Vaginal bleeding in early pregnancy is a relatively frequent occurrence, with 15% to 28% of pregnant women reporting bleeding in the first trimester.^1–4 Despite the high frequency of this concerning symptom, approximately half of women with bleeding in early pregnancy will continue to have an ongoing pregnancy.^3,5 The other half will experience early pregnancy loss (EPL). The term EPL is used in this chapter to describe abnormal intrauterine pregnancies (IUPs) in the first trimester and includes a variety of conditions encompassed by the terms miscarriage or spontaneous abortion (listed in Table 54-1). Like vaginal bleeding in early pregnancy, EPL is common, with miscarriage rates of approximately 15%.^6,7 Ectopic pregnancy and molar pregnancy, though rare, also may present with vaginal bleeding in early pregnancy.

It is not surprising, then, that vaginal bleeding is a common complaint for reproductive-aged women seen in the Emergency Department (ED). One study reports a chief complaint of vaginal bleeding in pregnancy in 1.6% of ED visits.⁸ In the ED/hospital setting, the overall rate of EPL is 30% for women presenting with bleeding, cramping, or both in early pregnancy.⁹ While pregnancy viability and diagnosis of pregnancy failure are important, a missed diagnosis of other rare pregnancy complications, such as ectopic pregnancy or hydatidiform molar pregnancy, can have life-threatening consequences. The clinical picture may be complicated further by pregnancy intention and patient preference. For these reasons, vaginal bleeding in early pregnancy can be clinically challenging. See Box 54-1 for differential diagnosis of first trimester vaginal bleeding.

EPIDEMIOLOGY

The most recent data available from the National Center for Health Statistics reports 6.4 million pregnancies in the United States in 2009, with the following percentage breakdown of outcomes: 65% live birth, 18% induced abortion, and 17% spontaneous fetal losses.¹⁰ One in four women will experience EPL¹¹ during her reproductive life, with advancing maternal age strongly associated with increased risk of miscarriage.¹² Patients in a prospective trial presenting with vaginal bleeding and pelvic pain/cramping were found to have a miscarriage hazard ratio of 5.03 [95% confidence interval (CI) 2.07–12.20].¹³

Early Pregnancy Loss

Greater than 80% of spontaneous abortions occur at < 12 weeks gestation.⁷ Karyotype abnormalities are frequent in EPL, with 50% of first-trimester pregnancies found to have abnormal chromosomal complements. Nearly half of EPLs are anembryonic pregnancies, with no embryonic pole shown on ultrasound. Less common causes of EPL include maternal anatomic defects, infection, environmental toxins, and immunologic factors. A significant number of EPL cases have unknown etiology.

Ectopic Pregnancy

Implantation of the blastocyst anywhere other than the endometrial lining of the uterine cavity defines an ectopic pregnancy. While ectopic pregnancies comprise only 1% to 2% of all first-trimester pregnancies in the United States, they are disproportionately responsible for 9% of all pregnancy-related deaths.¹⁴ More than 90% of ectopic pregnancies implant in the Fallopian tube. Other rare implantation sites include the peritoneal cavity, ovary, cervix, or prior cesarean scar (Fig. 54-1). Rarely, a multifetal pregnancy will include an IUP and an ectopic pregnancy.

Historically, these heterotopic pregnancies were thought to occur spontaneously in approximately 1 per 30,000 to 40,000 pregnancies. However, with increased use of assisted reproductive technologies (ARTs), the incidence of heterotopic pregnancy has increased to 1 in 7000 overall, with even higher rates seen for some methods of ART.¹⁵

A more significant risk factor for ectopic pregnancy than ART, however, is prior history of ectopic pregnancy. The rate of ectopic pregnancy increases to 10% after one prior ectopic pregnancy and 25% after two prior ectopic pregnancies.¹⁶ Conditions that cause distortions of Fallopian tube anatomy, such as prior sterilization surgery and formation of peritubal adhesions after intraabdominal surgeries for appendicitis or endometriosis, also increase the risk of ectopic pregnancy. In addition, infectious etiologies, such as Chlamydia trachomatis and Neisseria gonorrheae, can elevate the risk of ectopic pregnancy. Some studies report an increase of ectopic pregnancy incidence of up to 9% with a single episode of salpingitis,¹⁷ and an association of a history of pelvic inflammatory disease (PID) and ectopic pregnancy was reported in 2006.¹⁸ Recognition of risk and correct diagnosis of ectopic pregnancy are critical because of the potentially lethal outcome of a ruptured ectopic pregnancy. It is also important to note the potential impact that prior ectopic pregnancy history has on a patient’s future ability to become pregnant, with fertility depending largely upon the status of the remaining Fallopian tube or tubes.¹⁹

Hydatidiform Molar Pregnancy

The term gestational trophoblastic disease (GTD) refers to abnormal trophoblast proliferation and the resulting tumors. GTD includes the benign complete hydatidiform mole (CM) and partial hydatidiform mole (PM) as well as the malignant invasive mole. Differences in karyotype, the presence or absence of embryonic elements, and other criteria are used to classify CMs and PMs (see Table 54-2). The most common presenting symptom of GTD is vaginal bleeding, with 98% of 551 women with molar pregnancy reporting vaginal bleeding in one study.²⁰ In addition, 75% of patients had significant anemia, with hemoglobin < 10. On average, CMs present at earlier gestational ages due to earlier onset of symptoms such as nausea due to higher levels of human chorionic gonadotropin (hCG), and higher incidence of early vaginal bleeding. CMs present on average around 9 weeks, while PMs present on average at 12 weeks.²¹ Molar pregnancies most often occur in women at the extremes of reproductive age.²²

A patient presenting with vaginal bleeding in early pregnancy requires evaluation for hemodynamic stability as well as quantification of bleeding. Laboratory testing includes hemoglobin/hematocrit and Rh status, and a pelvic exam²⁴ may be appropriate. If Rh-negative, the patient should receive 50 µg of Rh(D)-immune globulin (MICRhoGAM).⁷ The combination of transvaginal ultrasonography (TVUS) and serum quantitative hCG allows the diagnosis of IUP, EPL, ectopic pregnancy, and molar pregnancy.²⁵ Definitive diagnosis is often not possible with a single patient encounter, and serial visits may be required.

For undesired pregnancies or pregnancies with abnormally rising hCG, the addition of uterine aspiration can facilitate the exclusion or diagnosis of ectopic pregnancy. Throughout the evaluation process, it is important to communicate frequently with the patient and explain the significance of any diagnostic studies carefully. A patient-centered approach includes addressing questions and providing support and reassurance, while also setting realistic expectations for outcomes based on the clinical scenario.

ULTRASOUND

TVUS is the first essential tool in the evaluation of vaginal bleeding in early pregnancy. Markers of IUP include the gestational sac, yolk sac, embryo, and cardiac activity. These can be readily assessed with bedside TVUS in the ED, often providing immediate diagnosis and appropriate counseling for concerned patients. A finding of cardiac activity on TVUS in early pregnancy without vaginal bleeding has a miscarriage rate of around 5%, compared to 16% with vaginal bleeding.²⁶ In a recent study of 715 pregnant women presenting to the ED with vaginal bleeding, 77% received a diagnosis after initial TVUS: 44% with a viable pregnancy and 33% with a nonviable pregnancy. The remaining 23% had a nondiagnostic ultrasound²⁷ and required additional testing for diagnosis.

Other recent data has challenged the traditional 1500–2000-mI/U hCG level of the discriminatory zone, or the serum hCG level at which a normal IUP’s gestational sac should be visible via TVUS.^28,29 For 99% detection of a normal IUP, a discriminatory level of 3510 mI/U hCG should be used for singleton pregnancies.²⁸

Table 54-3 provides a summary of ultrasound characteristics of early pregnancy by gestational age, including hCG threshold levels and discriminatory levels for the gestational sac, yolk sac, and embryo. In addition, the ultrasonographic criteria for confirming miscarriage for patients with desired pregnancies have been updated recently to prevent misdiagnosis of miscarriage in the case of a normal IUP.^30,31 A nonviable IUP is confirmed with a mean sac diameter (MSD) of ≥ 25 mm without an embryo; in addition, it can be confirmed with a fetal pole of ≥ 7 mm and no cardiac activity.

Ultrasound evaluation of pregnancies that do not meet the criteria for a normal viable IUP may be challenging. Pregnancies with corresponding serum hCG below the discriminatory zone will not be visible on TVUS and may include normal early pregnancies, abnormal IUPs, and ectopic pregnancies. Molar pregnancy always should be considered on the differential for abnormal-appearing ultrasound in the first trimester of pregnancy.³² While ectopic pregnancies sometimes are visualized outside the uterine cavity, frequently TVUS is nondiagnostic in cases of ectopic pregnancy. A final caveat for the use of TVUS is that a fluid collection known as a pseudosac forms in the uterus with some ectopic pregnancies and can be mistaken for a gestational sac. The double decidual reaction (Fig. 54-2) may be used to help differentiate between a pseudosac and a gestational sac.

SERUM HUMAN CHORIONIC GONADOTROPIN

Serum hCG is the second essential tool used in the evaluation of vaginal bleeding in early pregnancy. During normal early pregnancy, the rise in hCG concentration is exponential until about 9 to 10 weeks (Fig. 54-3). Thus a common rule of thumb used in the evaluation of early pregnancy uses the doubling of hCG in 48 hours as confirmation of a normal IUP. It is important to realize, however, that the minimum increase in hCG for a normal IUP in 48 hours is 53%, and the change in hCG over 48 hours in 85% of normal pregnancies is only a 66% increase, rather than 100%.³³ In addition, for a normal IUP, the rate of change of hCG over time as well as the initial hCG value for a given gestational age can differ by race.³⁴ Moreover, studies have confirmed that 17% to 21% of ectopic pregnancies present with a doubling of hCG in 48 hours, paralleling the hCG increase found in a normal IUP (Fig. 54-4).^35,36 Therefore the rule of hCG doubling in 48 hours for a normal IUP should be used with caution. If TVUS has not provided a definitive diagnosis, the use of a third hCG at 96 hours after the initial hCG might be considered, which has been shown to increase pregnancy diagnostic accuracy by 9.3%.³⁷

Similarly, with EPL, there is a 50% decrease of hCG in 48 hours. This rule of thumb should be used carefully, however, as the minimum decline in hCG for resolving pregnancies is 35% to 50% at 48 hours and 66% to 87% at 7 days.³⁸ A slowly falling hCG may indicate EPL, retained trophoblastic tissue, or ectopic pregnancy. In addition, a 2006 study showed that 8% of ectopic pregnancies had a decrease in hCG in 48 hours of > 50%, mimicking the hCG decline in 48 hours for miscarriage (Fig. 54-4).³⁶ The use of hCG for diagnosing a patient with vaginal bleeding in early pregnancy can be very useful, but the limitations of the rules of thumb should be considered carefully within the clinical context. The combined use of additional TVUS and hCG testing beyond 48 hours can confirm the diagnosis.

NONDIAGNOSTIC TESTING AND FUTURE DIRECTIONS IN EARLY-PREGNANCY-LOSS MANAGMENT

A limited amount of data indicates that serum progesterone level is not useful when differentiating among ectopic pregnancy, miscarriage, and normal IUP.³⁹ In a study published in 2013, a serum progesterone level of 10 ng/mL was only 79.3% sensitive for diagnosing nonviable pregnancy, but 93.3% specific for the diagnosis of viable pregnancy.⁴⁰ Biomarkers other than progesterone, such as CA-125,⁴¹ are currently under investigation as indicators of continuing viable pregnancy in patients with bleeding in early pregnancy; however, reported results thus far are inconclusive. In addition, studies have reported conflicting results about the relationship between subchorionic hemorrhage/hematoma and risk of miscarriage.^42,43 However, a 2013 meta-analysis of observational studies reported a possible association between the finding of subchorionic hematoma and increased risk of pregnancy loss of 8.9% to 17.6%, with an odds ratio (OR) of 2.18 (95% CI 1.29–3.68).⁴⁴

The management method of vaginal bleeding in early pregnancy depends upon the working diagnosis (Fig. 54-5). It may not be possible to make a definitive diagnosis in a single encounter,⁴⁵ despite the use of TVUS and hCG. The term pregnancy of unknown location (PUL) is used to describe a situation where a diagnosis of IUP or ectopic pregnancy has not been established. Management of PUL should be guided by the patient’s preferences, while establishing the diagnosis. Even after the diagnosis of IUP, EPL, ectopic pregnancy, or molar pregnancy is established, the treatment options and follow-up vary based upon patient preference and pregnancy intention.

NORMAL INTRAUTERINE PREGNANCY

Unplanned pregnancy is common in the United States, with 3.3 million unintended pregnancies reported in 2008.⁴⁶ In addition, even the circumstances leading up to a planned pregnancy may have changed significantly by the time that a patient presents with bleeding in early pregnancy. The pregnancy may be unexpected and desired/undesired, anticipated and desired/undesired, or anything in between. A patient may also be ambivalent or undecided about pregnancy intent, regardless of the initial pregnancy plans. If appropriate, counseling on the pregnancy options of continuation (parenting or adoption) and abortion (medical or surgical) should be provided, while conveying to the patient that up to 50% of pregnancies with vaginal bleeding will end in EPL. Counseling a patient with vaginal bleeding in early pregnancy should be based on the patient-centered approach and the provider’s clinical judgment as well as the individual patient’s circumstances. Once counseling has been provided, medically appropriate follow-up should be recommended.