Ectopic and Heterotopic Pregnancies

Ectopic and Heterotopic Pregnancies

Omri Zamstein

Eyal Sheiner

Arnon Wiznitzer

Ectopic Pregnancy


Ectopic pregnancy, ie, implantation of a fertilized ovum outside the uterus (Figure 3.1), is a major health problem for women of reproductive age and is a leading cause of pregnancy-related death during the early stages of gestation.1 The actual incidence of ectopic pregnancy is difficult to determine because a significant portion of cases can now be safely treated in an ambulatory setting. In addition, incidence rates vary among different populations (ie, there is increased risk among African American women compared with Caucasian women) and between different geographical locations (ie, in developed vs low- to middle-income countries).2 Nonetheless, rates have been observed to steadily increase during the last decades3, owing to more sensitive diagnostic measures and higher prevalence of predisposing conditions, such as pelvic inflammatory disease, among high-risk populations.4 Ectopic pregnancy is currently believed to account for 2% of all pregnancies, with an annual rate of up to 0.6% among women of reproductive age.2 Importantly, ruptured ectopic pregnancy accounts for around 3% of all pregnancy-related mortality, and thus accurate diagnosis and treatment of ectopic pregnancy decrease this risk and additionally optimize subsequent fertility outcomes.1

Etiology and Risk Factors

The leading site of ectopic pregnancy is the fallopian tube, although implantation may take place in the abdominal cavity or the adjacent pelvic viscera (ie, ovary, cervix, broad ligament, and cesarean scar) with less frequency.5 The most commonly cited risk factors for ectopic pregnancy share a common etiology of tubal obstruction and injury. Previous episodes of pelvic inflammatory disease, especially when caused by Chlamydia trachomatis, are also major risk factors for ectopic pregnancy.6 This pathogen has been suggested to enhance the expression of a chemoattractant protein along the tubal epithelium, thus promoting ectopic implantation.7 In comparison to normal pregnancies, the adjusted odds ratio for ectopic pregnancy after a pelvic infectious disease was found to be 3.4 (95% confidence interval: 2.4-5.0).8 Other factors associated with an increased risk of ectopic pregnancy include prior ectopic pregnancy (which increases the risk for subsequent ectopic pregnancy 10-fold), a history of infertility (and specifically in vitro fertilization), cigarette smoking (causing alterations in tubal motility and ciliary activity), prior tubal surgery, diethylstilbestrol exposure (which alters fallopian tube morphology), and advanced maternal age older than 35 years.

Intrauterine contraceptive devices (IUDs), progesterone-only contraceptives, estrogen/progestin contraceptives, and sterilization hinder conception at any location and thus protect women against developing an ectopic pregnancy.9,10,11 However, if a woman using these contraception methods becomes pregnant, her risk for an ectopic pregnancy is increased, as these methods of contraception provide greater protection against intrauterine pregnancy than against ectopic pregnancy. For example, one large multicenter study found a 7- and 21-fold higher risk of ectopic pregnancy after failure of tubal sterilization and IUD contraception, respectively.10 The risk for ectopic pregnancy also varies with the method of tubal sterilization, with laparoscopic electrodestruction and partial salpingectomy conferring the highest risk,11 but decreases to some extent after reversal of sterilization.10

Although the risk of ectopic pregnancy for women who undergo assisted reproductive technology treatments has generally declined throughout the years,12 these women are still at increased risk for ectopic pregnancy as fallopian tube pathology underlies both the need for in vitro fertilization and the tendency for abnormal implantation.13 Other contributing factors include transfer of multiple embryos, fresh versus frozen cycles, and implanting cleavage state compared to blastocyst transfer.12,14

Hormonal alterations during ovulation induction have been suggested to affect tubal function and peristalsis and increase uterine contractility, thus promoting a retrograde movement of the embryo toward the fallopian tube.12 Other less common causes of ectopic pregnancy include salpingitis isthmica nodosa (anatomic thickening of the fallopian tube with epithelium leading to multiple lumen diverticula) and possibly vaginal douching and multiple sexual partners, which both lead to a higher risk of pelvic infections.15,16

Laboratory Assessment

β-Human Chorionic Gonadotropin

The first stage in the evaluation of women with a suspected ectopic pregnancy is to determine if the patient is pregnant. The β-human chorionic gonadotropin (β-hCG) enzyme immunoassay, with a sensitivity of 25 mIU/mL, is an accurate screening test and is positive in virtually all cases of normal as well as ectopic pregnancies.20

The levels of β-hCG increase during early stages of gestation to reach a peak of approximately 100,000 mIU/mL at 8 to 12 weeks.1,20 Several studies have evaluated the increase of β-hCG in normal and abnormal pregnancies. The level of β-hCG in normal pregnancies usually doubles every 2 days, and thus clinicians rely on a normal “doubling time” to characterize a viable gestation. Although there is a consensus that the predictable rise in serial β-hCG values in a viable pregnancy is different from the slow rise or plateau of an ectopic pregnancy, it should be remembered that a slower rise does not rule out normal pregnancy. This observation was encountered during multiple consultations given by the United States hCG Reference Service of pregnancies, which reported lower-than-expected rates of increase of β-hCG in women who eventually had normal term deliveries.20 Similar conclusions were drawn by Barnhart and coauthors21 who showed a slower rise in serial β-hCG values among women with viable intrauterine pregnancies. The slowest rise for a normal viable intrauterine pregnancy was 24% at 1 day and 53% at 2 days.

The discriminatory threshold is a level of β-hCG above which intrauterine gestation is expected to be visualized. If no intrauterine gestation is seen, it
is often assumed to be ectopic and treated accordingly. However, given the overlap of the discriminatory threshold of β-hCG in viable intrauterine pregnancies and ectopic pregnancies, the chance of unintended termination of a normal pregnancy, and the treatment consequences of nonviable pregnancy, β-hCG alone cannot accurately determine the viability and location of pregnancy.22 Further complicating laboratory evaluation based on β-hCG alone is the presence of a multifetal gestation, which is associated with elevated rates of β-hCG.23 Therefore, choosing a higher discriminatory threshold of β-hCG >3500 mIU/mL24 and carrying out additional testing, if hemodynamic status permits, can help consolidate the diagnosis.25

Serum Progesterone

Serum progesterone levels are of limited clinical value in the diagnosis of ectopic pregnancy but can be useful in evaluating the chances of early pregnancy failure. If a normal interaction between the trophoblast and corpus luteum is established, serum progesterone levels are expected to gradually increase.26 A baseline serum progesterone level of >60 nmol/L usually indicates a normal pregnancy, whereas levels <20 nmol/L can be used to identify abnormal pregnancy (either intra- or extrauterine) with a positive predictive value (PPV) of ≥95%.26,27 A meta-analysis that evaluated the utility of single progesterone measurement during early pregnancy found progesterone levels between 10.2 and 19.1 nmol/L effectively rule in a diagnosis of
nonviable pregnancy. However, progesterone levels had low accuracy for distinction between an ectopic and a nonectopic pregnancy.28 Although not routinely obtained in adjunct, low progesterone levels combined with low β-hCG levels can suggest spontaneous resolution of ectopic pregnancy.29 In summary, serum progesterone levels cannot distinguish ectopic pregnancy from spontaneous abortion. Thus, progesterone levels at defined times can be used to predict the immediate viability of a pregnancy, but cannot be used reliably to predict its location.30


Transvaginal ultrasound is the most sensitive tool for determining the location of pregnancy1 and is especially useful for the diagnosis of ectopic pregnancy.31 Unfortunately, although ultrasonographic visualization of extrauterine pregnancy with a yolk sac or embryo has a specificity and PPV approaching 100% in detecting ectopic pregnancy,32 it is not seen at all events, and up to 31% of suspected cases do not exhibit radiological signs of either uterine or extrauterine pregnancy.25 Factors that may impede visualization of ectopic pregnancy include lower gestational age, smaller ectopic mass, large body habitus, and uterine or ovary anatomical pathology that obscure the adnexa.31 It is generally agreed that a normal intrauterine pregnancy should be seen by transvaginal ultrasound beginning 5 weeks of gestation or when β-hCG levels reach between 1000 and 2000 mIU/mL, although higher β-hCG levels have been suggested as the discriminatory threshold for ultrasound, thus avoiding injury to a not-yet-visualized but viable pregnancy.24,33When the β-hCG level exceeds the transvaginal discriminatory zone, the absence of an intrauterine gestational sac is suggestive of ectopic pregnancy, but the differential diagnosis includes failed intrauterine pregnancy.

If an intrauterine pregnancy is detected, this is taken to exclude a diagnosis of ectopic pregnancy because coexistent intra- and extrauterine pregnancies (heterotopic) following spontaneous cycles are rare, with an estimated incidence of 1 in 30,000 normal pregnancies. However, the incidence of heterotopic pregnancy is increased by the use of assisted reproductive technology, with an incidence of up to 1 in 100 pregnancies.34

The early sonographic appearance of a normal gestational sac is characterized by the double decidual sac sign, that is, two concentric echogenic rings separated by a hypoechogenic space (see Chapter 12 for additional discussion). The double sac is believed to be the decidua capsularis and decidua parietalis. The double decidual sign is useful to the physician for early diagnosis of intrauterine pregnancy and for the exclusion of ectopic pregnancy. Based on the evaluation of 67 intrauterine fluid collections, Richardson and coauthors concluded that the double decidual sign had a sensitivity of 93.9%, specificity of 100%, and a PPV of 100% for predicting an intrauterine pregnancy even prior to identification of embryonic contents.35 However, the appearance of an intrauterine sac can be seen in up to 15% cases of ectopic pregnancy owing to intrauterine fluid or blood collection, that is, a pseudosac. A pseudosac is a uterine sac without a double decidual ring or a yolk sac. Indeed, the report of a pseudosac is significantly associated with a false-positive diagnosis of ectopic pregnancy.35

Other sonographic findings suggestive of an ectopic pregnancy are an empty uterus, adnexal mass, and free fluid in the pouch of Douglas, although all have poor sensitivity and thus do not effectively rule out the possibility of a tubal pregnancy.36 The presence of peritrophoblastic low-resistance, high-velocity blood flow pattern (“ring of fire”) evident by Doppler ultrasound is of limited diagnostic value as it is also a typical feature of corpus luteum cysts.37

Dilation and Curettage

When serial β-hCG levels do not rise or fall appropriately, an abnormal gestation exists. When the pregnancy has been confirmed to be nonviable and ultrasound is not sufficient, a uterine dilation and curettage can help distinguish between an ectopic pregnancy and a miscarriage.38 Detection of villi in the tissue obtained indicates the occurrence of spontaneous intrauterine abortion with high accuracy and avoids unnecessary exposure to methotrexate, whereas the absence of chorionic villi in the curettage specimen reinforces the possibility of an ectopic pregnancy. A decrease in β-hCG levels of 15% or more a day after the evacuation indicates a complete abortion.39 A plateau or a rise in the β-hCG levels is diagnostic for ectopic pregnancy. Once the possibility of an abortion is excluded, medical or surgical treatment for ectopic pregnancy should be pursued.


Culdocentesis was used as a diagnostic technique for ectopic pregnancy before the widespread availability of the vaginal ultrasound and β-hCG assay. Culdocentesis is positive in around 80% of women with ectopic pregnancy who have hemoperitoneum. In the remaining 20% of cases, the results are nondiagnostic. A nondiagnostic finding cannot be used to exclude ectopic pregnancy, and the test alters management only when it is positive. Thus, it is rarely indicated and is performed only in places where facilities for pregnancy testing and ultrasound are limited.40

Treatment of Ectopic Pregnancy

Cases of ectopic pregnancy can be treated, surgically, medically (methotrexate), expectantly, and occasionally by combinations thereof (Algorithm 3.2). Choice of treatment depends on the clinical scenario, available resources, and the site of ectopic pregnancy and carries prognostic implications on future fertility.41 While laparoscopy is the most common surgical approach,42 laparotomy may be preferred in cases of unceasing intraperitoneal bleeding, clinical signs of impending shock or inadequate visualization of the site of intervention.25 It should be emphasized that ectopic pregnancy is a major cause of hemorrhagic-related death during pregnancy in the United States.43

Medical Treatment With Methotrexate

Methotrexate interferes with DNA synthesis, repair, and cellular replication; therefore, actively proliferating cells, such as the trophoblasts of an ectopic pregnancy, are generally more sensitive to treatment.60,61 Although methotrexate is associated with wide array of adverse reactions, severe toxicity during short-duration treatment for ectopic pregnancy is rarely encountered, and carefully selected patients can benefit from this noninvasive option with similar efficacy and fertility outcomes as compared to the various surgical approaches.58,62 Single-dose and multiple-dose methotrexate regimens exist,63 and the drug is usually given intramuscularly to achieve therapeutic levels. The prerequisites for successful pharmacological treatment are vigilance for the development of complications and adequate follow-up to prove resolution.64

Candidates for Medical Therapy

Hemodynamically stable patients without active bleeding or signs of hemoperitoneum are candidates for medical therapy. Contraindications for methotrexate treatment are summarized in Table 3.1. Absolute contraindications to medical therapy include breastfeeding; immunodeficiency; alcohol abuse; hepatic, pulmonary, renal, or hematological dysfunction; known sensitivity to methotrexate; blood dyscrasias; or peptic ulcer disease.1 Factors that may predict treatment failure and are regarded as relative contraindications for methotrexate treatments include embryonic cardiac activity, gestational sac greater than 4 cm in size, and serum β-hCG levels of more than 5000 mIU/mL.1,65 The presence of any of these suggest a relatively established gestation that would be less likely to respond to medical treatment alone.

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Ectopic and Heterotopic Pregnancies
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