Perinatal mortality

INTRODUCTION — Mortality rates in the perinatal period are used to evaluate the outcome of pregnancy and monitor the quality of perinatal (prenatal and neonatal) care. The perinatal mortality rate encompasses late fetal and early neonatal mortality.

TERMINOLOGY — The use of standard terminology facilitates comparisons of mortality rates among states and countries. A 2016 clinical report from the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn established standard terminology for fetal, infant, and perinatal deaths, based on standards set by the World Health Organization (WHO) and the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) [1]. The following definitions are recommended and used in this review. Revised standard definitions for reporting reproductive health statistics are published by the NCHS [2].

Live birth — Live birth is defined as complete expulsion or extraction from the mother of a product of human conception, irrespective of the duration of pregnancy, which shows any evidence of life (ie, heartbeats, umbilical cord pulsations, breathing, or voluntary muscle movement), regardless of whether the umbilical cord has been cut or the placenta is attached. Heartbeat should be distinguished from transient cardiac contractions and breathing distinguished from fleeting respiratory efforts or gasps.

Fetal death (stillbirth) — A fetus is defined from weeks after conception until term while in the uterus. Death of the fetus occurs prior to complete expulsion or extraction from the mother, irrespective of the duration of the pregnancy, which is not an induced pregnancy termination. Fetal death is indicated by no signs of life after delivery (eg, heartbeat umbilical cord pulsations, breathing, or voluntary muscle movement, as noted above). Heartbeats should be distinguished from transient cardiac contractions, and breathing from fleeting respiratory efforts or gasps. (See "Stillbirth: Incidence, risk factors, etiology, and prevention".)

The NCHS reports fetal deaths that occur ≥20 weeks gestation, which are also referred to as "stillbirth." For statistical purposes, the NCHS further subdivides fetal death as "early" (20 to 27 weeks gestation) or "late" (≥28 weeks gestation). The WHO defines stillbirth as at or after 28 weeks gestation. Pregnancies resulting in fetal demise before 20 weeks are categorized as miscarriages.

Fetal death rate — The fetal death rate is the number of fetal deaths ≥20 weeks gestation that occur during a year divided by the sum of live births plus fetal deaths during the same year, expressed per 1000 live births plus fetal deaths. The NCHS defines late fetal death rate as the number of fetal deaths ≥28 weeks gestation during a year divided by the sum of live births plus late fetal deaths during the same year, expressed per 1000 live births plus late fetal deaths.

Infant death and mortality rate — Infant death is defined as a live birth that results in death within the first year of life (<365 days). The infant mortality rate (IMR) 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.

Neonatal death and mortality rate — 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.

The neonatal mortality rate (NMR) is the number of neonatal deaths during a year, divided by the number of live births during the same year, expressed per 1000 live births.

Postneonatal death — Postneonatal death is defined as an infant death occurring between 28 and 365 days of age.

Perinatal death — Perinatal deaths refer to a combination of fetal deaths and live births with only brief survival (days or weeks) and are grouped on the assumption that similar factors are associated with these losses. The NCHS does not report this as a vital statistic [1].

Three different definitions are used for perinatal death, which vary globally:

●Definition 1 – Sum of infant deaths that occur at less than 7 days of age and fetal deaths with a gestational age of 28 weeks or more.

●Definition 2 – Sum of infant deaths that occur at less than 28 days of age and fetal deaths with a gestational age of 20 weeks or more.

●Definition 3 – Sum of infant deaths that occur at less than 7 days of age and fetal deaths with a gestational age of 20 weeks or more.

The NCHS uses both definition 1 and 2 to classify perinatal deaths. The WHO and NCHS use definition 1 to make international comparisons, which accounts for variability in registering fetal death between 20 and 27 weeks gestation. However, definition 2 is more inclusive and is more appropriate to monitor perinatal death throughout gestation.

UNITED STATES REPORTING REQUIREMENTS — In the United States, live births, deaths, and fetal deaths are reported as vital events. The National Association for Public Health Statistics and Information Systems (NAPHSIS) has developed a flowchart to assist hospitals with the appropriate reporting of fetal and infant deaths, and live births (algorithm 1) based on the National Center for Health Statistics (NCHS) definitions.

Although the Model State Vital Statistics Act and Regulations recommends reporting all fetal deaths with birth weights (BW) ≥350 g or, if the BW is unknown, gestational age (GA) >20 weeks [3], states have the right to determine registration criteria, which results in variation of the reporting of these events [1]. In addition, the quality and quantity of reported clinical information also varies among the states.

In addition to demographic information (ie, maternal ethnicity and age) and maternal medical history, including risk factors, the following minimal information should be obtained for each of these events [1]:

●For live births, reported information should include BW, GA, and delivery information. In the event of infant death, the time to survival, and the cause of death should be listed.

●For fetal deaths, deaths should be reported based on the state criteria and should include BW, GA, cause of fetal demise, and, if pertinent, delivery information.

Medical record documentation should use accurate definitions based on state criteria to ensure that reliable data on perinatal death are recorded [1]. If a delivery of a fetus of uncertain viability is considered to be a live birth, the event is reported as a live birth regardless of BW, length of gestation, survival time, or other clinical information (eg, Apgar scores) [1]. However, if there are no signs of life at delivery, the event is assigned as a fetal death. Apgar scores should not be assigned, and the fetus should not be admitted to the nursery or neonatal intensive care unit (NICU).

COMPARISON OF MORTALITY RATES — Comparison of mortality statistics across states or countries is challenging for the following reasons:

●Differences in the definitions employed − In the United States (US), the minimum gestational age (GA) used to calculate fetal death is 20 weeks, and the postnatal days used to calculate perinatal mortality rate (PMR) is either 7 or 28 days [1,4,5]. In comparison, the minimum GA ranges from 16 to 28 weeks among European countries, and the perinatal period used to calculate PMR ranges from 7 to 28 postnatal days [4].

●Birth weight (BW) versus GA − Use of BW rather than GA may further limit some comparisons because BW data do not identify fetal growth restriction (FGR), which frequently compounds prematurity [6].

●Differences in birth and death registration − The process of birth and death registration varies considerably among countries, especially when infants are born very prematurely or die soon after delivery. Perinatal statistics are particularly unreliable in resource-limited countries, and whenever a substantial number of births takes place outside of hospitals or birthing centers unattended by trained individuals. (See 'Prematurity' below.)

Other countries — Japan has the lowest infant mortality rate (IMR) at 2.1 per 1000 live births [7]. There are 29 other nations with at least 40,000 births per year that have a lower IMR than the United States. It is possible that the higher IMR in the US is due in part to the higher percentage of preterm births. (See 'Prematurity' below and "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality", section on 'Incidence of prematurity'.)

Resource-limited countries — In 2000, neonatal deaths accounted for 38 percent of all child deaths worldwide [8]. Almost all of the four million neonatal deaths (99 percent) occurred in resource-limited countries. Poverty was strongly associated with neonatal mortality rate (NMR). NMR was almost 10 times greater in countries with moderate and low income than in high-income countries (33 versus <4 deaths per 1000 live births). The highest NMR occurred in sub-Saharan Africa (over 45 deaths per 1000 live births), but the greatest absolute number of deaths occurred in south-central Asia. The main causes of death were prematurity (28 percent), infection (26 percent), and perinatal hypoxic insult (23 percent).

In a population-based study performed in Bangladesh, maternal complications during labor increased NMR fivefold and accounted for 30 percent of deaths [9]. Complications included prolonged or obstructed labor, abnormal fetal position, and hypertensive disorders of pregnancy.

A systematic review and cost analysis identified 16 cost-effective interventions (including maternal folic acid supplementation, detection and treatment of mothers with asymptomatic bacteriuria, and antibiotics for preterm rupture of membranes) that would improve neonatal survival in resource-limited countries [10]. This analysis provided a health system structure to implement these interventions at the family-community and individual patient level (pregnancy, delivery, and birth). With universal application, the study estimated that mortality rates would decrease by 59 percent.

Effect of prenatal diagnosis — Differences in the availability of timely/accurate prenatal diagnosis and pregnancy termination facilities, as well as population acceptance of termination of anomalous pregnancies can greatly influence regional PMR. In resource-abundant countries, timely and accurate prenatal diagnosis followed by termination of anomalous pregnancies has been shown to cut PMR by half [11-13]. In areas where access to pregnancy termination services becomes limited, the PMR is likely to increase.

Ongoing research and technological advances have led to an ever-increasing number of live births of fetuses that have undergone in-utero interventions for anomalies. For example, in-utero treatment of arrhythmias and some cardiac defects, twin oligo-polyhydramnios sequence, myelomeningocele, diaphragmatic hernia, lower urinary tract obstruction, and others. These interventions increasingly affect both perinatal and neonatal mortality [13].

PERINATAL AND NEONATAL MORTALITY RATES — In the United States, the perinatal mortality rate (PMR) has declined from a reported rate of 6 per 1000 live births, which was relatively constant through 2016, to a rate of 5.69 per 1000 live births in 2019 [7,14,15]. Over 40 years, the early neonatal mortality rate (NMR, <7 days of age) has also declined to 3.22 per 1000 live births in 2012 (figure 1) and the overall NMR (<30 days of age) was 3.94 per 1000 live births in 2013.

Major factors that influence mortality rates include ethnicity, gestational age (GA), congenital malformations and multifetal pregnancies.

Ethnicity — The relative disparities in perinatal and neonatal mortality among different racial/ethnic populations persist. The PMR and neonatal mortality rates for Black infants are two-fold greater than White infants (table 1) [16,17]. The racial disparity may be explained largely by the higher incidence of prematurity in Black populations. (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality", section on 'Race'.)

Gestational age

Post-term versus term infants — The mortality rate is higher for post-term compared to term infants, mostly due to the increased rate of stillbirth in post-term pregnancies. This is illustrated in the following studies:

●In a report of US infant mortality in 2017, infants born after 42 weeks gestation and those born at term had mortality rates of 3.98 and 1.51 per 1000 live births, respectively [17].

●In a meta-analysis of cohort studies, delivery at 39 weeks, compared to expectant pregnancy management beyond that gestational age, was associated with a 73 percent reduction in perinatal mortality [18].

●An analysis of a national registry of all pregnancies in the Netherlands showed that the prospective risk of early neonatal death for infants born at 39 weeks was lower than the risk of stillbirth in pregnancies continuing beyond 39 weeks and 6 days [19].

The “39-week rule” refers to avoidance of elective deliveries prior to 39 weeks of gestation. In a large US historical cohort study, overall perinatal mortality rates remained stable in the 2-year period immediately following adoption of the 39-week rule across the US, despite an increase in stillbirths [20].

Prematurity — Prematurity is a major contributor to neonatal and infant mortality. PMR and NMR increase with decreasing GA in preterm infants (GA <37 weeks). (See 'Low birth weight' below and "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality", section on 'Risk factors for mortality'.)

The NMR of extremely low birth weight infants (ELBW) with BW <750 g may be underreported. This was illustrated by a report that demonstrated the deaths of 7 percent of ELBW infants who died in Ohio between January and June of 2006 were not registered [21]. The failure to register deaths was attributed to the short lifespan of these infants, resulting in the potential for their deaths to be misclassified as fetal deaths, thereby falsely lowering the early NMR and increasing the late fetal death rate.

Multifetal pregnancies — Multiple gestations are a strong risk factor for neonatal mortality, as a high proportion of multiple births (approximately one-half of twins, and the majority of triplets, quadruplets, and quintuplets) are preterm or low BW, which contributes to the higher mortality rate. They also are at higher risk for birth defects [22]. (See "Neonatal complications of multiple births", section on 'Incidence' and "Twin pregnancy: Overview" and "Neonatal complications of multiple births".)

CAUSES OF FETAL DEATH (STILLBIRTH) — Approximately 30 percent of fetal deaths remain unexplained [23]. In the remaining fetal deaths, identifiable causes include:

●Fetal (eg, structural defects, arrhythmias, syndromes, infections, aberrant growth) (see "Fetal arrhythmias" and "Stillbirth: Incidence, risk factors, etiology, and prevention")

●Placental (eg, chorioamnionitis, abruption, large chorioangiomas, vasa previa, umbilical cord accidents, prolonged pregnancy, vascular insults) (see "Velamentous umbilical cord insertion and vasa previa", section on 'Vasa previa' and "Postterm pregnancy" and "Stillbirth: Incidence, risk factors, etiology, and prevention", section on 'Umbilical cord abnormalities' and "Stillbirth: Incidence, risk factors, etiology, and prevention", section on 'Placental abruption')

●Maternal (eg, obesity, hypertension, diabetes mellitus, autoimmune disorders, intrahepatic cholestasis of pregnancy, infections) (see "Obesity in pregnancy: Complications and maternal management", section on 'Perinatal mortality' and "Infants of mothers with diabetes (IMD)", section on 'Fetal effects' and "Intrahepatic cholestasis of pregnancy" and "Treatment of hypertension in pregnant and postpartum patients")

Maternal factors that increase the risk of fetal death include extremes of maternal age, unmarried status, smoking, prior stillbirth, and multiple gestation [24,25]. Black race is a strong confounding factor. As noted above, Black populations had twice the perinatal mortality rate (PMR) and have a higher ratio of late fetal to neonatal deaths compared with White populations [23,26]. This difference persisted even when rates were adjusted for socioeconomic status and medical complications.

From 1980 to 2015 to 2017, the United States fetal death rate decreased from 9.1 to 5.8 per 1000 live births plus late fetal deaths [23,27]. This decline is likely related to the widespread use of prenatal sonography, fetal surveillance (eg, biophysical profile, Doppler velocimetry) in high-risk pregnancies, and improved obstetrical management of gestational disorders (eg, twin oligo-polyhydramnios sequence, fetal anemia) [24,28].

CAUSES OF INFANT DEATH

Country differences

●United States – In 2017, the five leading causes of infant death in the United States were as follows [17]:

•Congenital malformations or chromosome abnormalities − 21 percent

•Low birth weight (BW) or prematurity − 17 percent

•Sudden infant death syndrome (SIDS) − 6 percent

•Neonatal death due to maternal complications − 6 percent

•Unintentional injuries − 6 percent

Among term infants, the major causes of neonatal death were asphyxia and infection, and in postneonatal infancy, SIDS [29].

Substantial reduction in the number of deaths caused by prematurity has been associated with improved perinatal care, increased use of antenatal glucocorticoids and the availability of surfactant treatment of respiratory distress syndrome. (See "Spontaneous preterm birth: Overview of risk factors and prognosis" and "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery" and "Overview of neonatal respiratory distress and disorders of transition".)

●China – In China, the neonatal mortality rate has fallen from 34 to 10.2 deaths per 1000 live births, and the postnatal infant (1 to 11 months of age) mortality rate from 53.5 to 14.9 deaths per 1000 live births from 1990 to 2008 [30]. In 2008, the proportional contribution of causes of neonatal deaths included the following:

•Birth asphyxia − 29 percent

•Other (eg, tetanus, intracranial hemorrhage, accidents, scleroderma, accidental asphyxia, and meningitis) − 27 percent

•Prematurity − 26 percent

•Congenital anomalies − 10 percent

•Infections (ie, sepsis, diarrhea, and pneumonia) − 6 percent

The proportional contribution of causes of postnatal infant deaths included the following:

•Pneumonia − 47 percent

•Congenital abnormalities − 16 percent

•SIDS − 12 percent

•Diarrhea − 9 percent

•Accidents − 7 percent

•Other (birth asphyxia, neonatal sepsis, prematurity) − 9 percent

Low birth weight — BW is a major determinant of neonatal morbidity and mortality (figure 2). Low BW includes infants with fetal growth restriction (FGR) and those born preterm.

In the United States, while infants born before 32 weeks represent only 2 percent of all births, they contribute to one-third to one-half of infant deaths [31]. The rate of infant mortality for babies born very low birth weight (VLBW) (BW <1500 g) is 100 times higher than that for babies born weighing more than 2500 g. (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality".)

The mortality rates of preterm infants and limit of viability are discussed in greater detail separately. (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality".)

United States regional differences — Regional differences exist in the United States in the incidence of perinatal mortality and neonatal deaths [17]. Neonatal mortality also may differ among local institutions, even when adjustments are made for prematurity rates. These differences may be due in part to specific characteristics of newborn care, and suggest that infants at high risk should be delivered in hospitals with tertiary level neonatal intensive care units (NICU) [32,33].

The availability of neonatologists likely affects neonatal mortality. In a study of the relationship of the distribution of neonatologists and neonatal death, the supply of specialized services varied across regions and was not consistently related to improved outcome, even after adjustment for the numbers of extremely low birth weight infants (ELBW) (BW <1000 g) [34].

Congenital anomalies — Congenital malformations, including syndromes and chromosomal abnormalities, account for approximately 20 percent of neonatal deaths. These conditions are associated with higher rates of fetal death, preterm birth, and FGR. Congenital anomalies occur in 3 percent of live-born infants. (See "Congenital cytogenetic abnormalities" and "Congenital anomalies: Approach to evaluation".)

Timely and accurate prenatal diagnosis can reduce morbidity and mortality from congenital anomalies by modifying perinatal management. More importantly, timely and accurate prenatal diagnosis of fetal structural defects, followed by termination of anomalous pregnancies, substantially decreases the neonatal mortality rate (NMR). (See 'Effect of prenatal diagnosis' above.)

Other factors — Other maternal characteristics are associated with increased infant mortality and are similar to risk factors for fetal death. These include age less than 20 years or more than 40 years, late or no prenatal care, unmarried status, smoking, lower education level [17,35]. In addition, very preterm infants born to mothers with severe morbidity, defined as life-threatening conditions or receiving life-saving therapy, had a greater risk of infant death than those born to mothers without severe morbidity (11 versus 8 percent) [36]. (See "Severe maternal morbidity".)

PREVENTION — As noted above, reducing preterm and post-term birth would decrease infant morbidity and mortality. Although there are interventions to reduce the incidence of spontaneous preterm birth, many preterm births occur in women with no known risk factors, in whom preventive intervention is not feasible. Prevention of spontaneous preterm birth is discussed in greater detail separately. (See "Spontaneous preterm birth: Overview of risk factors and prognosis".)

Additionally, periconceptional and gestational folic acid intake prevents many fetal anomalies, and therefore has the potential to further decrease adverse pregnancy outcomes. Niacin has also emerged as a vitamin with the potential to prevent congenital anomalies based on animal data [37]. However, confirmatory human data is needed. Nevertheless, women considering or carrying a pregnancy should consume prenatal vitamins that contain folic acid and niacin, as a safe and inexpensive intervention. (See "Preconception and prenatal folic acid supplementation" and "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Folate deficiency'.)

SUMMARY AND RECOMMENDATIONS

●Terminology – Mortality rates in the perinatal period are used to evaluate the outcome of pregnancy and monitor the quality of perinatal (prenatal and neonatal) care. The use of standard terminology facilitates comparisons of mortality rates among states and countries. Standard definitions for reporting reproductive health statistics are published by the National Center for Health Statistics (NCHS) (algorithm 1). (See 'Terminology' above and 'United States reporting requirements' above.)

●Comparison of mortality rates – Comparison of mortality rates across states or countries is challenging because different definitions are often used, and there are regional differences in the level of perinatal care, the availability of prenatal diagnosis and pregnancy termination facilities, and societal acceptance of termination of anomalous pregnancies. Neonatal mortality rates (NMR) are almost 10 times greater in resource-limited countries than in resource-abundant countries. (See 'Comparison of mortality rates' above and 'United States regional differences' above.)

●Perinatal and neonatal mortality rates – In the United States, the perinatal mortality rate (PMR) declined to 5.69 per 1000 live births plus late fetal deaths in 2019 (figure 1). Neonatal mortality rates are higher in infants who are non-Hispanic, Black, preterm, or a product of a multifetal pregnancy (table 1). (See 'Perinatal and neonatal mortality rates' above.)

●Causes of fetal and infant death

•Fetal death – The etiology of fetal death can be divided into fetal (eg, structural defects, syndromes, and aberrant growth (figure 2)), placental (eg, chorioamnionitis, umbilical cord accidents, abruption, infarction, prolonged pregnancy), and maternal causes (eg, obesity, hypertension, diabetes mellitus, autoimmune disorders, intrahepatic cholestasis of pregnancy). However, one-third of fetal deaths remain unexplained. (See 'Causes of fetal death (stillbirth)' above.)

•Infant death – The majority of infant deaths are attributed to congenital malformations or chromosome abnormalities, low birth weight (BW) or prematurity, sudden infant death syndrome (SIDS), maternal complications, unintentional injuries, and complications of the placenta, cord, or membranes. (See 'Causes of infant death' above.)