Prematurity and Stillbirth: Causes and Prevention

Preterm Birth and Stillbirth: Burden in the United States and Global Estimates

Preterm birth, defined as birth prior to 37 weeks gestation, affects 15 million newborns globally every year. It is the leading cause of under-five child mortality worldwide and accounts for one million deaths annually. More than 10% of newborns in the United States are born preterm, the annual cost of which exceeds $26 billion. Globally, among survivors, preterm birth is a major cause of disability-adjusted life years due to lifelong neurologic and developmental sequelae. The rate of preterm birth in the United States increased dramatically in the late 20th century from less than 7% in the 1960s to a peak of 12.8% in 2006; the preterm birth rate was 10.2% in 2019. Globally, the preterm birth rate was estimated at 10.6% in 2014, though significant regional and country variation exists ( Fig. 6.1 ).

In the United States, stillbirth is typically defined as a fetal death at 20 weeks gestation or later or at a birth weight greater than or equal to 350 g. Estimates of stillbirth in the United States are complicated by inconsistent reporting criteria by state, with variable gestational age and birth weight cutoffs used. In 2019, there were 21,478 stillbirths reported in the United States via the National Vital Statistics System; annual stillbirths in the United States exceed the number of neonatal deaths. Comparison of stillbirth rates across countries and regions are challenging given differential reporting mechanisms and metrics and difficulty differentiating between fresh stillbirths or fetal deaths during labor and delivery and early neonatal deaths in very low resource settings. The World Health Organization (WHO) definition of stillbirth incorporates both early fetal deaths (500 to 999 g or 22 0/7 to 27 6/7 weeks) and late fetal deaths (≥1000 grams or ≥28 0/7 weeks; Fig. 6.2 ). In 2020, the United Nations Inter-agency Group for Child Mortality Estimation released its first-ever report on the global burden of stillbirths, reporting an estimated 2 million late fetal deaths globally in 2019. Approximately half of stillbirths occur in six countries: India, Pakistan, Nigeria, the Democratic Republic of the Congo, China, and Ethiopia; 27% of global stillbirths occur in low income countries, which account for only 16% of the world’s live births.

Preterm birth and stillbirth should not be considered distinct entities but rather as occurring along the same spectrum, both in terms of overlapping pathophysiology and targets for prevention. This is particularly true in the case of fresh stillbirths, a significant proportion of which could be averted with improved access to care and earlier obstetric intervention. Approximately 40% of stillbirths worldwide occur during labor ( Fig. 6.3 ).

Pathophysiology of Preterm Birth and Stillbirth

Preterm birth can be spontaneous, in which labor starts too soon, or medically indicated, in which cesarean delivery or induction of labor is performed to avoid the risks of continued pregnancy to the mother or fetus, e.g., due to preeclampsia or intrauterine growth restriction. Another subtype of spontaneous preterm birth is associated with premature preterm rupture of membranes (PPROM), in which rupture of amniotic membranes occurs both prior to 37 weeks gestation and prior to the onset of labor ( Fig. 6.3 ). Approximately 45% of preterm births result from spontaneous preterm labor, 30% from medically indicated delivery, and 25% from PPROM, though recent data suggest a rise in medically indicated preterm deliveries. The extent to which the etiologic pathways leading to each type of preterm delivery are distinct versus overlapping is uncertain. Etiologic differences also exist between early preterm birth (e.g., <28 weeks gestation) and late preterm birth, although the definition of “early” versus “late” preterm birth is somewhat arbitrary in the context of continuous gestational progression.

Spontaneous preterm birth is an exceedingly complex phenomenon that is not well understood. Physiologic or disease processes that induce uterine contractility, cervical dilatation, or rupture of amniotic membranes prior to 37 weeks gestation can lead to preterm birth ( Fig. 6.4 ). There is evidence that spontaneous preterm birth may be related to perturbations in the maternal-fetal environment, such as abnormal placental development, infection, uterine overdistension, and inflammation. While the majority of preterm births remain unexplained, the biology underlying disease states that contribute to preterm birth is beginning to be elucidated.

Stillbirth, preterm delivery, and growth restriction exist along a spectrum, with overlapping etiologies. Fetal growth restriction is a marker of placental insufficiency, which is often implicated in both stillbirth and preterm delivery ( Fig. 6.5 ). Other common clinical antecedents of stillbirth and preterm delivery include spontaneous preterm labor or rupture of membranes and infection. Increasingly, inflammation is implicated as a common pathway contributing to stillbirth and preterm birth. However, approximately 40% of stillbirths are unexplained. Further understanding of gestational biology and preterm birth will likely provide insight into the etiology of stillbirth. More frequent inclusion of stillbirth in studies of preterm delivery—especially early preterm delivery—will be important to fully understanding either outcome.

Demographic Factors and Disparities

Multiple studies have demonstrated elevated risk of preterm birth among black women. The rate of preterm birth among non-Hispanic black women is as high as 14.4%, compared with 10.2% in the general United States population. From 2015 to 2017, preterm births in the United States were most common among non-Hispanic black mothers and non-Hispanic black fathers and least common among non-Hispanic white mothers and non-Hispanic white fathers (10.8% vs. 6.5%). Such disparities are augmented in early preterm birth (<28 weeks gestation), with preterm birth rates up to three to four times higher among black women. Elevated risk remains after controlling for socioeconomic status and psychosocial risk factors, which themselves are associated with preterm birth. Disparities are more modest to nonexistent for Hispanic women, despite social disadvantage within this group. Other studies have found that the rate of preterm birth varies greatly based on geographic location and is driven by socioeconomic and demographic characteristics of those locales but possibly less so for blacks than whites. Other factors associated with lower socioeconomic status, including educational background, extremes of maternal age, short interval between pregnancies (<6 months), and single marital status, have been independently associated with preterm birth.

Some portion of the racial/ethnic and socioeconomic disparities in preterm birth can be explained by increased psychosocial stress among these populations. Several studies have found that maternal stress, as measured by a survey of life events and/or biomarkers of activation of the hypothalamic-pituitary-adrenal axis, is also strongly associated with preterm birth. However, interventions to reduce stress have had limited success in preventing preterm birth. Other factors proposed to contribute to disparities include nutrient deficiencies and infection, although further research is needed to clarify their roles.

The longstanding disparities in preterm birth and perinatal outcomes which have been observed and studied over the last several decades have illuminated the role of structural racism on equity in health and health outcomes. While “race” has been considered in medical research as a demographic characteristic, it should be noted that “race” is not a biological construct per se but rather a sociopolitical construct that reflects the impacts of generational oppression, discrimination, and racism. Maternal exposure to interpersonal racism has been associated with preterm birth rates and very low birth weight, and further, chronic “worry” about racial discrimination among African-American women was associated with elevated preterm birth rates. The effect of structural racism on birth outcomes can also be gleaned from studies of preterm birth disparities by region. For example, in the United States, states with higher rates of police killings among unarmed black people were observed to have higher disparities in preterm birth rates. Generational effects of racism, discrimination and oppression have affected economic mobility, housing security, access to education, exposure to stress and violence, environmental exposures, access to healthcare, quality of healthcare, and other factors which have been associated with adverse perinatal outcomes.

Environmental Factors

Exposure to toxins—both self-inflicted and environmental—has been shown to increase the risk of preterm birth. Tobacco smoking during pregnancy is one of the most significant of these exposures. The mechanism is unclear but may involve systemic inflammation (leading to spontaneous preterm birth) or placental vasoconstriction from nicotine causing fetal growth restriction, which, in turn, may lead to a medically indicated preterm birth. Environmental tobacco smoke exposure has also been linked to adverse birth outcomes, including preterm birth. Electronic nicotine delivery systems have been insufficiently studied in pregnancy, though increased risk of preterm birth was described in electronic cigarette users participating in the United States Pregnancy Risk Assessment Monitoring System, a large nationally representative surveillance program for adverse pregnancy outcomes. Marijuana use during pregnancy has been linked to preterm birth, including when used simultaneously with tobacco.

Alcohol has not been consistently linked to risk of preterm birth, although cocaine and other illicit substances increase preterm birth risk, likely via alteration of placental blood flow and/or placental abruption. Polysubstance use, including concurrent tobacco smoking and use of either stimulant or depressant drugs, is associated with preterm birth.

Caffeine use during pregnancy has been associated with stillbirth in several observational studies; findings regarding its association with preterm birth have been inconsistent. Higher levels of caffeine use are more frequently associated with these adverse pregnancy outcomes, suggesting possible causation. American College of Obstetrics guidance, most recently reaffirmed in 2020, states that moderate caffeine consumption–less than 200 mg/day–is safe in pregnancy.

Environmental air pollution has been associated with increased risk of preterm birth. There are myriad air pollutants that have been investigated, including ozone, carbon monoxide, sulfur dioxide, and lead, among others. Both cumulative air pollution over the course of the pregnancy and during the week prior to delivery have been linked to increased risk of preterm birth.

Exposure to other toxicants, including various pesticides and heavy metals, such as lead and cadmium, has also been associated with preterm birth. Heavy metals can induce oxidative stress and inflammation in the placenta, thereby increasing risk of preterm birth. Per- and polyfluoroalkyl substances (PFAS), which can be found in food packaging, commercial household products, and drinking water, have been linked to disruption of placental vasculogenesis and a proinflammatory state, though association with increased preterm birth has not been consistently demonstrated in studies to date. Further studies are needed to examine the relationship between these exposures and risk of preterm birth and other adverse pregnancy outcomes.