Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial
Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial
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DOI：
10.1136/bmj.e3799
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发表时间：
2012-06-13
影响因子：
105.7
通讯作者：
Thornton, James G.
中科院分区：
文献类型：
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作者：
Chappell, Lucy C.;Gurung, Vinita;Thornton, James G.
目的探讨熊去氧胆酸是否能减轻妊娠期肝内胆汁淤积症妇女的瘙痒，早产是否不会增加剖宫产的发生率，以及招募妊娠期肝内胆汁淤积症妇女参与这些干预试验的可行性。设计：半因子随机对照试验的第一阶段。背景：英国，九个顾问领导的产科单位。参与者125名妊娠期肝内胆汁淤积（瘙痒和血清胆汁酸水平升高）或瘙痒和谷丙转氨酶水平升高（bbb100 IU/L）的妇女在妊娠24周后招募，并随访至分娩。56名妇女随机接受熊去氧胆酸治疗，55名接受安慰剂治疗，30名接受早产治疗，32名接受待产治疗。干预措施：熊去氧胆酸500 mg，每日2次，或根据症状或生化改善的需要增加安慰剂剂量，直至分娩；早产（引产或在37+0至37+6之间开始分娩）或待产管理（自然分娩等到妊娠40周或根据正常产科指南进行剖腹产，通常在妊娠39周之后）。主要结局指标熊去氧胆酸的主要结局指标为产妇瘙痒（24小时内最严重瘙痒的算术平均值（100 mm视觉模拟量表）），分娩时机为剖宫产。次要结局是其他孕产妇和围产期结局和招募率。结果熊去氧胆酸减少瘙痒-16 mm(95%置信区间-27 mm至-6 mm)，小于临床医生和女性预先指定的30 mm的临床意义差异。32%（14/44）随机分配到熊去氧胆酸组的女性，与16%（6/37）随机分配到安慰剂组的女性相比，最严重的瘙痒减少了至少30毫米。差异为16%(95%置信区间-3 ~ 34)；这将表示需要处理6的数字，但它没有达到意义。早产并未增加剖宫产率(早产组为7/30(23%)，而准管理组为11/32(33%)（相对危险度0.70,95%可信区间0.31 ~ 1.57）。两项试验均未发现严重危害。22%（73/325）符合条件的妇女参加了药物试验，19%（39/209）参加了分娩时间试验；两组患者的疾病严重程度与非参与者相似。结论熊去氧胆酸可显著减轻瘙痒，但其益处可能太小，大多数医生不推荐，大多数妇女也不愿意服用。然而，女性在是否认为这种好处值得方面可能会有所不同。计划中的早产似乎不会增加剖腹产的发生率，尽管不能排除有少量的增加。测试熊去氧胆酸是否能减少围产期不良结局的试验必须是大规模的，但这是可行的。一项测试早产对不良胎儿结局影响的试验必须要有更大的规模，而且可能不可行。
Objectives To test whether ursodeoxycholic acid reduces pruritus in women with intrahepatic cholestasis of pregnancy, whether early term delivery does not increase the incidence of caesarean section, and the feasibility of recruiting women with intrahepatic cholestasis of pregnancy to trials of these interventions.Design First phase of a semifactorial randomised controlled trial.Setting Nine consultant led maternity units, United Kingdom.Participants 125 women with intrahepatic cholestasis of pregnancy (pruritus and raised levels of serum bile acids) or pruritus and raised alanine transaminase levels (>100 IU/L) recruited after 24 weeks' gestation and followed until delivery. 56 women were randomised to ursodeoxycholic acid, 55 to placebo, 30 to early term delivery, and 32 to expectant management.Interventions Ursodeoxycholic acid 500 mg twice daily or placebo increased as necessary for symptomatic or biochemical improvement until delivery; early term delivery (induction or delivery started between 37+0 and 37+6) or expectant management (spontaneous labour awaited until 40 weeks' gestation or caesarean section undertaken by normal obstetric guidelines, usually after 39 weeks' gestation).Main outcome measures The primary outcome for ursodeoxycholic acid was maternal itch (arithmetic mean of measures (100 mm visual analogue scale) of worst itch in past 24 hours) and for the timing of delivery was caesarean section. Secondary outcomes were other maternal and perinatal outcomes and recruitment rates.Results Ursodeoxycholic acid reduced itching by -16 mm (95% confidence interval -27 mm to -6 mm), less than the 30 mm difference prespecified by clinicians and women as clinically meaningful. 32% (14/44) of women randomised to ursodeoxycholic acid experienced a reduction in worst itching by at least 30 mm compared with 16% (6/37) randomised to placebo. The difference of 16% (95% confidence interval -3 to 34); this would represent a number needed to treat of 6, but it failed to reach significance. Early term delivery did not increase caesarean sections (7/30 (23%) in the early term delivery group versus 11/32 (33%) in the expectant management group (relative risk 0.70, 95% confidence interval 0.31 to 1.57). No serious harms were noted in either trial. 22% (73/325) of eligible women participated in the drug trial and 19% (39/209) in the timing of delivery trial; both groups had a similar spectrum of disease severity to non-participants.Conclusions Ursodeoxycholic acid significantly reduces pruritus, but the size of the benefit may be too small for most doctors to recommend it, or for most women to want to take it. Women are, however, likely to differ in whether they consider the benefit to be worthwhile. Planned early term delivery seems not to increase incidence of caesarean section, although a small increase cannot be excluded. A trial to test whether ursodeoxycholic acid reduces adverse perinatal outcomes would have to be large, but is feasible. A trial to test the effect of early term delivery on adverse fetal outcomes would have to be significantly larger and may not be feasible.