Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality

INTRODUCTION — Prematurity is defined as a birth that occurs before 37 completed weeks (less than 259 days) of gestation. It is associated considerable risk of morbidity and mortality, particularly among extremely preterm infants (ie, gestational age [GA] <28 weeks).

This topic will review the definitions of prematurity, the incidence of preterm birth, and risk factors for infant mortality among preterm infants.

The pathogenesis of preterm birth, interventions for risk reduction, and short- and long-term complications of preterm birth are discussed separately:

●(See "Spontaneous preterm birth: Overview of risk factors and prognosis".)

●(See "Spontaneous preterm birth: Pathogenesis".)

●(See "Overview of short-term complications in preterm infants".)

●(See "Overview of the long-term complications of preterm birth".)

DEFINITIONS

Prematurity — Different degrees of prematurity are defined by gestational age (GA), which is calculated from the first day of the mother's last period, or birth weight (BW).

●BW classification – The classification based upon BW includes the following categories (table 1):

•Low birth weight (LBW) – BW <2500 g

•Very low birth weight (VLBW) – BW <1500 g

•Extremely low birth weight (ELBW) – BW <1000 g

We will primarily use this classification in this topic review.

BW percentiles have been established for the appropriate GA (table 2 and figure 1).

●GA classification – The classification based upon GA is as follows (table 1):

•Late preterm infants – GA between 34 weeks and 36 weeks and 6 days

•Moderate preterm infants – GA between 32 weeks and 33 weeks and 6 days

•Very preterm (VPT) infants – GA <32 weeks

•Extremely preterm (EPT) infants – GA <28 weeks

Neonatal and infant mortality

●Neonatal death is defined as an infant death before 28 days of age. Early neonatal deaths occur before the first seven days from birth, and late neonatal deaths occur between 7 and 27 days of age.

●Infant death is defined as a live birth that results in death within the first year of life (<365 days).

●The infant mortality rate is the number of infant deaths less than one year of age (0 to 365 days of life) during a year, divided by the number of live births reported during the same year, expressed per 1000 live births.

PATHOGENESIS FOR PRETERM BIRTH — Most preterm deliveries occur spontaneously as a result of either preterm labor or preterm rupture of membranes. Less commonly, preterm induction of labor or cesarean delivery may be performed for obstetrical indications (eg, maternal, placental, or fetal problems).

The four primary causes that lead to preterm labor and delivery are:

●Activation of the maternal or fetal hypothalamic-pituitary-adrenal axis

●Infection

●Decidual hemorrhage

●Pathological uterine distention

These are discussed in detail separately. (See "Spontaneous preterm birth: Pathogenesis".)

EPIDEMIOLOGY

Incidence of prematurity — Worldwide, the incidence of preterm birth is estimated to be approximately 10 percent (range 5 percent in parts of Europe to 18 percent in parts of Africa), and approximately 15 million children are born preterm each year (range 12 to 18 million) [1,2]. Of these preterm births, 85 percent occurred at 32 to 36 weeks gestational age (GA), 10 percent occurred at 28 to <32 weeks GA, and 5 percent occurred at <28 weeks GA.

In the United States, approximately 550,000 preterm infants are born each year, with about 10 percent of all live births born before 37 weeks GA and almost 3 percent born <34 weeks GA (table 3) [3].

The incidence of preterm births varies by race and ethnicity. In the United States, the proportion of live births in 2018 that were preterm by race and ethnicity were as follows [4]:

●Among non-Hispanic Black infants, 14.1 percent were preterm

●Among Hispanic infants, 9.7 percent were preterm

●Among non-Hispanic White infants, 9.1 percent were preterm

Similar findings were noted in a study from England, which reported percentages of LBW live births of 11.5, 9.4, and 5.4 percent in Asian, Black, and White mothers, respectively [5].

Risk factors for preterm birth — Risk factors for preterm birth are summarized in the table (table 4) and discussed in detail separately. (See "Spontaneous preterm birth: Overview of risk factors and prognosis".)

RISK FACTORS FOR MORTALITY — Many variables impact the risk of mortality in preterm infants. Key risk factors include:

●Degree of prematurity

●Sex

●Race

●Congenital anomalies

●Intrauterine growth restriction

●Level of neonatal care

Birth weight and gestational age — Mortality rates in preterm infants correlate inversely with birth weight (BW) and (GA) (ie, lower BW and/or GA are associated with higher mortality) [6-9]. Thus, infants in the lowest BW and GA categories have the largest impact on overall infant mortality rates because they have the greatest risk of death [9].

Mortality rates according to GA in the United States in 2019 were as follows [9]:

●≥42 weeks or more –5.72 per 1000 live births

●37 to 41 weeks GA –2.03 per 1000 live births

●34 to 36 weeks GA – 8.21 per 1000 live births

●32 to 33 weeks GA – 19.21 per 1000 live births

●<32 weeks – 180.40 per 1000 live births

Extremely preterm (EPT) infants (GA<28 weeks) have the highest mortality at approximately 25 percent overall and as high as 50 percent for infants born at ≤25 weeks GA [10-13]. However, survival for infants between 24 and 26 weeks gestation has improved with advances in prenatal and neonatal care [11,14-16]. (See 'Trends over time' below and "Periviable birth (limit of viability)", section on 'Survival'.)

Mortality data for infants born at ≤25 weeks GA who are at the limit of viability are summarized in the table (table 5) and reviewed separately. (See "Periviable birth (limit of viability)".)

Late preterm infants (born between 34 weeks and 36 weeks and 6 days gestation) are an "at-risk population" with a three- to five-fold greater risk of mortality than term infants. The mortality of later preterm infants is discussed separately. (See "Late preterm infants", section on 'Mortality'.)

The risk of mortality increases with decreasing five- and ten-minute Apgar scores for each GA category [6]. In particular, for EPT infants, the risk of death for patients who require cardiopulmonary resuscitation (CPR) in the delivery room is almost twice as high compared with infants who do not require CPR [17,18].

Sex — Male preterm infants have a higher risk of early mortality compared with female infants [19,20]. Male infants also are more likely to have major morbidity (bronchopulmonary dysplasia [BPD], retinopathy of prematurity [ROP], necrotizing enterocolitis [NEC], and late-onset sepsis) and adverse neurologic outcome (defined as moderate to severe functional disability at two to three years of age).

Race — Infant mortality rates infants vary by race, as summarized in the table (table 6). For any given BW or GA category, mortality rates are higher for Black infants compared with other racial groups. Health care disparities in part explain this finding [21].

For infants with very low birth weight (VLBW; BW <1500 g), mortality rates according to race in the United States in 2018 were as follows [22]:

●Overall – 244.5 per 1000 live births

●White infants – 231.9 per 1000 live births

●Black infants – 274 per 1000 live births

●Asian or Pacific Islander infants – 222.7 per 1000 live births

Similar differences in infant mortality rates by race were reported among very preterm infants (GA <32 weeks) [22]:

●Overall – 182.5 per 1000 live births

●White infants – 168.4 per 1000 live births

●Black infants – 216.2 per 1000 live births

●Asian or Pacific Islander infants – 173.2 per 1000 live births

Congenital anomalies — Birth defects are an important contributor to infant mortality in preterm infants. In population-based studies, approximately 5 to 6 percent of VLBW infants were reported to have birth defects [23,24]. Mortality rates among VLBW infants with a birth defect were three to ten times higher compared with infants without birth defects.

In particular, major chromosomal anomalies in VLBW infants are associated with poor survival [24,25]. This was illustrated in a prospective study from the Vermont Oxford Network (VON) that noted the prevalence and birth hospital mortality of the following chromosomal trisomies among liveborn VLBW infants [25]:

●Trisomy 21 – Prevalence 0.31 percent; mortality 33 percent

●Trisomy 18 – Prevalence 0.26 percent; mortality 89 percent

●Trisomy 13 – Prevalence 0.08 percent; mortality 92 percent

Intrauterine growth restriction — Mortality is higher for preterm infants who are small for gestational age (SGA) due to intrauterine growth restriction compared with preterm infants with BW appropriate for gestational age (AGA) [26]. Mortality increases with increasing severity of SGA in conjunction with decreasing GA. (See "Infants with fetal (intrauterine) growth restriction", section on 'Prematurity' and "Infants with fetal (intrauterine) growth restriction", section on 'Mortality'.)

Level of neonatal care — Variation in neonatal care impacts infant mortality rates.

Trends over time — Improvements in perinatal and neonatal care, including the use antenatal steroid therapy and surfactant to prevent and treat neonatal RDS, have decreased mortality rates for preterm infants [11,12,27-31]. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery" and "Respiratory distress syndrome (RDS) in preterm infants: Management".)

●Periviable infants – Infants at the limit of viability (ie, ≤25 weeks GA), have a high risk of mortality; however, mortality rates for this population vary considerably depending on the initial management approach (active treatment versus comfort measures only), as summarized in the table and discussed in detail separately (table 5). (See "Periviable birth (limit of viability)", section on 'Survival'.)

●Extremely preterm (EPT) infants – Large prospective studies from different parts of the world have shown improved survival for EPT infants over time [13,15,16]. The studies differed somewhat in the population studied (some defined EPT as ≤28 weeks GA, others focused on infants ≤26 weeks GA). However, the findings were generally consistent:

•A study from the US National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) reported improved survival to hospital discharge among EPT infants over time (72.5 percent in the earlier period [2000 to 2003] versus 74.2 percent in the later period [2008 to 2011]) [15]. This correlated with improvements in measures of quality care (eg, increased rates of prenatal care and antenatal steroid administration).

•A subsequent NICHD NRN study reported improved one-year survival over two time periods (76 percent in 2013 versus 78.3 percent in 2018) [13].

•Similarly, a population-based study from Sweden reported one-year survival for EPT infants improved from 70 percent in the earlier era (2004 to 2007) to 77 percent in the later era (2014 to 2016) [16]. Of note, survival of infants born at 22 weeks gestation increased from 3.6 to 20 percent and for infants born at 23 weeks from 29 to 44 percent between the two time periods.

•An earlier population-based study from England showed that survival for EPT infants increased from 1995 to 2006 and the degree of improvement varied by GA [32]. Survival increased by 9.5 percent for infants born at 23 weeks, 12 percent for infants born at 24 weeks, and 16 percent for infants born at 25 weeks gestation.

●Very low birth (VLBW) infants – Mortality for VLBW infants (BW <1500 g corresponding to GA <32 weeks) also has declined as illustrated by the following:

•In reports from the US NICHD NRN, survival for VLBW infants improved from 74 percent in 1988 to 85 percent in 1997 to 2002 [27,28].

•A subsequent study from VON reported that survival among VLBW infants increased from 86 percent in 2000 to 88 percent in 2009 [31]. In this study, survival for infants with BW between 501 and 750 g improved from 58 percent in 2000 to 63 percent in 2009.

Standard of neonatal care

●Regionalization – Survival rates for very preterm (VPT) and EPT infants are higher in centers that care for a high volume of preterm infants and that provide a high level of neonatal intensive care (ie, level 3 neonatal intensive care units [NICUs]) [33-40].

As a result, women who are at risk of delivering at <32 weeks GA should be transported to a regional perinatal center with the appropriate level of neonatal care rather than transferring the neonate to such a facility after birth [40-42]. This is discussed in greater detail separately. (See "Inter-facility maternal transport".)

This practice is supported by a population-based study of VPT infants which demonstrated lower mortality for infants born at a tertiary center (including those whose mothers presented to the tertiary center and those whose mothers were transferred prior to delivery) compared with infants who were born at a non-tertiary center (10 versus 17 percent, respectively) [43].

●Effect of evidence-based practice – Implementation of evidence-based practice is associated with improved outcomes [44,45]. This was illustrated in an observational multinational European study that assessed the following evidence-based practices among infants born at <32 weeks GA [45]:

•Delivery in a maternity unit with appropriate level of neonatal care (see "Inter-facility maternal transport")

•Administration of antenatal corticosteroids (see "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery")

•Prevention of hypothermia (temperature on admission to neonatal unit ≥36°C) (see "Overview of short-term complications in preterm infants", section on 'Hypothermia')

•Early nasal continuous positive airway pressure (nCPAP) or surfactant administration within two hours of birth (see "Respiratory distress syndrome (RDS) in preterm infants: Management")

After adjusting for other variables, the study found that infants who received all four of these evidence-based practices were at lower risk of in-hospital mortality compared with those who did not (5.6 versus 14.1 percent; adjusted risk ratio 0.72, 95% CI 0.60-0.87) [45].

Global and regional variation — The relationship between decreasing GA and increased mortality risk remains fairly consistent from region to region. However, absolute mortality rates for any given GA vary globally [46]. In one study that analyzed data from 10 different national networks, overall mortality rates for infants born at 24 to 29 weeks GA varied from 7 to 22 percent [46]. There was particularly high between-network variability for infants born at 24 weeks GA, with reported mortality rates ranging from 35 to 84 percent. Survival rates increased and differences between networks diminished with increasing GA. Differences in the initial management of periviable infants (active treatment versus comfort measures only) may explain some of the observed variability. This is discussed separately. (See "Periviable birth (limit of viability)", section on 'Survival'.)

Even within a single country, there can be substantial variation in mortality rates from center to center. In a report from the United States NICHD NRN, in-hospital mortality rates for ELBW infants ranged from 11 to 53 percent overall and from 28 to 90 percent for infants <25 weeks gestation [47]. The study also found considerable between-center variation in care provided (eg, use of antenatal steroids ranged from 35 to 93 percent; use of continuous positive airway pressure ranged from 4 to 53 percent; surfactant use ranged from 50 to 88 percent); however, these differences did not fully account for the observed variability in mortality, especially in infants born at ≥25 weeks GA.

CAUSES OF DEATH — Common causes of death among preterm infants in high-resource settings include [9,15,32,48-50]:

●Respiratory failure (especially in extremely preterm infants) (see "Approach to mechanical ventilation in very preterm neonates", section on 'Respiratory failure in VPT neonates')

●Infection (see "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Mortality')

●Congenital anomalies (see 'Congenital anomalies' above)

●Intraventricular hemorrhage (see "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Mortality')

●Necrotizing enterocolitis (see "Neonatal necrotizing enterocolitis: Management and prognosis", section on 'Mortality')

In low-resource areas, data are less reliable in determining the cause of death in preterm infants [51]. In these settings, prematurity is often listed as the cause of death.

EARLY VERSUS LATE MORTALITY

Early mortality — Overall, more than two-thirds of infant deaths occur within the first 28 days after birth. As discussed above, the risk of dying within this neonatal period increases with decreasing GA and BW. (See 'Birth weight and gestational age' above.)

In VLBW infants, approximately 50 percent of deaths occur in the first three days after delivery [52]. For EPT infants, mortality is not only higher, but death occurs earlier as 40 to 50 percent of deaths occur within the first 12 to 24 hours after birth [15,52].

Post-discharge mortality — Following discharge from the neonatal intensive care unit (NICU), preterm infants continue to be at risk for mortality. In studies that followed infants to age 22 to 26 months corrected age, approximately 1 to 2 percent of EPT infants died after NICU discharge [13,53]. In one study, independent risk factors for post-discharge mortality included NICU length of stay >120 days, Black race, and uncertain maternal insurance status [53].

Surviving preterm infants continue to have an increased risk of mortality throughout childhood relative to the general pediatric population. For EPT survivors, the risk is approximately five to seven times higher than that of children who were born at term [54].

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: When a baby is born premature (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Preterm birth is defined as birth occurring before 37 completed weeks (less than 259 days) of gestation. Degrees of prematurity are typically defined by birth weight (BW) or gestational age (GA); the definitions are provided in the tables (table 7 and table 2 and figure 1). (See 'Definitions' above.)

●Incidence and risk factors for preterm birth – Worldwide, the incidence of preterm birth is approximately 10 percent. Most preterm births occur at 32 to 36 weeks GA; approximately 10 percent occur at 28 to <32 weeks GA, and approximately 5 percent occur at <28 weeks GA (table 3). (See 'Incidence of prematurity' above.)

Risk factors for preterm birth are summarized in the table (table 4) and discussed in detail separately. (See "Spontaneous preterm birth: Overview of risk factors and prognosis".)

●Risk factors for infant mortality – Key factors that impact the risk of mortality in preterm infants include (see 'Risk factors for mortality' above):

•Degree of prematurity (the risk increases with decreasing BW and GA) (see 'Birth weight and gestational age' above)

•Sex (the risk is higher in males) (see 'Sex' above)

•Race and ethnicity (the risk is highest among Black infants) (see 'Race' above)

•Congenital anomalies (see 'Congenital anomalies' above)

•Intrauterine growth restriction (see 'Intrauterine growth restriction' above)

•Lower level of neonatal care (see 'Level of neonatal care' above)

●Trends over time – Improvements in perinatal and neonatal care, including the use antenatal steroid therapy and surfactant to prevent and treat neonatal respiratory distress syndrome (RDS), have resulted in decreased mortality rates for preterm infants. However, there is substantial global and regional variation in survival. (See 'Trends over time' above and 'Global and regional variation' above.)

●Causes of death – Common causes of death among preterm infants in high-resource settings include:

•Respiratory failure (especially in extremely preterm infants) (see "Approach to mechanical ventilation in very preterm neonates", section on 'Respiratory failure in VPT neonates')

•Infection (see "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Mortality')

•Congenital anomalies (see 'Congenital anomalies' above)

•Intraventricular hemorrhage (see "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Mortality')

•Necrotizing enterocolitis (see "Neonatal necrotizing enterocolitis: Management and prognosis", section on 'Mortality')