Abstract
Background and aim Physical activity (PA) in pregnancy is important for maternal and possibly offspring health. To study the early origins of lung function we aimed to determine whether PA in the first half of pregnancy is associated with lung function in healthy 3-month-old infants.
Methods From the general population-based Preventing Atopic Dermatitis and Allergies in Children birth cohort recruiting infants antenatally in Norway and Sweden, all 812 infants (48.8% girls) with available tidal flow–volume measures in the awake state at 3 months of age and mid-pregnancy data on PA were included. PA was self-reported by the mothers and, based on intensity, we categorised them as active or inactive during pregnancy. Furthermore, we defined active mothers as fairly or highly active. The main outcome was a ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) <0.25. Associations were analysed by logistic regression, adjusting for maternal age, education, parity, pre-pregnancy body mass index, in utero nicotine exposure and parental atopy.
Results The mean±sd tPTEF/tE was 0.391±0.08 and did not differ significantly according to maternal PA level in pregnancy. The 290 infants of inactive mothers had higher odds of having tPTEF/tE <0.25 compared to infants of all active mothers (OR 2.07, 95% CI 1.13–3.82; p=0.019) and compared to infants (n=224) of fairly active (OR 2.83, 95% CI 1.26–7.24; p=0.018) but not highly active mothers (n=298).
Conclusion Based on self-reported maternal PA in the first half of pregnancy, 3-month-old infants of inactive compared to active mothers had higher odds of a low tPTEF/tE.
Abstract
There is an association between self-reported maternal physical activity in the first half of pregnancy and lung function in healthy 3-month-old infants, with higher odds of low lung function among infants of inactive compared to active mothers https://bit.ly/3BVVv39
Introduction
Impaired infant lung function precedes wheezing and asthma both in childhood [1–3] and adulthood [4] as well as persistently lower lung function values [5, 6], suggesting that asthma likely originates in early life. Development of the respiratory system starts in the first weeks of fetal life [6, 7], and both genetics and the intrauterine environment impact lung function at birth [8].
Regular physical activity (PA) is an important contributor to a healthy lifestyle and is recommended during pregnancy in many countries [9, 10]. Staying physically active during pregnancy is safe for the fetus [11, 12], beneficial for maternal wellbeing, and reduces the risk of pregnancy complications [13–17] and the risk of caesarean deliveries in nonobese women [13, 14, 18]. For healthy women, PA in pregnancy is not associated with preterm delivery [10, 12–14] or abnormal birth weight [12, 13]. Accordingly, Norwegian guidelines recommend ≥150 min moderate or high intensity PA per week [19] although many women do not meet these recommendations [20]. However, the potential impact of maternal PA on early fetal airways and lung development is not clear.
Tidal flow–volume (TFV) loops in awake or naturally sleeping infants is a feasible method to measure lung function from the first day of life. The TFV ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) is a measure of expiratory airflow that correlates with maximal flow at functional residual capacity, using the rapid thoracoabdominal compression technique in sedated infants [5, 21]. Maternal asthma [22, 23], maternal hypertension in pregnancy [22] and smoking in pregnancy [22, 24] are among risk factors that have been associated with impaired lung function observed as lower tPTEF/tE values in offspring. A tPTEF/tE ≤0.25 is associated with obstructive lung disease, while values ≥0.30 are usually considered normal [1, 3, 7, 21, 25, 26] and higher ratios are unlikely to represent improved health. Previous studies have shown lung function differences between girls and boys, with infant tPTEF/tE values tending to be higher in girls [6, 23, 27].
Tidal volume (VT) increases after birth [28, 29], with lower volumes in early infancy observed with prematurity [30] and lung hypoplasia [31]. While most studies exploring lung function in infancy have been performed in sleeping or sedated infants, both tPTEF/tE and VT seem to be higher in the awake compared to the sleeping state [32].
In the quest to identify modifiable factors during pregnancy that may impact infant lung health, here, we hypothesise that PA positively influences infant lung function and that lack of PA may be associated with lower lung function. The aim of the present study was therefore to determine, in a large cohort of infants from a general population, whether self-reported maternal PA in the first half of pregnancy is associated with infant lung function at 3 months of age primarily as lower lung function by tPTEF/tE <0.25 and, secondarily, by VT corrected for body weight (in kilograms).
Subjects and methods
Study design and setting
3-month-old infants with available lung function measurements and information on maternal PA in the first half of pregnancy from the Preventing Atopic Dermatitis and Allergies in Children (PreventADALL) cohort were included in this prospective observational study (figure 1). The PreventADALL study, described in detail elsewhere [33], is a Scandinavian general population-based mother–child birth cohort study including 2394 antenatally recruited mother–child pairs. Pregnant women planning to give birth at Oslo University Hospital or Østfold Hospital Trust, Norway, or in the region of Stockholm, Sweden, were eligible for participation. From December 2014 to October 2016, 2697 women at approximately 18 weeks of pregnancy (range 15.7–22.7 weeks) were recruited. Their healthy singletons or twins, born at ≥35.0 gestational weeks, were included at birth.
Study population. The present study population includes all 812 infants from the Preventing Atopic Dermatitis and Allergies in Children (PreventADALL) cohort with a successful tidal flow–volume (TFV) measurement in the awake state at 3 months of age and available information on maternal physical activity in the first half of pregnancy. To ensure independency of all participants, the second-born twin was consecutively excluded.
Informed consent was signed by the mothers at recruitment and by both parents at birth. The study was approved by the regional committees for medical and health research ethics in Norway (2014/518) and Sweden (2014/2242–31/4), and registered at www.clinicaltrials.gov (identifier number NCT02449850).
Participants
In this substudy, we included all 812 3-month-old infants with a successful TFV measure of lung function in the awake state and available information on self-reported maternal PA in the first half of pregnancy. Lung function was measured at the Oslo and Stockholm study sites. Except for somewhat higher gestational age (GA) at birth, a higher rate of breastfeeding and less exposure to maternal use of nicotine after the first few weeks of pregnancy, the included infants were similar to the remaining infants (n=1582) from the PreventADALL cohort (table 1). The mothers of the included, compared to the remaining, infants were slightly older, had lower pre-pregnancy body mass index (BMI) and weight gain in the first half of pregnancy, and more were nullipara and highly educated, in line with previously described differences between the PreventADALL study sites [33]. Lung function measurements missing, unsuccessful or performed in the sleeping state were the main reasons for exclusion from the present study.
Baseline characteristics of the 812 infants included in the present study and the 1582 remaining infants from the Preventing Atopic Dermatitis and Allergies in Children (PreventADALL) mother–child birth cohort
Methods
Maternal PA in the first half of pregnancy was self-reported using electronic questionnaires sent to the mothers in relation to study recruitment. They answered how frequently they had performed different types of activities (strolling, brisk walking, jogging, bicycling, strength training, aerobics, skiing, ballgames, swimming, horse riding, yoga/Pilates and other types of PA) so far in their pregnancy. The usual intensity (low, moderate or high) and duration (<30 min, 30–60 min, 1–2 h or >2 h) of exercise was also reported. Low intensity was defined as “no sweating or shortness of breath”, moderate as “sweaty and some shortness of breath” and high as “very sweaty and very heavy breathing”. Based on all available answers, the general activity level for 2349 women in the PreventADALL cohort was estimated [20]. We defined women reporting PA of moderate or high intensity as “active” and calculated their minimum number of active minutes per week by multiplying the minimum number of sessions per week with their usual duration of exercise. Women with active minutes per week at or above the median of 120 min were further defined as “highly active” and those below the median as “fairly active”. Women reporting only low intensity or no exercise at all were defined as “inactive”. For further information, see the supplementary material.
Additionally, the questionnaire included questions on socioeconomic factors, health and lifestyle as well as family history of atopic diseases.
TFV loops were measured in calm infants by trained study personnel at the 3-month follow-up visit, using the Exhalyzer D (Eco Medics, Duernten, Switzerland) equipment [35]. An appropriately sized face mask was connected to the ultrasonic flow head with a dead space reducer, a filtering spirette and a carbon dioxide adapter with a Capnostat carbon dioxide sensor in between. The face mask was held tight over the infant's nose and mouth while as many TFV loops as possible were recorded (supplementary table S1). All infants included in the present study were awake, with measurements performed with head and neck on the midline in the supine position on a firm pillow on their caregiver's lap or in a stroller/bed. A procedure for selection of TFV loops in awake infants was tested and validated prior to analyses, with details on visual inspection and loop selection reported elsewhere [35]. Mean values for tPTEF/tE, VT and respiratory rate were registered for each infant.
Information about the delivery and the newborn was taken from electronic hospital records. At 3 months post partum, the mothers answered questions about their infants' health and nutrition. Infant weight and length were measured at the follow-up visit by trained study personnel.
Variables
Primary outcome
The primary outcome, lower lung function, was defined as a tPTEF/tE ratio <0.25.
Secondary outcome
The secondary outcome, VT corrected for body weight, was recorded as a continuous variable.
Exposure
The maternal general activity level was based on self-reported intensity of exercise in the first half of pregnancy [20]. Primarily, we compared infants of inactive mothers to those of all active mothers, and secondarily, to infants of active mothers in the subgroups of fairly active and highly active.
Covariates
All multivariable regression models were adjusted for maternal age, education, parity, pre-pregnancy BMI, in utero nicotine exposure and parental atopy. These potential confounders of the association between maternal PA in pregnancy and infant lung function were identified using a directed acyclic graph (DAG) [36] prior to statistical analyses (supplementary figure S1). Only conditions arising before the first half of pregnancy and potentially affecting both the exposure and outcome could be considered as confounders and adjusted for in the regression models.
Statistical analysis
Continuous variables are presented as mean (range), mean±sd or mean (95% CI). Categorical variables are presented as n (%).
We used logistic regression models to analyse the association between maternal general activity level and tPTEF/tE <0.25, presented as odds ratios with 95% confidence intervals and p-values. For the continuous VT corrected for body weight outcome, linear regression models are presented with regression coefficients (: estimate), R2, 95% confidence intervals and p-values.
To assess a potential interaction with infant sex, we added the interaction term “maternal PA×infant sex” to our regression models.
We compared the infants included in the present study to all remaining infants in the PreventADALL cohort with the independent sample t-test (continuous variables), the Chi-squared test (nominal variables) or the Mann–Whitney U-test (ordinal variables). p-values <0.05 were regarded as significant.
IBM SPSS statistics version 27, RStudio version 4.1.0 and Microsoft Excel 2016 were used for statistical analyses.
Results
The 812 infants (48.8% girls) included in the present study were born at mean (range) GA of 40.1 (35.3–42.3) weeks (table 1). Their mean (range) age at the time of lung function testing was 93 (57–137) days and their weight, 6.3 (4.4–8.9) kg.
Approximately one third of the mothers (290 (35.7%) out of 812) were defined as inactive in the first half of pregnancy. Of the 522 (64.3% out of 812) active mothers, 224 (27.6% out of 812) were fairly active and 298 (36.7% out of 812) were highly active.
Mean±sd (range) tPTEF/tE for the included infants was 0.39±0.08 (0.19–0.63), with the distribution shown in figure 2a. Few had low values; while 47 infants (5.8%) had a tPTEF/tE <0.25, only five (0.6%) had values <0.20. The mean±sd number of TFV loops was 21±14 per infant (supplementary table S1).
Histograms showing the distribution of the infant ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) in a) all included infants (n=812) and b) infants of inactive (n=290) compared to all active (n=522) mothers, presented with partly overlapping bars. While the y-axis in a) shows frequency, the two overlapping histograms in b) have percentage on the y-axis to enable comparison of the distribution of infant tPTEF/tE in subgroups of different size.
The mean±sd tPTEF/tE was similar among infants of inactive and active mothers: 0.387±0.09 compared to 0.393±0.08 (figure 3 and supplementary table S2); however, as shown in the histogram in figure 2b, the tPTEF/tE distribution appears to be different in the lower tail between the two groups and tPTEF/tE variability greater among infants of inactive mothers.
Infant ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) at 3 months of age according to maternal general activity level, shown for infants of a) inactive and active mothers, and b) inactive, fairly active and highly active mothers. Mean tPTEF/tE for infants of inactive and active mothers was compared with the independent sample t-test (p=0.321), and for infants of inactive, fairly active and highly active mothers, with one-way ANOVA (p=0.594). No statistically significant difference was observed between the groups. Symbols represent means and whiskers represent 95% confidence intervals.
Infants of inactive mothers had significantly higher odds of having a tPTEF/tE <0.25 compared to infants of all active mothers as well as when compared to the infants of fairly active mothers only, in both univariable and multivariable regression models (table 2).
The association between maternal general activity level in the first half of pregnancy and the infant ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) <0.25, analysed with logistic regression models
The mean±sd VT corrected for body weight for all included infants was 7.05±2.12 mL·kg−1, with no significant difference between infants of inactive mothers compared to those of all active mothers (results not shown). However, when active mothers were subdivided into fairly and highly active, VT corrected for body weight differed significantly between the three groups (figure 4a and supplementary table S3a). Infants of highly active mothers had the lowest mean±sd VT corrected for body weight of 6.79±2.05 mL·kg−1, which was significantly lower than that of the infants of fairly active mothers (7.25±2.13 mL·kg−1, p=0.035), while they did not differ significantly from the infants of inactive mothers (7.17±2.16 mL·kg−1). A significant association was observed between high maternal activity and lower infant VT corrected for body weight in both univariable and multivariable models (table 3).
Infant a) tidal volume (VT) corrected for body weight and b) respiratory rate at 3 months of age according to maternal general activity level in three categories. a) Mean VT corrected for body weight was compared between groups with one-way ANOVA (p=0.023). Mean VT corrected for body weight differed significantly between infants of fairly active and highly active mothers (mean difference 0.47 mL·kg−1, 95% CI 0.026–0.905 mL·kg−1; p=0.035). b) Mean respiratory rate was compared between groups with one-way ANOVA (p=0.053). Mean respiratory rate differed significantly between infants of highly active and fairly active mothers (mean difference 2.84, 95% CI 0.09–5.59 breaths per min; p=0.041). Symbols represent means and whiskers represent 95% confidence intervals.
The association between maternal general activity level in the first half of pregnancy and infant tidal volume corrected for body weight, analysed with linear regression models
There was no significant interaction between maternal PA in the first half of pregnancy and infant sex, and neither did the association between maternal PA and infant lung function change by including infant sex in the regression models (results not shown).
Discussion
Maternal PA in the first half of pregnancy was significantly associated with lung function in 812 healthy awake 3-month-old infants born after ≥35.0 weeks of pregnancy. Infants of physically inactive mothers were more likely to have low tPTEF/tE values, with twice the odds of having a tPTEF/tE <0.25 compared to infants of active mothers. High maternal activity was associated with lower VT corrected for body weight.
The significant association between maternal inactivity in the first half of pregnancy and lower tPTEF/tE at 3 months of age is a novel finding, although studies that have examined the fetus during maternal exercise may support our results [37, 38]. Fetal breathing movements, observed as early as the first trimester, are important for development of the lungs and the respiratory system [8, 39]. While maternal exercise can transiently affect both fetal breathing and body movements [37, 38], little is known about potential associations between breathing movements in the fetus and postnatal lung function. In addition, an increased variability in fetal heart rate during maternal exercise may, together with higher blood flow in the umbilical cord and the placental circulation, indicate an improved in utero environment in active women and lower the risk of fetal adverse outcomes [38].
Higher odds of low tPTEF/tE were observed among infants born to inactive mothers compared to all active and to fairly active mothers. We explored potential associations of PA on lung function values within a normal, healthy infant population, and based upon clinically relevant cut-off values from previous studies, we chose tPTEF/tE <0.25 to represent low lung function [1, 3, 7, 25, 26]. Future studies of the PreventADALL cohort may reveal whether maternal inactivity in the first half of pregnancy is associated with an increased risk of obstructive lung diseases in the offspring. Infants of highly active mothers did not have significantly lower odds of having a low tPTEF/tE, suggesting that the observed association did not depend on the most active mothers.
The present study is based on maternal PA reported around mid-pregnancy, while complications such as excessive gestational weight gain, hypertension and diabetes, improvable and partly preventable [13, 15, 16] by PA, often arise later. One may speculate that the higher prevalence of these pregnancy complications in physically inactive women could partly explain the association with lower infant tPTEF/tE. To explore the association between maternal PA level in the first half of pregnancy and infant lung function we have only adjusted for variables potentially affecting both the exposure and the outcome. Thus, neither pregnancy complications nor infant factors such as sex, GA, birth weight or breastfeeding [6, 8, 23, 27, 30, 40], previously shown to affect lung function, were regarded as potential confounders.
While VT corrected for body weight was similar among infants of inactive and active mothers overall, a significantly lower VT corrected for body weight was observed among infants of highly active compared to fairly active mothers. We are unaware of similar findings reported elsewhere. The potential reasons for the association between high-level PA and lower VT corrected for body weight are not clear and could not be fully explained by the slightly higher respiratory rate observed in infants of highly active mothers (figure 4b and supplementary material). Although weight-bearing exercise in the supine position and late in pregnancy has been associated with transient fetal bradycardia, reduced uterine blood flow and reduced fetoplacental growth, increasing the risk of fetal growth restriction [38], our study cannot elucidate such potential mechanisms. However, although not significant, infants of highly active mothers had the smallest placentas and lowest birthweight, with the subsequent highest weight gain until 3 months of age (supplementary figure S2b), in line with previous findings of lower birthweight in relation to vigorous maternal exercise and exercise during pregnancy in previously inactive women [12, 41]. Low birth weight and high infant weight gain are associated with asthma and lower lung function values in childhood [40]. Important stages of airway development complete during the second trimester [6, 8] while the third trimester of pregnancy is mainly associated with fetal growth and weight gain. It is possible that high activity levels in late pregnancy, causing slower fetal growth, could lead to discrepancy in airway development and lung growth that may partly explain the lowest VT corrected for body weight and normal tPTEF/tE in infants of highly active women. A smaller lung size relative to the airway calibre results in higher expiratory flow and tPTEF/tE [6] and even though a “catch-up” body growth is observed, lung growth might not catch up as fast, reflected by lower VT corrected for body weight at 3 months of age.
The large group of healthy infants, with lung function measured in the awake state at a relatively similar age, is a strength of this study. The general activity level was slightly higher for the mothers of the infants included in the present study compared with the whole PreventADALL cohort [20] and some maternal differences related to study sites were observed [33]. Nevertheless, we believe our results are representative of the general Scandinavian population. Prior to analyses, we identified confounders by constructing a DAG based on available knowledge. Apart from nonsignificantly lower birthweight and higher weight gain in the first 3 months of life, no differences in infant characteristics according to maternal PA level were observed, supporting our DAG and findings.
Due to the design of the study, all information on maternal PA was self-reported, with certain limitations arising from the questionnaire. Although our analyses are based on an estimate of active minutes per week, as the women were not asked about the total weekly duration or frequency of exercise, we believe that the classification of active women into fairly and highly active is reasonable. In this study, we addressed the role of PA in the first half of pregnancy for early fetal respiratory development, using detailed PA data collected at enrolment. Information on maternal PA in the second half of pregnancy was limited to changes in PA habits from mid-pregnancy until 34 weeks gestation and after this time no information on maternal PA was available. In addition, to account for potential pregnancy complications that may impact on activity levels, more likely to be present in the last part of pregnancy, would necessitate a larger cohort than ours.
Conclusion
Maternal PA in pregnancy was significantly associated with infant lung function, with higher odds of low tPTEF/tE in infants of inactive compared to active mothers, and an association between high maternal activity and lower VT. The observed association between maternal inactivity and lower infant lung function may have clinical implications, adding to the importance of advising and supporting pregnant women to adhere to guidelines on PA during pregnancy. Nevertheless, there might be confounders for which we have not adjusted and, potentially, maternal PA level could be a proxy for general health or an unknown factor associated with lung function in the offspring.
Supplementary material
Supplementary Material
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Supplementary material 00172-2022.SUPPLEMENT
Acknowledgements
We sincerely thank all our study participants and their families. We thank all those who contributed to the planning of the study, recruitment of participants, clinical examinations and biological sampling, as well as those facilitating and running the study, especially: Hilde Aaneland (Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Ann Berglind (Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden), Åshild Wik Despriée (VID Specialized University, Oslo, Norway), Kim M.A. Endre (Department of Dermatology and Venereology, Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Berit Granum (Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway), Malén Gudbrandsgard (Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway), Gunilla Hedlin (Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden), Katarina Hilde (Division of Obstetrics and Gynaecology, Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Ina Kreyberg (Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Live S. Nordhagen (Division of Paediatric and Adolescent Medicine, Oslo University Hospital; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo; and VID Specialized University, Oslo, Norway), Carina M. Saunders (Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Birgitte Kordt Sundet (Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, and Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway), Cilla Söderhäll (Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden), Sandra Ganrud Tedner (Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden), Ellen Tegnerud (Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden), Magdalena R. Værnesbranden (Department of Obstetrics and Gynaecology, Østfold Hospital Trust, Kalnes, and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Johanna Wiik (Department of Obstetrics and Gynaecology, Østfold Hospital Trust, Kalnes, Norway; Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University; and Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden) and, in memoriam, Kai-Håkon Carlsen (Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway).
Footnotes
Provenance: Submitted article, peer reviewed.
This study is registered at www.clinicaltrials.gov with identifier number NCT02449850.
The study was performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment).
Conflict of interest: M. LeBlanc reports personal fees from MSD, outside the submitted work. E.M. Rehbinder reports personal fees from Sanofi-Genzyme, Novartis, Leo-Pharma, Perrigo, and The Norwegian Asthma and Allergy Association, outside the submitted work. The other authors have no financial relationships relevant to this article to disclose.
Support statement: This study was a part of a PhD project and H.K. Gudmundsdóttir has received funding as a doctoral research fellow from the University of Oslo, Norway. The PreventADALL study was supported by a number of public and private funding bodies with no influence on design, conduct or analyses. The PreventADALL study has received funding from the following sources: The Regional Health Board South East, The Norwegian Research Council, Oslo University Hospital, The University of Oslo, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden (Vårdalstiftelsen), The Swedish Asthma and Allergy Association's Research Foundation, The Swedish Research Council – the Initiative for Clinical Therapy Research, The Swedish Heart–Lung Foundation, SFO-V Karolinska Institutet, Østfold Hospital Trust, by unrestricted grants from the Norwegian Association of Asthma and Allergy, The Kloster foundation, Thermo-Fisher, Uppsala, Sweden (through supplying allergen reagents) and Fürst Medical Laboratory, Oslo, Norway (through performing IgE analyses), Norwegian Society of Dermatology and Venerology, Arne Ingels Legat, Region Stockholm (ALF-project and individual grants), Forte, Swedish Order of Freemasons Foundation Barnhuset, The Sven Jerring Foundation, The Hesselman foundation, The Magnus Bergwall foundation, The Konsul Th.C. Bergh Foundation, The Swedish Society of Medicine, The King Gustaf V 80th Birthday Foundation, KI grants, The Cancer and Allergy Foundation, The Pediatric Research Foundation at Astrid Lindgren Children's Hospital, The Samaritan Foundation for Pediatric research, Barnestiftelsen at Oslo University Hospital, Roche, and The Frithjof Nansen Institute. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 8, 2022.
- Accepted July 14, 2022.
- Copyright ©The authors 2022
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