# Maternal asthma in relation to infant size and body composition

Danielle R Stevens, Edwina Yeung, Stefanie N Hinkle, William Grobman, Andrew Williams, Marion Ouidir, Rajesh Kumar, Leah M Lipsky, Matthew C H Rohn, Jenna Kanner, et al.

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Danielle R Stevens, Edwina Yeung, Stefanie N Hinkle, William Grobman, Andrew Williams, et al. Maternal asthma in relation to infant size and body composition. Journal of Allergy and Clinical Immunology: Global, 2023, 2 (3), pp.100122. 10.1016/j.jacig.2023.100122. hal-04662323

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# Maternal asthma in relation to infant size and body composition

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Danielle R. Stevens, PhD,<sup>a,b</sup> Edwina Yeung, PhD,<sup>b</sup> Stefanie N. Hinkle, PhD,<sup>b,c</sup> William Grobman, MD,<sup>d</sup>

Andrew Williams, PhD,<sup>e</sup> Marion Ouidir, PhD,<sup>b</sup> Rajesh Kumar, MD,<sup>f</sup> Leah M. Lipsky, MD,<sup>b</sup> Matthew C. H. Rohn, MD,<sup>b,g</sup>

Jenna Kanner, BS,<sup>b</sup> Seth Sherman, PhD,<sup>h</sup> Zhen Chen, PhD,<sup>i</sup> and Pauline Mendola, PhD<sup>b,j</sup> Research Triangle Park, NC;
Bethesda and Rockville, Md; Philadelphia, Pa; Columbus, Ohio; Grand Forks, ND; Chicago, Ill; Washington, DC; and Buffalo, NY

**Background:** Asthma affects 10% of pregnancies and may influence offspring health, including infant size and body composition, through hypoxic and inflammatory pathways.

**Objective:** We sought to determine associations between maternal asthma and asthma phenotypes during pregnancy and infant size and body composition.

**Methods:** The B-WELL-Mom study (2015-19) is a prospective cohort of 418 pregnant persons with and without asthma recruited in the first trimester of pregnancy from 2 US obstetric clinics. Exposures were maternal self-reported active asthma (n = 311) or no asthma (n = 107), and asthma phenotypes were classified on the bases of atopy, onset, exercise induced, control, severity, symptomology, and exacerbations. Outcomes were infant weight, length, head circumference, and skinfold measurements at birth and postnatal follow-up, as well as fat and lean mass assessed by air displacement plethysmography at birth. Adjusted multivariable linear regression examined associations of maternal asthma and asthma phenotypes with infant outcomes.

**Results:** Offspring were born at a mean ± SD of 38 ± 2.3 weeks' gestation and were 18 ± 2.2 weeks of age at postnatal follow-up. Infants of participants with asthma had a mean ± SD fat mass of 11.0 ± 4.2%, birth weight of 3045.8 ± 604.3 g, and postnatal follow-up weight of 6696.4 ± 964.2 g, which were not different from infants of participants without asthma (respectively, β [95% confidence interval]: -0.1 [-1.4, 1.3], -26.7 [-156.9, 103.4], and 107.5 [-117.3, 332.3]). Few associations were

observed between asthma or asthma phenotypes and infant size or body composition.

**Conclusions:** In a current obstetric cohort, maternal asthma during pregnancy was not associated with differential infant size or body composition. (J Allergy Clin Immunol Global 2023;2:100122.)

**Key words:** Infant, pregnancy, asthma, atopy, adiposity, anthropometry, prospective study

Asthma is the most common chronic disease complicating pregnancy.¹ With over 10% of women affected and an increasing global prevalence,² there is a critical need to address gaps in our understanding of how maternal asthma during pregnancy influences offspring health and development. Research suggests that pregnant persons with asthma are at an increased risk for having adverse neonatal outcomes including congenital malformations, preterm birth, and neonatal death.³⁻¹² A 2011 meta-analysis indicated that infants of pregnant persons with asthma were 93 g lighter than infants of those without asthma, although there was significant heterogeneity across studies, potentially due to differences in study population or design.¹³ These decrements in infant birth weight have been attributed to asthma-induced maternal hypoxia.¹³⁻¹⁵

Birth weight is easily ascertained and has a well-established U-shaped association with morbidity and mortality.¹⁶⁻¹⁹ However, birth weight is composed of both lean (skeletal and organ weights) and fat (adipose) mass, with fat mass accounting for about 15% of birth weight.²⁰ In animal models, maternal hypoxia increases infant fat mass through proinflammatory pathways and enhanced peroxisome proliferator-activated receptor γ expression.²¹ Thus, human studies examining measures of body composition will provide improved insight into potential developmental effects of maternal asthma status. Few prior studies have examined associations between maternal asthma and neonatal measures other than birth weight.²² Furthermore, follow-up of affected infants beyond delivery has rarely been conducted,⁴,²³⁻²⁵ with no prior studies tracking offspring size or body composition beyond the neonatal period. If differences in neonatal size and body composition by maternal asthma status exist, then these disparities may persist into infancy and beyond, influencing long-term physical development and health.

Asthma is a highly heterogeneous disease characterized by multiple phenotypes.²⁶,²⁷ Retrospective studies, which constitute much of the birth weight literature, have been unable to assess differences across phenotypes.⁷,⁹,²⁸,²⁹ A 2021 meta-analysis found modest (4-24%) increased odds of delivering a low birth weight and small-for-gestational age infant among pregnant persons with severe compared to mild asthma.¹⁴ However, there are few data regarding other phenotypes, such as exercise-induced or

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<footnote>From <sup>a</sup>the Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park; <sup>b</sup>the Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda; <sup>c</sup>the Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia; <sup>d</sup>Wexner Medical Center, The Ohio State University, Columbus; <sup>e</sup>the School of Medicine and Health Sciences, University of North Dakota, Grand Forks; <sup>f</sup>the Feinberg School of Medicine, Northwestern University, Chicago; <sup>g</sup>the Department of Obstetrics and Gynecology, George Washington University, Washington; <sup>h</sup>the Emmes Company, Rockville; <sup>i</sup>the Biostatistics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda; and <sup>j</sup>the Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo.</footnote>

<footnote>Received for publication September 1, 2022; revised November 25, 2022; accepted for publication February 2, 2023.</footnote>

<footnote>Available online May 30, 2023.</footnote>

<footnote>Corresponding author: Pauline Mendola, PhD, Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, 270 Farber Hall, Buffalo, NY 14214. E-mail: pmendola@buffalo.edu.</footnote>

<footnote>The CrossMark symbol notifies online readers when updates have been made to the article such as errata or minor corrections</footnote>

<footnote>2772-8293</footnote>

<footnote>Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</footnote>

<footnote>https://doi.org/10.1016/j.jacig.2023.100122</footnote>
atopic asthma. Identifying characteristics of asthma resulting in differential infant outcomes could inform interventions to optimize offspring health.

Therefore, the primary aim of this study was to examine associations of maternal asthma and asthma phenotypes with infant size and body composition in a contemporary obstetric cohort.

# METHODS

## Study design

The B-WELL-Mom study was a prospective pregnancy cohort of persons with (n = 311) and without (n = 107) active asthma. Study staff reviewed electronic medical records to identify potentially eligible participants before a clinic visit. Eligible participants were at least 18 years of age, in the first trimester of a singleton pregnancy, and spoke English or Spanish. Individuals with a diagnosis of human immunodeficiency virus, multiple sclerosis, lupus, rheumatoid arthritis, or mixed connective tissue disease were ineligible for study participation. An initial assessment of asthma status was made on the basis of the medical record. Study staff approached potentially eligible participants to perform recruitment procedures including informed consent after confirming eligibility and asthma status. The study was introduced to the potential subjects, and a formal informed consent form was presented to and obtained from willing participants before any study-related procedures. Individuals with a diagnosis of asthma in the medical record were asked whether they had either used prescription medication for asthma or had asthma symptoms in the year before the pregnancy. Individuals were ineligible if they did not confirm their asthma diagnosis or if they reported no asthma symptoms and no prescription medications for asthma in the year before pregnancy. Individuals who confirmed their asthma diagnosis, medication, and symptoms in the year before the pregnancy were recruited for the asthma group. Individuals without a diagnosis of asthma in the medical record were asked to confirm they had no history of asthma and no prior use of asthma medications before being recruited for the no-asthma group.

Participants were followed across pregnancy and postnatally with 4 in-person clinical assessments and questionnaires. Visits occurred at 6-14 weeks' gestation, 20-22 weeks' gestation, 30-32 weeks' gestation, and 9-28 weeks after birth (mean, 18 weeks after birth). Daily diaries and medical record abstraction collected additional data on maternal and infant health. Study materials are available online (b-well-mom.org). Data collection was for research purposes only, and study data were not provided or used by clinical care providers to direct clinical management of asthma. Asthma management was not part of the study protocol and was determined by individual study sites and clinical care providers in accordance with standard practice.³⁰ Human subject approval was obtained from all participating sites, and mothers provided informed consent.

## Outcome assessment

Primary study outcomes included infant weight (g), length (cm), head circumference (cm), fat (g, percent), and lean mass (g). Infant anthropometric and skinfold measurements were collected in triplicate within 12 to 24 hours of birth and at postnatal follow-up by trained research staff, and triplicate measurements

were averaged for analyses. When missing, chart abstraction provided measures of birth weight (n = 89), length (n = 93), and head circumference (n = 83) assessed according to standard hospital procedures. Correlations between study and chart assessments of weight, length, and head circumference were 0.97 (n = 391), 0.96 (n = 387), and 0.90 (n = 376), respectively. Infant body composition was obtained from air displacement plethysmography (Pea Pod, Cosmed) administered once at birth and included measures of fat and lean mass. Percentage of fat mass was calculated as: (fat mass/[fat mass + lean mass]) × 100.³¹

Secondary study outcomes included sex- and age-specific z scores for weight, weight for length, and head circumference based on the World Health Organization's growth standards;³² the sum of skinfold measurements from the subscapular, abdominal flank, triceps, and anterior thigh;³³ other infant anthropometrics (chest circumference [cm], abdominal circumference [cm], umbilical circumference [cm], upper arm length [cm], mid-upper arm circumference [cm], upper thigh length [cm], mid-upper thigh circumference [cm]), and fat and lean mass indexes (kg/m²).³⁴

## Exposure assessment

Asthma status was ascertained at enrollment. Asthma-related phenotypes included: self-reported atopy status (nonatopic or atopic); age at asthma onset (child onset [<18 years] or adult onset [≥18 years]); exercise-induced asthma (exercise induced, don't exercise, or not exercise induced);³⁵ prepregnancy asthma control (poor or good based on the Asthma Control Test³⁶ score at enrollment); gestational asthma control (same or worse as determined by symptomology);³⁷ exacerbated asthma (exacerbated or not exacerbated as determined by self-reported asthma-related hospitalization, emergency department, or unscheduled doctor's visit);¹⁴ and asthma severity (step 1, step 2, step 3, or step 4+). Asthma severity was determined according to self-reported medications from the 6 months before the baseline questionnaire and categorized on the basis of the guidelines of the American College of Obstetricians and Gynecology (see Table E1 in this article's Online Repository at www.jaci-global.org).³⁰

## Covariates

Confounders for adjustment were selected using a directed acyclic graph (see Fig E1 in the Online Repository at www.jaci-global.org). These were self-reported at baseline and included maternal age (years), self-identified race and ethnicity (White, Black, Hispanic, other), household income (quartiles as follows: $14,999 or less; $15,000 to $39,999; $40,000 to $119,999; and $120,000 or more), marital status (married and/or living with partner, divorced/separated or widowed, single), education (high school or less, associate's/some college, bachelor's degree, master's or advanced degree), parity (nulliparous, multiparous), prepregnancy cigarette smoke exposure (yes/no), prepregnancy body mass index (BMI; ≤24.9, 25.0-29.9, and ≥30.0 kg/m²), and prepregnancy diabetes (yes/no) and/or hypertension (yes/no). Race is a social construct and was included in models as a proxy for unmeasured cultural or social factors influencing asthma status³⁸,³⁹ and infant outcomes.⁴⁰,⁴¹

All models additionally included adjustment for study site and infant sex assigned at birth, and models for outcomes at postnatal follow-up additionally adjusted for infant age. We did not adjust
<figure><img src="image_4.png" /><figcaption>FIG 1. Flow diagram of study population by asthma status in B-WELL-Mom study, 2015-19, with analytic sample at infant birth and postnatal follow-up by maternal asthma status.</figcaption></figure>

for downstream factors (eg, gestational age at birth, pregnancy complications) that may mediate associations.⁴²

## Statistical analyses

The aim of analyses was to estimate the association of maternal asthma and asthma phenotypes with infant size and body composition. Outcome and covariate distributions were visualized, and descriptive statistics (means ± SDs and no. [%]) by maternal asthma and asthma phenotypes were examined for the study population. Adjusted linear regression models examined mean differences (β) and 95% confidence intervals (CIs) for infant size and body composition at birth and at postnatal follow-up by maternal asthma or asthma phenotype. Models were run separately for outcomes at birth and postnatal follow-up. The reference group for analyses was participants without asthma. A Benjamini-Hochberg false discovery rate⁴³ q value of <0.10 was used to determine statistical significance due to multiple comparisons.

On the basis of prior literature,²³,⁴⁴⁻⁴⁷ we examined whether associations between asthma and infant outcomes differed by maternal BMI or infant sex using interaction terms. P < .10 was

used to determine statistically significant interactions.⁴⁸ SAS v9.4 (SAS Institute, Cary, NC) and R v3.6.1 (R Project; www.r-project.org) were used for analyses.

A small percentage of participants (<1%) were missing responses for asthma phenotype variables, and 72 participants (18.4%) were unable to recall prepregnancy weight. Thus, missing data were imputed in 10 data sets using multivariate imputation by chained equations and included all variables from analyses as well as self-reported employment and student status, health insurance, receipt of federal aid, asthma control variables from the Asthma Control Test, highest recalled weight before pregnancy, lowest recalled weight before pregnancy, and body shape reported as standardized prepregnancy somatotype, and measured weight collected at the first study visit.

## Access to data

B-WELL-Mom data may be accessed via the Eunice Kennedy Shriver National Institute of Child Health and Human Development Division of Intramural Population Health Research Bio-specimens Repository Access and Data Sharing website after proposal submission and data-use agreement. More details on the
<table><caption>TABLE I. Patient characteristics</caption><thead><tr><th>Characteristic</th><th>Asthma (n = 292)</th><th>No asthma (n = 99)</th><th>Total (n = 391)</th></tr></thead><tbody><tr><td>Study site</td><td></td><td></td><td></td></tr><tr><td>NWU</td><td>162 (55.5)</td><td>50 (50.5)</td><td>212 (54.2)</td></tr><tr><td>UAB</td><td>130 (44.5)</td><td>49 (49.5)</td><td>179 (45.8)</td></tr><tr><td>Maternal age (years)</td><td>29.7 ± 5.9</td><td>28.4 ± 5.8</td><td>29.3 ± 5.9</td></tr><tr><td>Maternal race and ethnicity</td><td></td><td></td><td></td></tr><tr><td>White</td><td>92 (31.5)</td><td>31 (31.3)</td><td>123 (31.5)</td></tr><tr><td>Black</td><td>151 (51.7)</td><td>58 (58.6)</td><td>209 (53.5)</td></tr><tr><td>Hispanic</td><td>29 (9.9)</td><td>5 (5.1)</td><td>34 (8.7)</td></tr><tr><td>Other*</td><td>20 (6.8)</td><td>5 (5.1)</td><td>25 (6.4)</td></tr><tr><td>Household income (quartiles)</td><td></td><td></td><td></td></tr><tr><td>≤$14,999</td><td>62 (21.2)</td><td>21 (21.2)</td><td>83 (21.2)</td></tr><tr><td>$15,000-$39,999</td><td>74 (25.3)</td><td>22 (22.2)</td><td>96 (24.6)</td></tr><tr><td>$40,000-$119,999</td><td>84 (28.8)</td><td>34 (34.3)</td><td>118 (30.2)</td></tr><tr><td>≥$120,000</td><td>72 (24.7)</td><td>22 (22.2)</td><td>94 (24.0)</td></tr><tr><td>Marital status</td><td></td><td></td><td></td></tr><tr><td>Divorced/separated or widowed</td><td>13 (4.5)</td><td>3 (3.0)</td><td>16 (4.1)</td></tr><tr><td>Married and/or living with partner</td><td>163 (55.8)</td><td>44 (44.4)</td><td>207 (52.9)</td></tr><tr><td>Single</td><td>116 (39.7)</td><td>52 (52.5)</td><td>168 (43.0)</td></tr><tr><td>Maternal education</td><td></td><td></td><td></td></tr><tr><td>High school or less</td><td>94 (32.2)</td><td>41 (41.4)</td><td>135 (34.5)</td></tr><tr><td>Associate's/some college</td><td>86 (29.5)</td><td>26 (26.3)</td><td>112 (28.6)</td></tr><tr><td>Bachelor's degree</td><td>47 (16.1)</td><td>15 (15.2)</td><td>62 (15.9)</td></tr><tr><td>Master's or advanced degree</td><td>65 (22.3)</td><td>17 (17.2)</td><td>82 (21.0)</td></tr><tr><td>Parity</td><td></td><td></td><td></td></tr><tr><td>Multiparous</td><td>158 (54.1)</td><td>59 (59.6)</td><td>217 (55.5)</td></tr><tr><td>Nulliparous</td><td>134 (45.9)</td><td>40 (40.4)</td><td>174 (44.5)</td></tr><tr><td>Prepregnancy smoke exposure</td><td></td><td></td><td></td></tr><tr><td>No</td><td>186 (63.7)</td><td>69 (69.7)</td><td>255 (65.2)</td></tr><tr><td>Yes</td><td>105 (36.0)</td><td>30 (30.3)</td><td>135 (34.5)</td></tr><tr><td>Missing</td><td>1 (0.3)</td><td>0 (0.0)</td><td>1 (0.3)</td></tr><tr><td>Prepregnancy hypertension</td><td></td><td></td><td></td></tr><tr><td>No</td><td>263 (90.1)</td><td>90 (90.9)</td><td>353 (90.3)</td></tr><tr><td>Yes</td><td>29 (9.9)</td><td>9 (9.1)</td><td>38 (9.7)</td></tr><tr><td>Prepregnancy diabetes</td><td></td><td></td><td></td></tr><tr><td>No</td><td>277 (94.9)</td><td>97 (98.0)</td><td>374 (95.7)</td></tr><tr><td>Yes</td><td>15 (5.1)</td><td>2 (2.0)</td><td>17 (4.3)</td></tr><tr><td>Maternal prepregnancy BMI</td><td></td><td></td><td></td></tr><tr><td>≤24.9 kg/m²</td><td>101 (34.6)</td><td>36 (36.4)</td><td>137 (35.0)</td></tr><tr><td>25.0-29.9 kg/m²</td><td>48 (16.4)</td><td>24 (24.2)</td><td>72 (18.4)</td></tr><tr><td>≥30.0 kg/m²</td><td>88 (30.1)</td><td>22 (22.2)</td><td>110 (28.1)</td></tr><tr><td>Missing</td><td>55 (18.8)</td><td>17 (17.2)</td><td>72 (18.4)</td></tr><tr><td>Infant sex assigned at birth</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>146 (50.0)</td><td>48 (48.5)</td><td>194 (49.6)</td></tr><tr><td>Female</td><td>146 (50.0)</td><td>51 (51.5)</td><td>197 (50.4)</td></tr><tr><td>Gestational age at delivery (weeks)</td><td>37.9 ± 2.4</td><td>38.1 ± 2.0</td><td>38.0 ± 2.3</td></tr><tr><td>Postnatal follow-up (weeks)</td><td>18.0 ± 2.3</td><td>18.1 ± 1.9</td><td>18 ± 2.2</td></tr></tbody></table>

Data are presented as nos. (%) or means ± SDs. NWU, Northwestern University; UAB, University of Alabama-Birmingham.

*"Other" category includes self-identified Asian (n = 9) and other race and ethnicity (n = 16).

available data and how to request access are available online (brads.nichd.nih.gov/OurCollections/BWell/).

## RESULTS

In total, 391 infants (94%) were followed for birth outcomes and 317 infants (82%) were measured for postnatal outcomes (Fig 1). Approximately half of the participants were non-Hispanic Black (53.5%). The average gestational age at delivery was 38 weeks (SD, 2.3 weeks), and the average age at postnatal follow-up was 18 weeks (SD, 2.2 weeks) (Table I), with no differences by asthma status. Participants with asthma (n = 292)

predominantly had atopic (81.5%), child-onset (76.4%), exercise-induced (47.7%), poor control (51.0%), and less severe asthma (step 1: 59.6%, step 2: 17.1%, step 3: 11.6%, and step 4: 11.6%). During pregnancy, 40.4% of participants with asthma experienced worsening asthma control. Further, most participants (77.3%) had no asthma exacerbations.

Among participants with asthma, the mean ± SD infant adiposity at birth was 11.0 ± 4.2% fat mass, birth weight was 3045.8 ± 604.3 g, and weight at postnatal follow-up was 6696.4 ± 964.2 g. Among participants without asthma, the mean ± SD infant adiposity at birth was 10.8 ± 4.2% fat mass, birth weight was 3072.2 ± 556.3 g, and weight at postnatal
<table><caption>TABLE II. Infant size and body composition among participants with and without asthma</caption><thead><tr><th rowspan="3">Characteristic</th><th colspan="4">Birth</th><th colspan="4">Postnatal visit</th></tr><tr><th rowspan="2">No.</th><th colspan="2">Mean ± SD</th><th rowspan="2">β (95% CI)*</th><th rowspan="2">No.</th><th colspan="2">Mean ± SD</th><th rowspan="2">β (95% CI)*</th></tr><tr><th>Asthma</th><th>No asthma</th><th>Asthma</th><th>No asthma</th></tr></thead><tbody><tr><td>Size</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weight (g)</td><td>391</td><td>3045.8 ± 604.3</td><td>3072.2 ± 556.3</td><td>-26.7 (-156.9, 103.4)</td><td>314</td><td>6696.4 ± 964.2</td><td>6593.0 ± 782.4</td><td>107.5 (-117.3, 332.3)</td></tr><tr><td>Weight-for-age z score</td><td>391</td><td>-0.6 ± 1.4</td><td>-0.5 ± 1.2</td><td>-0.1 (-0.4, 0.2)</td><td>314</td><td>-0.2 ± 1.2</td><td>-0.3 ± 0.9</td><td>0.1 (-0.2, 0.4)</td></tr><tr><td>Length (cm)</td><td>387</td><td>49.6 ± 3.9</td><td>49.9 ± 3.2</td><td>-0.3 (-1.1, 0.6)</td><td>311</td><td>61.8 ± 4.0</td><td>61.6 ± 5.3</td><td>0.4 (-0.7, 1.5)</td></tr><tr><td>Length-for-age z score</td><td>387</td><td>0.1 ± 2.1</td><td>0.2 ± 1.6</td><td>-0.1 (-0.6, 0.3)</td><td>311</td><td>-0.7 ± 1.8</td><td>-0.8 ± 2.4</td><td>0.2 (-0.3, 0.7)</td></tr><tr><td>Weight-for-length z score</td><td>362</td><td>-1.1 ± 1.5</td><td>-1.2 ± 1.6</td><td>0.1 (-0.2, 0.5)</td><td>309</td><td>0.5 ± 1.5</td><td>0.2 ± 1.1</td><td>0.3 (-0.1, 0.6)</td></tr><tr><td>Head circumference (cm)</td><td>380</td><td>33.4 ± 2.4</td><td>33.3 ± 2.0</td><td>0.0 (-0.5, 0.6)</td><td>317</td><td>40.9 ± 1.9</td><td>41.1 ± 1.7</td><td>-0.1 (-0.6, 0.3)</td></tr><tr><td>Head circumference-for-age z score</td><td>380</td><td>-0.6 ± 2.0</td><td>-0.7 ± 1.6</td><td>0.0 (-0.4, 0.5)</td><td>317</td><td>-0.2 ± 1.4</td><td>-0.1 ± 1.3</td><td>-0.1 (-0.5, 0.3)</td></tr><tr><td>Sum of skinfold measurements (mm)</td><td>297</td><td>17.1 ± 4.6</td><td>17.0 ± 4.8</td><td>-0.1 (-1.3, 1.2)</td><td>317</td><td>42.5 ± 8.3</td><td>42.5 ± 7.4</td><td>-0.2 (-2.1, 1.8)</td></tr><tr><td>Chest circumference (cm)</td><td>297</td><td>32.1 ± 2.8</td><td>31.5 ± 3.2</td><td>0.5 (-0.2, 1.3)</td><td>316</td><td>41.7 ± 2.7</td><td>41.1 ± 2.3</td><td>0.6 (-0.1, 1.3)</td></tr><tr><td>Abdominal circumference (cm)</td><td>297</td><td>32.0 ± 3.3</td><td>31.8 ± 2.7</td><td>0.0 (-0.8, 0.8)</td><td>316</td><td>42.3 ± 3.1</td><td>41.8 ± 2.6</td><td>0.6 (-0.2, 1.3)</td></tr><tr><td>Umbilical circumference (cm)</td><td>295</td><td>30.5 ± 3.4</td><td>30.1 ± 3.4</td><td>0.3 (-0.6, 1.1)</td><td>316</td><td>41.0 ± 3.6</td><td>40.4 ± 3.1</td><td>0.7 (-0.2, 1.6)</td></tr><tr><td>Upper arm length (cm)</td><td>297</td><td>9.9 ± 1.7</td><td>10.0 ± 1.8</td><td>-0.1 (-0.6, 0.3)</td><td>317</td><td>11.5 ± 1.6</td><td>11.6 ± 1.4</td><td>-0.1 (-0.4, 0.3)</td></tr><tr><td>Mid-upper arm circumference (cm)</td><td>297</td><td>10.1 ± 1.6</td><td>10.3 ± 1.6</td><td>-0.2 (-0.6, 0.3)</td><td>317</td><td>13.2 ± 1.6</td><td>13.2 ± 1.5</td><td>-0.0 (-0.4, 0.4)</td></tr><tr><td>Upper thigh length (cm)</td><td>297</td><td>11.2 ± 2.2</td><td>11.2 ± 2.6</td><td>-0.0 (-0.7, 0.6)</td><td>317</td><td>13.6 ± 1.9</td><td>13.7 ± 1.9</td><td>-0.1 (-0.6, 0.4)</td></tr><tr><td>Mid-upper thigh circumference (cm)</td><td>297</td><td>13.7 ± 2.2</td><td>13.6 ± 2.1</td><td>-0.0 (-0.6, 0.5)</td><td>316</td><td>20.2 ± 2.6</td><td>20.6 ± 2.1</td><td>-0.6 (-1.2, 0.1)</td></tr><tr><td>Body composition</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fat mass (%)</td><td>214</td><td>11.0 ± 4.2</td><td>10.8 ± 4.2</td><td>-0.1 (-1.4, 1.3)</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Fat mass (g)</td><td>214</td><td>351.3 ± 166.7</td><td>339.4 ± 157.5</td><td>3.5 (-49.9, 56.9)</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Fat mass index (kg/m²)</td><td>214</td><td>1.4 ± 0.6</td><td>1.3 ± 0.6</td><td>31.1 (-70.0, 132.1)</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Lean mass (g)</td><td>214</td><td>2776.3 ± 347.3</td><td>2713.8 ± 372.7</td><td>0.0 (-0.2, 0.2)</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Lean mass index (kg/m²)</td><td>214</td><td>11.0 ± 1.1</td><td>10.7 ± 1.2</td><td>0.2 (-0.1, 0.6)</td><td>—</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

follow-up was 6593.0 ± 782.4 g. After adjustment for multiple comparisons (q values not shown), adjusted multivariable linear regression models found no statistically significant differences in infant size or body composition for maternal asthma (Table II) or asthma phenotypes (see Tables E2-E15 in the Online Repository at www.jaci-global.org) compared to no maternal asthma at birth (Fig 2) or at postnatal follow-up (Fig 3). Although results were nonsignificant after correction for multiple comparisons, we note that infants of participants with asthma who did not exercise had reduced size at birth compared to infants of participants without asthma (β = -246.8, 95% CI -460.7, -32.9 g). This difference in weight may be attributed to decreased lean (β = -144.2, 95% CI -302.3, 13.9 g) rather than fat (β = -25.8, 95% CI -111.4, 59.8 g) mass.

Interactions between maternal asthma status and infant sex were not statistically significant (data not shown), and we did not observe notable sex-based differences in infant size or body composition (see Table E16 in the Online Repository at www.jaci-global.org). Interactions between maternal asthma status and BMI were not statistically significant (data not shown), although we observed increasingly negative associations between maternal asthma and measures of infant size and body composition with increasing maternal BMI (see Table E17 in the Online Repository). For example, participants with asthma had 23.4 g (95% CI -188.5, 235.3) larger neonates than participants without asthma among participants with a BMI of ≤24.9 kg/m², and

participants with asthma had 110.3 g (95% CI -337.8, 117.2) smaller neonates than participants without asthma among participants with a BMI of ≥30.0 kg/m².

## DISCUSSION

Our study, with prospectively collected data among a diverse population including participants with asthma treated in the context of current clinical guidelines, suggests infant size and body composition were not meaningfully different based on maternal asthma status. Contrary to prior research,¹³ the current study found that neonates of participants with asthma were similar in birth weight to neonates of participants without asthma. We expand on prior studies by additionally examining neonatal adiposity and other anthropometrics, which have been shown to be highly predictive of later health and development.⁴⁹,⁵⁰ To our knowledge, this is the first study to examine whether maternal asthma during pregnancy is associated with offspring adiposity and postnatal size. We also evaluated novel associations between asthma phenotypes and infant outcomes; our results suggest neither asthma nor asthma phenotype substantially influences infant size or body composition.

Maternal asthma has been established as a potential risk factor for low birth weight, fetal growth restriction, and small-for-gestational-age children since the 20th century.¹²,¹³,⁵¹ However, prior studies have typically been retrospective and have focused

<footnote>*Linear regression estimates from models adjusted for maternal age, race and ethnicity, household income, marital status, education, parity, prepregnancy cigarette smoke exposure, prepregnancy body mass index, prepregnancy diabetes, prepregnancy hypertension, infant sex, and study site. Postnatal models were additionally adjusted for infant age at follow-up visit. Reference category for analyses was participants without asthma.</footnote>
<figure><img src="image_5.png" /><figcaption>FIG 2. Adjusted linear regression estimates of infant size and body composition at birth by maternal asthma phenotypes compared to no asthma. Beta and 95% CI values are presented from models adjusted for maternal age, race and ethnicity, household income, education, parity, prepregnancy cigarette smoke exposure, prepregnancy body mass index, prepregnancy diabetes, prepregnancy hypertension, infant sex, and study site. Reference category for analyses was participants without asthma.</figcaption></figure>

on predominantly non-Hispanic White populations treated according to standard practice at the time. Prospective cohorts have generally reported fewer significant differences in birth weight or fetal growth by maternal asthma status,¹⁰,¹³,²²,⁵² suggesting that some of the heterogeneity in the epidemiologic literature with respect to maternal asthma and birth size may be due to differences in study designs.¹³ The current US-based prospective cohort was conducted among a racially diverse population, half of whom were non-Hispanic Black. Non-Hispanic Black Americans bear a disproportionate asthma-related prevalence and mortality burden⁵³ and experience higher rates of low birth weight than non-Hispanic White Americans.⁵⁴ Thus, their inclusion in studies of asthma and infant outcomes is highly warranted. Finally, given recent changes in asthma prevalence and treatment⁵⁵,⁵⁶ and evolving clinical perceptions regarding asthma medication safety during pregnancy,⁴ contemporary studies are needed to understand whether maternal asthma treated according to current clinical guidelines is associated with neonatal and postnatal outcomes.

Maternal chronic diseases have been implicated in the development of offspring chronic diseases through nutritional imprinting, structural changes, and epigenetic programming as part of the developmental origins of health and disease hypothesis.⁵⁷ Although reviews have suggested similar associations may exist for maternal asthma during pregnancy,⁵⁸ there have been few studies with follow-up of infants beyond the neonatal period. Findings from the Danish National Birth Cohort (n = 66,712, 1996-2002) have reported heightened incidence of diagnostic codes for “endocrine, metabolic, and nutritional disorders” in 4145 children ~6 years of age born to participants with asthma, although they did not examine specific conditions (eg, obesity) in the children, which makes comparisons to the current study challenging.²⁴,²⁵ Nevertheless, our results do not suggest statistical or clinically significant differences in infant size at the postnatal visit by maternal asthma or asthma phenotype. Given the discrepancies between our findings and these suggestions from the earlier literature, further prospective studies as well as follow-up beyond the postnatal period is warranted.
<figure><img src="image_6.png" /><figcaption>FIG 3. Adjusted linear regression estimates of infant size at postnatal follow-up by maternal asthma phenotypes compared to no asthma. Beta and 95% CI values are presented from models adjusted for maternal age, race and ethnicity, household income, marital status, education, parity, prepregnancy cigarette smoke exposure, prepregnancy body mass index, prepregnancy diabetes, prepregnancy hypertension, infant sex, study site, and infant age at follow-up. Reference category for analyses was participants without asthma.</figcaption></figure>

Asthma—particularly poorly controlled, exacerbated, or severe asthma—has long been hypothesized to contribute to reduced infant size and body composition through pathways involving maternal hypoxia.²¹,²³ The link between maternal hypoxia and infant size and body composition is supported by animal models,²¹,⁵⁹ and a Mendelian randomization study reported inverse associations between maternal lung capacity and birth weight.¹⁵ The latter study examined and did not find clear associations between maternal asthma status and birth weight, suggesting that asthma alone (ie, in the absence of maternal hypoxia) may be insufficient to induce fetal growth restriction. Despite almost half of B-WELL-Mom participants with asthma reporting poor asthma control on the Asthma Control Test in the first trimester and 40% experiencing worsening gestational asthma control according to symptomology, most had mild and nonexacerbated asthma. Asthma control is distinct from severity and exacerbations, which may be more likely to induce hypoxia and influence fetal growth.⁶⁰ This dichotomy of poorly controlled but less severe and nonexacerbated asthma in our study may have contributed to the lack of significant findings. It may also represent a more realistic exposure scenario, as 70% of asthma cases are of a mild form.⁶¹ These patients with mild asthma tend to demonstrate suboptimal control with less frequent exacerbations.⁶¹ Similarly, asthma atopy, onset, and exercise had no notable associations with infant size or body composition. We observe some potential associations for the “don’t exercise” group, which may be due to uncontrolled confounding. For example, those who selected “don’t exercise” may exhibit other health conditions or have an unsafe environment in which to exercise, which may be associated with infant outcomes. Metabolic factors (eg, gestational weight gain, gestational diabetes) may also play roles along the causal pathway between maternal asthma and infant size and body composition.⁴⁷,⁶²,⁶³ In secondary analyses, we examined whether associations between maternal asthma status and infant outcomes differed by prepregnancy BMI. Although none of these associations was statistically significant, the association between maternal asthma and neonatal size was generally

positive in participants with a BMI of ≤24.9 kg/m² and became increasingly negative with increasing BMI category. Our prior work⁶⁴ showed that the obese asthma phenotype appears to contribute to a restrictive pattern on spirometry and more frequent asthma symptoms and emergency department/urgent care visits. Thus, effects of maternal asthma may have been most pronounced in this group; these novel results merit further study. Finally, asthma during pregnancy has been found to result in sex-specific placental dysfunction,⁴⁵ reduced fetal growth,³¹ and differential gut microbiota,⁶⁵ which could mediate associations of maternal asthma with offspring size and body composition. Although prior studies have suggested female infants are disproportionately affected by maternal asthma status, we did not observe sex-specific differences in infant outcomes in the current study.

Our findings must be considered within the context of study limitations and strengths. While prepregnancy weight was missing for 18.4% of participants, self-reported prepregnancy weights were highly correlated with measured baseline weights (n = 343, *r* = 0.98) as well as chart-abstracted prepregnancy weights (n = 118, *r* = 0.94) for our cohort. Thus, a missing-data imputation for prepregnancy BMI enabled us to produce unbiased and efficient estimates for our associations of interest.⁶⁶ Findings did not differ when complete case analyses were conducted (data not shown). This study possessed a relatively small sample size, especially for some phenotypes, which may have hindered detection of small differences. However, we noted no clinically meaningful differences in infant size or body composition by maternal asthma or asthma phenotype. For example, all adjusted differences (β) in percentage fat mass were <1%. Models were adjusted for many potential factors, including maternal sociodemographics, health, and behavioral factors. This may have resulted in overadjustment. However, unadjusted results did not meaningfully differ (data not shown). Participants were treated according to standard clinical practice and were receiving medication regimens appropriate for their given asthma severity level. However, half of participants with asthma reported poorly
controlled asthma at enrollment, suggesting that participants may have needed higher medication regimens to control their asthma or that current medications may not have been received appropriately (ie, faulty administration or adherence).⁶⁷ Ultimately, it is impossible to completely parse the complicated interrelationships among asthma severity, medication use, and control in this or other observational studies. Despite these limitations, the current study included comprehensive, prospective data collection across pregnancy from a racially diverse cohort, which allowed us to address novel questions related to the association between maternal asthma and infant size and body composition.

In conclusion, in our contemporary, prospective pregnancy cohort of pregnant persons with and without asthma, including detailed information on phenotypes, we observed no differences in offspring adiposity and size by maternal asthma or asthma phenotype. With obstetric care delivered in the context of current clinical guidelines, our results suggest that a maternal diagnosis of asthma does not confer increased risk for adverse infant size or body composition.

## DISCLOSURE STATEMENT

Supported by the National Institutes of Health's Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (clinical site contracts HHSN275201300013C to Northwestern University, HHSN275201300014C to the University of Alabama at Birmingham; and the Emmes Company for the Data Coordinating Center HHSN275201300026I, HHSN27500001, HHSN275000017) and in part by the National Institute of Environmental Health Sciences. Funding sources were not involved in the study design, collection, analysis, and interpretation of the data, or in the writing and decision to submit the report for publication.

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

### Key messages

* In a contemporary prospective cohort of 418 pregnant persons with and without asthma, no differences were observed in infant size and body composition by maternal asthma status.

* Compared to no asthma, maternal asthma treated according to current clinical guidelines was not associated with differential infant size or body composition.

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