Catherine S. Gibson

Neurotropic viruses and cerebral palsy: population based case-control study

Abstract Objective To investigate the association between cerebral palsy and direct evidence for perinatal exposure to neurotropic viruses. Design Population based case-control study. Setting Adelaide Womens and Childrens Hospital Research Laboratory. Participants and main outcome measures Newborn screening cards of 443 white case patients with cerebral palsy and 883 white controls were tested for viral nucleic acids from enteroviruses and herpes viruses by using polymerase chain reaction. Herpes group A viruses included herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 8 (HHV-8), and herpes group B viruses included varicella zoster virus (VZV) and human herpes viruses 6 and 7 (HHV-6 and HHV-7). Results The prevalence of viral nucleic acids in the control population was high: 39.8% of controls tested positive, and the prevalence was highest in preterm babies. The detection of herpes group B viral nucleic acids increased the risk of developing cerebral palsy (odds ratio 1.68, 95% confidence interval 1.09 to 2.59). Conclusions Perinatal exposure to neurotropic viruses is associated with preterm delivery and cerebral palsy.

Genetic polymorphisms and spontaneous preterm birth.

OBJECTIVE: To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. METHODS: Exploratory case–control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986–1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. RESULTS: In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the β2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and alpha adducin (ADD1, P=.047). CONCLUSION: We confirm previous observations that variants of the β adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and alpha adducin may be contributors to risk of spontaneous preterm birth. LEVEL OF EVIDENCE: II

Epidemiologic associations with cerebral palsy

OBJECTIVE: To estimate epidemiologic risk factors for cerebral palsy. METHODS: Data were collected by linkage to state-based perinatal repositories and cerebral palsy registers and using a maternal questionnaire. The cohort included 587 individuals with cerebral palsy and 1,154 non–cerebral palsy controls. RESULTS: The following factors were associated with cerebral palsy: recorded maternal infection during pregnancy (41.4% patients compared with 31.3% controls; odds ratio [OR] 1.55, 95% confidence interval 1.26–1.91), small for gestational age ([birth weight less than third customized centile] 43.9% patients compared with 6.3% controls; OR 11.75, 6.25–22.08), gestational age less than 32 weeks (29.3% patients compared with 0.7% controls; OR 59.20, 28.87–121.38), multiple birth (OR 6.62, 4.00–10.95), a relative with cerebral palsy (OR 1.61, 1.12–2.32), breech position (13.7% patients compared with 6.0% controls; OR 2.48, 1.76–3.49), bleeding at any time in pregnancy (29.3% patients compared with 16.9% controls; OR 2.04, 1.61–2.58), male sex (58.8% patients compared with 45.8% controls; OR 1.68, 1.38–2.06), multiple miscarriage (7.7% patients compared with 3.5% controls; OR 2.30, 1.38–3.82), smoking (14.0% patients compared with 10.6% controls; OR 1.37, 1.02–1.85), and illicit drug use (3.3% patients compared with 1.5% controls; OR 2.22, 1.14–4.30). Factors not associated with cerebral palsy were “disappearing twin,” diabetes, maternal body mass index, hypertension, alcohol consumption, anemia, maternal hypothyroidism, forceps or vacuum delivery, and maternal age. CONCLUSION: Preterm birth, intrauterine growth restriction, perinatal infection, and multiple birth present the largest risks for a cerebral palsy outcome. Reassuringly, upper respiratory tract and gastrointestinal infections during pregnancy were not associated with cerebral palsy. LEVEL OF EVIDENCE: II

Candidate Genes and Cerebral Palsy: A Population-Based Study

OBJECTIVE. The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy. METHODS. A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986–1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay. RESULTS. For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin α, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the β-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys. CONCLUSIONS. Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy.

Antenatal causes of cerebral palsy: associations between inherited thrombophilias, viral and bacterial infection, and inherited susceptibility to infection

Cerebral palsy rates of 2 in every 1000 births have varied little over the last 40 years, despite improvements in obstetric care. In the past, cerebral palsy was thought to be due to poor obstetric care and management; however, epidemiological studies have refuted this, suggesting that there is usually an antenatal timing to the neuropathology of cerebral palsy. There are many known risk factors for cerebral palsy, including multiple gestation, prematurity, and low birth weight. Recently, intrauterine infection, maternal pyrexia, and the presence of thrombophilic disorders (thrombophilia) have been identified as major risk factors for subsequent cerebral palsy. This review examines the links between intrauterine infection, the fetal inflammatory response, and thrombophilia as possible causes of cerebral palsy. The interactions of viral or bacterial infections during pregnancy, normal or abnormal fetal cytokine responses, and hereditary fetal thrombophilias as antenatal causes of the neuropathology of cerebral palsy are now areas of research priority. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to describe the condition cerebral palsy, list the risk factors for the development of cerebral palsy, ouline the ultrasound findings associated with cerebral palsy, and point out other conditions associated with cerebral palsy.

Fetal exposure to herpesviruses may be associated with pregnancy‐induced hypertensive disorders and preterm birth in a Caucasian population*

Objective  To investigate the role of fetal viral infection in the development of a range of adverse pregnancy outcomes (APOs), including pregnancy‐induced hypertensive disorders (PIHD), antepartum haemorrhage (APH), birthweight <10th percentile (small for gestational age, SGA) and preterm birth (PTB).

Rare copy number variation in cerebral palsy

Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.

Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.

Aim: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll‐like receptor‐4 (TLR‐4) Asp299Gly, interleukin‐6 G‐174C and interleukin‐4 C‐589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples.

Fetal and Maternal Candidate Single Nucleotide Polymorphism Associations With Cerebral Palsy: A Case-Control Study

OBJECTIVE: Previous studies have suggested associations between certain genetic variants and susceptibility to cerebral palsy (CP). This study was designed to assess established and novel maternal and child genetic and epidemiologic risk factors for CP along with their interactions. METHODS: DNA from 587 case and 1154 control mother-child pairs was analyzed. A panel of 35 candidate single nucleotide polymorphisms (SNPs) were examined and included SNPs in genes associated with (1) thrombophilia, (2) inflammation, and (3) risk factors for CP (eg, preterm birth). Comparisons were specified a priori and made by using a χ2 test. RESULTS: There were 40 fetal and 28 maternal associations with CP when analyzed by CP subtype, gestational age, genotypes of apolipoprotein E, and haplotypes of mannose-binding-lectin. After Bonferroni correction for multiple testing, no fetal or maternal candidate SNP was associated with CP or its subtypes. Only fetal carriage of prothrombin gene mutation remained marginally associated with hemiplegia in term infants born to mothers with a reported infection during pregnancy. Odds ratio directions of fetal SNP associations were compared with previously reported studies and confirmed no trend toward association. CONCLUSIONS: Except for the prothrombin gene mutation, individual maternal and fetal SNPs in our candidate panel were not found to be associated with CP outcome. Past reported SNP associations with CP were not confirmed, possibly reflecting type I error from small numbers and multiple testing in the original reports.

The prevalence of inherited thrombophilias in a Caucasian Australian population.

Aims: To describe the prevalence of four inherited thrombophilias and their combinations for the first time in a large Caucasian Australian population. Methods: Newborn screening cards of 883 Caucasian babies born in South Australia in 1986–1999 were de‐identified and tested for the following inherited thrombophilic polymorphisms: factor V Leiden (G1691A), prothrombin gene mutation (G20210A), methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C, as well as compound heterozygosity for the MTHFR polymorphisms. Results: The birth prevalences of heterozygosity and homozygosity for the four thrombophilic polymorphisms were: factor V Leiden 9.5% and 0.7%, prothrombin gene 4.1% and 0.2%, MTHFR C677T 37.3% and 12.4%, and MTHFR A1298C 38.3% and 11.8%, respectively. Compound heterozygosity for MTHFR C677T and A1298C was seen in 16.6% of the population. Overall, 64.2% and 24.5% of the population studied were homozygous and heterozygous, respectively, for at least one of the four polymorphisms studied. Conclusion: Inherited thrombophilic polymorphisms are common in the Caucasian Australian population. Knowledge of the background prevalence of these polymorphisms will allow further study of their associations in future disease research.