# In utero exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts

Alicia Abellan, Sara M Mensink-Bout, Raquel Garcia-Esteban, Andrea

Beneito, Leda Chatzi, Talita Duarte-Salles, Mariana F Fernandez, Judith
Garcia-Aymerich, Berit Granum, Carmen Iñiguez, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Alicia Abellan, Sara M Mensink-Bout, Raquel Garcia-Esteban, Andrea Beneito, Leda Chatzi, et al. In utero exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts. Environment International, 2022, 162 (8), pp.107178. 10.1016/j.envint.2022.107178. hal-04302866

HAL Id: hal-04302866

https://hal.science/hal-04302866v1

Submitted on 23 Nov 2023

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
Full length article

# *In utero* exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts

<figure><img src="image_3.png" /></figure>

Check for
updates

Alicia Abellan<sup>a, b, c, d</sup>, Sara M. Mensink-Bout<sup>e, f</sup>, Raquel Garcia-Esteban<sup>a, b, d</sup>, Andrea Beneito<sup>g</sup>, Leda Chatzi<sup>h</sup>, Talita Duarte-Salles<sup>c</sup>, Mariana F. Fernandez<sup>d, i</sup>, Judith Garcia-Aymerich<sup>a, b, d</sup>, Berit Granum<sup>j</sup>, Carmen Iñiguez<sup>d, g, k</sup>, Vincent W.V. Jaddoe<sup>e, l</sup>, Kurunthachalam Kannan<sup>m</sup>, Aitana Lertxundi<sup>d, n, o</sup>, Maria-Jose Lopez-Espinosa<sup>d, g, p</sup>, Claire Philippat<sup>q</sup>, Amrit K. Sakhi<sup>j</sup>, Susana Santos<sup>e, l</sup>, Valérie Siroux<sup>q</sup>, Jordi Sunyer<sup>a, b, d</sup>, Leonardo Trasande<sup>m</sup>, Marina Vafeiadi<sup>r</sup>, Fernando Vela-Soria<sup>s</sup>, Tiffany C. Yang<sup>t</sup>, Carlos Zabaleta<sup>u</sup>, Martine Vrijheid<sup>a, b, d</sup>, Liesbeth Duijts<sup>e, f, v, 1</sup>, Maribel Casas<sup>a, b, d, *, 1</sup>

ARTICLE INFO

Handling Editor: Adrian Covaci

Keywords:
Bisphenol A
Pregnancy

A B S T R A C T

**Background:** *In utero* exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only.

**Objective:** To examine the associations of *in utero* exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex.

**Abbreviations:** BMI, body mass index; BPA, bisphenol A; BPF, bisphenol F; BPS, bisphenol S; CI, confidence interval; DAG, directed acyclic graph; FEV₁, forced expiratory volume in 1s; FEF₂₅-75%, mid-expiratory flow; FVC, forced vital capacity; GLI, Global Lung Function Initiative; IPD, individual participant data; ISAAC, International Study on Asthma and Allergy in Childhood; LOD, limit of detection; OR, odds ratio.

* Corresponding author at: ISGlobal, Barcelona, Spain.

E-mail address: maribel.casas@isglobal.org (M. Casas).

¹ Shared last authorship.

<footnote><sup>a</sup> ISGlobal, Barcelona, Spain</footnote>

<footnote><sup>b</sup> Universitat Pompeu Fabra (UPF), Barcelona, Spain</footnote>

<footnote><sup>c</sup> Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain</footnote>

<footnote><sup>d</sup> Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain</footnote>

<footnote><sup>e</sup> The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands</footnote>

<footnote><sup>f</sup> Division of Respiratory Medicine and Allergology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands</footnote>

<footnote><sup>g</sup> Epidemiology and Environmental Health Joint Research Unit, FISABIO–Universitat Jaume I–Universitat de València, Valencia, Spain</footnote>

<footnote><sup>h</sup> Department of Preventive Medicine, University of Southern California, Los Angeles, USA</footnote>

<footnote><sup>i</sup> Centro de Investigación Biomédica, University of Granada, Granada, Spain</footnote>

<footnote><sup>j</sup> Norwegian Institute of Public Health, Oslo, Norway</footnote>

<footnote><sup>k</sup> Department of Statistics and Operational Research. Universitat de València. València, Spain</footnote>

<footnote><sup>l</sup> Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands</footnote>

<footnote><sup>m</sup> Departments of Pediatrics and Environmental Medicine, New York University School of Medicine, New York, NY, United States</footnote>

<footnote><sup>n</sup> Preventive medicine and public health department, University of Basque Country (UPV/EHU), Leioa, Spain</footnote>

<footnote><sup>o</sup> Biodonostia Health research institute, Donostia-San Sebastian, Spain</footnote>

<footnote><sup>p</sup> Faculty of Nursing and Chiropody, University of Valencia, Valencia, Spain</footnote>

<footnote><sup>q</sup> University Grenoble Alpes, Inserm, CNRS, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Institute for Advanced Biosciences (IAB), Grenoble, France</footnote>

<footnote><sup>r</sup> Department of Social Medicine, University of Crete, Greece</footnote>

<footnote><sup>s</sup> Instituto de Investigación Biosanitaria (ibs.GRANADA), Granada, Spain</footnote>

<footnote><sup>t</sup> Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom</footnote>

<footnote><sup>u</sup> Paediatrics Service, Hospital Zumarraga, Gipuzkoa, Spain</footnote>

<footnote><sup>v</sup> Division of Neonatology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands</footnote>
**Asthma**
**Wheezing**
**Lung function**
**Mother-child cohort**

**Methods:** We included 3,007 mother–child pairs from eight European birth cohorts. Bisphenol concentrations were determined in maternal urine samples collected during pregnancy (1999–2010). Between 7 and 11 years of age, current asthma and wheeze were assessed from questionnaires and lung function by spirometry. Wheezing patterns were constructed from questionnaires from early to mid-childhood. We performed adjusted random-effects *meta*-analysis on individual participant data.

**Results:** Exposure to BPA was prevalent with 90% of maternal samples containing concentrations above detection limits. BPF and BPS were found in 27% and 49% of samples. *In utero* exposure to BPA was associated with higher odds of current asthma (OR = 1.13, 95% CI = 1.01, 1.27) and wheeze (OR = 1.14, 95% CI = 1.01, 1.30) (p-interaction sex = 0.01) among girls, but not with wheezing patterns nor lung function neither in overall nor among boys. We observed inconsistent associations of BPF and BPS with the respiratory outcomes assessed in overall and sex-stratified analyses.

**Conclusion:** This study suggests that *in utero* BPA exposure may be associated with higher odds of asthma and wheeze among school-age girls.

# 1. Introduction

Impaired development of the respiratory and immune systems resulting from adverse environments *in utero* might predispose individuals to respiratory morbidity later in life (Miller and Marty, 2010; Håland et al., 2006; Bui et al., 2018; Drazen and Martinez, 2016; Var-davas et al., 2016; Gehring et al., 2015; Bui et al., 2017). There is growing concern over the role of chemical pollutants on early life origins of respiratory diseases (Gascon et al., 2013; Vrijheid et al., 2016; Casas and Gascon, 2020; Abellan and Casas, 2021), specifically on bisphenols due to their large production worldwide (CHEMTrust, 2018) and its widespread exposure to human populations (Calafat et al., 2008; Haug et al., 2018). Bisphenol A (BPA) is the most commonly used bisphenol. It is present in polycarbonate plastics and epoxy resins, used in many consumer products, and diet is the main source of exposure (Liao and Kannan, 2013). In 2017, the European Chemical Agency considered BPA as a "substance of very high concern" (Calafat et al., 2008; Agency and Bisfenol, 2017). Consequently, BPA production is restricted in some countries, which has resulted in the emergence of substitutes such as bisphenol F (BPF) and bisphenol S (BPS), with suspected similar toxicity (Lehmler et al., 2018; Rochester and Bolden, 2015). Bisphenols can cross the placenta and are also found in breastmilk, which results in exposure to foetuses and newborns (Lee et al., 2018). Individual prospective cohort studies investigated *in utero* exposure to BPA, assessed from maternal urine during pregnancy, in relation to asthma-related symptoms from birth to 12 years of age and lung function from 4 to 12 years of age, but showed inconsistent results (Spanier et al., 2012; Spanier et al., 2014; Vernet et al., 2017; Agier et al., 2019; Berger et al., 2020; Gascon et al., 2015; Zhou et al., 2017; Buckley et al., 2018; Donohue et al., 2013; Berger et al., 2019). Because bisphenols can interfere with sex hormones (Lan et al., 2017), their potential effects may be sex-dependent. However, previous published studies reported an increased risk of wheeze associated with BPA among girls (Zhou et al., 2017), among boys (Buckley et al., 2018), or no sex differences (Spanier et al., 2012; Gascon et al., 2015). Limited sample size of previous studies may have hindered consistent and sex-specific effects. Additionally, no study has investigated the influence of *in utero* exposure to bisphenols other than BPA on asthma-related outcomes and lung function.

Therefore, we aimed to investigate whether *in utero* exposure to bisphenols is associated with current asthma, wheeze, and lung function at school-age, and wheezing patterns from early to mid-childhood. We also investigated whether any of these associations differ by sex.

# 2. Methods

## 2.1. Study population

We included 3,007 mother–child pairs from 8 European population-based birth cohorts: Generation R, The Netherlands (Jaddoe et al., 2006); INMA (INFancia y Medio Ambiente) Sabadell, INMA Gipuzkoa,

INMA Valencia, Spain (Guxens et al., 2012); BiB (Born in Bradford), UK (Wright et al., 2013); EDEN (Etude des Déterminants pré et post nátals du développement et de la santé de l'Enfant), France (Heude et al., 2016); MoBa (Norwegian Mother, Father and Child Cohort Study), Norway (Magnus et al., 2016; Paltiel et al., 2014); and RHEA (Mother-Child Cohort in Crete), Greece (Chatzi et al., 2017). Cohorts recruited the population between 1999 and 2010 (Table 1). Five of these were part of the HELIX (Human Early Life Exposome) Project and followed common standardised protocols, questionnaires and lung function measurements (Maitre et al., 2018). Mother-child pairs that had concentrations of bisphenols measured during pregnancy and information on asthma, wheeze or lung function during childhood were included in the study (Figure S1). All cohorts received approval from the ethics committees of the centres involved and written informed consent was obtained from all participants.

## 2.2. Bisphenol exposure assessment

Concentrations of BPA, BPF and BPS were determined in maternal urine samples. BPA was measured in all included cohorts; BPF and BPS were measured in Generation R and in the three INMA cohorts. Concentrations were determined in a single spot urine sample collected throughout pregnancy in all cohorts except in the INMA cohorts where two spot urine samples were available (1st and 3rd trimester). In INMA Sabadell and Valencia, bisphenols were quantified in each spot sample and we used the average of both measurements as main exposure variable, whereas in INMA Gipuzkoa bisphenols were quantified in a pool of both urines (Table 2). Bisphenols concentrations were adjusted for creatinine to correct for urine dilution. See Supplementary Methods 1 for complete details.

## 2.3. Asthma, wheeze, and lung function

We defined current asthma (Hohmann et al., 2014) as having a positive answer to two of the following: i) ever asthma diagnosis; ii) wheezing in the last year; iii) asthma medication in the last year. Ever asthma diagnosis, and wheeze and asthma medication in the last year were assessed from parental-administered questionnaires adapted from the International Study on Asthma and Allergy in Childhood (ISAAC) at school-age (Asher et al., 1995). Information on wheezing was collected from 1 to 11 years (Table S1) and was used to construct wheezing patterns: i) never wheezing; ii) early wheezing, $\leq 4$ years; iii) late wheezing, $> 4$ years; and iv) persistent wheezing, $\leq 4$ and $> 4$ years. Lung function was assessed by spirometry performed at school-age following the ATS/ERS guidelines (Miller et al., 2005). All children with at least one acceptable manoeuvre were included. Lung function parameters selected for the study were forced vital capacity (FVC), $FEV_1$, $FEV_1/FVC$ and mid-expiratory flow (FEF$_{25-75\%}$). For comparability between cohorts, we standardised lung function parameters into sex-, age-, height- and ethnicity-adjusted z-scores based on the Global Lung Function
Initiative (GLI) reference values (Quanjer et al., 2012).

## 2.4. Covariates

Relevant covariates were selected from literature and summarised in a directed acyclic graph (DAG) (Figure S2) to depict the known and hypothesised causal relations between variables and to avoid adjusting for mediators or colliders. Information on maternal and child characteristics was obtained from questionnaires, medical records, antenatal healthcare visits and physical measurements during the cohort's follow-ups. We collected information on maternal age, pre-pregnancy body mass index (BMI), education, smoking during pregnancy, and children's ethnicity, sex, weeks of gestation at birth, birth weight, and age and height at the time of spirometry. Data collection and harmonisation was similar across cohorts. For maternal education, smoking during pregnancy and child ethnicity, cohort-specific categories were harmonised for our analyses (Table S2).

## 2.5. Statistical analyses

We imputed missing values in covariates and BPA concentrations below the limit of detection (LOD) using multiple imputation by chained equations methods in which 25 complete datasets were generated.

Imputation was performed in each cohort separately (Supplementary Methods 2). Since the number of samples with BPF and BPS concentrations below the LOD was very high (>50%), these two compounds were dichotomised (<LOD, ≥LOD) and "<LOD" was set as the reference category. Because distributions of BPA concentrations were skewed, they were log2 transformed. This means that all estimates referring to BPA are expressed per doubling of BPA concentration.

**Main analyses** To assess the associations between bisphenols and respiratory outcomes, we first performed a 1-stage *meta*-analysis on individual participant data (IPD) using mixed-effect models to account for the clustering of individuals within cohorts (random intercepts models). For the associations of bisphenols with current asthma and wheeze, we performed multivariable logistic models. For the associations with wheezing patterns, we performed three multivariable logistic regression models; one for each wheezing category (early, late, persistent) and establishing "never wheezing" as the reference category in each model. For the associations of bisphenols with lung function parameters, we performed multivariable linear models. Current asthma and wheeze models were adjusted for covariates selected from the DAG: maternal education, age, pre-pregnancy BMI, smoking during pregnancy, and child's sex, age, and ethnicity. Lung function models were adjusted for the same set as the above models except child's sex and age. Although ethnicity was also accounted for in the z-scores, we additionally adjusted

<table><caption>**Table 1**
Maternal and child characteristics of participating cohorts (n = 3007).</caption><thead><tr><th></th><th>Overall<br>(n = 3007)</th><th>Generation<br>R<br>(n = 1151)</th><th>INMA<br>Gipuzkoa<br>(n = 280)</th><th>INMA<br>Sabadell<br>(n = 379)</th><th>INMA<br>Valencia<br>(n = 331)</th><th>BiB<sup>a</sup><br>(n = 204)</th><th>EDEN<sup>a</sup><br>(n = 197)</th><th>MoBa<sup>a</sup><br>(n = 268)</th><th>RHEA<sup>a</sup><br>(n = 197)</th></tr></thead><tbody><tr><td>Years of recruitment</td><td></td><td>2002-2006</td><td>2006-2008</td><td>2004-2006</td><td>2004-2005</td><td>2007-2010</td><td>2003-2006</td><td>1999-2009</td><td>2007-2008</td></tr><tr><td><strong>Maternal characteristics</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Maternal age (years), mean (SD)</td><td>31.3<br>(4.52)</td><td>31.0 (4.6)</td><td>32.8 (3.1)</td><td>32.0 (4.1)</td><td>31.9 (3.9)</td><td>28.7 (5.8)</td><td>30.6 (4.9)</td><td>32.7 (3.7)</td><td>30.8 (4.8)</td></tr><tr><td>Pre-pregnancy BMI, (kg/m<sup>2</sup>)<br>mean (SD)</td><td>24.0 (4.4)</td><td>24.3 (4.3)</td><td>23.0 (3.6)</td><td>23.7 (4.6)</td><td>23.4 (4.1)</td><td>28.4 (5.4)</td><td>23.3 (4.2)</td><td>22.6 (3)</td><td>24.0 (4.2)</td></tr><tr><td>Maternal education, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ Primary</td><td>13</td><td>6.7</td><td>11.1</td><td>21.5</td><td>27.8</td><td>47.8</td><td>6.2</td><td>0</td><td>4.6</td></tr><tr><td>Secondary</td><td>38</td><td>39.4</td><td>35.8</td><td>42.6</td><td>40.5</td><td>17.8</td><td>36.9</td><td>20.9</td><td>55.9</td></tr><tr><td>University</td><td>49</td><td>53.9</td><td>53.1</td><td>35.9</td><td>31.7</td><td>34.4</td><td>56.9</td><td>79.1</td><td>39.5</td></tr><tr><td>Smoking during pregnancy, %</td><td>15</td><td>13.4</td><td>13.7</td><td>14.4</td><td>22.7</td><td>13.8</td><td>23.4</td><td>3.5</td><td>21.4</td></tr><tr><td><strong>Child characteristics at birth</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Child ethnicity, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Caucasian</td><td>86</td><td>78.2</td><td>99.2</td><td>94.2</td><td>97.3</td><td>43.5</td><td>99.5</td><td>96.5</td><td>100</td></tr><tr><td>African/American</td><td>3</td><td>6.9</td><td>0</td><td>0</td><td>0</td><td>2.6</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Asian</td><td>6</td><td>6.5</td><td>0</td><td>0</td><td>0</td><td>49.7</td><td>0.5</td><td>2.7</td><td>0</td></tr><tr><td>Other or Mixed</td><td>5</td><td>8.4</td><td>0.8</td><td>5.8</td><td>2.7</td><td>4.2</td><td>0</td><td>0.8</td><td>0</td></tr><tr><td>Child sex, % girls</td><td>48</td><td>49</td><td>50</td><td>47</td><td>48</td><td>47</td><td>46</td><td>49</td><td>43</td></tr><tr><td>Preterm birth, % yes</td><td>3</td><td>2.4</td><td>3.2</td><td>2.1</td><td>2.7</td><td>3.9</td><td>5.6</td><td>4.6</td><td>10.2</td></tr><tr><td>Low birth weight, % yes</td><td>3</td><td>2.4</td><td>5.0</td><td>4.0</td><td>3.6</td><td>6.9</td><td>3.1</td><td>3.1</td><td>3.1</td></tr><tr><td><strong>Child characteristics at respiratory<br>outcomes assessment</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Child age (years), mean (SD)</td><td>8.4 (1.4)</td><td>9.7 (0.2)</td><td>7.9 (0.2)</td><td>6.8 (0.4)</td><td>7.5 (0.2)</td><td>6.6 (0.2)</td><td>10.8 (0.6)</td><td>8.5 (0.5)</td><td>6.5 (0.3)</td></tr><tr><td>Child height (cm), mean (SD)</td><td>131.8<br>(10.6)</td><td>141.1 (6.4)</td><td>127.9 (5.5)</td><td>121.6 (5.7)</td><td>126 (5.1)</td><td>119.8 (5)</td><td>143.6 (7.4)</td><td>133.4 (6.1)</td><td>120.4 (4.8)</td></tr><tr><td>Current asthma, % yes</td><td>9</td><td>6.7</td><td>7.9</td><td>8.8</td><td>7.3</td><td>22.1</td><td>14.7</td><td>7.8</td><td>10.2</td></tr><tr><td>Wheeze in the last year, % yes</td><td>9</td><td>4.1</td><td>8.7</td><td>10.6</td><td>11.5</td><td>25.5</td><td>12.7</td><td>7.5</td><td>7.6</td></tr><tr><td>Wheezing patterns, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>56</td><td>49.7</td><td>51.3</td><td>43.7</td><td>47.9</td><td>46.3</td><td>69.7</td><td>81.8</td><td>84.8</td></tr><tr><td>Early</td><td>32</td><td>37.1</td><td>39.9</td><td>45.9</td><td>40.8</td><td>23.9</td><td>9.5</td><td>9.8</td><td>7.6</td></tr><tr><td>Late</td><td>4</td><td>2.8</td><td>3.4</td><td>0.5</td><td>1.5</td><td>13.4</td><td>13.1</td><td>5.6</td><td>5.6</td></tr><tr><td>Persistent</td><td>8</td><td>10.4</td><td>5.4</td><td>9.9</td><td>9.8</td><td>16.4</td><td>7.7</td><td>2.8</td><td>2.0</td></tr><tr><td>FVC z-score, mean (SD)</td><td>0.19<br>(1.02)</td><td>0.16 (0.94)</td><td>0.63 (0.96)</td><td>0.32 (0.96)</td><td>0.26 (0.91)</td><td>0.28 (1.37)</td><td>-0.65<br>(0.82)</td><td>0.11 (0.91)</td><td>0.15 (1.31)</td></tr><tr><td>FEV<sub>1</sub> z-score, mean (SD)</td><td>0.01<br>(1.02)</td><td>0.12 (0.99)</td><td>0.26 (0.94)</td><td>-0.00 (0.97)</td><td>0.26 (0.94)</td><td>-0.36<br>(1.22)</td><td>-0.79<br>(0.92)</td><td>-0.22<br>(0.95)</td><td>-0.06<br>(1.03)</td></tr><tr><td>FEV<sub>1</sub>/FVC z-score, mean (SD)</td><td>-0.31<br>(1.20)</td><td>-0.10<br>(0.98)</td><td>-0.61 (0.97)</td><td>-0.55 (0.95)</td><td>-0.01 (0.93)</td><td>-1.07<br>(1.00)</td><td>-0.19<br>(0.95)</td><td>-0.58<br>(0.83)</td><td>-0.51<br>(0.95)</td></tr><tr><td>FEF<sub>25-75%</sub> z-score, mean (SD)</td><td>-1.84<br>(3.41)</td><td>0.52 (1.08)</td><td>-0.24 (1.07)</td><td>-0.36 (1.01)</td><td>-0.12 (0.90)</td><td>-1.19<br>(1.14)</td><td>-0.90<br>(0.98)</td><td>-0.63<br>(1.07)</td><td>-0.62<br>(0.97)</td></tr></tbody></table>

Abbreviations: BMI: body mass index; FVC: forced vital capacity; FEV₁: forced expiratory volume in 1 s; FEF₂₅-7₅%: mid expiratory flow; SD: standard deviation.

<footnote>a Subsample included in the HELIX Project.</footnote>
for it to avoid any residual confounding (Quanjer et al., 2012). We reported all primary analyses stratified by sex, testing for interaction (p ≤ 0.1), in addition to reporting estimates for boys and girls combined. Sex-stratified models between BPF, BPS and wheezing patterns could not be performed because numbers in each category were too small.

Sensitivity analyses We performed a 2-stage *meta*-analysis to assess the associations between BPA and current asthma, wheeze, and lung function. We did not perform 2-stage *meta*-analysis neither for BPF and BPS, only available in 4 cohorts, nor for wheezing patterns, because of the low number of individuals in each wheezing category. We estimated the effect estimates in each cohort separately and calculated the combined estimate by a random effects *meta*-analysis model. We used multivariable logistic regression models for the associations of BPA with current asthma and wheeze, and multivariable linear regression models for the associations with lung function. All models were adjusted for the same set of covariates as the 1-stage *meta*-analysis. To test whether results were not explained by birth outcomes, we repeated the analyses excluding preterm (<37 weeks) and low weight (<2500 g) births as these children are at higher risk of respiratory symptoms and lower lung function (Sonnenschein-Van Der Voort et al., 2014; Den Dekker et al., 2016). Additionally, we ran the models using the complete case datasets and further repeated them excluding one cohort at a time to determine the influences of any particular cohort in the overall estimates. To account for exposure misclassification due to the high variability of bisphenols, we ran the models correcting for measurement error applying regression calibration methods, a regression method that aims to estimate the true exposure value based on the exposure within-subject temporal variability. We considered a reliability coefficient for BPA of 0.14 (Supplementary Methods 3). We also performed the lung function models including only children with at least two acceptable and reproducible spirometry manoeuvres and excluding children with an asthma diagnosis. All sensitivity analyses were performed in the 1-stage *meta*-analysis models.

# 3. Results

## 3.1. Characteristics of study population

Table 1 shows the main maternal and child characteristics in each cohort. EDEN, MoBa, and RHEA showed the lowest percentage of early wheezers and BiB showed the largest percentage of persistent wheezers (Table 1). There were no differences in main characteristics between the observed and imputed datasets (Table S3). Median BPA concentrations ranged from 1.56 (Generation R) to 9.54 (MoBa) µg/g. Overall, BPA was detected in 90% of the samples. BPF and BPS were detected in fewer samples except in Generation R, where 40% and 70% of samples had

detectable levels of BPF and BPS, respectively (Table 2).

## 3.2. Bisphenols and asthma and wheeze

Results from the 1-stage *meta*-analysis showed that overall, *in utero* BPA exposure tended to be associated with higher odds of wheeze at school-age (OR = 1.05, 95%CI = 0.97, 1.13 per doubling of BPA concentration) but not with current asthma nor with wheezing patterns (Table 3). Associations with asthma and wheeze at school-age were modified by child's sex (p-interaction = 0.01). Stratified analyses showed that, among girls, each doubling in BPA concentration during pregnancy was associated with higher odds of having current asthma (OR = 1.13, 95%CI = 1.01, 1.27) and wheeze (OR = 1.14, 95%CI = 1.01, 1.30) (Table 3). We did not observe sex differences with wheezing patterns. We did not observe associations with BPF. *In utero* BPS levels above the LOD seemed to be associated with lower odds of late (OR = 0.43, 95%CI = 0.19, 1.00) and persistent wheeze (OR = 0.56, 95%CI = 0.35, 0.90). The 2-stage *meta*-analysis of the association between BPA and current asthma and wheeze showed similar results than the 1-stage *meta*-analysis with some heterogeneity across cohorts (Fig. 1). BPA estimates with asthma and wheeze (in the overall population, in girls and boys) were similar when excluding preterm and low weight births (Table S4), and when using the complete case datasets (Table S5). When excluding cohort by cohort, results did not show notable changes (Table S6). Associations between BPS and wheezing patterns did not change substantially in complete case analysis (Table S5).

## 3.3. Bisphenols and lung function

The 1-stage *meta*-analysis showed small or no associations of increasing *in utero* BPA concentrations with lung function parameters. In the overall population, each doubling in BPA concentrations was associated with a 0.02 (95% CI = 0.00, 0.04) higher z-score in FEV₁ (Table 3). No associations were observed with FVC and FEV₁/FVC. Associations with FEV₁ were modified by child's sex (p-interaction < 0.10). In sex-stratified analysis, we observed higher FEV₁ associated with BPA exposure among boys (z-score = 0.03, 95%CI = 0.00, 0.06). BPF levels above the LOD during gestation were associated with higher FEV₁ (z-score = 0.12, 95% CI = 0.01, 0.23) and FEF₂₅-₇₅% (z-score = 0.13, 95% CI = 0.01, 0.25) (Table 3). Associations of BPF with FVC and FEV₁ were modified by child's sex, observing associations with higher FVC (z-score = 0.17, 95%CI = 0.02, 0.32) and FEV₁ (z-score = 0.15, 95%CI = -0.00, 0.29) among girls (p-interaction < 0.10). No associations were observed between BPS and lung function parameters (Table 3). Results from the 2-stage *meta*-analysis showed overall null effects in the associations between *in utero* BPA exposure and lung function with low

<table><caption>**Table 2**
Maternal urinary bisphenol levels and percentage of bisphenol samples above the LOD.</caption><thead><tr><th></th><th>Overall</th><th>Generation R</th><th>INMA Gipuzkoa</th><th>INMA Sabadell</th><th>INMA Valencia</th><th>BiB<sup>a</sup></th><th>EDEN<sup>a</sup></th><th>MoBa<sup>a</sup></th><th>RHEA<sup>a</sup></th></tr></thead><tbody><tr><td>Trimester measurement</td><td>-</td><td>1st</td><td>1st and 3rd</td><td>1st and 3rd</td><td>1st and 3rd</td><td>3rd</td><td>3rd</td><td>2nd</td><td>1st</td></tr><tr><td><strong>BPA</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>LOD BPA (ng/ml)</td><td>-</td><td>0.15</td><td>0.12</td><td>0.10</td><td>0.03</td><td>0.03</td><td>0.40</td><td>0.03</td><td>0.03</td></tr><tr><td>BPA, % &gt;LOD</td><td>90</td><td>78</td><td>80</td><td>99</td><td>100</td><td>99</td><td>100</td><td>100</td><td>100</td></tr><tr><td>BPA µg/g, median (IQR)</td><td>2.50 (3.70)</td><td>1.56 (3.03)</td><td>2.95 (4.23)</td><td>2.51 (2.25)</td><td>3.51 (3.99)</td><td>1.59 (1.58)</td><td>2.50 (2.31)</td><td>9.54 (13.22)</td><td>1.98 (2.77)</td></tr><tr><td>BPA ng/ml, median (IQR)</td><td>2.30 (3.37)</td><td>1.65 (2.93)</td><td>2.74 (3.91)</td><td>2.13 (2.28)</td><td>2.80 (3.02)</td><td>1.50 (1.92)</td><td>2.56 (2.71)</td><td>5.50 (5.29)</td><td>2.44 (3.45)</td></tr><tr><td><strong>BPF</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>LOD BPF (ng/ml)</td><td>-</td><td>0.18</td><td>0.06</td><td>0.07</td><td>0.10</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>BPF, % &gt;LOD</td><td>27</td><td>40</td><td>10</td><td>8</td><td>5</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><strong>BPS</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>LOD BPS (ng/ml)</td><td>-</td><td>0.05</td><td>0.05</td><td>0.10</td><td>0.33</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>BPS, % &gt;LOD</td><td>49</td><td>71</td><td>30</td><td>17</td><td>10</td><td>-</td><td>-</td><td>-</td><td>-</td></tr></tbody></table>

Abbreviations: BPA: bisphenol A; BPS: bisphenol F; BPS: bisphenol S; IQR: interquartile range; LOD: limit of detection.

<footnote>a Subsample included in the HELIX Project.</footnote>
<table><caption>**Table 3**
Overall and sex-stratified associations between creatinine adjusted bisphenols and respiratory outcomes from 1-stage *meta*-analysis.</caption><thead><tr><th></th><th>N Overall</th><th>Overall</th><th>P interaction</th><th>N Girls</th><th>Girls</th><th>N Boys</th><th>Boys</th></tr></thead><tbody><tr><td><strong>BPA (µg/g)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><em>Asthma and wheeze, OR (95% CI)<sup>a</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Current asthma</td><td>2831</td><td>1.01 (0.94, 1.09)</td><td>0.009</td><td>1323</td><td>1.13 (1.01, 1.27)</td><td>1431</td><td>0.95 (0.87, 1.03)</td></tr><tr><td>Wheeze in the last year</td><td>2846</td><td>1.05 (0.97, 1.13)</td><td>0.013</td><td>1327</td><td>1.14 (1.01, 1.30)</td><td>1442</td><td>0.99 (0.90, 1.09)</td></tr><tr><td><em>Wheezing patterns, OR (95% CI)<sup>b,c</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Early</td><td>2023</td><td>0.99 (0.94, 1.04)</td><td>0.572</td><td>962</td><td>0.97 (0.90, 1.04)</td><td>1026</td><td>1.00 (0.93, 1.08)</td></tr><tr><td>Late</td><td>1378</td><td>1.02 (0.90, 1.15)</td><td>0.463</td><td>665</td><td>1.06 (0.90, 1.25)</td><td>658</td><td>0.95 (0.80, 1.12)</td></tr><tr><td>Persistent</td><td>1474</td><td>0.97 (0.89, 1.06)</td><td>0.288</td><td>702</td><td>1.00 (0.87, 1.16)</td><td>741</td><td>0.94 (0.84, 1.05)</td></tr><tr><td><em>Lung function, z-score (95% CI)<sup>b</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>FVC</td><td>2677</td><td>0.01 (-0.01, 0.03)</td><td>0.397</td><td>1292</td><td>0.01 (-0.01, 0.04)</td><td>1385</td><td>0.02 (-0.01, 0.04)</td></tr><tr><td>FEV<sub>1</sub></td><td>2729</td><td>0.02 (0.00, 0.04)</td><td>0.044</td><td>1318</td><td>0.01 (-0.01, 0.04)</td><td>1411</td><td>0.03 (0.00, 0.06)</td></tr><tr><td>FEV<sub>1</sub>/FVC</td><td>2662</td><td>0.00 (-0.01, 0.02)</td><td>0.111</td><td>1288</td><td>-0.00 (-0.03, 0.03)</td><td>1374</td><td>0.01 (-0.02, 0.04)</td></tr><tr><td>FEF<sub>25-75%</sub></td><td>2741</td><td>0.01 (-0.01, 0.03)</td><td>0.869</td><td>1291</td><td>0.01 (-0.02, 0.04)</td><td>1384</td><td>0.02 (-0.01, 0.05)</td></tr><tr><td><strong>BPF (≥LOD vs &lt; LOD)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><em>Asthma and wheeze, OR (95% CI)<sup>a</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Current asthma</td><td>1776</td><td>1.09 (0.69, 1.73)</td><td>0.029</td><td>871</td><td>0.44 (0.17, 1.14)</td><td>905</td><td>1.55 (0.89, 2.67)</td></tr><tr><td>Wheeze in the last year</td><td>1791</td><td>1.12 (0.66, 1.90)</td><td>0.024</td><td>875</td><td>0.46 (0.15, 1.45)</td><td>916</td><td>1.59 (0.87, 2.94)</td></tr><tr><td><em>Wheezing patterns, OR (95% CI)<sup>b,c</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Early</td><td>1302</td><td>0.98 (0.73, 1.31)</td><td>0.495</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Late</td><td>757</td><td>1.12 (0.48, 2.62)</td><td>0.938</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Persistent</td><td>851</td><td>0.94 (0.57, 1.56)</td><td>0.011</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><em>Lung function, z-score (95% CI)<sup>b</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>FVC</td><td>1808</td><td>0.10 (-0.01, 0.20)</td><td>0.035</td><td>892</td><td>0.17 (0.02, 0.32)</td><td>916</td><td>0.01 (-0.14, 0.16)</td></tr><tr><td>FEV<sub>1</sub></td><td>1806</td><td>0.12 (0.01, 0.23)</td><td>0.099</td><td>891</td><td>0.15 (-0.00, 0.29)</td><td>915</td><td>0.08 (-0.07, 0.24)</td></tr><tr><td>FEV<sub>1</sub>/FVC</td><td>1806</td><td>0.02 (-0.09, 0.13)</td><td>0.256</td><td>891</td><td>-0.09 (-0.24, 0.06)</td><td>915</td><td>0.13 (-0.03, 0.29)</td></tr><tr><td>FEF<sub>25-75%</sub></td><td>1806</td><td>0.13 (0.01, 0.25)</td><td>0.934</td><td>891</td><td>0.14 (-0.02, 0.31)</td><td>915</td><td>0.14 (-0.03, 0.31)</td></tr><tr><td><strong>BPS (≥LOD vs &lt; LOD)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><em>Asthma and wheeze, OR (95% CI)<sup>a</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Current asthma</td><td>1776</td><td>0.73 (0.47, 1.14)</td><td>0.405</td><td>871</td><td>1.08 (0.51, 2.27)</td><td>905</td><td>0.61 (0.36, 1.05)</td></tr><tr><td>Wheeze in the last year</td><td>1791</td><td>0.64 (0.40, 1.04)</td><td>0.382</td><td>875</td><td>0.66 (0.29, 1.50)</td><td>916</td><td>0.69 (0.38, 1.25)</td></tr><tr><td><em>Wheezing patterns, OR (95% CI)<sup>b,c</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Early</td><td>1302</td><td>1.01 (0.77, 1.32)</td><td>0.928</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Late</td><td>757</td><td>0.43 (0.19, 1.00)</td><td>0.624</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Persistent</td><td>851</td><td>0.56 (0.35, 0.90)</td><td>0.440</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><em>Lung function, z-score (95% CI)<sup>b</sup></em></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>FVC</td><td>1808</td><td>0.05 (-0.05, 0.16)</td><td>0.216</td><td>892</td><td>0.06 (-0.08, 0.20)</td><td>916</td><td>0.04 (-0.10, 0.19)</td></tr><tr><td>FEV<sub>1</sub></td><td>1806</td><td>0.09 (-0.02, 0.19)</td><td>0.084</td><td>891</td><td>0.10 (-0.03, 0.23)</td><td>915</td><td>0.09 (-0.06, 0.24)</td></tr><tr><td>FEV<sub>1</sub>/FVC</td><td>1806</td><td>0.06 (-0.05, 0.16)</td><td>0.846</td><td>891</td><td>0.01 (-0.14, 0.15)</td><td>915</td><td>0.11 (-0.04, 0.26)</td></tr><tr><td>FEF<sub>25-75%</sub></td><td>1806</td><td>0.02 (-0.09, 0.14)</td><td>0.870</td><td>891</td><td>0.02 (-0.14, 0.18)</td><td>915</td><td>0.04 (-0.12, 0.21)</td></tr></tbody></table>

Note: discrepancies between the overall N and sex-stratified N are due to missing values in sex. Overall N in each wheezing pattern includes also never wheezers.

Abbreviations: BPA: bisphenol A; BPF: bisphenol F; BPS: bisphenol S; FVC: forced vital capacity; FEV₁: forced expiratory volume in 1 s; FEF₂₅-7₅%: mid expiratory flow;

LOD: limit of detection; OR: odds ratio; CI: confidence interval.

heterogeneity between cohorts (Fig. 1). Results remained similar when excluding preterm and low birth weight babies (Table S4), when using the complete case datasets (Table S5), when including only children with at least two acceptable and reproducible spirometry manoeuvres, and when excluding children with asthma (Table S7). The estimates of the association between BPA and FEV₁ shifted towards the null when we excluded Generation R from the model (Table S6). The association between BPA and FEV₁ (z-score = 0.02 (95% CI: 0.00, 0.04) also disappeared when we repeated the models applying regression calibration (z-score = 0.00 (95% CI = -0.13, 0.13). Regression calibration could not be applied in logistic regression models for wheezing and asthma. Associations observed for BPF diluted and disappeared when including children with at least two acceptable and reproducible spirometry manoeuvres, and when excluding children with asthma (Table S7).

## 4. Discussion

Results from this prospective IPD *meta*-analysis of 3,007 mother–child pairs suggest that *in utero* exposure to BPA may be associated with higher odds of asthma and wheeze at school-age among girls. The associations did not seem to be explained by lung function adaptations, as results did not show consistent associations of *in utero* BPA exposure with lung function. Substitute bisphenols were associated with higher

FEV₁ and FEF₂₅-7₅% (BPF) and lower risk of late and persistent wheezing (BPS).

### 4.1. Comparison with previous studies

Our findings support the hypothesis that *in utero* BPA may increase the risk of asthma-related symptoms during childhood reported in some (Spanier et al., 2012; Spanier et al., 2014; Vernet et al., 2017; Berger et al., 2020; Gascon et al., 2015; Zhou et al., 2017; Buckley et al., 2018) but not all (Donohue et al., 2013; Berger et al., 2019) previous studies. Our study adds evidence for potential sex-dependent effects of BPA exposure on the risk of asthma-related symptoms, only assessed in few studies that yielded contradicting results (Gascon et al., 2015; Zhou et al., 2017; Buckley et al., 2018). Two studies reported higher risk in girls, one showed higher odds of infant allergic diseases (including wheeze and eczema) at 6 months of age (Zhou et al., 2017), and another reported higher risk of asthma at 7 years (Gascon et al., 2015), but without statistical evidence that BPA effects differed between sexes. One study reported higher odds of asthma diagnosis at 7 years among boys (Buckley et al., 2018). A cohort study that involved only boys also reported a tendency of higher risk of asthma at 5 years, but not with wheeze at the same age, from *in utero* BPA exposure (Vernet et al., 2017). The lack of consistency of sex-specific effects of previous studies might

<footnote>a Models adjusted for maternal age, education, pre-pregnancy BMI, smoking during pregnancy, and child's age, sex and ethnicity.</footnote>

<footnote>b Models adjusted for maternal age, education, pre-pregnancy BMI, smoking during pregnancy, and child's ethnicity.</footnote>

<footnote>c Reference base category: Never wheezers.</footnote>
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**Fig. 1.** Overall associations between creatinine adjusted bisphenol A (µg/g) and respiratory outcomes from 2-stage meta-analysis<sup>a, b</sup>. Values represent OR (95 %CI) in associations between bisphenol A and current asthma and wheeze; and z-score (95% CI) in associations between BPA and lung function parameters. Current asthma and wheeze models were adjusted for maternal education, age, pre-pregnancy BMI, smoking during pregnancy, and child's sex, age, and ethnicity. Lung function models were adjusted for maternal education, age, pre-pregnancy BMI, smoking during pregnancy, and child's ethnicity. Abbreviations: BPA: bisphenol A; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; FEF25-75%: mid expiratory flow; OR: odds ratio; CI: confidence interval.</figcaption></figure>

be partly explained by their small sample size. In our study population, with a large sample size after stratification, we observed that *in utero* exposure to BPA was associated with higher odds of current asthma and wheeze at school-age in girls. Further, most previous studies have focused on children of ages ≤ 7 years; only one study (Donohue et al., 2013) assessed current asthma until 12 years of age and reported no associations in relation to *in utero* BPA; in that study sex-dependent effects were not examined. The urinary BPA levels measured during pregnancy in this study are similar to those reported in previous studies that assessed *in utero* BPA exposure in relation to respiratory outcomes in North American (Spanier et al., 2012; Spanier et al., 2014), European (Vernet et al., 2017; Agier et al., 2019), and Chinese (Zhou et al., 2017) cohort studies and higher than those reported in three North American studies (Berger et al., 2020; Buckley et al., 2018; Donohue et al., 2013).

To our knowledge, there is no previous study assessing *in utero* exposure to BPA on wheezing patterns across childhood, preventing comparison of our findings of no associations between increasing BPA exposure with any wheezing pattern.

Literature on *in utero* BPA exposure and lung function is scarce. Only one cohort study associated *in utero* BPA exposure with lower %FEV₁ at 4 years but this association disappeared at 5 years of age (Spanier et al., 2014). This association was not observed in three other cohorts that assessed lung function from 5 to 12 years (Vernet et al., 2017; Agier et al., 2019; Berger et al., 2020). In our study, BPA was associated with higher lung function from 6 to 12 years of age only among boys, but estimates were small and generally towards the null. Such associations disappeared in sensitivity analyses when using complete case datasets and when excluding Generation R from the analyses, the cohort with the
largest sample size. Further studies are warranted to study the role of BPA on lung function growth.

To our knowledge, this is the first study to assess the associations of *in utero* BPF and BPS exposure with respiratory health. In our study we observed higher FEV₁ and FEF₂₅-75% associated with detectable levels of BPF and lower odds of late and persistent wheezing associated with detectable levels of BPS. These associations could have been at least partly explained by exposure misclassification (high temporal variability of BPF and BPS) and residual confounding arisen by the dichotomisation of exposure variables into detected and undetected. Mothers among the detected group tended to smoke less and had a higher educational level compared to those among the undetected group (data not shown). We suspect mothers with higher education and a healthier lifestyle tend to use more BPA-free products which in turn may contain BPA substitute, similar as observed for parabens (Montazeri et al., 2019). Of interest, the Generation R cohort presented the highest proportion of study participants with detectable levels of BPF and BPS. This might indicate that the introduction of BPA substitutes in the Netherlands was earlier than in other countries, as previously reported (Philips et al., 2018). In other countries where these bisphenols were not as present in the market as they are currently, we expect current population's exposure to be higher, which guarantees the need for further investigation.

## 4.2. Interpretation of findings

Our results suggest that *in utero* exposure to BPA may increase the risk of asthma and wheeze at school-age through immunomodulatory mechanisms without notable lung function adaptations. This could be explained by the ability of bisphenols to cross the placenta (Lee et al., 2018) and interfere with the developing respiratory and immune systems by binding to a number of receptors related to inflammatory and oxidative stress pathways (Welshons et al., 2006; Vandenberg et al., 2007; Rogers et al., 2013; Kim et al., 2020). Immunomodulatory alterations from exposure to BPA have been observed in *in vitro*, animal, and human studies and include the increase in serum immunoglobulin-E, eosinophilic inflammation in the airways, stimulation of pro-inflammatory cytokines, T helper (Th) 1/Th2 cell shifts, and alterations in Th17 and β-cell counts (Rogers et al., 2013; Kim et al., 2020; Luo et al., 2016). Although animal studies have observed deleterious effects on the structural development of the lung after *in utero* exposure to BPA (Van Winkle et al., 2013; Hijazi et al., 2015), we could not confirm that in our study. We did not observe an association with notable lung function adaptations that could relate to the effects observed with asthma and wheeze. However, children with asthma usually present a normal spirometry (Dufetelle et al., 2018; Bacharier et al., 2004). On a population level, children without a current asthma exacerbation or with adequately controlled asthma, might present spirometry results within the healthy standards (Bacharier et al., 2004; Baatenburg de Jong et al., 2006). Additionally, BPA presents obesogenic properties acting through different pathways including the interference with thyroid hormones and its affinity to estrogenic and glucocorticoid receptors (Andrianou et al., 2016; Prasanth et al., 2010). In rodents, *in utero* exposure to BPA has been shown to increase adiposity and circulating lipid levels (Wassenaar et al., 2017). In epidemiological studies, BPA has been associated with increased risk of obesity in children (Kim et al., 2019), which in turn is a risk factor for asthma development in children (Lang et al., 2018), which may partially explain the results observed in our study.

Sexually dimorphic effects of bisphenols on diverse health outcomes have been reported, including asthma and obesity (Braun et al., 2011; Buckley et al., 2016; Doherty et al., 2017; Ilagan et al., 2017; Pu et al., 2017; Harley et al., 2013). Given the endocrine disrupting capacity of bisphenols, they can alter key hormone-signalling pathways and thus induce changes in sex hormones, which may partly explain the results found in this study. Fluctuations of sex hormones and their

consequences on immune functions can play a role in asthma pathogenesis. The sexual dimorphism of asthma is especially observed in hormonally changing periods such as puberty, pregnancy, and menopause (Shah and Newcomb, 2018). Observational, clinical, and animal studies have highlighted changes in oestrogen and testosterone levels to influence incidence and severity of asthma (Han et al., 2020; DeBoer et al., 2018; Cephus et al., 2017; Bonds and Midoro-Horiuti, 2013).

## 4.3. Strengths and limitations

The strengths of this study rely on its prospective IPD *meta*-analysis design with multiple bisphenols, detailed, harmonized, and objective respiratory outcomes, and large sample size, which enabled us to assess the subtle effects usually associated with exposure to environmental hazards (Frey and Usemann, 2019) and potential effect modifiers. By performing prospective IPD *meta*-analyses, we increased the strength of evidence without relying on published data and thus limited potential publication bias, a common limitation of retrospective *meta*-analysis (Seidler et al., 2019). Also, current asthma status was constructed based on having two of three conditions (ever asthma diagnosis, wheeze in the last year, medication in the last year), which may have reduced outcome misclassification.

This study has however several limitations. First, exposure to bisphenols was determined in 1 or 2 spot urine samples, which given the short biological half-life of bisphenols, might have led to exposure misclassification. To overcome this bias, we applied regression calibration. After this correction, the increase in FEV₁ associated with prenatal BPA exposure disappeared, which tells us that it is unlikely that BPA is associated with an increase, although small, in lung function. Regression calibration models could not take into account the clustering of individuals within cohorts (random intercepts) like the main analyses. In addition, regression calibration could not be performed for asthma and wheeze because in logistic models, the bias in the regression calibration corrected analysis is high when the measurement error variance is high (Nab and Groenwold, 2021), as it was in our case. Further studies collecting repeated biospecimens per subject during pregnancy are needed (Casas et al., 2018; Vernet et al., 2018). Second, due to the low number of samples with detectable levels of BPF and BPS, we were not able to consider the exposure as continuous and categorised them into detected and undetected. This may have led to residual confounding since detected and undetected groups differed in socioeconomic and lifestyle characteristics as mentioned before. Third, bisphenols were analysed in different laboratories with some showing poor correlations (Supplementary Methods 2). However, after excluding the cohorts that conducted the analyses in these laboratories from the analyses, results did not change. Fourth, bisphenols were quantified at different trimesters of pregnancy in the cohorts. However, we tested whether trimester of the sampling was an explanatory factor of the heterogeneity, and it did not explain it (data not shown). Fifth, although we were able to construct childhood wheezing phenotypes, the data on wheezing episodes available across ages differed between cohorts (Supplementary Table S1). We were able to create four patterns, which might not be sufficient to capture effects on a specific age. Sixth, although lung function parameters were obtained following the ATS/ERS criteria, these estimates need to be carefully interpreted since the spirometry measurement error might be greater than the estimates, when these estimates are expected to be small. Finally, the included population tended to be of somewhat higher educated and socioeconomic status families. Although our results might not be generalised to the general population, this study encompasses the largest number of participants from different regions of Europe to date, and it is unlikely this might affect the internal validity of the study.

## 4.4. Conclusions

Our study suggests that *in utero* exposure to BPA may increase the risk of asthma and wheeze among school-age girls but shows no
evidence of an association with lung function at school-age. Identification of early determinants of respiratory health in childhood is of utmost importance, given their long-term effect on disease throughout life. Further research is needed on the assessment of temporal variabilities in exposure in relation to health outcomes, in order to improve current EU chemical legislation. Current regulation is focused on BPA, obviating analogues that are suspected to have similar toxicity (Rosenmai et al., 2014), and needs to move forward by avoiding entire chemical classes instead of individual compounds.

## Funding

The research leading to these results has received funding from Instituto de Salud Carlos III and European Union's FEDER funds (CP16/00128 – the ENDOLUNG project, and PI17/01194 – the INMA-Ado-Respi Project), the European Community's Seventh Framework Programme (FP7/2007–2016) under grant agreement No 308,333 - the HELIX project –, and from the EC's Horizon 2020 research and innovation programme under grant agreement No 874,583 – the ATHLETE project.

**Generation R:** This study was funded by The Erasmus MC, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. The project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect grant agreement No 824989; ATHLETE, grant agreement No 874583). Dr. Vincent Jaddoe received a grant from the European Research Council (ERC-2014-CoG-648916). This study was supported by grant R01-ES022972 and R01-ES029779 from the National Institutes of Health, USA. The researchers are independent from the funders. The study sponsors had no role in the study design, data analysis, interpretation of data, or writing of this report.

**INMA Gipuzkoa:** This study was funded by grants from Instituto de Salud Carlos III (FIS-PI13/02187 and FIS-PI18/01142 incl. FEDER funds), CIBERESP, Department of Health of the Basque Government (2015111065), and the Provincial Government of Gipuzkoa (DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain).

**INMA Sabadell:** This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació La marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l'Alimentation de l'Environnement et du Travail (1262C0010), European Commission (261357, 308333, 603,794 and 634453). Alicia Abellan holds a LifeCycle fellowship, funded from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733206. Maribel Casas holds a Miguel Servet fellowship (CP16/00128) funded by Instituto de Salud Carlos III and co-funded by European Social Fund "Investing in your future". We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.

**INMA Valencia:** INMA Valencia was funded by Grants from UE (FP7-ENV-2011 cod 282,957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, and PI19/1338; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), Alicia Koplowitz Foundation, and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, UGP-15-249, and AICO/2020/285).

**BiB:** This report is independent research funded by the National Institute for Health Research Yorkshire and Humber ARC (NIHR200166)

and BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.

**EDEN:** The EDEN study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l'Éducation Nationale a complementary health insurance (MGEN), French national agency for food security, French-speaking association for the study of diabetes and metabolism (ALFEDIAM).

**MoBa:** The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research.

**RHEA:** The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211,250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226,285 ENRIECO, EU-FP7- HEALTH-2012 Proposal No 308,333 HELIX, H2020 LIFECYCLE, grant agreement No 733206, H2020 ATHLETE, grant agreement No 874583), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). Additional funding from NIEHS supported Dr Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, R21ES028903, and P30ES007048).

The funding sources had no involvement in the study design, the collection, analysis and interpretation of data or in the writing of the report and in the decision to submit the article for publication.

## Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

We are grateful to all the participating children, parents, practitioners and researchers in the eight cohorts who took part in this study.

**Generation R:** We gratefully acknowledge the contribution of the participating children, their mothers, general practitioners, hospitals, midwives, and pharmacies in Rotterdam.

**INMA Gipuzkoa, Sabadell and Valencia:** The authors would particularly like to thank all the participants for their generous collaboration. A full roster of the INMA Project Investigators can be found at https://www.proyectoinma.org/en/inma-project/inma-project-researchers/.

**BiB:** Born in Bradford is only possible because of the enthusiasm and commitment of the Children and Parents in BiB. We are grateful to all the participants, practitioners and researchers who have made Born in Bradford happen.

**EDEN:** The authors thank all the participants of the EDEN study and the EDEN mother-child cohort study group, whose members are I. Annesi-Maesano, J.Y. Bernard, M.A. Charles, P. Dargent-Molina, B. de
Lauzon-Guillain, P., Ducimetière, M., de Agostini, B., Foliguet, A., Forhan, X., Fritel, A., Germa, V., Goua, R., Hankard, B., Heude, M., Kaminski, B., Larroquey, N., Lelong, J., Lepeule, G., Magnin, L., Marchand, M., Nabet, F., Pierre, R., Slama, M.J., Saurel-Cubizolles, M., Schweitzer, and O. Thiebaugeorges.

**MoBa:** We are grateful to all the participating families in Norway who take part in this on-going cohort study.

**RHEA:** We are grateful to all the participating families who took part in this cohort study.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.envint.2022.107178.

## References

Miller, M.D., Marty, M.A., 2010. Impact of Environmental Chemicals on Lung Development. Environ Health Perspect 118 (8), 1155-1164.

Håland, G., Carlsen, K.C.L., Sandvik, L., Devulapalli, C.S., Munthe-Kaas, M.C., Pettersen, M., Carlsen, K.-H., 2006. Reduced Lung Function at Birth and the Risk of Asthma at 10 Years of Age. N Engl J Med 355 (16), 1682-1689.

Bui, D.S., Lodge, C.J., Burgess, J.A., Lowe, A.J., Perret, J., Bui, M.Q., Bowatte, G., Gurrin, L., Johns, D.P., Thompson, B.R., Hamilton, G.S., Frith, P.A., James, A.L., Thomas, P.S., Jarvis, D., Svanes, C., Russell, M., Morrison, S.C., Feather, I., Allen, K. J., Wood-Baker, R., Hopper, J., Giles, G.G., Abramson, M.J., Walters, E.H., Matheson, M.C., Dharmage, S.C., 2018. Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. Lancet Respir Med. 6 (7), 535-544.

Drazen, J.M., Martinez, F.D., 2016. Early-Life Origins of Chronic Obstructive Pulmonary Disease. Drazen JM, editor. N Engl J Med. 375 (9), 871-878.

Vardavas, C.I., Hohmann, C., Patelarou, E., Martinez, D., Henderson, A.J., Granell, R., Sunyer, J., Torrent, M., Fantini, M.P., Gori, D., Annesi-Maesano, I., Slama, R., Duijts, L., de Jongste, J.C., Aurrekoetxea, J.J., Basterrechea, M., Morales, E., Ballester, F., Murcia, M., Thijcs, C., Mommers, M., Kuehni, C.E., Gaillard, E.A., Tischer, C., Heinrich, J., Pizzi, C., Zugna, D., Gehring, U., Wijga, A., Chatzi, L., Vassilaki, M., Bergström, A., Eller, E., Lau, S., Keil, T., Nieuwenhuijsen, M., Kogevinas, M., 2016. The independent role of prenatal and postnatal exposure to active and passive smoking on the development of early wheeze in children. Eur Respir J. 48 (1), 115-124.

Gehring, U., Wijga, A.H., Hoek, G., Bellander, T., Berdel, D., Brüske, I., Fuertes, E., Gruzieva, O., Heinrich, J., Hoffmann, B., de Jongste, J.C., Klümper, C., Koppelman, G.H., Korek, M., Krämer, U., Maier, D., Melén, E., Pershagen, G., Postma, D.S., Standl, M., von Berg, A., Anto, J.M., Bousquet, J., Keil, T., Smit, H.A., Brunkeertf, B., 2015. Exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence: A population-based birth cohort study. Lancet Respir Med. 3 (12), 933-942.

Bui, D.S., Burgess, J.A., Lowe, A.J., Perret, J.L., Lodge, C.J., Bui, M., Morrison, S., Thompson, B.R., Thomas, P.S., Giles, G.G., Garcia-Aymerich, D., Jarvis, D., Abramson, M.J., Walters, E.H., Matheson, M.C., Dharmage, S.C., 2017. Childhood lung function predicts adult chronic obstructive pulmonary disease and asthma-chronic obstructive pulmonary disease overlap syndrome. Am J Respir Crit Care Med. 196 (1), 39-46.

Casas, M., Morales, E., Sunyer, J., Vrijheid, M., 2013. Effects of persistent organic pollutants on the developing respiratory and immune systems: A systematic review. Environ Int. 52, 51-65.

Vrijheid, M., Casas, M., Gascon, M., Valvi, D., Nieuwenhuijsen, M., 2016. Environmental pollutants and child health-A review of recent concerns. Int J Hyg Environ Health. 219 (4-5), 331-342.

Casas, M., Gascon, M., 2020. Prenatal exposure to endocrine-disrupting chemicals and asthma and allergic diseases. J Investig Allergol Clin Immunol. 30 (4), 215-228.

Abellan, A., Casas, M., 2021. In Utero Exposure to Organic Pollutants and Lung Function in the Offspring. BRN Rev. 7 (1) https://doi.org/10.23866/BRNRev:2020-0004.

CHEMTRUST - Protecting humans and wildlife from harmful chemicals. From BPA to BPZ: a toxic soup? CHEMTRUST. 2018.

Heude, B., Forhan, A., Slama, R., Douhaud, L., Bedel, S., Saurel-Cubizolles, M.-J., Hankard, R., Thiebaugeorges, O., De Agostini, M., Annesi-Maesano, I., Kaminski, M., Charles, M.-A., 2016. Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol. 45 (2), 353-363.

Magnus, P., Birke, C., Vejrup, K., Haugen, A., Alsaker, E., Daltveit, A.K., Handal, M., Haugen, M., Høiseth, G., Knudsen, G.P., Paltiel, L., Schreuder, P., Tambs, K., Vold, L., Stoltenberg, C., 2016. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa). Int J Epidemiol. 45 (2), 382-388.

Liao, C., Kannan, K., 2013. Concentrations and profiles of bisphenol A and other bisphenol analogues in foodstuffs from the united states and their implications for human exposure. J Agric Food Chem. 61 (19), 4655-4662.

European Chemical Agency. Bisphenol A-ECHA [Internet]. 2017. Available from: https://echa.europa.eu/es/hot-topics/bisphenol-a.

Lehmler HJ, Liu B, Gadogbe M, Bao W. Exposure to Bisphenol A, Bisphenol F, and Bisphenol S in U.S. Adults and Children: The National Health and Nutrition Examination Survey 2013-2014. ACS Omega. 2018;3:6523-32.

Rochester, J.R., Bolden, A.L., 2015. Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes. Environ Health Perspect. 123 (7), 643-650.

Lee, J., Choi, K., Park, J., Moon, H.-B., Choi, G., Lee, J.J., Suh, E., Kim, H.-J., Eun, S.-H., Kim, G.-H., Cho, G.J., Kim, S.K., Kim, S., Kim, S.Y., Kim, S., Eom, S., Choi, S., Kim, Y. D., Kim, S., 2018. Bisphenol A distribution in serum, urine, placenta, breast milk, and umbilical cord serum in a birth panel of mother-neonate pairs. Sci Total Environ. 626, 1494-1501.

Spanier, A.J., Kahn, R.S., Kunselman, A.R., Hornung, R., Xu, Y., Calafat, A.M., Lanphear, B.P., 2012. Prenatal exposure to bisphenol A and child wheeze from birth to 3 years of age. Environ Health Perspect. 120 (6), 916-920.

Spanier, A.J., Kahn, R.S., Kunselman, A.R., Schaefer, E.W., Hornung, R., Xu, Y., Calafat, A.M., Lanphear, B.P., 2014. Bisphenol A exposure and the development of wheeze and lung function in children through age 5 years. JAMA Pediatr. 168 (12), 1131. https://doi.org/10.1001/jamapediatrics.2014.1397.

Vernet, C., Pin, I., Giorgis-Allemand, L., Philippat, C., Benmerad, M., Quentin, J., Calafat, A.M., Ye, X., Annesi-Maesano, I., Siroux, V., Slama, R., 2017. In utero exposure to select phenols and phthalates and respiratory health in five-year-old boys: A prospective study. Environ Health Perspect. 125 (9), 097006. https://doi.org/10.1289/EHP1015.

Agier, L., Basagaña, X., Maitre, L., Granum, B., Bird, P.K., Casas, M., Oftedal, B., Wright, J., Andrusaityte, S., de Castro, M., Cequier, E., Chatzi, L., Donaire-Gonzalez, D., Grazuleviciene, R., Haug, L.S., Sakhi, A.K., Leventakou, V., McEachan, R., Nieuwenhuijsen, M., Petraviciene, I., Robinson, O., Roumeliotaki, T., Sunyer, J., Tamayo-Uria, I., Thomsen, C., Urquiza, J., Valentin, A., Slama, R., Vrijheid, M., Siroux, V., 2019. Early-life exposome and lung function in children in Europe: an analysis of data from the longitudinal, population-based HELIX cohort. Lancet Planet Heal. 3 (2), e81-e92.

Berger, K., Coker, E., Rauch, S., Eskenazi, B., Balmes, J., Kogut, K., Holland, N., Calafat, A.M., Harley, K., 2020. Prenatal phthalate, paraben, and phenol exposure and childhood allergic and respiratory outcomes: Evaluating exposure to chemical mixtures. Sci Total Environ. 725, 138418. https://doi.org/10.1016/j.scitotenv.2020.138418.

Casgan, M., Casas, M., Morales, E., Valvi, D., Ballesteros-Gómez, A., Luque, N., Rubio, S., Monfort, N., Ventura, R., Martínez, D., Sunyer, J., Vrijheid, M., 2015. Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy. J Allergy Clin Immunol. 135 (2), 370-378.e7.

Zhou, A., Chang, H., Huo, W., Zhang, B., Hu, J., Xia, W., Chen, Z., Xiong, C., Zhang, Y., Wang, Y., Xu, S., Li, Y., 2017. Prenatal exposure to bisphenol A and risk of allergic diseases in early life. Pediatr Res. 81 (6), 851-856.

Buckley, J.P., Quirós-Alcalá, L., Teitelbaum, S.L., Calafat, A.M., Wolff, M.S., Engel, S.M., 2018. Associations of prenatal environmental phenol and phthalate biomarkers with respiratory and allergic diseases among children aged 6 and 7 years. Environ Int. 115, 79-88.

Donohue, K.M., Miller, R.L., Perzanowski, M.S., Just, A.C., Hoepner, L.A., Arunajadai, S., Canfield, S., Resnick, D., Calafat, A.M., Perera, F.P., Whyatt, R.M., 2013. Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children. J Allergy Clin Immunol. 131 (3), 736-742.e6.

Berger, K., Eskenazi, B., Balmes, J., Kogut, K., Holland, N., Calafat, A.M., Harley, K.G., Kalayci, Ö., 2019. Prenatal high molecular weight phthalates and bisphenol A, and childhood respiratory and allergic outcomes. Pediatr Allergy Immunol. 30 (1), 36-46.

Lan, H.-C., Wu, K.-Y., Lin, I-W., Yang, Z.-J., Chang, A.-A., Hu, M.-C., 2017. Bisphenol A disrupts steroidogenesis and induces a sex hormone imbalance through c-Jun phosphorylation in Leydig cells. Chemosphere. 185, 237-246.

Jaddoe, W.V.V., Mackenbach, J.P., Moll, H.A., Steegers, E.A.P., Tiemeier, H., Verhulst, F., C., Witteman, J.C.M., Hofman, A., 2006. The Generation R Study: Design and cohort profile. Eur J Epidemiol. 21 (6), 475-484.

Guxens, M., Ballester, F., Espada, M., Fernández, M.F., Griment, J.O., Ibarluzea, J., Olea, N., Rebagliato, M., Tardón, A., Torrent, M., Vioque, J., Vrijheid, M., Sunyer, J., 2012. Cohort profile: The INMA-Infancia y Medio Ambiente-environment and childhood) project. Int J Epidemiol. 41 (4), 930-940.

Wright, J., Small, N., Raynor, P., Tuffnell, D., Bhopal, R., Cameron, N., Fairley, L., Lawlor, D.A., Parslow, R., Petherick, E.S., Pickett, K.E., Waiblinger, D., West, J., 2013. Cohort profile: The born in bradford multi-ethnic family cohort study. Int J Epidemiol. 42 (4), 978-991.

Heude, B., Forhan, A., Slama, R., Douhaud, L., Bedel, S., Saurel-Cubizolles, M.-J., Hankard, R., Thiebaugeorges, O., De Agostini, M., Annesi-Maesano, I., Kaminski, M., Charles, M.-A., 2016. Cohort Profile: The EDEN mother-child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol. 45 (2), 353-363.

Magnus, P., Birke, C., Vejrup, K., Haugen, A., Alsaker, E., Daltveit, A.K., Handal, M., Haugen, M., Høiseth, G., Knudsen, G.P., Paltiel, L., Schreuder, P., Tambs, K., Vold, L., Stoltenberg, C., 2016. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa). Int J Epidemiol. 45 (2), 382-388.

Paltiel, L., Anita, H., Skjerdен, T., Harbak, K., Bækken, S., Nina Kristin, S., Knudsen, G.P., Magnus, P., 2014. The biobank of the Norwegian mother and child cohort study – Present status. Nor J Epidemiol. Norwegian Epidemiological Society 24 (1-2). https://doi.org/10.5324/nje.v24i1-2.1755.

Chatzi, J., Leventakou, V., Vafeiadi, M., Koutra, K., Roumeliotaki, T., Chalkiadaki, G., Karachaliou, M., Daraki, V., Kyriklaki, A., Kampouri, M., Fthenou, E., Sarri, K., Vassilaki, M., Fasoulaki, M., Bitsios, P., Koutis, A., Stephanou, E.G., Kogevinas, M.,
2017. Cohort Profile: The Mother-Child Cohort in Crete, Greece (Rhea Study). Int J Epidemiol. 46 (5), 1392-1393k.

Maitre, L., de Bont, J., Casas, M., Robinson, O., Aasvang, G.M., Agier, L., Andrušaitytė, S., Ballester, F., Basagaña, X., Borràs, E., Brochot, C., Bustamante, M., Carracedo, A., de Castro, M., Dedele, A., Donaire-Gonzalez, D., Estivill, X., Evandt, J., Fossati, S., Giorgis-Allemand, L., R Gonzalez, J., Granum, B., Grazuleviciene, R., Bjerve Gützkow, K., Småstuen Haug, L., Hernandez-Ferrer, C., Heude, B., Ibarluzea, J., Julvez, J., Karachaliou, M., Keun, H.C., Hjertager Krog, N., Lau, C.-H., Leventakou, V., Lyon-Caen, S., Manzano, C., Mason, D., McEachan, R., Meltzer, H. M., Petracviene, I., Quentin, J., Roumeliotaki, T., Sabido, E., Saulnier, P.-J., Siskos, A.P., Siroux, V., Sunyer, J., Tamayo, I., Urquiza, J., Vafeiadi, M., van Gent, D., Vives-Usano, M., Waiblinger, D., Warenboult, C., Chatzi, L., Coen, M., van den Hazel, P., Nieuwenhuijsen, M.J., Slama, R., Thomsen, C., Wright, J., Vrijheid, M., 2018. Human Early Life Exposome (HELIX) study: A European population-based exposome cohort. BMJ Open. 8 (9), e021311. https://doi.org/10.1136/bmjopen-2017-021311.

Hohmann, C., Pinart, M., Tischer, C., Gehring, U., Heinrich, J., Kull, I., Melén, E., Smit, H.A., Torrent, M., Wijga, A.H., Wickman, M., Bachert, C., Lødrup Carlsen, K.C., Carlsen, K.-H., Bindslev-Jensen, C., Eller, E., Esplugues, A., Fantini, M.P., Annesi-Maesano, I., Momas, I., Porta, D., Vassilaki, M., Waiblinger, D., Sunyer, J., Antó, J. M., Bousquet, J., Keil, T., 2014. The development of the MEdALL core questionnaires for a harmonized follow-up assessment of eleven European birth cohorts on asthma and allergies. Int Arch Allergy Immunol. 163 (3), 215-224.

Asher, M.I., Keil, U., Anderson, H.R., Beasley, R., Crane, J., Martinez, F., Mitchell, E.A., Pearce, N., Sibbald, B., Stewart, A.W., Strachan, D., Weiland, S.K., Williams, H.C., 1995. International study of asthma and allergies in childhood (ISAAC): Rationale and methods. European Respiratory Journal. 8 (3), 483-491.

Miller, M.R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., et al., 2005. Standardisation of spirometry. Eur Respir J. 26, 319-338.

Quanjer, P.H., Stanojevic, S., Cole, T.J., Baur, X., Hall, G.L., Culver, B.H., Enright, P.L., Hankinson, J.L., Ip, M.S.M., Zheng, J., Stocks, J., 2012. Multi-ethnic reference values for spirometry for the 3-95-yr age range: The global lung function 2012 equations. Eur Respir J. 40 (6), 1324-1343.

Sonnenschein-Van Der Voort, A.M.M., Aremes, L.R., De Jongste, J.C., Annesi-Maesano, I., Arshad, S.H., Barros, H., et al., 2014. Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children. J Allergy Clin Immunol. 133, 1317-1329.

Den Dekker, H.T., Sonnenschein-Van Der Voort, A.M.M., De Jongste, J.C., Annesi-Maesano, I., Arshad, S.H., Barros, H., et al., 2016. Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children. J Allergy Clin Immunol. 137, 1026-1035.

Montazeri, P., Thomsen, C., Casas, M., de Bont, J., Haug, L.S., Maitre, L., Papadopoulou, E., Sakhi, A.K., Slama, R., Saulnier, P.J., Urquiza, J., Grazuleviciene, R., Andrusaityte, S., McEachan, R., Wright, J., Chatzi, L., Basagaña, X., Vrijheid, M., 2019. Socioeconomic position and exposure to multiple environmental chemical contaminants in six European mother-child cohorts. Int J Hyg Environ Health. 222 (5), 864-872.

Philips, E.M., Jaddoe, W.V.V., Asimakopoulos, A.G., Kannan, K., Steegers, E.A.P., Santos, S., Trasande, L., 2018. Bisphenol and phthalate concentrations and its determinants among pregnant women in a population-based cohort in the Netherlands, 2004-5 HHS Public Access Author manuscript. Env Res. 161, 562-572.

Welshons W.V., Nagel SC, Vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Vol. 147, Endocrinology. Endocrinology. 2006.

Vandenberg, L.N., Hauser, R., Marcus, M., Olea, N., Welshons, W.V., 2007. Human exposure to bisphenol A (BPA). ReprodToxicol. 24 (2), 139-177.

Rogers, J.A., Metz, L., Yong, V.W., 2013. Review: Endocrine disrupting chemicals and immune responses: A focus on bisphenol-A and its potential mechanisms. Molecular Immunology 53 (4), 421-430.

Kim, J.J., Kumar, S., Kumar, V., Lee, Y.M., Kim, Y.S., Kumar, V., 2020. Bisphenols as a legacy pollutant, and their effects on organ vulnerability. International Journal of Environmental Research and Public Health. MDPI AG 17.

Luo, S., Li, Y., Li, Y., Zhu, Q., Jiang, J., Wu, C., Shen, T., 2016. Gestational and lactational exposure to low-dose bisphenol A increases Th17 cells in mice offspring. Environ Toxicol Pharmacol. 47, 149-158.

Van Winkle, L.S., Murphy, S.R., Boetticher, M.V., VandeVoort, C.A., 2013. Fetal exposure of rhesus macaques to bisphenol a alters cellular development of the conducting airway by changing epithelial secretory product expression. Environ Health Perspect. 121 (8), 912-918.

Hijazi, A., Guan, H., Cernea, M., Yang, K., 2015. Prenatal exposure to bisphenol A disrupts mouse fetal lung development. FASEB J. 29 (12), 4968-4977.

Dufetelle, E., Bokov, P., Delclaux, C., Beydon, N., 2018. Should reversibility be assessed in all asthmatic children with normal spirometry? Eur Respir J. 52 (2), 1800373. https://doi.org/10.1183/13993003.00373-2018.

Bacharier, L.B., Strunk, R.C., Mauger, D., White, D., Lemanske, R.F., Sorkness, C.A., 2004. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med. 170 (4), 426-432.

Baatenburg de Jong, A., Brouwer, A.F.J., Roorda, R.J., Brand, P.L.P., 2006. Normal lung function in children with mild to moderate persistent asthma well controlled by inhaled corticosteroids. J Allergy Clin Immunol. 118 (1), 280-282.

Andrianou, X.D., Gängler, S., Piciu, A., Charisiadis, P., Zira, C., Aristidou, Piciu, D., Hauser, R., Makris, K.C., Carvalho, D.P.d., 2016. Human Exposures to Bisphenol A, Bisphenol F and Chlorinated Bisphenol A Derivatives and Thyroid Function. PLoS One. 11 (10), e0155237.

Prasanth, G.K., Divya, L.M., Sadasivan, C., 2010. Bisphenol-A can bind to human glucocorticoid receptor as an agonist: an in silico study. J Appl Toxicol. 30 (8), 769-774.

Wassenaar, P.N.H., Trasande, L., Legler, J., 2017. Systematic Review and Meta-Analysis of Early-Life Exposure to Bisphenol A and Obesity-Related Outcomes in Rodents. Environ Health Perspect. 125 (10), 106001. https://doi.org/10.1289/EHP1233.

Kim, K.Y., Lee, E., Kim, Y., 2019. The Association between Bisphenol A Exposure and Obesity in Children-A Systematic Review with Meta-Analysis. Int J Environ Res Public Health. 16 (14), 2521. https://doi.org/10.3390/ijerph16142521.

Lang, J.E., Bunnell, H.T., Hossain, M.J., Wysocki, T., Lima, J.J., Finkel, T.H., Bacharier, L., Dempsey, A., Sarzynski, L., Test, M., Forrest, C.B., 2018. Being Overweight or Obese and the Development of Asthma. Pediatrics. 142 (6) https://doi.org/10.1542/peds.2018-2119.

Braun, J.M., Kalkbrenner, A.E., Calafat, A.M., Yolton, K., Ye, X., Dietrich, K.N., Lanphear, B.P., 2011. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 128 (5), 873-882.

Buckley, J.P., Herring, A.H., Wolff, M.S., Calafat, A.M., Engel, S.M., 2016. Prenatal exposure to environmental phenols and childhood fat mass in the Mount Sinai Children's Environmental Health Study. Environ Int. 91, 350-356.

Doherty, B.T., Engel, S.M., Buckley, J.P., Silva, M.J., Calafat, A.M., Wolff, M.S., 2017. Prenatal phthalate biomarker concentrations and performance on the Bayley Scales of Infant Development-II in a population of young urban children. Environ Res. 152, 51-58.

Iagan, Y., Mamillapalli, R., Goetz, T.G., Kayani, J., Taylor, H.S., 2017. Bisphenol-A exposure in utero programs a sexually dimorphic estrogenic state of hepatic metabolic gene expression. Reprod Toxicol. 71, 84-94.

Pu, Y., Gingrich, J.D., Steibel, J.P., Veiga-Lopez, A., 2017. Sex-Specific Modulation of Fetal Adipogenesis by Gestational Bisphenol A and Bisphenol S Exposure. Endocrinology. 158 (11), 3844-3858.

Harley, K.G., Schall, R.A., Chevrier, J., Tyler, K., Aguirre, H., Bradman, A., Holland, N.T., Lustig, R.H., Calafat, A.M., Eskenazi, B., 2013. Prenatal and Postnatal Bisphenol A Exposure and Body Mass Index in Childhood in the CHAMACOS Cohort. Environ Health Perspect. 121 (4), 514-520.

Shah, R., Newcomb, D.C., 2018. Sex Bias in Asthma Prevalence and Pathogenesis. Front Immunol. 9, 2997.

Han, Y.-Y., Forno, E., Celedón, J.C., 2020. Sex steroid hormones and asthma in a nationwide study of U.S. adults. Am J Respir Crit Care Med. 201 (2), 158-166.

DeBoer, M.D., Phillips, B.R., Mauger, D.T., Zein, J., Erzurum, S.C., Fitzpatrick, A.M., Gaston, B.M., Myers, R., Ross, K.R., Chmiel, J., Lee, M.J., Fahy, J.V., Peters, M., Ly, N.P., Wenzel, S.E., Fajt, M.L., Holguin, F., Moore, W.C., Peters, S.P., Meyers, D., Bleecker, E.R., Castro, M., Coverstone, A.M., Bacharier, L.B., Jarjour, N.N., Sorkness, R.L., Ramratnam, S., Irani, A.-M., Israel, E., Levy, B., Phipatanakul, W., Gaffin, J.M., Gerald Teague, W., 2018. Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. BMC Pulm Med. 18 (1) https://doi.org/10.1186/s12890-018-0612-x.

Cephus, J.-Y., Stier, M.T., Fuseini, H., Yung, J.A., Toki, S., Bloodworth, M.H., Zhou, W., Goleniewska, K., Zhang, J., Garon, S.L., Hamilton, R.G., Poloshukin, V.V., Boyd, K.L., Peebles, R.S., Newcomb, D.C., 2017. Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation. Cell Rep. 21 (9), 2487-2499.

Bonds RS, Midor-Horiuchi T. Estrogen effects in allergy and asthma. Vol. 13, Current Opinion in Allergy and Clinical Immunology. NIH Public Access; 2013. p. 92-9.

Frey U, Usemann J. Addressing the complexity of prenatal and postnatal environmental exposures affecting childhood lung function. Vol. 3, The Lancet Planetary Health. Elsevier B.V.; 2019. p. e51-2.

Seidler, A.L., Hunter, K.E., Cheyne, S., Ghersi, D., Berlin, J.A., Askie, L., 2019. A guide to prospective meta-analysis. BMJ. 367.

Nab, L., Groenwold, R.H.H., 2021. Sensitivity analysis for random measurement error using regression calibration and simulation-extrapolation. Glob Epidemiol. 3, 100067. https://doi.org/10.1016/j.gloepi.2021.100067.

Casas, M., Basagaña, X., Sakhi, A.K., Haug, L.S., Philippat, C., Granum, B., Manzano-Salgado, C.B., Brochot, C., Zeman, F., de Bont, J., Andrusaityte, S., Chatzi, L., Donaire-Gonzalez, D., Giorgis-Allemand, L., Gonzalez, J.R., Gracia-Lavedan, E., Grazuleviciene, R., Kampouri, M., Lyon-Caen, S., Pañella, P., Petracviene, I., Robinson, O., Urquiza, J., Vafeiadi, M., Vernet, C., Waiblinger, D., Wright, J., Thomsen, C., Slama, R., Vrijheid, M., 2018. Variability of urinary concentrations of non-persistent chemicals in pregnant women and school-aged children. Environ Int. 121, 561-573.

Vernet, C., Philippat, C., Calafat, A.M., Ye, X., Lyon-Caen, S., Siroux, V., Schisterman, E. F., Slama, R., 2018. Within-Day, Between-Day, and Between-Week Variability of Urinary Concentrations of Phenol Biomarkers in Pregnant Women. Environ Health Perspect. 126 (3), 037005. https://doi.org/10.1289/EHP1994.

Rosenmai, A.K., Dybdahl, M., Pedersen, M., Alice van Vugt-Lussenburg, B.M., Wedbye, E.B., Taxvig, C., Vinggaard, A.M., 2014. Are structural analogues to bisphenol A safe alternatives? Toxicol Sci. 139 (1), 35-47.