ABSTRACT
Aim
We examined if sex and puberty are associated with respiratory health, and if associations were modified by ethnicity, body mass index or allergic sensitization.
Methods
Among 3418 children of a multi‐ethnic population‐based cohort study, medical records provided information on sex. Questionnaires provided information on pubertal stages, wheezing from birth until age 13 years and current asthma at age 13 years. Pre/early, mid, and late developmental stages of breast (girls only), genital (boys only), and pubic hair were based on Tanner stages 1–2, 3–4, and 5, respectively. Spirometry was performed at age 13 years.
Results
Girls had a consistently lower risk of wheezing from birth until age 13 years than boys (overall OR (95% CI) 0.86 (0.74, 0.98)). Additionally, allergic girls had a lower risk of current asthma at age 13 years (0.66 (0.46, 0.94)). Only underweight and overweight/obese girls had lower and higher, respectively, FEV1 and FVC (Z‐score difference (95% CI): −0.25 (−0.40, −0.10) and −0.23 (−0.38, −0.08); 0.26 (0.09, 0.42) and 0.24 (0.09, 0.40), respectively). Girls with a late breast stage, boys with a late genital stage, and both sexes with a late pubic hair stage had higher FEV1, FVC and/or FEF75, compared with those with pre/early pubertal stages at school age (range 0.18 (0.01, 0.34)–0.22 (0.03, 0.41)).
Conclusion
Our findings suggest a different risk of respiratory morbidity between girls and boys partly modified by BMI or allergic sensitization, not ethnicity, and that puberty has a positive effect on lung function measures in both sexes.
Keywords: childhood, hormonal influence, respiratory health
1. Introduction
Sex differences in airway dimensions, structure, and function, and in the clinical manifestations of respiratory diseases occur throughout the human life span [1]. While in children boys have a higher prevalence of asthma symptoms than girls [2], studies in adults report that women have more adverse respiratory health outcomes than men [3]. The observed sex differences in the incidence of respiratory disease have been linked to changes in circulating levels of sex hormones that start around puberty [4]. Puberty may influence asthma prevalence and lung function [5, 6]. Indeed, it has been shown that age at menarche in girls [5] and body hair growth in boys [6] are associated with lung function in later life. However, the precise role of different pubertal stages in lung maturation is unclear mostly because the study populations are relatively small and restricted to girls where menarche is a easily signpost of puberty differently to boys. In children, a Dutch population‐based cohort observed that the prevalence of asthmatic wheeze was significantly higher in boys than in girls at the age of 1 year, and that this higher prevalence persisted during the first 7 years of life [7]. A New Zealand birth cohort of 1037 children showed that boys were more likely than girls to develop wheeze by age 10, whereas girls were more likely than boys to develop wheeze between age 10 and 26 [8]. Additionally, whether sex‐related differences in asthma or lung function parameters are present in children of different ethnic background is also unknown. Children of creolic background tend to reach their puberty at an earlier age [9]. Importantly, the risk of asthma was highest among black girls with earlier pubarche, suggesting a modifying effect by ethnicity [10]. Additionally, body mass index and allergy may modify associations of sex or puberty with respiratory outcomes [11, 12]. Based on previous findings, we hypothesized that sex and pubertal stage would be associated with wheezing, asthma, and lung function in adolescence, and that these associations might be modified by ethnicity, body mass index (BMI), and allergic sensitization. Therefore, the aim of this study was to assess whether sex and pubertal stage are associated with wheezing trajectories from birth to adolescence, current asthma, and changes in lung function at age 13.5 years in a population‐based cohort of 3418 children. We also examined whether these associations were modified by ethnicity, BMI, or inhalant allergic sensitization.
2. Methods
2.1. Study Design
This study was embedded in the Generation R Study, a multi‐ethnic population‐based prospective cohort study from early fetal life onwards in Rotterdam, the Netherlands [13]. The study has been approved by the Medical Ethical Committee of the Erasmus MC, University Medical Centre in Rotterdam (METC number: Generation R Phase 4 MEC 2015‐749 NL55105.078.15). Written informed consent was obtained from all participants. Children without information on sex or all respiratory outcomes at the age of 13 years where excluded. A total of 3418 mothers and their children were included for the current analyses (Figure 1).
FIGURE 1.
Flow‐chart of the study.
2.2. Sex and Puberty
Information on sex was obtained from midwife and medical records. Pubertal stage was assessed by self‐report at a median age of 13.5 years (range 12.6–16.6), using standard Tanner staging diagrams [14, 15]. Participants completed questionnaires showing sex‐specific illustrations: boys selected images reflecting genital and pubic hair development, and girls selected images for breast and pubic hair development. For boys, genital development was used as the primary marker of pubertal progression, as it correlates more closely with testicular volume and central activation of puberty. Additionally, we used of pubic hair as a marker of puberty in males and were thus unable to differentiate between central puberty and adrenarche. We grouped participants into three pubertal categories based on Tanner staging: pre/early puberty (Tanner stages 1–2), mid‐puberty (Tanner stages 3–4), and late puberty (Tanner stage 5). These groupings reflect pubertal progression as observed in early adolescence, around the median age of our sample (13.5 years). According to a large Dutch population‐based study including 14,507 native Dutch and 5759 Turkish and Moroccan children [16], Tanner stages 3–4 are typical for this age. Therefore, we defined Tanner stages 1–2 as below the expected tempo for age (pre/early), stages 3–4 as age‐appropriate (mid‐puberty), and stage 5 as advanced (late puberty). While this classification was age‐informed, it was based on absolute Tanner stage rather than relative pubertal timing. We acknowledge that some older adolescents in the sample may have been expected to have completed puberty by this age. To account for residual variation, all models involving Tanner stage were additionally adjusted for exact chronological age (in years) at the time of assessment.
2.3. Respiratory Morbidity in Childhood
We obtained information on wheezing in the past 12 months by annual (parental or self‐reported) questionnaires from birth to age 4 years, and at ages 6, 9, and 13 years. Information on asthma medication use in the past 12 months was obtained during the visits at the research center at the ages of 9 and 13 years (median age 9.7 years; 5%–95% range 8.5–12.7 years; median age 13.5 years; 5%–95% range 12.6–16.6 years, respectively). Asthma was defined as ever diagnosis of physician diagnosed‐asthma, obtained by parental or self‐reported questionnaires at the ages of 9 and 13 years, with either wheezing or medication use in the past 12 months. All questions on wheezing and asthma were based on the International Study on Asthma and Allergy in Childhood (ISAAC) Questionnaire [17]. Spirometry was performed at the ages of 9 and 13 years according to the American Thoracic Society and European Respiratory Society recommendations [18]. Lung function measures included FEV₁, FVC, FEV₁/FVC, and FEF₇₅, assessed at ages 9 and 13 years according to ATS/ERS standards. We constructed internal z‐scores for each parameter using the formula: (observed value – cohort mean)/cohort standard deviation (SD), with means and SDs calculated for the full cohort stratified by age and height, but not by sex, as sex was used as a primary exposure in our analyses. This internal standardization enabled us to examine associations and interactions with sex and ethnicity, which are accounted for in GLI‐based scores and thus inappropriate for our research objectives.
2.4. Covariates
Information on maternal age, educational level, psychiatric symptoms, smoking during pregnancy, history of asthma or atopy was obtained by multiple questionnaires during pregnancy [13]. Midwife and hospital records at birth provided information on mode of delivery, gestational age at birth, and birth weight. Child′s ethnicity was based on country of birth of parents and grandparents and obtained by questionnaires during pregnancy. Main non‐Dutch populations were Cape Verdean, Moroccan, Dutch Antillean, Surinamese and Turkish population, which represent the largest populations with a migration background in the Netherlands, and European and “other” populations (African, Asian, American, Oceanean, Indonesian). Questionnaires after birth provided information about child′s breastfeeding and day care attendance [13]. Allergic sensitization was determined by a skin prick test using the “scanned area method at age 9 years [19].”
2.5. Statistical Analysis
Continuous data was expressed as mean (SD) or median (interquartile range), and categorical data was presented as percentage and count. We compared characteristics of those included in our study and those lost to follow‐up by using independent samples T‐tests, Mann‐Whitney U tests, and Pearson′s Chi‐square tests. Associations of sex with wheezing prevalence was studied longitudinally by using generalized estimating equations (GEE). We tested unstructured, independent and first‐order autoregressive correlation structures, and the difference among these matrices was assessed by means of the quasilikelihood under the independence model criterion (QIC) statistic. Given that all correlation structures yielded similar results, but with a lower QIC for the independent structure, this structure was used in the final model. Next, to assess associations between pubertal stage and respiratory outcomes at age 13 (wheezing, current asthma, and lung function), we used multivariable logistic and linear regression models, stratified by sex. This stratification reflects known physiological differences in pubertal development, including thelarche and pubarche in girls, and gonadarche and pubarche in boys [20]. All models were adjusted for age at follow‐up (in years) and height gain from 9 to 13 years, to account for variation in biological growth and to isolate the effect of pubertal stage from age‐ or size‐related effects on respiratory outcomes. To minimize the potential reverse causation we adjusted the findings for wheezing/current asthma or lung function at the age of 9 years. Confounders were selected from literature first, and were subsequently tested for their association with both the determinant and the outcome, or a change of the unadjusted effect estimates of 10% when added to the univariate model [21, 22, 23]. A directed acyclic graph was created to visualize the relationship between exposure, outcome and possible covariates (Supporting Figure S1). Effect modification by child′s ethnicity, BMI, and inhalant allergic sensitization was assessed by inclusion of the interaction terms in the model and stratified analysis. To make the clinical interpretation easier, we categorized BMI z‐scores into “low” (z‐score < −1.00), “normal” (z‐score ≥ −1.00 and ≤ 1.00), and “high” (z‐score > 1.00), which reflect the 11th and 87th percentiles. Missing data in covariates and in repeated measures of current wheezing were imputed by the multiple imputation method using chained equations to select the most likely value for a missing response, creating 10 new datasets. Since we observed no major differences in the magnitude or direction of the effect estimates between analyses with imputed missing data and complete cases only, we only present the results based on imputed datasets. All measures of association are presented as odds ratios or z‐score differences and their corresponding 95% confidence intervals. Statistical analyses were performed using SPSS version 24.0 for Windows software (IBM Corp) and STATA/IC 15.1 (StataCorp LLC 4905 Lakeway Drive College Station, Texas 77845‐4512, USA).
3. Results
3.1. Subject Characteristics
Maternal and child characteristics are presented in Table 1. Among girls (50.1%, n = 1713), 62.4% (n = 1069) and 50.3% (n = 862) had mid‐pubertal breast and pubic hair development, respectively. Among boys, 47.8% (n = 815) and 50.0% (n = 853) had mid‐pubertal genital and pubic hair development, respectively. The overall prevalence of wheezing from age 1 to 13 years ranged from 29.4% to 5.1%. The overall prevalence of current asthma at age 13 years was 8.4%. Children not included in the study had a lower gestational age at birth and birth weight, were more often of non‐European ethnicity, and adolescent boys had a higher genital development, compared to those included (Table S1). Additional characteristics of children and their mothers are presented in Table S2.
TABLE 1.
Characteristics of children and their mothers before and after multiple imputation (n = 3418).
| Total population | Before multiple imputation | P value | After multiple imputation | P value | |||
|---|---|---|---|---|---|---|---|
| Boys | Girls | Boys | Girls | ||||
| 3418 | 1705 | 1713 | 1705 | 1713 | |||
| Maternal characteristics | |||||||
| Mode of delivery (%) | 0.551 | 0.395 | |||||
| Caesarian section | 406 (11.9) | 208 (12.2) | 198 (11.6) | 234 (13.7) | 217 (12.7) | ||
| Spontaneous | 2661 (77.8) | 1321 (77.5) | 1340 (78.2) | 1471 (86.3) | 1496 (87.3) | ||
| Missing | 351 (10.3) | 107 (10.3) | 175 (10.2) | 0 | 0 | ||
| Educational level (%) | 0.896 | 0.867 | |||||
| Low/middle | 1448 (42.4) | 717 (42.1) | 731 (42.7) | 789 (46.3) | 791 (46.2) | ||
| Higher | 1787 (52.3) | 889 (52.1) | 898 (52.4) | 916 (53.7) | 922 (53.8) | ||
| Missing | 183 (5.3) | 99 (5.8) | 84 (4.9) | 0 | 0 | ||
| Psychiatric symptomsa | 4.6 (0.0) | 4.6 (0.0) | 4.6 (0.0) | 0.179 | 4.6 (0.0) | 4.6 (0.0) | 0.292 |
| Missing | 753 (22.0) | 395 (23.2) | 358 (20.1) | 0 | 0 | ||
| Smoking during pregnancy (%) | 0.655 | 0.712 | |||||
| No | 2362 (69.1) | 1160 (68.0) | 1,202 (70.2) | 1310 (76.8) | 1326 (77.4) | ||
| Yes | 701 (20.5) | 351 (20.6) | 350 (20.4) | 395 (23.2) | 387 (22.6) | ||
| Missing | 355 (10.4) | 194 (11.4) | 161 (9.4) | ||||
| History of asthma/allergy (%) | 0.117 | 0.102 | |||||
| No | 1960 (57.3) | 986 (57.8) | 974 (56.9) | 1165 (68.3) | 1123 (65.6) | ||
| Yes | 976 (28.6) | 461 (27.0) | 515 (30.11) | 540 (31.7) | 590 (34.4) | ||
| Missing | 482 (14.1) | 258 (15.2) | 224 (13.1) | ||||
| Child characteristics | |||||||
| Gestational age at birth (weeks)1 | 40.1 (26.7–43.6) | 40.1 (26.7–43.6) | 40.1 (27.2–43.1) | c0.240 | 40.1 (26.7–43.6) | 40.1 (27.3–44.2) | c 0.258 |
| Missing | 23 (0.7) | 12 (0.7) | 11 (0.6) | 0 | 0 | ||
| Birth weight (grams) | 3457 (553) | 3527 (572) | 3387 (525) | < 0.001 | 3527 (572) | 3387 (525) | < 0.001 |
| Missing | 5 (0.1) | 3 (0.2) | 2 (0.1) | 0 | 0 | ||
| Ethnicity (%) | 0.060 | 0.072 | |||||
| Dutch | 2223 (65.3) | 1101 (64.6) | 1,132 (66.1) | 1101 (64.6) | 1132 (66.1) | ||
| Cape verdean | 85 (2.5) | 46 (2.7) | 39 (2.3) | 47 (2.7) | 41 (2.4) | ||
| Maroccan | 129 (3.8) | 76 (4.5) | 53 (3.1) | 77 (4.5) | 54 (3.1) | ||
| Turkish | 126 (3.7) | 62 (3.6) | 64 (3.7) | 63 (3.7) | 64 (3.7) | ||
| Dutch antilles | 91 (2.7) | 43 (2.5) | 48 (2.8) | 44 (2.6) | 49 (2.9) | ||
| European | 270 (7.9) | 117 (6.9) | 153 (8.9) | 117 (6.9) | 153 (8.9) | ||
| Surinamese | 212 (6.2) | 115 (6.7) | 97 (5.7) | 116 (6.8) | 99 (5.8) | ||
| Other | 243 (7.1) | 132 (7.7) | 111 (6.5) | 140 (8.2) | 121 (7.1) | ||
| Missing | 29 (0.8) | 13 (0.8) | 16 (0.9) | 0 | 0 | ||
| Ever breastfeeding (%) | 0.984 | 0.723 | |||||
| No | 196 (5.7) | 96 (5.6) | 100 (5.8) | 193 (11.3) | 188 (11.0) | ||
| Yes | 2595 (75.9) | 1273(74.7) | 1322 (77.2) | 1512 (88.7) | 1525 (89.0) | ||
| Missing | 627 (18.4) | 336 (19.7) | 291 (17.0) | 0 | 0 | ||
| Day care attendance 1st (%)^ | 0.699 | 0.425 | |||||
| No | 356 (10.4) | 175 (10.3) | 181 (10.6) | 468 (27.4) | 468 (27.3) | ||
| Yes | 1435 (42.0) | 689 (40.4) | 746 (43.5) | 1,237 (72.6) | 1,245 (72.7) | ||
| Missing | 1627 (47.6) | 841 (49.3) | 786 (45.9) | 0 | 0 | ||
| SPT at age 9 ys (%)§ | < 0.001 | 0.002 | |||||
| No | 1498 (43.8) | 698 (40.9) | 800 (46.7) | 909 (53.3) | 818 (47.8) | ||
| Yes | 807 (23.6) | 438 (25.7) | 369 (21.5) | 796 (46.7) | 895 (52.2) | ||
| Missing | 1113 (32.6) | 569 (33.4) | 544 (31.8) | ||||
| Age at assessment (ys) | 13.5 (12.6–16.6) | 13.5 (12.6–16.4) | 13.5 (12.6–16.6) | 0.423 | 13.5 (12.6–16.4) | 13.5 (12.6–16.6) | 0.423 |
| BMI at age 13 ys (Kg/m2) | 19.0 (13.0–40.3) | 18.6 (13.0–36.7) | 19.4 (13.4–40.3) | c < 0.001 | 18.6 (13.0–36.7) | 19.38 (13.0–40.3) | c < 0.001 |
| Missing | 4 (0.1) | 2 (0.1) | 2 (0.1) | ||||
| GD in boys (%)b | |||||||
| Tanner stage 1 | 16 (0.9) | ||||||
| Tanner stage 2 | 167 (9.8) | ||||||
| Tanner stage 3 | 461 (27.0) | ||||||
| Tanner stage 4 | 354 (20.8) | ||||||
| Tanner stage 5 | 67 (4.0) | ||||||
| Missing | 640 (37.5) | ||||||
| PHD in boys (%) b | |||||||
| Tanner stage 1 | 60 (3.5) | ||||||
| Tanner stage 2 | 230 (13.5) | ||||||
| Tanner stage 3 | 434 (25.4) | ||||||
| Tanner stage 4 | 419 (24.6) | ||||||
| Tanner stage 5 | 67 (4.0) | ||||||
| Missing | 495 (29.0) | ||||||
| BD in girls (%) b | |||||||
| Tanner stage 1 | 16 (0.9) | ||||||
| Tanner stage 2 | 161 (9.4) | ||||||
| Tanner stage 3 | 562 (32.8) | ||||||
| Tanner stage 4 | 507 (29.6) | ||||||
| Tanner stage 5 | 107 (6.2) | ||||||
| Missing | 360 (21.1) | ||||||
| PHD in girls (%) b | |||||||
| Tanner stage 1 | 17 (1.0) | ||||||
| Tanner stage 2 | 110 (6.4) | ||||||
| Tanner stage 3 | 337 (19.7) | ||||||
| Tanner stage 4 | 525 (30.6) | ||||||
| Tanner stage 5 | 253 (14.8) | ||||||
| Missing | 471 (27.5) | ||||||
| Lung function measures at 13 ys b yr b | |||||||
| FEV1 (L) | 3.1 (0.5) | 3.1 (0.6) | 3.0 (0.5) | < 0.001 | |||
| FVC (L) | 3.6 (0.6) | 3.7 (0.7) | 3.5 (0.5) | < 0.001 | |||
| FEV1/FVC (%) | 86 (6.0) | 85 (6.0) | 88 (5.6) | < 0.001 | |||
| FEF75 (L/s) | 1.8 (0.6) | 1.7 (0.6) | 1.8 (0.6) | < 0.001 | |||
| FEV1 z‐score+ | 0.0001 (1.0) | −0.0001 (1.0) | 0.0003 (1.0) | 0.991 | |||
| FVC z‐score | 0.0009 (1.0) | 0.0021 (1.0) | −0.0003 (1.0) | 0.943 | |||
| FEV1/FVC z‐score | 0.0008 (1.0) | 0.0087 (1.0) | −0.0070 (1.0) | 0.647 | |||
| FEF75 z‐score | 0.0000 (1.0) | 0.0000 (1.0) | 0.0000 (1.0) | 1.000 | |||
| Missing | 4 (0.1) | 2 (0.1) | 2 (0.1) | ||||
| Current asthma (%) at 13 ys b | 0.239 | ||||||
| No | 3063 (89.6) | 1516 (88.9) | 1547 (90.3) | ||||
| Yes | 288 (8.4) | 153 (9.0) | 135 (7.9) | ||||
| Missing | 67 (2.0) | 36 (2.1) | 31 (1.8) | ||||
Note: Data are expressed as means (SD), medians and range, percentages and absolute numbers; +z‐scores adjusted for height and age at time of lung function measurements. BMI: body mass index; ys:years; ^day care attendance at 1st year (hours a week, from > 8 to < 32 h/week); §SPT: Skin prick test for inhalant allergens. “Yes” indicates a positive result (i.e., presence of allergic sensitization), “No” indicates a negative result; GD: genital development; PHD: pubic hair development; BD: breast development; “pre/early puberty” (Tanner stages 1–2), “mid‐puberty” (Tanner stages 3–4), and “late puberty” (Tanner stage 5) evaluated at median age of 13 years; Bold p value < 0.05; p value obtained from Chi squared test.
Data for maternal psychiatric symptoms are expressed as natural logarithm.
Data not imputed; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF75: forced expiratory flow at 75% of FVC.
p value obtained from Mann‐Whitney U test; ¶ p value from Unpaired t‐test.
3.2. Sex, Wheezing, Asthma and Lung Function
Compared with boys, girls had a lower prevalence and decreased overall odds of wheezing from birth until age 13 years (OR (95% Confidence Interval (CI)): 0.86 (0.74, 0.98)), and tended to have a lower odds of current asthma at the age of 13 years (0.80 (0.60, 1.08) (Figure 2, Table 2) (Figure S2)). The overall odds ratio represents an average adjusted association across all time points, while the time point‐specific ORs reflect individual cross‐sectional estimates. Differences between the prevalence values shown in Figure S2 and the odds ratios in Figure 2 may arise due to covariate adjustment and the distinction between absolute (prevalence) and relative (OR) measures. We observed no associations of sex with lung function parameters (Table 2). Results did not materially change when we adjusted for asthma or lung function parameters at age 9 years (data not shown). We observed effect modification by allergic sensitization, not ethnicity or BMI, for the associations of sex with current asthma (pinteraction < 0.001) (Tables S3–S5 and 5). Among those with allergic sensitization, girls had a lower risk of current asthma and boys did not, while among those without allergic sensitization no differences in the association of sex with current asthma was found (0.66 (0.46, 0.94) and 1.04 (0.54, 2.00), respectively) (Table S4). We found effect modification by BMI, not ethnicity or allergic sensitization, for the association of sex with lung function parameters (range pinteraction < 0.001–0.076). Among those with underweight, girls had a lower FEV1 and FVC (z‐score difference (95% CI): −0.25 (−0.40, −0.10) and −0.23 (−0.38, −0.08), respectively), compared to boys, while among those with overweight or obesity, girls had a higher FEV1 and FVC (0.26 (0.09, 0.42) and 0.24 (0.09, 0.40)) than boys (Table S3). Among normal weight children, no differences in the associations of sex with lung function measures was observed.
FIGURE 2.
Associations of sex with wheezing in the last 12 months from birth to the age of 13 years. Odds ratios with 95% confidence intervals are derived from generalized estimating equation models and represent odds for wheezing among girls, compared to boys. Model is adjusted for maternal asthma or allergy, educational level, psychiatric symptoms, mode of delivery and smoking during pregnancy, and child′s ethnicity, gestational age and birth weight, breastfeeding, and day care attendance in the first year of life.*p value < 0.05. [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 2.
Association of sex with asthma and lung function outcomes at 13 years of age.
| Current wheezing OR (95% CI) | Current Asthma OR (95% CI) | FEV1 z‐score Difference (95% CI) | FVC z‐score Difference (95% CI) | FEV1/FVC z‐score Difference (95% CI) | FEF75 z‐score Difference (95% CI) | |
|---|---|---|---|---|---|---|
| n = 3418 | n = 3351 | n = 3414 | n = 3414 | n = 3414 | n = 3414 | |
| Girls versus Boys | ||||||
| Basic modela | 1.06 (0.77, 1.47) | 0.83 (0.62–1.11) | 0.02 (−0.03 to 0.07) | −0.00 (−0.05 to 0.04) | 0.02 (−0.03 to 0.07) | 0.03 (−0.03 to 0.08) |
| 0.710 | 0.209 | 0.413 | 0.867 | 0.507 | 0.326 | |
| Confounder modelb | 1.01 (0.72, 1.40) | 0.80 (0.60–1.08) | 0.00 (−0.05 to 0.05) | −0.03 (−0.07 to 0.02) | 0.02 (−0.03 to 0.07) | 0.02 (−0.03 to 0.08) |
| 0.976 | 0.144 | 0.911 | 0.289 | 0.388 | 0.411 |
Note: Data are presented as change in OR or Z‐score difference derived from linear and logistic regression models, respectively. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF75: forced expiratory flow at 75% of FVC.
Basic model adjusted for age and BMI, height gain between ages 9–13 years, and current wheezing or asthma, or lung function parameters at 9 years.
additionally adjusted for maternal educational level, psychiatric symptoms, smoking during pregnancy, maternal history of asthma or allergy, and child′s ethnicity, ever breastfeeding, day care attendance in the first year, mode of delivery, gestational age at birth and birth weight.
3.3. Puberty, Wheezing, Asthma and Lung Function
We observed no associations of pubertal stages with overall wheezing and current asthma at age 13 years in both girls and boys (Table 3). In our confounder models, we observed that girls with a mid‐ and late ‐pubertal stage of breast development had a higher FEV1, FVC, and FEF75 (range Z‐score difference (95% CI) 0.47 (0.08, 0.22) to 0.17 (0.09, 0.25), not FEV1/FVC, compared with those with a pre/early stage of pubertal breast development (Table 3). Girls with a late‐pubertal, not mid‐, stage of pubic hair development had a higher FEV1 and FEF75 (Z‐score difference (95% CI): 0.15 (0.05, 0.25) and 0.19 (0.08, 0.31), respectively). Boys with a late‐pubertal, not mid‐, stage of genital development showed a higher FEV1 and FVC (z‐score difference (95% CI): 0.21 (0.02, 0.40) and 0.19 (0.01, 0.36), respectively), compared with those with pre/early stage of genital development. Likewise, boys with late‐pubertal, not mid‐, stage of pubic hair development had a higher FEV1 and FVC (z‐score difference (95% CI): 0.22 (0.03, 0.41) and 0.20 (0.01, 0.39), respectively). Results did not materially change when we adjusted for wheezing, asthma or lung function at age 9 years (data not shown). The interaction term between ethnicity and puberty was statistically significant. However, stratified analyses in Dutch or non‐Dutch ethnic groups were underpowered, with small sample sizes leading to wide confidence intervals and unstable estimates (data not shown).
TABLE 3.
Associations of puberty stages with wheezing, asthma and lung function outcomes at 13 years of age.
| Girls | Current wheezing OR (95% CI) | Current asthma OR (95% CI) | FEV1 z‐score difference (95% CI) | FVC z‐score difference (95% CI) | FEV1/FVC z‐score difference (95% CI) | FEF75 z‐score difference (95% CI) |
|---|---|---|---|---|---|---|
| n = 1713 | n = 1713 | n = 1682 | n = 1711 | n = 1711 | n = 1711 | n = 1711 |
| Pre/early BD | Reference | Reference | Reference | Reference | Reference | Reference |
| Mid‐puberty BD | ||||||
| Basic modela | 0.96 (0.57–1.63) | 0.99 (0.62–1.58) | 0.19 (0.12–0.26) | 0.16 (0.09–0.23) | 0.06 (−0.02 to 0.14) | 0.17 (0.09–0.26) |
| 0.962 | < 0.001 | < 0.001 | 0.143 | < 0.001 | ||
| Confounder modelb | 0.91 (0.54–1.54) | 0.95 (0.59–1.53) | 0.18 (0.11–0.25) | 0.47 (0.08–0.22) | 0.06 (−0.02 to 0.14) | 0.17 (0.09–0.25) |
| 0.716 | 0.590 | < 0.001 | < 0.001 | 0.126 | < 0.001 | |
| Late BD | ||||||
| Basic model | 0.60 (0.18‐2.03) | 1.10 (0.66‐1.75) | 0.22 (0.07‐0.37) | 0.20 (0.06‐0.34) | 0.04 (−0.13‐0.21) | 0.18 (0.01‐0.34) |
| 0.408 | 0.880 | 0.003 | 0.005 | 0.632 | 0.035 | |
| Confoundermodel | 0.50 (0.14–1.76) | 1.00 (0.38–2.61) | 0.20 (0.05–0.35) | 0.18 (0.04–0.33) | 0.04 (−0.12 to 0.20) | 0.18 (0.01–0.34) |
| 0.282 | 0.379 | 0.008 | 0.012 | 0.630 | 0.040 | |
| Pre/early PHD | Reference | Reference | Reference | Reference | Reference | Reference |
| Mid‐puberty PHD | ||||||
| Basic model | 1.04 (0.61–1.76) | 1.10 (0.66–1.69) | 0.05 (−0.02 to 0.13) | 0.05 (−0.02 to 0.12) | 0.01 (−0.07 to 0.09 | 0.07 (−0.01 to 0.15) |
| 0.896 | 0.834 | 0.176 | 0.129 | 0.772 | 0.103 | |
| Confounder model | 0.99 (0.58–1.70) | 0.97 (0.60–1.56) | 0.05 (−0.02 to 0.12) | 0.05 (−0.02 to 0.12) | 0.02 (−0.06 to 0.10) | 0.20 (0.08–0.31) |
| 0.981 | 0.967 | 0.179 | 0.200 | 0.694 | 0.001 | |
| Late PHD | ||||||
| Basic model | 1.02 (0.50–2.06) | 1.18 (0.84–1.64) | 0.16 (0.06–0.26) | 0.11 (0.01–0.21) | 0.10 (−0.01 to 0.21) | 0.20 (0.08–0.31) |
| 0.964 | 0.626 | < 0.001 | 0.029 | 0.078 | 0.001 | |
| Confounder model | 0.91 (0.44–1.89) | 0.87 (0.45–1.69) | 0.15 (0.05–0.25) | 0.10 (−0.00 to 0.20) | 0.10 (−0.01 to 0.22) | 0.19 (0.08–0.31) |
| 0.802 | 0.874 | 0.004 | 0.050 | 0.075 | 0.001 | |
| Boys | Current wheezing OR (95%CI) | Current asthma OR (95%CI) | FEV 1 z‐score difference (95%CI) n = 1703 | FVC z‐score difference (95%CI) | FEV 1 /FVC z‐score difference (95%CI) | FEF 75 % z‐score difference (95%CI) |
| n = 1705 | n = 1669 | n = 1669 | n = 1703 | n = 1703 | n = 1703 | |
| Pre/early GD | Reference | Reference | Reference | Reference | Reference | Reference |
| Mid‐puberty GD | ||||||
| Basic model | 1.08 (0.68–1.73) | 0.92 (0.62–1.38) | 0.01 (−0.06 to 0.08) | 0.02 (−0.05 to 0.08) | −0.02 (−0.09 to 0.06) | 0.01 (−0.07 to 0.09) |
| 0.740 | 0.688 | 0.825 | 0.669 | 0.687 | 0.778 | |
| Confounder model | 1.16 (0.72–1.87) | 0.89 (0.59–1.33) | 0.00 (−0.07 to 0.07) | 0.01 (−0.06 to 0.08) | −0.01 (−0.09 to 0.06) | 0.01 (−0.07 to 0.09) |
| 0.550 | 0.565 | 0.928 | 0.774 | 0.693 | 0.802 | |
| Late GD | ||||||
| Basic model | 1.45 (0.51–4.15) | 0.74 (0.27–2.07) | 0.22 (0.03–0.40) | 0.20 (0.02–0.38) | 0.03 (−0.16 to 0.21) | 0.08 (−0.13 to 0.29) |
| 0.485 | 0.567 | 0.020 | 0.034 | 0.781 | 0.450 | |
| Confounder model | 1.44 (0.48–4.32) | 0.77 (0.27–2.21) | 0.21 (0.02–0.40) | 0.19 (0.01–0.36) | 0.03 (−0.16 to 0.22) | 0.08 (−0.13 to 0.29) |
| 0.512 | 0.623 | 0.026 | 0.045 | 0.778 | 0.469 | |
| Pre/early PHD | Reference | Reference | Reference | Reference | Reference | Reference |
| Mid‐pubertyl PHD | ||||||
| Basic model | 0.96 (0.60–1.54) | 0.90 (0.60–1.37) | 0.01 (−0.06 to 0.08) | 0.01 (−0.07 to 0.08) | 0.01 (−0.07 to 0.08) | 0.00 (−0.07 to 0.08) |
| 0.873 | 0.632 | 0.733 | 0.845 | 0.872 | 0.886 | |
| Confounder model | 0.95 (0.59–1.54) | 0.91 (0.60–1.39) | 0.01 (−0.06 to 0.08) | 0.00 (−0.07 to 0.07) | 0.00 (−0.07 to 0.08) | −0.04 (−0.12 to 0.04) |
| 0.845 | 0.672 | 0.825 | 0.951 | 0.886 | 0.316 | |
| Late PHD | ||||||
| Basic model | 1.28 (0.42–3.88) | 0.63 (0.23–1.72) | 0.23 (0.04–0.42) | 0.21 (0.02–0.40) | 0.06 (−0.14 to 0.25) | 0.05 (−0.17 to 0.27) |
| 0.688 | 0.366 | 0.018 | 0.029 | 0.583 | 0.645 | |
| Confounder model | 1.20 (0.38–3.78) | 0.65 (0.23–1.83) | 0.22 (0.03–0.41) | 0.20 (0.01–0.39) | 0.06 (−0.14 to 0.26) | 0.05 (−0.17 to 0.27) |
| 0.755 | 0.651 | 0.025 | 0.042 | 0.567 | 0.648 |
Note: Data are presented as change in z‐score difference or odds ratio derived from linear and logistic regression models, respectively, with their corresponding 95% confidence intervals; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; FEF75: forced expiratory flow at 75% of FVC. BD: breast development; PHD: pubic hair development; GD: genital development; “pre/early puberty” (Tanner stages 1–2), “mid‐puberty” (Tanner stages 3–4), and “late puberty” (Tanner stage 5).
Basic model adjusted for age, BMI, height gain between ages 9 and 13 years, current wheezing or asthma, or lung function parameters at 9 years.
additionally adjusted for maternal educational level, psychiatric symptoms, smoking during pregnancy, maternal history of asthma or allergy, and child′s ethnicity, ever breastfeeding, day care attendance in the first year, mode of delivery, gestational age at birth and birth weight. Bold: p value < 0.05.
4. Discussion
4.1. Main Findings and Interpretation
In this population‐based multi‐ethnic cohort, girls had consistently lower odds of wheezing than boys from infancy through age 13 years. At age 13 years, allergic girls showed a lower risk of current asthma than allergic boys, and pubertal development was associated with better lung function in both sexes. We also observed that BMI modified the associations between sex and lung function, with obese girls showing higher FEV₁ and FVC than obese boys.
4.2. Comparison With Previous Studies
Our finding of lower wheezing prevalence in girls until adolescence is consistent with previous cohort studies reporting higher asthma and wheezing rates in boys during childhood [7, 8, 24]. However, other studies suggest this sex difference may reverse in later adolescence or early adulthood [8, 25]. For example, the Avon Longitudinal Study of Parents and Children (ALSPAC) study found that boys were more likely to report wheeze until age 16.5 [26], while the the TRacking Adolescents′ Individual Lives Survey (TRAILS) study found no sex difference at age 13.6, but a higher prevalence in girls by age 16.3 [27]. These inconsistencies may reflect demographic and methodological differences, as well as variations in timing of pubertal onset. Although the age range from 12.6 to 16.6, our cohort′s median age of 13.5 years may be too early to observe the full transition to female predominance. We found that greater pubertal maturation was associated with higher lung function in both sexes, particularly FEV₁, FVC, and FEF75. This aligns with prior findings suggesting that pubertal growth contributes to lung development [28] [29]. In girls, menarche is associated with near‐complete lung maturation, and earlier menarche may prolong estrogen exposure, potentially enhancing lung capacity [30]. Ethnicity did not significantly modify associations of sex or puberty with asthma or lung function. This finding should be interpreted cautiously due to the overrepresentation of Dutch children and small numbers in ethnic subgroups.
4.3. Sex, BMI, and Allergic Sensitization
The observed interaction between BMI and sex on lung function is supported by prior research. Wang et al. [31] reported that increased BMI was associated with higher FEV₁ and FVC in girls but not in boys, suggesting sex‐specific mechanical or hormonal effects of adiposity. We also found that allergic girls had lower odds of asthma than allergic boys, possibly due to differential immune and hormonal responses. Estrogens and androgens influence airway inflammation differently, which may contribute to emerging sex differences in asthma after puberty [32, 33].
4.4. Biological Mechanisms
Sex differences in lung development likely begin in utero [34]. Girls have earlier surfactant production and smaller airway resistance, while boys demonstrate dysanaptic lung growth with relatively narrower airways for a given lung volume [35]. During adolescence, girls enter puberty earlier than boys and tend to experience faster airway growth, which may explain the stronger association of pubertal stage with FEF75 in girls [29]. Hormonal changes, including increases in growth hormone and IGF‐1 during puberty, may contribute to increased lung volume via changes in thoracic dimensions [36, 37].
4.5. Strengths and Limitations
The major strength of this study is that it is embedded in a large multi‐ethnic prospective population‐based cohort with longitudinal measurement of multiple respiratory outcomes and adjustment for relevant confounders. We minimized the potential reverse causation by adjusting findings for lung function or current wheezing/asthma at age of 9 years. The study was performed in a low‐risk population, which increases generalizability to the general population.
Some methodological limitations should be discussed. As in any prospective cohort study, our population was subjected to loss to follow‐up, and could have led to bias if the associations of sex and puberty with lung function and wheezing/asthma were different between those included and not included in the study. It could lead to both an under‐ or overestimation of the associations, and, although this is unlikely, it cannot be excluded [38]. Self‐reporting of puberty and wheezing/asthma could potentially lead to information bias which could cause misclassification. Tanner stage based on questionnaire may not fully capture hormonal changes, for example pubic hair as a marker of puberty in males may not be able to differentiate between central puberty and adrenarche, but is widely used in large‐scale epidemiologic studies. Our sample had relatively low prevalence of underweight, obesity, and advanced puberty, potentially limiting statistical power in some subgroups. Ethnic diversity was limited, and small numbers in some ethnic groups reduced our ability to explore effect modification by ethnicity in detail. Future large‐scale studies with more balanced ethnic representation are needed to explore potential effect modification by ethnicity in detail. Pubertal categories were based on Tanner stage regardless of age, which may lead to misclassification among older adolescents. However, we adjusted for the exact chronical age in all models. Additionally, we used internally derived z‐scores for lung function to preserve variability in sex and ethnicity—key exposures in our study—which limits direct comparability with studies using GLI equations. Lastly, although we adjusted for numerous confounders, we might not have had information on all possible confounding factors. Although some of their effects might be minimal and are highly correlated with presently used confounders, they could potentially have a substantial effect given the relatively small prevalence of asthma.
5. Conclusions
Our findings suggest that sex differences in asthma and lung function emerge early and may be modified by puberty, BMI, and allergic sensitization. Pubertal development appears to enhance lung function across sexes. Ethnicity did not significantly modify these associations, but future research in more ethnically balanced populations is warranted. Further studies should explore biological mechanisms—including hormonal and immune factors—that underlie these sex‐specific respiratory outcomes during adolescence.
Author Contributions
Marina Attanasi: conceptualization, writing – original draft, writing – review and editing, formal analysis, methodology. Annemiek Mian: conceptualization, methodology, supervision, investigation, writing – review and editing. Tarik Karramass: formal analysis, supervision, methodology. Liesbeth Duijts: conceptualization, methodology, validation, writing – review and editing, project administration, supervision, investigation.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Differences between those included and not included in the study. Table S2: Additional characteristics of children and their mothers before and after multiple imputation (n = 3,418). Table S3: Association of sex with wheezing, asthma and lung function at age 13, stratified for BMI. Table S4: Association of sex with wheezing, asthma and lung function at age 13, stratified for inhalant sensitization. Table S5: Association of sex with wheezing, asthma and lung function at age 13, stratified for ethnicity. Figure S1: Directed Acyclic Graph. Figure S2: Sex differences in the prevalence of wheezing in the last 12 months from birth to the age of 13 years.
Acknowledgments
The Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. This project received funding for projects from the European Union's Horizon 2020 research and innovation programme (ATHLETE, grant agreement No 874583; and ENDOMIX, grant agreement No 101136566). 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. Generation R Study is conducted by the Erasmus Medical Centre in close collaboration with the School of Law and the Faculty of Social Sciences at the Erasmus University, Rotterdam, the Municipal Health Service, Rotterdam area, and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond (Star‐MDC), Rotterdam. We gratefully acknowledge the contribution of children and their parents, general practitioners, hospitals, midwives and pharamacies in Rotterdam.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Differences between those included and not included in the study. Table S2: Additional characteristics of children and their mothers before and after multiple imputation (n = 3,418). Table S3: Association of sex with wheezing, asthma and lung function at age 13, stratified for BMI. Table S4: Association of sex with wheezing, asthma and lung function at age 13, stratified for inhalant sensitization. Table S5: Association of sex with wheezing, asthma and lung function at age 13, stratified for ethnicity. Figure S1: Directed Acyclic Graph. Figure S2: Sex differences in the prevalence of wheezing in the last 12 months from birth to the age of 13 years.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.