John Keogh

A systematic review of risk factors for cerebral palsy in children born at term in developed countries

Aim  The aim of this study was to conduct a systematic review in order to identify the risk factors for cerebral palsy (CP) in children born at term. The secondary aim was to ascertain if the potential for prevention of these risk factors has been adequately explored.

The origins of cerebral palsy.

Purpose of reviewCerebral palsy is the most common and visible motor disability of childhood. Its aetiology remains a topic of hot debate between those who see it as a reflection of medical mismanagement of an avoidable complication and those who see its origins in the development of the fetal brain affected at many points along a causal pathway to damage. This review outlines the themes of research publications over the year 2004/2005. Recent findingsThe review looks at recent findings relating to epidemiology, infection and inflammation, prematurity, multiple pregnancy, thrombophilias, genetics, placenta, neuroimaging and rescue therapies in cerebral palsy. SummaryPapers this year have helped clarify risk groups and identify some areas (e.g. the management of thrombophilias and the potential of induced hypothermia) with the potential to be rapidly introduced into clinical practice. In this enigmatic and multifactorial condition, however, progress remains slow. New tools such as magnetic resonance imaging are providing valuable insights into the lesions that result in cerebral palsy but the pathways to injury remain unclear. The future of cerebral palsy research lies in understanding the complex interactions of multiple factors on the road to cerebral palsy or in looking for final common pathways such as inflammation which may be amenable to manipulation.

Cerebral palsy following term newborn encephalopathy : a population-based study

Cerebral palsy (CP) can occur in term infants with or without preceding newborn encephalopathy. We compared the type and severity of CP and associated disability in these two groups. Participants from a population-based case-control study of term newborn encephalopathy were followed up for 6 years and linked to the Western Australian Cerebral Palsy Register. The remaining term infants with CP for the same period were also identified from the Cerebral Palsy Register. 13% of neonatal survivors of term newborn encephalopathy had CP, a rate of 116 per 1000 term live births. Overall, 24% of term infants with CP followed newborn encephalopathy. CP following newborn encephalopathy was more likely to: affect males (72% vs 56%); be severe (47% vs 25%); and be of spastic quadriplegia or dyskinetic types. Cognitive impairment was more common (75% vs 43%) and severe (41% vs 16%), as was epilepsy (53% vs 29%) in survivors of encephalopathy. These children were also more likely to: be non-verbal (47% vs 22%); have a severe composite disability score (47% vs 26%); and die between time of diagnosis of CP and age 6 years (5-year cumulative mortality 19% vs 5%). Children born at term who develop CP following newborn encephalopathy have a poorer prognosis than those with CP who were not encephalopathic in the first week of life.

Trends in mode of delivery during 1984–2003: can they be explained by pregnancy and delivery complications?

Objectives  To describe trends in mode of delivery, to identify significant factors which affected mode of delivery, and to describe how these factors and their impact have changed over time.

Antecedents of cerebral palsy and perinatal death in term and late preterm singletons.

OBJECTIVE: To examine the antecedents of cerebral palsy and of perinatal death in singletons born at or after 35 weeks of gestation. METHODS: From a total population of singletons born at or after 35 weeks of gestation, we identified 494 with cerebral palsy and 508 neonates in a matched control group, 100 neonatal deaths, and 73 intrapartum stillbirths (all deaths in selected birth years). Neonatal death and cerebral palsy were categorized as without encephalopathy, after neonatal encephalopathy, or after neonatal encephalopathy considered hypoxic–ischemic. We examined the contribution of potentially asphyxial birth events, inflammation, fetal growth restriction, and birth defects recognized by age 6 years to each of these outcomes and to intrapartum stillbirths. RESULTS: The odds of total cerebral palsy after potentially asphyxial birth events or inflammation were modestly increased (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1–3.2 and OR 2.2, 95% CI 1.0–4.2, respectively). However, potentially asphyxial birth events occurred in 34% of intrapartum stillbirths and 21.6% of cerebral palsy after hypoxic–ischemic encephalopathy. Inflammatory markers occurred in 13.9% and 11.9% of these outcomes, respectively. Growth restriction contributed significantly to all poor outcome groups. Birth defects were recognized in 5.5% of neonates in the control group compared with 60% of neonatal deaths and more than half of cases of cerebral palsy without hypoxic–ischemic encephalopathy. In children with cerebral palsy, a potentially asphyxial birth event, inflammation, or both were experienced by 12.6%, whereas growth restriction, a birth defect, or both were experienced by 48.6% (P<.001). CONCLUSION: Fetal growth restriction and birth defects recognized by age 6 years were more substantial contributors to cerebral palsy and neonatal death than potentially asphyxial birth events and inflammation. LEVEL OF EVIDENCE: II

Autism following a history of newborn encephalopathy: More than a coincidence?

Between June 1993 and December 1996, 276 term newborn infants with encephalopathy and 564 randomly selected term controls were enrolled in a population‐based study of moderate and severe term newborn encephalopathy (NE) in Western Australia. During comprehensive neurobehavioural and cognitive follow‐up of all patients and controls at 3 years and again at 5 years of age we found an unexpected but strong association between NE and autism spectrum disorders (ASDs). A diagnosis of ASD by age 5 years was reached using criteria according of the Diagnostic Statistical Manual, 4th edition. Linking records to the Western Australian Disability Services Commission Register ensured that no child in the study with ASD was missed. By age 5 years, 37 (13.4%) infants with NE and one (0.2%) control had died. Among the 239 survivors of NE, 12 (5%) were diagnosed with an ASD. Of these, 10 (4.2%) met the full criteria for autism, one had pervasive developmental disorder‐not otherwise specified, and one had Asperger syndrome. Among the 563 surviving controls, five (0.8%) were diagnosed with an ASD: three with autism, one with autism/possible Asperger syndrome, and one with Asperger syndrome. Compared with the controls, the children who had experienced NE were 5.9 times (95% confidence interval 2.0–16.9) more likely to have been diagnosed with an ASD.

Causal pathways in cerebral palsy

In 1977, the National Health and Medical Research Council (NHMRC), the peak funding body for medical research in Australia, allocated

Why is the placenta being ignored

4000 to a junior researcher from Perth, Western Australia (WA). The brief was to set up a populationbased register of cerebral palsy (CP) in a state with a relatively stable and non-mobile population. CP, the most common disability of childhood, is a non-progressive, motor disorder of infancy and childhood, frequently but not invariably linked with other conditions such as epilepsy and intellectual disability. It affects one in 500 liveborn babies and, until recently, was stubbornly resistant to all efforts to reduce its incidence. Currently, nearly 40 000 Australians live with CP. In 1977, with preterm babies beginning to receive neonatal intensive care and neurological follow-up showing a high chance of longterm disability, it seemed possible that we were on the edge of a CP epidemic. Conventional wisdom, then largely unchallenged for 200 years, stated that CP was almost invariably due to ‘birth asphyxia’ (hypoxia and cerebral ischaemia during the birth process); in other words, a failure of obstetric care. Around this assumption had grown an industry of punitive litigation, where families in great need of assistance sought to fund the expenses of care for their disabled child through an expensive and personally destructive legal system. The system was slow, unwieldy and confrontational. Moreover, it required a villain to be identified responsible for each victim. It was, in effect, a modification of a criminal code to deal with a situation where it was believed that the outcome was invariably a result of negligence. Obstetricians largely bought into this story. Watching their professional indemnity premiums soar, they sought to improve their capacity to identify where they were going wrong. Believing that the answer to this seemingly insoluble problem must lie in their practice around labour, they focused almost exclusively on this window and sought to identify a monitoring system where an early warning would allow them to intervene and thus avoid injury. Electronic fetal monitoring was accepted wholesale into care, despite the fact that it was completely unproven. Caesarean section rates soared as clinicians responded to abnormal fetal heart rate patterns in labour, the significance of which were, in fact, uncertain. Birth increasingly became identified with risk, and yet, in all of this, CP rates stayed frustratingly constant. The acceptance of this dogma held back research into the wider picture of CP for a generation, and although it is the most common disability of childhood, progress in this area remains well behind other less common conditions such as childhood cancer. To be fair, the pressure on the obstetricians was unreasonable. Any clinician who has looked after a woman through her pregnancy knows how close that bond becomes by the time of birth. The thought that a doctor might be responsible for a child in his/her care’s lifelong disability was, and remains, too terrible to face. The knowledge that this was going to be highlighted and reinforced through years of court action only made this feeling of despair more acute. It was no wonder that they became less and less tolerant of any variation of labour and moved more and more quickly to Caesarean section, where no one could say that they had not done everything that was possible. Entering into this state of dogma, dispute and defensive medicine are Karin Nelson and the Collaborative Perinatal Project. Somewhat unexpectedly, her research demonstrated that many cases of CP had uneventful births and newborn periods. Many strong associations were suggested during pregnancy and even before pregnancy. Conventional wisdom was, it seemed, potentially flawed. Interestingly, Sigmund Freud had previously asked the question why, with 280 days in pregnancy, all neurological injury should be assumed to take place in the last 12 h of pregnancy, often the last minutes. This radical idea had gained little traction, and in general, there was great resistance to the findings of Nelson and her colleagues. Fiona Stanley, who recently returned to WA and embarking on a research career, decided that if we were to make any headway in the field of CP, it was time to stop being informed by expert opinion and to start collecting some hard data. The princely sum of

Developmental outcomes of newborn encephalopathy in the term infant

4000 allocated by the NHMRC must remain one of the best investments ever made by any funding body in the world. Out of that seed fund grew the Western Australian Cerebral Palsy (WA CP) Register, which identified and collected extensive data on all cases of CP in WA. It could later be linked to the Maternal and Child Health Research Data Base and the Birth Defects Register (another innovation of Stanley’s team). Cases were notified from multiple sources, and case ascertainment was remarkably robust. This allowed not only data collection on cases but also, unlike so many previous case series, comparison with contemporaneous controls. Stanley and Blair started to produce data demonstrating that, far from most CP being due to birth injury, at most 10% of CP could be attributed to events in this epoch. Suddenly, because someone was looking, all sorts of new associations were being Correspondence: Professor Nadia Badawi, Grace Centre for Newborn Care, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Fax: +61 29845 2251; email: nadia.badawi@ health.nsw.gov.au

Incidence of fetal macrosomia and birth complications in Chinese immigrant women

The relationship between the frequency of published recommended indications for placental pathological examination and the frequency of requests for such examination in a population‐based study of term newborn encephalopathy was examined. Only 11.2% of placentas among 276 case infants and 0.7% of placentas among 564 term control infants were examined. Using the criteria set out in a consensus statement by the American College of Pathologists, all 276 cases fulfilled multiple maternal, fetal and placental indications for placental examination. Furthermore 43.3% of control infants fulfilled at least one criterion. Of the 25 case placentas that underwent pathological review, 16 were reported as having no diagnostic abnormality. Six cases (24%) showed clinically important findings: four had evidence of infection, one had multiple chorangiomata and one had thrombosis and rupture of the umbilical vein. Of the three remaining placentas, one showed funisitis, one showed minor lymphohistiocytic villitis and one was from monochorionic twins. To our knowledge there are no agreed Australian guidelines for when a placenta should be submitted for pathological examination. We suggest that until guidelines based on properly designed studies are developed it may be appropriate to store all placentas for at least 72 hours. If the infant develops neurological symptoms or requires unexpected admission to a neonatal intensive care unit then placental examination may reveal important aetiological diagnostic and prognostic information.