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Original Investigation |

Bisphenol A Exposure and the Development of Wheeze and Lung Function in Children Through Age 5 Years FREE

Adam J. Spanier, MD, PhD, MPH1,2,3; Robert S. Kahn, MD, MPH4; Allen R. Kunselman, MA2; Eric W. Schaefer, MS2; Richard Hornung, DrPH4; Yingying Xu, MS4; Antonia M. Calafat, PhD5; Bruce P. Lanphear, MD, MPH6
[+] Author Affiliations
1Department of Pediatrics, Penn State University Hershey Medical Center, Hershey, Pennsylvania
2Department of Public Health Sciences, Penn State University Hershey Medical Center, Hershey, Pennsylvania
3currently with the Department of Pediatrics, University of Maryland School of Medicine, Baltimore
4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
5Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia
6Child and Family Research Institute, British Columbia Children’s Hospital and Faculty of Health Sciences, Simon Fraser University, Vancouver, Canada
JAMA Pediatr. 2014;168(12):1131-1137. doi:10.1001/jamapediatrics.2014.1397.
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Published online

Importance  Bisphenol A (BPA), a prevalent endocrine-disrupting chemical, has been associated with wheezing in children, but few studies have examined its effect on lung function or wheeze in older children.

Objectives  To test whether BPA exposure is associated with lung function, with wheeze, and with pattern of wheeze in children during their first 5 years.

Design, Setting, and Participants  A birth cohort study, enrolled during early pregnancy in the greater Cincinnati, Ohio, area among 398 mother-infant dyads. We collected maternal urine samples during pregnancy (at 16 and 26 weeks) and child urine samples annually to assess gestational and child BPA exposure.

Main Outcomes and Measures  We assessed parent-reported wheeze every 6 months for 5 years and measured child forced expiratory volume in the first second of expiration (FEV1) at age 4 and 5 years. We evaluated associations of BPA exposure with respiratory outcomes, including FEV1, child wheeze, and wheeze phenotype.

Results  Urinary BPA concentrations and FEV1 data were available for 208 children and urinary BPA concentrations and parent-reported wheeze data were available for 360 children. The mean maternal urinary BPA concentration ranged from 0.53 to 293.55 µg/g of creatinine. In multivariable analysis, every 10-fold increase in the mean maternal urinary BPA concentration was associated with a 14.2% (95% CI, −24.5% to −3.9%) decrease in the percentage predicted FEV1 at 4 years, but no association was found at 5 years. In multivariable analysis, every 10-fold increase in the mean maternal urinary BPA concentration was marginally associated with a 54.8% increase in the odds of wheezing (adjusted odds ratio, 1.55; 95% CI, 0.91-2.63). While the mean maternal urinary BPA concentration was not associated with wheeze phenotype, a 10-fold increase in the 16-week maternal urinary BPA concentration was associated with a 4.27-fold increase in the odds of persistent wheeze (adjusted odds ratio, 4.27; 95% CI, 1.37-13.30). Child urinary BPA concentrations were not associated with FEV1 or wheeze.

Conclusions and Relevance  These results provide evidence suggesting that prenatal but not postnatal exposure to BPA is associated with diminished lung function and the development of persistent wheeze in children.

Figures in this Article

Asthma rates have risen during the past 3 decades, and 1 in 10 US children has asthma.1,2 Environmental factors such as tobacco exposure and airborne pollutants have been identified as risk factors for asthma, but reasons for the increased prevalence of asthma remains poorly understood.3,4 Some investigators have suggested that exposure to endocrine-disrupting chemicals such as phthalates and bisphenol A (BPA) may contribute to the development of asthma in children.58

As a chemical used in some plastics and epoxy resins, BPA is found in many consumer products, and most Americans have detectable BPA concentrations in their urine.9 Mice pups that were exposed to BPA prenatally developed an asthma phenotype.10,11 Our group previously reported an association of prenatal BPA exposure with increased odds of developing parent-reported wheeze in children through age 3 years but did not examine objective measures of lung function such as spirometry.12 Other investigators have reported that postnatal BPA exposure was associated with child asthma and wheeze, but they found no association of prenatal BPA exposure.13

Spirometry is a valuable diagnostic tool for identification of respiratory diseases in children.1416 Most guidelines recommend using forced expiratory volume in the first second of expiration (FEV1) for assessing respiratory status in children.16 The objectives of this study were to test whether BPA exposure is associated with lung function using FEV1, with wheeze, and with pattern of wheeze in children during their first 5 years.

This study included participants in the Health Outcomes and Measures of the Environment (HOME) study, a prospective birth cohort designed to investigate the effects of exposure to environmental toxicants on child health.12,17 The Cincinnati Children’s Hospital Medical Center and the Centers for Disease Control and Prevention Institutional Review Boards approved the HOME study. Written informed consent was obtained from all participants. Between March 26, 2003, and January 12, 2006, we enrolled 398 English-speaking women who were 18 years or older, at 16 (±3) weeks’ gestation, and lived in a home built before 1979. We tracked the women through pregnancy and followed up their children through age 5 years. Women resided within 5 counties surrounding Cincinnati, Ohio, received prenatal care from 9 participating obstetrical clinics, and delivered at 3 participating hospitals. The study included an embedded randomized trial of a lead hazard reduction intervention and injury hazard reduction.

This study included the subset of 398 live-born HOME study infants for whom both urinary BPA concentrations and respiratory outcome data were available. The BPA and wheeze data were available for 360 children (90.5%). The BPA and spirometry data were available for at least 1 time point (age 4 or 5 years) for 208 children (155 at age 4 years and 193 at age 5 years). Reasons for missing spirometry data included failure to complete the 4-year or 5-year clinic visit, completion of the visit before institutional review board approval of FEV1, child noncooperation, and parental time constraints.

BPA Assessment

We measured BPA concentrations in serial spot maternal and child urine samples. We collected urine samples in glass containers at 16 weeks’ gestation and 26 weeks’ gestation home visits and annual child visits. The Centers for Disease Control and Prevention quantified total urinary BPA concentrations using online solid-phase extraction coupled with high-performance liquid chromatography isotope dilution tandem mass spectrometry.18,19 We replaced approximately 10% of BPA concentrations below the limit of detection (0.4 µg/L) with a value equal to the limit of detection divided by √2 according to the method by Hornung and Reed.20 We standardized BPA concentrations for urinary creatinine concentrations (micrograms of BPA per gram of creatinine) at each time point and log10 transformed BPA concentrations. We used the mean of creatinine standardized maternal urinary BPA concentrations as our primary measure of maternal BPA exposure.

Covariates

Research assistants conducted surveys at baseline and every 6 months after the children were born to collect demographic characteristics (child sex, child health insurance status, household income, and maternal education, occupation, and self-reported race/ethnicity). We measured covariates with plausible FEV1 or wheeze associations, including prenatal tobacco exposure, season, breastfeeding history, family history of asthma, family history of allergy, child eczema, child allergy, birth weight, maternal parity, pet ownership, and cockroach exposure (by self-report).2125

We measured prenatal tobacco exposure using maternal serum cotinine concentrations. Cotinine concentrations at 16 weeks, 26 weeks, and delivery were determined using high-performance liquid chromatography–atmospheric pressure chemical ionization tandem mass spectrometry.26,27 We imputed values for undetectable concentrations (approximately 35%) by sampling randomly from the left tail of the log-normal distribution of serum cotinine concentrations (excluding smokers), and then we calculated the mean of maternal cotinine measures as the measure of prenatal tobacco exposure.

Outcome Measures

During the 4-year and 5-year clinic visits, research assistants measured FEV1 using a portable device (PiKo-1; nSpire Health, Inc).28,29 We attempted to collect at least 3 acceptable (meter determined) FEV1 measures from each child. The FEV1 was recorded in liters (resolution, 0.01 L). We used the maximum acceptable FEV1 obtained as the FEV1 for each participant. We calculated the percentage predicted FEV1 (%FEV1) and multiplied the calculated %FEV1 value by 0.9 for children whose mothers reported their race/ethnicity as black.30

Research assistants surveyed parents every 6 months for 5 years to collect parent-reported wheeze data. We used a question from the National Health and Nutrition Examination Survey31 that asked “Has [child’s name] had wheezing or whistling in his/her chest in the last 6 months?” We used this dichotomous value as our child wheeze outcome. We also conducted a trajectory analysis to identify distinct groups of wheeze trajectories and phenotypes.32,33

Statistical Analysis

We calculated descriptive statistics for all demographic, exposure, and outcome data. We used the geometric mean (95% CI) to describe central tendency and dispersion for BPA concentrations. We used statistical software (SAS, version 9.3; SAS Institute, Inc) and a 2-sided 5% level to test statistical significance. We log10 transformed urinary BPA concentrations; therefore, the β estimates represent a 10-fold change in BPA concentration.

We analyzed the association of the mean maternal urinary BPA concentration and child urinary BPA concentration at 4 and 5 years with %FEV1 at 4 and 5 years after adjusting for covariates using mixed-effects linear regression.34 We first evaluated associations of the mean maternal urinary BPA concentration, then child urinary BPA concentration, and then both in the same analysis.

We analyzed the association of the mean maternal urinary BPA concentration with wheeze during the previous 6 months using generalized estimating equations with a logit link to account for within-individual correlation resulting from repeated outcome measurements.12 We made some assumptions for the analysis of associations of child BPA concentration with wheeze because wheeze was measured twice a year and BPA concentration was measured annually. First, we evaluated the intraclass correlation coefficient of child BPA concentration to determine if the mean child BPA concentration could be a proxy for child exposures. Second, we evaluated associations of the annual child BPA concentration with concurrent wheeze outcomes collapsed over each year (ie, 12-month BPA concentration aligned with child wheeze during 0-12 months). Third, we evaluated associations of the annual child BPA concentration projected on future wheeze outcomes collapsed over each year (ie, 12-month BPA concentration aligned with child wheeze during 12-24 months). Fourth, we added the mean maternal urinary BPA concentration to these concurrent and future child BPA concentration and wheeze analyses.

We also analyzed the association of the mean maternal urinary BPA concentration with wheeze phenotype using developmental trajectory analysis.32,33 This method identifies rather than assumes groups of trajectories using an objective algorithm for determining groups, and it estimates the probability that each participant belongs to each distinctive group. Individuals with missing data are estimated with less certainty using this approach. We did not adjust for other covariates, except creatinine concentration (where appropriate), because of inherent power limitations.

We tested the interactions of urinary BPA concentration with time (where applicable) in multivariable analyses. We also conducted secondary analyses to explore potential windows of vulnerability by replacing the mean maternal urinary BPA concentration variable with urinary BPA concentrations measured at each of the maternal time points (ie, 16 or 26 weeks) in separate analyses; we used nonstandardized BPA concentrations and adjusted for concurrent urinary creatinine concentrations in these analyses. Last, to determine the consistency of results, we repeated all analyses with BPA concentrations without accounting for creatinine concentrations.

Participants with available FEV1 outcome data were more likely to be of white race/ethnicity, have a mother with higher than a high school education, have married parents, have a higher household income, and have a lower prenatal cotinine concentration than participants without FEV1 outcome data (Table 1). Maternal urinary BPA concentrations were similar between the children with and without FEV1 data. The mean maternal urinary BPA concentration ranged from 0.53 to 293.55 µg/g of creatinine, with a geometric mean of 2.4 (95% CI, 2.1-2.7) µg/g of creatinine. Maternal urinary BPA concentrations at 16 and 26 weeks’ gestation were weakly correlated (r = 0.18, P = .03).

Table Graphic Jump LocationTable 1.  Characteristics and Exposures of Study Participants With Available Maternal Urinary BPA Concentration and FEV1 Data or Wheeze Dataa

The frequency of parent-reported wheeze during the previous 6-month period (n = 360) varied between 15.9% and 24.1% (Table 2). The correlation of %FEV1 at 4 and 5 years was 0.34 (95% CI, 0.18-0.48).

Table Graphic Jump LocationTable 2.  Respiratory Outcomes at Each Child Age
Percentage Predicted FEV1

In adjusted analysis of the association of maternal urinary BPA concentration with %FEV1, a significant interaction of BPA with time was observed (P = .03). The interaction demonstrated an association of increasing mean maternal BPA concentration with decreasing %FEV1 at 4 years (β = −14.2; 95% CI, −24.5 to −3.9; P = .007). In contrast, no statistically significant association was observed at 5 years (β = 0.04; 95% CI, −9.04 to 9.12; P = .99).

In an adjusted analysis evaluating the association of child urinary BPA concentration with %FEV1, no statistically significant association and no interaction with time were observed. In addition, when maternal urinary BPA concentration was added to the analysis, the results were almost identical to the analysis of maternal urinary BPA concentration alone (no association of child BPA concentration with %FEV1).

We examined the effect of the timing of maternal urinary BPA exposure by evaluating the 2 maternal BPA measures separately. Adjusting for the same factors and creatinine concentration, we found a significant interaction of 16-week maternal BPA concentration with time (P = .04). The interaction demonstrated a borderline association of increasing 16-week maternal urinary BPA concentration with decreasing %FEV1 at 4 years (β = −7.6; 95% CI, −16.4 to 1.3; P = .09) but no association at 5 years (β = 2.4; 95% CI, −5.4 to 10.2; P = .55). The relationships were similar for 26-week maternal urinary BPA concentration, with the interaction demonstrating a significant association (P = .03) of increasing 26-week maternal BPA concentration with decreasing %FEV1 at 4 years (β = −9.7; 95% CI, −18.2 to −1.3; P = .03) but no association at 5 years (β = −0.2; 95% CI, −8.1 to 7.7; P = .95). These findings were statistically unchanged when evaluating BPA concentration without creatinine concentration adjustment.

Wheeze in the Previous 6 Months

In adjusted analysis, the mean maternal urinary BPA concentration was marginally associated with wheeze (adjusted odds ratio [aOR], 1.55; 95% CI, 0.91-2.63; P = .11). No statistically significant interaction of the mean maternal BPA concentration with time was observed.

The intraclass correlation coefficient for child urinary BPA concentration was 0.15, so we did not evaluate the mean child BPA concentration. In the analysis of child BPA concentration with concurrent wheeze, no statistically significant association was observed (aOR, 1.06; 95% CI, 0.75-1.51; P = .74), and no statistically significant association was observed in the analysis of child BPA concentration and future wheeze (aOR, 1.08; 95% CI, 0.65-1.78; P = .76). These associations (concurrent or future) did not change when maternal urinary BPA concentration was added to the analysis.

We used separate multivariable models to estimate associations of wheeze with creatinine concentration–adjusted log-transformed maternal urinary BPA concentration at both time points during pregnancy (16 and 26 weeks’ gestation). An increase in maternal urinary BPA concentration at 16 weeks’ gestation was associated with wheeze (aOR, 1.79; 95% CI, 1.16-2.78; P = .01), but maternal urinary BPA concentration at 26 weeks’ gestation was not associated with wheeze (aOR, 1.06; 95% CI, 0.65-1.74; P = .81). No statistically significant interaction of maternal BPA concentration with time was observed. These findings were statistically unchanged when evaluating BPA concentration without creatinine concentration adjustment.

Wheeze Phenotype

We identified 4 distinct developmental trajectories of wheeze, which we categorized as (1) never (31.2%), (2) early (early onset or transient) (41.4%), (3) late (late onset) (15.7%), and (4) persistent (11.7%) (Figure).35 The mean maternal urinary BPA concentration was not associated with wheeze phenotype, but a 10-fold increase in 16-week BPA concentration (adjusted for log-transformed urinary creatinine concentration) was associated with a 4.27-fold increase in the odds of persistent wheeze compared with no wheeze (Table 3). These findings were statistically unchanged when we evaluated BPA concentration without creatinine concentration adjustment. We did not evaluate child BPA concentration in the trajectory analyses because of the low intraclass correlation coefficient of child BPA concentration.

Place holder to copy figure label and caption
Figure.
Developmental Trajectories of Wheeze

We identified 4 distinct developmental trajectories of wheeze, which we categorized as (1) never (31.2%), (2) early (early onset or transient) (41.4%), (3) late (late onset) (15.7%), and (4) persistent (11.7%).

Graphic Jump Location
Table Graphic Jump LocationTable 3.  Association of Log10 Maternal Urinary BPA Concentration With Developmental Trajectories of Wheeze

We found that prenatal BPA exposure, measured using maternal urinary BPA concentrations at 2 time points during gestation, was associated with a decrease in children’s lung function at age 4 years but not at age 5 years; child BPA concentrations were not associated with lung function at either age. Maternal urinary BPA concentration was marginally associated with increased odds of parent-reported wheeze, and a trend was observed for increased odds of persistent wheeze. Child BPA concentrations were not associated with wheeze. BPA exposure during early and later pregnancy was associated with %FEV1, but BPA exposure during early pregnancy was more strongly associated with wheeze and wheeze phenotype. These results confirm and extend the observed increase in the odds of child wheeze associated with prenatal BPA exposure previously described in this same cohort at a younger age.12

Investigators have noted an association of exposure to plastic materials with the development of respiratory disorders in animal and epidemiologic studies.58 Evidence in animals suggests that BPA may affect lung development. Specifically, perinatal exposure to BPA increased airway inflammation and responsiveness in a mouse model of asthma.10 In another study,11 prenatal but not postnatal BPA exposure promoted the development of allergic asthma in mice. The mechanism for this association is unclear, but a recent study36 noted that rhesus macaques exposed to BPA had accelerated development of secretory cells in the proximal airways. However, the authors of another animal study37 reported that maternal exposure to BPA has only a subtle association with allergic inflammation, which did not lead to airway responsiveness. Human investigations have found an association of BPA exposure and asthma, but the risks of exposure and the timing of exposure are inconsistent. Our group noted an association of prenatal BPA exposure with child wheeze in young children12; however, another study13 reported a postnatal association of BPA exposure with child asthma and wheeze but did not find an association of prenatal BPA exposure. In an analysis of the 2005-2006 National Health and Nutrition Examination Survey data, Vaidya and Kulkarni38 reported a cross-sectional association of urinary BPA concentration with allergic asthma only for female sex. The design of these studies varied such that it is impossible to directly compare the timing of exposures and associated outcomes.

Spirometry is a valuable tool for the early diagnosis of respiratory diseases in preschool children.1416 The FEV1 is the key spirometric measure in asthma management; it has been shown to predict future asthma symptoms and exacerbations.14,39 Moreover, prospective studies40,41 showed that children with wheeze have persistently lower FEV1 than children without wheeze and that poor airway function in early life is an important risk factor for poor airway function later. However, the intraindividual variability of FEV1 over time has implications for its use as a long-term vs short-term measure of lung function.42 The FEV1 can be useful in the assessment of current status, but a spot measure of FEV1 may not represent long-term trends.43 The association of maternal BPA exposure with a decrease in child lung function in the present study was inconsistent, but the association at age 4 years represents an objective and clinically relevant effect that extends our group’s earlier work showing that maternal BPA exposure was associated with the development of wheeze in young children.12 When we evaluated these patterns of wheeze, we found that gestational BPA exposure has a marginal association with increased odds of wheeze through age 5 years, especially the persistent wheeze phenotype. Although these results need to be confirmed in other cohorts, this study raises questions about the role of BPA exposure in the development of asthma and the asthma epidemic.

We also tested whether gestational urinary BPA concentrations at different time points were more strongly associated with FEV1, wheeze, and wheeze phenotype. Higher BPA concentration at 16 weeks’ gestation was associated with an increased odds of wheeze and a persistent wheeze phenotype and a borderline association with FEV1 deficits, whereas higher BPA concentration at 26 weeks’ gestation was associated with decreased FEV1 but not wheeze or wheeze phenotype. These results taken from a small birth cohort suggest that maternal BPA exposure is a risk factor for diminished lung function and wheeze in children, as well as that earlier gestation exposure may be more important than later gestation exposure.

Our study has some limitations. First, BPA concentration was weakly correlated at 16 and 26 weeks, and it is known to vary widely over time4447; this may result in exposure misclassification. We had serial measures of urinary BPA concentration, which diminishes but does not dismiss this limitation. Exposure misclassification would likely reduce rather than enhance the association of gestational BPA exposure with wheeze or lung function. Second, FEV1, which was available for only a subset of the children, may not predict future lung health and may not fully discriminate the effects of BPA. Third, the cohort’s mean %FEV1 was below 100%, which suggests that these children had poorer lung function than the healthy children who were used to generate the reference sample. Fourth, wheezing was based on parental report and may have been underreported or overreported. Fifth, differential attrition occurred: minority, low-income families were more likely to drop out of the cohort over time than affluent families of white race/ethnicity, which could influence the generalizability of our results. In addition, the cohort was limited to English-speaking families. Sixth, these findings may reflect concurrent exposures to other chemicals or other unknown factors that were not accounted for in this analysis.

We found that prenatal BPA exposure that occurred during early pregnancy was inconsistently associated with diminished lung function, increased odds of wheeze, and a persistent wheeze phenotype in young children. Additional research is needed to clarify the contrasting findings in recent human studies. If future studies confirm that prenatal BPA exposure may be a risk factor for impaired respiratory health, it may offer another avenue to prevent the development of asthma.

Accepted for Publication: June 19, 2014.

Corresponding Author: Adam J. Spanier, MD, PhD, MPH, Department of Pediatrics, University of Maryland School of Medicine, 300 Armory Place, Ste 2B2042, Baltimore, MD 21201 (aspanier@peds.umaryland.edu).

Published Online: October 6, 2014. doi10.1001/jamapediatrics.2014.1397.

Author Contributions: Dr Spanier and Mr Schaefer had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Spanier, Kahn, Hornung, Xu, Lanphear.

Acquisition, analysis, or interpretation of data: Spanier, Kunselman, Schaefer.

Drafting of the manuscript: Spanier, Hornung, Xu, Calafat, Lanphear.

Critical revision of the manuscript for important intellectual content: Kahn, Kunselman, Schaefer, Lanphear.

Administrative, technical, or material support: All authors.

Study supervision: Calafat, Lanphear.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by Flight Attendant Medical Research Foundation Young Clinical Scientist Award 1K23ES016304, PO1ES11261, and 5R01ES014575-02 from the National Institute of Environmental Health Sciences.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Additional Contributions: Xiaoyun Ye, MS, Amber Bishop, Xiaoliu Zhou, Ryan Hennings, Tao Jia, and Pam G. Olive (Centers for Disease Control and Prevention) provided technical assistance. John T. Bernert, PhD (Centers for Disease Control and Prevention), measured the urinary bisphenol A and creatinine concentrations and the serum cotinine concentrations.

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Taussig  LM, Wright  AL, Holberg  CJ, Halonen  M, Morgan  WJ, Martinez  FD.  Tucson Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol. 2003;111(4):661-676.
PubMed   |  Link to Article
Bernert  JT  Jr, Turner  WE, Pirkle  JL,  et al.  Development and validation of sensitive method for determination of serum cotinine in smokers and nonsmokers by liquid chromatography/atmospheric pressure ionization tandem mass spectrometry. Clin Chem. 1997;43(12):2281-2291.
PubMed
Bernert  JT  Jr, McGuffey  JE, Morrison  MA, Pirkle  JL.  Comparison of serum and salivary cotinine measurements by a sensitive high-performance liquid chromatography–tandem mass spectrometry method as an indicator of exposure to tobacco smoke among smokers and nonsmokers. J Anal Toxicol. 2000;24(5):333-339.
PubMed   |  Link to Article
Aguilar-Fernández  AJ, Villa-Asensi  JR, Castro-Codesal  M, Almería-Gil  E, González-Alvarez  MI, Romero-Andújar  F.  Concordance between the PiKo-1 portable device and pneumotachography in measuring PEF and FEV1 in asthmatic children. Allergol Immunopathol (Madr). 2009;37(5):244-248.
PubMed   |  Link to Article
Gochicoa-Rangel  L, Larios-Castañeda  PJ, Miguel-Reyes  JL,  et al.  PiKo-6 vs. forced spirometry in asthmatic children [published online February 5, 2014]. Pediatr Pulmonol. doi:10.1002/ppul.22996.
PubMed
Eigen  H, Bieler  H, Grant  D,  et al.  Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med. 2001;163(3, pt 1):619-623.
PubMed   |  Link to Article
 Plan and operation of the Third National Health and Nutrition Examination Survey, 1988-94. Series 1: programs and collection procedures. Vital Health Stat 1. 1994;(32):1-407.
PubMed
Nagin  DS.  Analyzing development trajectories: a semiparametric, group-based approach. Psychol Methods. 1999;4:139-157.
Link to Article
Twisk  J, Hoekstra  T.  Classifying developmental trajectories over time should be done with great caution: a comparison between methods. J Clin Epidemiol. 2012;65(10):1078-1087.
PubMed   |  Link to Article
Hastie  T, Tibshirani  R, Friedman  J. The Elements of Statistical Learning: Data Mining, Inference, and Prediction. 2nd ed. New York, NY: Springer-Verlag; 2009:chap 7.
Martinez  FD, Wright  AL, Taussig  LM, Holberg  CJ, Halonen  M, Morgan  WJ; Group Health Medical Associates.  Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332(3):133-138.
PubMed   |  Link to Article
Van Winkle  LS, Murphy  SR, Boetticher  MV, VandeVoort  CA.  Fetal exposure of rhesus macaques to bisphenol A alters cellular development of the conducting airway by changing epithelial secretory product expression. Environ Health Perspect. 2013;121(8):912-918.
PubMed   |  Link to Article
Bauer  SM, Roy  A, Emo  J, Chapman  TJ, Georas  SN, Lawrence  BP.  The effects of maternal exposure to bisphenol A on allergic lung inflammation into adulthood. Toxicol Sci. 2012;130(1):82-93.
PubMed   |  Link to Article
Vaidya  SV, Kulkarni  H.  Association of urinary bisphenol A concentration with allergic asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Asthma. 2012;49(8):800-806.
PubMed   |  Link to Article
Fuhlbrigge  AL, Weiss  ST, Kuntz  KM, Paltiel  AD; CAMP Research Group.  Forced expiratory volume in 1 second percentage improves the classification of severity among children with asthma. Pediatrics. 2006;118(2):e347-e355. doi:10.1542/peds.2005-2962.
PubMed   |  Link to Article
Morgan  WJ, Crain  EF, Gruchalla  RS,  et al; Inner-City Asthma Study Group.  Results of a home-based environmental intervention among urban children with asthma. N Engl J Med. 2004;351(11):1068-1080.
PubMed   |  Link to Article
Stern  DA, Morgan  WJ, Wright  AL, Guerra  S, Martinez  FD.  Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet. 2007;370(9589):758-764.
PubMed   |  Link to Article
Hutchison  AA, Erben  A, McLennan  LA, Landau  LI, Phelan  PD.  Intrasubject variability of pulmonary function testing in healthy children. Thorax. 1981;36(5):370-377.
PubMed   |  Link to Article
Quanjer  PH, Borsboom  GJ, Kivastik  J,  et al.  Cross-sectional and longitudinal spirometry in children and adolescents: interpretative strategies. Am J Respir Crit Care Med. 2008;178(12):1262-1270.
PubMed   |  Link to Article
Braun  JM, Kalkbrenner  AE, Calafat  AM,  et al.  Variability and predictors of urinary bisphenol A concentrations during pregnancy. Environ Health Perspect. 2011;119(1):131-137.
PubMed   |  Link to Article
Ye  X, Wong  LY, Bishop  AM, Calafat  AM.  Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections. Environ Health Perspect. 2011;119(7):983-988.
PubMed   |  Link to Article
Meeker  JD, Cantonwine  DE, Rivera-González  LO,  et al.  Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico. Environ Sci Technol. 2013;47(7):3439-3447.
PubMed
Quirós-Alcalá  L, Eskenazi  B, Bradman  A, Ye  X, Calafat  AM, Harley  K.  Determinants of urinary bisphenol A concentrations in Mexican/Mexican–American pregnant women. Environ Int. 2013;59:152-160.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Developmental Trajectories of Wheeze

We identified 4 distinct developmental trajectories of wheeze, which we categorized as (1) never (31.2%), (2) early (early onset or transient) (41.4%), (3) late (late onset) (15.7%), and (4) persistent (11.7%).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Characteristics and Exposures of Study Participants With Available Maternal Urinary BPA Concentration and FEV1 Data or Wheeze Dataa
Table Graphic Jump LocationTable 2.  Respiratory Outcomes at Each Child Age
Table Graphic Jump LocationTable 3.  Association of Log10 Maternal Urinary BPA Concentration With Developmental Trajectories of Wheeze

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Akinbami  LJ, Moorman  JE, Liu  X.  Asthma prevalence, health care use, and mortality: United States, 2005-2009. Natl Health Stat Report. 2011;(32):1-14.
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Spanier  AJ, Kahn  RS, Kunselman  AR,  et al.  Prenatal exposure to bisphenol A and child wheeze from birth to 3 years of age. Environ Health Perspect. 2012;120(6):916-920.
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Donohue  KM, Miller  RL, Perzanowski  MS,  et al.  Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children. J Allergy Clin Immunol. 2013;131(3):736-742.
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Ye  X, Kuklenyik  Z, Needham  LL, Calafat  AM.  Automated on-line column-switching HPLC-MS/MS method with peak focusing for the determination of nine environmental phenols in urine. Anal Chem. 2005;77(16):5407-5413.
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Ye  X, Kuklenyik  Z, Needham  LL, Calafat  AM.  Quantification of urinary conjugates of bisphenol A, 2,5-dichlorophenol, and 2-hydroxy-4-methoxybenzophenone in humans by online solid phase extraction–high performance liquid chromatography–tandem mass spectrometry. Anal Bioanal Chem. 2005;383(4):638-644.
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Oddy  WH, Peat  JK, de Klerk  NH.  Maternal asthma, infant feeding, and the risk of asthma in childhood. J Allergy Clin Immunol. 2002;110(1):65-67.
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Ball  TM, Castro-Rodriguez  JA, Griffith  KA, Holberg  CJ, Martinez  FD, Wright  AL.  Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med. 2000;343(8):538-543.
PubMed   |  Link to Article
Young  S, Sherrill  DL, Arnott  J, Diepeveen  D, LeSouëf  PN, Landau  LI.  Parental factors affecting respiratory function during the first year of life. Pediatr Pulmonol. 2000;29(5):331-340.
PubMed   |  Link to Article
Gold  DR, Burge  HA, Carey  V, Milton  DK, Platts-Mills  T, Weiss  ST.  Predictors of repeated wheeze in the first year of life: the relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking. Am J Respir Crit Care Med. 1999;160(1):227-236.
PubMed   |  Link to Article
Taussig  LM, Wright  AL, Holberg  CJ, Halonen  M, Morgan  WJ, Martinez  FD.  Tucson Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol. 2003;111(4):661-676.
PubMed   |  Link to Article
Bernert  JT  Jr, Turner  WE, Pirkle  JL,  et al.  Development and validation of sensitive method for determination of serum cotinine in smokers and nonsmokers by liquid chromatography/atmospheric pressure ionization tandem mass spectrometry. Clin Chem. 1997;43(12):2281-2291.
PubMed
Bernert  JT  Jr, McGuffey  JE, Morrison  MA, Pirkle  JL.  Comparison of serum and salivary cotinine measurements by a sensitive high-performance liquid chromatography–tandem mass spectrometry method as an indicator of exposure to tobacco smoke among smokers and nonsmokers. J Anal Toxicol. 2000;24(5):333-339.
PubMed   |  Link to Article
Aguilar-Fernández  AJ, Villa-Asensi  JR, Castro-Codesal  M, Almería-Gil  E, González-Alvarez  MI, Romero-Andújar  F.  Concordance between the PiKo-1 portable device and pneumotachography in measuring PEF and FEV1 in asthmatic children. Allergol Immunopathol (Madr). 2009;37(5):244-248.
PubMed   |  Link to Article
Gochicoa-Rangel  L, Larios-Castañeda  PJ, Miguel-Reyes  JL,  et al.  PiKo-6 vs. forced spirometry in asthmatic children [published online February 5, 2014]. Pediatr Pulmonol. doi:10.1002/ppul.22996.
PubMed
Eigen  H, Bieler  H, Grant  D,  et al.  Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med. 2001;163(3, pt 1):619-623.
PubMed   |  Link to Article
 Plan and operation of the Third National Health and Nutrition Examination Survey, 1988-94. Series 1: programs and collection procedures. Vital Health Stat 1. 1994;(32):1-407.
PubMed
Nagin  DS.  Analyzing development trajectories: a semiparametric, group-based approach. Psychol Methods. 1999;4:139-157.
Link to Article
Twisk  J, Hoekstra  T.  Classifying developmental trajectories over time should be done with great caution: a comparison between methods. J Clin Epidemiol. 2012;65(10):1078-1087.
PubMed   |  Link to Article
Hastie  T, Tibshirani  R, Friedman  J. The Elements of Statistical Learning: Data Mining, Inference, and Prediction. 2nd ed. New York, NY: Springer-Verlag; 2009:chap 7.
Martinez  FD, Wright  AL, Taussig  LM, Holberg  CJ, Halonen  M, Morgan  WJ; Group Health Medical Associates.  Asthma and wheezing in the first six years of life. N Engl J Med. 1995;332(3):133-138.
PubMed   |  Link to Article
Van Winkle  LS, Murphy  SR, Boetticher  MV, VandeVoort  CA.  Fetal exposure of rhesus macaques to bisphenol A alters cellular development of the conducting airway by changing epithelial secretory product expression. Environ Health Perspect. 2013;121(8):912-918.
PubMed   |  Link to Article
Bauer  SM, Roy  A, Emo  J, Chapman  TJ, Georas  SN, Lawrence  BP.  The effects of maternal exposure to bisphenol A on allergic lung inflammation into adulthood. Toxicol Sci. 2012;130(1):82-93.
PubMed   |  Link to Article
Vaidya  SV, Kulkarni  H.  Association of urinary bisphenol A concentration with allergic asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Asthma. 2012;49(8):800-806.
PubMed   |  Link to Article
Fuhlbrigge  AL, Weiss  ST, Kuntz  KM, Paltiel  AD; CAMP Research Group.  Forced expiratory volume in 1 second percentage improves the classification of severity among children with asthma. Pediatrics. 2006;118(2):e347-e355. doi:10.1542/peds.2005-2962.
PubMed   |  Link to Article
Morgan  WJ, Crain  EF, Gruchalla  RS,  et al; Inner-City Asthma Study Group.  Results of a home-based environmental intervention among urban children with asthma. N Engl J Med. 2004;351(11):1068-1080.
PubMed   |  Link to Article
Stern  DA, Morgan  WJ, Wright  AL, Guerra  S, Martinez  FD.  Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet. 2007;370(9589):758-764.
PubMed   |  Link to Article
Hutchison  AA, Erben  A, McLennan  LA, Landau  LI, Phelan  PD.  Intrasubject variability of pulmonary function testing in healthy children. Thorax. 1981;36(5):370-377.
PubMed   |  Link to Article
Quanjer  PH, Borsboom  GJ, Kivastik  J,  et al.  Cross-sectional and longitudinal spirometry in children and adolescents: interpretative strategies. Am J Respir Crit Care Med. 2008;178(12):1262-1270.
PubMed   |  Link to Article
Braun  JM, Kalkbrenner  AE, Calafat  AM,  et al.  Variability and predictors of urinary bisphenol A concentrations during pregnancy. Environ Health Perspect. 2011;119(1):131-137.
PubMed   |  Link to Article
Ye  X, Wong  LY, Bishop  AM, Calafat  AM.  Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections. Environ Health Perspect. 2011;119(7):983-988.
PubMed   |  Link to Article
Meeker  JD, Cantonwine  DE, Rivera-González  LO,  et al.  Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico. Environ Sci Technol. 2013;47(7):3439-3447.
PubMed
Quirós-Alcalá  L, Eskenazi  B, Bradman  A, Ye  X, Calafat  AM, Harley  K.  Determinants of urinary bisphenol A concentrations in Mexican/Mexican–American pregnant women. Environ Int. 2013;59:152-160.
PubMed   |  Link to Article

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