INTRODUCTION — Late preterm infants are born at a gestational age between 34 weeks, and 36 weeks and 6 days. They have higher morbidity and mortality rates than term infants (gestational age ≥ 37 weeks) due to their relative physiologic and metabolic immaturity, even though they are often the size and weight of some term infants [1-4]. Late preterm term has replaced near term to describe this group of infants, since near term incorrectly implies that these infants are "almost term" and only require routine neonatal care [5].

The epidemiology, outcome, and management of late preterm infants will be reviewed here.

The views reported in this article are those of the author and do not necessarily represent the Centers for Disease Control and Prevention.

DEFINITION — It is well established that gestational age has a major impact upon clinical outcome. Thus, it is necessary to standardize medical terminology related to neonatal maturation by gestational age so that gestational-age appropriate care can be administered, and data from different studies can be compared.

• Premature birth — The World Health Organization, the American Academy of Pediatrics (AAP), and the American College of Obstetrics and Gynecology (ACOG) define premature birth as the delivery of an infant before completion of 37 weeks gestation. This occurs on or before the 259th day after the first day of the last menstrual period (LMP) of the mother.

The National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) generally reports data on three categories of preterm birth: overall preterm (<37 weeks gestation), moderately preterm (between 32 and 36 weeks gestation), and very preterm births (<32 weeks gestation). By convention, only completed weeks of gestation are reported. Thus, infants born five days after completing 35 weeks are reported as 35 weeks gestation, and are not rounded up to 36 weeks gestation. If a more precise gestational age is desired, a superscript to specify the number of days after the completed week of gestation is usually used.

• Late preterm infants — The AAP, ACOG, and NCHS define late preterm birth as the delivery of an infant between 34 weeks, and 36 weeks and 6 days of gestation (ie, 239 to 259 days after the first day of the LMP).

EPIDEMIOLOGY — Preterm deliveries occur as a result of spontaneous preterm labor, including cases when premature rupture of membrane precedes the onset of labor, or medical interventions (ie, labor induction or cesarean delivery) that are initiated to reduce poor outcome associated with specific maternal or fetal conditions (table 1).

In the United States, premature births have increased from 10.6 percent in 1990 to a high of 12.8 percent of all live births in 2006, which declined to 12.7 percent in 2007 [6]. The rise of preterm births during the last three decades was primarily due to a rise in late preterm births from 7.3 to 9.1 percent of all live births in 2006 (table 2) (graph 1). However, there was a slight decline of late preterm infants to 9.0 percent in 2007, perhaps reflecting progress in the prevention of late preterm delivery. (See 'Prevention' below.)

Risk factors for premature infants (table 3) are similar for the three different categories of preterm infants (ie, late preterm births, births between 32 and 33 weeks gestation, and very preterm infants), and are discussed in greater detail separately. (See "Risk factors for preterm labor and delivery".)

In one study based upon data from the British Columbia Perinatal Database Registry, maternal risk factors that were more common in late preterm (defined as 33 to 36 weeks gestation) compared to term infants included chorioamnionitis, hypertension, diabetes, thrombophilia, premature rupture of membranes, primigravida, and teenage pregnancy [7].

Factors associated with increased late preterm birth — As mentioned previously, the overall rise in preterm birth rates over the last three decades is primarily due to an increase in late preterm births. This change is attributed to increased obstetrical surveillance that detects maternal and fetal conditions, which results in medically indicated births (ie, induction of labor or cesarean delivery) (graph 2), and the increase in assisted reproductive technology births resulting in multiple deliveries (multiple deliveries occur earlier in gestation than singleton births), as well as singleton preterm births (graph 2) [6,8,9].

Improved obstetrical surveillance — In developed countries, obstetrical surveillance has increased as demonstrated by higher rates of fetal assessments, prenatal ultrasonography, and electronic fetal heart monitoring. The increase in surveillance is paralleled by a rise in the rate of medically indicated births.

In the United States, medically indicated births increased from 29 percent in 1992 to 41 percent of all births in 2002 with a parallel increase in premature births [10,11]. The rise in medically indicated preterm births primarily occurred in late preterm births (6.4 versus 7.4 percent) compared to a small decrease in very premature infants (1.6 versus 1.5 percent) and a much smaller increase in preterm infants born between 32 and 33 weeks (1.2 versus 1.3 percent) [10].

Fetal surveillance and the indication for medically indicated births are discussed in greater detail separately. (See "Intrapartum fetal heart rate assessment" and "The fetal biophysical profile" and "Induction of labor", section on 'Indications' and "Induction of labor", section on 'Contraindications',(See "Cesarean delivery: Preoperative issues", section on 'Indications and contraindications'.)

Multiple births — Infants who are products of multiple births generally deliver at an earlier gestational age than infants of a singleton birth [12,13]. In the United States, about 60 percent of twins were born prematurely with a mean gestational age of 35.2 weeks in 2006 [14]. Almost all triplets were born prematurely (93 percent) with a mean gestational age of 32 weeks.

Over the last several decades, multiple births rates have increased in the United States [14]. For example, twin births increased from 22.3 to 32.1 per 1000 live births from 1990 to 2006. This change was primarily due to the rise of twin births in late preterm infants from 29.1 to 38.3 per 1000 live births (graph 3). A similar observation was seen in triplet and higher orders multiple births with an increase from 23 to 33.7 per 1000 live births.

The rise in multiple births is primarily attributed to the following [14]:

• Increases in the number of mothers who are older than 30 years of age [6,14]. Women in their thirties are more likely than younger women to conceive multiple births spontaneously.
• Increased use of assisted reproductive technology (ART), which increases the likelihood for multifetal pregnancies and premature delivery. Singleton pregnancies following ART compared to spontaneously conceived pregnancies also are at higher risk for premature delivery. The estimated contribution of ART to the increase in preterm birth rate is about 10 percent [15]. (See "Pregnancy outcome after assisted reproductive technology".)

Other factors — In the United States, other factors that have increased preterm births, particularly late preterm births, include the following:

• Increasing maternal age — Higher maternal age (women in their thirties) is associated with an increase risk of premature birth than women who are between 21 and 24 years of age. In the United States, the birth rate of women over thirty years of age has risen to its highest level in more than four decades [6,14]. These women, as discussed previously, are more likely to conceive multiple fetuses spontaneously or seek ART, which also results in multiple births [6,16].
• Inaccurate gestational age — It appears that some late preterm births are a result of medically assisted deliveries of late preterm fetuses who were incorrectly thought to have reached term [17].

Elective induction of labor at term should be avoided if there is no medical/obstetrical indication for delivery due to increased risk morbidity (eg, respiratory distress). However, if elective induction is undertaken for nonmedical reasons, an accurate gestational age is important to prevent late preterm birth. Elective induction should only take place if the preinduction assessment ensures the gestational age is at least 39 weeks. (See "Induction of labor", section on 'Pediatric issues' and "Induction of labor", section on 'Preinduction assessment',(See 'Prevention' below.)

Prenatal gestational age may be determined by several methods. Clinical assessment by either history (ie, using the date of the last menstrual period [LMP] to calculate the estimated date of delivery) or physical examination of the uterus may be imprecise, resulting in an inaccurate gestational age [17]. Early fetal ultrasound is superior to either of these two clinical dating methods. (See "Prenatal assessment of gestational age".)

• Increasing maternal obesity — In the United States, the epidemic of overweight and obesity has led to a higher prevalence of maternal obesity. Women who are overweight or obese are more likely to have a preterm delivery than nonobese women due to obesity-related medical and antenatal complications (eg, maternal diabetes and hypertension, and multifetal pregnancy), which may lead to delivery interventions rather than an intrinsic predisposition to spontaneous preterm birth. (See "The impact of obesity on fertility and pregnancy", section on 'Preterm birth'.)

MORBIDITY — Compared to their term counterparts, late-preterm infants have a higher morbidity rate during birth hospitalization, higher rates of readmission during the neonatal period and first year of life, and may be at increased risk for long-term neurodevelopment impairment.

Birth hospitalization — During the birth hospitalization, late preterm infants have a seven-fold greater morbidity rate than term infants. This risk significantly rises in infants with other neonatal morbidity risk factors.

This was illustrated from a population-based study from Massachusetts that compared the outcome of 26,170 late preterm infants with 377,638 term infants using birth and death certificates, and linking it to infant and maternal hospital discharge records from the Massachusetts Pregnancy to Early Life Longitudinal data system [18]. The following findings were noted:

• Neonatal morbidity was 7 times greater in late preterm infants (22 versus 3 percent). Morbidity rate doubled for each gestational week earlier than 38 weeks.
• Morbidity rates were 10 to 14 fold-greater in late preterm infants with other known risk factors for neonatal morbidity when compared to similarly exposed term infants. These factors included maternal hypertension and diabetes, antepartum hemorrhage, infections, and maternal chronic disorders (eg, renal, lung, and cardiac disease). The observed joint morbidity rates for late preterm infants were higher than the expected additive effect for each maternal condition, except for maternal infection. As an example, the observed 12-fold increase in morbidity for antepartum hemorrhage in late preterm infants was greater than the expected risk of 7-fold increase.
• Morbidity rates increased with the number of additional maternal risk factors, and were 18, 29, and 37 percent in infants with none, one, and two other risk factors, respectively.

Late preterm infants compared to those delivered at term have a longer birth hospitalization and a higher cost of care. This was illustrated in a retrospective study that analyzed data from a cohort of commercially insured neonates in the United States. Results demonstrated late preterm infants had a longer average birth hospital stay (8.8 versus 2.2 days) with a ten-fold higher cost of care ($26,054 versus $2061) [19].

During the birth hospitalization, the late preterm infants compared to term infants are more likely to have the following complications [3,20]:

• Hypothermia
• Hypoglycemia
• Respiratory distress
• Apnea
• Hyperbilirubinemia
• Feeding difficulties

This was illustrated in a retrospective review of all spontaneous, low-risk late preterm deliveries between 1997 and 2006 at a single Israeli tertiary center [21]. Infants of multiple gestations, premature rupture of membranes, or with maternal or fetal complications were excluded. Short-term outcome was compared to a control group of term infants. Late preterm infants compared to term infants had a greater risk of jaundice requiring phototherapy (18 versus 2.5 percent), hypoglycemia (6.8 versus 0.4 percent), respiratory distress (4.2 versus 0.1 percent), sepsis (0.4 versus 0.04 percent), and intraventricular hemorrhage (0.2 versus 0.02 percent).

Hypothermia — Late preterm infants are more susceptible to hypothermia compared to term infants, as they have less white adipose tissue for insulation, cannot generate heat as effectively from brown adipose tissue, and lose heat more readily due to their larger ratio of surface area to weight [3,20,22]. In one study of 196 infants consecutively admitted to the newborn nursery, 49 percent were hypothermic (core temperature <36.5ºC) of whom half were late preterm infants [23].

Hypoglycemia — The risk of hypoglycemia is reported to be three times greater in late preterm infants than in term infants [3]. Hypoglycemia may occur in newborn infants of all gestational ages as the result of an insufficient metabolic response to the abrupt loss of maternal glucose supply after birth [19,20]. The incidence of hypoglycemia increases with decreasing gestational age. (See "Neonatal hypoglycemia".)

Respiratory distress — Late preterm infants have a reported incidence of respiratory distress that ranges from 4 to 29 percent [2-20,22-25]. One review of the literature reported that 8 percent of late preterm infants required supplemental oxygen for at least one hour, which was almost three times the rate observed in term infants [25].

Late preterm infants have immature lung structure, since lung development of the terminal respiratory sacs and alveoli maturation continues through gestational weeks 34 and 36. In addition, some late preterm infants may miss the surfactant surge, which generally occurs at 34 weeks. As a result, late preterm infants are at increased risk for respiratory distress syndrome (RDS), especially infants of mothers who did not receive antenatal steroids [3,20,26]. Since biochemical changes during labor enhance fetal lung maturation and clearance of pulmonary fluids, both infants of diabetic mothers and those born via cesarean delivery without labor also are more likely to have RDS [27]. Other common causes of respiratory distress in late preterm infants include transient tachypnea of the newborn, absorption atelectasis, and persistent pulmonary hypertension [17,20,28]. (See "Pathophysiology and clinical manifestations of respiratory distress syndrome in the newborn" and "Overview of neonatal respiratory distress: Disorders of transition" and "Persistent pulmonary hypertension of the newborn".)

Apnea — The reported incidence of apnea in late preterm infants (4 to 7 percent) is greater than in term infants (1 to 2 percent) [3,22,29-31]. In the Collaborative Home Infant Monitoring study (CHIME), the recorded rate of apnea (obstructive and central apnea) and bradycardia events was greater in late preterm infants versus term infants [29,30]. Late preterm infants are also at increased risk for sudden infant death syndrome compared to term infants. (See "Pathogenesis of apnea of prematurity" and "Sudden infant death syndrome", section on 'Prematurity'.)

Hyperbilirubinemia — Because of immaturity and delay in the development of hepatic bilirubin conjugation pathways, late preterm infants are twice as likely than term infants to have prolonged jaundice with significantly elevated serum bilirubin at five days of age [2,20,32]. Feeding difficulties also can lead to a delay in the resolution of enterohepatic recirculation of bilirubin thereby, causing an increase in serum bilirubin.

At a given serum bilirubin concentration, the risks for bilirubin-induced brain injury and kernicterus are greater in the late preterm infant compared to term infants due to the relative immaturity of the blood-brain barrier, lower circulating bilirubin-binding albumin concentrations, and higher risk of concurrent illness [33,34]. Hyperbilirubinemia is the most common reason for readmission for the late preterm infant [33]. (See 'Readmission' below and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".)

Feeding difficulties — Oro-buccal coordination and swallowing mechanisms are not fully matured in most late preterm infants, leading to some difficulty in establishing successful feeding, especially in those who are breastfed [3,20]. In addition, late preterm infants have a higher frequency of gastroesophageal reflux (GER) than term infants. These factors contribute to the increased risk of dehydration in late preterm infants, who may require intravenous infusion of fluids [3]. (See "Breastfeeding the preterm infant", section on 'Late preterm infants'.)

Readmission — Readmission rates are two to three times greater for late preterm compared to term infants [2,19,35-37]. As an example, in the previously discussed cohort study of commercially insured infants, readmission rates over the first year of life for late preterm infants were 15 compared to 8 percent in term infants [19].

In particular, late preterm infants are three times more likely to be admitted within the first 15 days after discharge from the birth hospitalization (3.8 versus 1.3 percent) [19]. The most common reasons for early readmission are jaundice, feeding difficulties, poor weight gain, dehydration, and apnea.

Respiratory (including bronchiolitis) and gastrointestinal disorders are the most common diagnoses for late readmission (≥15 days after the date of discharge) during the first year of life [19]. One study from California noted the largest cohort of infants readmitted to the hospital at least once during the first month of life were infants born at 35 weeks gestation, most commonly due to a respiratory illness [38]. The cost of hospital readmission for this cohort of infants was 92.9 million dollars.

Long-term outcome — It appears that late preterm compared to term infants are at increased risk for long-term neurodevelopmental morbidity as illustrated by the following studies:

• In a study of singleton infants born in Florida in 1996 to 1997 with a gestational age between 34 and 41 weeks, children who were born late preterm compared to those born at term had an increased risk for developmental delay or disability when evaluated in early childhood (4.2 versus 3 percent), prekindergarten at three years of age (4.5 versus 3.9 percent), and prekindergarten at four years of age (7.4 versus 6.6 percent) [39].
• In a retrospective cohort study from California, children born late preterm were three times more likely to be diagnosed with cerebral palsy, and had a modest increased risk of intellectual disability (mental retardation) and developmental delay (hazard ratio 1.25, 95% CI 1.01 to 1.54) [40].
• In a study based upon the Early Childhood Longitudinal Study-Kindergarten Cohort dataset, children who were born late preterm had lower reading scores and poorer teacher evaluations for math skills in kindergarten and first grade, and reading skills from kindergarten through 5th grade [41]. Late preterm survivors also had a higher rate of special education participation in early grades.
• In a population-based study of all infants who were born alive and without congenital anomalies in Norway between 1967 and 1983, adults born late preterm compared to those born at term were more likely to have cerebral palsy (RR 2.7, 95% CI 2.2 to 3.3), intellectual disability (RR 1.6, 95% CI 1.4 to 1.8), schizophrenia (RR 1.3 , 95% CI 1 to 1.7), disorders of psychological development, behavior, and emotion (RR 1.5, 95% CI 1. 2 to 1.8), and have other major disabilities including blindness, poor vision, hearing loss and seizures (RR 1.5, 95% CI 1.2 to 1.8) [42].

Brain immaturity may play a role in the observed long-term neurodevelopmental disabilities in some individuals who were born late preterm. Although data are limited upon the brain maturation of late-preterm infants, autopsy and magnetic resonance imaging demonstrate that at 35 weeks gestation, the brain weighs 65 percent of a full term infant's brain, and the external surface has fewer sulci [43,44]. This immaturity may increase the brain's vulnerability to long-term injury.

MORTALITY — Although the relative risk of mortality for late preterm infants versus term infants is modest compared to infants born at <32 weeks and term infants, about 10 percent of all neonatal deaths in the United States occurred in late preterm infants in 2005 (graph 4) [45].

Late preterm infants have a greater risk of mortality than term infants, as illustrated by the following studies:

• In the United States, there were significant declines in mortality rates for both late preterm and term infants from 1995 to 2002. The mortality rate in 2002 was three times higher in late preterm versus term infants (7.9 versus 2.4 deaths per 1000 live births) [46].
• In a population-based study from British Columbia between 1999 to 2002, infants with a gestational age between 33 and 36 weeks compared to term infants had an eight-fold greater perinatal, 5.5-fold greater neonatal, and a 3.5-fold greater infant mortality rates [7].
• In a population-based study of late preterm and term infants from Utah, the neonatal mortality rate increased with decreasing gestational age with the highest rate of 8.2 per 1000 live births in infants born at 34 weeks gestation compared to 0.5 per 1000 live births in term infants born at 40 weeks gestation [47]. Sixty-three percent of late preterm infant deaths were due to a birth defect. Other causes of death were related to immaturity and included respiratory distress, sudden infant death syndrome, and asphyxia.
• Another study from Utah, which used linked birth and death certificate data for all infants born between 1999 and 2005, found that late preterm infants who were small for gestational age (SGA) had an even greater mortality rate compared to infants born at term with an appropriate birth weight for gestational age (AGA) [48]. SGA late preterm infants were 44 times more likely than term AGA infants to die within the first month of life, and 22 times more likely to die in their first year of life. These differences persisted even when infants with congenital conditions were excluded.

MANAGEMENT

Prevention — To decrease the mortality and morbidity associated with late preterm births, prevention is one of the key components. One major step towards lowering late preterm birth is to ensure no elective delivery is done prior to 39 weeks gestation. The American College of Obstetrics and Gynecology (ACOG) does not recommend induced vaginal or planned cesarean delivery prior to 39 weeks gestation unless medically indicated [49]. If elective induction is undertaken for nonmedical reasons, it should only take place if the preinduction assessment ensures the gestational age is at least 39 weeks. (See "Induction of labor", section on 'Pediatric issues' and "Induction of labor", section on 'Preinduction assessment',(See "Prenatal assessment of gestational age".)

In addition, further research is needed to refine the management of the fetus and mother at late preterm gestation, such as better identification of pregnancies that require early delivery for medical conditions. Areas of research include [5]:

• Assess the risk/benefit ratio for diagnosis-specific indications for late preterm delivery, such as more accurate estimation of fetal well-being and outcome in the presence of maternal diseases (eg, hypertension and diabetes).
• Identify management strategies to improve specific outcomes in late preterm infants. One proposed strategy is the use of antenatal steroids in late preterm multiple-fetal pregnancies.
• Improve the precision of determining gestational age.
• Improve the ability to identify the fetus at risk for late pregnancy intrauterine death (ie, stillbirth). (See "Etiology and management of antepartum fetal death", section on 'Prevention strategies'.)

Neonatal management and discharge criteria — Clinicians who care for late preterm infants need to be aware that these infants are at increased risk for neonatal morbidity and mortality. They need to be familiar with the associated complications of late preterm birth and provide appropriate intervention. (See 'Birth hospitalization' above.)

Prior to hospital discharge, parents need to be educated that their infant is at increased risk for hyperbilirubinemia, feeding difficulties, and dehydration. Teaching should focus on developing the parents' skills to recognize these conditions and seek appropriate care after hospital discharge.

The American Academy of Pediatrics has established the following guidelines for discharge criteria for late preterm infants [20]:

• Determine the accurate gestational age, and ensure that there are no abnormalities or medical condition (ie, hyperbilirubinemia) that require further hospitalization.
• The infant demonstrates physiologic stability by demonstrating competency in the following:

• - Thermoregulation defined as an axillary temperature of 36.5 to 37.4ºC in an open crib.
• - Feeding defined as coordinated sucking, swallowing, and breathing while feeding, and weight loss not to exceed 7 percent of birth weight during birth hospitalization. If the infant is breastfed, twice daily documented observation by trained caregivers of successful position, latch, and milk transfer after birth also should be performed.
• - Cardiorespiratory control with stable vital signs of a respiratory rate less than 60 breaths per minute and a heart rate between 100 to 160 beats per minute, and absence of medical illness.
• - At least one stool has passed spontaneously.

• Other routine newborn care has been completed. This includes screening tests (ie, hearing and disorders that are threatening to life or long-term health), vaccinations (ie, hepatitis B vaccine), and prophylactic treatment (ie, vitamin K prophylaxis). (See "Overview of the routine management of the newborn infant".)

• Assessment of the family and home environment to identify any risk factors that may impact on the health of the infant.
• Successful training of the parents who have demonstrated competency in the care of their infant and the ability to assess for hyperbilirubinemia, feeding difficulties, and dehydration.
• A follow-up visit for 24 to 48 hours after discharge is scheduled with an identified primary care provider.

SUMMARY AND RECOMMENDATIONS

• Late preterm infants are infants with a gestational age between 34 to 36 weeks and 6 days. They have higher morbidity and mortality rates than term infants even though they are often the size and weight of some term infants. (See 'Definition' above and 'Morbidity' above and 'Mortality' above.)

• In the United States, the birth rate of late preterm infants has risen to about 9 percent of all births over the last several decades, in part due to increases in the rates of multiple births and early deliveries for medical indications. (See 'Epidemiology' above.)

• Late preterm infants have a reported seven-fold increase risk of morbidity compared to term infants during birth hospitalization, which results in a longer hospital stay and higher medical costs. The most common causes of morbidity include hypothermia, hypoglycemia, respiratory distress, apnea, hyperbilirubinemia, and feeding difficulties. (See 'Birth hospitalization' above.)

• Readmission rates are two to three times greater for late preterm compared to term infants. Early readmission (within 15 days of discharge from birth hospitalization) includes hyperbilirubinemia, feeding difficulties, poor weight gain, dehydration, and apnea. During the first year of life, respiratory and gastrointestinal disorders are the most common diagnoses for late readmission. (See 'Readmission' above.)

• Late preterm infants appear to be at increased risk for long-term neurodevelopmental impairment compared to term infants. (See 'Long-term outcome' above.)

• The mortality rate for late preterm infants is at least three-fold greater than that of term infants. (See 'Mortality' above.)

• Strategies to decrease the morbidity and mortality associated with late preterm infants include prevention of late preterm delivery, and management to prevent and treat the associated complications of late preterm birth. (See 'Management' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate, Inc. would like to acknowledge Dr. Tonse Raju, who contributed to an earlier version of this topic review.