2014). It is important that women are aware that although they may be able to conceive again, they are also at increased risk of having an ectopic in subsequent pregnancies. Recurrence rates vary, from 5% after a salpingectomy to 8% after a salpingotomy (Mol et al, 2014). Fernandez et al (2013), however, found no difference on future fertility when comparing conservative, medical or surgical management of ectopic pregnancy. This is very important when counselling women with regards to their options.
Women with recurrent ectopic pregnancies were analysed by Hurrell et al (2016). They found that for recurrent ectopic pregnancies, women were older by an average of 2 years, and presented at earlier gestations (generally before 6 weeks) with a significantly lower HCG level of 3176 IU/L on average. Risk factors of previous tubal or pelvic surgery were also thought to be far more likely. Health professionals should therefore be vigilant when women present early with symptoms. It is also necessary to be aware of these risk factors when booking patients in subsequent pregnancies.
There is a dearth of evidence to help advise women when to conceive following an ectopic pregnancy. Most health professionals advise to wait for a least three months, or two full menstrual cycles, before trying to conceive, but the actual evidence behind this is lacking. When advising women, the psychological impact must be taken into account, as some women may be frightened of becoming pregnant again due to the worry of another ectopic pregnancy.
RCOG guidance (Elson et al, 2016) states that women should have access to an early pregnancy unit, where care can be streamlined and women cabe be looked after by specialists to avoid delay in diagnosis.
Conclusion
Tubal ectopic pregnancy remains an important diagnosis in the early pregnancy setting due to the associated morbidity and mortality. Transvaginal ultrasound scan has replaced surgery as the diagnostic tool of choice. Earlier detection has seen the increase in expectant management allowing women to conserve their fallopian tube, although surgery remains the first line management in symptomatic patients. The role of the midwife as the first point of contact for many pregnant women means that knowledge of ectopic pregnancy is absolutely crucial. Not only will it aid prompt diagnosis and help woman through their patient journey, it may even save lives.