Re: 아토피 행진. 아이들에게 항생제 사용후 급격히 증가한다... 1400명 코호트연구

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Am J Epidemiol

. 2010 Dec 29;173(3):310–318. doi: 10.1093/aje/kwq400

Antibiotic Exposure by 6 Months and Asthma and Allergy at 6 Years: Findings in a Cohort of 1,401 US Children

Kari R Risnes, Kathleen Belanger, William Murk, Michael B Bracken *

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PMCID: PMC3105273  PMID: 21190986

This article has been corrected. See Am J Epidemiol. 2011 Jun 15;173(12):1475.

Abstract

Many studies have reported that antibiotic use may be associated with increased risk of childhood asthma. Respiratory tract infections in small children may be difficult to distinguish from early symptoms of asthma, and studies may have been confounded by “protopathic” bias, where antibiotics are used to treat early symptoms of asthma. These analyses of a cohort including 1,401 US children assess the association between antibiotic use within the first 6 months of life and asthma and allergy at 6 years of age between 2003 and 2007. Antibiotic exposure was associated with increased risk of asthma (adjusted odds ratio = 1.52, 95% confidence interval (CI): 1.07, 2.16). The odds ratio if asthma was first diagnosed after 3 years of age was 1.66 (95% CI: 0.99, 2.79) and, in children with no history of lower respiratory infection in the first year of life, the odds ratio was 1.66 (95% CI: 1.12, 3.46). The adverse effect of antibiotics was particularly strong in children with no family history of asthma (odds ratio = 1.89, 95% CI: 1.00, 3.58) (Pinteraction = 0.03). The odds ratio for a positive allergy blood or skin test was 1.59 (95% CI: 1.10, 2.28). The results show that early antibiotic use was associated with asthma and allergy at 6 years of age, and that protopathic bias was unlikely to account for the main findings.

요약

많은 연구에서 

항생제 사용이 소아 천식 발병 위험 증가와 관련이 있을 수 있다고 보고했습니다. 

소아의 호흡기 감염은 

천식의 초기 증상과 구별하기 어려울 수 있으며, 

연구가 항생제를 천식의 초기 증상을 치료하는 데 사용하는 “원발성” 편향에 의해 혼란을 겪었을 수 있습니다. 

1,401명의 미국 어린이를 대상으로 한 코호트 분석은 

생후 6개월 이내에 항생제를 사용한 경우 

6세 때 천식과 알레르기의 발생과 연관성을 평가했습니다(2003~2007년). 

항생제 노출은 

천식 위험 증가와 관련이 있었습니다(조정된 오즈비 = 1.52, 95% 신뢰 구간(CI): 1.07, 2.16). 

3세 이후에 처음으로 천식이 진단된 경우의 오즈비는 1.66(95% CI: 0.99, 2.79)이었고, 

생후 첫해에 하기도 감염 병력이 없는 어린이의 경우 오즈비는 1.66(95% CI: 1.12, 3.46)이었습니다. 

항생제의 부작용은 특히 

천식 가족력이 없는 어린이에게서 강하게 나타났습니다(교차비 = 1.89, 95% CI: 1.00, 3.58) (P 상호작용 = 0.03). 

알레르기 혈액 또는 피부 검사에서 양성 반응이 나온 확률은 1.59(95% CI: 1.10, 2.28)였습니다. 

이 결과는 

6세 때 항생제를 일찍 사용하면 

천식과 알레르기와 관련이 있으며, 

원시적 편향이 주요 결과를 설명할 가능성이 낮다는 것을 보여줍니다.

Keywords: anti-bacterial agents, asthma, child, cohort studies, hypersensitivity

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Asthma is one of the most common chronic diseases of childhood, affecting an estimated 1 in 4 urban children in the developed world (1). The “hygiene hypothesis” is a frequently cited explanation for the increasing preval‎ence of allergic diseases. Initial interpretation suggested that reduced exposure to bacteria and viruses may delay development of the immune system and promote atopic immune responses (2, 3). A broader understanding is that microflora, especially gastrointestinal flora, are important for developing a healthy immune system with resistance to allergic sensitization (4). Thus, antibiotic exposure in early life could increase the risk of atopic diseases through altered microbial exposure (5). If antibiotic exposure in early life is associated with allergic diseases, it is an additional reason to reduce unnecessary antibiotic use in children (6).

Many studies report a positive association between antibiotic use and childhood asthma (7–12), including a large prospective cohort study with more than 5,000 cases of childhood asthma that determined early antibiotic exposure to be one of the most important predictors of childhood asthma (11). However, interpretation of individual studies is controversial (13, 14). Respiratory tract infections in small children may be difficult to distinguish from early symptoms of asthma, and many studies may be confounded by “protopathic” bias, where antibiotics are used to treat respiratory tract infections that could be early symptoms of asthma.

Some studies report lack of an association in cohorts of children with a genetic predisposition to asthma (10, 15, 16), which has suggested that children with no predisposition are more susceptible to early effects of antibiotics than high-risk children genetically predisposed to asthma (10).

We hypothesize that early antibiotic use is associated with increased risk of childhood asthma. To reduce risk of protopathic bias, we assessed the association of antibiotic use within the first 6 months of life with asthma and allergy at 6 years of age. We considered whether the association differed according to parental history of asthma.

천식은 소아기 만성 질환 중 가장 흔한 질병 중 하나로, 선진국의 도시 어린이 4명 중 1명이 천식으로 고통받고 있는 것으로 추정됩니다(1). “위생 가설”은 알레르기 질환의 증가에 대한 설명으로 자주 인용되는 이론입니다. 초기 해석에 따르면, 박테리아와 바이러스에 대한 노출이 감소하면 면역 체계 발달이 지연되고 아토피성 면역 반응이 촉진될 수 있다고 합니다(2, 3). 보다 폭넓은 이해는 미생물, 특히 위장 미생물이 알레르기 민감화에 저항하는 건강한 면역 체계를 개발하는 데 중요하다는 것입니다(4).

따라서,

어린 시절의 항생제 노출은

미생물 노출의 변화를 통해 아토피 질환의 위험을 증가시킬 수 있습니다(5).

어린 시절의 항생제 노출이 알레르기 질환과 관련이 있다면,

어린이의 불필요한 항생제 사용을 줄여야 하는 추가적인 이유가 됩니다(6).

많은 연구에서

항생제 사용과 소아 천식 사이에 밀접한 연관성이 있다고

보고하고 있습니다(7-12).

여기에는

5,000건 이상의 소아 천식 사례를 대상으로 한 대규모 전향적 코호트 연구가 포함되어 있으며,

이 연구에서는 조기 항생제 노출이

소아 천식의 가장 중요한 예측 인자 중 하나라고 결론지었습니다(11).

그러나 개별 연구의 해석은 논란의 여지가 있습니다(13, 14). 어린 아이들의 호흡기 감염은 천식의 초기 증상과 구별하기 어려울 수 있으며, 많은 연구가 천식의 초기 증상일 수 있는 호흡기 감염을 치료하기 위해 항생제를 사용하는 “원발성” 편향에 의해 혼란을 겪을 수 있습니다.

일부 연구에서는 천식에 대한 유전적 소인이 있는 어린이 집단에서 연관성이 없다고 보고하고 있습니다(10, 15, 16). 이는 천식에 대한 유전적 소인이 있는 고위험군 어린이보다 천식에 대한 유전적 소인이 없는 어린이가 항생제의 조기 영향에 더 취약하다는 것을 시사합니다(10).

우리는 조기 항생제 사용이 소아 천식의 위험 증가와 관련이 있다고 가정합니다. 원발성 편향의 위험을 줄이기 위해, 우리는 생후 6개월 이내에 항생제를 사용한 경우와 6세에 천식 및 알레르기가 있는 경우의 연관성을 평가했습니다. 우리는 부모의 천식 병력에 따라 연관성이 다른지 고려했습니다.

MATERIALS AND METHODSStudy cohort

Between April 1997 and June 2000, pregnant women were recruited from 56 private obstetric practices and 15 public clinics across southern New England. Details of the enrolment procedure have been previously published (17, 18). A flow chart for inclusion is presented in Figure 1. For the present analysis, the Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) Study, 1,871 children, including those with mothers with physician-diagnosed asthma (n = 872), all children with mothers with asthma symptoms (n = 449), and a random sample of offspring of mothers without asthma or asthma symptoms (n = 550), were selected for follow-up (17). After non-English speakers (n = 61) and neonatal deaths (n = 3) were excluded, 1,807 women were eligible at the 6-year follow-up. Of the eligible women, 302 (16.7%) women were excluded because of refusal, inability to locate, and missed interviews. From September 2003 until January 2007, 1,505 women were interviewed at their child's sixth birthday (±3 months) to determine the child's asthma status. For the present analyses, we excluded participants who did not have complete information about antibiotic exposure before 6 months of age (n = 31) and 19 participants for whom perinatal information could not be retrieved. Children diagnosed with asthma before 6 months of age (n = 54) were excluded from all analysis with asthma as the outcome, leaving a total of 1,401 (93%) children for these analyses.

Figure 1.

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Number of subjects enrolled in the Yale Asthma in Pregnancy (AIP) Study, with flow diagram for inclusion in the present analysis, the PRAM Study, 1997–2007. PRAM, Perinatal Risk of Asthma in Infants of Asthmatic Mothers.

Data collection

Four discrete sources of data were used in this analysis. Questionnaires are available upon request.

Mothers were interviewed before 24 weeks’ gestation, usually at home. A standardized pregnancy interview included marital status, age, education, household characteristics, yearly income, lifestyle risk factors, medical conditions, medication during pregnancy, maternal anthropometry, and pregnancy complications. Detailed information about respiratory symptoms, hospitalization, and medication use the year before pregnancy was retrieved (19).

A postpartum interview was conducted within 1 month of delivery. Mothers were asked about pregnancy and delivery complications, asthma symptoms, medication use, and environmental exposures during late pregnancy.

Pregnancy, labor, delivery, and neonatal information was abstracted from hospital charts. Information included birth weight, gestational age at delivery, and complications at delivery. Gestational age in completed weeks was based on the earliest ultrasound or on the last menstrual period when information from ultrasound was not available. Preterm birth was defined as less than 37 weeks’ completed gestation, and low birth weight was defined as birth weight less than 2,500 g. Detailed neonatal information was abstracted from the hospital records: transfer to a neonatal intensive care unit (NICU), length of stay in NICU, Apgar score, resuscitation, and the use of mechanical ventilation. We abstracted the neonatal diagnosis from hospital charts. Respiratory problems were defined according to International Classification of Diseases, Ninth Revision, codes 770.0–770.9, and neonatal bacterial infections included diagnosis of sepsis or meningitis defined by positive culture of blood or cerebrospinal fluid.

At the child's sixth birthday (±3 months), standardized maternal interviews were conducted at home (87.4%) or by telephone. Trained interviewers unfamiliar with the research hypotheses and not performing the initial interview completed the interview using a standardized 70-item questionnaire. Questions included the child's medical history, asthma diagnosis, asthma symptoms, and medication use during the child's lifetime and the health of the child’s biologic father, including asthma status. The mother was asked about the child’s number of biologic siblings and whether each sibling had a physician's diagnosis of asthma. The mother was asked about nutrition, including months of breastfeeding, medication use, and antibiotic use while breastfeeding. She was asked whether the child had been diagnosed by a physician as having lower respiratory infections (bronchiolitis, bronchitis, pneumonia, or respiratory syncytial virus), ear infection, strep throat, sinus infection, croup, or tonsillitis. For each condition, she was asked how many times, in the first year of life and in the most recent 12 months, the child had been diagnosed with each condition.

Exposure variables

When the child was 6 years (±3 months) of age, the mother was asked about the medication the child had taken and, specifically, “Has your child ever taken antibiotics?” If yes, she responded to whether antibiotics were taken within the specified age intervals (0–6 months, 7–12 months, >1–2 years, and >2–6 years) and how many times at each age interval antibiotics were taken (once, twice, or 3 or more times). This information was used to create the primary exposure variable of whether or not the child had taken antibiotics and the number of antibiotic courses (0, 1, ≥2 courses) before 6 months of age.

Outcome variables

In the 6-year interview, mothers were asked, “Has the child ever been diagnosed by a doctor or health professional as having asthma?” and “How old was your child when s/he was first diagnosed as having asthma” (completed years and months). Mothers were asked, “Has your child had wheezing or whistling in the chest in the last 12 months?” The primary outcome in this analysis was physician-diagnosed asthma after 6 months of age with history of wheezing in the sixth year of life.

The mother was asked if the child had ever had an allergic reaction, whether blood immunoglobulin E or skin prick tests were performed, and the results of the tests. An allergic reaction and positive blood or skin prick test were considered a positive allergy outcome. Children with asthma at 6 years and a positive allergy test were classified as having allergic asthma.

Statistical analysis

We used logistic regression to calculate odds ratios with 95% confidence intervals for each potential confounding factor and for antibiotic exposure before 6 months of age. The same procedure was repeated for outcomes: asthma at 6 years of age and a positive allergy test. Covariates were initially selected for model inclusion by identifying those associated with both the exposure and the outcome at P ≤ 0.20. Adjusted models used a backward elimination procedure that preserved in the final models variables producing a 10% or greater change in the estimated association. Antibiotic exposure was analyzed as a dichotomous variable and as a categorical variable for the number of courses of antibiotics (0, 1, ≥2 courses). Two-sided P values from linear trend tests were calculated by treating dose categories as ordinal variables in the regression model.

To reduce the likelihood of protopathic bias, we repeated the analyses to assess the association between antibiotic exposure before 6 months of age and asthma using the first diagnosis after the age of 3 years.

Possible effect modification by history of parental asthma or by lower respiratory tract infection (LRTI) during the first year of life was eval‎uated by using a likelihood ratio test. We included a product term between antibiotic exposure and parental asthma in the analysis and, respectively, between antibiotic exposure and LRTI.

To eval‎uate potential bias from missing values, we conducted sensitivity analyses, assessing the association between antibiotic exposure and asthma in excluded individuals. To eval‎uate the accuracy of maternal recall, we compared selected answers given in the 6-year interview with information abstracted from hospital records after birth. Agreement is reported by the percentage of participants responding similarly. All statistical analyses were conducted by using STATA, release 10, statistical software (StataCorp LP, College Station, Texas).

The Human Investigations Committee at Yale University approved the study.

RESULTS

The majority of the population was white and had at least some college education (Table 1). One fourth of participants had a household income below 40,000 US dollars per year, the median US income at the time of the study. By design, a high proportion of the participants were children with a genetic predisposition for asthma; more than 50% of the participants had 1 or 2 parents with asthma. Half the children had 1 or more episodes of physician-diagnosed otitis, and 15% had 1 or more episodes of physician-diagnosed LRTI during their first year of life.

Table 1.

Characteristics of the Study Population in 1,401 Children Followed From the First Trimester in Utero for Antibiotic Use by 6 Months and Asthma at 6 Years of Life, the PRAM Study, 1997–2007a

	Total(N = 1,401)		Antibiotic Exposure by 6 Months (n = 464; 33.1%)			Asthma at 6 Years(n = 164; 11.7%)
	No.	%	Yes, %	OR	95% CI	Yes, %	OR	95% CI

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Abbreviations: CI, confidence interval; LRTI, lower respiratory tract infection (mother responded that child had a physician's diagnosis of ≥1 of the following before 1 year of age: bronchitis, bronchiolitis, pneumonia, respiratory syncytial virus); NICU, neonatal intensive care unit; OR, odds ratio; PRAM, Perinatal Risk of Asthma in Infants of Asthmatic Mothers.

a

Additional variables were eval‎uated for confounding: infant's/child's race, maternal parity, number in household, passive smoke in pregnancy, alcohol exposure in pregnancy, maternal hypertension, preterm labor, resuscitation at birth, admitted to NICU, length of NICU stay, mechanical ventilation in NICU, neonatal sepsis or bacteremia, neonatal meningitis, and breastfeeding.

b

Symptoms and medication use in year before pregnancy. Severity score adapted from Global Initiative for Asthma Severity Classification Guidelines (18).

c

n = 1,350.

One third of the children had been exposed to antibiotics by 6 months of age (Table 1). Antibiotic use was more common for children of single mothers, children of lower income families, and children with parental asthma, maternal diabetes, low birth weight, and a history of respiratory diagnosis in the neonatal period. Nearly 70% of children with a history of lower respiratory infections and more than 50% with otitis in the first year of life had received antibiotics.

Of the 1,401 children studied, 164 met the criteria for asthma. In unadjusted analyses, children of African-American or Hispanic mothers had twice the risk of asthma compared with children of white mothers (Table 1). Children of younger or single mothers and in lower income families were at increased risk of asthma. Maternal diabetes was associated with increased asthma risk in the child (odds ratio (OR) = 3.63, 95% confidence interval (CI): 1.46, 9.04). If one parent had a history of asthma, the odds ratio for asthma at 6 years of age was 2.40 (95% CI: 1.67, 3.47) compared with children with no history of parental asthma. The corresponding odds ratio if both parents had a history of asthma was 4.57 (95% CI: 2.54, 8.22). The odds ratios for childhood asthma associated with parental smoking in the first trimester were 1.71 (95% CI: 1.07, 2.73); with preterm birth, 1.83 (95% CI: 1.15, 3.14); and with respiratory diagnosis in the neonatal period, 1.61 (95% CI: 1.10, 2.36).

The unadjusted odds ratio for asthma associated with antibiotics exposure was 1.81 (95% CI: 1.31, 2.52), and the adjusted odds ratio was 1.52 (95% CI: 1.07, 2.16) (Table 2). Restricting the analyses to asthma cases diagnosed after 3 years of age did not attenuate the associations, but fewer cases yielded less precise estimates, and the result is no longer statistically significant (adjusted OR = 1.66, 95% CI: 0.99, 2.79). The adjusted odds ratio for a positive blood immunoglobulin E or skin prick allergy test was 1.59 (95% CI: 1.10, 2.28), and the adjusted odds ratio for allergic asthma (current asthma at 6 years and a positive allergy test by 6 years of age) was 1.76 (95% CI: 1.01, 3.09).

Table 2.

Results Assessing Associations of Antibiotic Exposure Before 6 Months of Age With Current Asthma and Allergy by 6 Years in 1,401 Children, the PRAM Study, 1997–2007

No. of Cases

Unadjusted OR

95% CI

Adjusted OR

95% CI

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Abbreviations: CI, confidence interval; OR, odds ratio; PRAM, Perinatal Risk of Asthma in Infants of Asthmatic Mothers.

a

Adjusted for household income (</≥40,000 US dollars), parental asthma (none, 1, 2), and physician's diagnosis of lower respiratory tract infections in first year of life (yes/no).

b

Report of a positive blood or skin prick test for 1 or more of the following allergens by 6 years of age: eggs, food, medication, cats, dogs, dust, mites, cockroaches, pollens, mold, trees, grass, ragweed, or others versus negative test/not tested.

c

Adjusted for parental asthma (none, 1, 2), maternal age (<25, 25–35, >35 years), and physician's diagnosis of lower respiratory tract infections in first year of life (yes/no).

d

Report of a physician's diagnosis of asthma after 6 months of age and current wheeze at 6 years of age combined with a positive allergy test as defined in footnote b.

The number of antibiotic courses before 6 months of age and asthma show a dose-response relation (Ptrend = 0.01) (Table 3). Compared with that for no exposure to antibiotics, the adjusted odds ratio associated with 1 antibiotic course was 1.40 (95% CI: 0.90, 2.15) and, for 2 or more courses, the odds ratio was 1.72 (95% CI: 1.11, 2.65).

Table 3.

Associations Between the Number of Courses of Antibiotics Before 6 Months of Age and Current Asthma at 6 Years of Age in 1,401 Children, the PRAM Study, 1997–2007

No. of Antibiotic Courses Within First 6 Months of Life

No. of Asthma Cases

No. of Individuals

ORa

95% CI

Ptrend

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Abbreviations: CI, confidence interval; OR, odds ratio; PRAM, Perinatal Risk of Asthma in Infants of Asthmatic Mothers.

a

Adjusted for household income (</≥40,000 US dollars, parental asthma (none, 1, 2), and physician's diagnosis of lower respiratory tract infections in first year of life (yes/no).

Stratified analyses (Table 4) show no strong evidence of an association between antibiotic exposure and the risk of asthma if at least 1 parent had asthma (adjusted OR = 1.35, 95% CI: 0.88, 2.06). The adjusted odds ratio for asthma in children who had no parental history of asthma was 1.89 (95% CI: 1.00, 3.58) (Pinteraction = 0.03). Analyses showed evidence of increased risk of asthma associated with antibiotic exposure in children who had no report of LRTI (adjusted OR = 1.66, 95% CI: 1.12, 3.46). There was no evidence of interaction by LRTI (Pinteraction = 0.28).

Table 4.

Stratified Analyses for the Associations of Antibiotic Exposure Within 6 Months of Age and Current Asthma at 6 Years in 1,401 Children, the PRAM Study, 1997–2007

No. of Asthma Cases

No. of Individuals

OR

95% CI

Pinteraction

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Abbreviations: CI, confidence interval; LRTI, lower respiratory tract infection; OR, odds ratio; PRAM, Perinatal Risk of Asthma in Infants of Asthmatic Mothers.

a

One or both parents have physician-diagnosed asthma.

b

Adjusted for household income (</≥40,000 US dollars) and lower respiratory tract infections in first year of life (yes/no).

c

Report of physician's diagnosis of bronchiolitis, respiratory syncytial virus infection, pneumonia, or bronchitis in first year of life.

d

Adjusted for household income (</≥40,000 US dollars) and parental asthma (none, 1, 2).

Incomplete antibiotic information was not associated with asthma in the child (P = 0.54). Analyses were rerun while assuming that all missing antibiotic exposures before 6 months were negative, then positive. These analyses did not meaningfully alter the association between antibiotic exposure and asthma. The association between antibiotic exposure and asthma did not change substantially when the individuals excluded because of missing values were included in the analysis (unadjusted OR = 1.81, 95% CI: 1.31, 2.50). Proportions of agreement between questionnaire data and hospital record data were 95% for NICU admission, 60% for length of stay in NICU, and 90% for the use of mechanical ventilation. Proportions of agreement did not differ by the child's asthma status. Information about pet ownership in the child's first year of life, first recorded in the postpartum interview and repeated at the 6-year interview, yielded agreement in 88% of participants.

DISCUSSION

There were several strengths to our study. We recruited pregnant women from many different clinics and pregnancy care providers. The original cohort was enriched so that 40% of mothers had asthma, providing increased power and enabling us to study the effects related to family history of asthma. In other respects, the study cohort is broadly representative of the southern New England population. The study was designed to determine pre- and perinatal risk factors for childhood asthma, and the detailed, prospectively collected measures of potential pre- and perinatal confounders are strengths of these analyses.

Asthma is a complex clinical manifestation that is difficult to diagnose reliably before the age of 6 years (1, 5). Our analyses included as cases children with a physician-verified diagnosis of asthma and current symptoms during the sixth year of life.

Many studies that have attempted to assess the association between antibiotic use and the development of asthma have been confounded by possible protopathic bias that applies if early asthma symptoms are the reason for antibiotic treatment (20).

Protopathic bias may be minimized by considering only antibiotic exposure that occurs several years before the onset of asthma symptoms (21). Protopathic bias may also be avoided by studying the associations when antibiotics are used for indications that do not include symptoms similar to asthma, typically lower respiratory tract infections. The present study developed several strategies to reduce the influence of protopathic bias: We excluded from all analyses cases of asthma diagnosed within the first 6 months of age, we conducted separate analyses for asthma first diagnosed after 3 years of age, and we assessed the association in children who had not reported a LRTI in the first year of life. The association between antibiotic exposure before 6 months age and asthma diagnosed after 3 years of age was quite strong. The strong association in children who did not report any diagnosis of lower respiratory infections during the first year of life further supports the interpretation that protopathic bias was limited. Other studies have found weaker results in asthma diagnosed after 3 years age compared with an earlier diagnosis (11, 22). In a large Canadian database study, however, age at diagnosis did not affect the estimated associations (12).

Ascertainment of antibiotic use in this study is dependent upon maternal recall after 5.5 years, warranting cautious interpretation of results. Inaccuracy in these retrospectively collected exposure data could bias estimated associations if mothers of asthmatic children overreported—or if mothers of nonasthmatic children underreported—antibiotic use. Inaccurate maternal recall that is unrelated to the child's asthma status will usually bias estimates toward the null. We did not have access to medical records to eval‎uate information on antibiotic exposure. The number of factors that could be validated for accuracy was limited, but the high level of observed agreement between interview data and hospital data and the agreement between cases and controls are reassuring regarding the quality of the data in the 6-year questionnaire. Several studies eval‎uating patient recall (23–25) report that agreement with medical records varies by medical condition. In one study, parental reports of asthma and bronchitis reached agreement with medical records by 85%–90% (24), while another study found that one third of parents had forgotten about first-year-of-life wheezing by the time the child was 11 years of age (26). Another report specifically validated parental antibiotic recall in a study about childhood atopic diseases and found agreement between questionnaire and medical records of 91% for antibiotic use (27). In the present study, it is reassuring that the level of exposure, about 30% of children receiving antibiotics by 6 months of age, corresponds well with findings from the largest and most recent database study (11) that also assessed antibiotic exposure before 6 months in their analyses. We conclude that the likelihood that associations are overestimated because of recall bias is limited.

The association of antibiotics and asthma in the present study was particularly strong in children with no family history of asthma. A similar finding was reported in a Canadian cohort (10) and corresponds to negative findings in cohorts that included only children with a family history of asthma (15, 16). One study reported a strong association in children of asthmatic parents (28), but no test for interaction was performed, and the study included only 53 cases of asthma.

The hygiene hypothesis, although controversial (29, 30), suggests that microbial exposure in early life enhances postnatal maturation of the immune system that may protect against development of allergic diseases (2, 4, 31). Normal postnatal development incurs a change from fetal predominantly T helper 2 (known as “TH2”) to more mature T helper 1 (known as “TH1”) immunity (4, 32). Overexpression‎ of TH2 responses to allergens is the hallmark of allergic diseases (33). One important mechanism to support the hygiene hypothesis is that microbial exposure, particularly in the intestinal tract, is necessary for postnatal transition to a balanced immune response in healthy children (3, 34). It has been suggested that the early postnatal period is particularly vulnerable to imbalances in immune response, and that delayed postnatal maturation of TH1 cell function is a key component of genetic risk for atopy (35, 36). The present findings are compatible with an interpretation that children with no family history of asthma are more susceptible to the proatopic effects of antibiotics than children with a genetic predisposition to asthma.

Information on antibiotic use did not include details about the type of antibiotics, and this may be a limitation for the biologic interpretation of our findings. Broad-spectrum antibiotics potentially alter microflora more than narrow-spectrum antibiotics. Some studies that could separately assess the effects of broad-spectrum antibiotics found stronger associations with atopic disease than did those with narrow spectrum (9, 10), possibly supporting the interpretation that early antibiotic exposure alters atopic disease risk through alterations in microflora. In contrast, a large database study (12) reported that penicillin exposure was associated with a particularly high risk of asthma. It may be of relevance to the strong association found in the present study that US outpatient data from the period of our study show increased use of broad-spectrum antibiotics in small children (37).

In our data, we found a strong association between early antibiotic exposure with reported positive immunoglobulin E blood or skin test reactivity. Studies that have assessed the association of antibiotic exposure with immunoglobulin E levels in children (13, 15, 16, 38, 39) did not report evidence of an association. Two studies assessed a possible association with a positive skin prick test (28, 39) and found none. Two studies included only high-risk children with a family history of asthma (15, 16). If antibiotics do not affect the immune response in children with a genetic predisposition to asthma, this could explain the negative findings in these studies. However, the same explanation cannot apply to the negative findings of studies in children more representative of the general population (28, 38–40). These studies allergy tested all participants at 7–8 years of age, and the study outcomes were positive allergy tests, regardless of allergy symptoms. The validity of blood or skin prick tests to diagnose allergy in a general population is limited. The positive predictive value for allergic reactions can be as low as 50% (41). The diagnosis of allergy, therefore, has to be based on clinical history, with supplementary testing (42). Our study was observational, and tests were performed in children who reported an allergic reaction, suggesting that a positive test result was a reasonably valid indicator of allergy in this cohort. Further studies are warranted to establish whether early antibiotic exposure is associated with childhood allergy.

We conclude that antibiotic exposure before 6 months of age is associated with asthma and allergy at 6 years of age and that protopathic bias is unlikely to account for the main findings. The adverse effect of antibiotics on asthma risk was particularly strong in children with no parental history of asthma, which should encourage physicians to avoid unnecessary antibiotic use in low-risk children with no genetic predisposition to asthma.

토론

이 연구에는 몇 가지 장점이 있습니다. 우리는 여러 다른 병원과 임신 관리 서비스 제공자로부터 임산부를 모집했습니다. 원래 코호트는 40%의 산모가 천식을 앓고 있는 것으로 보강되어, 그 효과가 더 커졌고, 천식 가족력과의 관련성을 연구할 수 있게 되었습니다. 다른 측면에서는, 이 연구 코호트는 뉴잉글랜드 남부 인구를 광범위하게 대표합니다. 이 연구는 소아 천식의 출생 전후 위험 요인을 파악하기 위해 설계되었으며, 잠재적인 출생 전후 혼란 요인에 대한 상세하고 전향적으로 수집된 측정값이 이 분석의 강점입니다.

천식은 6세 이전에 확실하게 진단하기 어려운 복잡한 임상 증상입니다(1, 5). 우리의 분석에는 의사가 천식 진단을 확인하고 생후 6년 동안 현재 증상이 있는 아동이 사례로 포함되었습니다.

항생제 사용과 천식 발병 사이의 연관성을 평가하려는 많은 연구들이 초기 천식 증상이 항생제 치료의 원인인 경우 적용되는 가능한 원생적 편향에 의해 혼란을 겪었습니다(20).

프로토패스틱 편향은 천식 증상이 나타나기 몇 년 전에 발생한 항생제 노출만을 고려함으로써 최소화할 수 있습니다(21). 프로토패스틱 편향은 또한 천식과 유사한 증상을 포함하지 않는 증상, 일반적으로 하기도 감염에 항생제를 사용하는 경우의 연관성을 연구함으로써 피할 수 있습니다. 본 연구는 프로토패스틱 편향의 영향을 줄이기 위한 몇 가지 전략을 개발했습니다. 우리는 모든 분석에서 생후 6개월 이내에 진단된 천식 사례를 제외했고, 3세 이후에 처음 진단된 천식에 대해서는 별도의 분석을 실시했으며, 생후 첫해에 LRTI를 보고하지 않은 어린이들의 연관성을 평가했습니다. 생후 6개월 이전의 항생제 노출과 3세 이후에 진단된 천식 사이의 연관성은 상당히 강했습니다. 생후 첫해에 하기도 감염 진단을 받은 적이 없는 어린이들 사이에서 강한 연관성이 발견된 것은 원발성 편향이 제한적이라는 해석을 뒷받침합니다. 다른 연구에서는 3세 이후에 진단된 천식에 비해 조기 진단의 경우 약한 결과가 나타났습니다(11, 22). 그러나 캐나다의 대규모 데이터베이스 연구에서는 진단 연령이 추정된 연관성에 영향을 미치지 않았습니다(12).

이 연구에서 항생제 사용에 대한 확인은 5.5년 후 산모의 회상에 의존하기 때문에 결과에 대한 신중한 해석이 필요합니다. 이러한 회고적 노출 데이터의 부정확성은 천식 아동의 어머니가 항생제 사용을 과대 보고하거나 비천식 아동의 어머니가 항생제 사용을 과소 보고할 경우 추정된 연관성에 편향을 유발할 수 있습니다. 아이의 천식 상태와 무관한 부정확한 산모의 기억은 일반적으로 추정치를 0으로 편향시킬 것입니다. 우리는 항생제 노출에 대한 정보를 평가하기 위해 의료 기록에 접근할 수 없었습니다. 정확성을 검증할 수 있는 요인의 수는 제한적이었지만, 인터뷰 데이터와 병원 데이터 간의 관찰된 높은 수준의 일치와 사례와 대조군 간의 일치로 인해 6년 설문지의 데이터 품질에 대한 확신을 가질 수 있었습니다. 환자 회상(23-25)을 평가하는 여러 연구에 따르면, 의료 기록과의 일치도는 건강 상태에 따라 달라진다고 합니다. 한 연구에서는 부모의 천식 및 기관지염 보고가 의료 기록과 85%-90% 일치하는 것으로 나타났고(24), 또 다른 연구에서는 부모의 3분의 1이 자녀가 11세가 되었을 때 첫해의 쌕쌕거림에 대해 잊어버린 것으로 나타났습니다(26). 또 다른 보고서는 소아 아토피성 질환에 관한 연구에서 부모의 항생제 복용에 대한 기억을 검증하는 데 특히 초점을 맞추었으며, 설문지와 의료 기록의 항생제 사용에 대한 일치율이 91%라는 것을 발견했습니다(27). 본 연구에서, 6개월이 되기 전에 항생제를 투여받은 어린이의 약 30%가 항생제 노출 수준이 가장 최근에 수행된 가장 큰 규모의 데이터베이스 연구(11)에서 6개월 이전의 항생제 노출을 평가한 결과와 잘 일치한다는 사실은 안심할 만한 것입니다. 우리는 회상 편향으로 인해 연관성이 과대평가될 가능성은 제한적이라고 결론을 내립니다.

이번 연구에서 항생제와 천식의 연관성은 천식 가족력이 없는 어린이에게서 특히 강하게 나타났습니다. 캐나다 코호트(10)에서도 유사한 결과가 보고되었으며, 천식 가족력이 있는 어린이만 포함된 코호트(15, 16)에서는 부정적인 결과가 나왔습니다. 한 연구는 천식 부모의 자녀들 사이에서 강한 연관성을 보고했지만(28), 상호작용에 대한 테스트는 수행되지 않았고, 이 연구는 천식 사례 53건만을 포함했습니다.

위생 가설은 논란의 여지가 있지만(29, 30), 유아기의 미생물 노출이 알레르기 질환의 발병을 막을 수 있는 면역체계의 출생 후 성숙을 촉진한다고 제안합니다(2, 4, 31). 정상적인 출생 후 발달 과정에서 태아의 T 헬퍼 2(TH2)가 우세한 면역 체계가 좀 더 성숙한 T 헬퍼 1(TH1) 면역 체계로 변화합니다(4, 32). 알레르기 항원에 대한 TH2 반응의 과다 발현은 알레르기 질환의 특징입니다(33). 위생 가설을 뒷받침하는 중요한 메커니즘 중 하나는 건강한 아이가 출생 후 균형 잡힌 면역 반응을 보이기 위해서는 특히 장에서 미생물에 노출되어야 한다는 것입니다(3, 34). 출생 후 초기 기간은 면역 반응의 불균형에 특히 취약하며, 출생 후 TH1 세포 기능의 성숙이 지연되는 것이 아토피의 유전적 위험 요소의 핵심 요소라는 주장이 제기되었습니다(35, 36). 이번 연구 결과는 천식에 대한 가족력이 없는 아이들이 천식에 대한 유전적 소인이 있는 아이들보다 항생제의 프로아토피 효과에 더 취약하다는 해석과 일치합니다.

항생제 사용에 대한 정보에는 항생제의 종류에 대한 세부 사항이 포함되어 있지 않으며, 이는 우리 연구 결과의 생물학적 해석에 한계가 있을 수 있습니다. 광범위 항생제는 좁은 스펙트럼 항생제보다 잠재적으로 미생물을 더 많이 변화시킬 수 있습니다. 광범위 항생제의 효과를 개별적으로 평가할 수 있는 일부 연구에서는 좁은 스펙트럼 항생제보다 아토피 질환과의 연관성이 더 강하게 나타났습니다(9, 10). 이는 항생제에 조기에 노출되면 미생물 군집의 변화를 통해 아토피 질환의 위험이 높아진다는 해석을 뒷받침할 수 있습니다. 이와는 대조적으로, 대규모 데이터베이스 연구(12)에서는 페니실린에 노출된 경우 천식 위험이 특히 높다고 보고했습니다. 이번 연구에서 발견된 강력한 연관성과 관련이 있을 수 있습니다. 본 연구 기간 동안 미국의 외래 환자 데이터에 따르면 소아에서 광범위 항생제 사용이 증가했습니다(37).

저희 데이터에서, 저희는 초기 항생제 노출과 보고된 면역글로불린 E 혈액 또는 피부 반응성 검사 양성 반응 사이에 강한 연관성을 발견했습니다. 어린이의 면역글로불린 E 수치와 항생제 노출의 연관성을 평가한 연구(13, 15, 16, 38, 39)에서는 연관성에 대한 증거를 보고하지 않았습니다. 두 연구에서는 피부 단자 검사 양성 반응과 가능한 연관성을 평가했지만(28, 39), 연관성을 발견하지 못했습니다. 두 연구에서는 천식 가족력이 있는 고위험 아동만을 대상으로 했습니다(15, 16). 항생제가 천식에 유전적 소인이 있는 아동의 면역 반응에 영향을 미치지 않는다면, 이 두 연구에서 부정적인 결과가 나온 이유를 설명할 수 있습니다. 그러나 일반 인구에 더 가까운 어린이를 대상으로 한 연구에서 나온 부정적인 결과에는 같은 설명이 적용되지 않을 수 있습니다(28, 38-40). 이 연구들은 7-8세에 모든 참가자를 대상으로 알레르기 검사를 실시했으며, 연구 결과는 알레르기 증상과 관계없이 알레르기 양성 반응이었습니다. 일반 인구에서 알레르기를 진단하는 혈액 또는 피부 단자 검사의 유효성은 제한적입니다. 알레르기 반응에 대한 양성 예측값은 50%에 불과할 수 있습니다(41). 따라서 알레르기 진단은 임상 병력을 바탕으로 추가 검사를 실시해야 합니다(42). 우리의 연구는 관찰 연구였고, 알레르기 반응을 보고한 어린이들을 대상으로 검사를 실시했기 때문에, 검사 결과가 양성인 경우 해당 집단에서 알레르기가 있는 것으로 간주할 수 있습니다. 항생제 조기 투여가 소아 알레르기와 관련이 있는지 확인하기 위해서는 추가 연구가 필요합니다.

우리는 6개월 이전의 항생제 노출이 6세 때

천식과 알레르기와 관련이 있으며,

원생적 편향이 주요 결과를 설명할 가능성이 낮다고 결론을 내렸습니다.

천식 위험에 대한 항생제의 부작용은

부모에게 천식 병력이 없는 어린이에게서 특히 강하게 나타났습니다.

따라서

의사는 천식에 대한 유전적 소인이 없는

저위험 어린이에게 불필요한 항생제 사용을 피하도록 권장해야 합니다.

Acknowledgments

Author affiliations: Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale University Schools of Public Health and Medicine, New Haven, Connecticut (Kari R. Risnes, Kathleen Belanger, William Murk, Michael B. Bracken); Department of Pediatrics, St. Olav University Hospital, Trondheim, Norway (Kari R. Risnes); and Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway (Kari R. Risnes).

This study was supported by grants AI41040 and DA05484 from the National Institutes of Health. K. R. R. was financially supported by a grant from the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology.

Conflict of interest: none declared.

GlossaryAbbreviationsCI

confidence interval

LRTI

lower respiratory tract infection

NICU

neonatal intensive care unit

OR

odds ratio

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