Bronchopulmonary dysplasia (BPD) is a complex disorder secondary to genetic–environmental interactions. The complexity in the pathogenesis of this developmental disorder has contributed to the difficulty in developing specific and effective preventative and therapeutic interventions to combat the devastating disease. The impact of this most common chronic lung disease of infancy extends beyond the neonatal intensive care unit (NICU), up to adulthood, and is a significant contributor to healthcare costs. Among the environmental factors contributing to the pathogenesis of BPD, the three most well established are exposure to invasive mechanical ventilation (MV), hyperoxia, and sepsis. While the first two are post-natal, sepsis (which could be localized to the lung or systemic) can be anteor post-natal in origin. In the antenatal scenario, the focus has been on the presence of chorioamnionitis. Interestingly, the role of chorioamnionitis (partly due to difficulties in diagnosis) as a contributory factor to BPD remains controversial. Downstream of all these factors has been the presence of persistent inflammation subverting the normal process of lung development. In the current issue of Pediatric Research, Mir et al. highlighted the potential role of a variety of placental pathologies and the outcomes of BPD/death and neurodevelopmental impairment (NDI) at 2 years. In their retrospective study of neonates <29 weeks gestation, the investigators categorized placental lesions into none, 1, or ≥2 and noted that as the number of placental lesions increased, the outcomes of BPD/death and NDI were significantly increased. After controlling for confounding factors, the association with the presence of moderate-severe BPD (odds ratio [OR]: 3.9; 95% confidence interval [CI]: 1.5–10; p < 0.01) remained significant, but did not hold for NDI (OR: 1.6; 95% CI: 0.7–3.7; p= 0.28). Previous investigators have evaluated different types of placental pathologies with neonatal outcomes; however, the current study is the first one to assess the number of placental pathologic lesions with the neonatal outcomes of mortality, BPD, and NDI. It is imperative to be aware of some of the limitations of the current study. There are some well-known shortcomings of a retrospective study, for example, missing or misclassification of data, among others. It is also important to recognize that causality cannot be established definitively in such retrospective epidemiologic studies. This study was not powered for the primary outcome. Moderate-severe BPD was defined solely as the need for supplemental oxygen at 36 weeks post-menstrual age. As the authors have also mentioned, data on clinical severity of illness was not collected. It is difficult to establish based on the study findings that multiple placental pathologies were the only contributing factor to NDI or was secondary to BPD or a combination of multiple factors during the NICU stay. Prolonged MV is associated with acute inflammatory changes that might affect outcomes in premature infants. Therefore, one of the confounding factors was the duration of MV and this was not adjusted in the logistic regression model. In addition, unknown variables could be further confounders, and the fact that, despite the separate categorization of the placental pathological lesions, there is an interaction between the vascular and inflammatory pathologies reflecting the severity of each or a combination of the insult/injury. The five independent significant placental pathologies assessed included acute histologic chorioamnionitis (AHC), high-grade villitis, maternal vascular underperfusion (MVU), fetal thrombotic vasculopathy (FTV), and small or large for gestational age (S/LGA) placentas. Among those with multiple significant placental lesions, the most common combinations were S/LGA or MVU with AHC. Interestingly, no single pathologic lesion was associated with BPD. As mentioned above, while the association of BPD with the presence of chorioamnionitis remains controversial, some of the other placental lesions appear to be associated with specific outcomes. For example, two studies have reported MVU/decreased villous vascularity in preterm infants who develop BPD-associated pulmonary hypertension (PH). A recent study reported that decreased levels of cord blood angiogenic factors (placental growth factor, granulocyte-colony-stimulating factor, and vascular endothelial growth factor A) were associated with placental MVU and BPDPH. Antenatal placental vasculopathy predisposing to disordered blood vessels in infants going on to develop BPD-PH might also be suggested with the association of maternal diabetes with BPD-PH, both for early and late PH, as recently reported. It is certainly exciting to investigate the possibility of antenatal placental vasculopathy as a continuum towards a predisposition for developing early and/or late PH in infants with BPD. Singlenucleotide polymorphisms of arginase-1 (ARG1 rs2781666), and/or dimethylarginine dimethylaminohydrolase-1 (DDAH1 rs480414), were associated with a decreased risk of developing of BPD-PH. Thus, to answer the question posed in the title, probably not, but the antenatal origins of the possibility of BPD-PH warrants active investigation. Concerted efforts to understand the pathogenesis of BPD-PH will certainly pave dividends for an earlier identification and improved therapeutic options for a condition that has such a high morbidity and mortality. The association between BPD and the presence of various placental pathologies such as MVU, FTV, chronic villitis, villous edema, and acute chorioamnionitis has been inconsistent and has not been studied prospectively in a well-powered study. Such studies could allow physicians in NICUs to utilize the findings of placental histopathology to help counsel parents about the possibility of

中文翻译：

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支气管肺发育不良是否在出生前决定？

支气管肺发育不良（BPD）是一种继发于遗传-环境相互作用的复杂疾病。这种发育障碍发病机制的复杂性导致难以制定具体有效的预防和治疗干预措施来对抗这种破坏性疾病。这种最常见的婴儿慢性肺病的影响超出了新生儿重症监护病房 (NICU)，直至成年，并且是医疗保健成本的重要来源。在导致 BPD 发病的环境因素中，最明确的三个是暴露于有创机械通气 (MV)、高氧和败血症。虽然前两种是产后的，但败血症（可能局限于肺或全身）可能是产前或产后的。在产前情景中，重点是绒毛膜羊膜炎的存在。有趣的是，绒毛膜羊膜炎（部分由于诊断困难）作为 BPD 的一个促成因素的作用仍然存在争议。所有这些因素的下游是持续性炎症的存在，破坏了肺发育的正常过程。在本期儿科研究中，Mir 等人。强调了各种胎盘病理的潜在作用以及 2 年后 BPD/死亡和神经发育障碍 (NDI) 的结果。在他们对<29 孕周新生儿的回顾性研究中，研究人员将胎盘病变分为无、1 或≥2 类，并指出随着胎盘病变数量的增加，BPD/死亡和 NDI 的结果显着增加。控制混杂因素后，与中重度 BPD 存在的关联（优势比 [OR]：3.9；95% 置信区间 [CI]：1.5-10；p < 0.01）仍然显着，但不适用于 NDI（OR：1.6；95 % CI：0.7–3.7；p = 0.28）。以前的研究人员评估了不同类型的胎盘病理与新生儿结局；然而，目前的研究是第一个评估胎盘病理病变数量与死亡率、BPD 和 NDI 新生儿结局的研究。必须意识到当前研究的一些局限性。回顾性研究存在一些众所周知的缺点，例如数据缺失或分类错误等。同样重要的是要认识到，在此类回顾性流行病学研究中无法明确确定因果关系。该研究没有针对主要结局的效力。中重度 BPD 仅被定义为在月经后 36 周需要补充氧气。正如作者还提到的，没有收集关于疾病临床严重程度的数据。根据研究结果，很难确定多种胎盘病理是 NDI 的唯一促成因素，或继发于 BPD 或在 NICU 住院期间多种因素的组合。延长的 MV 与可能影响早产儿结局的急性炎症变化有关。因此，混杂因素之一是 MV 的持续时间，这在逻辑回归模型中没有调整。此外，未知变量可能是进一步的混杂因素，事实上，尽管对胎盘病理病变进行了单独分类，血管和炎症之间存在相互作用，反映了每一种或多种损伤/损伤组合的严重程度。评估的五种独立的显着胎盘病理包括急性组织学绒毛膜羊膜炎 (AHC)、高级别绒毛炎、母体血管灌注不足 (MVU)、胎儿血栓性血管病变 (FTV) 和小于或等于胎龄 (S/LGA) 胎盘。在具有多个显着胎盘病变的患者中，最常见的组合是 S/LGA 或 MVU 与 AHC。有趣的是，没有单一的病理病变与 BPD 相关。如上所述，虽然 BPD 与绒毛膜羊膜炎的存在的关联仍然存在争议，但其他一些胎盘病变似乎与特定结果相关。例如，两项研究报告了发生 BPD 相关肺动脉高压 (PH) 的早产儿的 MVU/绒毛血管减少。最近的一项研究报道，脐带血血管生成因子（胎盘生长因子、粒细胞集落刺激因子和血管内皮生长因子 A）水平降低与胎盘 MVU 和 BPDPH 相关。正如最近报道的那样，产前胎盘血管病变易导致婴儿发生 BPD-PH 的血管紊乱，这也可能与母亲糖尿病与 BPD-PH 的关联有关，无论是早期还是晚期 PH。研究产前胎盘血管病变作为 BPD 婴儿早期和/或晚期 PH 易感性的连续统，这当然令人兴奋。精氨酸酶-1 (ARG1 rs2781666) 的单核苷酸多态性，和/或二甲基精氨酸二甲氨基水解酶-1 (DDAH1 rs480414) 与 BPD-PH 的风险降低有关。因此，要回答标题中提出的问题，可能不是，但 BPD-PH 可能性的产前起源值得积极调查。共同努力了解 BPD-PH 的发病机制肯定会为早期识别和改进具有如此高发病率和死亡率的病症的治疗选择铺平道路。BPD 与各种胎盘病理（如 MVU、FTV、慢性绒毛炎、绒毛水肿和急性绒毛膜羊膜炎）之间的关联一直不一致，并且尚未在一项强有力的研究中进行前瞻性研究。