ContextNeonatal infections are frequent complications of extremely low-birth-weight
(ELBW) infants receiving intensive care.ObjectiveTo determine if neonatal infections in ELBW infants are associated with
increased risks of adverse neurodevelopmental and growth sequelae in early
childhood.Design, Setting, and ParticipantsInfants weighing 401 to 1000 g at birth (born in 1993-2001) were enrolled
in a prospectively collected very low-birth-weight registry at academic medical
centers participating in the National Institute of Child Health and Human
Development Neonatal Research Network. Neurodevelopmental and growth outcomes
were assessed at a comprehensive follow-up visit at 18 to 22 months of corrected
gestational age and compared by infection group. Eighty percent of survivors
completed the follow-up visit and 6093 infants were studied. Registry data
were used to classify infants by type of infection: uninfected (n = 2161),
clinical infection alone (n = 1538), sepsis (n = 1922),
sepsis and necrotizing enterocolitis (n = 279), or meningitis with
or without sepsis (n = 193).Main Outcome MeasuresCognitive and neuromotor development, neurologic status, vision and
hearing, and growth (weight, length, and head circumference) were assessed
at follow-up.ResultsThe majority of ELBW survivors (65%) had at least 1 infection during
their hospitalization after birth. Compared with uninfected infants, those
in each of the 4 infection groups were significantly more likely to have adverse
neurodevelopmental outcomes at follow-up, including cerebral palsy (range
of significant odds ratios [ORs], 1.4-1.7), low Bayley Scales of Infant Development
II scores on the mental development index (ORs, 1.3-1.6) and psychomotor development
index (ORs, 1.5-2.4), and vision impairment (ORs, 1.3-2.2). Infection in the
neonatal period was also associated with impaired head growth, a known predictor
of poor neurodevelopmental outcome.ConclusionsThis large cohort study suggests that neonatal infections among ELBW
infants are associated with poor neurodevelopmental and growth outcomes in
early childhood. Additional studies are needed to elucidate the pathogenesis
of brain injury in infants with infection so that novel interventions to improve
these outcomes can be explored.

https://jamanetwork.com/journals/jama/articlepdf/199811/JOC41797.pdf

Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.

Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achievable because of recent neurobiologic insights into pathogenesis. The pathogenesis of this lesion relates to three major interacting factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter, and a maturation-dependent impairment in regulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturation-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals, known to be generated in abundance with ischemia-reperfusion. This vulnerability of OLs is maturation-dependent, with the OL precursor cell highly vulnerable and the mature OL resistant, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation. The result is generation of deadly reactive oxygen species and apoptotic OL death. Important contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PVL in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important contributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vasculature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elevations in extracellular glutamate, caused by ischemia-reperfusion, is suggested by demonstrations that glutamate causes toxicity to OL precursors by both nonreceptor- and receptor-mediated mechanisms. The former involves an exacerbation of the impairment in antioxidant defenses, and the latter, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-mediated cell death. Most importantly, these new insights into the pathogenesis of PVL suggest potential preventive interventions. These include avoidance of cerebral ischemia by detection of infants with impaired cerebrovascular autoregulation, e.g. through the use of in vivo near-infrared spectroscopy, the use of free radical scavengers to prevent toxicity by reactive oxygen species, the administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor antagonists to prevent glutamate-mediated injury, or the use of maternal antibiotics or anticytokine agents to prevent toxicity from maternal/fetal infection or inflammation and cytokines.

/pdf/neurobiology-of-periventricular-leukomalacia-in-the-4r5vysfn1x.pdf

Neurobiology of Periventricular Leukomalacia in the Premature Infant

Background Methylxanthines reduce the frequency of apnea of prematurity and the need for mechanical ventilation during the first seven days of therapy. It is uncertain whether methylxanthines have other short- and long-term benefits or risks in infants with very low birth weight. Methods We randomly assigned 2006 infants with birth weights of 500 to 1250 g during the first 10 days of life to receive either caffeine or placebo, until drug therapy for apnea of prematurity was no longer needed. We evaluated the short-term outcomes before the first discharge home. Results Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks, 350 (36 percent) received supplemental oxygen, as did 447 of the 954 infants (47 percent) assigned to placebo (adjusted odds ratio, 0.63; 95 percent confidence interval, 0.52 to 0.76; P<0.001). Positive airway pressure was discontinued one week earlier in the infants assigned to caffeine (median postmenstrual age, 31.0 weeks; interquartile range, 29.4 to 33.0) than in the infants in the placebo group (median postmenstrual age, 32.0 weeks; interquartile range, 30.3 to 34.0; P<0.001). Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving caffeine and the group receiving placebo was greatest after two weeks (mean difference, −23 g; 95 percent confidence interval, −32 to −13; P<0.001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ significantly between the two groups. Conclusions Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312.)

/pdf/caffeine-therapy-for-apnea-of-prematurity-2b9gf0ug96.pdf

Caffeine Therapy for Apnea of Prematurity

ContextChorioamnionitis has been implicated in the pathogenesis of cerebral
palsy, but most studies have not reported a significant association. Cystic
periventricular leukomalacia (cPVL) is believed to be a precursor of cerebral
palsy in preterm infants.ObjectivesTo determine whether chorioamnionitis is associated with cerebral palsy
or cPVL and to examine factors that may explain differences in study results.Data SourcesSearches of MEDLINE (1966-1999), Index Medicus (1960-1965), Doctoral
Dissertation Abstracts On-Line (1861-1999), bibliographies, and online conference
proceedings (1999) were performed for English-language studies with titles
or abstracts that discussed prenatal risk factors for cerebral palsy or cPVL.Study SelectionOf 229 initially identified publications, meta-analyses were performed
on studies that addressed the association between clinical (n = 19) or histologic
(n = 7) chorioamnionitis and cerebral palsy or cPVL in both preterm and full-term
infants. Inclusion criteria were: presence of appropriate exposure and outcome
measures, case-control or cohort study design, and provision of sufficient
data to calculate relative risks (RRs) or odds ratios with 95% confidence
intervals (CIs). Studies evaluating risk of cerebral palsy following maternal
fever, urinary tract infection, or other maternal infection were collected,
but not included in the meta-analysis.Data ExtractionInformation from individual studies was abstracted using standardized
forms by 2 independent observers blinded to authors' names, journal titles,
and funding sources.Data SynthesisUsing a random effects model, clinical chorioamnionitis was significantly
associated with both cerebral palsy (RR, 1.9; 95% CI, 1.4-2.5) and cPVL (RR,
3.0; 95% CI, 2.2-4.0) in preterm infants. The RR of histologic chorioamnionitis
and cerebral palsy was 1.6 (95% CI, 0.9-2.7) in preterm infants, and histologic
chorioamnionitis was significantly associated with cPVL (RR, 2.1; 95% CI,
1.5-2.9). Among full-term infants, a positive association was found between
clinical chorioamnionitis and cerebral palsy (RR, 4.7; 95% CI, 1.3-16.2).
Factors explaining differences in study results included varying definitions
of clinical chorioamnionitis, extent of blinding in determining exposure status,
and whether individual studies adjusted for potential confounders.ConclusionOur meta-analysis indicates that chorioamnionitis is a risk factor for
both cerebral palsy and cPVL.

https://jamanetwork.com/journals/jama/articlepdf/193084/JMA00019.pdf

Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis.

Background The prophylactic administration of indomethacin reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage in very-low-birth-weight infants (those with birth weights below 1500 g). Whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in renal, intestinal, and cerebral blood flow is not known. Methods Soon after they were born, we randomly assigned 1202 infants with birth weights of 500 to 999 g (extremely low birth weight) to receive either indomethacin (0.1 mg per kilogram of body weight) or placebo intravenously once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months. Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly within the same time frame. Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrh...

https://espace.library.uq.edu.au/view/UQ:387267/UQ387267_OA.pdf

Long-Term Effects of Indomethacin Prophylaxis in Extremely-Low-Birth-Weight Infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants or =1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8; p = 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9; p = 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

/pdf/maternal-infection-fetal-inflammatory-response-and-brain-30wgp42rj4.pdf

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Objective To employ multivariate analytic techniques to assess the association between neonatal cranial ultrasound (US) abnormalities and subsequent cerebral palsy (CP), defined as disabling CP (DCP) or nondisabling CP (NDCP) depending on the level of motor dysfunction. Design Prospective cohort study. Subjects and methods The Neonatal Brain Hemorrhage Study enrolled a geographically representative sample of 1105 newborns 501 to 2000 g and obtained follow-up data on 777 (86%) of the 901 survivors at age two. One hundred thirteen children (14.6%) had motor findings severe enough to classify them as having CP. The 61 (7.9%) of these children who were disabled by their motor impairment we classified as having DCP. The remaining 52 (6.7%) who had definite neurologic findings (usually mild spastic diplegia) but without evidence of interference with daily living, we classified as having NDCP. Results In a multivariate logistic regression model of perinatal and postnatal variables, the following factors were found to be significant risk factors for DCP: parenchymal echodensities/lucencies or ventricular enlargement (PEL/VE) on cranial US (OR = 15.4; 7.6, 31.1), germinal matrix/intraventricular hemorrhage (GM/IVH) (OR = 3.5; 1.7, 6.9) and mechanical ventilation (OR = 2.9; 1.2, 7.1). Fully 93.4% of infants were correctly classified as to presence or absence of DCP on the basis of this model. Birth weight, gestational age, length of hospital stay, gender, race, plurality, presence of labor and Apgar score were not significant independent predictors of DCP. For NDCP, the only risk factor significant in the multivariate model was PEL/VE (OR = 5.3; 2.2, 12.6). Conclusions Among perinatal and postnatal factors, cranial US abnormalities are by far the most powerful predictors of disabling CP in low birth weight infants. Although PEL/VE was the strongest predictor, GM/IVH also appeared to independently contribute to the risk of DCP. NDCP in low birth weight infants appears to have a different risk profile than DCP. In particular, it is less closely related to US evidence of perinatal brain injury.

Mervyn Susser

Papers

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Cranial Ultrasound Prediction of Disabling and Nondisabling Cerebral Palsy at Age Two in a Low Birth Weight Population

Neonatal White Matter Damage Maternal Receipt of Magnesium Sulfate Does Not Seem to Reduce the Risk of