Cerebral Palsy Research Group publications
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Item Metadata only The origins of cerebral palsy - A consensus statement(Australian Medical Publishing Co., 1995) MacLennan, A.; Stanley, F.; Blair, E.; Rice, G.; Stone, P.; Robinson, J.; Henderson-Smart, D.; Yu, V.; Harbord, M.; Stern, L.; Chambers, H.; Furness, M.; Hayward, T.; Eckert, K.; Boundy, C.; Merrett, S.; Kenny, M.Item Open Access A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement(BMJ PUBLISHING GROUP, 1999) MacLennan, A.Item Metadata only Risk management in cerebral palsy(RANZCOG, 2000) MacLennan, A.A protocol to reduce inappropriate recrimination if cerebral palsy ensues when perinatal asphyxia is suspected after birthItem Metadata only Who will deliver the next generation of Australians?(The Royal Australian and New Zealand College of Obstetricians and Gynaecologists, 2002) MacLennan, A.; Spencer, M.Item Metadata only Antenatal causes of cerebral palsy: associations between inherited thrombophilias, viral and bacterial infection, and inherited susceptibility to infection(Lippincott Williams & Wilkins, 2003) Gibson, C.; MacLennan, A.; Goldwater, P.; Dekker, G.Cerebral palsy rates of 2 in every 1,000 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, outline the ultrasound findings associated with cerebral palsy, and point out other conditions associated with cerebral palsy.Item Metadata only Cerebral palsy and clinical negligence litigation: a cohort study(Blackwell Publishing Ltd, 2004) MacLennan, A.; Robinson, J.Item Metadata only The prevalence of inherited thrombophilias in a Caucasian Australian population(Taylor & Francis, 2005) Gibson, C.; MacLennan, A.; Rudzki, Z.; Hague, W.; Haan, E.; Sharpe, P.; Priest, K.; Chan, A.; Dekker, G.; Khong, T.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.Item Metadata only Associations between inherited thrombophilias, gestational age, and cerebral palsy(Mosby Inc, 2005) Gibson, C.; MacLennan, A.; Hague, W.; Haan, E.; Priest, K.; Chan, A.; Dekker, G.Objective: This study was undertaken to investigate associations between inherited thrombophilic polymorphisms and cerebral palsy (CP) in a large case-control study. Study design: This is a population-based case-control study. Genomic DNA from newborn screening cards of 443 white CP cases and 883 white controls was tested for factor V Leiden (FVL, G1691A), prothrombin gene mutation (PGM, G20210A), and methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C. Results: MTHFR C677T was associated with an increased risk of developing any CP (32-36 weeks' gestation, homozygous odds ratio [OR] 2.55, 95% CI 1.12-5.74; heterozygous OR 1.91, 95% CI 1.01-3.66). MTHFR C677T was also associated with diplegia at both less than 32 weeks' gestation (homozygous OR 2.76, 95% CI 1.21-6.12) and all gestations (heterozygous OR 1.58 95%, CI 1.02-2.45). For children less than 32 weeks, FVL homozygosity may be associated with an increase in the risk of developing quadriplegia (OR 9.12, 95% CI 0.86-53.71). MTHFR A1298C (heterozygous) was associated with a reduced risk of diplegia developing at 32 to 36 weeks' gestation (OR 0.16, 95% CI 0.02-0.70). There were no associations between any type of CP and thrombophilia for children born 37 weeks or greater. Heterozygous PGM and homozygous MTHFR C677T combined were associated with quadriplegia at all gestational ages (OR 5.33, 95% CI 1.06-23.25). Conclusion: MTHFR C677T approximately doubles the risk of CP in preterm infants. A combination of homozygous MTHFR C677T and heterozygous PGM increases the risk of quadriplegia 5-fold at all gestational ages.Item Metadata only Who will deliver our grandchildren? Implications of cerebral palsy litigation(Amer Medical Assoc, 2005) MacLennan, A.; Nelson, K.; Hankins, G.; Speer, M.Item Metadata only Obstetric litigation is asphyxiating our maternity services(Lippincott Williams & Wilkins, 2006) Hankins, G.; MacLennan, A.; Speer, M.; Strunk, A.; Nelson, K.Obstetric care in the United States, as judged by maternal mortality, neonatal mortality, stillbirth rates, or any other metric, has never been better. Despite this, litigation over "bad outcomes" is threatening the specialty, not only now, but into the future. Despite damage to our specialty, the injured party often benefits little, if at all, from the process. Potential solutions include an emphasis on evidence-based medicine, a qualification and review process for medical experts, and a more rational and fair health court system.Item Metadata only Cerebral palsy and the application of the international criteria for acute intrapartum hypoxia(Lippincott Williams & Wilkins, 2006) Strijbis, E.; Oudman, I.; van Essen, P.; MacLennan, A.Objective
To apply objective criteria for the identification of acute intrapartum hypoxia in a cohort of cerebral palsy cases and to identify other cerebral palsy-related pathologies.Methods
A cohort of all 235 neonates with cerebral palsy from a single Australian tertiary care center born between 1986 and 2003. Cases were identified from the South Australian Cerebral Palsy Register. Maternal and pediatric case notes were audited with application of the 2003 American College of Obstetricians and Gynecologists/American Academy of Pediatrics criteria to identify acute intrapartum hypoxia.Results
Data were available for analysis in 213 cases (91%). Major antenatal or pediatric cerebral palsy-related pathologies were identified in 98.1% of all these cases. An isolated acute intrapartum hypoxic event was defined as likely in only 2 of the 46 neonates born at term and none born preterm. Neonatal nucleated red blood cell counts were often high in neonates born preterm and following antenatal pathologies.Conclusion
Cerebral palsy was seldom preceded by acute intrapartum hypoxia but antenatal cerebral palsy-related pathologies are often detectable. The objective American College of Obstetricians and Gynecologists/American Academy of Pediatrics criteria are useful to audit cerebral palsy causation and exclude primary intrapartum hypoxia.Level of evidence
II-3.Item Metadata only Only an expert witness can prevent cerebral palsy!(The Royal Australian and New Zealand College of Obstetricians and Gynaecologists, 2006) MacLennan, A.; Hankins, G.; Speer, M.Item Metadata only The association between inherited cytokine polymorphisms and cerebral palsy(Mosby Inc, 2006) Gibson, C.; MacLennan, A.; Goldwater, P.; Haan, E.; Priest, K.; Dekker, G.; Hague, W.; Morton, M.Objective The purpose of this study was to investigate associations between inherited cytokine polymorphisms and cerebral palsy. Study design This was a case-control study that used DNA from the newborn infant screening cards of 443 white infants with cerebral palsy and 883 white control infants to test for the following cytokine polymorphisms: tumor necrosis factor–alpha-308, mannose-binding lectin–221, and 3 polymorphisms in exon-1 of the mannose-binding lectin gene at codon-52, -54, and -57. Results At all gestational ages mannose-binding lectin codon-54 increased the risk of the development of diplegia (homozygous or heterozygous odds ratio, 1.55; 95% CI, 1.03-2.32). For babies who were born at term, the risk of the development of quadriplegia was associated with heterozygous tumor necrosis factor– α (odds ratio, 1.82; 95% CI, 1.04-3.15), and mannose-binding lectin codon-54 was associated with diplegia (homozygous or heterozygous odds ratio, 2.12; 95% CI, 1.10-4.05). The presence of any polymorphism in mannose-binding lectin exon–1 at term approximately doubled the risk of the development of diplegia (odds ratio, 1.94; 95% CI, 1.05-3.62). Homozygous or heterozygous tumor necrosis factor– α was associated with hemiplegia for babies who were born at <32 weeks of gestation (odds ratio, 2.38; 95% CI, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with cerebral palsy (odds ratio, 1.37; 95% CI, 1.02-1.84). Conclusion Carriage of polymorphisms in the tumor necrosis factor– α and mannose-binding lectin genes are associated with an increased risk of cerebral palsy.Item Metadata only Associations between fetal inherited thrombophilia and adverse pregnancy outcomes(Mosby Inc, 2006) Gibson, C.; MacLennan, A.; Janssen, N.; Kist, W.; Hague, W.; Haan, E.; Goldwater, P.; Priest, K.; Dekker, G.Objective: The purpose of this study was to investigate associations between fetal inherited thrombophilia and adverse pregnancy outcomes, including pregnancy-induced hypertensive disorders (PIHD), antepartum hemorrhage (APH), small-for-gestational age <10th percentile (SGA), and preterm birth (PTB). Study design: Seven hundred and seventeen cases and 609 controls were genotyped for Factor V Leiden (FVL, G1691A), Prothrombin gene mutation (PGM, G20210A), and Methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C using DNA from newborn screening cards. Results: For babies born <28 weeks' gestation, PGM was associated with an increased risk of SGA (OR 6.40, 95%CI 1.66-24.71) and APH with SGA (OR 6.35, 95%CI 1.63-24.75). Homozygous MTHFR A1298C was associated with an increased risk of SGA for babies born 28-31 weeks gestation (OR 4.00, 95%CI 1.04-15.37), and with APH and SGA for babies born <32 weeks' gestation (OR 3.57, 95%CI 1.09-11.66). Homozygous MTHFR C677T was associated with a reduced risk of PTB and SGA (OR 0.52, 95%CI 0.28-0.96) for babies born 32 to 36 weeks' gestation. Homozygous FVL decreased the risk of PTB <32 weeks' gestation (OR 0.55, 95%CI 0.31-0.98). Conclusion: Fetal thrombophilic polymorphisms may be related to adverse pregnancy outcomes, in particular SGA.Item Metadata only Cerebral palsy litigation - Reply(Amer Medical Assoc, 2006) MacLennan, A.; Nelson, K.; Hankins, G.; Speer, M.Item Open Access Neurotropic viruses and cerebral palsy: population based case-control study(British Med Journal Publ Group, 2006) Gibson, C.; MacLennan, A.; Goldwater, P.; Haan, E.; Priest, K.; Dekker, G.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 Women's and Children's 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.Item Metadata only Genetic polymorphisms and spontaneous preterm birth(Lippincott Williams & Wilkins, 2007) Gibson, C.; MacLennan, A.; Dekker, G.; Goldwater, P.; Dambrosia, J.; Munroe, D.; Tsang, S.; Stewart, C.; Nelson, K.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 beta2 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 beta 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.Item Metadata only Association between apolipoprotein E genotype and cerebral palsy is not confirmed in a caucasian population(Springer, 2008) McMichael, G.; Gibson, C.; Goldwater, P.; Haan, E.; Priest, K.; Dekker, G.; MacLennan, A.Apolipoprotein E (APOE) plays a significant role in lipid metabolism and has been implicated in the growth and repair of injured neurons. Two small studies have suggested an association between APOE genotype and cerebral palsy. We investigated if APOE genotype is associated with an increased risk for cerebral palsy, influences the type of cerebral palsy or interacts with prenatal viral infection to influence risk of cerebral palsy. The population-based case-control study comprised newborn screening cards of 443 Caucasian patients with cerebral palsy and 883 Caucasian matched controls. APOE genotyping was performed on DNA extracted from dried blood spots. Allelic and genotypic frequencies did not differ between cases and controls and combined frequencies were 0.10 (ε2), 0.76 (ε3), 0.14 (ε4), 0.03 (ε2/ε2), 0.10 (ε2/ε3), 0.03 (ε2/ε4), 0.02 (ε4/ε4), 0.21 (ε3/ε4), 0.61 (ε3/ε3). APOE genotype was correlated with cerebral palsy, type of cerebral palsy, gestation at birth and the presence of viral nucleic acids detected in previous work. Analysis by gestational age (all gestational ages, ≥37, 32–36 and <32 weeks) and type of cerebral palsy (all types, diplegia, hemiplegia and quadriplegia) showed no association between APOE genotype and cerebral palsy in this Caucasian population. An association between prenatal viral infection, APOE genotype and cerebral palsy was not demonstrated. These results did not confirm an association between APOE genotype, cerebral palsy, type of cerebral palsy and prenatal infection in a Caucasian population. Given the low frequency of APOE ε2 and some of the heterozygote and homozygote combinations in this study, a larger study is assessing this further.Item Open Access The antenatal causes of cerebral palsy - Genetic and viral associations(Cambridge University Press, 2008) Gibson, C.; MacLennan, A.; Goldwater, P.; Dekker, G.Cerebral palsy is the most common neurological disorder in children. Epidemiological evidence suggests that antenatal origins are a major cause. Currently there is no antenatal test for cerebral palsy, no proven preventable measures in late pregnancy, and no known cure. Cerebral palsy affects not only the diagnosed child, but also their family and the community, requiring considerable social and financial resources to assist these children in their daily lives.Item Metadata only Mannose-binding lectin haplotypes may be associated with cerebral palsy only after perinatal viral exposure(Mosby Inc, 2008) Gibson, C.; MacLennan, A.; Goldwater, P.; Haan, E.; Priest, K.; Dekker, G.Objective The objective of the study was to investigate the associations between infection, polymorphisms in the mannose-binding lectin gene (MBL), and cerebral palsy (CP). Study Design This was a case-control study using deoxyribonucleic acid from newborn screening cards of 443 Caucasian CP cases and 883 Caucasian controls to screen for 6 polymorphisms within the MBL gene. These polymorphisms combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL levels. Results χ² Analyses demonstrated significant differences between CP cases and controls (less than 37 weeks χ² 14.99, P = .02; less than 32 weeks χ² 13.62, P = .02). The MBL haplotype LYPA was associated with CP at all gestations (odds ratio [OR] 1.57, 95% confidence interval [CI], 1.00 to 2.46), less than 37 weeks (OR 2.43, 95% CI, 1.41 to 4.18), and less than 32 weeks (OR 2.54, 95% CI, 1.34 to 4.76). LYPA was also associated with hemiplegic CP for babies born at less than 37 weeks (OR 2.77, 95% CI, 1.02 to 7.26) and less than 32 weeks (OR 4.48, 95% CI, 1.55 to 12.65). HYPD was associated with quadriplegic CP at all gestations (OR 3.47, 95% CI, 1.41 to 8.31) as well as for babies born at less than 32 weeks (OR 7.86, 95% CI, 1.67 to 29.48). Subanalysis on samples previously testing positive for exposure to viral infection demonstrated similar patterns of significance as those presented above, whereas analysis on samples negative for exposure to viral infection showed no positive associations between any of the MBL haplotypes and CP. Potential type I error from multiple analyses is a caveat. Conclusion MBL haplotypes LYPA or HYPD may be associated with an increased risk of CP in the presence of exposure to viral infection and may act as susceptibility factors for CP.
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