Slaughter Jonathan L, Reagan Patricia B, Newman Thomas B, Klebanoff Mark A
Department of Pediatrics, The Ohio State University College of Medicine and Nationwide Children's Hospital, Columbus2Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
Department of Economics, The Ohio State University, Columbus4Center for Human Resource Research, The Ohio State University, Columbus.
JAMA Pediatr. 2017 Mar 6;171(3):e164354. doi: 10.1001/jamapediatrics.2016.4354.
Patent ductus arteriosus (PDA) is associated with increased mortality and worsened respiratory outcomes, including bronchopulmonary dysplasia (BPD), in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in closing PDA, but the effectiveness of NSAID-mediated PDA closure in improving mortality and preventing BPD is unclear.
To determine the effectiveness of NSAID treatment for PDA in reducing mortality and moderate/severe BPD at 36 weeks postmenstrual age.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 12 018 infants born at 28 gestational weeks or younger discharged between January 2006 and December 2013 from neonatal intensive care units in 25 US children's hospitals included in the Pediatric Health Information System. We performed an instrumental variable analysis that incorporated clinician preference-based, institutional variation in NSAID treatment frequency to determine the effect of NSAID treatment for PDA on mortality and BPD.
Proportion of NSAID-treated infants born at each infant's institution within ±6 months of that infant's birth.
The primary composite outcome was death, moderate, or severe BPD at 36 weeks postmenstrual age.
Of the 6370 male and 5648 female infants in this study, 4995 (42%) were white, 3176 (26%) were African American, 1823 (15%) were Hispanic, and 1555 (13%) were other races/ethnicities. The proportion of NSAID-treated infants at each infant's hospital within ±6 months of that infant's birth was associated with NSAID treatment and not associated with gestation, race/ethnicity, or sex. An infant's chances of receiving NSAID treatment increased by 0.84% (95% CI, 0.8-0.9; P < .001) for every 1% increase in the annual NSAID treatment percentage at a given hospital. An instrumental variable analysis demonstrated no association between NSAID treatment and the odds of mortality or BPD (odds ratio, 0.94; 95% CI, 0.70-1.25; P = .69), mortality (odds ratio, 0.73; 95% CI, 0.43-1.13; P = .18), or BPD (odds ratio, 1.01; 95% CI, 0.73-1.45; P = .94) in survivors.
When we incorporated clinician preference-based practice variation as an instrument to minimize the effect of unmeasured confounding, we detected no changes in the odds of mortality or moderate/severe BPD among similar preterm infants born at 28 weeks or younger following NSAID treatment for PDA initiated 2 to 28 days postnatally. Our findings agree with available randomized clinical trial evidence and support a conservative approach to PDA management.
动脉导管未闭（PDA）与早产儿死亡率增加及包括支气管肺发育不良（BPD）在内的呼吸结局恶化相关。非甾体类抗炎药（NSAIDs）在闭合PDA方面有效，但NSAID介导的PDA闭合在改善死亡率和预防BPD方面的有效性尚不清楚。
确定NSAID治疗PDA在降低月经龄36周时的死亡率和中度/重度BPD方面的有效性。
设计、设置和参与者：这项队列研究纳入了2006年1月至2013年12月期间从美国25家儿童医院的新生儿重症监护病房出院的12018名孕28周及以下出生的婴儿，这些医院均纳入了儿科健康信息系统。我们进行了一项工具变量分析，纳入了基于临床医生偏好的、机构间NSAID治疗频率的差异，以确定NSAID治疗PDA对死亡率和BPD的影响。
在每个婴儿出生后±6个月内，其所在机构接受NSAID治疗的婴儿比例。
主要复合结局为月经龄36周时的死亡、中度或重度BPD。
本研究中的6370名男婴和5648名女婴中，4995名（42%）为白人，3176名（26%）为非裔美国人，1823名（15%）为西班牙裔，1555名（13%）为其他种族/族裔。在每个婴儿出生后±6个月内，其所在医院接受NSAID治疗的婴儿比例与NSAID治疗相关，与孕周、种族/族裔或性别无关。在给定医院，年度NSAID治疗百分比每增加1%，婴儿接受NSAID治疗的几率增加0.84%（95%CI，0.8 - 0.9；P <.001）。工具变量分析表明，NSAID治疗与死亡率或BPD的几率（优势比，0.94；95%CI，0.70 - 1.25；P =.69）、死亡率（优势比，0.73；95%CI，0.43 - 1.13；P =.18）或幸存者中的BPD（优势比，1.01；95%CI，0.73 - 1.45；P =.94）均无关联。
当我们将基于临床医生偏好的实践差异作为一种工具以尽量减少未测量混杂因素的影响时，我们发现在出生后2至28天开始接受NSAID治疗PDA的孕28周及以下的相似早产儿中，死亡率或中度/重度BPD的几率没有变化。我们的研究结果与现有的随机临床试验证据一致，并支持对PDA管理采取保守方法。
