About one fourth of all pregnant women experience spotting or bleeding in the first several weeks of pregnancy, and one half of those who bleed will miscarry.¹ Family physicians who are familiar with the normal progression of early pregnancy anatomy, sonographic findings, and beta subunit of human chorionic gonadotropin (β-hCG) values can make a definitive diagnosis and proceed with appropriate treatment.

Managing First Trimester Bleeding

By definition, bleeding before 20 weeks of gestation constitutes threatened abortion (Table 1^2,3), but the majority of such pregnancies progress normally. The pace of evaluation depends on the patient's history, signs, and symptoms. If known, the time since the patient's last normal menses may be used to estimate the gestational age. In stable patients, the physical examination includes documentation of the size and position of the uterus, auscultation of fetal heart sounds by Doppler (if it has been at least 10 to 11 weeks since last normal menses), and bimanual examination for masses and tenderness. Guarded reassurance and watchful waiting are appropriate if fetal heart sounds are detected with Doppler, if the patient is stable, and if there is no adnexal mass, significant tenderness, or clinical sign of intraperitoneal bleeding.

Adnexal tenderness and the presence of a mass may indicate ectopic pregnancy. Hypotension with other symptoms of hemoperitoneum (e.g., shoulder pain, absent bowel sounds, distended doughy abdomen) may point to ruptured ectopic pregnancy and prompt immediate hospitalization for evaluation.

Examination with a vaginal speculum may reveal nonobstetric causes of bleeding, such as cervicitis, vaginitis, cystitis, trauma, cervical cancer, or polyps; or nonvaginal causes of bleeding, such as hemorrhoids. Significant cervical dilation or visible products of conception are indicative of an inevitable abortion. Tissue may be removed by gentle traction with ring forceps, and may be examined for the presence of chorionic villi (Figure 1) or sent for pathologic examination. Chorionic villi are indicative of spontaneous abortion. Table 2 shows risk factors of spontaneous abortion.^2–4

Cervical testing for gonorrhea and chlamydia may be performed. Fever and significant adnexal or peritoneal symptoms are found in septic abortion. Treatment of septic abortion is urgent, including prompt antibiotic administration and uterine evacuation. Infection, retained products of conception, and uterine perforation are more common if the history includes attempted abortion by someone who is untrained. Evidence does not support the routine use of antibiotics in all women with incomplete abortion.⁵

If history and physical examination do not yield a diagnosis, ultrasonography with or without β-hCG testing is required. Application and interpretation of this testing will help determine the differential diagnosis of early pregnancy failure.

Normal First Trimester Pregnancy Markers

HUMAN CHORIONIC GONADOTROPIN

The first measurable finding in pregnancy is an elevated β-hCG level, which is produced by the placenta after implantation of the blastocyst. This occurs at approximately 23 menstrual days' gestation, or as early as eight days after conception. Readily available home urine pregnancy tests detect β-hCG levels as low as 25 mIU per mL (25 IU per L) International Reference Preparation. Therefore, it is possible to diagnose pregnancy before a missed period.⁶

Quantitative serum β-hCG levels rise in a predictable fashion during the first four to eight weeks of normal pregnancy, increasing by 80 percent every 48 hours. This rate of increase in β-hCG levels is reassuring, but not indicative of normal pregnancy. Inadequately rising β-hCG levels do not distinguish between ectopic and failing intrauterine pregnancy. Unexpectedly high β-hCG levels require consideration of gestational trophoblastic disease.

ULTRASONOGRAPHY

Early detection of pregnancy depends on transvaginal ultrasonography using transducer frequency of 5 MHz or greater.¹ A 5-mm sonolucent gestational sac should be visible in the endometrium at the fundus by five menstrual weeks.¹ The normal sac of an intrauterine pregnancy consists of a central blastocyst surrounded by a double ring of echogenic chorionic villi and decidua. This distinguishes it from a pseudogestational sac associated with ectopic pregnancy.

The yolk sac is visible using transvaginal scanning by six menstrual weeks. This confirms an intrauterine pregnancy (Figure 2). By the end of the sixth week, a 2- to 5-mm embryo or fetal pole becomes visible (Figure 3). Measurement of the embryonic crown-rump length is the most accurate way to date pregnancy (Figure 4). Cardiac activity should be present when the embryo exceeds 5 mm in length.¹ Transabdominal scanning is less sensitive, and will show these landmarks about one week after they are visible transvaginally.

DISCRIMINATORY CRITERIA

The predictable, linked progression of laboratory and sonographic findings constitutes discriminatory criteria, as shown in Table 3.¹ A normal pregnancy should exhibit a gestational sac when β-hCG levels reach 1,500 to 2,000 mIU per mL (1,500 to 2,000 IU per L), a yolk sac when the gestational sac is greater than 10 mm in diameter, and cardiac activity when the crown-rump length is greater than 5 mm.¹ The absence of an expected discriminatory finding is consistent with pregnancy failure; however, because of the emotional impact of pregnancy loss, imaging may be repeated one week later to confirm the diagnosis. After an embryo with a heartbeat is confirmed using these criteria, continued follow-up by ultrasonography provides more specific information about the state of the pregnancy than serial measurements of β-hCG.

Making a Diagnosis

If the diagnosis is not clear from clinical examination alone, knowledge of discriminatory criteria based on transvaginal ultrasonography and β-hCG findings facilitates the differential diagnosis of first trimester bleeding (Table 3¹).

ECTOPIC PREGNANCY

Ectopic pregnancy is responsible for 6 percent of all U.S. maternal deaths.⁴ Intrauterine pregnancy with yolk sac or embryo rules out ectopic pregnancy, with the exception of a one in 4,000 chance of heterotopic pregnancy. Transvaginal ultrasonography demonstrates an intra-uterine gestational sac with nearly 100 percent sensitivity at β-hCG levels of 1,500 to 2,000 mIU per mL.¹ If the β-hCG level is above this discriminatory cutoff and a gestational sac is not visible, then there is a high likelihood of ectopic pregnancy.

An embryo with cardiac activity outside the uterus proves ectopic pregnancy. Conditions that impede the tubal transport of a fertilized ovum are associated with ectopic pregnancy⁷ (Table 2^2–4), although many ectopic pregnancies occur in women without risk factors. Early diagnosis is the key to preventing morbidity and mortality, and preserving fertility.

An adnexal mass or free pelvic fluid (Figure 5) signifies a high probability of ectopic pregnancy, even if the gestational sac or embryo is not visible. The presence of a corpus luteum cyst of pregnancy may confuse the picture.

SPONTANEOUS ABORTION AND EMBRYONIC DEMISE

Products of conception in the cervix or an intrauterine embryo without cardiac activity proves incomplete abortion, inevitable abortion, or embryonic demise. Their presence rules out ectopic pregnancy, although there is a one in 4,000 chance of heterotopic pregnancy. Anembryonic pregnancy is often suspected when the patient reports regression of pregnancy symptoms or when Doppler fails to detect fetal heart sounds by 10 to 11 weeks after the last normal menses.

GESTATIONAL TROPHOBLASTIC DISEASE

Gestational trophoblastic disease is characterized by a “snowstorm” of amorphous material filling the uterus in patients presenting in the first trimester.^8,9 Prompt surgical evacuation is required with close follow-up because of the risk of metastatic disease.⁹

SUBCHORIONIC HEMORRHAGE

Subchorionic hemorrhage (Figure 6) is a common finding with first trimester bleeding and may also be an incidental finding in uncomplicated pregnancies. It is important to note whether embryonic cardiac activity is present. Subchorionic hemorrhage may be mistaken for a twin gestational sac.

THE DIFFICULT DIAGNOSIS

It is common for β-hCG levels to be less than 1,500 mIU per mL with sonographic findings that are nondiagnostic. It is reasonable to perform repeat ultrasonography after one week in a stable patient. This interval allows significant growth of the gestational sac or embryo, both of which should grow at the rate of 1 mm per day. In this situation, serial quantitative β-hCG levels in combination with follow-up imaging are also useful. Based on a prospective study, the minimum β-hCG increase necessary for a living pregnancy over a 48-hour interval is 53 percent.¹⁰ When β-hCG rises more slowly than this, plateaus, or falls, the differential diagnosis is limited to failing intrauterine pregnancy or ectopic pregnancy.

When β-hCG levels are not rising normally and ultrasonography cannot confirm pregnancy location, a dilatation and curettage or manual vacuum aspiration may be helpful. Manual vacuum aspiration requires a specially-designed 60-mL syringe with attached cannula to apply suction to the uterine cavity. If evacuation of the uterus yields chorionic villi, then a failed intrauterine pregnancy is diagnosed and treatment for an ectopic pregnancy may be avoided. When ectopic pregnancy is suspected but cannot be confirmed with noninvasive testing, consultation for diagnostic laparoscopy or treatment with methotrexate is appropriate.

Management

THREATENED ABORTION

The presence of an intrauterine embryo with cardiac activity on ultrasonography should be reassuring because it essentially rules out ectopic pregnancy. It is also associated with a pregnancy loss rate of only 2 percent in women 35 years and younger and 16 percent in women older than 35 years.¹¹ If subchorionic hemorrhage (Figure 6) is present in an intrauterine pregnancy with fetal heart sounds, the likelihood of spontaneous abortion is 9 percent and may be even higher if the patient is older than 35 years or if the hematoma is large.¹² In this situation, the physician should caution patients to expect continued bleeding and possible impending miscarriage.

SPONTANEOUS ABORTION, EMBRYONIC DEMISE, AND ANEMBRYONIC PREGNANCY

Most first trimester miscarriages occur completely and spontaneously without intervention. Although dilatation and curettage has historically been the treatment of choice, several recent trials confirm that expectant management or medical management with misoprostol (Cytotec) can be as effective and safer while offering the patient more control over her care.^13–16

Clinical trials comparing expectant, medical, and surgical management reach several conclusions. In incomplete abortion, high success rates have been demonstrated for expectant management (86 percent) and medical management (100 percent).¹³ However, expectant management is more likely to fail in embryonic demise or anembryonic pregnancy; in these patients, the success of expectant management by day 7 drops to 29 percent, compared with 87 percent for medical management.¹³ Women treated expectantly have more outpatient visits than those treated medically.¹³ Women treated medically have more bleeding but less pain than those treated surgically.¹⁴ Surgery is associated with more trauma and infectious complications than medical treatment.^14,16 Misoprostol has fewer gastrointestinal side effects when given vaginally than when given orally.^13,15

Based on these findings, increased use of medical management has benefits for patients, although misoprostol is not approved by the U.S. Food and Drug Administration for use in treating miscarriage.¹⁷ The doses used in published studies are 800 mcg vaginally or 600 mcg orally.^13–15 If a single vaginal dose of 800 mcg does not result in complete expulsion by day 3, the dose should be repeated. If complete expulsion has not occurred by day 8, manual vacuum aspiration should be offered.¹⁸ Additional published protocols are available.¹⁹

Confirming a negative urine β-hCG four to six weeks after early pregnancy loss excludes the presence of persistent gestational trophoblastic disease.²⁰ Although there is solid evidence to support the use of prophylactic antibiotics for induced abortion, there is no evidence supporting this practice in early pregnancy failure.²¹

ECTOPIC PREGNANCY

Early diagnosis of ectopic pregnancy brings management into the outpatient setting. Current treatment options favor medical and laparoscopic management,²² with expectant management reserved for patients with a declining quantitative β-hCG of less than 1,000 mIU per mL (1,000 IU per L) and open surgical management reserved for patients with tubal rupture and hemoperitoneum. Medical management with methotrexate is appropriate for properly selected patients. Randomized trials have shown medical management to be safer, more effective, and less expensive than conservative surgical treatment, and to result in equal or better subsequent fertility.^23-26 Ectopic pregnancy management options, including methotrexate dosages and follow-up criteria, are shown in Table 4.^23–26

Care After Pregnancy Loss

Several follow-up issues must be addressed after any type of pregnancy loss. Women who are Rh negative and miscarry during the first trimester should receive 50 mcg of anti D immune globulin.²⁷ Contraception should be discussed and started immediately. All methods are equally safe immediately following spontaneous abortion or ectopic pregnancy. There is no good evidence suggesting an ideal interpregnancy interval,²⁸ but folic acid supplementation before attempts at future conception substantially reduces the risk of neural tube defects.²⁹ The psychological impact of pregnancy loss can be devastating to the patient and her partner.³⁰ Approaches to managing patient grief are shown in Table 5.³¹