Closing Research Gaps for Cerebral Palsy Prevention and Magnesium Sulphate Neuroprotection

Abstract

Background: Cerebral palsy (CP) is the leading cause of physical disability in childhood. Despite emerging evidence that the prevalence of CP has begun to decline, approximately one in 500 babies continue to be affected worldwide. While causes and risk factors for CP are well established, potential preventive interventions are under-researched. Aims: 1. To summarise and interpret the evidence regarding antenatal and intrapartum interventions for preventing CP. 2. To summarise and interpret the evidence regarding neonatal interventions for preventing CP. 3. To link data from a maternal perinatal randomised controlled trial (RCT) with a nationwide CP register to identify children with CP. 4. To assess whether antenatal magnesium sulphate is associated with perinatal death or other adverse neonatal outcomes. Methods: To achieve the above aims, the following methodologies were employed: 1. An overview of Cochrane reviews regarding antenatal and intrapartum interventions for CP prevention. 2. An overview of Cochrane reviews regarding neonatal interventions for CP prevention. 3. A de-identified linkage of Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) and Australian Cerebral Palsy Register (ACPR) data. 4. A systematic review of RCTs and non-randomised studies assessing antenatal magnesium sulphate, perinatal death and other adverse neonatal outcomes. Results: 1. The overview of antenatal and intrapartum interventions included 15 Cochrane reviews, with CP data from 27 RCTs (32,490 children). Magnesium sulphate for women at risk of very preterm birth for fetal neuroprotection reduced CP risk (high-quality evidence). CP risk was probably increased (moderate-quality evidence, 2 reviews), probably not changed (moderate-quality evidence, 1 review), or unclear (low- to very low-quality evidence, 11 reviews) with other interventions assessed. 2. The overview of neonatal interventions included 43 Cochrane reviews, with CP data from 96 RCTs (15,885 children). Therapeutic hypothermia in late preterm or term neonates with hypoxic-ischaemic encephalopathy reduced CP risk (high-quality evidence), and prophylactic methylxanthines for endotracheal extubation in preterm neonates probably reduced CP risk (moderate-quality evidence). CP risk was probably increased (moderate-quality evidence, 2 reviews), probably not changed (moderate-quality evidence, 5 reviews), or unclear (low- to very low-quality evidence, 26 reviews) with other interventions assessed. 3. Linkage of data from 913 ACTOMgSO4 children (born 1996-2000) and the ACPR was achieved. Differences in ACTOMgSO4 (at 2 years) and ACPR (up to 5 years) CP diagnoses were identified; attributed to limitations in CP diagnostic methods, and register under-ascertainment in this era. 4. The systematic review of adverse neonatal outcomes included 40 RCTs (19,265 women and their babies), 138 non-randomised studies, and 19 case reports. Perinatal death was not increased with antenatal magnesium sulphate in RCTs. RCTs showed no clear increased risks of other adverse neonatal outcomes; non-randomised studies identified a limited number of outcomes necessitating further evaluation. Conclusions: Antenatal magnesium sulphate for fetal neuroprotection in women at risk of very preterm birth, and therapeutic hypothermia in late preterm or term neonates with hypoxic-ischaemic encephalopathy reduce the risk of CP. There is an urgent need for further research regarding the effects of other identified interventions on CP, and on strategies to assess CP following maternal perinatal RCTs.