Ohlsson Arne, Shah Prakeshkumar S
University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, Toronto, Canada.
University of Toronto Mount Sinai Hospital, Department of Paediatrics and Institute of Health Policy, Management and Evaluation, 600 University Avenue, Toronto, ON, Canada, M5G 1XB.
Cochrane Database Syst Rev. 2020 Jan 27;1(1):CD010061. doi: 10.1002/14651858.CD010061.pub4.
In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported.
To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or low birth weight infants.
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials.
We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (≤ 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol.
We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (µmol/L).
We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence). Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence). Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD -0.01, 95% CI -0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group.
AUTHORS' CONCLUSIONS: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.
在早产新生儿中，动脉导管常常未能闭合，婴儿需要通过药物或手术来闭合动脉导管未闭（PDA）。PDA 可以通过手术治疗；也可以使用两种前列腺素抑制剂之一（吲哚美辛或布洛芬）进行药物治疗。病例报告表明，对乙酰氨基酚可能是闭合 PDA 的一种替代药物。有报道称，产前或产后接触对乙酰氨基酚与后来患自闭症或自闭症谱系障碍之间存在关联。
确定静脉注射或口服对乙酰氨基酚与安慰剂或不干预、静脉注射吲哚美辛、静脉注射或口服布洛芬，或与其他环氧化酶抑制剂相比，用于治疗经超声心动图诊断的早产或低出生体重婴儿 PDA 的有效性和安全性。
我们采用Cochrane新生儿组的标准检索策略，检索Cochrane对照试验中心注册库（CENTRAL 2017年第10期）、通过PubMed检索MEDLINE（1966年至2017年11月6日）、Embase（1980年至2017年11月6日）和CINAHL（1982年至2017年11月6日）。我们检索了临床试验数据库、会议论文集以及检索到的文章的参考文献列表，以查找随机对照试验（RCT）和半随机试验。
我们纳入了将对乙酰氨基酚与不干预、安慰剂或用于闭合PDA的其他药物进行比较的RCT，纳入的早产（月经龄≤34周）婴儿不考虑剂量、疗程和给药方式。我们既审查了检索结果，又通过讨论最终选定了可能符合条件的文章。我们纳入了对乙酰氨基酚预防性和治疗性使用的研究。
我们按照Cochrane新生儿综述组的方法进行数据收集和分析。当有数据时，我们采用GRADE方法评估以下结局的证据质量：首个疗程治疗后导管闭合失败；神经发育障碍；初次住院期间的全因死亡率（死亡）；胃肠道出血或大便潜血阳性；以及治疗后的血清肌酐水平（µmol/L）。
我们纳入了八项报告了916名婴儿的研究。其中一项研究将对乙酰氨基酚与布洛芬和吲哚美辛进行了比较。五项研究将对乙酰氨基酚治疗PDA与布洛芬进行了比较，共纳入559名婴儿。在首个疗程药物给药后，对乙酰氨基酚与布洛芬在导管闭合失败方面无显著差异（典型风险比（RR）0.95，95%置信区间（CI）0.75至1.21；典型风险差（RD）-0.02，95%CI -0.09至0.09）；RR和RD的I² = 0%；证据质量为中等。四项研究（n = 537）报告了胃肠道出血情况，对乙酰氨基酚组低于布洛芬组（典型RR 0.28，95%CI 0.12至0.69；典型RD -0.06，95%CI -0.09至-0.02）；RR和RD的I² = 0%；获得额外有益结局所需治疗人数（NNTB）为17（95%CI 11至50）；证据质量为中等。四项研究中，对乙酰氨基酚组的血清肌酐水平低于布洛芬组（证据质量为中等），两项研究（n = 290）中治疗后的血清胆红素水平也是如此。对乙酰氨基酚组的血小板计数和每日尿量高于布洛芬组。一项研究报告了对乙酰氨基酚与布洛芬治疗后至年龄18至24个月的长期随访情况。18至24个月时的神经学结局无显著差异（n = 61）；（证据质量低）。两项研究将对乙酰氨基酚预防性用于PDA与安慰剂或不干预在80名婴儿中进行了比较。与安慰剂或不干预相比，对乙酰氨基酚在治疗4至5天后导管闭合失败率较低，典型RR 0.49（95%CI 0.24至1.00；P = 0.05）具有临界显著性；但典型RD -0.21（95%CI -0.41至-0.02）具有显著性；RR和RD的I² = 0%；NNTB为5（95%CI 2至50）；（证据质量低）。两项研究（n = 277）将对乙酰氨基酚与吲哚美辛进行了比较。在PDA闭合失败方面无显著差异（典型RR 0.96，95%CI 0.55至1.65；I² = ；典型RD -0.01，95%CI -0.09至0.08；I² = 17%）（证据质量低）。对乙酰氨基酚组的血清肌酐水平显著低于吲哚美辛组，对乙酰氨基酚组的血小板计数和每日尿量显著更高。
根据GRADE，中等质量证据表明对乙酰氨基酚与布洛芬效果相当；低质量证据表明对乙酰氨基酚比安慰剂或不干预更有效；低质量证据表明对乙酰氨基酚在闭合PDA方面与吲哚美辛效果相当。与布洛芬相比，接触对乙酰氨基酚的儿童神经发育结局无差异；然而证据质量低且仅来自一项研究。鉴于产前和产后接触对乙酰氨基酚后对神经发育结局的担忧，在任何关于新生儿对乙酰氨基酚的研究中，必须纳入至少至出生后18至24个月的长期随访。至少有19项正在进行的试验已注册。在能够就对乙酰氨基酚在新生儿中可能的常规使用提出任何建议之前，需要进行此类试验。
