Overview of the long-term complications of preterm birth

INTRODUCTION — 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 decreasing gestational age. 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.

This topic will provide an overview of the long-term complications of preterm birth. Other related topics include:

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

●(See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors".)

●(See "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention".)

●(See "Care of the neonatal intensive care unit graduate".)

●(See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia".)

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 34 to <37 weeks

●Moderate preterm birth – GA 32 to <34 weeks

●Very preterm (VPT) birth – GA 28 to <32 weeks

●Extremely preterm (EPT) birth – GA <28 weeks

Preterm infants are also classified by BW:

●Low birth weight (LBW) – BW <2500 g

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

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

The above definitions are used throughout this review.

LONG-TERM PEDIATRIC COMPLICATIONS

Hospitalizations — Preterm survivors are far more likely to be hospitalized during childhood compared with term-born children. The risk of recurrent hospitalizations increases with decreasing gestational age (GA) [1-3]. This issue is discussed in greater detail separately. (See "Care of the neonatal intensive care unit graduate", section on 'Hospital readmissions'.)

Neurodevelopmental impairment — 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:

●Cognitive impairment

●Motor deficits including mild fine or gross motor delay, and cerebral palsy (CP)

●Sensory impairment including vision and hearing loss

●Behavioral and mental health problems (eg, attention deficit hyperactivity disorder [ADHD])

●Functional disabilities (eg, developmental coordination disorder, impaired executive function, impaired social interactive skills)

Long-term neurodevelopmental impairment in infants born preterm is discussed in detail separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors" and "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention".)

Vision problems — Preterm infants are at risk for vision problems, including retinopathy of prematurity (ROP), amblyopia, strabismus, myopia, and anisometropia. This is discussed separately. (See "Care of the neonatal intensive care unit graduate", section on 'Vision problems' and "Retinopathy of prematurity (ROP): Treatment and prognosis", section on 'Outcome'.)

Growth impairment — Children born preterm are more likely to have growth delays compared with those born at term [1,4,5]. For extremely low birth weight (ELBW) infants, poor growth persists into school age. This was demonstrated in 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 [4]. 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) [6].

Lung disease — Children who were born preterm are at risk of impaired lung function that may result in reduced exercise capacity and/or asthma [7-13]. (See "Risk factors for asthma", section on 'Prematurity'.)

The risk of asthma and other chronic pulmonary diseases is greatest in very or extremely preterm infants, particularly survivors who had BPD. This is discussed separately. (See "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia", section on 'Childhood'.)

The risk of asthma is lower in children who were born late preterm. However, the risk appears to be higher compared with children born at term. (See "Late preterm infants", section on 'Other potential long-term effects'.)

Other chronic health issues — Children who are born preterm, particularly extremely pre term (EPT) and ELBW infants, have higher rates of chronic medical conditions compared with children who were born at term [14,15]. Common health problems in this population include chronic respiratory disorders (eg, asthma), cognitive impairment, cerebral palsy, and behavioral and mental health conditions (eg, ADHD). The following sections summarize some of the chronic health issues children who are born preterm may experience. A more detailed discussion of problems preterm infants can experience after discharge from the neonatal intensive care unit is provided separately. (See "Care of the neonatal intensive care unit graduate", section on 'Medical care of specific conditions'.)

●Chronic kidney disease ‒ Preterm birth appears to be associated with increased risk of chronic kidney disease (CKD) [16-21]. 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 [21]. 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 [17-20].

●Hypertension ‒ In a study from the National Institutes of Child Health and Human Development Neonatal Research Network (NICHD NRN) that included 379 extremely preterm (EPT) infants who were evaluated at age six to seven years, 21 percent had systolic high systolic blood pressure (BP), 11 percent had systolic hypertension, 21 percent had high diastolic BP, and 11 had diastolic hypertension [22].

LONG-TERM HEALTHCARE 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 outcomes [15,23]. (See "Children and youth with special health care needs", section on 'Types of special needs'.)

In a study of 132 EPT infants (gestational age [GA] 23 to 25 weeks) who were assessed in adolescence (age range 10 to 15 years), 64 percent required supportive services above those routinely required by children [15]. This rate was considerably higher than for term-born controls (25 percent).

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, cerebral palsy (CP), or asthma), learning disabilities, and/or attention deficit or attention deficit hyperactivity disorders (ADHD) [24]. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors", section on 'Moderate to late preterm infants'.)

IMPACT ON ADULT HEALTH

Mortality — As survival for preterm infants improves, the potential impact of prematurity on long-term adult survival has become more apparent. The risk of premature mortality in adulthood increases with decreasing gestational age (GA).

●A systematic review identified eight studies that assessed GA at birth in relation to all-cause or cause-specific mortality in individuals ≥18 years of age (total of 6,594,424 participants) [25]. Overall, the studies found that premature birth is associated with modestly increased mortality in early to mid-adulthood. Individuals born extremely preterm (GA <27 weeks) had the highest risk of premature death in adulthood.

●In a population-based study of 6, 263, 286 individuals (ages 15 to 50 years) born between 1967 and 2002, mortality rates were higher for those born at <34 weeks GA compared with individuals born at term (adjusted hazard ratio [aHR], 1.44, 95% CI 1.34-1.55) [26]. 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 [27-29]:

●Insulin resistance – Insulin resistance is more common in adults who were born preterm compared with adults born full term [30-32]. In one study, adults (18 to 27 years of age) who were born preterm (birth weights [BW] below 1500 g and a mean GA of 29 weeks) compared with term controls had 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].

●Hypertension – 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. This is discussed in greater detail separately. (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 from Sweden that included >4 million participants, preterm birth was associated with an increased incidence of heart failure (HF) among individuals between 18 and 43 years of age (aHR, 1.42, 95% CI 1.19-1.71) [39]. The risk of HF was highest among individuals born extremely preterm.

●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 ≥85^th percentile and 10 percent were obese (ie, BMI ≥95^th percentile or ≥30) [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. (See "Definition, epidemiology, and etiology of obesity in children and adolescents", section on 'Environmental factors'.)

●Fertility – Prematurity has been associated with decreased female and male fertility 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 lower reproductive rates compared with individuals born full term [41]. Reproduction rates were lowest in adults with lower 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'.)

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 5^th to 6^th 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 10^th to 12^th 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

●Importance – Individuals who were born preterm are at increased risk of experiencing long-term health problems compared with those born at term. These health problems contribute to the increased mortality risk in this population. The risk of complications increases with decreasing gestational age (GA). Infants who are extremely preterm (EPT, GA <28 weeks) are at highest risk for long-term morbidity.

●Long-term complications in childhood and adolescence

•Recurrent hospitalizations – Preterm survivors are more likely to be hospitalized during childhood compared with term-born children. This issue is discussed in greater detail separately. (See "Care of the neonatal intensive care unit graduate", section on 'Hospital readmissions'.)

•Neurodevelopmental impairment (NDI) – Preterm survivors (especially EPT survivors) compared with those born at term are more likely to have the following neurodevelopment disabilities:

-Cognitive impairment

-Motor deficits including mild fine or gross motor delay, and cerebral palsy (CP)

-Sensory impairment including vision and hearing loss

-Behavioral and mental health problems (eg, attention deficit hyperactivity disorder [ADHD])

-Functional disabilities (eg, developmental coordination disorder, impaired executive function, impaired social interactive skills)

NDI in preterm survivors is discussed in detail separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors" and "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention".)

•Vision problems – Preterm infants are at risk for vision problems, including retinopathy of prematurity (ROP), amblyopia, strabismus, myopia, and anisometropia. This is discussed separately. (See "Care of the neonatal intensive care unit graduate", section on 'Vision problems' and "Retinopathy of prematurity (ROP): Treatment and prognosis", section on 'Outcome'.)

•Impaired growth – Children born preterm are more likely to have growth delays compared with those born at term. (See 'Growth impairment' above.)

•Lung disease – Preterm survivors are at risk of impaired lung function that may result in reduced exercise capacity and/or asthma. The risk of asthma and other chronic pulmonary diseases is greatest in very or extremely preterm infants, particularly survivors who had bronchopulmonary dysplasia (BPD). (See 'Lung disease' above and "Complications and long-term pulmonary outcomes of bronchopulmonary dysplasia".)

•Other chronic health issues – Preterm birth appears to be associated with increased risk of chronic kidney disease (CKD) and hypertension. (See 'Other chronic health issues' above.)

Other problems preterm infants can experience after discharge from the neonatal intensive care unit include gastroesophageal reflux, dental problems, osteopenia, orthopedic problems, inguinal and umbilical hernias, and other surgical problems (ie, issues related to bowel resection for necrotizing enterocolitis, tracheostomy tube placement, gastrostomy tube placement, and/or ventriculoperitoneal shunt placement). These issues are discussed separately. (See "Care of the neonatal intensive care unit graduate", section on 'Medical care of specific conditions'.)

●Healthcare and educational needs – 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 most healthy children. (See 'Long-term healthcare and educational needs' above.)

●Impact on adult health – Prematurity appears to have long-term effects upon adult health. Preterm adults compared with those born at term appear to have increased risk of insulin resistance, cardiovascular disease (hypertension, heart failure), infertility, and CKD. (See 'Impact on adult health' above and 'Other chronic health issues' above.)