Fetal death is defined as spontaneous intrauterine death at any gestational age. There is no complete uniformity concerning when fetal deaths are reported. The US National Center for Health Statistics uses the gestational cutoff of ≥20 weeks or 350 grams, excluding terminations for lethal fetal anomalies and inductions for previable rupture of membranes. Meanwhile, the World Health Organization (WHO) defines death as a fetus with no signs of life at ≥28 weeks gestation prior to complete expulsion from the mother, regardless of the duration of pregnancy for international comparison purposes.¹

In 2013, the fetal death rate was reported to be 5.96 per 1000 live births, or 1 in 160 deliveries in the United States. Of these, 50% occur between the gestational ages of 20 to 27 weeks gestation, 30% between 28 weeks and term, and 20% at or near term. The overall US fetal mortality rate has remained relatively unchanged since 2006. An appreciable 3% decline in fetal death rate between the gestational ages of 20 to 27 weeks gestation was noted between 2012 and 2013.²

GESTATIONAL AGE

The highest rates of stillbirth are at the earliest and latest gestational ages, with the lowest incidence between 29 and 33 weeks gestation and remaining low at 37 weeks, with a slow increase up to 42 weeks. The early fetal mortality rate is related to congenital anomalies, infections, growth restrictions, and underlying maternal conditions. In pregnancies >40 weeks gestation, the fetal mortality rate is generally related to problems surrounding the time of delivery; that is, placenta previa and abruption, cord prolapse and complications related to the labor and delivery (L&D) process.^2,3

RACE/ETHNICITY

The mortality rates vary considerably with race and ethnicity. The cause for this disparity remains largely unexplained. In the United States, non-Hispanic black women have the highest rate: 10.53 per 1000 live births.^2,4 The Stillbirth Collaborative Research Network conducted a multicenter, population-based, case control study of stillbirths and live births involving 59 tertiary-care and community hospitals. The study suggested that much of the excess rate of stillbirth among non-Hispanic black women resulted from obstetric complications, infections, or both, with stillbirth occurring intrapartum at <24 weeks gestation.⁴ Others have attributed this difference to a higher risk of preterm delivery, and in part to differences in maternal preconception health, infection, income, education, and access to quality healthcare. However, the higher rates of stillbirth persist despite early prenatal care.^4–12

AGES: YOUNGER AND ADVANCED MATERNAL AGE

Fetal mortality varies considerably by maternal age. The lowest rate was found between the ages of 25 and 34 years: 5.34 per 1000 live births; meanwhile, the highest rate was found among teenagers and women ≥35 years of age: 15.88 per 1000, and more specifically >45 years: 13.76 per 1000. The increased rate of stillbirth in women >45 years of age was an independent risk factor after controlling for medical comorbidities.¹³

MEDICAL COMORBIDITIES (DIABETES, OBESITY, HYPERTENSION)

Hypertension and diabetes increase the risk of stillbirth twofold to fivefold, while obesity has an associated fivefold increase in fetal death.^14–18

The causes of stillbirth result from maternal, fetal, or placental factors, or any combination of these factors. The causes of stillbirth differ between developing and developed countries.

INFECTION

Infectious causes contribute to 10%–20% of stillbirths in developed countries and >50% in low-income countries. It has been estimated that infection is implicated in up to 19% of stillbirths at less than 28 weeks gestation, but only 2% at term. The role of infection as the cause of death is difficulty to prove due to the following:

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  Inability to identify organisms such as Ureaplasma and viruses easily.

  
  
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  Identification of organisms in the placenta, fetus, or both does not necessarily prove causality.

  
  
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  Infection may initiate a chain of events leading to stillbirth, but it may be unable to appreciate at the time of diagnosis.

  
  
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  Positive serology does not prove causality.^8,19

The pathophysiology in which infection may lead to stillbirth includes severe systemic maternal illness; placental dysfunction due to placental infection, which prevents oxygen and nutrients from crossing to the fetus; fetal infection leading to congenital deformity that is incompatible with life; fetal infection leading to damage of vital organs; and preterm labor resulting in stillbirth during labor.¹⁹ The routes of infection leading to stillbirth include the following:

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  Ascending infection from the vagina into the space between maternal decidua and the fetal membranes

  
  
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  Hematogenous infection reaching the fetus through the placental villi

  
  
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  Transplacental infection¹⁹

Pathogens that are associated with stillbirth include parvovirus, syphilis, Listeria monocytogenes, and cytomegalovirus (CMV). Malaria is a preventable cause of stillbirth in the developing world.³

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

The mechanism by which antiphospholipid antibody syndrome (APAS) may lead to stillbirth includes inflammation, thrombosis, and infarction in the placenta. While it is unclear to what degree APAS increases the risk of stillbirth due to APAS, it can be considered a probable case of fetal death when accompanied by either or both of the following:²⁰

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  Clear histopathologic evidence of placental insufficiency with >30% infarction or thrombosis in fetal placental vessels

  
  
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  Clear clinical evidence of placental insufficiency with estimated fetal weight less than the third percentile for gestational age, severe preeclampsia, or abnormal fetal testing

HERITABLE THROMBOPHILIAS

Large, prospective, observational cohort, and case-control studies found no association for factor V Leiden, prothrombin gene mutation, and methylenetetrahydrofolate reductase (MTHFR) mutations associated with pregnancy loss.^21–23

FETOMATERNAL HEMORRHAGE

Fetomaternal hemorrhage is the transplacental passage of fetal cells to the maternal circulation. It is present in up to 3% to 14% of all stillbirths.²⁴ However, the threshold to cause stillbirth is unknown. Some of the risk factors for fetomaternal hemorrhage are abruption, maternal abdominal trauma, cesarean delivery, operative vaginal delivery, and multiple gestations. The presumed mechanism for fetomaternal hemorrhage leading to stillbirth is severe fetal anemia after a large, acute, fetomaternal hemorrhage leading to cardiovascular decompensation, disseminated intravascular coagulation, stroke, or stillbirth.

PLACENTAL ABRUPTION

Risk factors for placental abruption include cocaine and other illicit drugs, hypertension, preeclampsia, and smoking.^25–29 Specifically, cigarette smoking has been associated with stillbirth, with an OR of 1.36 (95% CI 1.27–1.46).³⁰ See Chapter 43 for more information about placental abruption.

UMBILICAL CORD ABNORMALITIES

Umbilical cord abnormalities account for 3% to 15% of possible or probable causes of death and were more common in stillbirths at >32 weeks gestation.^31,32 The abnormalities include velametous cord insertion, vasa previa, umbilical cord prolapse, cord occlusion, umbilical cord torsion, and cord entanglement or nuchal cord. In the Stillbirth Collaborative Research Network study, umbilical cord abnormalities accounted for 10% of probable causes of death, and these were more common in stillbirths >32 weeks gestation.^31,32

Nuchal cords are found in 30% of normal births, with multiple nuchal cords found in only 3.7% of all deliveries. Typically, this is a diagnosis of exclusion. Evidence of cord occlusion and hypoxia on perinatal postmortem examination, as well as histologic examination of the placenta and umbilical cord with suggested findings of vascular ectasia and thrombosis, suggests the nuchal cord as the etiology.³³

GENETIC FACTORS

The most common cause for first-trimester miscarriage is aneuploidy or genetic abnormalities. Fetal cytogenetic abnormalities account for 6% to 13% of all stillbirths. Of the stillborn fetuses with anatomic abnormalities, growth restriction, or both, >20% have chromosomal abnormalities, compared to only 4.6% of those without morphologic abnormalities.^34,35 Given that 50% of cell cultures for karyotype analysis are unsuccessful, this may be an underestimatation. The most common karyotypic anomalies are monosomy X, Trisomy 21, Trisomy 18, and Trisomy 13.^34,35

FETAL GROWTH RESTRICTION

Fetal growth restriction is associated with an increased risk of stillbirth. The cumulative risk of fetal death is 1.5%; it is even higher (2.5%) when the estimated fetal weight is < 5th percentiles.^36,37 The greatest risk occurs when the estimated fetal weight is < the 2.5th percentile.³⁸

UNEXPLAINED DEATHS

Unexplained deaths are stillbirths that cannot be attributed to an identifiable fetal, placental, or maternal etiology. It includes 25% to 60% of all fetal deaths, and two-thirds of the cases occur after 35 weeks gestation (see Table 35-1).³⁹