Preterm birth and neurodevelopmental outcome: a review
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- Arpino, C., Compagnone, E., Montanaro, M.L. et al. Childs Nerv Syst (2010) 26: 1139. doi:10.1007/s00381-010-1125-y
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The incidence of preterm delivery and the survival rate of preterm newborns are rising, due to the increased use of assisted reproductive technology associated with multiple gestations and improved technology in obstetrics and neonatology, which allow saving preterm infants at earlier gestational ages. As a consequence, the risk of developmental disabilities in preterm children is high, and clinical pictures need to be fully defined.
Narrative review including articles regarding neurodevelopmental disorders published in the international medical literature and reported in Pub Med between the years 2000 and January 2010.
Although survival rates of extremely low birth weight infants (ELBW) significantly increased during the last decade, the substantial stability of disability trends in this population was disappointing. Late-preterm infants, who account for about 75% of all preterm births and had not been considered at risk for adverse long-term neurodevelopmental outcomes in the past, are now reconsidered as more likely to develop such events, though their risk remains lower than in ELBW.
The findings of the studies discussed in our article support the importance of early diagnosis in order to make decision about appropriate treatment of preterm infants.
KeywordsCerebral palsyDevelopmental coordination disorderVisual impairment
The incidence of preterm delivery and the survival rate of preterm newborns are rising, due to the increased use of assisted reproductive technology, which is associated with multiple gestations, and the improvement of technology in obstetrics and in neonatology, which increase the probability of saving preterm infants at earlier gestational ages [1, 2]. The survival rate of infants born at 24–25 weeks of gestation has significantly increased in 2005 compared to 1994 (36 to 47%), probably due to the improvement of neonatal intensive care; care for infants born at 22–23 weeks of gestation, instead, remains unsuccessful with death of newborns in the immediate postnatal period . In preterm newborns, prenatal, perinatal, and postnatal determinants can give rise to adverse neurological outcomes through complex causal pathways, with hypoxia/ischemia and infection/inflammation of chorial membranes apparently playing a major role . The risk of brain injury (i.e. White Matter Damage, intraventricular hemorrhage, and cortical and deep gray matter damage), and subsequent adverse clinical outcomes increases with decreasing gestational age ; however, in late-preterm infants without brain injury, alteration of cerebral maturation can be detected . In fact, early birth has an influence on brain development and timing of neurobiological processes . These processes include neuronal migration and differentiation, axon and dendrite sprouting, synapse formation, myelination, programmed cell death, and the persistence of transient structures (i.e., the subplate), which are involved in the anatomical segregation of thalamic axons from the lateral geniculate nucleus into ocular dominance columns in primary visual cortex, and in the organization of somatosensory and auditory connections; the subplate is also supposed to play a role in the guidance of corticofugal pathways . A significant proportion of brain growth, development, and networking occur approximately during the last 6 weeks of gestation .
The spectrum of clinical disabilities in preterm children is wide and is represented by cerebral palsy (CP), developmental coordination disorder (DCD), neurosensorial impairment, including peripheral and/or central hearing and visual impairments, cognitive impairment, learning disabilities, and psychiatric disorders (i.e. attention deficit hyperactivity disorder, conduct problems, and emotional symptoms).
This narrative review includes articles regarding neurodevelopmental disorders published in the international medical literature and reported in Pub Med in the last 10 years (January 1, 2000–January 31, 2010).
Keywords for search strategy were: preterm birth and neurodevelopmental outcome, and neurological outcome, and CP, and DCD, and minor neuromotor dysfunction, and developmental dyspraxia, and visual hearing deficit/impairment/disorder, and learning, and cognition, and behavior, and psychiatric, and autism, and autism spectrum disorders, and ADHD, and conduct disorders/problems, and late preterm.
Preterm birth and neurodevelopmental–neurosensorial outcomes
CP represents one of the outcomes of major concern in the very/extremely preterm (VPT/EPT) newborn. The White Matter Damage (WMD), in particular the Periventricular Leukomalacia (PVL), is the main predictor of CP that is 20–80 times more likely to appear in these infants than in full-term controls . Frequency distribution of CP in preterm often shows inconsistencies between rates found in different studies; furthermore, most studies are focused on extremely preterm/very low birth weight (VLBW) babies and fail to evaluate the other age categories. However, results from a recent meta-analysis, including 26 studies, suggest that the prevalence of CP is about 14% at 22–27 gestational age (GA), 6% at 28–31 GA and <1% at 32–36 GA. The prevalent type is represented by bilateral spastic CP, while unilateral spastic CP seems to be more prevalent in full-term infants. A relationship between severity of CP and GA has not been identified, but different definitions of severity and different assessment used in different studies (i.e., categories of mild, moderate, and severe not otherwise specified; the Gross Motor Classification System; the Griffiths locomotor quotient) could affect this result . CP prevalence among VLBW increased during the 1980s and started decreasing early in the 1990s. This decline appears to be related to a reduction in the frequency of bilateral spastic CP among infants of 1,000–1,499 g birth weight, and it is not associated with a less severe clinical profile of children presenting this form. The prevalence of unilateral spastic CP seems not to have changed significantly . The causes of the decreasing prevalence of CP in these birth weight categories are not completely clear, but improvement in neonatal care, also resulting in increased survival, is supposed to play an important role. Finally late preterms (LPT), usually considered having the same risk profile as term infants have been recently shown to be three times more likely to be diagnosed with CP than children born at term .
Preterms with diffuse WMD show about a 33% reduction in cortical and deep gray matter volume, and/or reduction in complexity of cortical folding compared to healthy full-term infants . The most involved areas seem to be basal ganglia, amygdala, thalamus, hippocampus, and brainstem . Furthermore, primary hemorrhages of the cerebellum linked to vaso-occlusive events of inferior and posterior cerebellar arteries have also been reported, because of the immaturity of the cerebellar vascular supply. A significant impairment of cerebellar growth in preterm infants, even in the absence of obvious cerebellar injury, has been demonstrated by conventional MRI studies .
Neuroimaging plays a substantial role in identifying the “non-progressive lesion or abnormality of the developing/immature brain”, which is supposed to be the neurobiological substrate of CP. MRI and the introduction of the Diffusion Weighted MRI have led to the identification, in addition to PVL with or without cystic formation, of subtle WMD (i.e., parenchymal punctuate hemorrhages) that was previously misdiagnosed by means of Cerebral Ultrasound Scan [17, 18].
Diffusion Tensor imaging (DTI), allows for the measurement of Fractional anisotropy (FA), a measure of microstructure that helps in understanding normal development or the brain response to injury [19, 20]. Diffusion tensor tractography permits to assess connectivity in preterm birth .
The adoption of a well-described and internationally shared classification system, such as that proposed by the SCPE , and the inclusion of all age categories, are mandatory to clarify the effect of GA on prevalence, type, and distribution of CP, and to correlate neuroimaging findings with clinical picture.
Developmental coordination disorder
Developmental coordination disorders (DCD)/minor neuromotor dysfunctions (MND) in preterm children stratified by gestational age (GA) and birthweight (BW)
Goyen and Lui 
IQ < 84; Other disabilities
MABC (> −1SD)a
Wocadlo and Rieger 
Neurosensory disabilities; IQ ≤ 75
Davis et al. 
CP; IQ > −2 SD
MABC (<5th centile)a
Arnaud et al.  EPIPAGE Study
IQ < 50; Neurosensory disabilities
52.3 (mild MND)
5.1 (moderate MND)
40.2 (mild MND)
3.6 (moderate MND)
40.7 (mild MND)
2.3 (moderate MND)
38.4 (mild MND)
1.9 (moderate MND)
30.8 (mild MND)
0.1 (moderate MND)
De Klein et al. 
<32 weeks/<1,500 g
MABC (<5th centile)a
Foulder-Hughes and Cooke 
MABC (<5th centile)a
Holsti et al. 
Neurosensory disabilities; CP; IQ < 85
BOMP (>− 1SD)a
The reasons for prevalence variations are probably related to the case definition used (i.e., DCD or minor neuromotor dysfunction, developmental dyspraxia), to different motor assessment, and/or to the inconsistency in cut-offs adopted to quantify motor impairment .
In fact, in the absence of gold standard to identify the disorder both in preterm and term children, the diagnosis relies on different tests, which allow to identify the main functional difficulties that affect children presenting with DCD. These difficulties can be categorized into three areas: “poor postural control (moderate hypotonia, or hypertonia, poor distal control, static, and dynamic balance), difficulty in motor learning (learning new skills, planning of movement, adaptation to change, and automatization), and poor sensorimotor coordination (coordination within/between limbs, sequencing of movement, use of feedback, timing, anticipation, and strategic planning)” .
Neural correlates of DCD are not yet known, but it may be hypothesized that this impairment is associated with diffuse white matter damage, which is common in very preterm infants . The cerebellum, basal ganglia, parietal lobe, and corpus callosum may also play a role [26, 34]. The cerebellum has an important role in motor coordination, established by both animal models and human studies [35, 36], the capacity to modify a learned motor action in response to perceived changes in environmental context (motor adaptation) is also controlled by the cerebellum. Poor motor coordination and poor motor adaptation are common in DCD. Visual-spatial processing, facial emotion recognition, and motor imagery, which are reported to be poor in children with DCD, seems to be linked to parietal lobe involvement . This finding suggests that a network of regions, including parietal lobe, may be involved in this disorder .
Visual impairments are classified into disorders of peripheral origin (refraction errors, congenital cataract, coloboma of the retina, optical atrophy or sub-atrophy, retrolental fibroplasias, and retinopathy of prematurity) and disorders of central origin (cortical visual impairment, reduction of visual acuity with normal pupillar response and negative eye examination, disturbance of motility, strabismus, nistagmus, and impairment of fixation shift). The retinopathy of prematurity (ROP) is the most frequent peripheral visual alteration in preterms . The disease is characterized by proliferation of abnormal fibrovascular tissue at the border of the vascularized and non-vascularized retina. The etiology of this disease is complex, multifactorial, and not fully understood. Retinal blood vessel development begins during the fourth month of gestation. Therefore, infants born prematurely have incompletely vascularized retinas with a peripheral avascular zone. In premature infants, normal retinal vascular growth that would occur in utero ceases, and there is loss of some of the developed vessels (phase I of ROP). With maturation of the infant, the resulting non-vascularized retina becomes increasingly metabolically active and hypoxic. The second phase of ROP, retinal neovascularization, is induced by hypoxia and occurs at about 32–34 GA. The hypoxia-induced retinal neovascularization phase of ROP is similar to other proliferative retinopathies . The strongest risk factor for ROP is low gestational age at birth. Approximately 20% of infants born before 37 weeks will develop ROP of any stage; among infants ≤34 weeks, the prevalence of any ROP is reported to be 56% . In a regional study from New South Wales, Australia, ROP was detected in 29% of examined survivors with <32 GA and in 65% of survivors born at 23–26 weeks . Retinal cryotherapy and laser photocoagulation have both proven to be successful methods for treating active ROP.
A higher prevalence, of many types of refractive error (i.e., myopia, hypermetropia, anisometropia and astigmatism) compared with that of the general population, is described . Strabismus is also reported to be very common in preterm children, with a prevalence rate ranging from 12 to 20% . Hypoxia, to whom preterms are often exposed, is associated with defect of different types of eye movement, including saccades, smooth pursuit, and convergent/divergent movements 
Cerebral Visual Impairment (CVI) is a visual abnormality due to damage of central visual pathways (retrochiasmatic visual pathways and other cerebral areas involved in perception and processing of visual stimuli) . The severity of central visual dysfunctions is related to the extension and to the localization of brain lesions, with moderate or severe lesions of basal ganglia and WMD often reported associated with abnormal visual function .
Intraventricular hemorrhage (grades I and II) is generally associated with normal visual acuity. Infants with large hemorrhages show poor acuity at term age, but this deficit tends to improve after a few months. Visual acuity is generally normal in PVL types I and II, but visual impairment becomes evident in PVL type III and is usually severe in infants with subcortical cystic leukomalacia. The incidence of low acuity in children with PVL is about 60% .
However, and surprisingly, it has been reported that very/extremely preterm infants without brain lesions, in whom visual function has been assessed by using a validated test battery, tend to show a more mature visual function than term-born infants for ocular movements, vertical and arc ocular tracking, when evaluated at term-equivalent age. To explain this finding, it has been hypothesized that extrauterine experience may accelerate the maturation of these aspects .
Up to 3% of infants born at <28 GA show some hearing deficit, ranging from conductive disorders to sensorineural hearing loss, that is about 25 times higher compared with the prevalence of hearing deficits found in the pediatric population (1.1–1.3/1,000 within 40 dB) . Gestational age-specific prevalence of hearing loss among children aged 3–10 years, from a recent nested case-control study carried out in the context of the Metropolitan Atlanta Developmental Disabilities Surveillance Program, shows a rate of 1.43% in the age category 20–23 weeks, 0.63% at 24–28 weeks, 0.19% at 29–32 weeks, and 0.1 at 33–36 weeks .
This high prevalence of hearing impairment in preterms, in particular in very low birth weight, suggests that prenatal factors responsible for the pathway leading to preterm birth and perinatal/neonatal complications may damage the auditory function and its early development. Factors increasing the risk of hearing impairment in preterm babies are heterogeneous and include: hypoxia, hyperbilirubinaemia , the use of noisy incubators, and the exposure to antibiotics that are potentially ototoxic because of life-threatening infections. One of the most important consequences of severe hearing impairment is the delay of language development that plays a crucial role in the acquisition of communication abilities and social skills . Furthermore, hearing loss in children can affect cognition, educational levels, social and emotional development, and family–child interaction. Early identification of hearing loss and appropriate intervention within the first 6 months of life have been demonstrated to prevent many of the adverse consequences and facilitate language acquisition. Protocol of neonatal hearing screening is based on a two-step system: Evoked Otoacoustic Emissions test (EOAE) followed by the Brainstem Auditory Evoked Potentials (BAEP/ABR) for all infants failing the EOAE [51, 52]. Otoacoustic emissions provide an indication of the integrity of the cochlea . BAEP provide information related to hearing system functions, starting from the cochlea up to the inferior colliculum, and information about the maturation of the immature nervous system . The lifetime cost to society of prelingual onset of profound deafness is estimated to be $1 million per subject, largely because of special education and reduced work productivity. Interventions such as cochlear implants in profoundly deaf children have a positive effect on their quality of life at reasonable costs and seem to result in a net savings to society .
Cognitive impairment (IQ < 70) stratified by gestational age (GA) and birthweight (BW)
Percent impaired (IQ < 70)
Marret et al.  EPIPAGE Study
Seitz et al. 
Farooqi et al. 
Five to Fifteen (Parent report)
Marlow et al.  EPICure Study
Hintz et al. 
Hack et al. 
Major malformations; Tuberous sclerosis, AIDS
Mikkola et al.  Finnish ELBW Cohort Study
Larroque et al.  EPIPAGE Study
Vohr et al.  Multicenter Cohort Study
Shankaran et al. 
Anderson and Doyle  Victorian Infant Collaborative Study
<28 weeks/<1,000 g
Bohm et al.  Stockholm Neonatal Project
Differences in IQ scores between preterm and full term remain after adjustment for possible confounders, such as bilingual households, teenage mothers, maternal education, and socio-economic status , suggesting that environmental factors may be implicated in the cognitive outcome, but that early disruption of brain development seems to play an important role.
Preterm birth is associated with alteration of volumes of white and gray matter and delayed or disrupted patterns of neurodevelopment may represent the neurobiological substrate of cognitive impairment .
An early indicator of impaired cognitive development in preterm infants  can be represented by maturational changes in morphology and latency recorded through Mismatch Negativity (MMN), a pre-attentive change-specific component of event-related brain potentials. In fact changes in polarity of MMN are supposed to reflect the rapid development of thalamo-cortical connections, cortical lamination, and synaptic activity in early development .
Neuropsychological disabilities persist throughout adolescence and adulthood [61, 87–89], and only 56–74% of preterm children, significantly fewer than normal birth weight teens, graduate from high school [87, 88]. Moreover, 72% of ELBW adolescents, 53% of VLBW vs. 13% of normal birth weight controls show school difficulties .
School underachievement has been reported even in those without neurosensory impairment and normal IQ . Mild abnormalities of visual processing tasks [74, 92], memory, and adaptive functioning [74, 93] common in preterm children, could influence child’s school performances .
It has been suggested that deficits in visuo-spatial performances have implication beyond pencil skills and design because of poor spatial judgement, poor orientation, and directionality .
Finally VPT/VLBW is reported to be more likely than term children to perform poorer in mathematics, reading, and spelling . Vulnerability in the preterm population in dorsal stream, a pathway that projects to magnocellular layer of Lateral Geniculate Nucleus and then to parietal cerebral cortex, also called “where system”, important in processing motion, orientation, dynamic form, and stereopsis , could represent one of the factors contributing to learning difficulties.
Very low/extremely low birth weight or very/extremely preterms are reported to be at risk for, ADHD, behavioral disorders, anxiety/depression, and Autism Spectrum Disorders (ASD) [29, 48, 57, 58, 70, 74, 76, 96–104]. Studies focusing on the relationship between preterm birth and inattention/hyperactivity are relatively few, but consistently show that attention problems are most pronounced in VPT and/or VLBW children than in controls [56, 105]. Few studies tried to investigate the proportion of Attention Deficit Disorder/ADHD [106, 107]: attention deficit disorder, without hyperactivity, seems to be more common than ADHD in LBW children. However, the scarcity of studies aimed at evaluating the DSM-IV-TR-defined subtypes (i.e. predominantly inattentive, predominantly hyperactive-impulsive, and combined type of ADHD) makes it difficult to explore the causal pathways eventually involved in preterm birth-mediated ADHD. One of the most credited pathogenetic models of ADHD is that this condition reflects a primary executive function (EF) deficit. Results from a recent meta-analysis show that verbal fluency, working memory, and cognitive flexibility are significantly poorer in children born very preterm or in VLBW than in controls . A possible explanation for this association could be that preterm birth disrupts, in some way, cortical development and brain connectivity (including cortical/subcortical circuits connecting the frontal, striatal, and thalamic regions) and that this disruption increases when GA and birth weight decrease .
Internalizing (i.e., anxious/depressed symptoms, withdrawn, and somatic complaints) and externalizing (delinquent and aggressive behavior) disorders are reported to be more common in VPT/EPT and VLBW/ELBW than in controls . However, prevalence rates vary across studies; data from meta-analysis carried out in 2002 suggest a major predominance of externalizing with respect to internalizing disorders (i.e., 75 vs. 69%) , whereas another meta-analysis found no differences between the two groups . Finally, behavioral disorders seem to remain stable during development and persist into young adulthood . The association between autism and birth weight and/or preterm birth has been evaluated in several studies leading to somewhat controversial results, because of methodologic differences, small clinic-based samples, and lack of control for confounding factors [48, 97, 99, 100, 108–110]. However, even though the magnitude of the risk varies, the direction of the association is consistent across studies. A twofold increased risk for autism, adjusted for possible confounders, has been reported in LBW and/or preterm infants [97, 99–101, 103, 111, 112]. Data from a large cohort study show that the risk is higher for LBW girls than for LBW boys and further increases in LBW girls presenting with autism associated with mental retardation or other developmental disorders; no significant association between LBW boys and autism, without developmental disorders, has been found. When considering GA categories instead of birth weight, similar results are obtained even though the strength of the association is weaker compared to that found when birth weight is used as an independent variable .
With regard to gender difference, it has been hypothesized that girls, usually at lower risk for autism than boys, could require a prenatal/perinatal insult in order to develop autism with comorbid developmental disorders . In this case, LBW or preterm birth could represent a marker of an adverse prenatal course.
Taking into account the neurobiological substrate of neurobehavioral disorders described in preterms, it is also important to consider “environmental” risk factors such as maternal distress, duration of hospitalization, and disturbance in parent–child interactions. These factors can act as “effect modifier” either increasing or decreasing the risk of neurobehavioral disorders.
Thus, in order to prevent psychiatric morbidity, more studies focused on disentangling the contribution of several risk factors to the final outcome are needed.
Late-preterm birth and clinical outcomes
LPT infants, recently defined as those born between 34 and 36 weeks of gestation , account for about 75% of all preterm births  and for about 8% of live births . They increased from 7.3% in 1990 to 9.1% in 2005  and have come to be recognized as the fastest increasing and largest proportion of singleton preterm births in the United States [113, 116]. The reason for the increase in LPT births during the last decade is not well understood. One hypothesis is that it may be attributable, in part, to increased use of reproductive technologies resulting in an increase in multifetal pregnancies. Another hypothesis is that advances in obstetric practice have led to an increase in surveillance and medical interventions during pregnancy [114, 117]. Late-preterm infants are physiologically and metabolically immature. As a consequence, LPT infants are at higher risk than term infants of developing medical complications that result in higher rates of mortality and morbidity. LPT infants are also more likely than term infants to have longer initial hospital stays and to be admitted to NICU. A large cohort study found that 88% of infants born at 34 GA, 54% of infants born at 35 GA, 25% of infants born at 36 GA, 12% of infants born at 37 GA, and 2.6% of infants born at 38 through 40 GA are admitted at NICU . LPT infants have been reported to be three times more likely than terms to die before their first birthday and six times more likely to die in their first week of life, as a result of congenital malformations, deformations, and chromosomal abnormalities; bacterial sepsis; and maternal complication of pregnancy .
LPT infants have also a higher rate of immediate newborn morbidities, such as respiratory distress syndrome, apnea, transient tachypnea, hypoglycaemia, hypothermia, seizures, and feeding problems. LPT infants may also be at significant risk for brain injury and adverse long-term neurodevelopmental outcomes even though the risk is lower than that reported in ELBW . It is important to recognize that a significant proportion of brain growth, development, and networking occur during the last 6 weeks of gestation. In particular, active myelination persists in LPT period and for an additional 24 weeks postnatally; approximatively 25% of the cerebellar volume and its connections develop after preterm birth. Over the final 4 weeks of gestation, dramatic growth is seen in the gyri, sulci, synapses, dendrites, axons, oligodendrocytes, astrocytes, and microglia . It is estimated that at 35 GA, the surface of the brain shows significantly fewer sulci, and the weight of the brain is only about 60% than of term infants. Subplate neurons are still prominent in the late-preterm brain and axonal interconnections between the thalamus and cerebral cortex are not completely formed at this age . Cerebral tissues are vulnerable to injury during this critical period of development that may result in direct damage of critical pathway needed for neuronal and glial development. The LPT is also at risk for white matter injury through multiple potential mechanisms, including developmental vulnerability of the oligodendrocyte, cytokine and free radical-mediated injury, and a developmental lack of antioxidant enzymes to help regulate oxidative stress. LPT infants show a higher risk of developing significant hyperbilirubinemia and an increased risk for long-term sequelae compared with term infants because of immaturity of conjugation of enzymatic pathways, immature feeding patterns, and the age-dependent susceptibility of developing neurons and astrocytes to bilirubin-induced injuries .
The long-term neurodevelopmental outcome of LPT infants has been evaluated only in a few studies. Neurologic abnormalities, learning difficulties, poor scholastic achievement, and behavioral problems have been reported . CP has been found to be three times more likely in LPT compared with full-term children; Developmental Delay and Mental Retardation have been found 2 or 1.3 times more than full-term infants [13, 48]. No evidence of increased risk of autism has been reported in LPT compared with term children .
With regard to learning difficulties, LPT infants have 24% increased odds for reading scores below average in the first grade of education, compared to full term. A risk ranging from 1.4 to 2.1 for special education, compared to full-term infants, has also been reported .
More studies are needed in this GA category in order to set preventive strategies. In fact, it is not negligible that, although they are at lower risk than VPT for poor neurodevelopmental outcome, LPT account for about 75% of all preterm births.
Preterm infants are likely to present adverse neurodevelopmental outcomes covering motor, sensorial, cognitive, and behavioral domains. Although a large amount of data on ELBW and LBW/VPT is available, there is limited information about LPT. Moreover, the identification of trends is impaired by the lack of stratification of the data, with overlaps between different strata, which may provide conservative estimates of the difference between different GA/birth weight strata. This problem also affects comparisons between different studies which use different cut-off for stratifying relevant categories, such as gestational age and birth weight. Further limits derive from the use of different cut-off to define the presence/absence of disorders, and from limited availability and/or use of functional scales and quality-of-life indicators. The knowledge of these limits should guide further research in the field in order to gain evidence about best options for the treatment of preterm children.