Literature Review

Preterm birth and neurodevelopmental outcome: A review

Article· Literature Review (PDF Available)inChild s Nervous System 26(9):1139-49 · March 2010with 1,491 Reads
DOI: 10.1007/s00381-010-1125-y · Source: PubMed
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Abstract
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 PubMed 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.
REVIEW PAPER
Preterm birth and neurodevelopmental outcome: a review
Carla Arpino &Eliana Compagnone &Maria L. Montanaro &Denise Cacciatore &
Angela De Luca &Angelica Cerulli &Stefano Di Girolamo &Paolo Curatolo
Received: 13 February 2010 / Accepted: 3 March 2010 /Published online: 27 March 2010
#Springer-Verlag 2010
Abstract
Background 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.
Methods 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.
Results 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 neuro-
developmental outcomes in the past, are now reconsidered
as more likely to develop such events, though their risk
remains lower than in ELBW.
Conclusions 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.
Keywords Cerebral palsy .Developmental coordination
disorder .Visual impairment
Introduction
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 2425 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 2223 weeks of
gestation, instead, remains unsuccessful with death of
newborns in the immediate postnatal period [3]. 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 [4]. 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 [5];
however, in late-preterm infants without brain injury,
alteration of cerebral maturation can be detected [6]. In fact,
C. Arpino (*):E. Compagnone :D. Cacciatore :A. De Luca :
P. Curatolo
Department of Neurosciences, Pediatric Neurology Unit,
Tor VergataUniversity of Rome,
Via Montpellier 1,
00133 Rome, Italy
e-mail: carla.arpino@uniroma2.it
M. L. Montanaro :S. Di Girolamo
Department of Ear, Nose, Throat & Head Neck Surgery,
Tor VergataUniversity of Rome,
Rome, Italy
A. Cerulli
Department of Pharmacobiology, University of Calabria,
Arcavacata,
Cosenza, Italy
Childs Nerv Syst (2010) 26:11391149
DOI 10.1007/s00381-010-1125-y
early birth has an influence on brain development and timing
of neurobiological processes [7]. 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 [8]. A significant proportion of brain
growth, development, and networking occur approximately
during the last 6 weeks of gestation [9].
The spectrum of clinical disabilities in preterm children
is wide and is represented by cerebral palsy (CP),
developmental coordination disorder (DCD), neurosenso-
rial 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 neuro-
developmental disorders published in the international
medical literature and reported in Pub Med in the last
10 years (January 1, 2000January 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/impair-
ment/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 neurodevelopmentalneurosensorial
outcomes
Cerebral palsy
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 [10]. 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 2227 gestational age
(GA), 6% at 2831 GA and <1% at 3236 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 locomo-
tor quotient) could affect this result [11]. 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 1,0001,499 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 [12]. The
causes of the decreasing prevalence of CP in these birth
weight categories are not completely clear, but improve-
ment 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 [13].
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 [14]. The most involved areas
seem to be basal ganglia, amygdala, thalamus, hippocampus,
and brainstem [15]. 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 [16].
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 mea-
surement of Fractional anisotropy (FA), a measure of
microstructure that helps in understanding normal develop-
ment or the brain response to injury [19,20]. Diffusion
tensor tractography permits to assess connectivity in
preterm birth [21].
The adoption of a well-described and internationally
shared classification system, such as that proposed by the
SCPE [10], and the inclusion of all age categories, are
mandatory to clarify the effect of GA on prevalence, type,
1140 Childs Nerv Syst (2010) 26:11391149
and distribution of CP, and to correlate neuroimaging
findings with clinical picture.
Developmental coordination disorder
A high prevalence of DCD, isolated or associated with
other disorders, such as Attention Deficit Hyperactivity
Disorder (ADHD) [22,23], is common in very/extremely
preterm or low/extremely low birthweight children. In these
categories, DCD rates range between 9.5 and 51% [2430]
(Table 1), while it is estimated to be between 5 and 6% in
the general population [31].
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 [26].
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)[32].
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 [33]. The cerebellum, basal ganglia, parietal
lobe, and corpus callosum may also play a role [26,34].
The cerebellum has an important role in motor coordina-
tion, 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 [34]. This finding suggests that a network
of regions, including parietal lobe, may be involved in this
disorder [35].
Visual impairment
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
Table 1 Developmental coordination disorders (DCD)/minor neuromotor dysfunctions (MND) in preterm children stratified by gestational age
(GA) and birthweight (BW)
Reference GA/BW nExclusion criteria Tests used Percent DCD/MND
Goyen and Lui [24] <29 weeks/50 IQ< 84; Other disabilities MABC (> 1SD)
a
42 (DCD)
Wocadlo and Rieger [25] <30 weeks/323 Neurosensory disabilities; IQ75 BOMP 31.3 (DCD)
Davis et al. [26] <28 weeks/210 CP; IQ>2 SD MABC (<5th centile)
a
9.5 (DCD)
Arnaud et al. [27]
EPIPAGE Study
27 weeks 1,719 IQ < 50; Neurosensory disabilities Touwen 52.3 (mild MND)
2830 weeks 5.1 (moderate MND)
31 weeks 40.2 (mild MND)
32 weeks 3.6 (moderate MND)
3334 weeks 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. [28] <32 weeks/<1,500 g 396 Severe disabilities MABC (<5th centile)
a
22 (DCD)
Foulder-Hughes
and Cooke [29]
<32 weeks/280 MABC (<5th centile)
a
30.7 (DCD)
Holsti et al. [30]/<800 g 73 Neurosensory disabilities; CP; IQ< 85 BOMP (>1SD)
a
51 (DCD)
nnumber of sample size, MABC Movement Assessment Battery for Children, BOMP BruininksOseretsky Test of Motor Proficiency
a
Cut-off to denote children with DCD/MND
Childs Nerv Syst (2010) 26:11391149 1141
normal pupillar response and negative eye examination,
disturbance of motility, strabismus, nistagmus, and
impairment of fixation shift). The retinopathy of prema-
turity (ROP) is the most frequent peripheral visual
alteration in preterms [37]. 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 3234 GA. The hypoxia-induced
retinal neovascularization phase of ROP is similar to other
proliferative retinopathies [38]. 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% [39]. 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 2326 weeks [39]. 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 astigma-
tism) compared with that of the general population, is
described [40]. Strabismus is also reported to be very
common in preterm children, with a prevalence rate
ranging from 12 to 20% [41]. 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 [42]
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) [43]. 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 [44].
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 acuityis 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% [45].
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 [46].
Hearing impairment
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 (1.11.3/1,000 within 40 dB) [47]. Gestational
age-specific prevalence of hearing loss among children aged
310 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 2023 weeks, 0.63% at 2428 weeks,
0.19% at 2932 weeks, and 0.1 at 3336 weeks [48].
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 [49], 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 [50]. Furthermore, hearing loss in children can affect
cognition, educational levels, social and emotional develop-
ment, and familychild 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 [53]. 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 [54].
1142 Childs Nerv Syst (2010) 26:11391149
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 [55].
Cognitive impairment
Cognitive impairment (IQ<70) is the most common and
severe disability in preterm infants [5664] and its
prevalence is reported to be higher than motor, visual, or
hearing impairments [59,6570].Rates of cognitive
disability vary across the studies depending on sample size
and the inclusion of different GA categories, and have been
showntobeinverselyrelatedtoGAandbirthweight
[56,61,7174]. Data from several cohort studies suggest
that cognitive impairment ranges from 4 to 47% in the GA
categories between 22 and 34 weeks or between 750 g and
1,500 g [58,59,69,7583](Table2). Furthermore, when
comparing school-ages preterm without mental retardation
with full-term children, a mean difference of 10.9 points in
the cognitive scores has been found [56].
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 [61], suggesting that environ-
mental 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 [84].
An early indicator of impaired cognitive development in
preterm infants [85] 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 [86].
Neuropsychological disabilities persist throughout adoles-
cence and adulthood [61,8789], and only 5674% 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 [90].
School underachievement has been reported even in those
without neurosensory impairment and normal IQ [91]. Mild
abnormalities of visual processing tasks [74,92], memory,
and adaptive functioning [74,93] common in preterm
children, could influence childs school performances [94].
Table 2 Cognitive impairment (IQ < 70) stratified by gestational age (GA) and birthweight (BW)
Reference GA/BW nExclusion criteria IQ tests Percent impaired
(IQ<70)
Marret et al. [69]EPIPAGE Study 3034 weeks/1461 MPC 5.310.7
Seitz et al. [75]/<1,250 g 74 CP K-ABC 1020
Farooqi et al. [76] <26 weeks/86 Five to Fifteen
(Parent report)
14
Marlow et al. [59]EPICure Study 25 weeks/241 K-ABC 21
Hintz et al. [77] <25 weeks/366 BSID-II 40
473 47
Hack et al. [78]/<1,000 g 219 Major malformations;
Tuberous sclerosis, AIDS
K-ABC 15
Mikkola et al. [79]Finnish ELBW
Cohort Study
/<1,000 g 172 Severe disabilities WPPSI-R 9
Larroque et al. [80]EPIPAGE
Study
<33 weeks/1624 K-ABC 12
Vohr et al. [81]Multicenter
Cohort Study
2226 weeks/3785 BSID-II 37.2
2732 weeks/22.8
Shankaran et al. [82]24/750 g 246 BSID-II 46
Anderson and Doyle [58]Victorian
Infant Collaborative Study
<28 weeks/<1,000 g 258 Severe disabilities WISC-III 5
Bohm et al. [83]Stockholm
Neonatal Project
/<1,500 g 143 Severe disabilities WPPSI-R <10
nnumber of sample size, K-ABC Kaufman Assessment Battery for Children, MPC Mental Processing Composite (Kaufman Assessment Battery
for Children), BSID-II Bayley Scales of Infant Development-II, WPPSI-RWechsler Preschool and Primary Scale of Intelligence-Revised, WISC-
III Wechsler Intelligence Scale for Children 3rd Edition
Childs Nerv Syst (2010) 26:11391149 1143
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      Kathleen Powis
    Great gains were achieved with the introduction of the United Nations' Millennium Development Goals, including improved child survival. Transition to the Sustainable Development Goals (SDGs) focused on surviving, thriving, and transforming, representing an important shift to a broader public health goal, the achievement of which holds the promise of longer-term individual and societal benefits. A similar shift is needed with respect to outcomes for infants born to women living with HIV (WLHIV). Programming to prevent vertical HIV transmission has been successful in increasingly achieving a goal of HIV-free survival for infants born to WLHIV. Unfortunately, HIV-exposed uninfected (HEU) children are not achieving comparable health and developmental outcomes compared with children born to HIV-uninfected women under similar socioeconomic circumstances. The 3rd HEU Child Workshop, held as a satellite session of the International AIDS Society's 9th IAS Conference in Paris in July 2017, provided a venue to discuss HEU child health and development disparities. A summary of the Workshop proceedings follows, providing current scientific findings, emphasizing the gap in systems for long-term monitoring, and highlighting the public health need to establish a strategic plan to better quantify the short and longer-term health and developmental outcomes of HEU children.
  • Article
    • Nils J Bergman
    Maternal-neonate separation for human newborns has been the standard of care since the last century; low birth weight and preterm infants are still routinely separated from their mothers. With advanced technology, survival is good, but long-term developmental outcomes are very poor for these especially vulnerable newborns. The poor outcomes are similar to those described for adversity in childhood, ascribed to toxic stress. Toxic stress is defined as the absence of the buffering protection of adult support. Parental absence has been strictly enforced in neonatal care units for many reasons and could lead to toxic stress. The understanding of toxic stress comes from discoveries about our genome and epigenetics, the microbiome, developmental neuroscience and the brain connectome, and life history theory. The common factor is the early environment that gives (a) signals to epigenes, (b) sensory inputs to neural circuits, and (c) experiences for reproductive fitness. For human newborns that environment is direct skin-to-skin contact from birth. Highly conserved neuroendocrine behaviors determined by environment are described in this review. The scientific rationale underlying skin-to-skin contact is presented: autonomic development and regulation of the physiology leads to emotional connection and achieving resilience. Maternal-neonate separation prevents these critical neural processes from taking place, but also channel development into an alternative developmental strategy. This enables better coping in a stressful environment in the short term, but with permanently elevated stress systems that negatively impact mental and physical health in the long term. This may explain the increasing incidence of developmental problems in childhood, and also Developmental Origins of Health and Disease. Arguments are presented that maternal-neonate separation is indeed a source of toxic stress, and some suggestions are offered toward a "zero separation" paradigm.
  • Article
    Full-text available
    • Helene Lacaille
      Helene Lacaille
    • Claire-Marie Vacher
      Claire-Marie Vacher
    • Dana Bakalar
    • Anna A Penn
    Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism and schizophrenia. A common feature of these psychiatric disorders is prefrontal cortex (PFC) inhibitory circuit disruption due to GABAergic interneuron alteration. Cortical interneurons are generated and migrate throughout late gestation and early infancy, making them highly susceptible to perinatal insults such as preterm birth. Term and preterm PFC pathology specimens were assessed using immunohistochemical markers for interneurons. Based on the changes seen, a new preterm encephalopathy mouse model was developed to produce similar PFC interneuron loss. Maternal immune activation (MIA; modeling chorioamnionitis, associated with 85% of extremely preterm births) was combined with chronic sublethal hypoxia (CSH; modeling preterm respiratory failure), with offspring of both sexes assessed anatomically, molecularly and neurobehaviorally. In the PFC examined from the human preterm samples compared to matched term samples at corrected age, a decrease in somatostatin (SST) and calbindin (CLB) interneurons was seen in upper cortical layers. This pattern of interneuron loss in upper cortical layers was mimicked in the mouse PFC following the combination of MIA and CSH, but not after either insult alone. This persistent interneuron loss is associated with postnatal microglial activation that occurs during CSH only after MIA. The combined insults lead to long-term neurobehavioral deficits which parallel human psychopathologies that may be seen after extremely preterm birth. This new preclinical model supports a paradigm in which specific cellular alterations seen in preterm encephalopathy can be linked with a risk of neuropsychiatric sequela. Specific interneuron subtypes may provide therapeutic targets to prevent or ameliorate these neurodevelopmental risks.
  • Article
    • Lawrence D. Reid
    • Donna M. Strobino
    Objectives We examined biologic and social determinants of school readiness in an urban population and whether childcare altered these associations. Methods A retrospective cohort study was conducted using school readiness data linked to birth certificates of first-time kindergarten students (n = 39,463) in a large, urban public-school district during 2002–2012. Multivariate linear regression models compared mean readiness scores (MRS) for students born low birthweight (LBW) or preterm (PTB) and by childcare type, adjusting for other student and parent risk factors. Results MRSs for moderately LBW (1000–2499 g), extremely LBW (< 1000 g), moderately PTB (28–36 weeks), early-term (37–38 weeks) and post-term (42 + weeks) students were significantly lower than scores for their normal weight or full-term peers, adjusting for childcare type and other student and parent characteristics. Childcare was an important predictor of MRSs. MRSs were highest for district prekindergarten (PK) students and for students of mothers with greater years of education. Conclusions for Practice Social and biologic differences in MRSs for children entering school in a large urban public-school district suggest the need for greater attention to family and child health backgrounds. Increased enrollment in formal childcare may improve school readiness in these settings.
  • Article
    • Julia Jaekel
      Julia Jaekel
    • Megan Scott
    • Jacobus Donders
    • Scott J Hunter
      Scott J Hunter
    Neuropsychological Conditions Across the Lifespan - edited by Jacobus Donders August 2018
  • Article
    • Jacobus Donders
    • Scott J Hunter
      Scott J Hunter
    • Julia Jaekel
      Julia Jaekel
    • Christian Lobue
      Christian Lobue
    Cambridge Core - Neuropsychology - Neuropsychological Conditions Across the Lifespan - edited by Jacobus Donders
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