Abstract
Aim
Maternal asthma is associated with childhood asthma and low birthweight. We investigated whether maternal asthma, allergic asthma and lung function are associated with childhood asthma and growth.
Method
Data from a Swedish pregnancy cohort (Maternal Asthma Events Stress and Offspring (MAESTRO)) were linked to data from children (MAESTRO-Child) and to national health registers (529 mother–child pairs). Pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and bronchodilator response were measured in pregnancy. Maternal asthma, childhood asthma and childhood growth (at birth, 6, 12, 18 and 36 months) were defined from self/parent-reported questionnaires and/or register data. Maternal allergic asthma was defined as asthma and allergic sensitisation (positive PhadiatopTM in pregnancy). Associations between maternal asthma, allergic asthma or lung function and childhood asthma and growth were estimated using multivariable regression models.
Results
For maternal allergic asthma, there was an increased risk of “asthma ever by 6 years” (adjusted risk ratio (adjRR) 2.07, 95% confidence interval (CI) 1.33–3.22). Increasing pre- and post-bronchodilator FEV1 was associated with a reduced risk for childhood asthma (adjRR 0.50, 95% CI 0.30–0.81 and 0.45,95% CI 0.29–0.69, respectively for “asthma ever by 6 years”). No significant relationship was found for FVC, FEV1/FVC, bronchodilator response or between maternal measures and childhood growth.
Conclusion
Maternal asthma and allergic asthma are risk factors for childhood asthma. Higher lung function in pregnancy may be associated with a lower risk for childhood asthma in the offspring. Maternal measures did not have a statistically significant association with childhood growth in the offspring.
Shareable abstract
Asthma or allergic asthma in the mother increases the risk of asthma in the child. Higher maternal lung function in pregnancy leads to a lower risk of asthma in the child. Maternal measures are not statistically significantly associated with childhood growth. https://bit.ly/4cTSy3n
Introduction
Maternal atopy defined as asthma, atopic dermatitis or allergic rhinitis can confer an increased risk for the development of wheeze and asthma in children [1–7]. This increased risk is largely heritable; however, in utero exposures, such as uncontrolled asthma and severe asthma during pregnancy, may increase the risk. Increased levels of maternal blood serum cytokines from CD4+ type 2 helper T (Th2) cells, which have been found to increase the risk of offspring asthma, may explain this association [1, 8]. However, the fraction of exhaled nitric oxide in the mother, a measure of airway inflammation, is not significantly associated with offspring asthma [9]. Maternal asthma also increases the risk of offspring low birth weight and being born small for gestational age [10, 11]. Here too, increasing asthma severity and asthma exacerbations during pregnancy plays an important role, through mechanisms thought to be related to increased inflammatory markers and cortisol [12, 13]. As maternal asthma is common (with a prevalence of about 10%) and up to 50% of women with asthma experience worsening asthma symptoms during pregnancy, there is a large interest in understanding how asthma in the mother is associated with respiratory and growth outcomes in offspring. Of note, the relationship between maternal lung function in pregnancy and outcomes in the offspring are not well described [10, 12, 14].
Studies on the impact of pregnancy on lung function are few and not conclusive. Nor is it clear how maternal asthma effects maternal lung function during pregnancy. While it has been reported that lung function measurements of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC remain largely unchanged by pregnancy [15], Grindheim et al. [16] demonstrated that FVC increased significantly during pregnancy, whereas FEV1 remained unchanged. A recent study, using repeated lung function measurements in pregnant women with and without asthma, found that FEV1 and FEV1/FVC trajectories during the course of the pregnancy differed depending on maternal asthma status [17]. Lower FEV1 in pregnant women is associated with pregnancy-related hypertension, impaired fetal growth and preterm birth [18, 19]. Though the mechanism is unclear, this too could be related to asthma control and severity, or factors associated with both asthma and pregnancy complications [18, 19]. To the best of our knowledge, the association between allergic asthma and maternal lung function in pregnancy with childhood asthma in the offspring has not been studied, nor whether maternal asthma, allergic asthma or lung function in pregnancy impacts growth in childhood in the offspring.
Hence, this study aimed to further our understanding of the role of maternal asthma, allergic asthma and lung function in asthma and growth during childhood in the offspring (from here on, referred to as childhood asthma and childhood growth).
Methods
Study design and study population
This is a prospective cohort study from the Maternal Asthma Events, Stress and Offspring (MAESTRO)-Child cohort, which consists of the children who resulted from the pregnancies in the MAESTRO study [11]. The MAESTRO study recruited 1693 women attending antenatal clinics in Stockholm, Sweden from 2011 to 2016. Data collected included questionnaire, blood samples and lung function measurements (figure 1). Blood samples were drawn at recruitment and lung function was measured at one timepoint during pregnancy between 28–32 gestational weeks in a subset of 252 women. In total, 1556 women delivered live births between 2012 and 2016 (lost to follow-up, including spontaneous or induced abortions, n=137), resulting in 1580 children (figure 1 and supplementary material) [11]. Apart from a higher proportion of asthma than the general population, mothers who participated in the MAESTRO study were a healthy population of highly educated women and those with asthma were, in the main, well controlled [11].
FIGURE 1.
Flow diagram of the Maternal Asthma Events Stress and Offspring (MAESTRO) and MAESTRO-Child study. Full final cohort for this study includes 529 mother–child pairs. MBR: Medical Birth Register.
Recruitment into MAESTRO-Child occurred between 2017 and 2020. Mothers to the children of the MAESTRO study received written invitation to partake (n=1528 children's mothers contacted). The current address was missing for the mothers of 52 children and so they could not be reached. Informed consent was obtained for 550 children (36.0% of all contacted), the remaining 978 (64.0%) did not respond or declined participation (figure 1). Parents/guardians were asked to complete a questionnaire on health and background characteristics, including childhood growth (weight and height) measured at the children's health centre at 6, 12 18 and 36 months of age. Salivary samples, for analyses of saliva cortisol levels, were also collected from the children at inclusion into MAESTRO-Child but results are not reported in this manuscript.
Data from the MAESTRO and MAESTRO-Child studies were linked to national health registers: the Medical Birth Register (MBR), the National Patient Register (NPR) and the Swedish Prescribed Drug Register (PDR) using the personal identification number, which is a unique identifier held by every person residing in Sweden (supplementary material) [20–22]. Inclusion criteria for mothers in the current study was a singleton pregnancy and linked data to MBR n=1509 (95.5% of all deliveries). Of 550 children with consent in MAESTRO-Child, n=529 (96.2%) were from a singleton pregnancy and had linked MBR data (figure 1).
Exposures
Maternal asthma was defined prior to delivery as either self-reported doctor-diagnosed asthma from the MAESTRO questionnaires or in the MBR, a diagnosis of asthma in the NPR or at least two dispenses of asthma medication within 1 year from the PDR (details in supplementary material) [11, 23]. Blood samples from the mother were analysed for a mix of common aeroallergens by Phadiatop™ (Thermo Fisher Scientific, Uppsala, Sweden). Allergic sensitisation (allergy) was defined as positive Phadiatop™ ≥0.35 kU·L−1 [24]. By combining data from maternal asthma and allergic sensitisation, we defined mothers as having “no asthma, no allergy”, “allergy only”, “asthma only” or “asthma with allergy” (allergic asthma).
Lung function pre- and post-bronchodilator response was measured for FEV1 and FVC. These values were converted to z-scores for FEV1, FVC and FEV1/FVC using the Global Lung Initiative reference equations, which are adjusted for age, height, sex and ethnicity [25]. It should be noted that these reference values are derived from a cohort that does not include pregnant women. FEV1 and FVC bronchodilator response was also calculated, where >10% reversibility was considered a positive result.
Outcomes
Childhood asthma in the offspring was measured at three time points. From the MAESTRO-Child questionnaire, “asthma by 3 years” was defined as a positive response to “has your child received an asthma diagnosis from a doctor?” and/or “does your child currently take asthma medication?”. Using national health register data, “asthma ever by 6 years” and “current asthma at 6 years” were defined using a validated algorithm using data from NPR and PDR [23]. “Asthma ever by 6 years” was defined as the date of the first record with a primary diagnosis of asthma identified using International Statistical Classification of Diseases and Related Health Problems (10th Revision) codes J45 or J46 in the NPR; or as the date of the first dispensed asthma medication: using the Anatomical Therapeutic Chemical codes R03BA, R03AC, R03AK and R03DC. If an individual had dates recorded in both the NPR and the PDR, the earliest date was used and “asthma ever by 6 years” was defined at the latest prior to the date of the seventh birthday. “Current asthma at 6 years” was defined as at least one record of asthma in the NPR and/or a dispensed asthma medication from the PDR in the 12 months prior to the date of the seventh birthday. “Current asthma at 6 years” was studied because it minimises cases of preschool wheeze, which could be included in the “asthma ever by 6 years” group [1].
Data for childhood growth in the offspring were retrieved from the MBR (birthweight) and in childhood at 6, 12, 18 and 36 months (weight and height) from the MAESTRO-Child questionnaire and converted into z-scores [26, 27]. To study growth velocity, standardised weight difference was calculated as the difference between birthweight z-score and weight z-score at 6, 12, 18 and 36 months.
Covariates
Confounders were chosen a priori based on directed acyclic graphs (DAGs) of our current understanding and were the covariates: sex, maternal body mass index (BMI), maternal age at delivery, maternal country of birth, gestational diabetes, smoking during pregnancy, passive smoking exposure and socioeconomic status (see supplementary materials for details; supplementary figures S1 and S2) [28].
Statistical methods
Associations between maternal asthma, allergic asthma, lung function and childhood asthma were investigated using log binomial regression to estimate risk ratio (RR) with 95% confidence intervals (CIs) and adjusted for the potential confounders only. Associations between maternal asthma, allergic asthma or lung function and childhood growth were investigated using linear regression to estimate β-coefficients with 95% CI, adjusting for the potential confounders only, as listed above. We included all available measurement points as repeated measurements in all regression models together with age at measurement and used the sandwich estimator for the standard errors to account for repeated measurements within the same individual.
Finally, to understand if the association between maternal lung function and outcomes differed depending on the asthma status of the mother, effect modification was studied by introducing an interaction term between maternal asthma and the lung function measurement in the adjusted models (for childhood asthma and childhood growth) parameterised to get separate estimates by maternal asthma.
The MAESTRO and MAESTRO-Child study was approved by the Regional Ethical Review Board in Stockholm/Swedish Ethical Review Authority. Written informed consent from study participants was obtained for the MAESTRO study and from both parents for the MAESTRO-Child study. All statistical analyses were conducted using Stata v.17.
Results
The full final study cohort consisted of 529 mother–child pairs, of which lung function data during pregnancy was available for a subgroup of 144 mothers (figure 1). Of the 529 mothers, 18.9% had asthma and 11.7% had allergic asthma (table 1). Mothers (n=529) tended to be older at the age of delivery compared with mothers in the original MAESTRO cohort who were not included in this study (n=980) (supplementary table S1).
TABLE 1.
Descriptive characteristics of the final study cohort of 529 mother–child pairs from the MAESTRO and MAESTRO-Child cohort
| All | Mothers without asthma | Mothers with asthma | |
|---|---|---|---|
| n=529 | n=429 (81.1%) | n=100 (18.9%) | |
| Mothers’ characteristics | |||
| Allergic sensitisation (PhadiatopTM) | |||
| Positive | 181 (34.2) | 119 (27.7) | 62 (62.0) |
| Negative | 334 (63.1) | 300 (69.3) | 34 (34.0) |
| Missing | 14 (2.6) | 10 (2.3) | 4 (4.0) |
| No asthma, no allergy | 300 (56.7) | NA | NA |
| Allergy only | 119 (22.5) | NA | NA |
| Asthma only | 34 (6.4) | NA | NA |
| Asthma with allergy | 62 (11.7) | NA | NA |
| Missing | 14 (2.7) | NA | NA |
| BMI, kg·m−2 | |||
| ≤25 | 389 (73.5) | 318 (74.1) | 71 (71.0) |
| 26–30 | 94 (17.8) | 78 (18.2) | 16 (16.0) |
| >30 | 14 (2.7) | 8 (1.9) | 6 (6.0) |
| Missing | 32 (6.1) | 25 (5.8) | 7 (7.0) |
| Gestational diabetes | |||
| Yes | 0 | 0 | 0 |
| No | 529 | 429 | 100 |
| Country of birth | |||
| Sweden | 486 (91.9) | 396 (92.3) | 90 (90.0) |
| Other | 43 (8.1) | 33 (7.7) | 10 (10.0) |
| Missing | 0 | 0 | 0 |
| Smoking during pregnancy | |||
| Yes | 0 | 0 | 0 |
| No | 526 (99.4) | 427 (99.5) | 99 (99.0) |
| Missing | 3 (0.6) | 2 (0.5) | 1 (1.0) |
| Passive smoking | |||
| Yes | 10 (1.9) | 10 (2.4) | 0 (0) |
| No | 460 (87.0) | 367 (85.6) | 93 (93.0) |
| Missing | 59 (11.1) | 52 (12.0) | 7 (7.0) |
| Maternal age at delivery, years | |||
| <29 | 38 (7.2) | 33 (7.7) | 5 (13.2) |
| 29–32 | 173 (27.6) | 138 (32.2) | 35 (35.0) |
| >32 | 318 (60.1) | 258 (60.1) | 60 (60.0) |
| Missing | 0 | 0 | 0 |
| Socioeconomic status (years in education) | |||
| 0–9 years | 0 | 0 | 0 |
| 10–12 years | 38 (7.2) | 27 (6.3) | 11 (11.0) |
| >12 years | 427 (80.7) | 348 (81.5) | 79 (79.0) |
| Missing | 64 (12.1) | 54 (12.5) | 10 (10.0) |
| Lung function data available | |||
| Yes | 144 (27.2) | 99 (23.1) | 45 (45.0) |
| No | 385 (72.8) | 330 (76.9) | 55 (55.0) |
| Offspring characteristics | |||
| Sex | |||
| Male | 269 (50.8) | 219 (51.1) | 50 (50.0) |
| Female | 260 (49.2) | 210 (49.9) | 50 (50.0) |
| Birth weight, g | |||
| <2500 | 10 (1.9) | 6 (1.4) | 4 (4.0) |
| 2500–3500 | 231 (43.7) | 186 (43.4) | 45 (45.0) |
| ≥3500 | 288 (54.4) | 237 (55.2) | 51 (51.0) |
| Missing | 0 | 0 | 0 |
| Preterm (<37 weeks) | |||
| Yes | 16 (3.0) | 10 (2.3) | 6 (6.0) |
| No | 513 (97.0) | 419 (97.7) | 94 (94.0) |
| Growth data available | |||
| At least one observation (of height or weight) | 396 (74.9) | 317 (73.9) | 79 (79.0) |
| No data | 133 (25.1) | 112 (26.3) | 21 (21.0) |
| All four weight observations | 327 (61.8) | 262 (60.9) | 65 (65.0) |
| All four height observations | 318 (60.1) | 254 (59.1) | 64 (64.0) |
Data are presented as n (%). MAESTRO: Maternal Asthma Events Stress and Offspring; BMI: body mass index; NA: not applicable.
Apart from a higher proportion of mothers with asthma, which was expected, the subgroup of women with lung function data (n=144) was largely similar to the full final study cohort (n=529) (supplementary table S2). The mean FEV1/FVC z-scores (pre-bronchodilator response) for mothers with and without asthma were 0.75 (range −2.19–2.35) and −0.44 (range −2.57–2.41), respectively. A positive FEV1 bronchodilator response (BDR) was found in 4.2% of mothers and a positive FVC BDR was found in 2.8%.
Of the 529 children (offspring) in the cohort, questionnaire data were available from 504 (95.3%) and growth data were available for 396 (74.9%) (table 1). “Asthma by 3 years” was found in 8.5%, “current asthma at 6 years” in 7.0% and “asthma ever by 6 years” in 14.9% of the child study population (supplementary table S3, including means for weight and height).
Main results
Maternal asthma and maternal allergic asthma were associated with asthma in the offspring. For mothers with asthma, there was an increased risk for offspring “asthma by 3 years” (adjusted (adj) RR 2.77, 95% CI 1.49–5.13), “current asthma at 6 years” (adjRR 2.88, 1.42–5.83) and “asthma ever by 6 years” (adjRR 2.07, 1.33–3.22) compared with mothers without asthma. When divided into subcategories, maternal “asthma with allergy” was associated with “asthma by 3 years” (adjRR 3.35, 1.65–6.81), “current asthma at 6 years” (adjRR 6.18, 2.72–14.01) and “asthma ever by 6 years” (adjRR 2.30, 1.39–3.80) compared with children of mothers with “no asthma, no allergy”. Only estimates for childhood asthma defined as “current asthma at 6 years” reached statistical significance for mothers with “allergy only”. Whereas no estimates for childhood asthma reached statistical significance for mothers with “asthma only” compared with mothers with “no asthma, no allergy”, there were no significant differences between “asthma only” and “asthma with allergy” (figures 2 and 3 and supplementary table S4).
FIGURE 2.
Adjusted risk ratio (adjRR) and 95% confidence interval (CI) for the association between maternal asthma and childhood asthma (asthma by 3 years, current asthma at 6 years and asthma ever by 6 years) using full final cohort (n=529). Model adjusted for potential confounders: sex, maternal body mass index (BMI), maternal age at birth, maternal country of birth, smoking during pregnancy, passive smoking exposure, gestational diabetes and socioeconomic status (maternal education).
FIGURE 3.
Adjusted risk ratio (adjRR) and 95% confidence interval (CI) for the association between maternal allergic asthma and childhood asthma (asthma by 3 years, current asthma at 6 years and asthma ever by 6 years) (n=515). Model adjusted for potential confounders: sex, maternal body mass index (BMI), maternal age at birth, maternal country of birth, smoking during pregnancy, passive smoking exposure, gestational diabetes and socioeconomic status (maternal education).
Higher maternal lung function measured as FEV1 was associated with a lower risk of childhood asthma. A higher FEV1 pre-bronchodilator z-score was associated with a lower risk for “asthma ever by 6 years” (adj RR 0.50, 95% CI 0.30–0.81). A higher FEV1 post-bronchodilator z-score was also associated with a lower risk for “asthma by 3 years” (adjRR 0.47, 95% CI 0.24–0.92) and “asthma ever by 6 years” (adjRR 0.45, 95% CI 0.29–0.69), but not statistically significant for “current asthma at 6 years” (adjRR 0.64, 95% CI 0.27–1.54). The weight of the evidence suggests no association in either the unadjusted or adjusted model for FVC or FEV1/FVC (table 2) nor for the association between FEV1 or FVC bronchodilator response and childhood asthma (supplementary table S5). When effect modification by maternal asthma was investigated, there was evidence of differences with regard to FEV1/FVC (p=0.004 for pre-bronchodilation FEV1/FVC in “asthma every by 6 years”) but not for FEV1 or FVC (table 2).
TABLE 2.
The unadjusted and adjusted risk ratio (RR) and 95% confidence intervals (CIs) for the relationship between maternal lung function, pre and post-bronchodilator response in pregnancy, and childhood asthma using a subcohort of 144 mother–child pairs
| FEV1 z-score | FVC z-score | FEV1/FVC z-score | ||||
|---|---|---|---|---|---|---|
| Pre (95% CI) | Post (95% CI) | Pre (95% CI) | Post (95% CI) | Pre (95% CI) | Post (95% CI) | |
| Childhood asthma | ||||||
| Asthma at 3 years (n=143) | ||||||
| Unadjusted RR | 0.67 (0.37–1.17) | 0.62 (0.35–1.10) | 0.73 (0.42–1.27) | 0.70 (0.39–1.28) | 0.84 (0.47–1.52) | 0.74 (0.38–1.44) |
| Adjusted RR# | 0.57 (0.31–1.05) | 0.47 (0.24–0.92) | 0.63 (0.34–1.18) | 0.57 (0.28–1.15) | 0.77 (0.42–1.43) | 0.62 (0.32–1.21) |
| Adjusted RR#, no maternal asthma | 0.59 (0.22–1.54) | 0.43 (0.15–1.30) | 0.68 (0.25–1.84) | 0.39 (0.11–1.31) | 0.62 (0.21–1.82) | 1.00 (0.25–3.93) |
| Adjusted RR#, with maternal asthma | 0.61 (0.27–1.35) | 0.54 (0.25–1.20) | 0.59 (0.29–1.22) | 0.63 (0.29–1.35) | 1.14 (0.60–2.14) | 0.71 (0.35–1.45) |
| p-value¶ | 0.96 | 0.74 | 0.83 | 0.51 | 0.35 | 0.67 |
| Current asthma at 6 years (n=144) | ||||||
| Unadjusted RR | 0.71 (0.35–1.45) | 0.71 (0.34–1.48) | 0.74 (0.37–1.50) | 0.75 (0.35–1.60) | 1.03 (0.50–2.12) | 0.88 (0.37–2.11) |
| Adjusted RR# | 0.60 (0.26–1.39) | 0.64 (0.27–1.54) | 0.70 (0.32–1.54) | 0.74 (0.30 1.78) | 0.99 (0.44–2.20) | 0.81 (0.31–2.08) |
| Adjusted RR#, no maternal asthma | 0.86 (0.21–3.57) | 0.90 (0.20–4.05) | 1.31 (0.34–5.12) | 1.03 (0.24–4.36) | 0.49 (0.11–2.21) | 0.72 (0.12–4.33) |
| Adjusted RR#, with maternal asthma | 0.43 (0.15–1.25) | 0.56 (0.21–1.46) | 0.33 (0.16–0.71) | 0.50 (0.19–1.30) | 2.19 (1.39–3.17) | 1.26 (0.41–3.82) |
| p-value¶ | 0.44 | 0.60 | 0.09 | 0.41 | 0.07 | 0.60 |
| Asthma ever at 6 years (n=144) | ||||||
| Unadjusted RR | 0.65 (0.41–1.04) | 0.64 (0.40–1.04) | 0.76 (0.48–1.21) | 0.68 (0.41–1.12) | 0.78 (0.48–1.28) | 0.84 (0.47–1.48) |
| Adjusted RR# | 0.50 (0.30–0.81) | 0.45 (0.29–0.69) | 0.67 (0.41–1.11) | 0.57 (0.33–1.00) | 0.67 (0.40–1.11) | 0.69 (0.39–1.22) |
| Adjusted RR#, no maternal asthma | 0.48 (0.25–0.93) | 0.42 (0.21–0.85) | 0.71 (0.35–1.44) | 0.49 (0.22–1.07) | 0.46 (0.23–0.93) | 0.67 (0.26–1.70) |
| Adjusted RR#, with maternal asthma | 0.55 (0.25–1.19) | 0.56 (0.27–1.15) | 0.56 (0.29–1.08) | 0.59 (0.29–1.22) | 1.59 (1.02–2.48) | 0.91 (0.43–1.90) |
| p-value¶ | 0.79 | 0.58 | 0.62 | 0.73 | 0.004 | 0.61 |
FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; RR: risk ratio; BMI: body mass index. #: Adjusted for the potential confounders: sex, maternal BMI, maternal age at birth, maternal country of birth, gestational diabetes, smoking during pregnancy, passive smoking exposure and socioeconomic status (maternal education). ¶: p-value for the interaction with maternal asthma.
Overall, there were no significant differences in childhood growth associated with maternal asthma. The adjusted β-coefficient (adjβ) for the association between maternal asthma and childhood growth were weight z-score adjβ 0.12 (95% CI −0.13–0.37), height z-score adjβ −0.02 (−0.26–0.23) and weight difference z-score adjβ 0.14 (−0.15–0.43). Further, in the adjusted models there were no differences seen for maternal allergic asthma and childhood growth (figures 4 and 5 and supplementary table S6), nor for maternal lung function measures (including bronchodilator response). There was evidence of effect modification of maternal asthma and lung function in association with childhood height (p=0.008 for pre-bronchodilation FEV1, p=0.008 for post-bronchodilation FEV1 and p=0.02 for post-bronchodilation FVC); however, results indicated associations in different directions for mothers with and without asthma (table 3 and supplementary table S7).
FIGURE 4.
The adjusted β (adjβ) coefficients and 95% confidence interval (CI) for the association between maternal asthma and childhood growth (weight z-score, height z-score and weight difference z-score) (n=396). Model adjusted for potential confounders: age, sex, maternal body mass index (BMI), maternal age at birth, maternal country of birth, smoking during pregnancy, passive smoking exposure, gestational diabetes and socioeconomic status (maternal education).
FIGURE 5.
The adjusted β coefficients and 95% confidence interval (CI) for the association between maternal allergic asthma and childhood growth (weight z-score, height z-score and weight difference z-score) (n=324). Model adjusted for potential confounders: age, sex, maternal body mass index (BMI), maternal age at birth, maternal country of birth, smoking during pregnancy, passive smoking exposure, gestational diabetes and socioeconomic status (maternal education).
TABLE 3.
The unadjusted and adjusted β coefficients and 95% confidence intervals (CIs) for the relationship between maternal lung function, pre- and post-bronchodilator response in pregnancy, and childhood growth using a subcohort of 144 mother–child pairs
| FEV1 z-score | FVC z-score | FEV1/FVC z-score | ||||
|---|---|---|---|---|---|---|
| Pre (95% CI) | Post (95% CI) | Pre (95% CI) | Post (95% CI) | Pre (95% CI) | Post (95% CI) | |
| Childhood growth | ||||||
| Weight z-score (n=114) | ||||||
| Unadjusted β | 0.04 (−0.13–0.20) | 0.02 (−0.17–0.21) | 0.06 (−0.12–0.24) | 0.07 (−0.13–0.28) | 0.07 (−0.32–0.18) | −0.17 (−0.42–0.07) |
| Adjusted β# | 0.03 (−0.15–0.21) | −0.00 (−0.21–0.20) | 0.04 (−0.15–0.24) | 0.04 (−0.19–0.26) | −0.05 (−0.33–0.22) | −0.15 (−0.42–0.11) |
| Adjusted β#, no maternal asthma | 0.01 (−0.10–0.30) | 0.04 (−0.18–0.26) | 0.08 (−0.13–0.29) | 0.05 (−0.18–0.28) | −0.00 (−0.33–0.33) | −0.06 (−0.41–0.28) |
| Adjusted β#, with maternal asthma | −0.14 (−0.44–0.17) | −0.13 (0.52–0.25) | −0.12 (−0.51–0.26) | −0.11 (−0.57–0.36) | 0.01 (−0.53–0.51) | −0.16 (−0.67–0.34) |
| p-value¶ | 0.22 | 0.45 | 0.37 | 0.56 | 0.99 | 0.75 |
| Height z-score (n=113) | ||||||
| Unadjusted β | 0.03 (−0.17–0.23) | 0.02 (−0.18–0.22) | −0.03 (−0.22–0.17) | 0.02 (−0.19–0.23) | 0.12 (−0.16–0.39) | −0.02 (−0.30–0.26) |
| Adjusted β# | 0.09 (−0.12–0.30) | 0.06 (−0.14–0.27) | −0.00 (−0.20–0.20) | 0.04 (−0.18–0.26) | 0.17 (−0.12–0.47) | 0.05 (−0.23–0.32) |
| Adjusted β#, no maternal asthma | 0.26 (0.03–0.49) | 0.24 (0.03–0.45) | 0.11 (−0.16–0.39) | 0.20 (−0.05–0.45) | 0.29 (−0.09–0.67) | 0.19 (−0.20–0.58) |
| Adjusted β#, with maternal asthma | −0.25 (−0.53–0.03) | −0.29 (−0.60–0.03) | −0.24 (−0.50–0.03) | −0.28 (−0.60–0.04) | −0.04 (−0.54–0.46) | −0.15 (−0.62–0.32) |
| p-value¶ | 0.008 | 0.008 | 0.09 | 0.02 | 0.30 | 0.27 |
| Weight difference z-score (n=114) | ||||||
| Unadjusted β | 0.16 (−0.04–0.37) | 0.13 (−0.09–0.35) | 0.20 (0.01–0.40) | 0.18 (−0.04–0.39) | −0.09 (−0.32–0.15) | −0.13 (−0.42–0.16) |
| Adjusted β# | 0.14 (−0.06–0.35) | 0.08 (−0.15–0.31) | 0.17 (−0.04–0.37) | 0.11 (−0.12–0.34) | −0.05 (0.30–0.19) | −0.10 (−0.40–0.20) |
| Adjusted β#, no maternal asthma | 0.14 (−0.15–0.42) | 0.07 (−0.22–0.37) | 0.15 (−0.13–0.42) | 0.11 (−0.17–0.40) | −0.02 (−0.35–0.31) | −0.11 (−0.58–0.35) |
| Adjusted β#, with maternal asthma | 0.12 (−0.16–0.39) | 0.02 (−0.33–0.38) | 0.09 (−0.19–0.37) | −0.05 (−0.40–0.30) | 0.01 (−0.07–0.09) | −0.15 (−0.17–0.47) |
| p-value¶ | 0.92 | 0.84 | 0.77 | 0.49 | 0.51 | 0.34 |
FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity. #: Adjusted for the potential confounders: sex, maternal body mass index (BMI), maternal age at birth, maternal country of birth, gestational diabetes, smoking during pregnancy, passive smoking exposure and socioeconomic status (maternal education). ¶: p-value for the interaction with maternal asthma.
Discussion
In this prospective study of a unique mother–child cohort born in Stockholm, Sweden we demonstrate that maternal asthma and maternal allergic asthma are associated with childhood asthma measured at 3 and 6 years. Higher pre-bronchodilator FEV1 was associated with decreased risk of “asthma ever by 6 years” and post-bronchodilator FEV1 was associated with a decreased risk for “asthma by 3 years” and “asthma ever by 6 years” with results suggesting that an increase of 1 z-score in maternal FEV1 in pregnancy is associated with decrease in the risk of asthma in the offspring by half. There were no differences seen with pre- and post-bronchodilator FVC or FEV1/FVC ratio, nor with FEV1 or FVC bronchodilator response and childhood asthma. Further, for the relationship between maternal asthma/maternal allergic asthma or lung function and childhood growth, we did not find evidence of a difference for childhood growth measured as weight, height and weight difference z-score. The results for the effect modification analyses do not point in a conclusive direction and ought to be interpreted with caution.
Though the result is not novel and is expected due to the heritability of asthma, our findings demonstrate an increased risk of childhood asthma among the offspring of mothers with asthma [29–31]. Further we have shown that the risk of childhood asthma is increased in offspring whose mothers have allergic asthma confirming other studies [6, 32]. In our cohort, the absence of significant association between “asthma only” in the mothers and childhood asthma could be explained by small sample size; however, it should be noted that there were no significant differences between “asthma only” and “asthma with allergy” in all three asthma outcomes measured in the children. Nevertheless, no previous studies have explored lung function in pregnancy and asthma in the offspring, so our finding that lung function in pregnancy may be associated with childhood asthma is novel.
Several mechanisms have been suggested to be responsible for the relationship between asthma in pregnancy and adverse outcomes in the offspring, such as the role of asthma exacerbations, the switch in the woman's immune system towards a Th2 cell response, maternal cytokines, and maternal hypoxia [1, 8, 12, 33]. All these factors could be related to the mother's lung function during pregnancy. We did not find that bronchodilator response in the mother was associated with asthma in the offspring. It is, however, known that lung function is heritable so it would not be implausible to speculate that the children of mothers with higher lung function values have a lower risk of wheeze/asthma in early childhood [34]. Nevertheless, if higher lung function in the mother is associated with a reduced risk of asthma in childhood, then this underpins the importance of managing respiratory disease in the pregnant woman [13]. Future studies could include mothers with poorer asthma control and/or reduced lung function and explore the relationship between maternal allergic asthma and lung function and childhood asthma phenotypes (such as allergic asthma) in the offspring or the presence of effect modification by the sex of the offspring.
There is evidence that maternal asthma and reduced lung function are associated with low birth weight [10, 18, 19]. Further, fetal growth, low birthweight, rate of weight gain in the first few years of life and higher BMI in early childhood are risk factors for childhood asthma [4, 35–37]. However, we found no convincing evidence for the relationship between maternal asthma or lung function in pregnancy with growth in early childhood, which may explain part of the relationship seen between maternal asthma and childhood asthma. A replication study using another cohort would be useful to understand this further. Additionally, it should be noted that we have only studied growth until 3 years of age, and future studies could look at growth further into childhood.
Strengths and limitations
The strength of this study is its use of prospectively collected questionnaire data, which are combined with blood results, lung function and national health register data. PhadiatopTM, lung function and asthma variables were measured using validated methods [23, 24, 38]. As the mothers of this cohort are largely similar to the other mothers of the MAESTRO cohort, albeit somewhat older than the MAESTRO cohort on the whole, the bias that is introduced by those who did not respond or declined participation is believed to be minimal and strengthens the internal validity. However, the cohort consists of children born to mothers who are a healthy population of highly educated women living in a high resource setting with ample access to healthcare and asthma medication, and 60% had an age at delivery of 33 years or older. These factors may reduce the generalisability to other populations. Further, there are no standardised values for lung function during pregnancy, and lung function was only recorded at one timepoint in pregnancy. We cannot exclude the presence of a type 1 error due to multiple testing and a type 2 error in the lung function estimates due to sample size; hence these results ought to be verified in studies of larger cohorts.
Conclusion
In this unique cohort of pregnant women and their children up to 6 years of age, we found convincing evidence that maternal asthma and allergic asthma is a risk factor for childhood asthma and that higher lung function in pregnancy may also be associated with a lower risk of childhood asthma which needs further exploration. No significant association was found between maternal asthma/allergic asthma/lung function and growth in childhood.
Acknowledgements
We thank the participants of the MAESTRO and MAESTRO-Child study; Aki Tuuliainen, Mikael Broms and the database managers at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet; and Eva Warghammar who coordinated both the MAESTRO and MAESTRO-Child study. This study would not have existed without their invaluable contributions. Allergen extracts for IgE analyses were provided by Thermo Fisher, Uppsala, Sweden.
Footnotes
Provenance: Submitted article, peer reviewed.
Ethics statement: Ethical approval for the study was granted by the Regional Ethical Review Board in Stockholm, Sweden (DNR 2016/1059-31) and the amendment by the Swedish Ethical Review Authority (2021-02677).
Author contributions: Study concept and design: E. Caffrey Osvald, C. Lundholm and C. Almqvist. Data acquisition and funding: C. Almqvist, E. Caffrey Osvald, G. Rejnö and S. Rhedin. Data analysis: E. Caffrey Osvald and C. Lundholm. Data interpretation: C. Almqvist, E. Caffrey Osvald, B.K. Brew, C. Lundholm, S. Rhedin, G. Rejnö and H. Karim. Drafting of the manuscript: E. Caffrey Osvald. E. Caffrey Osvald, C. Lundholm and C. Almqvist had full access to all the data in the study, and take responsibility for the integrity and the accuracy of the data. All authors critically reviewed and revised the manuscript and approved the final version. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Conflicts of interest: All authors have completed the International Committee of Medical Journal Editors uniform disclosure form and declare: no support from any organisation for the submitted work other than that detailed in funding section; no financial relationships with any organisations that might have an interest in the submitted work; and no other relationships or activities that could appear to have influenced the submitted work.
Support statement: Financial support was provided from the Swedish Research Council (grant numbers 2018-02640 and 2023-02327), the Strategic Research Program in Epidemiology at Karolinska Institutet, the Swedish Heart–Lung Foundation (grant numbers 20180512 and 20210416 and 20240974), the Swedish Asthma and Allergy Association Research Fund (grant numbers 2020-0008 and 2024-0010) and grants provided by Region Stockholm (ALF-project RS2022-0674). Research stipends were awarded by the Foundation Frimurare Barnhuset in Stockholm and Stiftelsen Samariten. Funding information for this article has been deposited with the Crossref Funder Registry.
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References
- 1.Lebold KM, Jacoby DB, Drake MG. Inflammatory mechanisms linking maternal and childhood asthma. J Leukoc Biol 2020; 108: 113–121. doi: 10.1002/JLB.3MR1219-338R [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Papi A, Brightling C, Pedersen SE, et al. Asthma. Lancet 2018; 391: 783–800. doi: 10.1016/S0140-6736(17)33311-1 [DOI] [PubMed] [Google Scholar]
- 3.Harvey SM, Murphy VE, Gibson PG, et al. Maternal asthma, breastfeeding, and respiratory outcomes in the first year of life. Pediatr Pulmonol 2020; 55: 1690–1696. doi: 10.1002/ppul.24756 [DOI] [PubMed] [Google Scholar]
- 4.Henderson AJ, Warner JO. Fetal origins of asthma. Semin Fetal Neonatal Med 2012; 17: 82–91. doi: 10.1016/j.siny.2012.01.006 [DOI] [PubMed] [Google Scholar]
- 5.Wadonda-Kabondo N, Sterne JA, Golding J, et al. Association of parental eczema, hayfever, and asthma with atopic dermatitis in infancy: birth cohort study. Arch Dis Child 2004; 89: 917–921. doi: 10.1136/adc.2003.034033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wen HJ, Chiang TL, Lin SJ, et al. Predicting risk for childhood asthma by pre-pregnancy, perinatal, and postnatal factors. Pediatr Allergy Immunol 2015; 26: 272–279. doi: 10.1111/pai.12374 [DOI] [PubMed] [Google Scholar]
- 7.Sternthal MJ, Coull BA, Chiu YH, et al. Associations among maternal childhood socioeconomic status, cord blood IgE levels, and repeated wheeze in urban children. J Allergy Clin Immunol 2011; 128: 337–345. doi: 10.1016/j.jaci.2011.05.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Liu X, Agerbo E, Schlunssen V, et al. Maternal asthma severity and control during pregnancy and risk of offspring asthma. J Allergy Clin Immunol 2018; 141: 886–892. doi: 10.1016/j.jaci.2017.05.016 [DOI] [PubMed] [Google Scholar]
- 9.Morten M, Collison A, Murphy VE, et al. Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma. J Allergy Clin Immunol 2018; 142: 1765–1772. doi: 10.1016/j.jaci.2018.02.039 [DOI] [PubMed] [Google Scholar]
- 10.Rejno G, Lundholm C, Gong T, et al. Asthma during pregnancy in a population-based study--pregnancy complications and adverse perinatal outcomes. PLoS ONE 2014; 9: e104755. doi: 10.1371/journal.pone.0104755 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Rejnö G, Lundholm C, Saltvedt S, et al. Maternal asthma and early fetal growth, the MAESTRO study. Clin Exp Allergy 2021; 51: 883–891. doi: 10.1111/cea.13864 [DOI] [PubMed] [Google Scholar]
- 12.Meakin AS, Saif Z, Seedat N, et al. The impact of maternal asthma during pregnancy on fetal growth and development: a review. Expert Rev Respir Med 2020; 14: 1207–1216. doi: 10.1080/17476348.2020.1814148 [DOI] [PubMed] [Google Scholar]
- 13.Robijn AL, Brew BK, Jensen ME, et al. Effect of maternal asthma exacerbations on perinatal outcomes: a population-based study. ERJ Open Res 2020; 6: 00295-2020. doi: 10.1183/23120541.00295-2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Huang J, Namazy J. Asthma in Pregnancy. JAMA 2023; 329: 1981–1982. doi: 10.1001/jama.2023.5588 [DOI] [PubMed] [Google Scholar]
- 15.Tan EK, Tan EL. Alterations in physiology and anatomy during pregnancy. Best Pract Res Clin Obstet Gynaecol 2013; 27: 791–802. doi: 10.1016/j.bpobgyn.2013.08.001 [DOI] [PubMed] [Google Scholar]
- 16.Grindheim G, Toska K, Estensen ME, et al. Changes in pulmonary function during pregnancy: a longitudinal cohort study. BJOG 2012; 119: 94–101. doi: 10.1111/j.1471-0528.2011.03158.x [DOI] [PubMed] [Google Scholar]
- 17.Murphy VE, Jensen ME. Longitudinal changes in upper and lower airway function in pregnancy. Immunol Allergy Clin North Am 2023; 43: 17–26. doi: 10.1016/j.iac.2022.07.005 [DOI] [PubMed] [Google Scholar]
- 18.Schatz M, Zeiger RS, Hoffman CP. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Kaiser-Permanente Asthma and Pregnancy Study Group. Chest 1990; 98: 389–392. doi: 10.1378/chest.98.2.389 [DOI] [PubMed] [Google Scholar]
- 19.Schatz M, Dombrowski MP, Wise R, et al. Spirometry is related to perinatal outcomes in pregnant women with asthma. Am J Obstet Gynecol 2006; 194: 120–126. doi: 10.1016/j.ajog.2005.06.028 [DOI] [PubMed] [Google Scholar]
- 20.Cnattingius S, Källén K, Sandström A, et al. The Swedish medical birth register during five decades: documentation of the content and quality of the register. Eur J Epidemiol 2023; 38: 109–120. doi: 10.1007/s10654-022-00947-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11: 450. doi: 10.1186/1471-2458-11-450 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wettermark B, Hammar N, Fored CM, et al. The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf 2007; 16: 726–735. doi: 10.1002/pds.1294 [DOI] [PubMed] [Google Scholar]
- 23.Ortqvist AK, Lundholm C, Wettermark B, et al. Validation of asthma and eczema in population-based Swedish drug and patient registers. Pharmacoepidemiol Drug Saf 2013; 22: 850–860. doi: 10.1002/pds.3465 [DOI] [PubMed] [Google Scholar]
- 24.Vidal C, Gude F, Boquete O, et al. Evaluation of the Phadiatop test in the diagnosis of allergic sensitization in a general adult population. J Investig Allergol Clin Immunol 2005; 15: 124–130. [PubMed] [Google Scholar]
- 25.Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012; 40: 1324–1343. doi: 10.1183/09031936.00080312 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Marsál K, Persson PH, Larsen T, et al. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996; 85: 843–848. doi: 10.1111/j.1651-2227.1996.tb14164.x [DOI] [PubMed] [Google Scholar]
- 27.WHO Multicentre Growth Reference Study Group . WHO child growth standards based on length/height, weight and age. Acta Paediatr Suppl 2006; 450: 76–85. doi: 10.1111/j.1651-2227.2006.tb02378.x [DOI] [PubMed] [Google Scholar]
- 28.Tennant PWG, Murray EJ, Arnold KF, et al. Use of directed acyclic graphs (DAGs) to identify confounders in applied health research: review and recommendations. Int J Epidemiol 2021; 50: 620–632. doi: 10.1093/ije/dyaa213 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Dietert RR. Maternal and childhood asthma: risk factors, interactions, and ramifications. Reprod Toxicol 2011; 32: 198–204. doi: 10.1016/j.reprotox.2011.04.007 [DOI] [PubMed] [Google Scholar]
- 30.Gatford KL, Wooldridge AL, Kind KL, et al. Pre-birth origins of allergy and asthma. J Reprod Immunol 2017; 123: 88–93. doi: 10.1016/j.jri.2017.07.002 [DOI] [PubMed] [Google Scholar]
- 31.Lim RH, Kobzik L, Dahl M. Risk for asthma in offspring of asthmatic mothers versus fathers: a meta-analysis. PLoS One 2010; 5: e10134. doi: 10.1371/journal.pone.0010134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Schoos AM, Hansen BR, Stokholm J, et al. Parent-specific effects on risk of developing allergic sensitization and asthma in childhood. Clin Exp Allergy 2020; 50: 915–921. doi: 10.1111/cea.13670 [DOI] [PubMed] [Google Scholar]
- 33.Rothers J, Stern DA, Lohman IC, et al. Maternal cytokine profiles during pregnancy predict asthma in children of mothers without asthma. Am J Respir Cell Mol Biol 2018; 59: 592–600. doi: 10.1165/rcmb.2017-0410OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Williams PT. Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution. PeerJ 2020; 8: e9145. doi: 10.7717/peerj.9145 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Schäfer S, Wang K, Sundling F, et al. Modelling maternal and perinatal risk factors to predict poorly controlled childhood asthma. PLoS ONE 2021; 16: e0252215. doi: 10.1371/journal.pone.0252215 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Pike KC, Crozier SR, Lucas JS, et al. Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years. Thorax 2010; 65: 1099–1106. doi: 10.1136/thx.2010.134742 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Tsai HJ, Wang G, Hong X, et al. Early life weight gain and development of childhood asthma in a prospective birth cohort. Ann Am Thoracic Soc 2018; 15: 1197–1204. doi: 10.1513/AnnalsATS.201712-921OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 26: 319–338. doi: 10.1183/09031936.05.00034805 [DOI] [PubMed] [Google Scholar]
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