Unmedicated, medicated and copper-coated IUCDs prevent both intrauterine and extrauterine pregnancies. However, a woman who conceives with an IUCD in situ is seven times more likely to have a tubal pregnancy compared with conception without contraception (Vessey et al 1974). IUCDs are more effective in preventing intrauterine than extrauterine implantation. With copper IUCDs, 4% of all accidental pregnancies are tubal, whereas with progesterone-coated IUCDs, 17% of all contraceptive failures are tubal pregnancies. The different mechanisms of action of the two devices could partially explain the difference in failure rates. Although both devices prevent implantation, copper IUCDs also interfere with fertilization by inducing cytotoxic and phagocytotic effects on the sperm and oocytes. Progesterone-containing IUCDs are probably less effective in preventing fertilization. Although the incidence of pregnancy diminishes with long-term use of the IUCD, among women who become pregnant, the likelihood of ectopic pregnancy increases. Women who have used the IUCD for more than 24 months are 2.6 times more likely to have an ectopic pregnancy compared with short-term users (<24 months). The ‘lasting effect’ of the IUCD may be related to the loss of the cilia from the tubal epithelium, especially if the IUCD has been in situ for 3 years or more (Wollen et al 1984, Ory HW 1981).

Termination of pregnancy

Data from two French case–control studies suggest that induced abortion may be a risk factor for ectopic pregnancy for women with no history of ectopic pregnancy. There is an association between the number of previous induced abortions and ectopic pregnancy [odds ratio (OR) 1.4 for one previous induced abortion and 1.9 for two or more] (Tharaux-Deneux et al 1998). Whether this is related to the spread of asymptomatic C. trachomatis infection or to the procedure itself is uncertain.

Assisted conception

Induction of ovulation with either clomiphene citrate or human menopausal gonadotrophin is a predisposing factor to tubal implantation (McBain et al 1980; Marchbanks et al 1985). A number of studies indicate that 1–4% of pregnancies achieved following induction of ovulation are ectopic pregnancies. The majority of these patients had a normal pelvis and patent tubes. The incidence of tubal pregnancy following oocyte retrieval and embryo transfer is approximately 4.5%. It must be noted that some women who undergo an in-vitro fertilization (IVF) cycle have risk factors for an ectopic pregnancy (i.e. previous ectopic pregnancy, tubal pathology or surgery).

Salpingitis isthmica nodosa

Salpingitis isthmica nodosa (SIN) is diagnosed by the histological evidence of tubal isthmic diverticula, and may be suggested by characteristic changes on hysterosalpingogram. Its incidence in healthy women ranges from 0.6% to 11%, but it is significantly more common in the setting of ectopic pregnancy. Persaud (1970) reported that 49% of fallopian tubes excised for tubal pregnancy had diverticula and evidence of SIN. The reason for the high incidence of ectopic gestation in women with SIN remains largely unknown. Defective myoelectrical activity has been demonstrated over the diverticula. Entrapment of the embryo into the diverticula is a possible mechanical explanation.

Smoking

A French study found that the risk of ectopic pregnancy is significantly higher in women who smoke. The risk increases according to the number of cigarettes per day (Bouyer et al 1998). The relative risk for ectopic pregnancy is 1.3 for women who smoke one to nine cigarettes per day, 2 for women who smoke 10–12 cigarettes per day, and 2.5 for women who smoke more than 20 cigarettes per day. Inhibition of oocyte cumulus complex pick-up by the fimbrial end of the fallopian tube and a reduction of ciliary beat frequency are associated with nicotine intake (Knoll and Talbot 1998).

Diethylstilboestrol

Results of a collaborative study indicate that the risk of ectopic pregnancy in diethylstilboestrol (DES)-exposed women was 13% compared with 4% for women who had a normal uterus (Barnes et al 1980). A meta-analysis on risk factors for ectopic pregnancy confirms that exposure to DES in utero significantly increases the risk of ectopic pregnancy (Ankum et al 1996).

Pathology

Sites of ectopic pregnancy

A 21-year survey of 654 ectopic pregnancies (Breen 1970) revealed that the most common sites of ectopic pregnancy are as shown in Table 25.2. Similar distribution for tubal and abdominal pregnancy sites have been reported by Bouyer et al (2002) [ampullary (70.0%), isthmic (12.0%), fimbrial (11.1%), interstitial (2.4%), abdominal (1.3%)]. In this population, no cervical pregnancies were observed and slightly increased incidence was seen for ovarian pregnancies (3.2%) (Bouyer et al 2002).

Table 25.2 Sites of ectopic gestation

Fallopian tube
Ampullary segment	80%
Isthmic segment	12%
Fimbrial end	5%
Interstitial and cornual	2%
Abdominal	1.4%
Ovarian	0.2%
Cervical	0.2%

Natural progression of a tubal pregnancy

Unruptured tubal pregnancy

Occasionally, in the very early stages of a tubal pregnancy, there are no obvious macroscopic features, and an ectopic pregnancy could be overlooked even after a laparoscopy. However, as pregnancy progresses, local enlargement of the tube occurs at the point of implantation. At a later stage, a large segment of the tube is distended and the tubal wall appears discoloured, dark red or purple.

Tubal rupture

One of the fundamental aspects of ectopic pregnancy is the inability of the tissues into which the blastocyst implants to offer resistance or respond to the invading trophoblast. Uncontrolled invasion of the trophoblast results in destruction of vessels, local haemorrhage and thinning of the tubal wall. Rupture of the tubal wall results in the escape of large amounts of blood, with or without the products of conception, into the peritoneal cavity. The embryo rarely survives. In rare cases, pregnancy continues if an adequate portion of the placenta is retained or if secondary implantation occurs in other organs of the pelvic or peritoneal cavity. Rupture occurs more often at the antimesenteric part of the tubal wall. Rupture of the inferior and mesenteric part of the tubal wall results in haemorrhage between the two layers of the broad ligament. Intraligamentous haemorrhage could cause rupture of anterior or posterior layers of the broad ligament.

Spontaneous involution

Usually, the conceptus dies at an early stage without any notable symptoms.

Complete tubal miscarriage

At an early stage, the conceptus is extruded via the fimbriated end of the fallopian tube into the peritoneal cavity, and subsequently absorbed by the surrounding tissues.

Incomplete tubal miscarriage

The conceptus is partially extruded via the fimbrial end of the tube, and intervention is usually required.

Tubal blood mole or carneous mole

In some cases, recurrent choriodecidual haemorrhage around the dead conceptus contributes to the formation of a tubal blood mole or carneous mole. The presence and development of cellular and biochemical elements of connective tissue around the mole give rise to a semi-solid structure which could remain unresolved for years.

Time of rupture at various sites in the tube

Isthmic implantation

The isthmic segment of the fallopian tube is narrow and less distensible than the ampullary or interstitial segments. Isthmic rupture often occurs at 6–8 weeks of gestation and is usually dramatic.

Ampullary implantation

Rupture of an ampullary pregnancy usually occurs at 8–12 weeks of gestation. The ampulla is the wider segment of the fallopian tube and the site of 80% of all ectopic pregnancies.

Interstitial implantation

The interstitial segment of the fallopian tube is surrounded by myometrium which can hypertrophy to accommodate the enlarging conceptus. Rupture therefore occurs at a relatively late stage of 12–14 weeks of gestation. Rupture of an interstitial pregnancy causes damage of the highly vascularized cornual end of the uterus, resulting in severe intra-abdominal haemorrhage.

Histological changes

In the early stages of pregnancy, the myometrium responds in an identical pattern under the influence of hormones, irrespective of whether the gestation is ectopic or eutopic. The uterus becomes softened and slightly enlarged as a consequence of hypertrophy and hyperplasia of the myometrial cells. Where the gestation is ectopic, the endometrial glands demonstrate an atypical histological pattern referred to as the ‘Arias-Stella phenomenon’, which is characterized histologically by: hyperplasia of glandular cells, closely packed glands with evidence of hypersecretion, large irregular hyperchromatic nuclei, cytoplasmic vacuolation and loss of cellular polarity. It is important to note that the Arias-Stella reaction is non-specific and can be found in the endometrium of patients with an intrauterine pregnancy. However, the presence of the Arias-Stella reaction and the absence of chorionic villi from endometrial curettings are both highly suspicious signs of an extrauterine pregnancy. The presence of chorionic villi is the most reliable histological feature for the definite diagnosis of pregnancy.

Simultaneous with the glandular changes, the stroma is converted into decidual tissue containing large polyhedral cells with hyperchromatic nuclei. A failing pregnancy and lower levels of associated hormones results in gradual disintegration of the decidua, giving rise to the intermittent, occasionally heavy, vaginal bleeding of uterine origin that occurs in ectopic pregnancy. In some cases, the decidua may be detached abruptly and passed as a flat, triangular, reddish-brown piece of tissue called a ‘decidual cast’.

Diagnosis

Symptoms and signs

Ectopic pregnancy remains a diagnostic challenge. It should be considered as an important differential in any woman of reproductive age who presents with the triad of amenorrhoea, abdominal pain and irregular vaginal bleeding. This philosophy is particularly useful if the patient has any of the risk factor(s) identified in Table 25.1. The frequency with which various symptoms and signs were reported from a series of 300 consecutive cases are shown in Table 25.3 (Droegemueller 1982).

Table 25.3 Symptoms and signs in 300 consecutive cases of ectopic pregnancy at admission

Symptoms and signs	Cases (%)
Abdominal pain	99
Generalized	44
Unilateral	33
Radiating to the shoulder	22
Abnormal uterine bleeding	74
Amenorrhoea ≤2 weeks	68
Syncopal symptoms	37
Adenexal tenderness	96
Unilateral adenexal mass	54
Uterus
Normal size	71
6–8-week size	26
9–12-week size	3
Uterine cast passed away vaginally	7
Admission temperature >37°C	2

Abdominal pain

This is the most common symptom; however, it should be emphasized that there is no typical pain that is pathognomonic of ectopic pregnancy. Women can present with generalized abdominal or localized pain in the pelvis (unilateral or bilateral) and/or pain radiating to the shoulder.

The generalized abdominal pain is usually due to rupture of ectopic pregnancy and intraperitoneal haemorrhage. The pain is often severe. Shoulder pain is also an indirect indication of intraperitoneal haemorrhage. Accumulation of blood in the subdiaphragmatic region stimulates the phrenic nerve and creates shoulder tip pain. Localized pain may be due to distension of the fallopian tube. The pain may be sudden or progressive, and continuous or intermittent.

Amenorrhoea and abnormal uterine bleeding

Most patients present with amenorrhoea of at least 2 weeks duration. One-third of the women will either not recall the date of their last menstrual period or have irregular periods. Abnormal uterine bleeding occurs in 75% of women with an ectopic pregnancy. The bleeding is often light, recurrent and results from detachment of the uterine decidua. According to Stabile (1996a), ‘If a patient who is a few weeks pregnant complains of a little pain and heavy vaginal bleeding, the pregnancy is probably intrauterine, whereas if there is more pain and little bleeding, it is more likely to be an ectopic pregnancy’.

Other symptoms

Although abdominal pain, amenorrhoea and abnormal vaginal bleeding are the most common and typical symptoms, patients may present with additional features such as syncopal attacks. These are related to sudden-onset haemorrhage or to hypovolaemia or anaemia. Other atypical symptoms include diarrhoea or vomiting. In the 2003–2005 Confidential Enquiry into Maternal and Child Health report (Lewis, 2007), some women who presented with these symptoms were undiagnosed and subsequently died.

Physical examination

Physical examination should include an assessment of vital signs and examination of the abdomen and pelvis. Depending on the rate and amount of blood loss, the general condition of the patient may vary from slight pallor to haemodynamic shock. Palpation of the abdomen may reveal generalized or localized mild tenderness. Occasionally, guarding and rebound tenderness are also elicited.

An unusual feature is the Cullen’s sign. This is bluish discoloration of the skin around the umbilicus caused by a considerable quantity of free blood in the peritoneal cavity. However, this sign is rare and its absence does not exclude massive intraperitoneal haemorrhage.

The findings on pelvic examination vary from completely negative examination to the presence of a large, fixed, soft and tender mass. An adnexal mass may be palpable in up to 55% of cases. In many cases, the mass is ill defined and it may consist not only of tubal pregnancy but also of adherent omentum, small and large bowel. The mass may also be an enlarged corpus luteum. The uterus may be slightly enlarged but its size does not normally correspond to the gestational age. Cervical motion tenderness may or may not be present. A tender boggy mass in the pouch of Douglas, when present, represents either a collection of blood or a dilated tube adherent to the posterior uterine wall.

Types of presentation

The presentation of symptomatic patients with a tubal ectopic pregnancy may be acute or subacute.

Acute presentation

This is usually a consequence of rupture of the ectopic gestation and the ensuing intraperitoneal haemorrhage and haemodynamic shock. These symptoms are due to the intra-abdominal haemorrhage and collection of blood into the subdiaphragmatic region and pouch of Douglas. The patient is often pale, hypotensive and tachycardic. She may complain of shoulder tip pain or urge to defaecate. Abdominal examination reveals generalized and rebound tenderness. Vaginal examination will reveal tenderness in the adnexal region and cervical motion tenderness. However, vaginal examination in patients who present with an acute abdomen due to a ruptured ectopic pregnancy is generally considered unnecessary and potentially dangerous for the following reasons: (a) generalized haemoperitoneum and pain often mean that specific information cannot be elicited, (b) the patient is very uncomfortable and the assessment is often difficult and inadequate, and (c) it could result in total rupture of the ectopic pregnancy and delay management of the patient. Although it is reported that 30% of all women with an ectopic pregnancy present after rupture (Barnhart et al 1994), acute presentation is becoming less common. This is due primarily to increased patient awareness and early referral to the hospital for evaluation of ‘suspected ectopic’ pregnancies. Finally, the availability of more sensitive and rapid biochemical tests for beta-human chorionic gonadotrophin (β-hCG) quantification and the wider availability of transvaginal ultrasonography and laparoscopy have significantly reduced the interval between presentation and treatment.

Subacute presentation

When the process of tubal rupture or abortion is very gradual, the presentation of ectopic pregnancy is subacute. According to Stabile (1996a,b), this is the group of women who are symptomatic but clinically stable. A history of a missed period and recurrent episodes of light vaginal bleeding may exist. The circulatory system adjusts the blood pressure, and the patient is haemodynamically stable. Progressively increasing lower abdominal pain and, occasionally, shoulder pain are typical symptoms. On bimanual examination, there may be localized tenderness in one of the fornices, and cervical motion tenderness is often present. Subacute presentation occurs in 80–90% of ectopic pregnancies. In cases with such a presentation, the establishment of an accurate diagnosis becomes more difficult, hence the need for further investigations.

Further Investigations

Biochemical tests

Quantitation of β-hCG subunit

hCG is a glycoprotein with a mass of 36,700 Da that is secreted by the syncytiotrophoblasts. It is heterodimeric, composed of two non-covalently linked α and β subunits. The α subunit is identical to that of follicle-stimulating hormone and luteinizing hormone, whereas the β subunit is specific to hCG. In response to β-hCG, the corpus luteum produces increasing concentrations of progesterone and other steroid hormones required to maintain early pregnancy, until the placenta takes over by the eighth week of gestation. β-hCG first enters the maternal circulation on the day of blastocyst implantation, i.e. 6–7 days after conception. Serum concentrations of β-hCG are approximately 1000 IU/l (third international standard) at approximately 4 weeks of pregnancy, increase exponentially during the first 6 weeks of gestation, and reach 20,000–250,000 IU/l at 10 weeks of gestation. Concentrations then decrease to 10,000–20,000 IU/l by 20 weeks of gestation and plateau thereafter.

Using highly sensitive assays (detection limit 0.1–0.3 IU/l), β-hCG can be detected in the maternal circulation around the time of implantation. This will appear in urine approximately 2 days after it appears in the blood. Most commercially available monoclonal-antibody-based urine pregnancy tests can detect β-hCG concentrations above 25 IU/l, which corresponds to day 24–25 of a regular 28-day cycle. The sensitivity of modern assays is 99–100%.

Single β-hCG measurement

A single serum β-hCG concentration has been used as a discriminatory level to detect an ectopic pregnancy as described below. A single measurement, however, has limited clinical value as there is considerable overlap of values for normal and abnormal pregnancies. When using radioimmunometric assays with a detection limit of 5 IU/l, a single measurement of β-hCG may be useful because, if negative, it can exclude the diagnosis of an ectopic pregnancy.

Serial β-hCG measurements

Serum β-hCG concentrations double every 1.4–1.6 days from the time of first detection up to the 35th day of pregnancy, and then double every 2.0–2.7 days from the 35th to the 42nd day of pregnancy (Pittaway et al 1985). Since the normal doubling time of β-hCG is 2.2 days and its half-life is 32–37 h, serial quantitative assessments of β-hCG may help to distinguish normal from abnormal pregnancies. Kadar et al (1981) first reported a method for screening for ectopic pregnancy based on β-hCG doubling time. An increase in serum β-hCG of less than 66% over 48 h was suggestive of an ectopic pregnancy (using an 85% CI for β-hCG levels). More recently, studies have used an increase in serum β-hCG levels of 35–53% (using 99% CI) to diagnose viable intrauterine pregnancies and to reduce the potential risk of terminating an intrauterine pregnancy (Seeber et al 2006). However, another method used to help with the diagnosis of an ectopic pregnancy is the ‘plateau’ in serum β-hCG levels. Plateau is defined as a β-hCG doubling time of 7 days or more (Kadar and Romero 1988). If the half-life of serum β-hCG is less than 1.4 days, spontaneous miscarriage is likely, whereas a half-life of more than 7 days is more likely to be indicative of an ectopic pregnancy. Therefore, falling levels of β-hCG can distinguish between an ectopic pregnancy and a spontaneous miscarriage. As a proportion of ectopic pregnancies are tubal miscarriages (with biochemical changes similar to those of intrauterine miscarriages), and approximately 15–20% of all ectopic pregnancies can have doubling serum β-hCG levels similar to those of normal intrauterine pregnancies (Silva et al 2006), suboptimal serial β-hCG changes are not specific or sensitive enough to diagnose ectopic pregnancies.

Serum progesterone

Progesterone, a C-21 hormone, is essential in early pregnancy for decidual function, implantation, reduction in immune response and myometrial quiescence. It is produced entirely by the corpus luteum until the sixth week of gestation. The trophoblastic contribution begins from the seventh week and becomes the predominant source by the 12th week. Progesterone concentrations continue to rise until 7 weeks of gestation and then plateau until 10 weeks, after which there is a gradual increase until term. In the conception cycle, progesterone concentrations are 2–4 nmol/l on the day of the luteinizing hormone surge and rise to 20–70 nmol/l a week later. At term, concentrations vary from 200 to 600 nmol/l.

Progesterone concentrations have been widely used for the diagnosis and management of pregnancies of unknown location (PUL, i.e where ultrasound is inconclusive). In failing pregnancies, whether ectopic or miscarriage, progesterone concentrations are expected to be low compared with values in healthy ongoing pregnancies (Hahlin et al 1990). Most studies report cut-off concentrations of less than 16 nmol/l for failing pregnancies and more than 80 nmol/l for healthy ongoing pregnancies (Mathews et al 1986, Sau and Hamilton-Fairley 2003, Bishry and Ganta 2008). Progesterone levels over 25 nmol/l are ‘likely to indicate’ and levels over 60 nmol/l are ‘strongly associated with’ pregnancies subsequently shown to be normal. A progesterone concentration below 25 nmol/l in an anembryonic pregnancy has been shown to be diagnostic of non-viability (Elson et al 2003). Concentrations less than 20 nmol/l have a sensitivity of 93% and a specificity of 94% for the prediction of spontaneous resolution of PULs (Banerjee et al 2001). A meta-analysis has demonstrated that a single serum progesterone measurement is good at predicting a viable intrauterine or failed pregnancy, but is not useful for locating the site of pregnancy (Mol et al 1998). When interpreting progesterone measurements, variations in concentrations should be taken into account because of the assay methods, and a departmental protocol should state the normal range for that unit.