Shepherd Emily, Salam Rehana A, Middleton Philippa, Han Shanshan, Makrides Maria, McIntyre Sarah, Badawi Nadia, Crowther Caroline A
ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, South Australia, Australia, 5006.
Cochrane Database Syst Rev. 2018 Jun 20;6(6):CD012409. doi: 10.1002/14651858.CD012409.pub2.
Cerebral palsy is an umbrella term that encompasses disorders of movement and posture attributed to non-progressive disturbances occurring in the developing foetal or infant brain. As there are diverse risk factors and aetiologies, no one strategy will prevent cerebral palsy. Therefore, there is a need to systematically consider all potentially relevant interventions for prevention.
PrimaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions for preventing cerebral palsy (reducing cerebral palsy risk).SecondaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions that may increase cerebral palsy risk.
We searched the Cochrane Database of Systematic Reviews (27 November 2016) for reviews of neonatal interventions reporting on cerebral palsy. Two review authors assessed reviews for inclusion, extracted data, and assessed review quality (using AMSTAR and ROBIS) and quality of the evidence (using the GRADE approach). Reviews were organised by topic; findings were summarised in text and were tabulated. Interventions were categorised as effective (high-quality evidence of effectiveness); possibly effective (moderate-quality evidence of effectiveness); ineffective (high-quality evidence of harm); probably ineffective (moderate-quality evidence of harm or lack of effectiveness); and no conclusions possible (low- to very low-quality evidence).
Forty-three Cochrane Reviews were included. A further 102 reviews pre-specified the outcome cerebral palsy, but none of the included randomised controlled trials (RCTs) reported this outcome. Included reviews were generally of high quality and had low risk of bias, as determined by AMSTAR and ROBIS. These reviews involved 454 RCTs; data for cerebral palsy were available from 96 (21%) RCTs involving 15,885 children. Review authors considered interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathy (3); interventions for neonates born preterm and/or at low or very low birthweight (33); and interventions for other specific groups of 'at risk' neonates (7). Quality of evidence (GRADE) ranged from very low to high.Interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathyEffective interventions: high-quality evidence of effectivenessResearchers found a reduction in cerebral palsy following therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.54 to 0.82; seven trials; 881 children).No conclusions possible: very low-quality evidenceOne review observed no clear differences in cerebral palsy following therapeutic hypothermia versus standard care.Interventions for neonates born preterm and/or at low or very low birthweightPossibly effective interventions: moderate-quality evidence of effectivenessResearchers found a reduction in cerebral palsy with prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants (RR 0.54, 95% CI 0.32 to 0.92; one trial; 644 children).Probably ineffective interventions: moderate-quality evidence of harmResearchers reported an increase in cerebral palsy (RR 1.45, 95% CI 1.06 to 1.98; 12 trials; 1452 children) and cerebral palsy in assessed survivors (RR 1.50, 95% CI 1.13 to 2.00; 12 trials; 959 children) following early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants.Probably ineffective interventions: moderate-quality evidence of lack of effectivenessTrial results showed no clear differences in cerebral palsy following ethamsylate versus placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (RR 1.13, 95% CI 0.64 to 2.00; three trials, 532 children); volume expansion versus no treatment (RR 0.76, 95% CI 0.48 to 1.20; one trial; 604 children); gelatin versus fresh frozen plasma (RR 0.94, 95% CI 0.52 to 1.69; one trial, 399 children) for prevention of morbidity and mortality in very preterm infants; prophylactic indomethacin versus placebo for preventing mortality and morbidity in preterm infants (RR 1.04, 95% CI 0.77 to 1.40; four trials; 1372 children); synthetic surfactant versus placebo for respiratory distress syndrome in preterm infants (RR 0.76, 95% CI 0.55 to 1.05; five trials; 1557 children); or prophylactic phototherapy versus standard care (starting phototherapy when serum bilirubin reached a pre-specified level) for preventing jaundice in preterm or low birthweight infants (RR 0.96, 95% CI 0.50 to 1.85; two trials; 756 children).No conclusions possible: low- to very low-quality evidenceNo clear differences in cerebral palsy were observed with interventions assessed in 21 reviews.Interventions for other specific groups of 'at risk' neonatesNo conclusions possible: low- to very low-quality evidenceReview authors observed no clear differences in cerebral palsy with interventions assessed in five reviews.
AUTHORS' CONCLUSIONS: This overview summarises evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions on cerebral palsy, and can be used by researchers, funding bodies, policy makers, clinicians, and consumers to aid decision-making and evidence translation. To formally assess other benefits and/or harms of included interventions, including impact on risk factors for cerebral palsy, review of the included Reviews is recommended.Therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy can prevent cerebral palsy, and prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants may reduce cerebral palsy risk. Early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants may increase cerebral palsy risk.Cerebral palsy is rarely identified at birth, has diverse risk factors and aetiologies, and is diagnosed in approximately one in 500 children. To date, only a small proportion of Cochrane Systematic Reviews assessing neonatal interventions have been able to report on this outcome. There is an urgent need for long-term follow-up of RCTs of such interventions addressing risk factors for cerebral palsy (through strategies such as data linkage with registries) and for consideration of the use of relatively new interim assessments (including the General Movements Assessment). Such RCTs must be rigorous in their design and must aim for consistency in cerebral palsy outcome measurement and reporting to facilitate pooling of data and thus to maximise research efforts focused on prevention.
脑瘫是一个统称，涵盖了因胎儿或婴儿发育中的大脑发生非进行性紊乱而导致的运动和姿势障碍。由于存在多种风险因素和病因，没有一种策略能够预防脑瘫。因此，有必要系统地考虑所有可能相关的预防干预措施。
主要目的是总结Cochrane系统评价中关于新生儿干预措施预防脑瘫（降低脑瘫风险）效果的证据。次要目的是总结Cochrane系统评价中关于可能增加脑瘫风险的新生儿干预措施效果的证据。
我们检索了Cochrane系统评价数据库（2016年11月27日），以查找报告脑瘫情况的新生儿干预措施的评价。两位评价作者评估评价是否纳入，提取数据，并评估评价质量（使用AMSTAR和ROBIS）以及证据质量（使用GRADE方法）。评价按主题进行组织；研究结果以文字形式总结并制成表格。干预措施分为有效（高质量的有效性证据）；可能有效（中等质量的有效性证据）；无效（高质量的危害证据）；可能无效（中等质量的危害或无效证据）；以及无法得出结论（低至极低质量的证据）。
纳入了43篇Cochrane评价。另有102篇评价预先设定了脑瘫这一结局，但纳入的随机对照试验（RCT）均未报告这一结局。根据AMSTAR和ROBIS的评估，纳入的评价总体质量较高，偏倚风险较低。这些评价涉及454项RCT；有96项（21%）RCT涉及15885名儿童提供了脑瘫数据。评价作者考虑了针对围产期窒息或有新生儿脑病证据的新生儿的干预措施（3项）；针对早产和/或低出生体重或极低出生体重新生儿的干预措施（33项）；以及针对其他特定“高危”新生儿群体的干预措施（7项）。证据质量（GRADE）从极低到高不等。针对围产期窒息或有新生儿脑病证据的新生儿的干预措施有效干预措施：高质量的有效性证据研究人员发现，对于患有缺氧缺血性脑病的新生儿，治疗性低温与标准护理相比，脑瘫发生率降低（风险比（RR）0.66，95%置信区间（CI）0.54至0.82；7项试验；881名儿童）。无法得出结论：极低质量的证据一项评价观察到，治疗性低温与标准护理相比，脑瘫方面无明显差异。针对早产和/或低出生体重或极低出生体重新生儿的干预措施可能有效干预措施：中等质量的有效性证据研究人员发现，对于早产儿气管插管，预防性使用甲基黄嘌呤（咖啡因）与安慰剂相比，脑瘫发生率降低（RR 0.54，95%CI 0.32至0.92；1项试验；644名儿童）。可能无效干预措施：中等质量的危害证据研究人员报告，对于预防早产儿慢性肺病，早期（出生后8天内）使用产后皮质类固醇与安慰剂或不治疗相比，脑瘫发生率增加（RR 1.45，95%CI 1.06至1.98；12项试验；1452名儿童），且评估的存活者中脑瘫发生率增加（RR 1.50，95%CI 1.13至2.00；12项试验；959名儿童）。可能无效干预措施：中等质量缺乏有效性的证据试验结果显示，对于预防早产或极低出生体重婴儿的发病和死亡，氨甲环酸与安慰剂相比，脑瘫方面无明显差异（RR 1.13，95%CI 0.64至2.00；3项试验，532名儿童）；扩容与不治疗相比（RR 0.76，95%CI 0.48至1.20；1项试验；604名儿童）；明胶与新鲜冰冻血浆相比（RR 0.94，95%CI 0.52至1.69；1项试验，399名儿童）用于预防极早产儿的发病和死亡；预防性使用吲哚美辛与安慰剂相比用于预防早产儿的死亡和发病（RR 1.04，95%CI 0.77至1.40；4项试验；1372名儿童）；合成表面活性剂与安慰剂相比用于治疗早产儿呼吸窘迫综合征（RR 0.76，95%CI 0.55至1.05；5项试验；1557名儿童）；或预防性光疗与标准护理（当血清胆红素达到预先设定水平时开始光疗）相比用于预防早产或低出生体重婴儿的黄疸（RR 0.96，95%CI 0.50至1.85；2项试验；756名儿童）。无法得出结论：低至极低质量的证据在21篇评价中评估的干预措施，在脑瘫方面未观察到明显差异。针对其他特定“高危”新生儿群体的干预措施无法得出结论：低至极低质量的证据评价作者在5篇评价中评估的干预措施中，未观察到脑瘫方面的明显差异。
本综述总结了Cochrane系统评价中关于新生儿干预措施对脑瘫影响的证据，研究人员、资助机构、政策制定者、临床医生和消费者可利用这些证据来辅助决策和证据转化。为了正式评估纳入干预措施的其他益处和/或危害，包括对脑瘫风险因素的影响，建议对纳入的评价进行综述。对于患有缺氧缺血性脑病的新生儿，治疗性低温与标准护理相比可预防脑瘫，对于早产儿气管插管，预防性使用甲基黄嘌呤（咖啡因）与安慰剂相比可能降低脑瘫风险。对于预防早产儿慢性肺病，早期（出生后8天内）使用产后皮质类固醇与安慰剂或不治疗相比可能增加脑瘫风险。脑瘫在出生时很少被识别，有多种风险因素和病因，约每500名儿童中就有1名被诊断为脑瘫。迄今为止，评估新生儿干预措施的Cochrane系统评价中只有一小部分能够报告这一结局。迫切需要对这类干预措施的RCT进行长期随访，以解决脑瘫的风险因素（通过与登记处的数据链接等策略），并考虑使用相对较新的中期评估（包括全身运动评估）。此类RCT的设计必须严谨，必须力求在脑瘫结局测量和报告方面保持一致，以促进数据汇总，从而最大限度地加大专注于预防的研究力度。
