New research links parents’ metabolic health and a child’s birth weight to asthma severity, uncovering for the first time how paternal cholesterol may offer modest protection.
Study: Impact of natal and childhood metabolic markers on childhood asthma burden – a nationwide cohort study. Image credit: LightField Studios/Shutterstock.com
Childhood obesity is increasing worldwide, affecting more than 15% of American children. A rising risk of asthma has accompanied this. The role of parental metabolic abnormalities and obesity in the incidence of asthma in the offspring formed the focus of a recent study in Respiratory Research.
Introduction
Obesity is associated with chronic inflammation and multiple metabolic abnormalities in glucose and lipid pathways. Abdominal obesity predisposes to elevated blood cholesterol and insulin resistance. As a result, such individuals are at higher risk for cardiovascular disease, diabetes, and asthma.
About 17% of American adolescents, and 16% of children, are obese. These rates have tripled in Black and Hispanic children over the last forty years or so. Such trends are mirrored in Europe as well.
Unlike most asthma cases worldwide, the unique asthma phenotype found in most obesity-associated asthma patients reflects an inflammatory rather than allergic asthma. Obesity-related asthma in children reflects inflammatory cell activation with lipid and glucose homeostasis dysregulation. The mechanisms responsible for these associations remain poorly explained, providing one motivation for the current study.
Maternal pre-pregnancy obesity and pregnancy weight gain are linked to elevated blood lipids (total cholesterol, low-density lipoprotein (LDL or ‘bad’ cholesterol), and triglycerides). Additionally, their offspring are more prone to childhood obesity and respiratory illness, including new-onset wheezing and respiratory infection.
However, the association of paternal body weight and metabolic abnormalities with respiratory illness in the offspring remains unclear. The current study explored associations of parental obesity and metabolic markers with dyslipidemia and asthma in their offspring. It also examined whether birth weight itself, particularly being underweight for gestational age, was associated with asthma outcomes and assessed whether findings could generalize beyond children receiving inhaled corticosteroids (ICS).
About the study
The study included 29,851 children from the nationwide Danish REASSESS Youth cohort, including children 2 to 17 years old (mean age 9 years). Of these, approximately 8,500 had asthma. While 1,430 children (5%) had severe asthma, 4,750 (16%) had poor asthma control, and 2,353 (8%) had asthma with episodes of increasing severity. Because the cohort consisted only of children prescribed ICS, the findings primarily reflect children with persistent, more burdensome asthma rather than all pediatric asthma cases. They may not apply to those with milder or intermittent asthma.
Study findings
Lipid and glucose markers in children
Total cholesterol and LDL were elevated in 10% and 11% of approximately 2,000 children with lipid marker measurements, respectively. High-density lipoprotein (HDL, or ‘good’ cholesterol) was reduced in 15% of the cohort population, and approximately 14% showed elevated triglycerides. Hemoglobin A1c (HbA1c) elevation occurred in 1.7% of approximately 5,500 children. However, elevated HbA1c was not an independent predictor of asthma severity, control, or exacerbations.
Metabolic markers and asthma in children
In children, high LDL and triglycerides increased the odds of severe asthma and exacerbating asthma by 2.3-fold and 1.5-fold, respectively. Low HDL was linked to 1.5-fold higher odds of both uncontrolled and exacerbating asthma. In addition, children born underweight for gestational age (weight-for-gestational-age-z-score ≤ -2) had 1.44-fold higher odds of uncontrolled asthma.
Parental obesity and metabolic markers
The mean body mass index (BMI) before pregnancy began was 23.5 kg/m2, with almost 40% of mothers being overweight or obese. About 4% of mothers with HbA1c measurements had higher values than 8% of fathers.
Total and LDL cholesterol were each elevated in 30% of mothers, and triglycerides in roughly 20%. Among fathers, more than 40% each had high total cholesterol, LDL, and triglycerides. HDL was reduced in 18% and 24% of mothers and fathers, respectively.
Parental markers and asthma in children
Children born to mothers with elevated total cholesterol, LDL, and triglycerides were at higher risk for uncontrolled asthma. Increases in HbA1c were also linked to uncontrolled asthma. While associated with uncontrolled asthma (OR 1.16), maternal total cholesterol was paradoxically protective for severe asthma (OR 0.83).
Pre-pregnancy obesity and markers of metabolic dysregulation in the mother predicted 1.2 to 1.4-fold higher odds of uncontrolled asthma in the child. Maternal pre-pregnancy overweight and obesity themselves, independent of these metabolic markers, were also linked to a higher risk of poor asthma control in the offspring.
A higher HbA1c in fathers increased the odds of exacerbating asthma in the offspring, while reduced HDL predicted uncontrolled asthma. Higher total and LDL cholesterol was protective against exacerbating asthma. In contrast, higher paternal total cholesterol (OR 0.96) and LDL cholesterol (OR 0.86) were modestly protective against exacerbating asthma.
Comparison with former studies
The findings of the current study are not completely concordant with prior studies, some of which showed increased asthma risk in obese children. Other research indicates that by adolescence, children with either low birth weight or consistently high BMI were prone to asthma. Again, some reports suggest that low-birth-weight children are more likely to have later-onset asthma compared to babies born large.
Perhaps this is because lighter babies tend to gain weight over time or do not develop large lungs in early life. Alternatively, they could suffer from a poor maternal diet, limited energy transfer through the placenta, or adverse environmental exposures in pregnancy.
Similarly, conflicting findings were obtained in meta-analyses of lipid markers and asthma studies in children. The consensus is that dyslipidemia is associated with asthma in children. The current study adds evidence that the different components of blood cholesterol predispose to the clinical features of asthma in various ways, with some components, such as paternal LDL, potentially protective in specific outcomes.
Maternal obesity predicts poorly controlled asthma in the current study, agreeing with earlier studies but not atopic conditions. This further confirms the non-allergic origin of asthma in obesity. Potential explanations include gut dysbiosis, altered glucose metabolism, and dietary differences in obese mothers compared to those with normal weight.
Conclusion
Parental or childhood dyslipidemia was a risk factor for asthma in this Danish cohort of children with persistent asthma. It suggests that dysregulated fat metabolism has a transgenerational impact that drives asthma through various mechanisms beyond the direct effects of parental body weight. However, this was a cross-sectional, registry-based analysis with no control group, and data were collected only from children already receiving ICS for persistent asthma. The findings reflect associations rather than proven causal relationships and may not be generalized to all pediatric asthma cases.
For the first time, this study shows that markers of altered paternal metabolism are associated with asthma outcomes in children. Further research is required to frame interventions to prevent asthma in the offspring.
The role of genetic or epigenetic markers in driving inflammatory and metabolic changes in obesity-related asthma remains to be explained.
“The link between maternal weight, gestational weight gain, weight for gestational age and asthma risk also warrant further investigation in order to recommend possible lifestyle interventions prior to or at onset of pregnancy to the mother and early life of the child that may improve respiratory outcomes throughout childhood."
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