Perspective

Miscarriage, the most common serious complication of pregnancy, is defined as the spontaneous termination of pregnancy before 20 weeks of gestation. Fetal demise after 20 weeks of gestation or when the fetus is more than 500 g is considered premature birth. Loss of early pregnancy, defined as detection of human chorionic gonadotropin (hCG) within 6 weeks of the last normal menstrual period, occurs in approximately 20 to 30% of pregnancies.1–3 Embryonic and fetal loss after implantation occurs in up to one third of detectable pregnancies. The risk of miscarriage rises with increasing maternal age (fivefold increase in those older than 40 years compared with those 25 to 29 years), increasing paternal age, alcohol use, increased parity, history of prior miscarriage, poorly controlled diabetes mellitus and thyroid disease, low pre-pregnancy body mass index, maternal stress, and history of vaginal bleeding.^4–6 Approximately 80% of miscarriages occur during the first trimester; the rest occur before 20 weeks of gestation.

Threatened or actual miscarriage is a common presentation of patients in the emergency department (ED). Approximately one fourth of clinically pregnant patients experience some bleeding. It is estimated that up to 50% of all women who have bleeding during early pregnancy miscarry, although the risk is probably higher in the ED population.7,8 Patients who have a viable fetus visualized on ultrasound examination have a much lower risk of miscarriage (3-6%), although vaginal bleeding is a high-risk indicator, even when a viable fetus is present.⁹ Those with a history of bleeding who do not miscarry may have otherwise normal pregnancies, although they have an approximately twofold increased risk of premature birth and low-birth-weight infants.¹⁰

Principles of Disease

Clinical Features

Patient history should include the estimated length of the gestation; time since last menstrual period; symptoms of pregnancy (including evolution or loss of pregnancy symptoms); degree of bleeding; duration of bleeding; presence of cramps, pain, or fever; and attempts by the patient to induce miscarriage. Whereas the history is important, it is not helpful in the classification of the type of miscarriage. In addition, the severity of symptoms does not correlate well with the risk of miscarriage, although cramping and passage of clots are thought more likely to occur as the miscarriage becomes inevitable.

The assessment of the patient who experiences first-trimester vaginal bleeding includes a careful abdominal examination to evaluate for tenderness or peritoneal irritation from a potential ectopic pregnancy as well as to determine uterine size (the uterus should not be palpable abdominally). Pelvic examination should be performed to evaluate whether the cervix is closed or open, to look for clots or the products of conception, and to determine the degree of vaginal bleeding as well as uterine size and tenderness. The cervix should be gently probed with a ring forceps (not a cotton-tipped applicator) to determine whether the internal os (1.5 cm deep to the external os) is open or closed. This is unnecessary in the patient who has a clearly open os or visible products of conception but can be safely performed during the first trimester as long as the forceps are used gently and do not penetrate the cervix more than 2 or 3 cm. In the patient with second-trimester bleeding, probing should not be done because the uterus is more vascular and the organized placenta may overlie the cervical os. Parous women normally have an open or lax external os, a finding of no significance. The adnexa may be enlarged, often unilaterally, either because the corpus luteum is cystic or because the pregnancy is ectopic. Significant adnexal or uterine tenderness should always raise the possibility of an ectopic pregnancy. Much less commonly, pelvic infection can cause uterine and adnexal tenderness during early pregnancy.

Any tissue that is passed should be suspended in saline or tap water (or viewed under low-power microscopy) to differentiate sloughing endometrium and organized clot from chorionic villi, which form fronds and appear feathery in the saline suspension. Except in the rare instance of heterotopic pregnancy (combined intrauterine and ectopic pregnancies), this reliably excludes ectopic pregnancy. Passage of tissue called the decidual cast in ectopic pregnancy can easily be confused with intrauterine miscarriage if the physician does not confirm the absence of chorionic villi in the tissue.¹²

Diagnostic Strategies

A hemoglobin level is useful to provide a baseline measurement and to evaluate the degree of blood loss in women whose bleeding persists. In addition, an Rh type should be obtained. Ultrasonography is the primary means of evaluating the health of the fetus as well as its location (Table 178-1). Because historical and clinical estimations of gestational age are often inaccurate, ultrasonography is useful to provide an accurate measure of fetal age and viability (Box 178-1).

In the stable patient with threatened miscarriage, expectant management may be sufficient to determine when intervention is needed as long as ectopic pregnancy has been excluded. Serial quantitative hCG levels are used to assess the health of the fetus if sonographic findings are indeterminate or if the gestational age is less than 6 or 7 weeks. The sonographic “discriminatory zone” is defined as the quantitative hCG level at which a normally developing IUP should reliably be seen. This is considered to be 6500 mIU/mL for transabdominal ultrasonography and 1000 to 2000 mIU/mL for transvaginal ultrasonography.¹³ Ultrasonography can be performed or repeated when hCG levels rise to 1500 to 3000 mIU/mL. If hCG levels are flat or decline or if sonographic criteria for fetal demise are demonstrated (see Box 178-1), the patient should be referred to an obstetrician for follow-up to ensure miscarriage completion and to rule out subsequent complications.

Differential Considerations

Ectopic pregnancy can masquerade as a threatened miscarriage in the early stages of pregnancy and should always be considered in the differential diagnosis. Even in the patient with painless vaginal bleeding, the diagnosis of ectopic pregnancy must be considered.¹² Thus early ultrasonography is imperative to locate the pregnancy in the patient who has bleeding or pain.

Other diagnoses should also be considered. A small amount of bleeding occurs at the time of implantation of the blastocyst into the endometrium and occasionally at the time of the first missed menses. Molar pregnancy is also characterized by vaginal bleeding, usually during the late first trimester or the second trimester. This condition can be identified by ultrasonography. Cervical and vaginal lesions can also cause local bleeding and can usually be seen on vaginal inspection.

Management

After assessment of hemodynamic status and management of blood loss, a patient with a threatened miscarriage requires very little specific medical treatment. Anti-D immune globulin should be administered if the patient is Rh negative (unless the father is also known to be Rh negative). A 50-µg dose is used during the first trimester and a full 300-µg dose after the first trimester.¹⁴ Once ectopic pregnancy has been excluded, ultrasonography can be scheduled more routinely at a later time in the patient without significant pain as long as the patient is aware that the potential for ectopic pregnancy exists until it is excluded by identification of an IUP. In the patient who is planning pregnancy termination, prompt referral should be encouraged and chorionic villi confirmed at the time of uterine evacuation.

Unless an IUP is diagnosed, the patient with threatened miscarriage should be given careful instructions on discharge to return if she has signs of hemodynamic instability, significant pain, or other symptoms that might indicate ectopic pregnancy (so-called ectopic precautions). In conjunction with gynecologic colleagues, an ED protocol is useful to determine when follow-up sonographic evaluation and serial hCG measurements should be obtained as ultrasonography can be an inaccurate diagnostic tool if the hCG level is significantly low, if vaginal bleeding is significant, or if ultrasonographic findings do not include a fetal pole or yolk sac.¹⁵

Although 50% or more of women with threatened miscarriage who are seen in the ED ultimately miscarry, treatment to “prevent” miscarriage is not useful as most fetuses can be shown to be nonviable 1 to 2 weeks before symptoms occur. In most cases, spontaneous miscarriage is the body’s natural method of expelling an abnormal or undeveloped (blighted) pregnancy. Thus a major goal of early management should be patient education and support. Patients should be advised that moderate daily activities do not affect the pregnancy. Tampons, intercourse, and other activities that might induce uterine infection should be avoided as long as the patient is bleeding, and she should return immediately for fever, abdominal pain, or a significant increase in bleeding. Cramping from a known IUP can be safely treated with oral synthetic narcotics, if needed. If the patient passes tissue, it should be brought to a provider to be examined for products of conception because differentiation of fetal parts or villi from decidual slough or casts is difficult.

Patient counseling is paramount with threatened miscarriage.16,17 Determination of fetal viability can be helpful in either reassuring the mother or preparing her for probable fetal loss. Miscarriages are associated with a significant grieving process, which is frequently more difficult because early pregnancy is unannounced and early fetal death is not publicly recognized. Because many women consider that small falls, injuries, or stress during the first trimester can precipitate miscarriage, patients should be reassured that they have done nothing to cause miscarriage. It is important to make them aware that miscarriage is common, grieving is normal, and counseling may be beneficial.^18,19 A follow-up appointment should be scheduled after miscarriage to support the patient in resolving such issues.

Treatment of the patient with incomplete miscarriage includes expectant management, medical management with misoprostol, or surgical evacuation.18,20 When the miscarriage is incomplete, the uterus may be unable to contract adequately to limit bleeding from the implantation site. Bleeding may be brisk, and gentle removal of fetal tissue from the cervical os with ring forceps during the pelvic examination often slows bleeding considerably.

Management of patients with presumed completed miscarriage is more complicated. If the patient brings tissue with her, this should be sent to the pathology department for evaluation. Unless an intact gestational sac or fetus is visualized, it is rarely clear clinically whether miscarriage is “complete.” Studies have shown that in women with a history consistent with miscarriage who have minimal remaining intrauterine tissue as determined by ultrasonography, expectant management is safe, but only if ectopic pregnancy can be excluded.²⁰ If endometrial tissue is not seen with ultrasonography, bleeding is mild, and gestational age is less than 8 weeks, curettage is frequently unnecessary and the patient can be safely observed by a gynecologist for serial hormonal assays. Up to 80% of women with first-trimester miscarriage complete the miscarriage without intervention.²¹ However, the need for later visits and procedures may be decreased by uterine curettage, particularly if the fetal pole or a gestational sac is visible on the sonogram at the time of evaluation.²⁰ Medical management with misoprostol instead of D&C is also an option and has a success rate of up to 96%.^18,22,23 The patient should be instructed to return if uncontrolled bleeding, severe pain or cramping, fever, or tissue passage occurs. Follow-up is recommended in 1 or 2 weeks to ensure that the miscarriage is complete.

After miscarriage, the patient should be advised that fetal loss, even during the first trimester, can cause significant psychological stress.¹⁶ Follow-up in 1 or 2 weeks with a gynecologist should be provided. Some physicians prescribe antibiotics after D&C (usually doxycycline or metronidazole), particularly in populations of patients at high risk for genital tract infections. Ergonovine or methylergonovine (0.2 mg orally twice daily) can be used to stimulate uterine involution. The patient should be advised to return if signs of infection (fever or uterine tenderness) occur, if bleeding resumes, or if further tissue is passed.

Perspective

Ectopic pregnancy, or pregnancy implanted outside the uterus, is an increasingly frequent problem that poses a major health risk to women during the childbearing years. It is the third leading cause of maternal death, responsible for 6% of maternal mortality.²⁴ The incidence of ectopic pregnancy has risen steadily during several decades and now accounts for approximately 2% of all pregnancies. Although the incidence of ectopic pregnancy is highest in women aged 25 to 34 years, the rate is highest among older women and women belonging to minority groups. Simultaneous intrauterine and extrauterine gestations (heterotopic pregnancy) have historically been rare, occurring in approximately 1 in 4000 pregnancies; more recently, women who have undergone assisted reproduction techniques with embryo transfer have demonstrated a risk of one of the pregnancies being ectopic of 4% or greater. The incidence of ectopic pregnancy among women presenting to the ED with vaginal bleeding or pain in the first trimester is consistently approximately 10% in several series.^25,26

Principles of Disease

Implantation of the fertilized ovum occurs approximately 8 or 9 days after ovulation. Risk factors for an abnormal site of implantation include prior tubal infection (50% of cases), anatomic abnormalities of the fallopian tubes, and abnormal endometrium (host factors). These result in failure of the embryo to implant in the endometrium. The risk of ectopic pregnancy increases approximately threefold after a patient has had pelvic inflammatory disease (PID). In recent studies, one fourth of patients with ectopic pregnancies have had tubal surgery, including tubal sterilization or removal of ectopic pregnancy.²⁷ If the patient is currently using an intrauterine device, increased risk can occur from complicating PID or from failure of the intrauterine device to prevent pregnancy while preventing endometrial implantation. All forms of contraception except the intrauterine device and tubal sterilization decrease the incidence of ectopic pregnancy. After an ectopic pregnancy, the risk of a subsequent ectopic pregnancy was 22% in one series of women trying to conceive again (Box 178-2).²⁸

When abnormal implantation occurs in the fallopian tubes, on the ovaries, or in the cervix, the pregnancy usually grows at a less than normal rate, which can result in abnormally low or declining hCG production. Blood leaks intermittently through the tubal wall or out the fimbrial ends, with spillage into the peritoneal cavity. Bleeding and other symptoms are usually intermittent. Three outcomes are possible: spontaneous involution of the pregnancy, tubal abortion into the peritoneal cavity or vagina, or rupture of the pregnancy with internal or vaginal bleeding. Implantation in the uterine horn (cornual pregnancy) is particularly dangerous because the growing embryo can use the myometrial blood supply to grow larger (10-14 weeks of gestation) before rupture occurs.

Clinical Features

The classic clinical picture of ectopic pregnancy is a history of delayed menses, followed by abdominal pain and vaginal bleeding in a patient with known risk factors. Unfortunately, this history is neither sensitive nor specific. Risk factors for ectopic pregnancy are absent in almost half of patients. Fifteen percent to 20% of patients with symptomatic ectopic pregnancy have not missed a menstrual period, and occasionally the patient has no history of vaginal bleeding. Abdominal pain is most commonly severe, peritoneal in nature, and constant. Shoulder pain implies free fluid in the peritoneal cavity and is suggestive of an ectopic pregnancy with significant hemorrhage. The pain of ectopic pregnancy can also be crampy, intermittent, or even absent.12,29

The physical examination findings in ectopic pregnancy are likewise variable. Vaginal bleeding, uterine or adnexal tenderness, or both in the patient with a positive pregnancy test result should trigger consideration of ectopic pregnancy. Tachycardia is not always present, even with significant hemoperitoneum; hemoglobin level is usually normal, and hypotension may be seen.²⁹ The presence of peritoneal signs, cervical motion tenderness, or lateral or bilateral abdominal or pelvic tenderness indicates increased likelihood of an ectopic pregnancy. If significant peritoneal irritation is present, pain can preclude accurate bimanual examination. Adnexal masses are felt in only 10 to 20% of patients with ectopic pregnancy.^12,29 Vaginal bleeding is often mild. Heavy bleeding with clots or tissue usually suggests a threatened or incomplete miscarriage, although the patient with an ectopic pregnancy who has decreasing hormonal levels may experience endometrial sloughing, which can be mistaken for passage of fetal tissue. Passed tissue should be examined, as with cases of miscarriage, in tap water or saline (or under low-power microscopy). Unless fetal parts or chorionic villi are seen, ectopic pregnancy should not be excluded in the patient with bleeding or passage of “tissue.”

Diagnostic Strategies

Because both the history and the physical examination of the patient with ectopic pregnancy are insensitive and nonspecific, ancillary studies are essential to locate the pregnancy in any patient who has abdominal pain or vaginal bleeding and a positive pregnancy test result. Technologic advances have allowed accurate detection or exclusion of ectopic pregnancy in the assessment of the woman with first-trimester vaginal bleeding or pelvic pain. Ultrasonography and hormonal assays are the most commonly used ancillary tests. Laparoscopy may be the most efficient diagnostic tool in some instances.

Differential Considerations

The spectrum of clinical presentations in ectopic pregnancy is wide, so the differential diagnosis includes essentially all first-trimester complications. Threatened miscarriage, the most common alternative diagnosis, can be recognized by sonographic evidence of an IUP, either healthy or failed. Hypovolemia may be seen, particularly in incomplete miscarriage, but hypotension without significant vaginal hemorrhage is highly suggestive of ectopic pregnancy. Identification of fetal parts or chorionic villi in tissue expelled or obtained during D&C is useful to confirm a complication of IUP, although this is not sufficient to exclude ectopic pregnancy in the patient who has received infertility treatment and has an increased risk of heterotopic gestation.

A ruptured corpus luteum cyst should also be considered in the patient who has first-trimester bleeding associated with peritoneal pain or irritation. The corpus luteum normally supports the pregnancy during the first 7 or 8 weeks. Rupture causes pelvic pain and peritoneal irritation. Ultrasonography is helpful if it reveals an IUP (except in patients with in vitro fertilization). During early gestation, when ultrasonography is nondiagnostic, free fluid is usually visible by ultrasonography, and serial observation may be required (see Fig. 178-4). If the patient is unstable (especially if an IUP cannot be identified by ultrasonography), laparoscopy or, rarely, laparotomy may be required to differentiate between the two conditions.

Management

Classically, approximately 20% of women with ectopic pregnancies manifest signs and symptoms warranting immediate intervention.⁴¹ This includes patients with significant hypovolemia, large amounts of peritoneal fluid, or an open cervical os. For patients with significant signs of hypovolemia, rapid volume resuscitation should be instituted with intravenous fluids and blood products as necessary, and a baseline hemoglobin level and type and crossmatch should be obtained. A D&C or evacuation procedure with examination of endometrial contents for products of conception can be performed urgently in the unstable patient with an open cervical os.

If the patient remains unstable, immediate surgery is warranted. Laparoscopy may be indicated for patients who stabilize with treatment or for those who are hemodynamically stable but exhibit significant peritoneal signs. One study reported that identification of free fluid in Morison’s pouch on bedside ultrasonography predicted the need for operative intervention in the majority of cases in patients with suspected ectopic pregnancies.²⁶ All patients with ectopic pregnancy who are Rh negative should be given Rh immune globulin 50 µg intramuscularly, unless the father is known to be Rh negative.

The majority of patients who seek treatment for bleeding or pain during the first trimester of pregnancy are stable. In such patients, the goal should be to exclude ectopic pregnancy in a timely manner. In the patient with significant pain by history or examination or significant risk factors for ectopic pregnancy, ultrasonography should be performed before discharge. If the results are indeterminate, a quantitative hCG level may be helpful in determining the patient’s risk for ectopic pregnancy.

In low-risk patients with only minor symptoms or bleeding, ectopic pregnancy is still a possibility. Two general outpatient approaches can be considered. In most institutions, ultrasonography is the initial screening tool (Fig. 178-6). If an IUP is not seen, quantitative hCG levels help stratify patients by risk. In all cases, if the patient is discharged, careful instructions are given for symptoms that would require her earlier return (ectopic precautions).

An alternative strategy uses hCG levels first. However, waiting times for the serum assay can increase ED length of stay. In addition, ultrasonography is usually diagnostic of IUP or ectopic pregnancy, even if the hCG level is less than 1000 mIU/mL.29,30 In most hands, the initial sonogram provides more rapid and accurate information.

A significant minority of patients have indeterminate sonographic results and hCG levels below 1000 mIU/mL. When the hCG levels never rise to the discriminatory zone, the differential diagnosis includes intrauterine fetal demise and ectopic pregnancy. Early D&C with identification of products of conception can be useful in the patient with nonrising hCG levels to detect chorionic villi and to confirm a failed IUP or to strongly suggest ectopic pregnancy.⁴⁰ Alternatively, hCG levels can be followed until they reach zero, particularly if initial levels are low.

Although laparotomy may be required for patients who have ectopic pregnancies, an increasing number of surgeries are being performed through the laparoscope. Salpingostomy is preferred to salpingectomy if the patient is stable and the procedure is technically feasible. Overall, the advent of transvaginal ultrasonography has resulted in a decreased number of surgeries and a trend toward nonoperative management.⁴²

Medical management has become standard in many areas for the stable patient with minimal symptoms and is cost-effective when subsequent fertility is being considered.⁴¹ Methotrexate is the drug most commonly used to treat early ectopic pregnancy. It causes destruction of rapidly dividing fetal cells and involution of the pregnancy. Medical treatment is most often used for patients who are hemodynamically stable with a tubal mass smaller than 3.5 cm in diameter, no fetal cardiac activity, and no sonographic evidence of rupture. Although there is no agreed on cutoff for single-dose methotrexate, a systematic review found that patients with an hCG level above 5000 mIU/mL had an increased failure rate.⁴³ Medical therapies are associated with an 85 to 93% success rate, with no significant difference between single- and multiple-dose protocols.⁴⁴ Pelvic pain is common (60%) in patients receiving methotrexate, even when it is used successfully.⁴⁵ Indications of methotrexate failure and need for rescue surgery include decreasing hemoglobin levels, significant pelvic fluid, and unstable vital signs. All patients receiving methotrexate require close follow-up until the hCG level reaches zero, which may take 2 or 3 months.

Perspective

Bleeding during the second half of pregnancy occurs in approximately 4% of pregnancies. Only 20% of miscarriages occur after the first trimester, and the most important differential diagnoses after 12 to 14 weeks of gestation are abruptio placentae and placenta previa. The cause is often not determined, although occult marginal placental separations (which can be recognized only by placental inspection at delivery) are held to be a common source of bleeding from above the cervix. Other causes of late vaginal bleeding include early labor, various cervical and vaginal lesions, lower genital tract infections, and hemorrhoids.

Bleeding during the second trimester before the fetus is potentially viable (14-24 weeks) is not benign. One third of fetuses are ultimately lost when maternal bleeding occurs. Management is supportive and expectant because fetal rescue is impossible at this level of fetal immaturity. In the third trimester, vaginal bleeding is still associated with significant morbidity in approximately one third of women, but the treatment includes consideration of urgent delivery.⁵³

Abruptio Placentae