Ectopic Pregnancy

Pavitra Kotini-Shah

Komal Paladugu

OVERVIEW

Ectopic pregnancy (EP) is a high-risk pregnancy in which the fertilized ovum implants outside of the endometrium of the uterus. It affects approximately 2% of all pregnancies and is linked to 9% of all pregnancy-related deaths in the United States.¹ Of all first-trimester pregnancies presenting to the emergency department (ED) with vaginal bleeding, lower abdominal pain, or both, up to 18% go on to be diagnosed with an EP.¹^,² According to the Centers for Disease Control and Prevention (CDC), the number of EPs increased from 17,800 cases diagnosed in 1970 (0.5% of all pregnancies) to 108,800 cases (2% of all pregnancies) in 1992, the final year of the national surveillance data update.³ The higher rate of EP is attributed to increasing incidence of pelvic inflammatory disease (PID), invasive gynecologic procedures, infertility treatments, and earlier detection.²

BACKGROUND

In contrast to the increased rate of EPs, its mortality rate has drastically decreased. The mortality rate 200 years ago exceeded 60%, whereas it is now 8% to 9% of all pregnancy-related mortality and less than 1% of all-cause mortality.⁴ The most frequent causes of death from EP are hemorrhage, anesthetic complications, and infection. The clinical presentation of EP varies widely as patients may present anywhere along the spectrum of hemodynamically stable to hemorrhagic shock. Confounding factors for EPs include initially being misdiagnosed as an intrauterine pregnancy (IUP), PID, gastrointestinal disorder, or psychiatric disorder. Delay in diagnosis and treatment can have significant and devastating repercussions.

Historically, EP was primarily managed as an inpatient admission. However, advances in sensitive immunologic assays (beta human chorionic gonadotropin [β-hCG]), accessibility of transvaginal ultrasounds, the ability to detect a gestational sac less than 3 mm, and the availability of diagnostic laparoscopy have allowed for earlier diagnosis prior to rupture. These advances have resulted in an 80% reduction in mortality rate.⁴ This reduction in mortality has in turn changed the management of EPs, which is now primarily a multiple outpatient encounter process.

PATHOPHYSIOLOGY

Fertilization generally takes place when the oocyte and sperm meet in the ampullary portion of the fallopian tube. The zygote transitions into a morula, with further differentiation into a trophoblast, followed by an embryoblast, occurring concomitantly with movement into the uterine fundus, with implantation taking place approximately 6 to 7 days after conception. Epithelial cilia assist in
tubal transport of the fertilized egg to the uterus and implantation site. Estrogen and progesterone have antagonistic effects on the growth and movement of the epithelial cilia. Estrogen promotes growth and differentiation of the cilia, whereas progesterone causes loss and atrophy of these cells.⁵

Figure 13.1: Possible sites for ectopic pregnancies. (Reproduced with permission from Auckland A. Sonographic assessment of the ectopic pregnancy. In: Stephenson SR, Dmitrieva J, eds. Diagnostic Medical Sonography: Obstetrics and Gynecology. Philadelphia, PA: Wolters Kluwer; 2018:375.)

The most common locations for EPs are the ampulla (70%), isthmus (11%-12%), fimbriae (11%-12%), and interstitial part of the fallopian tube (3%) (Figure 13.1).⁶^,⁷ Overall, the fallopian tube, which consists of the ampulla, isthmus, fimbriae, and interstitial part of the tube, accounts for 90% to 95% of EP locations. Other rare locations in decreasing frequency are hysterotomy scar, abdomen, ovary, cervix, and rudimentary horn. The locations most often associated with an early diagnosis of EP of less than 6 weeks, diagnosis at lower β-hCG levels, and with hemoperitoneum were ampulla, isthmus, followed by fimbriae.⁶

RISK FACTORS

Emergency providers should identify historical risk factors and assess for clinical risk factors for EP. Conditions that affect the ciliary motility and smooth muscle contractions in the transport of the fertilized ovum through the fallopian tubes may predispose a woman to develop an EP.⁵ Four major factors increase the risk of EP: (1) abnormalities in the tubal epithelium due to prior infection or tubal surgery, (2) prior EP, (3) external factors such as use of an intrauterine device (IUD), and (4) assisted reproductive techniques.⁵^,⁶^,⁷^,⁸^,⁹ Table 13.1 lists the multitude of risk factors that cause adhesions in the fallopian tubes, thereby preventing transport of the zygote to the uterine cavity. Additional risk factors for EP include being non-Caucasian, T-shaped uterus, fibroids, and progestin-only IUD use. IUD use is highly effective at preventing pregnancy; however, if a pregnancy does occur, there is a 53% chance of developing an EP.¹⁰ IUD usage has specifically been linked to an increased risk of ovarian or abdominal implantations.⁶

Studies show that there is no associated increased risk of EP with oral contraceptive pill (OCP) use, prior elective pregnancy termination, pregnancy loss, or cesarean section delivery.⁸ Prior EP increases the recurrence risk of an EP, with proportions increasing relative to the number of prior EPs.¹¹ In women with one prior EP there is a threefold higher chance of having a recurrent EP. With two or more prior EPs, there is a 16 times higher likelihood of recurrence.⁸^,¹¹ Furthermore, 30% of women treated for EPs have difficulty conceiving. The conception rate in females with a history of EP is 77%.⁹ Women with a history of infertility and using assisted reproductive techniques are at risk of having an EP in concurrence with a live IUP, referred to as a heterotopic
pregnancy.¹² Heterotopic pregnancy is extremely rare in naturally conceived pregnancies, ranging from 1 in 4,000 to 1 in 30,000, whereas with in vitro fertilization (IVF)-supplemented pregnancies, it can be as high as 1 in 100.¹²^,¹³

TABLE 13.1 Risk Factors That Predispose to Ectopic Pregnancies

Risk Factors		Odds Ratio (OR), Confidence Interval (CI)
Prior tubal surgery		21, 9.3%-47%
Sterilization techniques		9.3, 4.9%-18%
Prior ectopic pregnancy		8.3, 6%-11.5%
In utero exposure to diethylstilbestrol		5.6, 2.4%-13%
Current intrauterine device use		5, 1.1%-2.8%
History of pelvic inflammatory disease		3.4, 2.4%-5.0%
Infertility > 2 y		2.7, 1.8%-4.2%
Advanced maternal age
	>40 y	2.9, 1.4%-6.1%
	35-39 y	1.4, 1-2%
Smoking
	≥ 20 cigarettes/d	3.9, 2.6%-5.9 %
	10-19 cigarettes/d	3.1, 2.2%-4.3 %
	1-9 cigarettes/d	1.7, 1.2%-2.4 %
	Past smoker	1.5, 1.1%-2.0%
From Barash JH, Buchanan EM, Hillson C. Diagnosis and management of ectopic pregnancy. Am Fam Physician. 2014;90(1):34-40; Lozeau A, Potter B. Diagnosis and management of ectopic pregnancy. Am Fam Physician. 2005;72(9):1707-1714.

CLINICAL FEATURES

History

Common symptoms of EP include lower abdominal pain and vaginal bleeding; however, fewer than 50% of women presenting for evaluation have these classic symptoms, and in fact, these particular symptoms may be more indicative of a spontaneous abortion.¹⁴ Many of the symptoms of EP are similar to those of early pregnancy such as breast fullness, amenorrhea, nausea, vomiting, and fatigue. Therefore, a high index of suspicion is warranted in any female of childbearing age, especially in the setting of syncope, to evaluate pregnancy status and EP. The findings of a positive pregnancy test, abdominal pain, and vaginal bleeding have a positive likelihood ratio of 15% for having an EP.¹⁴ Abdominal fullness and abnormal uterine bleeding may be present as the uterus cannot sustain a stable endometrium in the setting of an EP.

Any female patient of reproductive potential presenting with abdominal symptoms must be asked about her last menstrual period (LMP) including timing, regularity, and characteristics of the menses, as well as prior pregnancies or complications, risk factors for EP, quality of the abdominal pain, vaginal bleeding or spotting, and syncopal episodes. Any referred pain to the shoulder or neck in the setting of a positive pregnancy test may indicate rupture, with blood causing diaphragmatic and phrenic nerve irritation with C3-C5 nerve root involvement. Additionally, patients may present with symptoms of nausea, vomiting, weakness, and dizziness. Abdominal pain can be alternating and spasmodic with pain-free periods.⁴ Regardless of whether a patient is using contraceptives or not, due to the potentially devastating effects of a missed or delayed diagnosis of EP, all sexually active women of reproductive age require a pregnancy test for any abdominal, vaginal, or urinary symptoms. Up to 40% of EPs have a delay in diagnosis beyond their initial presentation.¹⁴
Rare types of EP, such as interstitial pregnancy and cervical pregnancy, present later (8-10 weeks) and with catastrophic bleeding. Hence, it is prudent to check the pregnancy status of any female of reproductive potential beyond the common classically described symptoms.

Physical Examination

The physical examination of the patient should always begin with vital signs and assessing for hemodynamic compromise such as hypotension, tachycardia, or shock. Bradycardia is a well-established presentation of a ruptured EP caused by hemoperitoneum and vagal stimulation from the left ventricular mechanoreceptors.¹⁵ These are late stage presentations that require an emergent evaluation by a gynecologist and surgical management. The examination may yield focal unilateral lower quadrant tenderness, flank pain, back pain, a peritonitic abdomen with rebound, guarding, and diffuse tenderness, cervical motion tenderness (CMT), or adnexal fullness/mass.¹⁴ The absence of findings such as CMT, adnexal mass/tenderness, or peritonitis does not exclude EP. If products of conception are seen in the cervical os, the most likely etiology is a spontaneous abortion. Overall, the physical examination itself is not sufficient for the diagnosis of EP and requires additional imaging and laboratory workup. Modern transvaginal ultrasound in combination with β-hCG testing has augmented the diagnostic ability of the physical examination for the emergency provider.

DIAGNOSTIC TESTING

If a urine pregnancy test is positive, further laboratory analysis is necessary including a serum quantitative β-hCG level, complete blood count (CBC), and a blood type and screen. A CBC is necessary to assess for evidence of blood loss. A blood type and screen identifies Rh status to determine if Rho(D) immune globulin is indicated and to prepare blood typing if transfusion is needed. The urine pregnancy test is positive with levels of β-hCG ˜50 mIU/mL or above and is often detectable 7 to 10 days after the first missed menstrual cycle. To increase the accuracy of the test, especially in early pregnancy, it is useful to get the most concentrated urine such as the first morning urine. The urine pregnancy test is a chromatographic immunoassay. There are several reasons a urine pregnancy test can have a false negative, including testing too soon after a missed menstrual cycle or dilute urine from drinking coffee or excessive fluids. Definitive diagnosis of an EP is confirmed via ultrasonography or laparoscopy.

Hormonal Assays

β-hCG, a hormone released by the placenta in response to pregnancy, promotes maintenance of the corpus luteum during the initial stages of pregnancy. As a result, the corpus luteum secretes progesterone that enables the uterus to increase the endometrial lining with enough vascularity to sustain the growing fetus.

Serum pregnancy tests are highly accurate, being able to detect β-hCG levels as low as 5 mIU/mL. This quantitative measure is most important at less than 12 weeks’ gestation, as the β-hCG level doubles approximately every 2 days until 9 to 10 weeks gestation, after which there is a steady plateau, followed by a decline. Therefore, the quantitative β-hCG is not useful in the assessment of pregnancy beyond during the first trimester. There is individual variation in β-hCG hormone levels with each pregnancy; therefore, trends of β-hCG are more important than a single level. There is no β-hCG level that can be used as a cutoff for the evaluation of EP using a transvaginal or transabdominal ultrasound.

To increase the diagnostic accuracy of identifying a live IUP, levels of β-hCG, referred to as discriminatory zones, have been established. The discriminatory threshold is the β-hCG level at which the sensitivity of the ultrasound is thought to approach 100% for the detection of an IUP or a presumptive diagnosis of EP if IUP is not visualized. The discriminatory zone for a transvaginal ultrasound is a β-hCG greater than 1,500 mIU/mL and for a transabdominal ultrasound a β-hCG

of greater than 5,000 to 6,000 mIU/mL.¹⁶ A β-hCG level of 6,000 to 6,500 mIU/mL correlates with 5 to 6 weeks gestational age.

TABLE 13.2 Differential Diagnosis for a Pregnant Female

	Clinical Presentation and Physical Examination							Labs	Ultrasound Findings
Type of Pregnancy	Missed Menses	Lower Abdominal Pain/Cramping	Vaginal Bleeding	Nausea	Vomiting	Syncope	Clot Passage	UPreg/β-hCG	Ultrasound Findings
Ectopic	X	X	X	X	X	X		+	No evidence of live IUP
Ectopic	Physical Examination: os closed, blood in os, no CMT/adnexal tenderness, ± unilateral adnexal TTP± peritonitis								No evidence of live IUP
Threatened	X	X	X	X	X			+
Threatened	Physical Examination: os closed, blood in os, no CMT/adnexal tenderness, BLQ ± lower abdominal TTP								Evidence of gestational sac/yolk sac ± fetal heart tones
Incomplete	X	X	X	X	X		X	+
Incomplete	Physical Examination: os open, blood in os, visualized products of conception, no CMT/adnexal tenderness, BLQ ± lower abdominal TTP								Evidence of gestational sac/yolk sac ± fetal heart tones
Inevitable	X	X	X	X	X		X	+
Inevitable	Physical Examination: os open, blood in os, visualized products of conception, no CMT/adnexal tenderness, BLQ ± lower abdominal TTP								Evidence of gestational sac/yolk sac ± fetal heart tones OR
Missed	X	X	X	X	X		X	+
Missed	Physical Examination: os closed, ± blood in os, no CMT/adnexal tenderness, BLQ ± lower abdominal TTP								Evidence of fetal demise inappropriate for dates
Heterotopic	X	X	X	X	X		X	+
Heterotopic	Physical Examination: os closed/open, ± blood in os, no CMT, ± unilateral adnexal tenderness, BLQ ± lower abdominal TTP, ± peritonitis								Evidence of intrauterine gestational sac/yolk sac ± fetal heart tones ± adnexal mass ± pelvic free fluid
β-hCG, beta human chorionic gonadotropin; BLQ, bilateral lower quadrant; CMT, cervical motion tenderness; IUP, intrauterine pregnancy; TTP, tenderness to palpation.