Chapter 161

Ectopic Pregnancy

Marie Elena Botte

Definition and Epidemiology

Ectopic pregnancy (from the Greek ektopos, meaning “out of place”) occurs when a fertilized ovum implants anywhere outside of the uterus. Ectopic pregnancy occurs in up to 2.6% of pregnancies¹ and in 6% to 16% of women who visit the emergency department with pain or bleeding (or both) in early pregnancy. The mortality rate related to ectopic pregnancy is still high,³ even in developed countries; ectopic pregnancy is the second leading cause of maternal mortality and the leading cause of pregnancy-related death in the first trimester, representing approximately 6% to 9% of maternal deaths.²^,⁴ The rate of ectopic pregnancy in the United States has risen dramatically in the past few decades.⁴ Prevalence has risen sixfold since 1970, peaking in the late 1980s, perhaps because of an attendant increase in sexually transmitted diseases, increased frequency of sterilization procedures, and delayed childbearing. The incidence plateaued around the turn of the 21st century and has since increased, perhaps in part related to worldwide increases in chlamydia infections.⁵ The rate of ectopic pregnancy has been found to increase dramatically after the age of 30 years, especially beyond the age of 35 years.

Identified risk factors⁶ for ectopic pregnancy are all maternal, and include tubal pathologic conditions and infections, prior tubal surgery including sterilization, particularly at younger (<28) age,⁷ prior ectopic gestation,⁸ in vitro fertilization (embryo transfer and assisted hatching), endometriosis,⁹ irritable bowel syndrome,¹⁰ and smoking. In one Danish historical prospective controlled cohort study, daughters of mothers who experienced ectopic pregnancy had a 50% higher risk of ectopic gestation.¹¹ Prior medical abortion is not associated with increased risk. Risk of rupture is increased with parity and previous ectopic gestation.

Risk factors for ectopic pregnancy should be elicited for any woman when pregnancy is suspected, although identifiable factors may be absent in many women with ectopic gestation. Risk factors that interfere with fallopian tube function include past or current history of sexually transmitted infections and pelvic inflammatory disease (PID) (including recurrent chlamydial infection), pregnancy occurring while taking oral contraceptives (because of the mechanism of action of the birth control pill on the ciliary movement of the fallopian tube), previous history of ectopic pregnancy, history of infertility, in utero diethylstilbestrol (DES) exposure, documented tubal pathologic condition, prior appendectomy or pelvic operation, cesarean section, prior tubal sterilization or operation (Essure¹²), history of in vitro fertilization, and congenital malformation of the fallopian tubes. Cigarette smoking, vaginal douching, multiple sexual partners, and early age at first intercourse have weaker evidence for association. Although intrauterine devices do not increase the risk for ectopic pregnancy, pregnancies that occur with these devices in place are more likely to be ectopic. Previous induced abortion has not been associated with subsequent ectopic pregnancy.

Pathophysiology

Proposed pathophysiologic explanations for ectopic pregnancy include abnormal embryogenesis (with serious chromosomal aberration in one third of cases), ascending Chlamydia trachomatis infection that scars the fallopian tubes, and luteal phase defects. History of or current PID and in utero DES exposure may also result in ectopic gestation. Cases have been reported that involve clear cell hyperplasia of the fallopian tube development in a cesarean section scar and occurrence after ethinyl estradiol–levonorgestrel for emergency contraception. Although implantation can occur anywhere on the cervix, in the abdomen, or on the ovary, 95% of ectopic pregnancies implant in the distal portion of the fallopian tube, and on the ipsilateral side to the corpus luteal cyst.

Cervical pregnancy is the rarest form of ectopic pregnancy (accounting for less than 1% of all ectopic pregnancies), and has been associated with cervicouterine instrumentation. Ovarian pregnancy has been associated with ovulation induction, intrauterine insemination, and vaginal douching. Heterotopic pregnancy (simultaneous intrauterine and extrauterine gestations) is increasing in incidence, occurring in 0.3% to 0.8% of the general population and 1% to 3% of women whose pregnancies resulted from assisted reproductive technologies.² Persistent ectopic pregnancy involves residual trophoblastic activity and a beta-human chorionic gonadotropin (β-hCG) level that rises or plateaus, whereas chronic ectopic pregnancy contains no active trophoblastic tissue and results in an hCG level that is low or absent.

Clinical Presentation

Symptoms of unruptured ectopic pregnancy can be vague and subacute. The most common symptom of ectopic pregnancy is abdominal pain, which may manifest in isolation or in combination with vaginal bleeding or spotting, dizziness, and shoulder pain (which suggests blood irritating the diaphragm); symptoms typically appear between 6 and 12 weeks of gestation. Amenorrhea for 1 to 2 months and the usual early signs of pregnancy (nausea, fatigue, breast heaviness) are often part of the initial presentation. Women can also be seen with generalized or unilateral pelvic or abdominal pain described as sharp, cramping, continuous, or intermittent. Less common presenting symptoms include acute urinary retention and abnormal dark, scant vaginal bleeding. Painless vaginal bleeding is the most common presentation for cervical pregnancy. Pain that radiates to the shoulder is more common in a ruptured ectopic pregnancy. Acute syncopal episodes and hypotension are possible secondary to rupture-induced peritoneal hemorrhage. Chronic ectopic pregnancy usually appears as a pelvic mass, with minimum symptoms such as intermittent pain and a low or absent hCG titer.

Physical Examination

Any suspicion of ectopic pregnancy warrants a thorough physical examination, although the history and physical examination, with a combined sensitivity of 50%, can neither exclude nor confirm an ectopic pregnancy. Postural vital signs and temperature are essential to indicate the presence of hypotension or infection. Speculum examination may reveal a bulging cul-de-sac (indicative of hemoperitoneum in rupture), a bluish coloration of the cervix (a normal finding in any pregnancy), and vaginal bleeding or spotting (the uterus is not able to maintain a stable endometrium at low hCG levels). Uterine enlargement occurs in roughly one fourth of women with ectopic pregnancy, but its size may be less than expected according to dates (generally smaller than expected size at 8 weeks). Approximately 75% of women with ectopic pregnancies have abdominal tenderness, but the abdominal examination findings may be normal if the ectopic pregnancy has not ruptured; cervical motion tenderness may also be present. An adnexal mass, involuntary guarding, and peritoneal signs, although uncommon, are highly predictive of ectopic gestation.

The pelvic examination may also reveal signs that suggest a cause other than ectopic pregnancy as the source of the bleeding, such as hemorrhoids, urethral irritation, cervical lesions, or condyloma. Although tissue at the os is a sign of spontaneous abortion and an open os and heavy vaginal bleeding are predictive of an abnormal intrauterine pregnancy, absence of these signs does not differentiate ectopic from intrauterine gestation.

Diagnostics

Pregnancy tests have become increasingly sensitive in recent years and are the first step in the diagnosis of any suspected ectopic pregnancy. The slope of a rising hCG titer has been found to be a useful determinant of early ectopic pregnancy below the ultrasonographic discriminatory zone. In normal pregnancy, this titer doubles every 1.4 to 3.5 days, with a minimum of 66% increase suggesting viable pregnancy in clinical practice; a titer that plateaus or falls suggests either ectopic pregnancy or miscarriage, although some ectopic pregnancies (and nonviable intrauterine pregnancies) do have abnormally rising hCG levels.

One prospective study that sought to distinguish viable pregnancy from ectopic pregnancy and spontaneous miscarriage at presentation (of women to the emergency department with abdominal pain and a positive pregnancy test) with single point biomarkers¹³ found that a serum hCG level below 3736 mIU/mL was 100% sensitive, and 76% specific, for distinguishing ectopic from viable pregnancy, but that these measurements alone could not distinguish between ectopic gestation and spontaneous miscarriage. Serum CA-125 level below 41.98 U/mL, however, was 100% sensitive and 43% specific in distinguishing ectopic gestation from spontaneous miscarriage. The study suggested that the serial use of hCG and CA-125 cutoffs followed by ultrasound could detect 100% of ectopic pregnancies with 87% specificity for intrauterine gestation. Recent evidence suggests that declining hCG levels in spontaneous abortions can be distinguished from those in ectopic gestation; ectopic gestation (or retained trophoblastic tissue) has a rate of decline that is less than 21% at 2 days or 60% at 7 days. Because nearly all ectopic pregnancies have hCG titers less than 50,000 mIU/mL, a single value above this level can help rule out ectopic pregnancy.

Initial diagnostic tests also include a complete blood count (CBC) (because women with ectopic gestation are often anemic) and a blood type and Rh determination. Serum progesterone is a useful marker of viable pregnancy¹⁴ (levels above 22 ng/mL); levels below 16 ng/mL are consistent with a failing pregnancy (whether ectopic or miscarriage), and levels below 5 ng/mL indicate nonviable pregnancies with nearly 100% sensitivity.

Ultrasonography, particularly transvaginal sonography, is the single best diagnostic tool for demonstration of viable intrauterine pregnancy, nonviable pregnancy, and ectopic gestation.¹⁵ Ultrasound can reliably diagnose a failed pregnancy¹⁶ in an embryo larger than 7 mm (crown rump length) in the absence of cardiac activity or the absence of an embryo when the mean sac diameter is in excess of 25 mm. Spontaneous heterotopic pregnancy was once so rare that detection of intrauterine pregnancy on ultrasound essentially ruled out ectopic gestation, but the incidence of these simultaneous intrauterine and extrauterine pregnancies has been increasing.

At low hCG levels, ultrasound is often nondiagnostic; but when hCG levels are greater than 1800 mIU/mL, sonography is helpful in establishing the location and viability of the pregnancy and is an essential investigation for all women requesting termination of pregnancy. At hCG levels of 1500 to 1800 mIU/mL, a gestational sac should be visible⁴ on transvaginal ultrasound (in a singleton pregnancy); at more than 5000 mIU/mL, a yolk sac is visible. When hCG levels are 2000 mIU/mL or more and the mean sac diameter is 3 mm or more, the sensitivity for diagnosis of an intrauterine pregnancy is increased. The β-hCG discriminatory zone (the hCG level at which, if no intrauterine pregnancy is visualized on ultrasound, one can be reasonably confidant that a healthy singleton intrauterine pregnancy is not present¹⁷) is debated at somewhere between 1000 and 2500 mIU/mL¹⁸^,¹⁹ and is a surrogate marker for gestational age. Transvaginal ultrasound has been shown to be effective at diagnosis of ectopic gestation at even lower levels for some patients. Ultrasound can detect ectopic pregnancy in one third of women with β-hCG levels of less than 1000 mIU/mL. By 3 weeks after missed menses, virtually all viable intrauterine pregnancies, half of nonviable intrauterine and viable ectopic pregnancies, and one fourth of nonviable ectopic pregnancies can be detected with this method. A trilaminar pattern (specific but not sensitive in ectopic pregnancy) and the thickness of the endometrium (it is thinner in ectopic gestation) as well as something called the leash sign¹² have also been studied as ways to differentiate ectopic from viable uterine gestations on ultrasound examination.

There is broad agreement regarding the combined use of transvaginal sonography and β-hCG levels in evaluating possible ectopic gestation, because of an ability to detect earlier and smaller ectopic pregnancies without the attendant risks of a surgical procedure. When ultrasound findings are indeterminate, diagnostic laparoscopy is considered by many to be the definitive test for diagnosis of ectopic pregnancy. However, the advent of new strategies, particularly very sensitive pregnancy tests and ultrasonography, contributes to “nearly perfect” noninvasive diagnostic acumen and permits medical management of the condition in carefully selected instances.

Diagnostics

Ectopic Pregnancy

Laboratory