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Key Abbreviations
| Advanced maternal age | AMA |
| Antiphospholipid syndrome | APS |
| Body mass index | BMI |
| Cytomegalovirus | CMV |
| Dilation and evacuation | D&E |
| Fetal growth restriction | FGR |
| Initial causes of death | INCODE |
| Intrahepatic cholestasis of pregnancy | ICP |
| Maternal fetal medicine unit | MFMU |
| Premature rupture of membranes | PROM |
| Randomized controlled trail | RCT |
| Relative risk | RR |
| Systemic lupus erythematosus | SLE |
| Small for gestational age | SGA |
| Stillbirth collaborative research network | SCRN |
| United Kingdom | UK |
| United States | US |
Stillbirth, defined as fetal death at 20 weeks or more of gestation , is one of the most common adverse pregnancy outcomes worldwide, with an estimated 2.6 million stillbirths at 28 weeks or more of gestation per year. The majority (98%) of all stillbirths occur in low- and middle-income countries. In the United States, the frequency of stillbirths is 1 in 165 deliveries or 24,000 stillbirths annually, which is higher than most developed countries. The US stillbirth rate of 5.96 per 1000 births in 2013 is relatively unchanged since 2006. The stillbirth rate at 20 to 27 weeks’ gestation is equivalent to the stillbirth rate at 28 weeks or greater at 3.0 per 1000 births. This plateau in stillbirth rate, combined with a decline in infant mortality, has resulted in the stillbirth rate exceeding the infant mortality rate. This chapter reviews the risk factors for stillbirth, etiology, evaluation, and management.
Risk Factors
There is significant racial disparity in stillbirth rates in the United States; non-Hispanic black women have a stillbirth rate that is 2.2-fold higher than non-Hispanic white women (10.53 compared with 4.88 per 1000 births) . The rate for Hispanic women (5.29 per 1000 births) is 7% higher than for non-Hispanic white women. The Stillbirth Collaborative Research Network (SCRN) conducted a multicenter, population-based, case-control study of stillbirths and live births enrolled at delivery. SCRN found that much of the excess rate of stillbirth among non-Hispanic black women resulted from obstetric complications, infection, or both, with stillbirths often occurring intrapartum at less than 24 weeks’ gestation, with pathophysiology similar to that of spontaneous preterm birth.
Maternal age has a U-shaped relationship with stillbirth . Stillbirth rates (stillbirths per 1000 live births and stillbirths) for women younger than 15 years (15.88) and for women 45 and older (13.76) are more than twice the rate for 30- to 34-year-old women who are the lowest-risk group (5.34). Advanced maternal age (≥35 years) is also an independent risk factor for stillbirth, even after controlling for factors such as diabetes, hypertension, multiple gestation, and fetal abnormalities, which are more likely to occur in older women.
In pregnancy, obesity increases the risk for hypertension and diabetes and is an independent risk factor for stillbirth . A meta-analysis of 38 studies including 16,274 stillbirths noted absolute risks per 10,000 pregnancies of 40 (reference standard), 48 (95% confidence interval [CI], 46 to 51), and 59 (95% CI, 55 to 63) for body mass index (BMI) levels of 20, 25, and 30, respectively. Obese women are at increased risk of having congenital anomalies, stillbirth, macrosomia, and fetal growth restriction (FGR).
Multiple gestation is a major risk factor for stillbirth. The stillbirth rate is 2.5-fold higher for twins and 5.0-fold higher for triplet and higher-order pregnancies compared with singletons. The increased risk for multiple pregnancies is partly related to increased rates of preterm labor, FGR, maternal hypertension, and placental and cord issues (especially with monochorionic twins).
The association between previous adverse pregnancy outcomes and subsequent stillbirth is increased in cases of previous preterm birth or small-for-gestational-age (SGA) infants. A previous live birth of a growth-restricted infant before 32 weeks’ gestation was associated with a fivefold increased odds of stillbirth in a Swedish cohort study. In a UK study, 364 women who had a stillbirth in their first pregnancy were at increased risk for preeclampsia, placental abruption, induction of labor, instrumental delivery, elective or emergency cesarean delivery, prematurity, low birthweight, or malpresentation compared with women with a previous live birth. Previous stillbirth is associated with an increased rate of recurrent stillbirth in most epidemiologic studies, with a sixfold increased relative risk . The recurrence risk is higher for African Americans.
Smoking is associated with an increased risk of stillbirth , and there appears to be a dose-response. Fortunately, women who quit smoking between their first and second pregnancies have been shown to reduce their risk for stillbirth to the same level as nonsmokers in the second pregnancy.
Classification of Stillbirth
It is helpful to identify a cause of death in order to optimize prevention efforts, but this can be challenging. More than 80 classification systems have been proposed and there is no agreement on a uniform system that allows for comparison of causes of stillbirth among studies, hospitals, and countries. The SCRN developed a classification system, termed initial causes of death (INCODE), using rigorous definitions. One feature of INCODE is the assignment of a “level of certainty” for potential causes of death. Causes of stillbirth are deemed as “probable causes,” “possible causes,” or “condition present.”
Etiology
The SCRN used the INCODE classification system to systematically assign causes of death in 512 stillbirths with complete evaluation, including placental examination and perinatal autopsy. A probable cause of death was found in 60.9% of stillbirths, and possible or probable cause was found in 76.2% when a complete evaluation was performed. The distribution of causes of death were as follows: obstetric conditions, 29.3%; placental abnormalities, 23.6%; fetal genetic/structural abnormalities, 13.7%; infection, 12.9%; umbilical cord abnormalities, 10.4%; hypertensive disorders, 9.2%; and other maternal medical conditions, 7.8% .
Infection
Infection is associated with approximately 10% to 20% of stillbirths in developed countries and a much higher percentage in developing countries. In developed countries, infection accounts for a greater percentage of preterm stillbirths than term stillbirths. Pathogens may result in stillbirth by producing direct fetal infection, placental dysfunction, severe maternal illness, or by stimulating spontaneous preterm birth at a periviable gestational age.
Placental and fetal infections most commonly result from ascending bacterial infection from the vagina into the space between the maternal decidua and the chorion. Further spread may result in the organisms reaching the amniotic fluid or the fetus. Examples include group B streptococcus and E. coli . Maternal systemic infections may also spread hematogenously and reach the fetus through the placental villi (villitis). These types of infections typically involve the fetal liver, as it is the first major fetal organ reached, with relatively less-common organisms such as Listeria .
Syphilis, which is uncommon in the United States, is still responsible for some stillbirths, especially in endemic areas and in developing countries. Malaria is a cause of stillbirth in women who contract a first infection during pregnancy. This also is an extremely common cause of stillbirth in endemic areas in low resource settings.
Viral infection may also cause fetal death . Parvovirus is usually asymptomatic in adults but may result in stillbirth due to the destruction of erythropoietic tissue leading to severe anemia and hydrops. It also may cause myocarditis and myocardial dysfunction. Other viral pathogens include enteroviruses, such as coxsackieviruses and echoviruses, as well as cytomegalovirus (CMV). CMV is the most commonly acquired congenital viral infection, with a primary infection rate as high as 1% during pregnancy. A known cause of fetal and placental damage, it has been associated with sporadic stillbirths. Recently, the Zika virus has been implicated in stillbirth.
Maternal Medical Conditions
Hypertensive Disorders
Hypertensive disorders of pregnancy are an important cause of stillbirth. In SCRN, 9.2% of stillbirths were associated with hypertensive disorders. The risk for stillbirth increases with the severity of hypertensive disorder. In a prospective cohort study of 1948 women with hypertension during pregnancy, the stillbirth rate for women with isolated chronic hypertension was relatively low and similar to the rate in the general population. Women who developed preeclampsia with or without underlying chronic hypertension were at increased risk for perinatal mortality compared with women who had gestational hypertension. The subgroup with the highest perinatal mortality rate (9.2%) in this cohort were women with chronic hypertension with superimposed preeclampsia.
Diabetes Mellitus
Diabetes mellitus is associated with about 4% of stillbirths. In women with poor glycemic control, stillbirths occur most commonly as a result of congenital abnormalities, placental insufficiency and/or FGR, macrosomia or polyhydramnios, or obstructed labor (intrapartum stillbirth). Although outcomes of pregnancies in type 1 diabetic women have improved over the past several decades because of improved glycemic control, the stillbirth risk remains elevated. In a prospective study comparing 5000 type 1 diabetics to nondiabetic controls, the rate of stillbirth was 1.5% in diabetic pregnancies, five times that in the nondiabetic population, with the majority occurring between 34 and 40 weeks of gestation. Poor maternal glycemic control was the most consistent finding in women who had a stillbirth.
Thyroid Disease
Severe maternal hyperthyroidism is a rare cause of stillbirth. On the other hand, hypothyroidism is common (see Chapter 47 ) and overt hypothyroidism places women at increased risk for stillbirth with a rate of 12 to 20 per 1000 births. Most studies show little association of subclinical hypothyroidism with stillbirth, although the results are inconsistent.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) has an overall prevalence of less than 1%, with a stillbirth rate of 40 to 150 per 1000. The risk is increased in cases of active disease, renal involvement, and antiphospholipid syndrome (APS). Rarely, stillbirth is due to neonatal lupus erythematosus with congenital atrioventricular block. The presence of antiphospholipid antibodies and a prior fetal loss are major predictors of subsequent stillbirth in women with SLE. Antiphospholipid antibodies are present in more than one-third of patients with SLE and are associated with an increased risk for thrombosis and damage to the uteroplacental vasculature.
Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis of pregnancy (ICP) has been associated with an increased stillbirth rate of 12 to 30/1000 affected pregnancies. ICP is characterized by pruritus and an elevation in serum bile acid concentration. The exact mechanism of the associated stillbirth is unknown but may be due to abnormal cardiac function. In a prospective study in Sweden, more than 45,000 pregnant women were screened for ICP, and women with bile acid levels greater than 40 mol/L experienced significantly higher rates of fetal complications, such as asphyxia, spontaneous preterm delivery, and meconium staining of amniotic fluid, placenta, and membranes, compared with women with normal bile acid levels and women with mild ICP (bile acid levels of 40 mol/L or less). In the SCRN study, 581 women with stillbirth and 1546 women with live births had bile acids measured. Bile acid mean measurements were slightly higher in women with stillbirth compared to live births, but the difference was not significant after adjustment for other risk factors for stillbirth, indicating that testing for bile acids in cases of stillbirth without clinical evidence of ICP is not likely to be useful. Nonstress tests and other antenatal testing do not appear to reduce the stillbirth risk.
Inherited and Acquired Thrombophilias
APS is an uncommon but important cause of stillbirth. In the SCRN study, elevated levels of anticardiolipin and anti-β2-glycoprotein-I antibodies in maternal serum were associated with a three- to fivefold increased odds of stillbirth. These results support testing for antiphospholipid antibodies in some cases of stillbirth such as those associated with placental insufficiency.
In contrast to APS, the role in stillbirth of heritable coagulopathies or thrombophilias that involve deficiencies or abnormalities in anticoagulant proteins or an increase in procoagulant proteins is unclear. Case series and retrospective studies reported an increased stillbirth risk associated with the factor V Leiden mutation, the G20210A mutation in the prothrombin gene, and deficiencies of the anticoagulant proteins antithrombin and protein C and S. However, prospective studies found no association between these thrombophilias and stillbirth, and anticoagulant treatment does not appear to improve pregnancy outcomes. The SCRN found no association between most thrombophilias and stillbirth in their case-control study. Taken together, current data suggest a weak association, if any, between heritable thrombophilias and stillbirth.
Fetal Conditions
Genetic Abnormalities
Overall, fetal cytogenetic abnormalities occur in 6% to 13% of all stillbirths, but the proportion is higher in macerated or malformed fetuses. In SCRN, a population-based study of all stillbirths occurring in five catchment areas, 7% of all stillbirths were found to be aneuploid. In a Dutch study of 750 antepartum stillbirths, 38% of stillbirths with morphologic abnormalities had chromosomal abnormalities, compared with 4.6% of those without morphologic abnormalities. The distribution of chromosomal abnormalities associated with stillbirth was as follows: trisomy 21, 31%; monosomy X, 22%; trisomy 18, 22%; trisomy 13, 6%; and other chromosomal abnormalities, 19%. In addition to aneuploidy, chromosomal abnormalities that are not identified by traditional karyotype likely cause or contribute to stillbirth. For example, pathogenic copy number variants identified by chromosomal microarray—but not identified by karyotype—appeared to cause several stillbirths in the SCRN study. In rare cases, single gene disorders contribute to stillbirth. These may prove to be important causes of stillbirth as more data are obtained from whole genome sequencing in cases of stillbirth.
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