疑似胎儿缺氧时给予母体别嘌醇：一种新型神经保护干预措施？一项多中心随机安慰剂对照试验。

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

作者信息

Kaandorp Joepe J, Benders Manon J N L, Schuit Ewoud, Rademaker Carin M A, Oudijk Martijn A, Porath Martina M, Oetomo Sidarto Bambang, Wouters Maurice G A J, van Elburg Ruurd M, Franssen Maureen T M, Bos Arie F, de Haan Timo R, Boon Janine, de Boer Inge P, Rijnders Robbert J P, Jacobs Corrie J W F M, Scheepers Liesbeth H C J, Gavilanes Danilo A W, Bloemenkamp Kitty W M, Rijken Monique, van Meir Claudia A, von Lindern Jeannette S, Huisjes Anjoke J M, Bakker Saskia C M J E R, Mol Ben W J, Visser Gerard H A, Van Bel Frank, Derks Jan B

机构信息

Department of Perinatology, University Medical Center, Utrecht, The Netherlands.

Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.

出版信息

Arch Dis Child Fetal Neonatal Ed. 2015 May;100(3):F216-23. doi: 10.1136/archdischild-2014-306769. Epub 2014 Dec 15.

DOI:10.1136/archdischild-2014-306769

PMID:25512466

Abstract

OBJECTIVE

To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage.

DESIGN

A randomised double-blind placebo controlled multicentre trial.

PATIENTS

We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery.

SETTING

Delivery rooms of 11 Dutch hospitals.

INTERVENTION

When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT).

MAIN OUTCOME MEASURES

Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage.

RESULTS

222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)).

CONCLUSIONS

Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls.

TRIAL REGISTRATION NUMBER

NCT00189007, Dutch Trial Register NTR1383.

摘要

目的

确定在怀疑胎儿缺氧时给予母亲别嘌醇治疗是否会减少与新生儿脑损伤相关的生物标志物的释放。

设计

一项随机双盲安慰剂对照多中心试验。

患者

我们研究了足月分娩且有胎儿缺氧临床指标、需立即分娩的女性。

地点

11家荷兰医院的产房。

干预措施

当基于怀疑胎儿缺氧预计需立即分娩时，将女性分为接受500mg静脉注射别嘌醇（ALLO）组或静脉注射安慰剂（CONT）组。

主要观察指标

主要终点是脐血中S100β的差异，S100β是脑损伤的组织特异性生物标志物。

结果

222名女性被随机分为接受别嘌醇组（ALLO，n = 111）或安慰剂组（CONT，n = 111）。两组脐血S100β无显著差异：ALLO组为44.5 pg/mL（IQR 20.2 - 71.4），CONT组为54.9 pg/mL（IQR 26.8 - 94.7）（中位数差异为 -7.69（95%CI -24.9至9.52））。事后亚组分析显示，别嘌醇对脐血S100β值高于第75百分位数的女孩比例可能有治疗效果（ALLO组n = 5（12%），CONT组n = 10（31%）；风险比（RR）0.37（95%CI 0.14至0.99）），但对男孩无此效果（ALLO组n = 18（32%），CONT组n = 1（25%）；RR 1.4（95%CI 0.84至2.3））。此外，与接受安慰剂治疗的女孩相比，接受别嘌醇治疗的女孩脐血神经酮体水平显著降低：ALLO组为18.0 pg/mL（95%CI 12.1至26.9），CONT组为32.2 pg/mL（95%CI 22.7至45.7）（几何平均差异为 -16.4（95%CI -24.6至 -1.64））。