INTRODUCTION — Prematurity is defined as a birth that occurs before 37 completed weeks (less than 259 days) of gestation. It is associated with approximately one-third of all infant deaths in the United States and accounts for approximately 45 percent of children with cerebral palsy (CP), 35 percent of children with vision impairment, and 25 percent of children with cognitive or hearing impairment.
Complications of prematurity are the underlying reasons for the higher rate of infant mortality and morbidity in preterm infants compared with full-term infants. The risk of complications increases with increasing immaturity. Thus, infants who are born at the limit of viability, born before 28 weeks gestation, have the highest mortality rate (approximately 50 percent) and if they survive, are at the greatest risk for long-term morbidity.
In preterm survivors, there is a high rate of long-term neurodevelopment impairment (NDI) and chronic health problems. These chronic medical and neurodevelopmental complications often require additional healthcare and educational services, which add to the overall economic cost of caring for the preterm infant.
The long-term complications of prematurity and the long-term healthcare needs of preterm survivors will be reviewed here. The short-term complications of the preterm infant are discussed separately. (See "Short-term complications of the preterm infant".)
DEFINITIONS — Different degrees of prematurity are defined by gestational age (GA) or birth weight (BW) (table 1).
The classification based upon GA is as follows:
●Late preterm birth – GA between 34 and less than 37 weeks
●Moderate preterm birth – GA between 32 and <34 weeks
●Very preterm (VPT) birth – GA between 28 and <32 weeks
●Extremely preterm (EPT) birth – GA less than 28 weeks
Preterm infants are also classified by BW:
●Low birth weight (LBW) – BW less than 2500 g
●Very low birth weight (VLBW) – BW less than 1500 g
●Extremely low birth weight (ELBW) – BW less than 1000 g
BW by percentile for the appropriate GA have been established (table 2). The above definitions are used throughout this review.
LONG-TERM PEDIATRIC COMPLICATIONS — In preterm survivors, there is a high rate of recurrent hospitalizations, long-term neurodevelopment impairment (NDI), and chronic health problems.
Hospitalizations — The risk of recurrent hospitalizations increases with decreasing gestational age (GA) [1-3]. This was illustrated in a population-based study of over one million births between 2005 and 2006 that reported children born extremely preterm (GA <28 weeks) had the highest risk of hospitalization compared with those born at term (adjusted relative risk [RR] 4.92, 95% CI 4.58-5.30) through the first ten years of age [3]. In addition, children born at 38 weeks gestation had a higher risk of hospitalization than those born at term (adjusted RR 1.19, 95% CI 1.16-1.22). The association between GA and hospitalizations decreased with age. An observational study of 6385 very low birth weight (VLBW) survivors reported that the risk of rehospitalization persists throughout childhood and adolescence [4]. The risk was increased for those with neonatal morbidities that included necrotizing enterocolitis requiring surgery, severe intraventricular hemorrhage grades 3 to 4, periventricular leukomalacia, bronchopulmonary dysplasia, and retinopathy of prematurity stages 3 to 4.
The most common causes for rehospitalization were infection, respiratory disorders including respiratory infections, especially respiratory syncytial virus (RSV) infection and asthma, and gastrointestinal problems including gastroesophageal reflux and gastroenteritis [1,3]. Other chronic medical problems seen in preterm survivors include bronchopulmonary dysplasia (BPD), increased risk of sudden infant death syndrome (SIDS), and vision and hearing impairment. (See "Care of the neonatal intensive care unit graduate", section on 'Hospital readmissions' and "Care of the neonatal intensive care unit graduate", section on 'Medical care of specific conditions'.)
Neurodevelopmental outcome — Preterm survivors compared with those born full term are more likely to have the following neurodevelopment disabilities. The risk of these impairments increases with decreasing GA. These include:
●Impaired cognitive skills
●Motor deficits including mild fine or gross motor delay, and cerebral palsy (CP)
●Sensory impairment including vision and hearing losses
●Behavioral and psychological problems
The long-term neurodevelopmental outcome in preterm infants is discussed in detail separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors".)
Chronic health issues — Children who are born preterm, particularly those who were extremely low birth weight (ELBW) infants, have higher rates of chronic medical conditions compared with children who were born full term [5,6]. This was illustrated in a study from a United States tertiary center that showed overall rates of chronic conditions (asthma requiring medications, subnormal cognitive function, and functional limitations) for ELBW survivors were greater than age- and gender-matched normal-birth weight controls at eight years of age (75 versus 37 percent) and at 14 years of age (74 versus 47 percent) [5]. Similar results were noted in a Swedish study that reported adolescents (range 10 to 15 years of age) who were extremely preterm (GA between 23 and 25 weeks) were more likely to have chronic health issues (cerebral palsy, asthma, poor motor skills, and psychiatric conditions) than term-born controls [6].
Specifically, prematurity has been associated with the following conditions in childhood:
●Chronic kidney disease ‒ There are data that suggest prematurity increases the risk of chronic kidney disease (CKD) [7-12]. In a population-based study of over 4 million live births, 0.1 percent of the cohort were diagnosed with CKD based on discharge diagnostic coding, and after adjusting for confounding factors, the risk increased twofold for individuals born preterm (GA <37 weeks, adjusted hazard ratio [HR] 1.94, 95%CI 1.74-2.16) compared with those born at term (GA 39 to 41 weeks) from childhood to mid-adulthood [12]. The risk of CKD increased with decreasing GA with individuals who were extremely preterm (GA <28 weeks) having the greatest risk of CKD (adjusted HR 3.01, 95% CI 1.67-5.45).
Several case series have reported that children born prematurely were more likely to have smaller kidneys, higher blood pressure, and microalbuminuria (an early indicator of CKD) than those born at term [8-11].
●Hypertension and high blood pressure ‒ In one follow-up study from the National Institutes of Child Health and Human Development (NICHD) Neonatal Research Network of extremely preterm (EPT) infants (<28 weeks GA), both overweight and normal weight children who were EPT were at risk for high BP and hypertension at six and seven years of age [13].
Growth impairment — Very preterm children are also more likely to exhibit poor growth compared with those born full term [1,14,15]. Poor growth of ELBW children persists into school age as demonstrated by a follow-up study of 241 ELBW children who were assessed for growth and blood pressure at a median age of six years and four months [14]. Compared with normative growth data from normal children who were born full term, children who were ELBW infants were lighter, shorter, and had a lower body mass index (BMI) and smaller head circumference.
In a follow-up study of 950 children born with low birth weight (<1500 g), infants with persistent poor growth at 9 and 24 months (length for age Z-scores <-2) had lower motor and cognitive scores on the Bayley Scales of Infant Development than those with better growth measures (length for age Z-scores >-2) [16].
Impairment of lung function — Children who were born very or extremely preterm are at risk for impaired lung function that may result in reduced exercise capacity or an increase in respiratory symptoms including asthma [17-23]. In contrast, limited data suggest that there is minimal to no effect on respiratory function for adolescents who were born either moderately or late preterm [24]. (See "Risk factors for asthma", section on 'Prematurity'.)
In particular, survivors of prematurity who had BPD are more likely to have respiratory problems as children and adults. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Childhood'.)
LONG-TERM HEALTH AND EDUCATIONAL NEEDS — As discussed above, preterm survivors are at increased risk for chronic medical and neurodevelopmental complications, which often require additional healthcare and educational services. As the number of survivors of preterm birth increase and reach school age, it is imperative that their health and educational needs are identified and resources are committed to address their needs. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors", section on 'Extremely preterm infant'.)
Increased health and educational support are especially needed for extremely low birth weight (ELBW) survivors, who are at the greatest risk for poor health and neurodevelopmental outcome [6,25]. (See "Children and youth with special health care needs", section on 'Types of special needs'.)
●In a study from a tertiary center in the United States, ELBW school-aged children, who were more likely to have chronic medical conditions and disabilities (asthma, cerebral palsy, vision problems, poor motor skills, limited academic skills and adaptive function) than term-born controls, also had greater compensatory dependence needs (48 versus 23 percent; odds ratio [OR] 3.0, 95% CI 1.9-4.7), including medication use and need for help or equipment for walking and other daily routine activities (eg, feeding, dressing, and washing). In addition, the ELBW group utilized services beyond those routinely required by children (65 versus 27 percent; OR 5.4, 95% CI 3.4-8.5), including acute care visits to healthcare professionals and special school arrangements or an individualized education program.
●Similar results were observed in the previously mentioned Swedish study that reported that adolescents (age range 10 to 15 years) who were extremely preterm (gestational age [GA] 23 to 25 weeks) were more likely than term-born controls to have compensatory dependency needs (60 versus 29 percent; OR 3.8, 95% CI 2.2-6.6) and services above those routinely required by children (64 versus 25 percent; OR 5.4, 95% CI 3.0-9.6) [6].
Moderately low birth weight (LBW) infants (birth weight [BW] between 1500 and 2499 g) are also more likely than normal BW infants to have special healthcare needs (eg, use of medical services and/or medication), chronic conditions (eg, intellectual disability, CP, or asthma), learning disabilities, and/or attention deficit or attention deficit hyperactivity disorders (ADHD) [26].
IMPACT OF PREMATURITY ON ADULT HEALTH
Adulthood survival — As the survival rate of preterm infants improves, the potential impact of prematurity on long-term adult survival has become more apparent. Adult survival decreases with decreasing gestational age (GA).
●A systematic review that included six studies of individuals (greater than 18 years of age) born after 1967, reported that survival decreased with decreasing gestational age and that individuals born extremely preterm (GA <27 weeks) had the lowest survival compared with those born at term [27].
●In a subsequent population-based report of 6, 263, 286 individuals (ages between 15 to 50 years) born between 1967 and 2002, survival rates compared with individuals born full term were lower for those born very and extremely preterm with GA between 23 and 33 weeks (adjusted hazard ratio [aHR], 0.69, 95% CI 0.65-0.75), those born late preterm (0.81, 95% CI 0.77-0.85), and those born early term (GA 37 to 38 weeks, aHR 0.89, 95% CI 0.87-0.92) [28]. Preterm birth was associated with increased risk of death due to cardiovascular disease, diabetes, and chronic lung disease.
Morbidity — Long-term complications observed in adult survivors include the following [29]:
●Insulin resistance – Preterm adults appear to be more likely to have insulin resistance and higher blood pressure compared with adults born full term [30-32]. In one study, adults (18 to 27 years of age) who were born prematurely (birth weights [BW] below 1500 g and a mean GA of 29 weeks) compared with term controls had higher blood pressure (BP) and impaired glucose regulation when evaluated by a standard 75 g oral glucose tolerance test with higher serum glucose and insulin concentrations two hours after glucose administration [30]. Similar results were noted; increased likelihood of elevated BP and dysglycemia in older adults (mean age 31.8 years) born with ELBW (BW <1000 g) compared with term controls [32].
●Hypertension and high blood pressure – High blood pressure values have been observed in adults and adolescent born preterm compared with those born full term [31-37]. It has been proposed that low birth weight (LBW) may play a role in the development of primary hypertension (formerly called "essential" hypertension) in adulthood. (See "Possible role of low birth weight in the pathogenesis of primary (essential) hypertension".)
●Ischemic heart disease ‒ A population-based study of 2.1 million individuals reported an association between preterm birth and ischemic heart disease [38]. In this cohort, gestational age (GA) at birth was inversely associated with ischemic heart disease in adulthood (30 to 43 years of age), Adults born before 37 were 1.5 times more likely to have ischemic heart disease than those born at term (aHR 1.53, 95% CI 1.20-1.94).
●Heart failure ‒ In a population-based study (Sweden, 1973 to 2015) that included more than 4 million participants (maximum age 43 years, median age 22.5 years), preterm birth (<37 weeks gestation) was associated with a 2.7-fold increased incidence of heart failure (HF) compared with full-term (39 to 41 weeks gestation) birth (aHR 2.69, 95% CI 2.43-2.97) from infancy to adulthood [39]. The risk of HF increased with decreasing GA with extreme prematurity (<28 weeks gestation) associated with a 12.8-fold higher risk for HF compared with full-term birth (aHR 12.83, 95% CI 9.55-17.25), whereas late-preterm birth (34 to 36 weeks gestation) was associated with a 2.2-fold higher risk than for full-term birth (aHR 2.18, 95% CI 1.93-2.46). For individuals between 18 and 43 years of age, HF was increased for preterm birth (aHR, 1.42, 95% CI 1.19 to 1.71) and extremely preterm birth (4.72, 95% CI 2.11-10.52) compared with term birth.
●Obesity and overweight – Although growth impairment is most often observed in children who were EPT, a subset of survivors by school age become overweight or obese. In a report from the National Institute of Child Health and Human Development (NICHD) Neonatal Network SUPPORT Neuroimaging and Neurodevelopmental Outcomes study, 22 percent of 388 children by six and seven years of age had a body mass index (BMI) of ≥85th percentile and 10 percent were obese [40]. These children were more likely to be hypertensive and sedentary compared with those with normal BMI. As noted by the authors, the prevalence of obesity in this cohort is lower than the general population but higher than what is expected in children who were EPT and likely due to postnatal factors.
●Reproduction – Prematurity has been associated with decreased reproduction in adulthood. This was illustrated in a large population-based study from Norway of over 500,000 individuals born between 1967 and 1976 and followed through 2004 that demonstrated preterm adults had a lower reproductive rate compared with individuals born full term [41]. The reproductive rate was lowest in the adults with the lowest GA; rates were 25 and 68 percent in women born at 22 to 27 weeks and at term, respectively (adjusted relative risk [RR] 0.33, 95% CI 0.26-0.42), and were 14 and 50 percent in men born at 22 to 27 weeks and at term, respectively (adjusted RR 0.24, 95% CI 0.17-0.32). In addition, preterm women, but not men, were at increased risk of having preterm offspring.
●Neurodevelopmental, psychological, behavioral, and functional disability ‒ The risk of adulthood neurodevelopmental and social disabilities increases with decreasing GA and is discussed separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors", section on 'Outcomes in adulthood'.)
SOCIETAL COST — If preterm delivery could be avoided, there would be tremendous savings to society worldwide [2,42-47]. This is demonstrated by the following studies in several different developed countries:
●Sweden – In a Swedish cohort study based upon 2002 data from the National Board of Health and Welfare and Statistics Sweden registers of 522,310 young adults born between 1973 and 1979, decreasing gestational age (GA) was associated with a stepwise increase in disability rates in young adulthood, and a stepwise decrease in net salary and the likelihood of completing a university education [43]. Government economic assistance was provided to 13 percent of individuals born at 24 to 28 weeks gestation and 6 percent born at 29 to 32 weeks gestation. If preterm delivery could have been avoided, the 2002 estimated economic cost savings would have amounted to EUR €65 million.
●Norway – In a population-based study of all infants who were born alive and without congenital anomalies in Norway between 1967 and 1983, adults born prematurely at a GA between 23 and 27 weeks compared with those born full term were more likely to have cerebral palsy (CP) (9.1 versus 0.1 percent), have an intellectual disability (4.4 versus 0.4 percent), and receive a disability pension (10.6 versus 1.7 percent) [44]. Among adults without medical disabilities, the GA at birth was associated with the level of educational achievement, income level, receipt of Social Security benefits, and the ability to have a family, but did not correlate with rates of unemployment or criminal activity.
●United States – In 2001, the estimated cost of preterm and low birth weight (LBW) admissions in the United States was USD $5.8 billion, which represented 47 percent of costs for all infant hospitalizations and 27 percent of all pediatric stays [45]. The annual cost associated with preterm birth in the United States was estimated to be USD $26 billion [46]. This included the costs of the medical care of the infants and mothers, and expenditures for the long-term care of patients born preterm.
●England and Wales – Based upon 2006 estimates of the number of preterm births and the cost of medical care through the first 18 years of life in England and Wales, the total societal cost was estimated to be almost GBP £3 billion (USD $4.6 billion) at 2006 prices [47]. The mean incremental cost per child was approximately GBP £23,000 (USD $35,500) and the cost increased with decreasing GA with estimated costs for a very preterm child of GBP £62,000 (USD $96,000) and for an extremely preterm child GBP £95,000 (USD $147,000).
In addition, long-term morbidity is reduced when there is perinatal regionalization of care with maternal transport of women at risk to deliver a very low birth weight (VLBW) infant to a center that delivers a high volume of VLBW infants and provides level 3 neonatal care. This was illustrated in a cohort Finnish study that reported an increased risk of epilepsy and hyperkinetic disorders in VLBW survivors at five years of age who were cared for in a neonatal level 2 care facility compared with a level 3 center [48]. In addition, the risk of retinopathy of prematurity (ROP) and asthma was higher in survivors who had been transferred to a level 2 facility from a level 3 center. These data suggest that efforts to improve the level of neonatal care will improve long-term morbidity.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
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 — Complications of prematurity are the underlying reasons for the higher rate of infant mortality and morbidity in preterm infants compared with full-term infants. The risk of complications increases with increasing immaturity. Thus, infants who are extremely preterm, born at or before 28 weeks of gestation, have the highest mortality rate (approximately 50 percent) and if they survive, are at the greatest risk for long-term morbidity.
●In preterm survivors, long-term neurodevelopmental disability is the major cause of morbidity. In addition, chronic medical problems including respiratory abnormalities and poor growth are common in preterm children resulting in frequent hospitalizations. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors" and 'Chronic health issues' above and "Care of the neonatal intensive care unit graduate", section on 'Hospital readmissions' and "Care of the neonatal intensive care unit graduate", section on 'Medical care of specific conditions'.)
●Prematurity appears to have long-term effects upon adult health. Preterm adults compared with those born full-term appear to have increases in insulin resistance and blood pressure, decrease in reproductive rate, and an increased risk of chronic kidney disease. (See 'Impact of prematurity on adult health' above and 'Chronic health issues' above.)
●Because preterm children have a high rate of chronic medical conditions including neurodevelopmental disabilities that result in functional limitations, they commonly require additional healthcare and educational services beyond those routinely required by children. (See 'Long-term health and educational needs' above.)
●If preterm birth could be avoided, there would be tremendous savings to society from reduced expenditures from the initial medical costs for care in the neonatal period and additional health and educational costs in childhood and adulthood, and increased productivity in adulthood. (See 'Societal cost' above.)
