一个bstract
Maternal antibiotic use before, during and after pregnancy is associated with higher child asthma risk. Lack of specificity to the pregnancy period suggests the association is not causal or the window of susceptibility extends outside pregnancy.http://ow.ly/U29f30kFD2I
Global antibiotic use has risen 65% worldwide and 114% in low- and middle-income countries between 2000 and 2015 [1]。during pregnancy, anywhere from 20% to over 40% of women may receive a course of antibiotics [2,,,,3],抗生素占美国孕妇使用的药物的80%[4]。尽管怀孕中的抗生素可以治疗许多感染,包括细菌性阴道病和尿路感染,但它们也可能会产生意外的不良后果[4]。鉴于妊娠中无处不在的抗生素暴露,即使是母体抗生素对母亲或她的孩子健康结果的不利影响也可能带来重大的公共卫生问题。
自1970年代以来,哮喘的全球发病率和患病率显着增加,2014年全球范围估计有3.34亿例[5,,,,6]。我n children, asthma is the most common chronic disease, and for 5–14-year-olds, it is among the top 10 chronic conditions for disability-adjusted life years [5]。儿童哮喘的多因素病因始于母亲。孕产妇哮喘,在怀孕中暴露于香烟烟雾和空气污染是已知的因素之一,这会增加哮喘的后代风险[7,,,,8]。preterm birth and low birth weight have also been associated with asthma risk [9]。最近,几项调查提供了有趣的证据,表明对微生物生命的自然母亲到纽布尔的转移扰动也可能在哮喘发病机理中起重要作用。
得益于高通量测序方法的最新进展,我们现在知道,大多数身体的生态壁ches都含有数万亿微生物。抗生素治疗会影响整个微生物群落,也称为微生物群,以及它们生产的代谢产物数月或更长时间[10]。有趣的是,怀孕中服用的抗生素不仅与孕产妇微生物群的改变有关,而且与受影响的婴儿菌群相关[11,,,,12],提示抗生素可能影响胎儿微生物群或代谢物暴露。母体菌群和代谢物在子宫内may help train the fetal innate immune system and have been causally implicated in allergic airway disease in mice [13,,,,14]。当使用或出生后,抗生素可能disrupt mother-to-newborn transmission of healthy microbiota of the maternal gut, vagina, skin and/or breast milk [15,,,,16]。除了对微生物组和代谢组的影响外,抗生素还可能改变表观遗传学[17] and fetal development [18]。一个重要的问题是,通过这些机械性关联,母体对抗生素的暴露是否会增加免疫介导的疾病(例如哮喘)的风险。
在过去的几年中,迅速增加的研究研究了怀孕期间母体抗生素的使用与儿童哮喘的风险之间的关联,据我们所知,即使控制了多种潜在的混杂因素[19-24]。但是这个协会是因果关系吗?基于国家注册机构的两项最大研究得出结论,这种关系可能不是因果关系。使用来自2006 - 2010年出生的493 785个瑞典儿童的数据,Örtqvistet al。[[23] found that the association between prenatal antibiotics and child asthma disappeared in a sibling analysis. This finding suggested the link may be confounded by shared familial factors. In 910 301 Danish children born in 1997–2010, Stokholmet al。[[24]观察到母体抗生素的使用与后代哮喘的关联并非特定于妊娠期(在婚前和产后期间也观察到显着关联),并且针对呼吸道感染的抗生素更强。根据这些发现,他们得出结论,该关联可能是由于母体倾向感染而不是抗生素,本身。
在这个问题上european Respiratory Journal,,,,loewen等。[[25]提供新的证据,表明母体抗生素暴露与儿童哮喘风险的剂量依赖性增加有关。他们从1996年至2012年研究了加拿大曼尼托巴省的213 661个基于人群的队列研究的数据。几乎所有类别的抗生素都与哮喘的风险变化相关,并且在调整了多个混淆者和多个混淆者和多个混杂因素和通过分娩方法,儿童性和婴儿喂养方法保持一致。总体关联似乎也没有因怀孕的三个月而差异。但是,类似于S的研究tokholmet al。[[24],调查人员没有发现该关联是怀孕期的独特之处。
loewen等。[[25]解释了他们的发现,即在怀孕之前,期间和之后的孕期与儿童哮喘相关的孕产妇使用,这是妊娠服用抗生素的证据,特别是与儿童哮喘没有因果关系。他们为他们的发现提供了替代假设。首先,他们认为这种关联可能是由于对后代遗传的感染的遗传敏感性,从而赋予了哮喘的易感性。如果对感染的遗传敏感性与哮喘和可遗传性有关,那么人们会期望它与母亲的哮喘有关。然而,当作者调整了母体哮喘时,没有减弱这种关联,从而破坏了这一假设。作者还推测母体维生素D缺乏可以解释这种关联。维生素D参与胎儿免疫系统和肺的发展,低维生素D与妊娠感染风险更高有关[26)和后代哮喘(27]。已证明补充维生素D可降低感染的风险,而抗生素的使用无关紧要[28]。还有两项试验的证据表明,妊娠中补充维生素D可降低儿童哮喘或复发性喘息的风险25%[29]。Unfortunately, the current study did not have data on maternal vitamin D status; thus, future research is needed to test the hypothesis that vitamin D status may play a role in the association of maternal antibiotic use and child asthma.
还有关于L的发现的其他解释oewen等。[[25]。抗生素极大地改变了微生物群的组成及其代谢产物的产生。这些变化中的一些变化在停止抗生素治疗后的数周或几个月内消失。其他影响可能无限期地持续[10]。Thus, antibiotics taken preconception may have residual effects on the maternal microbiota during pregnancy, which has been associated with long-term risk of asthma in children [30]。母亲服用的抗生素post partummay perturb mother-to-newborn transmission of microbiota相反impacts on microbial communities in the maternal skin or breast milk [31]。because of these viable alternative explanations, we agree with the authors' conclusion that their results “do not firmly support nor refute a directly causal pregnancy-specific relationship”.
一个有趣的观察ervation, which was not explained by the authors, is that the rural population, which constituted nearly half of the study sample, had higher rates of antibiotic use, yet considerably lower incidence of asthma (7.6相对12。4cases per 1000 person-years). To our knowledge, this observation is novel and has not been reported in prior studies of antibiotics and asthma. One might speculate that this observation could be due to some rural populations having greater exposure to diverse microbial communities that may make them more resilient against the risk of asthma associated with antibiotics. Unfortunately, the authors did not directly examine whether the association of maternal antibiotics with child asthma was modified by rural相对urban residence in their study, but this should be explored in future studies.
several factors strengthened this study. The large sample size, made possible by use of comprehensive administrative health data from Manitoba, allowed the authors to conduct a series of subgroup analyses adjusted for or stratified by important variables. The authors were limited, however, by not having information on maternal or childhood infections, maternal vitamin D status, or intrapartum antibiotics among other factors. Also, because they had data from almost the entire province of Manitoba, there was minimal chance of biased selection into the study (e.g.自我选择或无反应)或退出研究(e.g.differential loss to follow-up). Recall bias was also unlikely, as covariates such as antibiotic use and maternal asthma were extracted from administrative databases rather than by participant questionnaire. Another strength of the study, although not novel, was the authors' ability to leverage maternal antibiotic data 9 months before and after pregnancy to determine if the association was specific to the pregnancy period.
The decision of whether or not to prescribe antibiotics in pregnancy is a delicate balancing act. On one hand, antibiotics treat bacterial infections and in many cases, avoiding these medications may be more harmful than taking them, as untreated infections may lead to serious maternal and fetal complications. On the other hand, antibiotic resistance and the potential risk of antibiotics on offspring health outcomes should also be considered. As with other clinicians, obstetricians should heed recommendations for judicious administration of pre- and perinatal antibiotics [32],鉴于30%的抗生素处方可能是不必要的[33] and antibiotic misuse poses a public health threat by generating antibiotic-resistant bacteria. Moreover, whether or not maternal antibiotics are causally associated with child asthma, clinicians should keep in mind they may be “treating for two” [34],鉴于某些抗生素与胎儿生长的关联[18], 出生缺陷 [35]和其他儿童健康结果。
总之,loewen等。[[25] should be commended for their rigorous examination of the association between maternal antibiotics and risk of childhood asthma in a large population-based study. Although the authors observed evidence for a biological gradient (dose–response association), they did not identify a particular window of susceptibility; thus, limiting their causal inference about the pregnancy-specific effects of antibiotics. Their study still does not rule out the possibility that maternal antibiotics taken before, during or after pregnancy are associated with offspring risk of asthma. More research is needed to understand the life course of antibiotic effects on the maternal vaginal, gut and breast milk microbiota and their metabolites, as well as to better understand possible rural–urban differences in the association of maternal antibiotics with child asthma. As even the most rigorous observational study cannot prove or disprove causality [36],解决这个问题的一种更明确的方法可能是利用先前的产前抗生素随机试验[37,,,,38],跟随后代和测量生物标志物和哮喘发病率。
脚注
利益冲突:A.A。Litonjua报告了从Uptodate,Inc。获得的作者特许权使用费,以及来自Astrazeneca,LP的咨询费,在已提交的工作之外。
支持声明:N.T。穆勒得到了国立卫生研究院的国家心脏,肺部和血液研究所的支持,奖励编号K01HL141589,并得到了中大西洋中大西洋营养肥胖研究中心(P30DK072488)的赠款,并获得了性别特定药物的基础。内容仅是作者的责任,不一定代表美国国立卫生研究院的官方观点。本文的资金信息已存入CrossRef资助人注册表。
- receivedMay 30, 2018.
- 公认2018年6月23日。
- 复制right ©ERS 2018