The impact of birthweight on the development of cerebral palsy: A population-based matched case-control study.

BACKGROUND: Cerebral palsy (CP) is a common cause of physical impairment in children, especially in newborns who are small for gestational age (SGA). AIMS: The aim of our study was to investigate the association between birth weight and the risk of developing CP, controlling for gestational age and plurality. STUDY DESIGN: This retrospective, observational, case-control study was based on Slovenian Registry of Cerebral Palsy (SRCP) and Slovenian National Perinatal Information System (NPIS) data for the period 2002 to 2010. SUBJECTS: For each pregnancy that resulted in the birth of the newborn(s) who later developed CP (n = 254), three pregnancies with newborns who did not develop CP (n = 762) were selected and matched for gestational age and plurality. OUTCOME MEASURES: Diagnosis of CP was made at age 5 years or older by a developmental pediatrician trained in child neurology or a child neurologist using standard measures. RESULTS: Risk of CP increased progressively as birth weight percentiles fell below the 50th centile, with children in the lowest percentiles at greatest risk. Birth weight percentiles traditionally classified as SGA were an independent risk factor for developing CP, with an odds ratio of 2.43 (95% confidence interval 1.57, 3.73). CONCLUSIONS: The results of this study suggest that the risk for developing CP is inversely related to birth weight, even at birth weights that do not meet the standard definitions of SGA. SYNOPSIS - STUDY QUESTION: Does birth weight represent a potential risk factor for the development of cerebral palsy (CP) when controlling for gestational age and plurality? WHAT'S ALREADY KNOWN: Newborns who are small for gestational age (SGA) are at higher risk of developing CP according to published studies. However, different definitions of SGA (birth weight below the 10th, 5th, or 3rd percentile for gestational age) have been used by researchers and clinicians, making it difficult to compare studies. WHAT THIS STUDY ADDS: This study suggests that the risk of developing CP is inversely related to birth weight, even at birth weights that do not meet standard definitions of SGA.

Genetic Polymorphisms, Gene-Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia.

Inflammation and oxidative stress after hypoxic-ischemic brain injury may be modified by genetic variability in addition to therapeutic hypothermia. The aim of our study was to evaluate the association between the polymorphisms in genes of antioxidant and inflammatory pathways in newborns treated with therapeutic hypothermia and the development of epilepsy or CP at two years follow-up. The DNA of 55 subjects was isolated from buccal swabs. Genotyping using competitive allele-specific PCR was performed for polymorphisms in antioxidant (SOD2 rs4880, CAT rs1001179, GPX1 rs1050450) and inflammatory (NLRP3 rs35829419, CARD8 rs2043211, IL1B rs1143623, IL1B rs16944, IL1B rs10716 76, TNF rs1800629) pathways. Polymorphic CARD8 rs2043211 T allele was less frequent in patients with epilepsy, but the association was not statistically significant. The interaction between CARD8 rs2043211 and IL1B rs16944 was associated with epilepsy after HIE: CARD8 rs2043211 was associated with lower epilepsy risk, but only in carriers of two normal IL1B rs16944 alleles (ORadj = 0.03 95% CI = 0.00-0.55; padj = 0.019). Additionally, IL1B rs16944 was associated with higher epilepsy risk only in carriers of at least one polymorphic CARD8 rs2043211 (ORadj = 13.33 95% CI = 1.07-166.37; padj = 0.044). Our results suggest that gene-gene interaction in inflammation pathways might contribute to the severity of brain injury in newborns with HIE treated with therapeutic hypothermia.

CARD8 and IL1B Polymorphisms Influence MRI Brain Patterns in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia.

Inflammation and oxidative stress are recognized as important contributors of brain injury in newborns due to a perinatal hypoxic-ischemic (HI) insult. Genetic variability in these pathways could influence the response to HI and the outcome of brain injury. The aim of our study was to evaluate the impact of common single-nucleotide polymorphisms in the genes involved in inflammation and response to oxidative stress on brain injury in newborns after perinatal HI insult based on the severity and pattern of magnetic resonance imaging (MRI) findings. The DNA of 44 subjects was isolated from buccal swabs. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1B rs16944, IL1B rs1143623, IL1B rs1071676, TNF rs1800629, CAT rs1001179, SOD2 rs4880, and GPX1 rs1050450. Polymorphism in CARD8 was found to be protective against HI brain injury detected by MRI overall findings. Polymorphisms in IL1B were associated with posterior limb of internal capsule, basal ganglia, and white matter brain patterns determined by MRI. Our results suggest a possible association between genetic variability in inflammation- and antioxidant-related pathways and the severity of brain injury after HI insult in newborns.

Antioxidant polymorphisms do not influence the risk of epilepsy or its drug resistance after neonatal hypoxic-ischemic brain injury.

PURPOSE: The aim of this study was to investigate if common functional antioxidant polymorphisms are associated with epilepsy after neonatal hypoxic-ischemic encephalopathy (HIE). The antioxidant enzymes manganese superoxide dismutase (SOD2), glutathione peroxidase 1 (GPX1) and catalase (CAT) represent the primary defence mechanism against reactive oxygen species (ROS). Evidence suggests that genetic variants in antioxidant enzymes could influence susceptibility to epilepsy, but to date the relationship between them remains unclear. METHODS: The study comprised 214 patients with epilepsy (64 with and 150 without neonatal HIE) as well as 95 healthy controls. Genomic DNA was isolated from buccal swabs or venous blood samples and genotyped for SOD2 rs4880, GPX1 rs1050450 and CAT rs1001179 using real-time PCR-based methods. RESULTS: The investigated polymorphisms influenced neither the overall risk of epilepsy nor the risk of epilepsy after HIE in comparison with healthy controls. Furthermore, no significant difference in genotype distribution was observed between patients with drug-resistant epilepsy and patients in remission in either the group with epilepsy but without HIE or in the group with epilepsy and HIE, although the frequency of drug-resistant cases was higher in the latter group (p=0.009, OR=2.52; 95% CI=1.22-4.15). CONCLUSION: According to this study, common GPX1, SOD2 and CAT polymorphisms do not influence the overall risk of epilepsy after HIE and its drug resistance.

The association between antioxidant enzyme polymorphisms and cerebral palsy after perinatal hypoxic-ischaemic encephalopathy.

BACKGROUND: Hypoxic-ischaemic perinatal brain injury leads to the formation of reactive oxygen species (ROS) and the resultant cell and tissue damage may cause neurological sequelae such as cerebral palsy and/or epilepsy. A decrease in the capacity for defending against ROS may increase the susceptibility to cerebral palsy. The aim of this study was to investigate the impact of common functional polymorphisms in the antioxidant genes SOD2, GPX1 and CAT, associated with a decreased capacity for defending against ROS, in patients with perinatal hypoxic-ischaemic encephalopathy (HIE). METHODS: 80 patients previously diagnosed with perinatal HIE were included. Genomic DNA was isolated from buccal swabs and genotyped for SOD2 rs4880, GPX1 rs1050450 and CAT rs1001179 using real-time PCR-based methods. RESULTS: Among patients with neonatal HIE, carriers of at least one polymorphic CAT rs1001179 T allele were significantly associated with development of cerebral palsy compared to non-carriers (univariate logistic regression, p = 0.026; OR = 3.36; 95% CI = 1.16-9.76). This difference remained statistically significant after accounting for prematurity. The investigated SOD2 and GPX1 polymorphisms were not associated with cerebral palsy after perinatal HIE. CONCLUSION: CAT rs1001179 polymorphism could be used to identify children that have a higher susceptibility to cerebral palsy after perinatal HIE.