Educational Aims
The reader will come to appreciate:
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The association between maternal asthma and neonatal, childhood, and adulthood respiratory morbidities.
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How respiratory outcomes associated with maternal asthma may differ with offspring sex.
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Potential mechanisms underlying how maternal asthma alters in utero fetal lung development.
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Interventions that may improve the respiratory health of offspring of asthmatic mothers.
Highlights
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The association between maternal asthma and neonatal, childhood, and adulthood respiratory morbidities.
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How respiratory outcomes associated with maternal asthma may differ with offspring sex.
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Potential mechanisms underlying how maternal asthma alters in utero fetal lung development.
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Interventions that may improve the respiratory health of offspring of asthmatic mothers.
Abstract
Maternal asthma affects up to 17% of pregnancies and is associated with adverse infant, childhood, and adult respiratory outcomes, including increased risks of neonatal respiratory distress syndrome, childhood wheeze and asthma. In addition to genetics, these poor outcomes are likely due to the mediating influence of maternal asthma on the in-utero environment, altering fetal lung and immune development and predisposing the offspring to later lung disease. Maternal asthma may impair glucocorticoid signalling in the fetus, a process critical for lung maturation, and increase fetal exposure to proinflammatory cytokines. Therefore, interventions to control maternal asthma, increase glucocorticoid signalling in the fetal lung, or Vitamin A, C, and D supplementation to improve alveologenesis and surfactant production may be beneficial for later lung function. This review highlights potential mechanisms underlying maternal asthma and offspring respiratory morbidities and describes how pregnancy interventions can promote optimal fetal lung development in babies of asthmatic mothers.
Introduction
Asthma affects up to 17 % of pregnancies worldwide . In addition to increased risks of pregnancy complications , maternal asthma in pregnancy increases the risk of neonatal respiratory morbidities including transient tachypnoea of the newborn (TTN), respiratory distress syndrome (RDS), and reduced lung function at 5–6 weeks ( Table 1 ) . These adverse impacts persist, with children of asthmatic mothers more likely to have asthma, wheeze, pneumonia, upper respiratory tract infection, and general respiratory morbidities . Further, maternal asthma is associated with poor lung function and asthma in adulthood . Therefore, prenatal preventative interventions to improve lung health are urgently required for babies of asthmatic mothers to prevent lifetime impacts on respiratory health .
| Study ID; country | Study design; number of participants | Definition of maternal asthma | Timing of maternal asthma diagnosis | Findings in offspring of asthmatic mothers (ref: controls) |
|---|---|---|---|---|
| Neonatal outcomes | ||||
| de Gouveia Belinelo et al 2021; Switzerland and Australia | Two large birth cohorts combined: n = 619 (n = 426 born to asthmatic mothers) | Both cohorts: Self-reported, doctor-diagnosed asthma. Breathing for Life Trial cohort: current asthma symptoms or inhaled asthma medication use | Breathing for life trial: asthma in current pregnancy Bern Infant Lung Development cohort: asthma in last 12 months | In male infants, poor infant lung function (Estimate −3.48 95 % CI −6.81 to −0.11) measured by time to reach peak expiratory flow as a percentage of total expiratory time (%) |
| Hodyl et al 2014; Australia | Retrospective cohort study; n = 172305 (n = 11512 born to asthmatic mothers) | Asthma medication to prevent or treat asthma or had symptoms of asthma during the current pregnancy | Asthma in current pregnancy | Resuscitation at birth (aOR 0.99 95 % CI 0.81–1.20) |
| Mendola et al 2014; USA | Retrospective cohort study; n = 223512 (n = 17044 born to asthmatic mothers) | ICD-9 code for asthma in maternal electronic medical record | Asthma ever | Respiratory distress syndrome (aOR 1.09 95 % CI 1.01–1.19)Transient tachypnoea of the newborn (aOR 1.10 95 % CI 1.02–1.19)Asphyxia (aOR 1.34 95 % CI 1.03–1.75) Resuscitation at birth (aOR 1.02 95 % CI 0.91–1.14)Apnoea (aOR 1.02 95 % CI 0.92–1.13) |
| Murphy et al 2013; N/A | Systematic review and meta -analysis; 21 included studies | Physician-diagnosed (whether confirmed or subject self-report), database-coded asthmadiagnosis, or asthma fulfilling American Thoracic Society criteria | Unspecified | Respiratory distress syndrome (2 studies, RR 1.57, 95 % CI 0.88–2.81) Transient tachypnoea of the newborn (2 studies, RR 1.54, 95 % CI 1.09–2.18) |
| Long term outcomes | ||||
| Berry et al 2016; USA | Birth cohort study; n = 589 (n = 64 born to asthmatic mothers) | Questionnaire at the time of enrolment | Asthma ever | Poor lung function trajectory, 11–32 years (offspring of asthmatic mothers: 20.0 % low trajectory vs. 9.9 % normal; (p = 0.02) measured by ratio of forced expiratory volume in 1 min to forced vital capacity (FEV 1 /FVC) |
| Crump 2011; Sweden | National cohort study; n = 622616 (n = 47818 born to asthmatic mothers) | Prescription of asthma medications (β-2 agonist inhalants, glucocorticoid inhalants, or combination inhalants containing a β −2 agonist and other drugs for obstructive airway diseases) | Asthma medication purchases when offspring are 25.5–35 years old | Purchase asthma medication, 25–35 years old (aOR 0.99 95 % CI 0.94–1.04) |
| Damgaard 2015; Denmark | National cohort study; n = 1790241 (n = 69456 born to asthmatic mothers) | Either a combination of at least one purchase of inhaled selective β-2 receptor agonist (R03AC) AND at least two purchases of one of the following other drugs for obstructive airway disease: inhaled glucocorticoids (R03BA), inhaled anticholinergics (R03BB), theophyllines (R03DA), oral leukotriene-receptor antagonists (R03DC), systemic steroid (H02AB), a combination inhaler (R03AK)—or at least two purchases of a combination inhaler containing a long-acting β-2 receptor agonist and either glucocorticoids or anticholinergics (R03AK) | Asthma medication purchases when offspring are 0–31 years old | Purchase asthma medication, 0–2 years old (aOR 2.14 95 % CI 1.86–2.47), 3–5 years (aOR 2.92 95 % CI 2.69–3.17), 6–11 years (aOR 3.23 95 % CI 3.02–3.46), 12–17 years (aOR 2.83 95 % CI 2.65–3.02), 18–24 years (aOR 2.40 95 % CI 2.23–2.57), 25–31 years (aOR 2.22 95 % CI 2.06–2.39) |
| Lim et al 2010; N/A | Meta-analysis; 33 included studies | Self-reported physician diagnosed asthma, self-reported asthma, self-reported recurrent/persistent wheeze, and self-reported recurrent asthma symptoms (or a combination of these), physician diagnosed asthma or asthma symptoms | Asthma in current pregnancy (n = 4), asthma ever (n = 29) | Adult asthma (4 studies, OR 5.33 95 % CI 2.51–11.3) |
| Pennington et al 2018; USA | Retrospective birth cohort; n = 17075 (n = 2075 born to asthmatic mothers) | One or more diagnosis of asthma (ICD-9 code 493.XX). | Asthma ever | Childhood asthma in males, 5 years (risk difference 13.4 % 95 % CI 8.6–18.2) Childhood asthma in females, 5 years (risk difference 14.0 % 95 % CI 9.1–18.8) |
| Roff et al 2023; N/A | Systematic review and meta -analysis; 120 studies | Diagnosed by a physician or using clinically-accepted criteria | Asthma in current pregnancy (n = 22), asthma ever (n = 98) | Childhood asthma by maternal asthma ever (61 studies, RR 1.75, 95 % CI 1.55–1.97) Childhood asthma by maternal asthma during the pregnancy with that child (13 studies; RR 1.73; 95 % CI 1.54–1.93) Childhood asthma by moderate-severe maternal asthma during the pregnancy with that child (ref: mild asthma, 5 studies; RR 1.23; 95 % CI 1.12–1.35) Childhood asthma by uncontrolled maternal asthma during the pregnancy with that child (ref: controlled asthma, 4 studies; RR 1.15; 95 % CI 1.07–1.23) |
| Spiegel et al 2018; Israel | Population based cohort study; n = 253808 (n = 3411 born to asthmatic mothers) | Bronchial asthma as defined in hospital database using ICD-9 codes | Unspecified; asthma in prenatal records | General respiratory morbidities (aOR 1.6 95 % CI 1.4–1.9)Childhood asthma (aOR 2.5 95 % CI 1.9–3.1) |
| Tse 2016; USA | Prebirth cohort study; n = 1623 (n = 219 born to asthmatic mothers) | Maternal reports at enrolment in the study or at the child’s birth | Asthma ever | Wheeze in male offspring (aOR 2.15, 95 % CI 1.74–2.66) Wheeze in female offspring (aOR 1.53, 95 % CI 1.19–1.9) |
| Venter et al 2021; USA | Longitudinal birth cohort; n = 1261 (n = 107 born to asthmatic mothers) | Maternal history of asthma was considered present if pregnant women answered “yes” to the question, “Has a health professional such as a doctor, physician assistant, or nurse practitioner ever told you that you have asthma?” | Asthma ever | Childhood asthma diagnosis (aHR 1.79 95 % CI 1.25–2.57) Child wheeze (aHR 1.67 95 % CI 1.20–2.31) |
Some of the effects of maternal asthma on child health are due to in utero exposure to maternal asthma and are not explained solely by genetic associations. For instance, maternal asthma is a stronger predictor for childhood asthma than paternal asthma ( Table 1 ) . Preclinical studies provide direct evidence for an environmental effect of in utero exposure to maternal asthma, as experimental maternal asthma increases allergic responses to allergen challenges in progeny . Lower risk of childhood asthma when maternal asthma is better controlled in pregnancy, further supports this hypothesis .
While the mechanisms underlying these associations are unclear, emerging preclinical evidence suggests altered fetal lung and immune development are significant contributors . In an ovine model of maternal asthma, lambs born to asthmatic ewes had immature lungs compared to lambs of non-asthmatic control ewes . In mice, asthmatic offspring of asthmatic mothers have a moderate-severe asthma phenotype compared to a milder phenotype in asthmatic offspring of control mothers . Greater understanding of how maternal asthma modifies in utero lung development will inform future interventions and therapies to improve postnatal respiratory health and prevent childhood asthma. This narrative review explores the impact of maternal asthma on newborn and child respiratory outcomes, and the underlying mechanisms, focusing on fetal lung and immune development and potential interventions to improve short- and longer-term respiratory outcomes.
Maternal asthma in pregnancy and offspring respiratory outcomes
Neonatal outcomes
The impact of maternal asthma on newborn respiratory health is observable immediately after delivery ( Table 1 ), suggesting impaired lung maturation. Maternal asthma increases the risk of TTN, RDS, and asphyxia ( Table 1 ) . TTN is caused by retained alveolar lung liquid postnatally, reflecting both immature lung fluid clearance and surfactant insufficiency while RDS is a result of surfactant deficiency related to pulmonary immaturity . TTN and RDS are common complications of prematurity, but in pregnancies complicated by asthma the risk of both is higher in term and preterm infants . Since respiratory morbidities account for 28.8 % of late preterm and 15.6 % of term neonatal intensive care unit (NICU) admissions , understanding the mechanisms underlying increased respiratory morbidity in offspring exposed to maternal asthma is crucial.
Not all studies indicate the same respiratory impact of maternal asthma on neonatal respiratory outcomes, which may be due to variable definitions and timing of maternal asthma ( Table 1 ). Both retrospective and prospective cohort studies report no difference in rates of resuscitation at birth , apnoea , or overall respiratory difficulties between babies of non-asthmatic and asthmatic mothers . A systematic review and meta -analysis found an association between maternal asthma and TTN but not RDS ( Table 1 ) , although the sample sizes for TTN and RDS were small (n = 2033 and n = 2225 mothers with asthma respectively) , while a later, larger study (n = 17044 mothers with asthma), reported increased risks of both . This may suggest that maternal asthma alters in utero lung development through pathways specific to TTN and RDS pathologies, rather than more generalised lung immaturity.
The above associations may also be sex-specific, but the data is limited. At 5–6 weeks, male sex alone was not predictive of poor lung function but male sex and maternal asthma combined was associated with poorer lung function . This may partly reflect greater susceptibility to environmental challenges and poorer baseline respiratory function . Compared to females, males have greater risk of requiring respiratory support, TTN, RDS and bronchopulmonary dysplasia, and lower peripheral oxygen saturation, culminating in a “male disadvantage” . These morbidities have long-term impacts; newborns with poor lung function more likely to have childhood asthma . With male sex and maternal asthma individually increasing the risk of poor respiratory health at birth and beyond, and the additive effect potentially worse, sex-specific effects of maternal asthma on the fetal lung warrant further investigation.
Confounding between maternal asthma and other maternal and neonatal factors makes it impossible to assess the extent to which respiratory outcomes are caused by asthma alone. Fetal growth restriction, small for gestational age, neonatal intensive care unit (NICU) admission, sepsis, and congenital abnormalities are all more common in infants of asthmatic mothers increasing the risks of pulmonary morbidity . While analyses controlling for some prenatal and pregnancy factors still demonstrate a maternal asthma effect , many factors are not adjusted for.
Childhood outcomes
Maternal asthma is also associated with increased risk of later childhood respiratory morbidities ( Table 1 ) including wheeze, asthma, and general respiratory morbidities . In a systematic review by our group, maternal asthma was associated with greater risks of childhood wheeze and asthma, regardless of whether the maternal asthma diagnosis was specific to the pregnancy . Amongst those with asthma in pregnancy, asthma risk in their children was higher with moderate-severe compared to mild asthma and when asthma was uncontrolled . However, genetics may confound the latter with more severe asthma before pregnancy associated with greater loss of control or asthma exacerbations during pregnancy .
Few studies have reported sex-specific childhood outcomes in the presence of maternal asthma. In a prospective US cohort of ∼1600 births, maternal asthma was predictive of wheeze in both sexes at 1–9 years old, with paternal asthma more predictive of childhood wheeze in male offspring ( Table 1 ) . In a retrospective US cohort of ∼17000 births, maternal asthma was associated with childhood asthma at age 5 in both sexes when analysed separately ( Table 1 ) , while male sex is associated with both neonatal respiratory morbidities and asthma in preschool age children .
The associations between longer-term outcomes and maternal asthma can be confounded by other respiratory diseases, since impaired lung development may both cause and be caused by asthma . Children of asthmatic mothers have an increased risk of respiratory infections, a risk factor for childhood asthma , with a higher prevalence of upper respiratory tract infection and pneumonia compared to children of non-asthmatic mothers ( Table 1 ) . Further, the risk of asthma after 5 years of age is associated with both current maternal asthma ( Table 1 ) and infant respiratory infections (aHR 1.51 95 % CI 1.47–1.54) .
Long term outcomes
Respiratory outcomes associated with maternal asthma extend into adulthood. In a meta -analysis of four studies, adult asthma was more likely when the mother had asthma ( Table 1 ) . Maternal asthma is also associated with a persistently low lung function trajectory in offspring between 11 and 32 years of age . Retrospective studies, however, report conflicting results. Offspring of mothers purchasing asthma medication during the period after delivery when offspring outcomes were assessed (offspring 0–31 years of age, Table 1 ) were more likely to have asthma medication themselves from childhood into adulthood . Conversely, offspring of mothers with an asthma medication prescription during the period after delivery when offspring outcomes were assessed (offspring age 25.5–35 years, Table 1 ) were reported to be no more likely to have an asthma medication prescription themselves, compared to controls ( Table 1 ) . This disparity may reflect limitations in the inability to determine whether the fetus was exposed to maternal asthma in utero using retrospective data linkage approaches. Further long-term follow-up studies exploring the impact of maternal asthma in progeny, including sex-specific analyses, are warranted.
Maternal asthma and the fetal lung: mechanisms
To address confounders and variability in human studies of maternal asthma and progeny health , combining preclinical and clinical findings on asthma in pregnancy may provide critical insights into the immune, genetic, epigenetic, and endocrine mechanisms linking maternal asthma and altered fetal lung development and function ( Fig. 1 ).
