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Management of ectopic pregnancy: a clinical approach
Case-based learning
Management of ectopic pregnancy: a clinical approach
100 000 maternities (Table 1). This is obviously disappointing, particularly as 70% of the deaths related to ectopic pregnancy in the last Confidential Enquiry were associated with substandard care. Maternal death also reflects the speed at which complications can occur and how rapidly a patient can deteriorate. Each department should develop protocols for the surgical and medical management of ectopic pregnancy (grade C recommendation) and training should be available to ensure surgeons can safely provide both laparoscopic and open surgery for the management of ectopic pregnancy. Ectopic pregnancy is expected to increase in parallel with higher rates of sexually-transmitted disease and the increased availability and use of assisted conception. Continued improvements in ultrasound and its application together with rapid access to serum human chorionic gonadotrophin (hCG) monitoring have increased the accuracy of diagnosis and may have contributed to an apparently increased incidence, although the number of ectopic pregnancies appears relatively stable over the past 10–15 years. Whilst ectopic pregnancies have classically been confirmed laparoscopically, recent advances in transvaginal ultrasonography, coupled with the introduction of sensitive serum hCG measurements, allows the diagnosis to be made without the need for laparoscopy in many cases. Laparoscopy has become the main form of treatment, although expectant management and medical treatment are valid options. The following series of hypothetical clinical cases has been designed to demonstrate the various steps in the management of a woman with a suspected or proven ectopic pregnancy. They could form the basis of a short answer in the MRCOG exam or be used to prepare for the OSCE. We suggest you consider each scenario and mentally formulate an answer before reading the discussion and explanation.
Nick Raine-Fenning James Hopkisson
Abstract Ectopic pregnancy is a common problem and one that is expected to increase in parallel with higher rates of sexually-transmitted disease and the increased availability and use of assisted conception. Continued improvements in ultrasound and its application, together with rapid access to serum human chorionic gonadotrophin (hCG) monitoring, have increased the accuracy of diagnosis and may have contributed to an apparently increased incidence, although the number of ectopic pregnancies appears relatively stable over the past 10–15 years. Laparoscopic surgery, rather than open surgery, is now the main method of treatment, although the medical treatment of ectopic pregnancy through the administration of methotrexate is popular in a number of centres. However, whilst the methods used for the diagnosis and management of ectopic pregnancy have changed significantly over the past 20 years, the death rate remains largely unchanged. This partly relates to substandard care, but also reflects the speed at which complications can occur and how rapidly a patient can deteriorate.
Keywords conservative management; ectopic pregnancy; follow-up; maternal mortality; methotrexate; surgical intervention
Introduction
Case 1
Ectopic pregnancy is relatively common and complicates around 1% of all pregnancies (10.9–11.1 per 1000 pregnancies). Fortunately, most of the women affected by ectopic pregnancy do not die: the estimated death rate is around 1 in every 300 000 ectopic pregnancies. Nevertheless, it remains an important cause of maternal morbidity and mortality, as 10 women died as a direct result of ectopic pregnancy between 2003 and 2005 according to the Confidential Enquiry into Maternal and Child Health (CEMACH) entitled Saving Mothers’ Lives. Whilst there appears to have been a steady decline in the number of deaths related to ectopic pregnancy since the late 1980s, when 15 women died in the triennium 1988–1990, the maternal death rate has actually remained largely unchanged at an approximate rate of 0.5–0.6 per
A 32-year-old Afro-Caribbean woman is referred to the Early Pregnancy Assessment Unit (EPAU) as she has developed lower abdominal pain and is known to be pregnant. She is unsure of the date of her last menstrual period but thinks she is around 6 weeks’ pregnant. The pain is in her lower abdomen and is not like a period. She has not had any bleeding. She is medically fit and well and has no risk factors for ectopic pregnancy. She is haemodynamically stable and has a soft abdomen on examination. Pelvic assessment, by speculum and bimanual examination, is unremarkable. A urinary pregnancy test confirms she is pregnant. What would you do next? This patient needs an ultrasound scan. An abdominal ultrasound may be sufficient and should be performed first, but a transvaginal ultrasound scan is required in many cases. The transvaginal transducer allows the user to be closer to the organs of interest and this facilitates the use of higher frequency ultrasound which improves spatial resolution and diagnostic capability. Ultrasound confirms pregnancy in the majority of cases and negates the need for measurement of the serum hCG level. Unfortunately, many junior doctors and staff working with patients of reproductive age request a quantitative hCG level, which is an unnecessary
Nick Raine-Fenning MBChB MRCOG PhD is a Consultant Gynaecologist and Associate Professor in Reproductive Medicine, Nottingham University Hospitals NHS Trust, Queen’s Medical Centre Campus, Nottingham, UK. James Hopkisson is a Consultant Gynaecologist at Nottingham University Research & Treatment Unit in Reproduction (NURTURE), Nottingham University Hospitals NHS Trust, Queen’s Medical Centre Campus, Nottingham, UK.
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Estimated incidence of ectopic pregnancy and related deaths (taken from CEMACH 2003–2005 report) Triennium
Total estimated pregnancies
Total estimated ectopic pregnancies
Ectopic pregnancies per 1000 pregnancies Rate
England and 1988–90 UK 1991–93 1994–96 1997–99 2000–02 2003–05
Wales 2 880 814 3 2 2 2 2
141 917 878 736 891
667 391 018 364 892
Deaths from ectopic pregnancies
95% CI
Death rate per 100 000 estimated ectopic pregnancies Rate
95% CI
24 775
8.6
8.5–8.7
15
0.52
0.31–0.86
30 33 31 30 32
9.6 11.5 11.1 11.0 11.1
9.5–9.7 11.4–11.6 11.0–11.2 10.9–11.1 10.9–11.1
9 12 13 11 10
0.29 0.41 0.45 0.40 0.35
0.15–0.55 0.24–0.72 0.26–0.77 0.22–0.72 0.19–0.64
160 550 946 100 100
Table 1
Measurement of serum progesterone may provide additional information in cases of pregnancy of unknown location (grade B recommendation). Levels below 25 nmol/L are invariably associated with non-viable pregnancies and the spontaneous resolution of pregnancy of unknown location, but this should not be used to guide intervention as viable pregnancies have been reported with low levels. Levels above 25 nmol/L are ‘likely to indicate’ and above 60 nmol/L are ‘strongly associated with’ pregnancies subsequently shown to be normal, although local laboratories may need to define their own levels. Results must be interpreted with caution and discussed with someone familiar with their use. The ultrasound scan should be conducted in a rigorous and methodical manner. The report is important and must provide detailed information to allow the appropriate management of patients. Unfortunately, many ultrasound reports are unclear and contain limited information. A report that states an ‘apparently empty sac is placed eccentrically in the fundus in association with a double-ring pattern’ suggests the presence of an intrauterine pregnancy and such information may make a difference to the decision to treat. Less informative are statements such as ‘an ectopic pregnancy cannot be excluded’ or ‘there is a possible intrauterine pregnancy’. Ultrasonographers and medical staff should be encouraged to document what they find in detail and to avoid open statements. The report may contain the opinion of the ultrasonographer which is acceptable and preferable, as it modifies the likelihood ratio for the presence of an ectopic or intrauterine pregnancy and does not incriminate the person making the comment. Once an ultrasound scan has revealed that there is no obvious intrauterine pregnancy and a mass, along with an hCG level greater than 1000 iu/L, the diagnosis is easier to make in the absence of symptoms.
and expensive test in the 70–90% or more of patients who are shown to have a viable or non-viable intrauterine pregnancy, an incomplete miscarriage or an ectopic pregnancy on ultrasound. Serum hCG levels are only useful in those patients where the location of the pregnancy cannot be confirmed or when a non-viable ectopic pregnancy has been confirmed ultrasonographically in an asymptomatic patient, and expectant or medical management is being considered; this is discussed below. Pregnancy of unknown location, defined as ‘no signs of either intra- or extra-uterine pregnancy or retained products of conception in a woman with a positive pregnancy test’, occurs in approximately 8–31% of pregnancies. Rates are lower, around 10%, in departments with a specialized scanning service or if the patient is assessed by an expert, and can be kept to a minimum by the critical application of transvaginal ultrasound and strict diagnostic criteria. The serial measurement of serum hCG is particularly useful in the diagnosis of asymptomatic ectopic pregnancy (grade B recommendation) and pregnancy of unknown location. The use of a ‘discriminatory zone’ for serum hCG above which an intrauterine pregnancy should be expected to be seen is recommended and employed by most units, but needs to be set and reviewed locally. An ectopic pregnancy will usually be visualized on transvaginal ultrasound when the hCG level is above 1500 iu/L but often occurs in association with lower levels, particularly those that plateau. The absence of an intrauterine gestation sac and an hCG titre of between 1000 and 1500 iu/L has been shown to be highly predictive of ectopic pregnancy (sensitivity 0–95%, specificity 95%). With an odds ratio of having an ectopic of 24.8, this makes intervention rather than expectant management appropriate. It is important to consider ectopic pregnancy in all cases where an intrauterine pregnancy has not been definitely confirmed by ultrasound, as ectopic pregnancy may occur in as many as 6% of women who give a good history and have ultrasound findings suggestive of a complete miscarriage. Access to serial serum hCG estimation is essential therefore and the results should be available within 24 h. All staff involved in the management of patients with early pregnancy problems must be able to interpret single and serial hCG levels and be aware of the limitations of monitoring.
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The ultrasound scan confirms the presence of an ectopic pregnancy. What would you do now? Whilst the diagnosis of ectopic pregnancy was classically made laparoscopically, recent advances in transvaginal ultrasonography, coupled with the introduction of sensitive serum hCG measurements, allows the diagnosis to be made without the need for laparoscopy. Indeed, laparoscopy is generally reserved for the surgical treatment of ectopic pregnancy, although there 20
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are equally effective non-surgical options. Ectopic pregnancies often follow a benign clinical course which allows a conservative approach to management in many cases. Options include expectant and medical treatment. Expectant management is only an option if the woman is asymptomatic and clinically stable. It is successful in around two-thirds (∼67%) of women and is more likely to be effective if the initial hCG level is less than 1000 iu/L or if the levels are decreasing rapidly. The presence of a mass on ultrasound does not preclude expectant treatment, but an extrauterine gestational sac reduces the chance of success by 5.6 times and treatment is not recommend if there is evidence of more than 100 ml of fluid in the pelvis, although this can be difficult to measure reliably and accurately. A detailed pre-treatment ultrasound assessment is important, and should be used to measure the size of the mass, qualify its contents and quantify the amount of free fluid in the pouch of Douglas. Follow-up is essential and involves twice-weekly assessment of the hCG level and weekly transvaginal ultrasound examinations, which should show a reduction in the average diameter of the adnexal mass by day 7; a good prognostic indicator of successful treatment and resolution. Weekly monitoring is required until serum hCG levels are less than 20 iu/L. If expectant management is not an option, medical therapy with methotrexate should be considered and offered to suitable women and if there are treatment and follow-up protocols for its use (grade B recommendation). Methotrexate is a chemotherapeutic agent that inhibits the enzyme dihydrofolate reductase; it therefore targets rapidly dividing tissue such as trophoblast by preventing the synthesis of purine nucleotides. It can be administered intravenously, intramuscularly or locally via injection directly into the ectopic pregnancy. There is no consensus on the best treatment protocol for its use. In 1999, the American College of Obstetrics and Gynecology produced a guideline for the medical management of ectopic pregnancy. Relative indications were that the ectopic should be less than 3.5 cm in diameter and show no cardiac activity, and that the hCG level should be between 6000 and 13 000 iu/L. Methotrexate is usually given as a single intramuscular dose calculated according to the patient’s body surface area (50 mg/ m2), and is somewhere between 75 and 90 mg for the majority of women. The effectiveness of treatment is evaluated by the serial measurement of serum hCG levels which are checked 4 and 7 days after treatment in initiated. A second dose may be given if the hCG levels do not fall by more than 15% over this time period, and is required in about 14% of women. Common side effects relate to the effect methotrexate has on mucosal surfaces and include conjunctivitis, stomatitis and gastrointestinal upset (Table 2). Women must be made aware of these symptoms and informed that further treatment may be necessary. A multidose protocol, which involves giving 1 mg/kg of methotrexate intramuscularly and alternating this with leucovorin 0.1 mg/kg for four doses of the drugs, is also available. In a meta-analysis comparing the single- and multi-dose regimens, the overall success rate for women treated with medical management of their ectopic pregnancy was 89% (1181/1327). The single dose was associated with a higher failure rate than the multidose regimen (OR 4.74, 95% CI 1.77–12.62). In the singledose regimen, 14% of women required a second dose but these
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Side effects of methotrexate therapy • Nausea and vomiting • Stomatitis • Diarrhoea • Abdominal pain • Pneumonitis • Impaired liver function tests • Alopecia • Neutropenia Table 2
women demonstrated fewer failures. In the multidose regimen, 53.5% of women received three or more doses of methotrexate. The single-dose regimen seems to be the more common protocol, however, probably because it requires fewer trips to hospital and facilitates compliance. Attempts have been made to predict the need for further treatment, regardless of whether that involves additional methotrexate or surgery (Table 3). The need for further treatment seems to relate to the baseline serum hCG concentration at presentation and medical treatment is not recommended when levels are higher than 3000 iu/L, although this is based on quality-of-life data. If the ectopic pregnancy is viable, as evident from the presence of cardiac activity, treatment is less likely to succeed. It is important to remember that these represent relative contraindications to medical therapy, and methotrexate can be used if there are exceptional circumstances or if the patient specifically wants medical treatment and is prepared to accept the associated risks and higher chance of failure and is aware of the potential need for prolonged follow-up. The medical management of patients with an ectopic pregnancy must be conducted by healthcare practitioners with knowledge and experience as it can be difficult and requires a certain degree of clinical acumen. The concentration of hCG increases initially and should be lower on day 7 than day 4. This transient increase is expected but it can confuse clinicians unfamiliar with the use of methotrexate. Whilst tubal rupture will only occur in around 7% of women during follow-up, the majority (∼75%) experience some degree of abdominal pain which is attributed to tubal miscarriage. Differentiating this ‘separation pain’ from pain due to tubal rupture is undoubtedly difficult and women should be admitted for observation and ultrasound assessment if there is any possibility of tubal rupture. Surgical intervention,
Factors increasing the risk of persistent trophoblast • Small ectopic pregnancies (<2 cm) • Early gestation (<7 weeks) • Rapid preoperative rise in serum hCG • High pretreatment hCG levels (43 000 iu/L) • Presence of active tubal bleeding • Milking of the ectopic pregnancy from the tube Table 3
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and the data must be interpreted with caution as they are derived from a series of studies with different subject populations, variable surgical procedures and inconsistent follow-up protocols. It is possible that there is a higher subsequent intrauterine pregnancy rate after salpingotomy but the magnitude of this benefit may be small. If the contralateral tube is damaged, laparoscopic salpingotomy should be considered as the primary treatment if there is a desire for future fertility (grade B recommendation). Under these circumstances salpingotomy is associated with greater subsequent intrauterine pregnancy and is more cost-effective in the long term as it allows the woman the chance to conceive without assisted reproduction treatment (ART). The short-term costs of salpingotomy are greater than salpingectomy however, due to the need for postoperative follow-up because of the potential risks of persistent trophoblast. It is essential that any woman treated in this way is informed that there is an approximate 20% risk of recurrence of ectopic pregnancy. Spontaneous conception is increasingly unlikely to happen if it has not occurred within 18 months of the salpingotomy and ART should be considered under such circumstances. Salpingotomy may be more effective if performed as an open procedure. Laparoscopic salpingotomy appears less successful in elimination of the tubal pregnancy (RR 0.90, 95% CI 0.83–0.97) than salpingotomy performed at laparotomy and is associated with higher rates of persistent trophoblast (RR 3.6, 95% CI 0.63–21.0). There may be a reduction in the number of repeat ectopic pregnancies after laparoscopic salpingotomy, however (RR 0.43, 95% CI 0.15–1.2), and at present there is insufficient evidence to warrant opening the abdomen to perform a salpingotomy which would increase intra- and post-operative morbidity considerably. The decision to perform a salpingectomy or a salpingotomy will also depend on the size of the ectopic pregnancy and the degree of damage to the affected tube. In some cases the ectopic pregnancy cannot be removed without inflicting considerable damage to the Fallopian tube, which may need to be removed if there is extensive or uncontrollable bleeding. The use of conservative surgical techniques exposes women to a small risk of tubal bleeding in the immediate postoperative period and the potential need for further treatment for persistent trophoblast. These issues must be discussed with the patient prior to surgery and following any operative intervention. The patient should be involved in the decision-making process whenever possible. Women should be advised of the potential advantages and disadvantages associated with the different approaches and treatments.
however, is required in less than 10% of women. Medical and expectant management must only be offered, therefore, if there are facilities for the woman to contact the unit and return easily for assessment at any time during follow-up (grade B recommendation). Treatment can be offered on an outpatient basis. This can be convenient and more acceptable to the woman and is associated with an approximately 50% reduction in the treatment cost compared to laparoscopic surgery, although this is dependent on the duration and intensity of follow-up, which will vary on a case-by-case basis. Women should also be advised to avoid sexual intercourse during treatment and to drink to thirst but to ensure they do not become dehydrated. All women must be provided with a reliable form of contraception for at least 3 months after methotrexate has been given. All women managed non-surgically should be counselled regarding the importance of compliance with followup and surgical treatment offered if this is likely to be an issue for geographical or social reasons. If the woman is not suitable for expectant or medical management, surgery must be considered. If surgery is indicated, a laparoscopic approach is recommended and preferred to an open approach if the patient is haemodynamically stable (grade A recommendation). This is because it is associated with less intraoperative blood loss, shorter operation times and lower analgesic requirements, all of which result in shorter hospital stays. Contrary to popular belief, there is no evidence to suggest that the laparoscopic approach is associated with less negative effects on the patient’s subsequent fertility or more favourable outcomes if pregnancy does ensue. Tubal patency rates are similar between the two approaches (RR 0.89, 95% CI 0.74–1.1), as are subsequent intrauterine pregnancy rates (RR 1.2, 95% CI 0.88–1.15). All operative procedures for ectopic pregnancy require an appropriately trained or supervised surgeon and are dependent on their skill and that of their assistants and the equipment available to them. Medical staff should be competent to manage ectopic pregnancy by open and laparoscopic methods. All surgeons must have attended an appropriate Royal College of Obstetricians and Gynaecologists (RCOG)-approved course in basic or intermediate laparoscopic skills and to be aware of how to use monopolar and bipolar diathermy safely. A decision is made to perform a laparoscopy. This reveals an unruptured right-sided ectopic pregnancy. How would you proceed? The whole pelvis must be inspected in detail. This requires the introduction of a second port, which is usually inserted suprapubically or laterally in the lower abdomen, to allow the introduction of an instrument to mobilize the pelvic organs and to remove any excess blood which can reduce the efficiency of the light source through absorption and limit the view. The contralateral tube must be inspected prior to any decision about how to proceed surgically. If the contralateral tube appears healthy, there is no clear evidence that salpingotomy should be used in preference to salpingectomy (grade A recommendation). This reflects studies which have shown no differences in the subsequent rate of intrauterine pregnancy and possibly a slightly higher chance of ectopic pregnancy. This is not logical as a higher fecundity would be expected in women treated conservatively
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How would you modify the initial management of this patient if she had been tachycardic and hypotensive? The patient must be appropriately and rapidly resuscitated. This requires the insertion of two large-bore cannulae and the infusion of crystalloid or blood if significant haemorrhage is thought to have occurred. Resuscitation can take place whilst the patient is being prepared for theatre and should not delay surgical intervention, although this cannot and must not go ahead until the patient is stable and the anaesthetic team is happy. Once the patient is stable she must be managed by the most expedient method if there is any evidence of haemodynamic 22
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week after surgery, many chose to start serial assessment 7 days after surgery. Methotrexate is recommended if levels fail to fall as expected. Repeat surgery is occasionally required and this may be performed laparoscopically or as an open procedure. The patient must be informed of the risks and strongly encouraged to see her general practitioner (GP), or preferably to return to the gynaecology ward or EPAU if she develops abdominal pain or persistent bleeding. The incidence of persistent trophoblast and the need for treatment partly depend upon the frequency of postoperative measurements and the cut-off used for the definition of persistence. Several factors increase the risk of persistent trophoblast (Table 3) but follow-up is required in all patients managed conservatively. Persistent trophoblast is very rarely seen with salpingectomy and follow-up is not required unless there were any concerns at the time of the operation. The psychological impact of an ectopic pregnancy is different for all couples and is difficult to predict, but may seriously affect a significant proportion of women and their partners. General follow-up is not always necessary, but should be offered to all patients as it provides an opportunity to discuss events and to assess postoperative recovery. This is also a more appropriate time to discuss the affect surgery may have had on the patient’s fertility, although this may be discussed, and invariably is, in the immediate postoperative period. Time to digest such information is needed and the patient and her partner should be given information leaflets and made aware of locally and nationally available support services. The plan should be agreed with the patient, documented in the notes and conveyed to her GP via the initial discharge letter and a formal letter.
instability. In the vast majority of cases this will be via laparotomy, but there may be a role for operative laparoscopy in certain cases as long as the surgeon has the necessary expertise and the anaesthetic team is informed and in agreement. The aim should be to prevent further blood loss as quickly as possible. Obviously there is no role for methotrexate. Once the abdomen has been opened, or a laparoscope safely inserted, the pelvis needs to be carefully inspected before proceeding as described above. An adequate view may be precluded by the presence of a large pneumoperitoneum and this must be addressed through the use of suction and irrigation. If this cannot be performed quickly or safely endoscopically, the abdomen must be opened to ensure further bleeding is stopped. The consultant gynaecologist on call must be informed and involved in the care of the patient. A team leader should be identified to ensure good communication. The timing of events must be noted and recorded and the whole event documented in detail, although this is often done in retrospect due to the urgency of the situation. How should the patient be managed following interventional surgery? The patient must be monitored in recovery in theatre and kept there until all vital signs are stable. Blood may already have been given but the need for transfusion should be considered if it has not. This can be a difficult decision as there are no absolute requirements and patients should be managed on a case-by-case basis. The estimated intraoperative blood loss, vital signs and the patient’s current and preoperative haemoglobin and haematocrit will inform the decision. In some cases, invasive monitoring is required, and these patients should be transferred to high dependency or intensive care in liaison with the anaesthetic team. Pain relief should be provided, ideally through a patient-controlled device, but the amount will depend on whether laparoscopic or open surgery has been performed. An indwelling urinary catheter will be required after a laparotomy and the need for thromboprophylaxis should be considered. Once stable and competent to understand, the patient and her partner or immediate family should be debriefed as to what has happened and given reasons for the route and type of surgery performed. The need for anti-D immunoglobulin should be considered and 250 iu (50 μg) given to non-sensitized women who are Rhesus negative (evidence level IV). If salpingostomy has been performed there is need for early postoperative follow-up to exclude the presence of persistent trophoblast as a result of incomplete removal; this occurs in 3–20% of cases. Persistent trophoblast is detected and defined as ‘the failure of serum hCG levels to fall as expected after initial treatment’. Management is based on the observation that whilst hCG levels often return to normal uneventfully, cases of delayed haemorrhage due to persistent trophoblast do occur. Follow-up involves serum monitoring of hCG levels. Once all trophoblastic tissue has been cleared, serum hCG levels fall and follow a predictable clearance curve over the next 2 weeks (range 2–49 days) to normal levels. It has been estimated that if there is a 50% fall in the preoperative hCG level, there is a less than 15% chance of persistent trophoblast. The time to initiate hCG monitoring is not universally agreed, but as persistent trophoblastic disease is unlikely to present or cause problems within the first
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Case 2 A 34-year-old woman receiving in-vitro fertilization (IVF) after two salpingectomies for ectopic pregnancy presented following her second cycle of IVF, after two-embryo replacement with a heterotopic pregnancy at the 8-week scan. Cardiac activity was noted in both the sacs. Using a three-dimensional scan, it was suggested that the sac was in the cornu, and this was confirmed at laparoscopy. The patient had undergone two laparotomies for removal of her previous ectopic pregnancies. The current ectopic was removed using bipolar diathermy and excision of the remaining portion of the tube. The remaining pregnancy progressed normally and the patient was delivered of a healthy female infant at 38 weeks by lower-segment caesarean section. Discussion Assisted reproductive technologies are associated with an increased number of ectopic pregnancies compared with spontaneous conception, the vast majority (82%) being tubal. Ectopic pregnancy following IVF and embryo replacement is associated with previous ectopic pregnancy, tubal disease and difficult embryo transfer. Heterotopic pregnancies (concomitant intrauterine and extrauterine gestations) are almost exclusive to assisted reproductive technologies. One study has shown an incidence of heterotopic pregnancy of 0.2% of 3500 cycles of IVF. In a study by Marcus et al, there were 20 heterotopic pregnancies in 2650 pregnancies. Of these, 45% were asymptomatic and 50% led to a live birth. The majority of the ectopics (17/20) were removed by 23
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salpingectomy, two were injected with potassium chloride and one resolved spontaneously.
Royal College of Obstetricians and Gynaecologists. The Management of Early Pregnancy Loss. Clinical Guideline No. 25. London: RCOG Press, 2006. Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F. Interventions for tubal ectopic pregnancy. Cochrane Database of Systematic Reviews 2007(Issue 1). Marcus SF, Macnamee M, Brinsden P. Heterotopic pregnancies after in-vitro fertilization and embryo transfer. Hum Reprod, 1995; 10: 1232–1236. Mol BW, Lijmer JG, Ankum WM, van der Veen F, Bossuyt PM. The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod 1998; 13: 3220–3227. Parker J, Bisits A, Proietto AM. A systematic review of single-dose intramuscular methotrexate for the treatment of ectopic pregnancy. Aust N Z J Obstet Gynaecol 1998; 38: 145–150. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboulghar H. Complications of medically assisted conception in 3500 cycles. Fertil Steril 1998; 70: 638–642. Tay JI, Moore J, Walker JJ. Ectopic pregnancy. BMJ 2000; 320: 916–919.
Case 3 A 24-year-old student nurse presented to the A&E Department with lower abdominal pain associated with diarrhoea and vomiting. The pain was increasing in severity and the patient felt faint. She was taking the progestogen-only pill as a form of contraception and had been having irregular bleeds since starting this. She told the staff that she did not think she could be pregnant and a pregnancy test was not undertaken. A junior doctor was asked to assess her and made a diagnosis of gastroenteritis. As the pain settled with simple analgesia the patient was allowed to go home and asked to contact her GP if things did not settle. She was found collapsed by her partner later that day when he returned home from work. He called an ambulance but the woman suffered a cardiac arrest on the way to the hospital and sadly was declared dead on arrival. Discussion There are several examples of substandard care in this tragic case. Unfortunately, this is not an uncommon situation and four of the women who died as a result of ectopic pregnancy in the latest Confidential Enquiry were misdiagnosed as they had gastrointestinal upset. It is essential that ectopic pregnancy is considered and excluded in any woman of reproductive age who presents with gastrointestinal disturbance and/or fainting. A pregnancy test was not undertaken and a positive result may have prompted the medical staff to contact the gynaecology team, or to arrange a pelvic ultrasound scan. Whilst all forms of contraception, including the intrauterine contraceptive device, decrease the risk of ectopic pregnancy as they decrease the chance of conception in the first place, ectopic implantation is much more likely when conception occurs in women using contraception, especially the intrauterine contraceptive device and the progestogen-only pill which reduces cilial motility. No form of contraception is 100% effective and a pregnancy test must be undertaken in all sexually-active women of reproductive age who present with abdominal pain, gastrointestinal upset or dizziness. In the event of a positive test, an ultrasound scan should be performed and a gynaecological opinion sought. A similar case described in the recent Confidential Enquiry was still misdiagnosed as gastroenteritis even after the patient was confirmed to be pregnant, which emphasizes the importance of further tests and re-evaluation. ◆
Practice points Assessment and diagnosis of suspected ectopic pregnancy • Incidence is relatively consistent at 10.9–11.1 per 1000 pregnancies • Diagnosis increasingly being made with transvaginal ultrasound and serial hCG measurements • Ultrasound is the primary investigation and the most informative • Serum hCG levels are not required in the majority of patients • Serum hCG levels are only useful in those patients where the location of the pregnancy cannot be confirmed ultrasonographically or when a non-viable ectopic pregnancy has been confirmed in an asymptomatic patient and expectant or medical management are being considered • Pregnancy of unknown location occurs in approximately 8–31% of pregnancies • The use of a ‘discriminatory zone’ for serum hCG above which an intrauterine pregnancy should be expected to be seen is recommended • An ectopic pregnancy will usually be visualized on transvaginal ultrasound when the hCG level is above 1500 iu/L but often occurs in association with lower levels, particularly those that plateau • Measurement of serum progesterone may provide additional information in cases of pregnancy of unknown location • With an hCG level >1000 iu/L and no intrauterine gestation sac, the odds ratio of having an ectopic pregnancy is 24.8. Intervention rather than expectant management is appropriate
Further reading Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing single dose and multidose regimens. Obstet Gynecol 2003; 101: 778–784. Grarcia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 2001; 97: 464–470. Lewis G, ed. Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer –2003–2005. The Seventh Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH, 2007. www.cemach.org. Royal College of Obstetricians and Gynaecologists. The Management of Tubal Pregnancy. Clinical Guideline No. 21. London: RCOG Press, 2004.
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General management of ectopic pregnancy • Management may be expectant, medical or surgical • Surgical treatment is suitable for all but certain criteria must be met for expectant and medical management • Follow-up is essential after expectant, medical, and conservative surgical management
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Expectant management of ectopic pregnancy • Only an option if the woman is asymptomatic and clinically stable • Is successful in around two-thirds (∼67%) of women • Is more likely to be effective if the initial hCG level is <1000 iu/L or if the levels are decreasing rapidly
Specific recommendations from CEMACH concerning early
pregnancy deaths
• Ectopic pregnancy is an important cause of maternal morbidity and mortality • Direct death related to ectopic pregnancy affects 0.5–0.6 per 100 000 maternities • Approximately 1 in every 300 000 women with an ectopic pregnancy dies • All patients must be appropriately and rapidly resuscitated in the first instance • Ectopic pregnancy must be considered/excluded in all women of reproductive age who present with diarrhoea and vomiting and/or fainting • Clinicians in primary care and emergency departments, in particular, need to be aware of atypical clinical presentations of ectopic pregnancy and the way in which it may mimic gastrointestinal disease. This needs to be highlighted in textbooks • Maternal deaths related to ectopic pregnancy are often due to substandard care • Medical treatment of ectopic pregnancy should be based on strict adherence to protocols, with women having immediate access to inpatient facilities if complications occur
Medical management of ectopic pregnancy • Methotrexate should be considered and offered to all women who meet certain criteria • Treatment may involve a single- or multiple-dose regimen • Treatment can be offered on an outpatient basis. • There must be treatment and follow-up protocols for its use • Tubal rupture occurs in around 7% of women during follow-up • 75% of women experience some degree of abdominal pain which is attributed to tubal miscarriage and differentiating this ‘separation pain’ from pain due to tubal rupture is undoubtedly difficult Surgical management of ectopic pregnancy • The contralateral tube must be inspected prior to any decision about how to proceed surgically • If the contralateral tube appears healthy, there is no clear evidence that salpingotomy should be used in preference to salpingectomy • If the contralateral tube is damaged, laparoscopic salpingotomy should be considered as the primary treatment if there is a desire for future fertility • Salpingotomy may be more effective if performed as an open procedure. • Training should be available to ensure surgeons can safely provide both laparoscopic and open surgery for the management of ectopic pregnancy
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Recommendations for use of methotrexate include • Baseline hCG level < 3000 iu/L • Asymptomatic or minimal symptoms • Non-viable pregnancy • Adnexal mass of ‘reasonable’ size • Suitable facilities/expertise available • Patient aware of side effects, risks and limitations • No known sensitivity to methotrexate
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Management of ectopic pregnancy: a clinical approach
100 000 maternities (Table 1). This is obviously disappointing, particularly as 70% of the deaths related to ectopic pregnancy in the last Confidential Enquiry were associated with substandard care. Maternal death also reflects the speed at which complications can occur and how rapidly a patient can deteriorate. Each department should develop protocols for the surgical and medical management of ectopic pregnancy (grade C recommendation) and training should be available to ensure surgeons can safely provide both laparoscopic and open surgery for the management of ectopic pregnancy. Ectopic pregnancy is expected to increase in parallel with higher rates of sexually-transmitted disease and the increased availability and use of assisted conception. Continued improvements in ultrasound and its application together with rapid access to serum human chorionic gonadotrophin (hCG) monitoring have increased the accuracy of diagnosis and may have contributed to an apparently increased incidence, although the number of ectopic pregnancies appears relatively stable over the past 10–15 years. Whilst ectopic pregnancies have classically been confirmed laparoscopically, recent advances in transvaginal ultrasonography, coupled with the introduction of sensitive serum hCG measurements, allows the diagnosis to be made without the need for laparoscopy in many cases. Laparoscopy has become the main form of treatment, although expectant management and medical treatment are valid options. The following series of hypothetical clinical cases has been designed to demonstrate the various steps in the management of a woman with a suspected or proven ectopic pregnancy. They could form the basis of a short answer in the MRCOG exam or be used to prepare for the OSCE. We suggest you consider each scenario and mentally formulate an answer before reading the discussion and explanation.
Nick Raine-Fenning James Hopkisson
Abstract Ectopic pregnancy is a common problem and one that is expected to increase in parallel with higher rates of sexually-transmitted disease and the increased availability and use of assisted conception. Continued improvements in ultrasound and its application, together with rapid access to serum human chorionic gonadotrophin (hCG) monitoring, have increased the accuracy of diagnosis and may have contributed to an apparently increased incidence, although the number of ectopic pregnancies appears relatively stable over the past 10–15 years. Laparoscopic surgery, rather than open surgery, is now the main method of treatment, although the medical treatment of ectopic pregnancy through the administration of methotrexate is popular in a number of centres. However, whilst the methods used for the diagnosis and management of ectopic pregnancy have changed significantly over the past 20 years, the death rate remains largely unchanged. This partly relates to substandard care, but also reflects the speed at which complications can occur and how rapidly a patient can deteriorate.
Keywords conservative management; ectopic pregnancy; follow-up; maternal mortality; methotrexate; surgical intervention
Introduction
Case 1
Ectopic pregnancy is relatively common and complicates around 1% of all pregnancies (10.9–11.1 per 1000 pregnancies). Fortunately, most of the women affected by ectopic pregnancy do not die: the estimated death rate is around 1 in every 300 000 ectopic pregnancies. Nevertheless, it remains an important cause of maternal morbidity and mortality, as 10 women died as a direct result of ectopic pregnancy between 2003 and 2005 according to the Confidential Enquiry into Maternal and Child Health (CEMACH) entitled Saving Mothers’ Lives. Whilst there appears to have been a steady decline in the number of deaths related to ectopic pregnancy since the late 1980s, when 15 women died in the triennium 1988–1990, the maternal death rate has actually remained largely unchanged at an approximate rate of 0.5–0.6 per
A 32-year-old Afro-Caribbean woman is referred to the Early Pregnancy Assessment Unit (EPAU) as she has developed lower abdominal pain and is known to be pregnant. She is unsure of the date of her last menstrual period but thinks she is around 6 weeks’ pregnant. The pain is in her lower abdomen and is not like a period. She has not had any bleeding. She is medically fit and well and has no risk factors for ectopic pregnancy. She is haemodynamically stable and has a soft abdomen on examination. Pelvic assessment, by speculum and bimanual examination, is unremarkable. A urinary pregnancy test confirms she is pregnant. What would you do next? This patient needs an ultrasound scan. An abdominal ultrasound may be sufficient and should be performed first, but a transvaginal ultrasound scan is required in many cases. The transvaginal transducer allows the user to be closer to the organs of interest and this facilitates the use of higher frequency ultrasound which improves spatial resolution and diagnostic capability. Ultrasound confirms pregnancy in the majority of cases and negates the need for measurement of the serum hCG level. Unfortunately, many junior doctors and staff working with patients of reproductive age request a quantitative hCG level, which is an unnecessary
Nick Raine-Fenning MBChB MRCOG PhD is a Consultant Gynaecologist and Associate Professor in Reproductive Medicine, Nottingham University Hospitals NHS Trust, Queen’s Medical Centre Campus, Nottingham, UK. James Hopkisson is a Consultant Gynaecologist at Nottingham University Research & Treatment Unit in Reproduction (NURTURE), Nottingham University Hospitals NHS Trust, Queen’s Medical Centre Campus, Nottingham, UK.
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Estimated incidence of ectopic pregnancy and related deaths (taken from CEMACH 2003–2005 report) Triennium
Total estimated pregnancies
Total estimated ectopic pregnancies
Ectopic pregnancies per 1000 pregnancies Rate
England and 1988–90 UK 1991–93 1994–96 1997–99 2000–02 2003–05
Wales 2 880 814 3 2 2 2 2
141 917 878 736 891
667 391 018 364 892
Deaths from ectopic pregnancies
95% CI
Death rate per 100 000 estimated ectopic pregnancies Rate
95% CI
24 775
8.6
8.5–8.7
15
0.52
0.31–0.86
30 33 31 30 32
9.6 11.5 11.1 11.0 11.1
9.5–9.7 11.4–11.6 11.0–11.2 10.9–11.1 10.9–11.1
9 12 13 11 10
0.29 0.41 0.45 0.40 0.35
0.15–0.55 0.24–0.72 0.26–0.77 0.22–0.72 0.19–0.64
160 550 946 100 100
Table 1
Measurement of serum progesterone may provide additional information in cases of pregnancy of unknown location (grade B recommendation). Levels below 25 nmol/L are invariably associated with non-viable pregnancies and the spontaneous resolution of pregnancy of unknown location, but this should not be used to guide intervention as viable pregnancies have been reported with low levels. Levels above 25 nmol/L are ‘likely to indicate’ and above 60 nmol/L are ‘strongly associated with’ pregnancies subsequently shown to be normal, although local laboratories may need to define their own levels. Results must be interpreted with caution and discussed with someone familiar with their use. The ultrasound scan should be conducted in a rigorous and methodical manner. The report is important and must provide detailed information to allow the appropriate management of patients. Unfortunately, many ultrasound reports are unclear and contain limited information. A report that states an ‘apparently empty sac is placed eccentrically in the fundus in association with a double-ring pattern’ suggests the presence of an intrauterine pregnancy and such information may make a difference to the decision to treat. Less informative are statements such as ‘an ectopic pregnancy cannot be excluded’ or ‘there is a possible intrauterine pregnancy’. Ultrasonographers and medical staff should be encouraged to document what they find in detail and to avoid open statements. The report may contain the opinion of the ultrasonographer which is acceptable and preferable, as it modifies the likelihood ratio for the presence of an ectopic or intrauterine pregnancy and does not incriminate the person making the comment. Once an ultrasound scan has revealed that there is no obvious intrauterine pregnancy and a mass, along with an hCG level greater than 1000 iu/L, the diagnosis is easier to make in the absence of symptoms.
and expensive test in the 70–90% or more of patients who are shown to have a viable or non-viable intrauterine pregnancy, an incomplete miscarriage or an ectopic pregnancy on ultrasound. Serum hCG levels are only useful in those patients where the location of the pregnancy cannot be confirmed or when a non-viable ectopic pregnancy has been confirmed ultrasonographically in an asymptomatic patient, and expectant or medical management is being considered; this is discussed below. Pregnancy of unknown location, defined as ‘no signs of either intra- or extra-uterine pregnancy or retained products of conception in a woman with a positive pregnancy test’, occurs in approximately 8–31% of pregnancies. Rates are lower, around 10%, in departments with a specialized scanning service or if the patient is assessed by an expert, and can be kept to a minimum by the critical application of transvaginal ultrasound and strict diagnostic criteria. The serial measurement of serum hCG is particularly useful in the diagnosis of asymptomatic ectopic pregnancy (grade B recommendation) and pregnancy of unknown location. The use of a ‘discriminatory zone’ for serum hCG above which an intrauterine pregnancy should be expected to be seen is recommended and employed by most units, but needs to be set and reviewed locally. An ectopic pregnancy will usually be visualized on transvaginal ultrasound when the hCG level is above 1500 iu/L but often occurs in association with lower levels, particularly those that plateau. The absence of an intrauterine gestation sac and an hCG titre of between 1000 and 1500 iu/L has been shown to be highly predictive of ectopic pregnancy (sensitivity 0–95%, specificity 95%). With an odds ratio of having an ectopic of 24.8, this makes intervention rather than expectant management appropriate. It is important to consider ectopic pregnancy in all cases where an intrauterine pregnancy has not been definitely confirmed by ultrasound, as ectopic pregnancy may occur in as many as 6% of women who give a good history and have ultrasound findings suggestive of a complete miscarriage. Access to serial serum hCG estimation is essential therefore and the results should be available within 24 h. All staff involved in the management of patients with early pregnancy problems must be able to interpret single and serial hCG levels and be aware of the limitations of monitoring.
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The ultrasound scan confirms the presence of an ectopic pregnancy. What would you do now? Whilst the diagnosis of ectopic pregnancy was classically made laparoscopically, recent advances in transvaginal ultrasonography, coupled with the introduction of sensitive serum hCG measurements, allows the diagnosis to be made without the need for laparoscopy. Indeed, laparoscopy is generally reserved for the surgical treatment of ectopic pregnancy, although there 20
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are equally effective non-surgical options. Ectopic pregnancies often follow a benign clinical course which allows a conservative approach to management in many cases. Options include expectant and medical treatment. Expectant management is only an option if the woman is asymptomatic and clinically stable. It is successful in around two-thirds (∼67%) of women and is more likely to be effective if the initial hCG level is less than 1000 iu/L or if the levels are decreasing rapidly. The presence of a mass on ultrasound does not preclude expectant treatment, but an extrauterine gestational sac reduces the chance of success by 5.6 times and treatment is not recommend if there is evidence of more than 100 ml of fluid in the pelvis, although this can be difficult to measure reliably and accurately. A detailed pre-treatment ultrasound assessment is important, and should be used to measure the size of the mass, qualify its contents and quantify the amount of free fluid in the pouch of Douglas. Follow-up is essential and involves twice-weekly assessment of the hCG level and weekly transvaginal ultrasound examinations, which should show a reduction in the average diameter of the adnexal mass by day 7; a good prognostic indicator of successful treatment and resolution. Weekly monitoring is required until serum hCG levels are less than 20 iu/L. If expectant management is not an option, medical therapy with methotrexate should be considered and offered to suitable women and if there are treatment and follow-up protocols for its use (grade B recommendation). Methotrexate is a chemotherapeutic agent that inhibits the enzyme dihydrofolate reductase; it therefore targets rapidly dividing tissue such as trophoblast by preventing the synthesis of purine nucleotides. It can be administered intravenously, intramuscularly or locally via injection directly into the ectopic pregnancy. There is no consensus on the best treatment protocol for its use. In 1999, the American College of Obstetrics and Gynecology produced a guideline for the medical management of ectopic pregnancy. Relative indications were that the ectopic should be less than 3.5 cm in diameter and show no cardiac activity, and that the hCG level should be between 6000 and 13 000 iu/L. Methotrexate is usually given as a single intramuscular dose calculated according to the patient’s body surface area (50 mg/ m2), and is somewhere between 75 and 90 mg for the majority of women. The effectiveness of treatment is evaluated by the serial measurement of serum hCG levels which are checked 4 and 7 days after treatment in initiated. A second dose may be given if the hCG levels do not fall by more than 15% over this time period, and is required in about 14% of women. Common side effects relate to the effect methotrexate has on mucosal surfaces and include conjunctivitis, stomatitis and gastrointestinal upset (Table 2). Women must be made aware of these symptoms and informed that further treatment may be necessary. A multidose protocol, which involves giving 1 mg/kg of methotrexate intramuscularly and alternating this with leucovorin 0.1 mg/kg for four doses of the drugs, is also available. In a meta-analysis comparing the single- and multi-dose regimens, the overall success rate for women treated with medical management of their ectopic pregnancy was 89% (1181/1327). The single dose was associated with a higher failure rate than the multidose regimen (OR 4.74, 95% CI 1.77–12.62). In the singledose regimen, 14% of women required a second dose but these
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Side effects of methotrexate therapy • Nausea and vomiting • Stomatitis • Diarrhoea • Abdominal pain • Pneumonitis • Impaired liver function tests • Alopecia • Neutropenia Table 2
women demonstrated fewer failures. In the multidose regimen, 53.5% of women received three or more doses of methotrexate. The single-dose regimen seems to be the more common protocol, however, probably because it requires fewer trips to hospital and facilitates compliance. Attempts have been made to predict the need for further treatment, regardless of whether that involves additional methotrexate or surgery (Table 3). The need for further treatment seems to relate to the baseline serum hCG concentration at presentation and medical treatment is not recommended when levels are higher than 3000 iu/L, although this is based on quality-of-life data. If the ectopic pregnancy is viable, as evident from the presence of cardiac activity, treatment is less likely to succeed. It is important to remember that these represent relative contraindications to medical therapy, and methotrexate can be used if there are exceptional circumstances or if the patient specifically wants medical treatment and is prepared to accept the associated risks and higher chance of failure and is aware of the potential need for prolonged follow-up. The medical management of patients with an ectopic pregnancy must be conducted by healthcare practitioners with knowledge and experience as it can be difficult and requires a certain degree of clinical acumen. The concentration of hCG increases initially and should be lower on day 7 than day 4. This transient increase is expected but it can confuse clinicians unfamiliar with the use of methotrexate. Whilst tubal rupture will only occur in around 7% of women during follow-up, the majority (∼75%) experience some degree of abdominal pain which is attributed to tubal miscarriage. Differentiating this ‘separation pain’ from pain due to tubal rupture is undoubtedly difficult and women should be admitted for observation and ultrasound assessment if there is any possibility of tubal rupture. Surgical intervention,
Factors increasing the risk of persistent trophoblast • Small ectopic pregnancies (<2 cm) • Early gestation (<7 weeks) • Rapid preoperative rise in serum hCG • High pretreatment hCG levels (43 000 iu/L) • Presence of active tubal bleeding • Milking of the ectopic pregnancy from the tube Table 3
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and the data must be interpreted with caution as they are derived from a series of studies with different subject populations, variable surgical procedures and inconsistent follow-up protocols. It is possible that there is a higher subsequent intrauterine pregnancy rate after salpingotomy but the magnitude of this benefit may be small. If the contralateral tube is damaged, laparoscopic salpingotomy should be considered as the primary treatment if there is a desire for future fertility (grade B recommendation). Under these circumstances salpingotomy is associated with greater subsequent intrauterine pregnancy and is more cost-effective in the long term as it allows the woman the chance to conceive without assisted reproduction treatment (ART). The short-term costs of salpingotomy are greater than salpingectomy however, due to the need for postoperative follow-up because of the potential risks of persistent trophoblast. It is essential that any woman treated in this way is informed that there is an approximate 20% risk of recurrence of ectopic pregnancy. Spontaneous conception is increasingly unlikely to happen if it has not occurred within 18 months of the salpingotomy and ART should be considered under such circumstances. Salpingotomy may be more effective if performed as an open procedure. Laparoscopic salpingotomy appears less successful in elimination of the tubal pregnancy (RR 0.90, 95% CI 0.83–0.97) than salpingotomy performed at laparotomy and is associated with higher rates of persistent trophoblast (RR 3.6, 95% CI 0.63–21.0). There may be a reduction in the number of repeat ectopic pregnancies after laparoscopic salpingotomy, however (RR 0.43, 95% CI 0.15–1.2), and at present there is insufficient evidence to warrant opening the abdomen to perform a salpingotomy which would increase intra- and post-operative morbidity considerably. The decision to perform a salpingectomy or a salpingotomy will also depend on the size of the ectopic pregnancy and the degree of damage to the affected tube. In some cases the ectopic pregnancy cannot be removed without inflicting considerable damage to the Fallopian tube, which may need to be removed if there is extensive or uncontrollable bleeding. The use of conservative surgical techniques exposes women to a small risk of tubal bleeding in the immediate postoperative period and the potential need for further treatment for persistent trophoblast. These issues must be discussed with the patient prior to surgery and following any operative intervention. The patient should be involved in the decision-making process whenever possible. Women should be advised of the potential advantages and disadvantages associated with the different approaches and treatments.
however, is required in less than 10% of women. Medical and expectant management must only be offered, therefore, if there are facilities for the woman to contact the unit and return easily for assessment at any time during follow-up (grade B recommendation). Treatment can be offered on an outpatient basis. This can be convenient and more acceptable to the woman and is associated with an approximately 50% reduction in the treatment cost compared to laparoscopic surgery, although this is dependent on the duration and intensity of follow-up, which will vary on a case-by-case basis. Women should also be advised to avoid sexual intercourse during treatment and to drink to thirst but to ensure they do not become dehydrated. All women must be provided with a reliable form of contraception for at least 3 months after methotrexate has been given. All women managed non-surgically should be counselled regarding the importance of compliance with followup and surgical treatment offered if this is likely to be an issue for geographical or social reasons. If the woman is not suitable for expectant or medical management, surgery must be considered. If surgery is indicated, a laparoscopic approach is recommended and preferred to an open approach if the patient is haemodynamically stable (grade A recommendation). This is because it is associated with less intraoperative blood loss, shorter operation times and lower analgesic requirements, all of which result in shorter hospital stays. Contrary to popular belief, there is no evidence to suggest that the laparoscopic approach is associated with less negative effects on the patient’s subsequent fertility or more favourable outcomes if pregnancy does ensue. Tubal patency rates are similar between the two approaches (RR 0.89, 95% CI 0.74–1.1), as are subsequent intrauterine pregnancy rates (RR 1.2, 95% CI 0.88–1.15). All operative procedures for ectopic pregnancy require an appropriately trained or supervised surgeon and are dependent on their skill and that of their assistants and the equipment available to them. Medical staff should be competent to manage ectopic pregnancy by open and laparoscopic methods. All surgeons must have attended an appropriate Royal College of Obstetricians and Gynaecologists (RCOG)-approved course in basic or intermediate laparoscopic skills and to be aware of how to use monopolar and bipolar diathermy safely. A decision is made to perform a laparoscopy. This reveals an unruptured right-sided ectopic pregnancy. How would you proceed? The whole pelvis must be inspected in detail. This requires the introduction of a second port, which is usually inserted suprapubically or laterally in the lower abdomen, to allow the introduction of an instrument to mobilize the pelvic organs and to remove any excess blood which can reduce the efficiency of the light source through absorption and limit the view. The contralateral tube must be inspected prior to any decision about how to proceed surgically. If the contralateral tube appears healthy, there is no clear evidence that salpingotomy should be used in preference to salpingectomy (grade A recommendation). This reflects studies which have shown no differences in the subsequent rate of intrauterine pregnancy and possibly a slightly higher chance of ectopic pregnancy. This is not logical as a higher fecundity would be expected in women treated conservatively
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How would you modify the initial management of this patient if she had been tachycardic and hypotensive? The patient must be appropriately and rapidly resuscitated. This requires the insertion of two large-bore cannulae and the infusion of crystalloid or blood if significant haemorrhage is thought to have occurred. Resuscitation can take place whilst the patient is being prepared for theatre and should not delay surgical intervention, although this cannot and must not go ahead until the patient is stable and the anaesthetic team is happy. Once the patient is stable she must be managed by the most expedient method if there is any evidence of haemodynamic 22
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week after surgery, many chose to start serial assessment 7 days after surgery. Methotrexate is recommended if levels fail to fall as expected. Repeat surgery is occasionally required and this may be performed laparoscopically or as an open procedure. The patient must be informed of the risks and strongly encouraged to see her general practitioner (GP), or preferably to return to the gynaecology ward or EPAU if she develops abdominal pain or persistent bleeding. The incidence of persistent trophoblast and the need for treatment partly depend upon the frequency of postoperative measurements and the cut-off used for the definition of persistence. Several factors increase the risk of persistent trophoblast (Table 3) but follow-up is required in all patients managed conservatively. Persistent trophoblast is very rarely seen with salpingectomy and follow-up is not required unless there were any concerns at the time of the operation. The psychological impact of an ectopic pregnancy is different for all couples and is difficult to predict, but may seriously affect a significant proportion of women and their partners. General follow-up is not always necessary, but should be offered to all patients as it provides an opportunity to discuss events and to assess postoperative recovery. This is also a more appropriate time to discuss the affect surgery may have had on the patient’s fertility, although this may be discussed, and invariably is, in the immediate postoperative period. Time to digest such information is needed and the patient and her partner should be given information leaflets and made aware of locally and nationally available support services. The plan should be agreed with the patient, documented in the notes and conveyed to her GP via the initial discharge letter and a formal letter.
instability. In the vast majority of cases this will be via laparotomy, but there may be a role for operative laparoscopy in certain cases as long as the surgeon has the necessary expertise and the anaesthetic team is informed and in agreement. The aim should be to prevent further blood loss as quickly as possible. Obviously there is no role for methotrexate. Once the abdomen has been opened, or a laparoscope safely inserted, the pelvis needs to be carefully inspected before proceeding as described above. An adequate view may be precluded by the presence of a large pneumoperitoneum and this must be addressed through the use of suction and irrigation. If this cannot be performed quickly or safely endoscopically, the abdomen must be opened to ensure further bleeding is stopped. The consultant gynaecologist on call must be informed and involved in the care of the patient. A team leader should be identified to ensure good communication. The timing of events must be noted and recorded and the whole event documented in detail, although this is often done in retrospect due to the urgency of the situation. How should the patient be managed following interventional surgery? The patient must be monitored in recovery in theatre and kept there until all vital signs are stable. Blood may already have been given but the need for transfusion should be considered if it has not. This can be a difficult decision as there are no absolute requirements and patients should be managed on a case-by-case basis. The estimated intraoperative blood loss, vital signs and the patient’s current and preoperative haemoglobin and haematocrit will inform the decision. In some cases, invasive monitoring is required, and these patients should be transferred to high dependency or intensive care in liaison with the anaesthetic team. Pain relief should be provided, ideally through a patient-controlled device, but the amount will depend on whether laparoscopic or open surgery has been performed. An indwelling urinary catheter will be required after a laparotomy and the need for thromboprophylaxis should be considered. Once stable and competent to understand, the patient and her partner or immediate family should be debriefed as to what has happened and given reasons for the route and type of surgery performed. The need for anti-D immunoglobulin should be considered and 250 iu (50 μg) given to non-sensitized women who are Rhesus negative (evidence level IV). If salpingostomy has been performed there is need for early postoperative follow-up to exclude the presence of persistent trophoblast as a result of incomplete removal; this occurs in 3–20% of cases. Persistent trophoblast is detected and defined as ‘the failure of serum hCG levels to fall as expected after initial treatment’. Management is based on the observation that whilst hCG levels often return to normal uneventfully, cases of delayed haemorrhage due to persistent trophoblast do occur. Follow-up involves serum monitoring of hCG levels. Once all trophoblastic tissue has been cleared, serum hCG levels fall and follow a predictable clearance curve over the next 2 weeks (range 2–49 days) to normal levels. It has been estimated that if there is a 50% fall in the preoperative hCG level, there is a less than 15% chance of persistent trophoblast. The time to initiate hCG monitoring is not universally agreed, but as persistent trophoblastic disease is unlikely to present or cause problems within the first
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Case 2 A 34-year-old woman receiving in-vitro fertilization (IVF) after two salpingectomies for ectopic pregnancy presented following her second cycle of IVF, after two-embryo replacement with a heterotopic pregnancy at the 8-week scan. Cardiac activity was noted in both the sacs. Using a three-dimensional scan, it was suggested that the sac was in the cornu, and this was confirmed at laparoscopy. The patient had undergone two laparotomies for removal of her previous ectopic pregnancies. The current ectopic was removed using bipolar diathermy and excision of the remaining portion of the tube. The remaining pregnancy progressed normally and the patient was delivered of a healthy female infant at 38 weeks by lower-segment caesarean section. Discussion Assisted reproductive technologies are associated with an increased number of ectopic pregnancies compared with spontaneous conception, the vast majority (82%) being tubal. Ectopic pregnancy following IVF and embryo replacement is associated with previous ectopic pregnancy, tubal disease and difficult embryo transfer. Heterotopic pregnancies (concomitant intrauterine and extrauterine gestations) are almost exclusive to assisted reproductive technologies. One study has shown an incidence of heterotopic pregnancy of 0.2% of 3500 cycles of IVF. In a study by Marcus et al, there were 20 heterotopic pregnancies in 2650 pregnancies. Of these, 45% were asymptomatic and 50% led to a live birth. The majority of the ectopics (17/20) were removed by 23
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salpingectomy, two were injected with potassium chloride and one resolved spontaneously.
Royal College of Obstetricians and Gynaecologists. The Management of Early Pregnancy Loss. Clinical Guideline No. 25. London: RCOG Press, 2006. Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F. Interventions for tubal ectopic pregnancy. Cochrane Database of Systematic Reviews 2007(Issue 1). Marcus SF, Macnamee M, Brinsden P. Heterotopic pregnancies after in-vitro fertilization and embryo transfer. Hum Reprod, 1995; 10: 1232–1236. Mol BW, Lijmer JG, Ankum WM, van der Veen F, Bossuyt PM. The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod 1998; 13: 3220–3227. Parker J, Bisits A, Proietto AM. A systematic review of single-dose intramuscular methotrexate for the treatment of ectopic pregnancy. Aust N Z J Obstet Gynaecol 1998; 38: 145–150. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboulghar H. Complications of medically assisted conception in 3500 cycles. Fertil Steril 1998; 70: 638–642. Tay JI, Moore J, Walker JJ. Ectopic pregnancy. BMJ 2000; 320: 916–919.
Case 3 A 24-year-old student nurse presented to the A&E Department with lower abdominal pain associated with diarrhoea and vomiting. The pain was increasing in severity and the patient felt faint. She was taking the progestogen-only pill as a form of contraception and had been having irregular bleeds since starting this. She told the staff that she did not think she could be pregnant and a pregnancy test was not undertaken. A junior doctor was asked to assess her and made a diagnosis of gastroenteritis. As the pain settled with simple analgesia the patient was allowed to go home and asked to contact her GP if things did not settle. She was found collapsed by her partner later that day when he returned home from work. He called an ambulance but the woman suffered a cardiac arrest on the way to the hospital and sadly was declared dead on arrival. Discussion There are several examples of substandard care in this tragic case. Unfortunately, this is not an uncommon situation and four of the women who died as a result of ectopic pregnancy in the latest Confidential Enquiry were misdiagnosed as they had gastrointestinal upset. It is essential that ectopic pregnancy is considered and excluded in any woman of reproductive age who presents with gastrointestinal disturbance and/or fainting. A pregnancy test was not undertaken and a positive result may have prompted the medical staff to contact the gynaecology team, or to arrange a pelvic ultrasound scan. Whilst all forms of contraception, including the intrauterine contraceptive device, decrease the risk of ectopic pregnancy as they decrease the chance of conception in the first place, ectopic implantation is much more likely when conception occurs in women using contraception, especially the intrauterine contraceptive device and the progestogen-only pill which reduces cilial motility. No form of contraception is 100% effective and a pregnancy test must be undertaken in all sexually-active women of reproductive age who present with abdominal pain, gastrointestinal upset or dizziness. In the event of a positive test, an ultrasound scan should be performed and a gynaecological opinion sought. A similar case described in the recent Confidential Enquiry was still misdiagnosed as gastroenteritis even after the patient was confirmed to be pregnant, which emphasizes the importance of further tests and re-evaluation. ◆
Practice points Assessment and diagnosis of suspected ectopic pregnancy • Incidence is relatively consistent at 10.9–11.1 per 1000 pregnancies • Diagnosis increasingly being made with transvaginal ultrasound and serial hCG measurements • Ultrasound is the primary investigation and the most informative • Serum hCG levels are not required in the majority of patients • Serum hCG levels are only useful in those patients where the location of the pregnancy cannot be confirmed ultrasonographically or when a non-viable ectopic pregnancy has been confirmed in an asymptomatic patient and expectant or medical management are being considered • Pregnancy of unknown location occurs in approximately 8–31% of pregnancies • The use of a ‘discriminatory zone’ for serum hCG above which an intrauterine pregnancy should be expected to be seen is recommended • An ectopic pregnancy will usually be visualized on transvaginal ultrasound when the hCG level is above 1500 iu/L but often occurs in association with lower levels, particularly those that plateau • Measurement of serum progesterone may provide additional information in cases of pregnancy of unknown location • With an hCG level >1000 iu/L and no intrauterine gestation sac, the odds ratio of having an ectopic pregnancy is 24.8. Intervention rather than expectant management is appropriate
Further reading Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing single dose and multidose regimens. Obstet Gynecol 2003; 101: 778–784. Grarcia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 2001; 97: 464–470. Lewis G, ed. Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer –2003–2005. The Seventh Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH, 2007. www.cemach.org. Royal College of Obstetricians and Gynaecologists. The Management of Tubal Pregnancy. Clinical Guideline No. 21. London: RCOG Press, 2004.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 19:1
General management of ectopic pregnancy • Management may be expectant, medical or surgical • Surgical treatment is suitable for all but certain criteria must be met for expectant and medical management • Follow-up is essential after expectant, medical, and conservative surgical management
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Case-based learning
Expectant management of ectopic pregnancy • Only an option if the woman is asymptomatic and clinically stable • Is successful in around two-thirds (∼67%) of women • Is more likely to be effective if the initial hCG level is <1000 iu/L or if the levels are decreasing rapidly
Specific recommendations from CEMACH concerning early
pregnancy deaths
• Ectopic pregnancy is an important cause of maternal morbidity and mortality • Direct death related to ectopic pregnancy affects 0.5–0.6 per 100 000 maternities • Approximately 1 in every 300 000 women with an ectopic pregnancy dies • All patients must be appropriately and rapidly resuscitated in the first instance • Ectopic pregnancy must be considered/excluded in all women of reproductive age who present with diarrhoea and vomiting and/or fainting • Clinicians in primary care and emergency departments, in particular, need to be aware of atypical clinical presentations of ectopic pregnancy and the way in which it may mimic gastrointestinal disease. This needs to be highlighted in textbooks • Maternal deaths related to ectopic pregnancy are often due to substandard care • Medical treatment of ectopic pregnancy should be based on strict adherence to protocols, with women having immediate access to inpatient facilities if complications occur
Medical management of ectopic pregnancy • Methotrexate should be considered and offered to all women who meet certain criteria • Treatment may involve a single- or multiple-dose regimen • Treatment can be offered on an outpatient basis. • There must be treatment and follow-up protocols for its use • Tubal rupture occurs in around 7% of women during follow-up • 75% of women experience some degree of abdominal pain which is attributed to tubal miscarriage and differentiating this ‘separation pain’ from pain due to tubal rupture is undoubtedly difficult Surgical management of ectopic pregnancy • The contralateral tube must be inspected prior to any decision about how to proceed surgically • If the contralateral tube appears healthy, there is no clear evidence that salpingotomy should be used in preference to salpingectomy • If the contralateral tube is damaged, laparoscopic salpingotomy should be considered as the primary treatment if there is a desire for future fertility • Salpingotomy may be more effective if performed as an open procedure. • Training should be available to ensure surgeons can safely provide both laparoscopic and open surgery for the management of ectopic pregnancy
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 19:1
Recommendations for use of methotrexate include • Baseline hCG level < 3000 iu/L • Asymptomatic or minimal symptoms • Non-viable pregnancy • Adnexal mass of ‘reasonable’ size • Suitable facilities/expertise available • Patient aware of side effects, risks and limitations • No known sensitivity to methotrexate
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