INTRODUCTION — Neurodevelopmental impairment (NDI) is a significant long-term complication associated with preterm birth; the risk of major disability increases with decreasing gestational age.
The epidemiology and risk factors for long-term NDI among survivors of preterm birth will be reviewed here. Issues related to follow-up care for preterm infants, including neurodevelopmental surveillance and early intervention, are discussed separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention" and "Care of the neonatal intensive care unit graduate".)
Other outcomes (mortality, short-term complications, and other long-term complications) are discussed separately:
●(See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality".)
●(See "Short-term complications of the preterm infant".)
●(See "Long-term outcome of the preterm infant".)
DEFINITIONS
Preterm birth — Degrees of preterm birth are typically defined by birth weight (BW) or gestational age (GA); the definitions are provided in the table (table 1).
Neurodevelopmental impairment (NDI) — The term NDI is a composite and typically includes cognitive, motor, sensory, behavioral, and/or psychologic impairments.
Severe NDI is commonly defined in research studies as the presence of any of the following:
●Cognitive delay based on scores on standardized cognitive tests that are 2 standard deviations (SD) below the mean. As an example, this would correspond to a score of ≤70 on the Mental Developmental Index of the Bayley Scales of Infant Development.
●Moderate to severe cerebral palsy (CP) defined as a score of ≥2 on the Gross Motor Function Classification System (GMFCS).
●Bilateral hearing deficit/loss requiring amplification.
●Severe visual impairment with visual acuity of 20/200 or less in the better-seeing eye with best conventional correction (definition of legal blindness).
In addition, behavioral, psychological, and functional outcomes are increasingly being recognized as important long-term neurodevelopmental outcomes and will be discussed within this review.
LIMITATIONS OF THE DATA — Interpretation of the neonatal outcomes literature is challenging because of differences in clinical practice (particularly in providing active treatment for periviable infants), study design (study population, evaluation tools, and outcomes measured), and changes in perinatal care over time. The challenge was illustrated in an analysis of three systematic reviews, which identified 107 different cohorts, but the individual studies varied considerably such that only eight cohorts were included in all three reviews [1].
Differences in study design
●Study population – Differences in defining the study population make it challenging to compare data from different studies.
•Birth weight (BW) classification versus gestational age (GA) can be problematic, as the population may include relatively more mature infants with intrauterine growth retardation (IUGR) within a given BW category. Outcome results may be impacted if there are a significant number of patients with IUGR because these infants have a greater risk of neonatal morbidities and poorer outcomes compared with their appropriate gestational age (AGA) counterparts, but typically have better outcomes compared with more preterm infants at equivalent BW [2] (see "Infants with fetal (intrauterine) growth restriction"). As dating techniques have improved, GA classifications have become predominant. Although GA groupings may allow for inclusion of large and small for GA infants in the same group, groups defined by this method are more likely to be at similar embryologic/fetal development stages than classification based on BW. As a result, GA classification is more commonly used in reporting of long-term outcome of preterm infants.
•Outborn versus inborn infants – Morbidity and mortality appear to be worse for preterm infants born at a center without a tertiary neonatal intensive care unit (NICU) requiring neonatal transport compared with inborn infants who do not require transfer [3,4]. In particular, infants with physiological instability during transport are at risk for significant neurodevelopmental impairment (NDI) and mortality [5]. Therefore, the mix of inborn and outborn infants between studies may impact on survival and long-term outcome.
●Definitions of outcome measures – Differing definitions of outcome, particularly the definition of severe NDI, alter results [6,7]. This was illustrated in an analysis of the database for preterm infants (GA 23 to 28 weeks) from the Canadian Neonatal Follow-up Network that reported the incidence of severe NDI ranged from 3.5 to 14.9 percent depending on the definition used for severe NDI [6]. NDI is commonly defined as having at least one of the following: cognitive or motor test scores more than 2 standard deviations below the mean; bilateral hearing loss that is not responsive to amplification; bilateral legal blindness; and moderate, severe, or profound cerebral palsy.
●Evaluation methods – There is variability in the evaluation tools used to assess outcomes in studies and results may not be directly comparable. For example, several studies have shown that results from the third edition of Bayley Scales of Infant Development (BSID III, 2006) resulted in higher cognitive scores than the 2nd edition (1992) [8-11]. It remains unclear whether Bayley III overestimates cognitive performance in comparison or is a more valid assessment of cognitive function than Bayley II. The Bayley IV edition was released in September 2019, but there are to date no studies that compare the Bayley IV with previous versions in assessing preterm survivors.
●Subsequent confounding factors – Subsequent factors that may affect neurodevelopmental development and school readiness include sociodemographic factors (eg, maternal education), household income (eg, Medicaid insurance as a marker of poverty), ongoing health issues, and participation in early intervention programs. The presence of these factors may vary, making it challenging to compare results from different studies. (See "School readiness for children in the United States", section on 'Factors related to a child's ability to learn'.)
Impact of improved survival — For extremely preterm (EPT; GA <28 weeks) infants, overall survival has improved dramatically as result of improved perinatal and neonatal care [12]. However, survival without NDI among EPT infants has not improved at the same pace as overall survival. This is because many surviving infants, particularly those at the limits of viability, have neurodevelopmental sequelae.
Data are inconsistent regarding whether neurodevelopmental outcomes for preterm infants have improved with advances in perinatal care. Some studies reported improved neurodevelopmental outcomes in later era cohorts (eg, infants born after 2005) compared with earlier cohorts (eg, infants born in the 1990s) [13-21], others did not find a difference [22,23]. Conflicting results may be explained by differences in GA, as discussed below. (See 'Risk of NDI by gestational age' below.)
Changes in practice over time — Observed changes in practices over time are felt to be major contributors to both improved neonatal survival and possibly neurodevelopmental outcome [12-16,24]. As a result, comparisons between birth cohort eras should be interpreted with caution. This is of particular importance when comparing adult prematurity outcomes with more recent birth cohorts because management of an EPT infant in the modern era is considerably different compared with an infant born in the 1990s.
In addition, there are variations in outcome across regions that persist after adjusting for known population, maternal, and infant factors [25,26]. Further work is needed to understand the impact of practice variation and regional disparities on outcomes.
Active treatment for periviable infants — Periviability refers to the earliest stage of fetal maturity wherein there is reasonable, though not high, chance of extrauterine survival (generally defined as GA between 22 and <26 weeks). There are global and regional differences in the level of initial care provided to periviable infants [27-29]. These differences in clinical practice impact survival neurodevelopmental outcomes (table 2A-B). As a result, it is challenging to compare survival and neurodevelopmental outcomes from studies that may differ in their approach to resuscitation for periviable infants and to interpret these data as it applies to individual patients. (See "Periviable birth (limit of viability)", section on 'Outcomes'.)
Issues regarding interpreting the data for periviable infants are discussed in greater detail separately. (See "Periviable birth (limit of viability)", section on 'Limitations of the data'.)
Specific interventions — Advances in perinatal and neonatal care have improved outcomes for preterm infants either directly or indirectly (by reducing associated complications such as periventricular-intraventricular hemorrhage [PIVH]). Examples include:
●Antenatal corticosteroid therapy, which is associated with reduced need for mechanical ventilation, reduced rates of risk of severe PIVH, and improved survival without NDI, including reduced rates of moderate to severe cerebral palsy (CP) [30,31]. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Evidence of efficacy'.)
●Limiting postnatal corticosteroid therapy, which may impact neurodevelopmental outcome [32-34]. The long-term effect of postnatal use of corticosteroid therapy is discussed in greater detail separately. (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)
●Advances in neonatal ventilation, particularly increased use of noninvasive modalities (eg, continuous positive airway pressure [cPAP]), which has improved survival and reduced morbidity (eg, bronchopulmonary dysplasia [BPD], severe PIVH, and pulmonary air leak), which may impact neurodevelopmental outcome. (See 'Comorbid conditions' below and "Overview of mechanical ventilation in neonates" and "Outcome of infants with bronchopulmonary dysplasia", section on 'Neurodevelopment outcome' and "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Prevention, management, and complications", section on 'Long-term outcome' and "Pulmonary air leak in the newborn".)
●Surfactant, which has been associated with increased survival, especially for extremely preterm infants. However, surfactant therapy has not been directly associated with improved neurodevelopment outcome. (See "Prevention and treatment of respiratory distress syndrome in preterm infants".)
●Antenatal magnesium sulfate, which has been associated with decreased risk of CP and severe motor dysfunction. Clinical trials have shown that preterm infants whose mothers receive magnesium sulfate have a lower risk of CP and severe motor dysfunction compared with nonexposed infants. (See "Neuroprotective effects of in utero exposure to magnesium sulfate", section on 'Evidence of efficacy from randomized trials and meta-analyses'.)
Ineffective preventive measures — Previous observational data had suggested prophylactic administration of recombinant erythropoietin (EPO) was neuroprotective, however, multicenter trials have reported no benefit in improved neurodevelopmental outcome. As a result, EPO should not be given prophylactically as a neuroprotective agent.
●In a multicenter trial of 941 EPT infants, infants assigned to recombinant erythropoietin (EPO) and placebo had similar rates of the primary outcome of death or severe neurodevelopmental outcome (defined as severe cerebral palsy or a composite motor or cognitive score of less than 70 on the Bayley Scales of Infant and Toddler Development, 3rd Edition) at 22 to 26 months postmenstrual age (26 versus 26 percent, relative risk 1.03, 95% CI 0.81 to 1.32) [35]. In this trial, placebo or EPO (dose of 1000 U/kg of body weight) was given within 24 hours after birth and every 48 hours for a total of six doses. The EPO and placebo groups also had similar rates of retinopathy of prematurity, intracranial hemorrhage, BPD, necrotizing enterocolitis, death or frequency of serious adverse effects. A subsequent report also found the two groups had similar brain magnetic resonance imaging (MRI) findings at term equivalent, which correlated with neurodevelopmental outcome as assessed by the Bayley Scales [36].
●In a multicenter study of 448 preterm infants (GA between 26 weeks and 31 weeks and 6 days), prophylactic EPO compared with placebo did not improved neurodevelopmental outcome at 2 and 5 years of age [37,38].
RISK OF NDI BY GESTATIONAL AGE — The risk of NDI increases with decreasing gestational age (GA) and birth weight (BW) [30,39-49].
The following sections review neurodevelopmental outcomes for survivors based on GA categories.
Periviable infants — Neurodevelopmental outcomes for infants born between 22 to 25 weeks GA are summarized in the table (table 2B) and discussed detail separately. (See "Periviable birth (limit of viability)", section on 'Neurodevelopmental outcome'.)
Extremely preterm infant — Among extremely preterm (EPT; GA <28 weeks) and/or extremely low birth weight (ELBW; birth weight <1000 g) infants, the likelihood of surviving without NDI decreases with decreasing GA (table 2B). For EPT survivors, impairments in cognition, motor function, vision, and/or hearing are common, may be severe, and can persist into school age and adulthood [50]. (See 'Outcomes in adulthood' below.)
The following is a summary of the outcomes we discuss with parents and care providers of EPT infants based upon the available literature. As noted above, synthesizing the information is challenging due to differences in study design and differences between older and more recent birth cohorts. (See 'Limitations of the data' above.)
●Major disability – Approximately 15 to 25 percent of surviving EPT infants have major disability (ie, severe NDI), defined as any of the following, when evaluated at 18 to 24 months corrected age; the relative frequencies for each type of disability are as follows [12,20,21,51]:
•Significant cognitive and/or motor impairment (ie, a score >2 standard deviations below the mean on a standardized test) – 10 to 15 percent
•Cerebral palsy (CP) - 6 to 12 percent
•Hearing loss requiring amplification devices – 1 to 3 percent
•Blindness – 1 to 2 percent
Infants with severe NDI at 18 to 24 months are likely to have persistent disability throughout childhood [52], however, some may have improvement in cognitive function [53]. Infants with milder disability are more likely to improve as they age.
Neurodevelopmental outcome is assessed more accurately at school age than in early childhood because there may be cognitive recovery over time as the brain continues to develop and/or the assessment tools used at two years of life are not as accurate in assessing cognition [52,54,55]. In one cohort of 802 surviving EPT infants born between 2002 and 2004, neurodevelopmental status at age 10 years improved in 27 percent, worsened in 5 percent, and remained unchanged in 67 percent compared with assessments performed at age 2 years [53]. Of note, one-third of individuals who were initially classified as having severe NDI improved to a milder degree of disability by age 10 years. Other studies evaluating EPT survivors at school age (ie, 6 to 10 years of age) reported rates of severe NDI ranging from 13 to 21 percent [52,56-58]. In a prospective cohort study of 486 surviving EPT infants born between 2004 to 2007 who were evaluated at 6.5 years of age, 36 percent had no disability, 30 percent had mild disability, 20 percent had moderate disability, and 13 percent had severe disability [58].
The estimates presented above are based upon data from cohorts of EPT infants born after 2005. Earlier cohorts reported higher rates of major disability (as high as 30 percent) [20,21].
●Learning disability and need for specialized educational intervention and services – Children born EPT are more likely to have learning difficulties in reading and mathematics and have lower teacher ratings [59-62]. These children often need additional educational intervention and special services [60,63].
●Adult outcome – Data on adult outcomes for EPT infants are limited. In one report of a birth cohort from 1995, 60 percent of individuals at nineteen years of age had at least one impairment in general cognitive functioning and visuomotor abilities, and a third had deficits in four or more domains [64]. Cognitive impairment was observed in 45 percent of EPT adults compared with 3 percent of controls. (See 'Outcomes in adulthood' below.)
Very preterm infant — The risk of severe NDI among very preterm (VPT, GA 28 to <32 weeks) or very low birth weight (VLBW) infants (BW <1500 g) infants is less than that of EPT or ELBW survivors. However, approximately 30 to 40 percent of VPT infants have some degree of NDI [21,63,65-72]. The findings in studies of VLBW infants may differ because the relative proportion of ELBW patients within each cohort varies. (See 'Differences in study design' above.)
In a prospective cohort of 441 VPT infants born in 1997, 36 percent had neurodevelopmental disabilities and 30 percent used special healthcare resources (eg, physiotherapy, speech therapy, occupational therapy, psychologist, and psychiatrist) at five years of age [63]. Even children without moderate or severe neurologic disabilities at discharge remained at risk for global developmental delay and discrepancies in academic achievement compared with full-term controls [65,66]. Risk factors for impaired outcome included lower GA at birth, presence of cerebral lesions on brain imaging, being born with intrauterine growth failure, lack of breastfeeding, and low parental socioeconomic status. In a subsequent cohort of infants born in 2011, 4.2 percent of infants born at 27 to 31 weeks of gestation had cerebral palsy (CP) and 41 percent had developmental delay at two years of age [21].
In a meta-analysis of individual participant data from eight birth cohorts of 2135 adults, individuals who were born very preterm or very low birth weight had lower intelligence quotient (IQ) scores than those born at term [73]. After adjusting for sex, maternal education, and excluding those with neurosensory impairment, mean IQ Z-scores were -0.65 standard deviation (95% CI -0.76 to -0.55 SD), which is equivalent to 9.8 IQ points. Other studies have reported VPT school-age children have poorer scores in memory and are more likely to have academic difficulties than those children born at term [49,71,74].
Moderate to late preterm infants — Moderate (GA between 32 and 33 6/7 weeks) and late preterm infants (GA between 34 and less than 37 weeks) are more likely to have long-term neurodevelopmental impairment compared with full-term infants [75]. Longitudinal international studies of moderate to late preterm infants from around the world have reported the following neurodevelopmental impairment based on age at assessment [76-84]:
●Two years of age – Poor cognitive testing, neuropsychological functioning and neurosensory impairment [76,84,85]
●Preschool – Developmental delay at preschool age based on parent report [78]
●School age – Poor cognitive testing, need for special educational services, and lower than expected grade level achievement on academic test or in teacher assessments [77,80,81,86-88]
A more complete discussion on the long-term neurodevelopmental outcome of late preterm infants (GA between 34 and 36 weeks) is presented separately. (See "Late preterm infants", section on 'Neurodevelopmental outcome'.)
RISK FACTORS FOR NDI — As discussed in the previous section, gestational age (GA) is one of the most important factors in determining risk of NDI in preterm infants.
Additional risk factors include male sex, twin pregnancy, congenital malformations, comorbid neonatal conditions, socioeconomic factors, and lack of adequate antenatal care [43,72,73,89,90]. These are summarized in the following sections. The approach to assessing risk of NDI in preterm infants is discussed in greater detail separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention", section on 'Identifying at-risk infants' and "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention", section on 'Tools'.)
Environmental factors — Although the association between preterm birth and NDI is well established, far less is known about the role of environment and experience in moderating the association. Several studies have reported that certain environmental factors (eg, higher maternal education level, parental interventions, home environment, daycare environment) have beneficial effects on cognition, speech, and language development [91-96]. Similarly, adverse early childhood experiences may negatively impact neurodevelopmental outcomes. In particular, there is an increased risk for cognitive delay at two years of age for infants who are discharged from the hospital with child protection service supervision [97].
Studies evaluating neurodevelopmental outcomes in preterm infants often attempt to control for some of these confounding factors (particularly maternal education level); however, it may be challenging to adequately control for all relevant environmental variables. (See 'Limitations of the data' above.)
Comorbid conditions — The risk of NDI is increased in preterm infants who have any of the following comorbidities:
●Bronchopulmonary dysplasia (BPD) [51,98,99]. (See "Outcome of infants with bronchopulmonary dysplasia", section on 'Neurodevelopment outcome'.)
In addition, postnatal use of glucocorticoids to treat BPD is associated with an increased risk of cerebral palsy (CP). (See "Prevention of bronchopulmonary dysplasia: Postnatal use of corticosteroids".)
●Perinatal infections, including [51,100,101]:
•Necrotizing enterocolitis (NEC) (see "Neonatal necrotizing enterocolitis: Management", section on 'Growth')
•Sepsis (see "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Morbidity')
•Meningitis (see "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Outcome')
●Retinopathy of prematurity (ROP). (See "Retinopathy of prematurity: Pathogenesis, epidemiology, classification, and screening".)
●Intraventricular hemorrhage (IVH). (See "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Prevention, management, and complications", section on 'Outcome'.)
●Fetal growth restriction. (See "Infants with fetal (intrauterine) growth restriction", section on 'Neurodevelopment'.)
●Poor postnatal growth – In very preterm infants, growth impairment, including poor head growth, has been associated with impaired cognitive and motor performance [102-104]. In for extremely low birth weight (ELBW) infants, better weight gain during neonatal intensive care unit (NICU) hospitalization is associated with reduced risk of CP and better scores on cognitive testing at 18 to 22 months corrected age [105].
●Congenital anomalies – Preterm survivors with congenital anomalies are more likely to have a cognitive impairment and motor and neurosensory deficits [106].
●Twin gestation for ELBW infants [107]. Similar data on higher order gestation are not available.
●Surgical procedures during birth hospitalization [108].
Care factors — The risk of NDI is increased in preterm infants born to mothers without adequate prenatal and perinatal care (eg, lack of antenatal corticosteroids). (See 'Specific interventions' above.)
OTHER NEURODEVELOPMENTAL SEQUELAE
Structural brain injury — Preterm survivors with severe neonatal brain injury, defined as abnormalities detected by head ultrasound, have the most severe neurodevelopment impairment (eg, requiring additional school services and major disability with motor, cognitive, or neurosensory impairments [such as CP]) [109-112]. Neonatal brain injury may also be associated with increased risk for psychiatric disorders (eg, major depression and obsessive-compulsive disorder [OCD]) in adolescence [113].
Subsequent structural brain changes in former preterm infants have been documented by magnetic resonance imaging at school age, adolescence, and adulthood. These include thinning of the corpus callosum, decreased brain volume, increased ventricular volume, and abnormal white matter development [114-124].
Speech and language delays — Speech and language impairments are common among preterm survivors, with risk and severity inversely proportional to GA. Delays may be observed in acquisition of expressive and/or receptive language, and articulation [9,91,125-127]. There is evidence of partial preterm catch-up in speech language functions compared with term controls, which increases with environmental factors such as maternal level of education [91,92]. Language outcomes are related to cognitive function, hearing, prenatal and postnatal socioeconomic status, environment, ethnicity, and structural changes at the level of the larynx related to prior intubation [127-130]. (See "Evaluation and treatment of speech and language disorders in children".)
Behavioral and mental health problems — Children who were born preterm, especially those who were extremely or very preterm, are more likely than children born full term to have behavioral and mental health problems [131].
●Extremely preterm and very preterm infants – Children who are born extremely or very preterm are more likely than children who were born at term to have behavioral and emotional problems. A study from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network of extremely preterm infants (gestational age <27 weeks) born between 2008 and 2012 reported one-third of the cohort had behavioral problems and one-quarter had deficits in socioemotional competence at 18 to 22 months corrected age [132]. Sociodemographic factors (eg, mothers with less than a high school education and lower maternal age) and deficits in cognitive and language function increase the risk of problems in behavior and socioemotional competence. However, preterm adolescent and young adult survivors tend to engage in less risky behavior and be shier than those born full term [133-137].
The following behavioral and emotional problems are more commonly observed in children and adolescents who were born extremely or very preterm compared with peers who were born full term.
•Difficulties in attention [133,137-147]
•Poor peer interaction [134,141-143,147,148]
•Hyperactivity [137,139-142,144-146,149]
•Emotional and conduct problems, including anxiety, depression, being withdrawn, and somatic complaints [133,137-139,141-143,145,146,150,151]
•Autism spectrum disorders [145,152-154]
•Psychiatric disorders [150,155,156]
●Moderate to late preterm infants – Although data are limited, moderate to late preterm infants at preschool age are at increased risk of behavioral and emotional problems compared with peers born at term based on parental assessment [157-159]. In addition, two studies have reported that children born moderate to late preterm compared with those born at term were more likely to have autism spectrum disorder, though recognized limitations include the changes between DSM-IV and DSM-5 [154,160].
Functional disabilities — School-age children who were extremely or very preterm have a greater risk for functional disabilities that impact on completing daily activities and quality of life compared with peers born at term. These may be subtle deficits that include problems with motor coordination (developmental coordination disorder, also referred to as noncerebral palsy motor impairment) [161,162], social interactive skills, and executive function (working memory, problem-solving, planning, and organization) [68,86,147,163-167]. The risk for functional disabilities increases with decreasing gestational age (GA) and is reported to occur in 40 percent of children born before 26 weeks gestation [59,68]. In some affected individuals, these deficits may contribute to academic, motor, and behavioral outcomes. (See "Developmental coordination disorder: Clinical features and diagnosis".)
OUTCOMES IN ADULTHOOD
Disabilities — In former preterm infants, the risk of adulthood medical and social disabilities increases with decreasing gestational age (GA).
Several studies have reported lower rates of educational achievement, independent living, lower net income, and permanent employment in preterm adult survivors compared with those born full term [168-173]. These results are most likely due to poor cognitive skills leading to impaired learning, especially in adults with birth weights (BW) below 1500 g or GA below 32 weeks, and increased risk of medical disabilities (cerebral palsy [CP], psychiatric and behavioral disorders, and physical disability) [168,174-176]. Higher socioeconomic status appears to decrease the effect of GA upon cognitive test scores [174].
In contrast, other studies suggest that despite their increased risk of neurodevelopmental disability, adults who were born preterm may overcome these difficulties and become functional young adults at a comparable rate to those who were born full term. These studies report similar rates of high school graduation, pursuit of postsecondary education, employment, independent living, marriage, and parenthood [177,178]. Differences in outcome among these studies have been attributed to higher socioeconomic status of the study population, an increase in educational support, or benefit from a national healthcare system [179].
Quality of life — Young adults who were born preterm and their parents report a greater prevalence and complexity of functional limitations than controls born at term and their parents/caregivers [180]. Longitudinal studies have reported that individuals born very preterm have lower health-related quality of life based on assessment using the Health Utility Index Mark 3 questionnaire [180-183]. In one systemic review of the literature, adults born preterm were less likely to experience romantic and sexual partnerships and parenting [184]. Nevertheless, in several studies, preterm adults and their families report a satisfactory quality of life similar to those who are born at term [185-189].
In addition, patients and their parents have a better perception of their quality of life than healthcare professionals [190]. As a result, it is important for healthcare providers to be aware of this discrepancy so that they do not only focus narrowly on neurodevelopmental disabilities of their patients but broaden their consideration of outcome to include the ability of adult survivors to overcome their limitations with a positive self-perception of their quality of life [177,191,192].
SUMMARY AND RECOMMENDATIONS
●Definition – Neurodevelopmental impairment (NDI) is a composite term that includes cognitive, motor, sensory, behavioral, and/or psychologic impairments. (See 'Definitions' above.)
Severe NDI is generally defined as having any of the following:
•Significant cognitive and/or motor impairment (ie, a score >2 standard deviations below the mean on a standardized test)
•Cerebral palsy (CP)
•Hearing loss requiring amplification devices
•Blindness
●Risk of NDI in preterm infants – Individuals born preterm are at increased risk for NDI compared with those born at term. The risk of NDI increases with decreasing gestational age (GA) (see 'Risk of NDI by gestational age' above):
•Periviable infants (GA 22 to 25 weeks) – Neurodevelopmental outcomes for infants born between 22 to 25 weeks GA are summarized in the table (table 2B) and discussed detail separately. (See "Periviable birth (limit of viability)", section on 'Neurodevelopmental outcome'.)
•Extremely preterm infants (EPT, GA <28 weeks) – For EPT survivors, NDI is common, may be severe, and can persist into school age and adulthood. Severe disability is seen in approximately 15 to 25 percent of surviving EPT infants; mild to moderate disability is seen in an additional 40 to 50 percent. (See 'Extremely preterm infant' above.)
•Very preterm infants (VPT, GA 28 to <32 weeks) – Approximately 30 to 40 percent of VPT infants have some degree of NDI; however, severe NDI is less common in VPT infants compared with EPT infants. (See 'Very preterm infant' above.)
•Moderate (GA between 32 and 33 6/7 weeks) and late preterm infants (GA between 34 and less than 37 weeks) – Infants in these categories are more likely to have long-term NDI compared with full-term infants; however, severe NDI is uncommon unless there are other risk factors. (See 'Moderate to late preterm infants' above and "Late preterm infants", section on 'Neurodevelopmental outcome'.)
●Risk factors for NDI – Risk factors for NDI include GA, twin pregnancy, male sex, congenital malformations, comorbid neonatal conditions, socioeconomic factors, and lack of adequate antenatal care. (See 'Risk factors for NDI' above.)
●Other neurodevelopmental sequelae – In addition to the disabilities discussed above, individuals born preterm commonly experience the following problems (see 'Other neurodevelopmental sequelae' above):
•Speech and language delays, including delays in acquisition of expressive and/or receptive language, and articulation. (See 'Speech and language delays' above.)
•Behavioral and emotional problems, including attention deficit hyperactivity disorder (ADHD), difficulty in peer interactions, general anxiety and depression, and autism spectrum disorder. (See 'Behavioral and mental health problems' above.)
•Functional disabilities, including problems of motor coordination, social skills, and executive function that impact managing daily activities. (See 'Functional disabilities' above.)
●Outcomes in adulthood – Adults who were born preterm are more likely to have medical and social disabilities compared with those born full term. Nevertheless, many report that they have a satisfactory quality of life similar to those who were born at term. (See 'Outcomes in adulthood' above.)
●Limitations of the data – Interpretation of data on long-term outcomes in preterm infants is challenging because of differences in clinical practice (particularly in providing active treatment for periviable infants), study design (study population, evaluation tools, and outcomes measured), and changes in perinatal care over time. These factors should be considered when using the data to inform decision-making in clinical practice. (See 'Limitations of the data' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Yvette Johnson, MD, MPH, who contributed to an earlier version of this topic review.
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33 : Policy statement--postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia.
34 : Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants.
35 : A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.
36 : Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.
37 : Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial.
38 : Neurodevelopmental Outcomes at Age 5 Years After Prophylactic Early High-Dose Recombinant Human Erythropoietin for Neuroprotection in Very Preterm Infants.
39 : Academic performance of children born preterm: a meta-analysis and meta-regression.
40 : The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability.
41 : Survival of very preterm infants: Epipage, a population based cohort study.
42 : Intensive care for extreme prematurity--moving beyond gestational age.
43 : Unimpaired outcomes for extremely low birth weight infants at 18 to 22 months.
44 : Prediction of neurodevelopmental and sensory outcome at 5 years in Norwegian children born extremely preterm.
45 : Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden.
46 : Visual and Hearing Impairments After Preterm Birth.
47 : Academic Outcomes of School-Aged Children Born Preterm: A Systematic Review and Meta-analysis.
48 : Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study.
49 : Gestational age at birth and child special educational needs: a UK representative birth cohort study.
50 : School-aged neurodevelopmental outcomes for children born extremely preterm.
51 : Determinants of developmental outcomes in a very preterm Canadian cohort.
52 : Neurologic and developmental disability at six years of age after extremely preterm birth.
53 : Changes in Neurodevelopmental Outcomes From Age 2 to 10 Years for Children Born Extremely Preterm.
54 : Change in cognitive function over time in very low-birth-weight infants.
55 : Predicting School-Aged Cognitive Impairment in Children Born Very Preterm.
56 : Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years.
57 : Changes in long-term prognosis with increasing postnatal survival and the occurrence of postnatal morbidities in extremely preterm infants offered intensive care: a prospective observational study.
58 : Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden.
59 : Neurodevelopmental disability through 11 years of age in children born before 26 weeks of gestation.
60 : Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.
61 : Learning problems in kindergarten students with extremely preterm birth.
62 : Educational Performance of Children Born Prematurely.
63 : Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study.
64 : Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm Birth.
65 : Neurodevelopment of children born very preterm and free of severe disabilities: the Nord-Pas de Calais Epipage cohort study.
66 : Predictors of the risk of cognitive deficiency in very preterm infants: the EPIPAGE prospective cohort.
67 : Adverse neurodevelopmental outcome in preterm infants: risk factor profiles for different gestational ages.
68 : Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children.
69 : Motor development in very preterm and very low-birth-weight children from birth to adolescence: a meta-analysis.
70 : Cognitive outcomes in children and adolescents born very preterm: a meta-analysis.
71 : Association of Gestational Age With Verbal Ability and Spatial Working Memory at Age 11.
72 : Prognostic Factors for Poor Cognitive Development in Children Born Very Preterm or With Very Low Birth Weight: A Systematic Review.
73 : Association of Very Preterm Birth or Very Low Birth Weight With Intelligence in Adulthood: An Individual Participant Data Meta-analysis.
74 : Academic trajectories of very preterm born children at school age.
75 : Neighborhood Disadvantage and Early Respiratory Outcomes in Very Preterm Infants with Bronchopulmonary Dysplasia.
76 : Neurodevelopmental outcomes following late and moderate prematurity: a population-based cohort study.
77 : Functioning at school age of moderately preterm children born at 32 to 36 weeks' gestational age.
78 : Developmental delay in moderately preterm-born children at school entry.
79 : Developmental delay in moderately preterm-born children with low socioeconomic status: risks multiply.
80 : Early school attainment in late-preterm infants.
81 : Long-term cognitive outcomes of infants born moderately and late preterm.
82 : ADHD and learning disabilities in former late preterm infants: a population-based birth cohort.
83 : Late Preterm Infants and Neurodevelopmental Outcomes at Kindergarten.
84 : Association Between Moderate and Late Preterm Birth and Neurodevelopment and Social-Emotional Development at Age 2 Years.
85 : Gestational age and developmental risk in moderately and late preterm and early term infants.
86 : Functioning of 7-year-old children born at 32 to 35 weeks' gestational age.
87 : School performance at age 7 years in late preterm and early term birth: a cohort study.
88 : Short-Term and Long-Term Educational Outcomes of Infants Born Moderately and Late Preterm.
89 : Characteristics of extremely low-birth-weight infant survivors with unimpaired outcomes at 30 months of age.
90 : Antenatal antecedents of cognitive impairment at 24 months in extremely low gestational age newborns.
91 : Language Trajectories of Children Born Very Preterm and Full Term from Early to Late Childhood.
92 : Evidence for catch-up in cognition and receptive vocabulary among adolescents born very preterm.
93 : Association of Socioeconomic Status and Brain Injury With Neurodevelopmental Outcomes of Very Preterm Children.
94 : Effects of sensitive parenting on the academic resilience of very preterm and very low birth weight adolescents.
95 : Does HOME add to the prediction of child intelligence over and above SES?
96 : Do effects of early child care extend to age 15 years? Results from the NICHD study of early child care and youth development.
97 : Developmental Outcomes of Extremely Preterm Infants with a Need for Child Protective Services Supervision.
98 : Chronic lung disease and developmental delay at 2 years of age in children born before 28 weeks' gestation.
99 : Cognitive Outcomes of Children Born Extremely or Very Preterm Since the 1990s and Associated Risk Factors: A Meta-analysis and Meta-regression.
100 : Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis.
101 : Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants.
102 : Growth impairment in the very preterm and cognitive and motor performance at 7 years.
103 : Growth and development in children born very low birthweight.
104 : Head growth trajectory and neurodevelopmental outcomes in preterm neonates
105 : Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants.
106 : Major congenital anomalies place extremely low birth weight infants at higher risk for poor growth and developmental outcomes.
107 : Twin gestation and neurodevelopmental outcome in extremely low birth weight infants.
108 : Early surgery and neurodevelopmental outcomes of children born extremely preterm.
109 : Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age.
110 : Functional outcome at school age of preterm infants with periventricular hemorrhagic infarction.
111 : Brain injury in very preterm children and neurosensory and cognitive disabilities during childhood: the EPIPAGE cohort study.
112 : Cerebellar hemorrhage: a major morbidity in extremely preterm infants.
113 : Neonatal head ultrasound abnormalities in preterm infants and adolescent psychiatric disorders.
114 : Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis.
115 : Decreased regional brain volume and cognitive impairment in preterm children at low risk.
116 : Segmental brain volumes and cognitive and perceptual correlates in 15-year-old adolescents with low birth weight.
117 : Longitudinal brain volume changes in preterm and term control subjects during late childhood and adolescence.
118 : Grey and white matter distribution in very preterm adolescents mediates neurodevelopmental outcome.
119 : Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: an investigation of group and gender effects.
120 : Effects of very low birthweight on brain structure in adulthood.
121 : Corpus callosum size and very preterm birth: relationship to neuropsychological outcome.
122 : Brain volume reductions within multiple cognitive systems in male preterm children at age twelve.
123 : Brain volumes in adult survivors of very low birth weight: a sibling-controlled study.
124 : Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T1-w/T2-w Ratio.
125 : Language functions in preterm-born children: a systematic review and meta-analysis.
126 : Effect of ethnicity and race on cognitive and language testing at age 18-22 months in extremely preterm infants.
127 : Predicting the outcome of specific language impairment at five years of age through early developmental assessment in preterm infants.
128 : Dysphonia in very preterm children: a review of the evidence.
129 : Laryngeal pathology at school age following very preterm birth.
130 : Language Skills in Children Born Preterm (<30 Wks' Gestation) Throughout Childhood: Associations With Biological and Socioenvironmental Factors.
131 : Childhood and adolescent mental health of NICU graduates: an observational study.
132 : Behavioral Problems and Socioemotional Competence at 18 to 22 Months of Extremely Premature Children.
133 : Behavioral outcomes and evidence of psychopathology among very low birth weight infants at age 20 years.
134 : Social lifestyle, risk-taking behavior, and psychopathology in young adults born very preterm or with a very low birthweight.
135 : Shyness and timidity in young adults who were born at extremely low birth weight.
136 : Self-reported adolescent health status of extremely low birth weight children born 1992-1995.
137 : Mental health of extremely low birth weight survivors in their 30s.
138 : Rates and Stability of Mental Health Disorders in Children Born Very Preterm at 7 and 13 Years.
139 : Biological and environmental predictors of behavioral sequelae in children born preterm.
140 : Preterm birth and attention-deficit/hyperactivity disorder in schoolchildren.
141 : Pervasive behavior problems at 6 years of age in a total-population sample of children born at</= 25 weeks of gestation.
142 : Mental health and social competencies of 10- to 12-year-old children born at 23 to 25 weeks of gestation in the 1990s: a Swedish national prospective follow-up study.
143 : Behavioral problems and cognitive performance at 5 years of age after very preterm birth: the EPIPAGE Study.
144 : Preterm Birth and Poor Fetal Growth as Risk Factors of Attention-Deficit/ Hyperactivity Disorder.
145 : Mental Health in Children Born Extremely Preterm Without Severe Neurodevelopmental Disabilities.
146 : Behavioral Patterns in Adolescents Born at 23 to 25 Weeks of Gestation.
147 : Quality of life of extremely preterm school-age children without major handicap: a cross-sectional observational study.
148 : Origins and Predictors of Friendships in 6- to 8-Year-Old Children Born at Neonatal Risk.
149 : Attention-Deficit/Hyperactivity Disorder and Very Preterm/Very Low Birth Weight: A Meta-analysis.
150 : The risk of psychiatric disorders in individuals born prematurely in Denmark from 1974 to 1996.
151 : Self-Reported Mental Health Problems Among Adults Born Preterm: A Meta-Analysis.
152 : Autism spectrum disorders in extremely preterm children.
153 : Positive screening on the Modified Checklist for Autism in Toddlers (M-CHAT) in extremely low gestational age newborns.
154 : Preterm or Early Term Birth and Risk of Autism.
155 : Psychiatric morbidity in adolescents and young adults born preterm: a Swedish national cohort study.
156 : Psychiatric Symptoms: Prevalence, Co-occurrence, and Functioning Among Extremely Low Gestational Age Newborns at Age 10 Years.
157 : Higher rates of behavioural and emotional problems at preschool age in children born moderately preterm.
158 : Patterns of functioning and predictive factors in children born moderately preterm or at term.
159 : Differentiating the Preterm Phenotype: Distinct Profiles of Cognitive and Behavioral Development Following Late and Moderately Preterm Birth.
160 : Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age.
161 : Developmental coordination disorder in school-aged children born very preterm and/or at very low birth weight: a systematic review.
162 : Risk for developmental coordination disorder correlates with gestational age at birth.
163 : Development of executive function and attention in preterm children: a systematic review.
164 : Executive function in adolescents born<1000 g or<28 weeks: a prospective cohort study.
165 : Executive Function and Academic Outcomes in Children Who Were Extremely Preterm.
166 : Trends in Executive Functioning in Extremely Preterm Children Across 3 Birth Eras.
167 : Executive functioning in low birth weight children entering kindergarten.
168 : Long-term medical and social consequences of preterm birth.
169 : Outcomes in young adulthood for very-low-birth-weight infants.
170 : Health, lifestyle, and quality of life for young adults born very preterm.
171 : Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth.
172 : Socio-economic achievements of individuals born very preterm at the age of 27 to 29 years: a nationwide cohort study.
173 : Health, Wealth, Social Integration, and Sexuality of Extremely Low-Birth-Weight Prematurely Born Adults in the Fourth Decade of Life.
174 : Preterm birth, social disadvantage, and cognitive competence in Swedish 18- to 19-year-old men.
175 : Slower reaction times and impaired learning in young adults with birth weight<1500 g.
176 : Preterm Cognitive Function Into Adulthood.
177 : Transition of extremely low-birth-weight infants from adolescence to young adulthood: comparison with normal birth-weight controls.
178 : Psychological functioning and health-related quality of life in adulthood after preterm birth.
179 : Young adult attainments of preterm infants.
180 : Health-Related Quality of Life Into Adulthood After Very Preterm Birth.
181 : Health-Related Quality of Life Trajectories of Extremely Low Birth Weight Survivors into Adulthood.
182 : Changes in quality of life into adulthood after very preterm birth and/or very low birth weight in the Netherlands.
183 : Health-Related Quality of Life from Adolescence to Adulthood Following Extremely Preterm Birth.
184 : Association of Preterm Birth and Low Birth Weight With Romantic Partnership, Sexual Intercourse, and Parenthood in Adulthood: A Systematic Review and Meta-analysis.
185 : Self-perceived health status and health-related quality of life of extremely low-birth-weight infants at adolescence.
186 : Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls.
187 : Self-perceived health-related quality of life of former extremely low birth weight infants at young adulthood.
188 : Most very low birth weight subjects do well as adults.
189 : Self-perceived health, functioning and well-being of very low birth weight infants at age 20 years.
190 : Differences in preferences for neonatal outcomes among health care professionals, parents, and adolescents.
191 : What matters in the long term: reflections on the context of adult outcomes versus detailed measures in childhood.
192 : Perception of health status and quality of life of extremely low-birth weight survivors. The consumer, the provider, and the child.