Chapter 13. Early Pregnancy Risks

Essentials of Diagnosis

• Suprapubic pain, uterine cramping, and/or back pain
• Vaginal bleeding
• Cervical dilation
• Passage of products of conception
• Quantitative β-human chorionic gonadotropin that is falling or not adequately rising
• Abnormal ultrasound findings (eg, empty gestational sac, lack of fetal growth or fetal cardiac activity)

General Considerations

Spontaneous abortion is the most common complication of pregnancy and is defined as the passing of a pregnancy at less than 20 weeks of gestation. It implies the spontaneous loss of an embryo or fetus weighing less than 500 g. Threatened abortion is bleeding arising from within the uterus that occurs before the 20th completed week in a viable pregnancy. The patient may or may not experience pain or cramping; however, there is no passage of products of conception and no cervical dilation. Complete abortion is the expulsion of all of the products of conception before the 20th completed week of gestation, whereas incomplete abortion is the expulsion of some, but not all, of the products of conception. Inevitable abortion refers to bleeding from within the uterus before the 20th week, with dilation of the cervix but without expulsion of the products of conception. The term missed abortion describes a nonviable pregnancy that has been retained in the uterus without cervical dilation and without the spontaneous passage of products of conception. In septic abortion, embryonic or fetal demise has occurred, and intrauterine infection has developed, which has the potential risk of spreading systemically.

Although the true incidence of spontaneous abortion is unknown, approximately 15% of clinically evident pregnancies and up to 50% of chemically evident pregnancies end in spontaneous abortion. Eighty percent of spontaneous abortions occur before 12 weeks' gestation.

The incidence of abortion is influenced by the age of the mother and by a number of pregnancy-related factors, including the number of previous spontaneous abortions, a previous intrauterine fetal demise, and a previous infant born with malformations or known genetic defects. Additionally, chromosomal abnormalities in either parent, such as balanced translocations, and medical comorbidities, such as thyroid disease and diabetes mellitus, may influence the rate of spontaneous abortion.

Pathogenesis

An abnormal karyotype is present in as many as 50% of spontaneous abortions occurring during the first trimester. The incidence decreases to 20–30% of second-trimester losses and to 5–10% of third-trimester losses. The majority of chromosome abnormalities are trisomies (56%), followed by polyploidy (20%) and monosomy X (18%).

Other suspected causes of spontaneous abortion are less common, and these include infection, anatomic defects, endocrine factors, immunologic factors, and exposure to toxic substances. In a significant percentage of spontaneous abortions, the etiology is unknown, even with genetic testing.

Genetic Abnormalities

Aneuploidy, an abnormal chromosomal number, is the most common genetic abnormality, accounting for up to 50% of clinical miscarriages. Monosomy X or Turner's syndrome is the single most common aneuploidy, comprising approximately 18% of these gestations. As a group, the autosomal trisomies account for more than half of aneuploid losses, with trisomy 16 being the most common. Autosomal trisomies have been noted for every chromosome except chromosome number 1. Most trisomic pregnancies end in miscarriage. The exceptions are trisomy 21, 18, and 13, which have survival to birth rates of 22%, 5%, and 3%, respectively.

Polyploidy, usually in the form of triploidy, is found in approximately 20% of all miscarriages. Polyploid conceptions typically result in an anembryonic gestation. Occasionally, these pregnancies will develop into partial hydatidiform moles.

The remaining half of early abortuses appear to have normal chromosomes. Of these, 20% have other genetic abnormalities that may account for the loss. Mendelian or polygenic factors resulting in anatomic defects may play a role. These factors tend to be more common in later fetal losses.

Maternal Factors

Systemic Disease

a. Maternal Infections—

Organisms such as Toxoplasma gondii, herpes simplex virus, cytomegalovirus, and Listeria monocytogenes have been implicated in spontaneous abortion. Although these agents, as well as Chlamydia trachomatis, have been found in women with first-trimester losses, a causal relationship has not been established.

B. Other Diseases—

Endocrine disorders such as hypothyroidism, hyperthyroidism, hyperprolactinemia, and poorly controlled diabetes mellitus; cardiovascular disorders, such as hypertensive or renal disease; and autoimmune disorders, such as systemic lupus erythematosus and antiphospholipid syndrome, are associated with spontaneous abortion. At less than 10 weeks, the association between antiphospholipid syndrome and early pregnancy loss is controversial and less well established.

Uterine and Cervical Factors

Congenital anomalies that distort or reduce the size of the uterine cavity, such as unicornuate, bicornuate, or septate uterus, are associated with poor pregnancy outcomes (Fig. 13–1). There is an increased risk of miscarriage, as well as placental abruption, intrauterine growth restriction, and preterm labor. Of all uterine anomalies, septate uterus is the most common and can be removed by hysteroscopic resection, resulting in higher pregnancy and live birth rates (Fig. 13–2). Upper and lower genital tract structural changes have been observed in 25–33% of women whose mothers took diethylstilbestrol (DES) during pregnancy. Uterine anomalies, such as a T-shaped or hypoplastic uterus, carry an increased risk of miscarriage. DES was banned from use in pregnant women in 1971. As a result, pregnancy complications in DES daughters are less and less common, as these women are now 40 years and older. Acquired anomalies, such as fibroids (especially submucosal) and endometrial polyps, have been associated with spontaneous abortions as well.

The formation of scar tissue, or synechiae, within the uterine cavity that leads to problems such as infertility or recurrent miscarriage is known as Asherman's syndrome. These intrauterine adhesions or fibrosis are most commonly found after dilation and curettage (D&C) of the gravid uterus, either for spontaneous miscarriage, termination, or treatment of postpartum hemorrhage. Diagnosis is often confirmed with hysterosalpingogram, saline infusion sonogram, or hysteroscopy. Treatment is by resection of the adhesions using hysteroscopy.

Cervical insufficiency (previously known as cervical incompetence) is painless cervical shortening or dilation in the second or early third trimester, up to 28 weeks, resulting in preterm birth. Congenital uterine anomalies and DES anomalies are associated with cervical insufficiency. Procedures to treat dysplasia of the cervix such as cervical conization appear to increase the risk for cervical insufficiency.

Toxic Factors

Exposure to antineoplastic drugs, anesthetic gases, alcohol, nicotine, or cocaine can result in spontaneous abortion. Other substances such as lead, ethylene oxide, and formaldehyde have also been associated with subsequent miscarriage.

Trauma

Direct trauma, such as a penetrating injury to the uterus, or indirect trauma, such as surgical removal of an ovary containing the corpus luteum, may result in spontaneous abortion. Amniocentesis or chorionic villus sampling are associated with a risk of pregnancy loss.

Pathology

In spontaneous abortion, hemorrhage into the decidua basalis often occurs. Necrosis and inflammation appear at the area of implantation. The pregnancy then becomes partially or entirely detached. Uterine contractions and dilation of the cervix result in expulsion of part or all of the products of conception.

Prevention

Some miscarriages can be prevented by early obstetric care and even preconception care, with adequate treatment of maternal comorbidities such as diabetes and hypertension, and by protection of pregnant women from environmental hazards and exposure to infectious diseases.

Clinical Findings

Threatened Abortion

Approximately 25% of pregnant women experience first-trimester bleeding. In most cases, this bleeding is caused by implantation into the endometrium. The cervix remains closed, and slight bleeding with or without cramping may be noted. Resolution of the bleeding and cramping carries a favorable prognosis; however, these women are at increased risk for subsequent miscarriage. First-trimester bleeding has also been associated with preterm premature rupture of membranes and preterm labor. Other causes, such as ectopic pregnancy and molar gestation, should also be considered.

Inevitable Abortion

Bleeding with cervical dilation, often with back or abdominal pain, indicate impending abortion. Unlike an incomplete abortion, the products of conception have not passed from the uterine cavity.

Incomplete Abortion

Incomplete abortion (Fig. 13–3) is defined as the passage of some but not all of the products of conception from the uterine cavity. Bleeding and cramping usually continue until all products of conception have been expelled. In general, severe pain and heavy bleeding occur and often require medical evaluation.

Complete Abortion

In a complete abortion (Fig. 13–4), all of the products of conception have passed from the uterine cavity and the cervix is closed. Slight bleeding and mild cramping may continue for several weeks.

Missed Abortion

Missed abortion is defined as a pregnancy that has been retained within the uterus after embryonic or fetal demise. Cramping or bleeding may be present, but often there are no symptoms. The cervix is closed, and the products of conception remain in situ.

Anembryonic Pregnancy

Anembryonic pregnancy (previously called blighted ovum) is an ultrasound diagnosis. It is a pregnancy in which the embryo fails to develop or is resorbed after loss of viability. On ultrasound, an empty gestational sac is seen without a fetal pole (Fig. 13–5). Clinical presentation is similar to that of a missed or threatened abortion: Mild pain or bleeding may be present; however, the cervix is closed, and the nonviable pregnancy is retained in the uterus.

Laboratory Findings

Complete Blood Count

If significant bleeding has occurred, the patient will be anemic. Both the white blood cell count and the sedimentation rate may be elevated, even without the presence of infection.

Pregnancy Tests

Falling or abnormally rising serum levels of β-human chorionic gonadotropin (hCG) are diagnostic of an abnormal pregnancy, either a failed intrauterine gestation or an ectopic pregnancy.

Ultrasound Findings

Transvaginal ultrasound is an essential diagnostic tool in diagnosing early normal and abnormal pregnancies. As early as 4–5 weeks of gestation, a gestational sac may be visualized in the uterus. In a normal intrauterine pregnancy, the sac is spherical and is eccentrically placed within the endometrium. At 5–6 weeks' gestation, a yolk sac will be present. In general, a gestational sac with a mean sac diameter (MSD) of ≥8 mm should contain a yolk sac. Similarly, a gestational sac with an MSD of >16 mm should also contain an embryo (Fig. 13–6). Pregnancies with a large gestational sac and no embryo are typically anembryonic gestations and are managed in a similar manner as a missed abortion (Fig. 13–5). Fetal heart motion is expected in embryos with a crown to rump length of >5 mm or at 6–7 weeks' gestation. If a repeat ultrasound in 1 week does not show embryonic cardiac activity, the diagnosis of embryonic demise is made.

In threatened abortion, ultrasound will reveal a normal gestational sac and a viable embryo. However, a large or irregular sac, an eccentric fetal pole, and/or a slow fetal heart rate (<85 beats/min) carry a poor prognosis. Miscarriage becomes increasingly less likely the further the gestation progresses. If a viable fetus of 6 weeks or less is seen on ultrasound, the risk of miscarriage is approximately 15–30%. The risk decreases to 5–10% at 7–9 weeks' gestation and to less than 5% after 9 weeks' gestation.

In an incomplete abortion, the gestational sac usually is irregularly shaped. Heterogenous, echogenic material representing retained products of conception is seen within the uterus. Endometrial thickness can be helpful in diagnosing an incomplete abortion; however, there is no consensus on a cutoff value to distinguish complete miscarriage from incomplete miscarriage. Color Doppler can be used to assess for flow within the tissue and can help differentiate retained products of conception that remain implanted within the uterus from tissue or blood that is in the process of expulsion. Thus, a combination of clinical and ultrasound findings must be used to determine management.

The diagnosis of complete abortion is also based on clinical findings. On ultrasound, the endometrial lining appears thin, and no products of conception are visible within the cavity. Importantly, a complete abortion is only diagnosed with certainty if a previous intrauterine gestation was documented on ultrasound. Otherwise, hCG levels must be followed to confirm the absence of ectopic pregnancy.

Ectopic pregnancy may cause similar symptoms of miscarriage, such as bleeding and abdominal or pelvic pain. An adnexal mass may or may not be present. The presence of an ectopic pregnancy is exceedingly rare if an intrauterine pregnancy (gestational sac plus yolk sac) is seen on ultrasound. The chance of a simultaneous intrauterine and extrauterine pregnancy (heterotopic pregnancy) is approximately 1 in 3900, including spontaneous pregnancies and those conceived with assisted reproductive technology (ART).

Hydatidiform molar pregnancies usually end in miscarriage before the fifth month of gestation. Theca lutein cysts are present in 50% of cases and appear as bilateral, large, multiseptated ovarian cysts. These cysts are caused by excessive production of hCG by the abnormal trophoblastic tissue. The uterus may also be unusually large and contain a heterogenous endometrial mass classically described on ultrasound as a “swiss cheese” or “snowstorm” pattern. An early molar gestation may present simply as an anembryonic gestation or spontaneous abortion. Only partial molar gestations will contain fetal parts.

When findings on ultrasound are nonspecific, correlation with hCG levels can improve the ability to distinguish normal and abnormal pregnancies. In a normal pregnancy, the minimal rise in hCG is 53% over 48 hours. hCG values that rise slower than expected may be consistent with a failed intrauterine or ectopic pregnancy. Decreasing levels of hCG are also diagnostic of an abnormal pregnancy. In spontaneous abortion, the hCG values are expected to drop 21–35% in 2 days (depending on the initial hCG value). A slower decline is suggestive of an ectopic pregnancy.

Complications

Severe or persistent bleeding during or after spontaneous abortion may be life-threatening. The more advanced the gestation, the greater the likelihood of excessive blood loss. Infection, intrauterine adhesions (Asherman's syndrome), and infertility are other complications of abortion.

Perforation of the uterus may occur during procedures to remove retained products of conception, namely D&C. The rate of perforation during the first and second trimesters is approximately 0.5% for both induced and spontaneous abortions. Uterine perforation is more common during D&C performed in pregnancy because of the soft uterine wall and may be accompanied by injury to the bowel and bladder, hemorrhage, and infection. Surgical evacuation may also lead to cervical trauma and subsequent cervical insufficiency.

Treatment of Abortions

Successful management of spontaneous abortion depends on early diagnosis. Every patient should have a complete history taken and a physical examination performed. Laboratory studies include a complete blood count, blood type, and cervical cultures to determine pathogens in case of infection.

If the diagnosis of threatened abortion is made, pelvic rest can be recommended, although it has not been shown to prevent subsequent miscarriage. Prognosis is good when bleeding and/or cramping resolve.

If the diagnosis of a missed or incomplete abortion is made, options include surgical, medical, or expectant management. In the past, surgery was the standard of care because of concern that medical or expectant management would lead to higher rates of retained pregnancy tissue and subsequent infection. More recently, expectant or medical management are acceptable alternatives and have even shown lower rates of infection despite their higher rates of retained products of conception. These patients also avoid the risks of surgery, including uterine perforation, intrauterine adhesions, and cervical insufficiency. The advantages of performing a D&C include convenient timing and low rates of retained products of conception.

Expectant management allows the spontaneous passage of products of conception and avoids risks of surgery. Risks and side effects include unpredictable timing until the abortion is completed with the possibility of significant pain and bleeding, occasionally requiring emergent D&C. Expectant management also has the highest rates of retained pregnancy tissue, necessitating treatment with misoprostol (prostaglandin E1) or D&C.

Patients who choose medical management are given misoprostol, a drug that induces uterine contractions and expulsion of the products of conception. The risk of retained products is lower than with expectant management; however, repeat doses of medication may be needed to complete the abortion. As with expectant management, timing can be unpredictable, and symptoms of pain and/or bleeding may necessitate emergent D&C. Expectant or medical management of abortion assumes that prompt medical evaluation is available. Those options should not be considered if medical care is not easily accessible.

If the diagnosis of complete abortion is made, the patient should be observed for further bleeding. If bleeding is minimal, no further treatment is necessary. All products of conception should be examined and sent for pathologic examination to confirm an intrauterine pregnancy. If an intrauterine pregnancy was not previously seen on ultrasound and no pathology specimen is available, serial hCG levels are followed to confirm spontaneous abortion. If hCG levels decline more slowly than expected (eg, <21–35%), an ectopic pregnancy or retained products of conception must be considered. Molar gestation is also a possible diagnosis if hCG levels plateau or rise abnormally without an intrauterine pregnancy.

If a complete or partial hydatidiform molar pregnancy is diagnosed, surgical evacuation with suction D&C should be performed. As long as hCG levels are decreasing and remain undetectable after molar evacuation, there is no need for chemotherapy. However, if hCG levels start rising, plateau, or are persistent for more than 6 months, evaluation for malignant postmolar gestational trophoblastic disease is indicated.

Treatment of Complications

Uterine perforation may result in intraperitoneal bleeding, as well as injury to the bladder and/or bowel. In many cases, uterine perforation is asymptomatic and goes unrecognized. When perforation and bowel or bladder injury is suspected or when heavy bleeding is encountered, laparoscopy and/or laparotomy are indicated to determine the extent of the perforation and to evaluate for injury to other adjacent organs.

Essentials of Diagnosis

• Three or more consecutive pregnancy losses before 20 weeks of gestation

General Considerations

Recurrent miscarriage is defined as 3 or more consecutive pregnancy losses before 20 weeks of gestation, each with a fetus weighing less than 500 g. Recurrent pregnancy loss affects up to 5% of couples, often with no identifiable cause. The prognosis for a successful subsequent pregnancy correlates with the number of previous miscarriages. The risk of spontaneous abortion in a first pregnancy is approximately 15%, and this risk is at least doubled in women experiencing recurrent pregnancy loss.

Overall, the prognosis after repeated losses is good, with most couples having an approximately 60% chance of a viable pregnancy.

Pathogenesis & Treatment

Determining the etiology of recurrent miscarriage involves a comprehensive workup. This evaluation can be divided into 6 categories of possible causes: genetic, immunologic, endocrinologic, anatomic, microbiologic, and thrombophilic.

Table 13–1 summarizes a diagnostic workup and possible therapies for recurrent abortion.

Genetic Errors

Genetic errors associated with recurrent pregnancy loss include maternal and paternal karyotype abnormalities and recurrent aneuploidy.

A structural genetic factor is found in either partner in up to 8% of couples with recurrent miscarriage. Of these, balanced translocations are the most common and are found more frequently in the female partner. Less frequent findings include chromosome insertions, deletions, and inversions. When a karyotypic abnormality is found, genetic counseling should be provided because the likelihood of a subsequent healthy birth depends on the chromosome(s) involved and the type of rearrangement. Although couples affected by a structural genetic defect are more likely to have a miscarriage, the subsequent live birth rate can be as high as 70%. Despite the good prognosis, some patients opt for treatment with ART. If the defect is paternal, artificial insemination by a donor is available. For a maternal defect, a donor egg may be fertilized by the husband's sperm. Preimplantation genetic diagnosis is also available for parents who wish to use their own gametes.

In couples with normal karyotypes, recurrent fetal aneuploidy can be the cause of miscarriage. The most common aneuploidies found are the trisomies. Although miscarriages caused by trisomies are usually random events, the frequency of such events increases with advancing maternal age. In the general reproductive population, however, a trisomic miscarriage does not increase the risk of having a similar outcome in the next pregnancy. As a result, recurrent pregnancy loss with normal fetal chromosomes carries an overall higher recurrence risk, as this subset is presumably caused by maternal or paternal etiologies.

Uterine & Cervical Abnormalities

Anatomic abnormalities were the first described causes of recurrent miscarriage and account for up to 15% of recurrent pregnancy losses. Defects include congenital uterine anomalies, cervical insufficiency, submucosal leiomyomas and endometrial polyps, malformations from DES exposure in utero, and Asherman's syndrome.

The most common uterine malformation is a uterine septum. This anomaly is associated with first-trimester losses, presumably because of implantation failure on the relatively avascular septum. Other müllerian fusion abnormalities such as bicornuate and unicornuate uterus are less common and are more likely to cause second-trimester miscarriage or preterm delivery. Similarly, anomalies caused by DES exposure (eg, T-shaped uterus) can lead to second-trimester loss.

Structural defects such as submucosal leiomyomas and endometrial polyps likely interfere with implantation. In Asherman's syndrome, implantation is impeded by the presence of intrauterine adhesions and fibrosis. This scarring can also impair adequate blood supply to the endometrium. Diagnosis of uterine defects is usually accomplished with transvaginal ultrasound. A specific type of transvaginal ultrasound, in which saline is infused into the endometrial cavity (eg, saline infusion sonography), can help delineate defects such as leiomyomas, polyps, and intrauterine adhesions. Hysterosalpingogram or magnetic resonance imaging can detect uterine malformations. Treatment is primarily surgical, and minimally invasive procedures using hysteroscopy can be performed in many cases.

Cervical insufficiency classically presents in the second trimester with painless cervical dilation. Although no definite cause is found in many patients, cervical insufficiency has been associated with congenital uterine anomalies, trauma from procedures that dilate the cervix (eg, D&C), and excisional procedures such as a loop electrosurgical excision procedure or cold-knife conization.

If other causes of recurrent pregnancy loss are excluded and the presumed etiology is cervical insufficiency, a cervical cerclage is recommended between 13 and 16 weeks' gestation. Success rates with cerclage are 85–90%. Complications include bleeding, infection, rupture of membranes, and miscarriage. Contraindications to cerclage placement include bleeding of unknown etiology, infection, labor, ruptured membranes, and known fetal anomalies.

Endocrine Factors

Possible endocrine causes of recurrent miscarriage include thyroid disorders, hyperprolactinemia, poorly controlled diabetes mellitus, and luteal phase defect (eg, progesterone insufficiency).

Luteal phase defect (LPD) is thought to result from a deficiency in progesterone; however, the diagnosis remains controversial. Critics of this diagnosis note intraobserver and interobserver variations in biopsy results, the presence of LPD in normal women, and inconsistent results in women diagnosed with LPD. Furthermore, controlled studies demonstrating an improvement in pregnancy outcome with progesterone treatment are lacking. For these reasons, many experts are skeptical about the importance of LPD as an etiology of recurrent pregnancy loss.

The proposed mechanism in LPD is a relative lack of progesterone that causes a delay in endometrial development, preventing normal implantation. Inadequate hormonal support of the embryo may also be involved. In the past, the diagnosis of LPD was made by luteal phase endometrial biopsies that showed a lag in endometrial development when compared with the current day of the cycle. More recently, midluteal progesterone levels of <10 ng/mL have been used to diagnose an inadequate luteal phase. LPD is treated with supplemental progesterone.

Untreated hypothyroidism increases the risk of miscarriage. Hypothyroidism is diagnosed with a sensitive thyroid-stimulating hormone test, and patients should be euthyroid before attempting pregnancy. Hyperprolactinemia may be associated with recurrent pregnancy loss by competing with the hypothalamic–pituitary–ovarian axis, resulting in insufficient folliculogenesis, oocyte maturation, and/or a LPD. Treatment of hyperprolactinemia with a dopamine agonist may improve pregnancy outcomes. Patients with poorly controlled diabetes mellitus can similarly have an increased risk of miscarriage. These risks for recurrent pregnancy loss highlight the importance of diagnosing and treating underlying medical problems.

Infection

Infections such as Toxoplasma gondii, Listeria monocytogenes, herpes simplex, and cytomegalovirus have been implicated in spontaneous abortion, although a causal relationship has not been defined. No infectious agents have been clearly linked to recurrent pregnancy loss.

Immunologic Factors

Antiphospholipid syndrome is an autoimmune disorder defined by the presence of characteristic clinical features and antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies). The most common and serious complications of this disorder are venous and arterial thrombosis, in which the majority of thrombotic events are venous. The risk of thrombosis is significantly increased during pregnancy. Although the exact mechanism is unclear, the increased thrombotic potential in women with antiphospholipid syndrome is associated with recurrent pregnancy loss after 10 weeks' gestation. Therapy with aspirin with or without heparin has been shown to reduce pregnancy loss.

Women with systemic lupus erythematosus (SLE) have a higher rate of miscarriage and pregnancy loss in all trimesters. The prevalence of antiphospholipid antibodies in patients with SLE is estimated at 37%, and such antibodies are the most sensitive indicator of poor pregnancy outcomes.

Previously, the sharing of human leukocyte antigens between partners was thought to be associated with recurrent pregnancy loss. More recent studies, including a large, randomized controlled trial, do not support this theory. Despite the lack of diagnostic tests to identify an alloimmune factor associated with early pregnancy loss, there is evidence that there are immunologic interactions between the mother and her allogeneic pregnancy. Investigation is currently underway looking at the efficacy of active and passive immunotherapy in preventing recurrent miscarriage.

Thrombophilia

Certain inherited or acquired thrombophilic factors are associated with an increased risk of venous thromboembolism. These include a group of inherited gene mutations that predispose to arterial and/or venous thrombosis: factor V Leiden mutation, prothrombin gene mutation, hyperhomocysteinemia, methylenetetrahydrofolate reductase polymorphisms, and deficiencies in protein S, protein C, and antithrombin III. Despite the association between inherited thrombophilias and venous thromboembolism, a definitive causal link cannot be made between these diseases and uteroplacental thrombosis leading to adverse pregnancy outcomes.

Testing for maternal inherited thrombophilia may be considered when there is a personal history of thromboembolism in the absence of other risk factors such as surgery or prolonged immobilization. Testing is also indicated when a first-degree relative has a history of a high-risk thrombophilia or venous thromboembolism before age 50 years in the absence of risk factors. Currently, recurrent pregnancy loss is not an indication to screen for thrombophilias, with the exception of antiphospholipid antibodies. Likewise, there are insufficient data that treatment with heparin or other anticoagulant therapies improves pregnancy outcomes in women with inherited thrombophilia and recurrent pregnancy loss.

Essentials of Diagnosis

• Intrauterine infection involving the endometrium and products of conception

Mortality from abortion is rare in developed countries such as the United States, where induced abortions are legal. Abortion continues to be a leading cause of maternal death in countries where abortion remains illegal. These abortion-related deaths are primarily from sepsis as a result of unsterile instruments and poor surgical technique. Hemorrhage also accounts for a proportion of these deaths.

In septic abortion, infection usually begins as endometritis involving the endometrium and any retained products of conception. These patients present with fevers, chills, abdominal pain, vaginal bleeding, and malodorous vaginal discharge. Without treatment, endometritis may spread beyond the uterus, leading to peritonitis, bacteremia, and sepsis.

The 2 most common causes of septic abortion are retained products of conception and bacteria that have been introduced into the uterus via ascending infection. Pathogens that cause septic abortion are usually those seen in normal vaginal flora as well as sexually transmitted bacteria. Before performing D&C, screening for sexually transmitted infections is essential.

In evaluating septic abortion, a complete blood count, urinalysis, endocervical cultures, blood cultures, and abdominal x-ray to rule out uterine perforation should be obtained. Ultrasound should be performed to look for retained products of conception.

Treatment

Treatment of septic abortion involves hospitalization and intravenous antibiotic therapy. Selection of antibiotic agents should provide for both anaerobic and aerobic coverage. If retained products of conception are diagnosed, a D&C is indicated.

Essentials of Diagnosis

• Pregnancy implanted outside the endometrial cavity.
• The most common site of ectopic pregnancy is a fallopian tube.

Pathogenesis

In ectopic pregnancy, a fertilized ovum implants outside the endometrial cavity (Fig. 13–7). Nearly all ectopic pregnancies (>95%) occur in the fallopian tube (tubal pregnancy); however, an ectopic pregnancy may also be found implanted within the endocervical canal (cervical pregnancy), on or in the ovary (ovarian pregnancy), within a scar from a prior caesarean delivery (caesarean scar pregnancy), or within the peritoneal cavity (abdominal pregnancy).

Ectopic pregnancy occurs in approximately 1.5–2.0% of all pregnancies. The incidence has increased from 4.5 per 1000 in 1970 to 19.7 per 1000 in 1992, the last time data were reported by the US Centers for Disease Control and Prevention. This may be due, at least in part, to a higher incidence of pelvic inflammatory disease, use of assisted reproductive technology, and higher rates of tubal sterilization.

The morbidity and mortality associated with ectopic pregnancy has decreased dramatically, mainly because of earlier diagnosis with ultrasound and hCG levels and subsequent treatment before rupture. Nevertheless, ectopic pregnancy is the leading cause of pregnancy-related death in the first trimester and accounts for 4–10% of all pregnancy-related deaths.

Classification & Incidence

Ectopic pregnancy can be classified as follows (Fig. 13–7).

Tubal (>95%)

Includes ampullary (70%), isthmic (12%), fimbrial (11%), and interstitial (2%).

Other (<5%)

Includes cervical, ovarian, caesarean scar, and abdominal. Primary abdominal pregnancies have been reported, but most abdominal pregnancies result from tubal abortion or rupture with subsequent implantation in the bowel, omentum, or mesentery. Caesarean scar pregnancy is becoming an increasingly recognized clinical entity, with its incidence presumably paralleling the rise in caesarean section rates.

Heterotopic Pregnancy

An ectopic pregnancy that occurs in combination with an intrauterine pregnancy. The risk of a heterotopic pregnancy is <1 in 30,000 of spontaneous pregnancies. The incidence ranges from 1 in 100 to 1 in 500 with assisted reproductive technologies.

There are many known risk factors for ectopic pregnancy, such as previous pelvic inflammatory disease, current and past smoking, and the presence of an intrauterine device (IUD). Despite our knowledge of these predisposing factors, up to one-third of ectopic pregnancies occur in women without any apparent risk factors.

Tubal Factors

Damage to the fallopian tube from a number of factors increases the risk of ectopic pregnancy. In pelvic inflammatory disease (PID), microorganisms ascend from the lower genital tract, infecting and causing inflammation of the uterus, fallopian tubes, and ovaries. Salpingitis can result in damage to fallopian tube cilia and blockage or closure of the tube. PID can also lead to adhesion formation among pelvic organs.

Other causes of distorted tubal anatomy leading to an increased risk of ectopic pregnancy include previous tubal surgery, endometriosis, uterine leiomyomas, and developmental abnormalities of the tube or abnormal tubal anatomy from in utero DES exposure. Up to one-third of pregnancies after tubal ligation and approximately 7% of pregnancies after sterilization reversal are ectopic. Additionally, one-third of pregnancies after an ectopic pregnancy are also ectopic implantations.

Assisted Reproductive Technology (ART)

The rate of ectopic pregnancy with ART ranges from 2.1% to as high as 8.6% of all clinical pregnancies. The etiology of ectopic pregnancy in patients undergoing ART and in vitro fertilization (IVF) is not completely understood, but several theories are currently under investigation.

Medications used to increase ovarian follicle production result in high levels of progesterone and estradiol that may affect tubal peristalsis and uterine relaxation. Women with tubal factor infertility undergoing IVF have even higher rates of ectopic pregnancy, and most physicians will recommend removal of diseased tubes before IVF. Ectopic pregnancy rates are associated with the number of transferred embryos as well as placement of the embryos.

Other Factors

Pregnancy is uncommon in women who use an IUD for contraception. However, approximately 5% of pregnancies that do occur in women using an IUD are ectopic pregnancies. Nevertheless, women with an IUD are overall less likely to develop an ectopic pregnancy than women who do not use contraception. Smoking also significantly increases the risk of ectopic pregnancy, likely because cigarette smoke affects cilia and smooth muscle function in the fallopian tube.

Timing of Rupture

Rupture of an ectopic pregnancy is usually spontaneous. Isthmic pregnancies tend to rupture earliest, at 6–8 weeks' gestation, because of the small diameter of this portion of the tube. Ampullary pregnancies rupture later, generally at 8–12 weeks. Interstitial pregnancies are the last to rupture, usually at 12–16 weeks, as the myometrium allows more room for the ectopic to grow. Interstitial rupture is quite dangerous because its proximity to uterine and ovarian vessels can result in massive hemorrhage.

Prevention

Prevention and early treatment of sexually transmitted diseases is important to prevent tubal damage and subsequent ectopic pregnancy. Smoking cessation can also help reduce the risk of ectopic pregnancy. Smoking decreases the motility of the fallopian tube cilia and makes a fertilized egg less likely to traverse the tube normally. Unfortunately, other known risk factors are more difficult to control, and up to one-third of ectopic pregnancies occur without any associated risk factors.

Clinical Findings

No specific symptoms or signs are pathognomonic for ectopic pregnancy, and many disorders can present similarly. Normal pregnancy, threatened or incomplete abortion, ovarian cyst rupture, ovarian torsion, gastroenteritis, and appendicitis can all be confused with ectopic pregnancy. Because early diagnosis is crucial, a high index of suspicion should be maintained when any pregnant woman in the first trimester presents with bleeding and/or abdominal pain.

Symptoms

The following symptoms may assist in the diagnosis of ectopic pregnancy.

Pain

Pelvic or abdominal pain is present in almost 100% of cases. Pain can be unilateral or bilateral, localized or generalized. The presence of subdiaphragmatic or shoulder pain is suggestive of intra-abdominal bleeding. In tubal ectopic pregnancy, implantation typically occurs in the wall of the tube, in the connective tissue beneath the serosa. There may be little or no decidual reaction within the tube and minimal defense against the permeating trophoblast. The trophoblast invades blood vessels, causing local hemorrhage. A hematoma in the subserosal space enlarges as the pregnancy grows, and progressive distention of the tube eventually leads to pain and rupture.

Bleeding

Abnormal uterine bleeding occurs in roughly 75% of cases and represents decidual sloughing. Bleeding usually presents as intermittent, light spotting; however, bleeding may be heavier. A decidua cast is passed in 5–10% of ectopic pregnancies and may be mistaken for products of conception. Vaginal bleeding is of endometrial origin and results when the decidua breaks down from lack of progesterone support, a hallmark of an abnormal pregnancy. Occasionally the entire decidua may be shed in one or more large pieces as a decidual cast of the endometrial cavity. On pathologic examination, only decidua is seen, whereas chorionic villi are notably absent.

Amenorrhea

Secondary amenorrhea is variable. Approximately half of women with ectopic pregnancies have some bleeding at the time of their expected menses and may not realize they are pregnant.

Syncope

Dizziness, lightheadedness, and/or syncope may be part of the initial presentation and should raise suspicion for intra-abdominal bleeding from a ruptured ectopic pregnancy.

Signs

On examination, the following signs are important in the diagnosis of ectopic gestation.

Tenderness

Diffuse or localized abdominal tenderness is present in the majority of patients with ectopic pregnancies. Adnexal and/or cervical motion tenderness is also a common finding.

Adnexal Mass

A unilateral adnexal mass is palpated in one-third to one-half of patients. More often, unilateral adnexal fullness rather than a discrete mass is appreciated. Occasionally, a cul-de-sac mass is noted.

Uterine Changes

The uterus may undergo the typical changes of pregnancy, including softening and a slight increase in size.

Hemodynamic Instability

Vital signs will reflect the hemodynamic status of patients with tubal rupture and intra-abdominal bleeding.

Laboratory Findings

Hematocrit

The hematocrit is an important initial test that indirectly assesses the hemodynamic status of the patient and reflects the amount of intra-abdominal bleeding.

β-HCG

The qualitative serum or urine hCG assay is positive in virtually 100% of ectopic pregnancies. A positive result, however, does not help distinguish an intrauterine from ectopic pregnancy. More helpful is a quantitative hCG value that, in conjunction with transvaginal ultrasound, can often make the diagnosis. If ultrasound is nondiagnostic (eg, in an early ectopic, early normal pregnancy, or early failed pregnancy), serial hCG values can be followed. The hCG level should rise at a minimum of 53% over 48 hours in a normal pregnancy. An inappropriate rise in hCG has a sensitivity of 99% for an abnormal gestation. Of note, two-thirds of ectopic pregnancies have abnormally rising values, whereas the remaining third show a normal progression.

Progesterone

Serum progesterone levels may help confirm an ectopic pregnancy diagnosis. Serum progesterone values are independent of hCG levels. A serum progesterone level less than 5 ng/mL has a 100% specificity for identifying an abnormal pregnancy, but does not identify the location of the pregnancy. Progesterone levels greater than 20 ng/mL are associated with normal intrauterine pregnancies. All values in between 5 and 20 ng/mL are equivocal.

Diagnostic Tests

Ultrasound

Ultrasound is an essential part of the evaluation for an ectopic pregnancy. An initial transvaginal ultrasound can be used to visualize an intrauterine pregnancy or a definite ectopic gestation. If neither diagnosis is made, the patient is considered to have a “pregnancy of unknown location.” Approximately 25–50% of women with an ectopic pregnancy initially present in this manner. An intrauterine pregnancy may not be visualized because the gestational sac has not yet developed or has collapsed. Likewise, an early ectopic pregnancy may be too small to be detected by ultrasound. When a diagnosis cannot be made, the patient is then followed with serial hCG levels and ultrasound until either an ectopic pregnancy, intrauterine gestation, or early pregnancy failure is confirmed.

In general, ultrasound should detect an intrauterine gestation when the hCG value falls within or surpasses the “discriminatory zone,” defined as an hCG value between 1500 and 2000 mIU/mL. If the hCG level is higher than the discriminatory zone, and the transvaginal ultrasound is nondiagnostic, ectopic pregnancy or early abnormal pregnancy is likely. Caution should be used when interpreting hCG values because they may be falsely elevated in a pregnancy with multiple gestations.

A normal intrauterine sac appears regular and well defined on ultrasound. It has been described as an echolucent area having a “double ring” or “double decidual” sign, which represents the decidual lining and the chorion around the early gestational sac. In ectopic pregnancy, ultrasound may reveal only a thickened, decidualized endometrium. Decidual sloughing results in intracavitary fluid or blood and creates the so-called pseudogestational sac, a small and irregular structure that may be confused with an intrauterine gestational sac.

The presence of an adnexal mass with an empty uterus raises the suspicion for an ectopic pregnancy, especially if the hCG titers are above the discriminatory zone. Visualization of a gestational sac with a yolk sac or embryo within the adnexa confirms the diagnosis; however, it is more common to find a hyperechoic “tubal ring” or complex mass within the adnexae (Fig. 13–8). If rupture has occurred, anechoic or echogenic free fluid in the cul-de-sac may be visualized.

Ultrasound is increasingly being relied on to differentiate several less common types of ectopic pregnancies. Both interstitial tubal and caesarean section scar pregnancies can be difficult to distinguish from intrauterine gestations because of their proximity to the intrauterine cavity.

The most likely alternative diagnosis of an adnexal mass in early pregnancy is a corpus luteum cyst, which can also rupture and bleed, thus making its distinction from an ectopic pregnancy challenging.

Laparoscopy

In the past, laparoscopy was often used to diagnosis ectopic pregnancy. In current practice, however, transvaginal ultrasound has replaced laparoscopy as the preferred diagnostic tool. Compared with laparoscopy, ultrasound is equally effective in confirming the presence or absence of ectopic pregnancy. Ultrasound also has the advantages of being both cost-effective and noninvasive. In terms of surgical treatment for ectopic pregnancy, laparoscopy is the standard method, assuming the patient is hemodynamically stable.

D&C

D&C can be performed to confirm or exclude intrauterine pregnancy. D&C is usually performed when an early ectopic or abnormal intrauterine gestation is suspected based on hCG levels and ultrasound. D&C should not be performed if a pregnancy is desired because it may remove a normal, early intrauterine gestation. If chorionic villi are seen on pathology examination of the D&C specimen, an intrauterine pregnancy is confirmed. On the other hand, if only decidua is obtained on D&C, ectopic pregnancy is highly likely.

Laparotomy

Immediate surgery is indicated in the hemodynamically unstable patient with a presumed ectopic pregnancy. Laparoscopy is generally the preferred surgical method for evaluation of suspected ectopic pregnancy in the stable patient; however, exploratory laparotomy can provide rapid access to control intra-abdominal hemorrhage. Laparotomy also may be performed if the laparoscopic approach does not allow adequate visualization or if scar tissue from previous surgeries makes the laparoscopic approach too difficult.

Culdocentesis

Culdocentesis, the vaginal passage of a needle into the posterior cul-de-sac, was once used to confirm the presence of hemoperitoneum. This technique has now been replaced by transvaginal ultrasound and is rarely performed in modern medicine.

Magnetic Resonance Imaging

Magnetic resonance imaging is a useful adjunct to ultrasound in cases in which an unusual ectopic location is suspected. The location of the ectopic pregnancy and recognition of cervical, caesarean scar, or interstitial pregnancy determines the options for treatment and management. In these types of ectopic pregnancy, conservative treatment with methotrexate is often preferred and usually attempted before surgery to avoid the potential catastrophic hemorrhage associated with surgical management in these cases.

Treatment

Expectant Management

Expectant management is appropriate and can be successful in a select population of patients. In general, these women should be asymptomatic, with lower starting hCG levels and evidence that the ectopic pregnancy is spontaneously resolving (eg, decreasing hCG levels). If the initial hCG level is less than 200 mU/mL, 88% of patients experience resolution with expectant management. These women should be educated about the potential risks of tubal rupture, intra-abdominal bleeding, and the need for emergent surgery.

Medical Management

Methotrexate (MTX) is a drug that inhibits the action of dihydrofolate reductase, thereby inhibiting DNA synthesis. MTX affects actively proliferating tissues such as bone marrow, intestinal mucosa, malignant cells, and trophoblastic tissue. This antimetabolite can be considered for women who are hemodynamically stable with a confirmed ectopic pregnancy or if clinical suspicion is high for an ectopic pregnancy. Although treatment of early ectopic pregnancy with MTX has significantly decreased the number of women who need surgery, there are several contraindications to its use.

Embryonic cardiac motion or the presence of a gestational sac larger than 3.5 cm are relative contraindications to MTX due to the higher rate of treatment failure in patients with either one of these findings. The level of hCG is also predictive of MTX success. With hCG values greater than 5000 mIU/mL, the failure rate is 14% with a single dose of MTX compared with 3.7% with a multiple-dose regimen. Because MTX affects rapidly dividing tissues within the body, it should not be given to women with blood dyscrasias or active gastrointestinal or respiratory disease. MTX is toxic to hepatocytes and is cleared by the kidneys; thus serum creatinine level and liver transaminases should be normal before administration. Patients must also be considered reliable for follow-up (Table 13–2).

There are three different regimens for giving MTX: single dose, two-dose, and a fixed multidose protocol. The single 50 mg/m2 dose of MTX is most commonly used, given as an intramuscular injection. hCG levels are measured at 4 and 7 days posttreatment with an expected 15% decrease from day 4 to day 7. Weekly hCG levels are then checked until zero. If hCG levels do not drop appropriately, a second MTX dose or surgical intervention is advised. Overall, the fixed multidose regimen has been shown to be the most effective regimen, especially in treating more advanced gestations and those with embryonic cardiac activity. However, these patients may experience more side effects, and adherence to the treatment plan may be more difficult.

It is not unusual for women given MTX to have an increase in abdominal pain 2–3 days after administration, likely from the effect of the drug on trophoblast tissue and tubal distention or tubal abortion. Despite this common finding, monitoring for tubal rupture during MTX therapy is extremely important, and worsening pain should prompt immediate evaluation.

Surgical Treatment

Once the mainstay of therapy for ectopic pregnancy, surgical treatment is now mainly reserved for patients with contraindications to medical management and for those with evidence of tubal rupture. Despite declining rates of surgical management, surgery remains the most definitive treatment for ectopic pregnancies.

In a hemodynamically stable patient, laparoscopy is the standard approach for surgical management of a known or suspected ectopic pregnancy that is not amenable to medical treatment. In some instances, previous surgeries with subsequent intra-abdominal adhesions makes laparotomy the preferred approach. Tubal pregnancies can be treated with either linear salpingostomy or salpingectomy. The decision to perform either procedure depends on the patient's desire for future fertility as well as the appearance of the contralateral tube. If the contralateral tube appears abnormal and fertility is desired, a linear salpingostomy can be performed, and future fertility seems to be improved. In this technique, an incision is made along the fallopian tube, proximal to the ectopic pregnancy. The gestational tissue is gently removed from the tube with an effort to remove the ectopic in one piece. Patients who undergo linear salpingostomy are at risk for having persistent trophoblastic tissue and must be evaluated with weekly hCG levels until undetectable. hCG levels may remain elevated in up to 20% of patients who have undergone salpingostomy. In these cases, MTX is given, with high rates of resolution. Linear salpingostomy also increases the risk of a second ectopic pregnancy occurring in this tube, with rates up to 15%. In general, if the contralateral tube is normal, salpingectomy should be performed to reduce the risk of subsequent ectopic pregnancy.

Salpingectomy (removal of the fallopian tube) is preferred if the patient has completed child bearing, if the affected tube appears damaged, or if salpingostomy has already been performed on that tube. Salpingectomy is a simpler technique and carries minimal risk of retained trophoblastic tissue and postoperative tubal bleeding.

Interstitial pregnancies are uncommon, accounting for only 2–4% of all ectopic pregnancies. MTX and surgery can be offered to these patients. Expectant management is currently not recommended because it has not been well studied in these patients and the risks are considered greater than for tubal ectopics. Interstitial pregnancies implant into the vascular uterine cornua, and subsequent rupture can cause significant bleeding. MTX is a reasonable first-line therapy for the treatment of asymptomatic patients with an unruptured interstitial pregnancy, with reported success rates of >80%. Similar to MTX treatment of tubal pregnancies, close follow-up and patient education are necessary. Surgery is an option for patients who desire definitive management. Laparotomy was once the standard surgical approach; however, several laparoscopic techniques have now been described. Earlier diagnosis has allowed for management of interstitial pregnancies with less invasive surgical procedures.

Emergency Treatment

Immediate surgery is indicated when the diagnosis of a ruptured ectopic pregnancy is made. Blood products should be requested immediately because transfusion is often necessary. There is no place for conservative management in a patient with a ruptured ectopic. Even patients who initially present with normal vital signs can quickly become hemodynamically unstable. Rho (D) immunoglobulin should be given to any Rh-negative mother with the diagnosis of ectopic pregnancy because sensitization may occur.

Many harmful agents are responsible for altering the biologic process of human development. Recognized teratogens include viruses (eg, rubella, cytomegalovirus, congenital lymphocytic choriomeningitis virus), environmental factors (eg, hyperthermia, irradiation), chemicals (eg, mercury, alcohol), and therapeutic drugs (eg, inhibitors of the renin–angiotensin system, thalidomide, isotretinoin, warfarin, valproic acid, carbamazepine).

Evaluation

When evaluating exposure to teratogens, it is important to consider gestational age at the time of exposure. Fetal development is most vulnerable during organogenesis (2–8 weeks postconception). Also important is the route of administration and dose of a particular medication, the length of exposure, and maternal and placental clearance. Passage into the placental circulation is necessary for a drug to cause a teratogenic effect. Table 13–3 lists some of the potential adverse effects related to the timing of exposure.

Evaluation of studies examining toxic exposures is difficult because of the large number of possible fetotoxic agents and the complex interaction between these agents, the presence or absence of influences that may alter the effects of an agent, and the presence or absence of certain genotypes that might alter an individual's susceptibility. Therefore, specific criteria for recognizing teratogens in humans have been defined (Table 13–4). Table 13–5 lists common teratogens and their potential fetotoxic effects.

Counseling of parents should include review of the exposure history and discussion of the particular agent involved, as well as possible sequelae. In some cases, intervention may be possible. In other cases, if a pregnancy is found to develop abnormally, the parents may elect to abort an affected fetus. Effective counseling should provide the best information available to assist parents in what can be a very difficult decision.

The United States Food and Drug Administration standards for drug labeling with regard to teratogenicity are listed in Table 13–6.