Female reproductive factors were associated with risk of chronic obstructive pulmonary disease (COPD), including age at menarche, number of children, miscarriage, stillbirth, and age at natural menopause, according to an analysis of three cohorts.

Among nearly 300,000 women, a U-shaped association was observed between age at menarche and COPD (≤11 vs 13 years: HR 1.17, 95% CI 1.11-1.23; ≥16 vs 13 years: HR 1.24, 95% CI 1.21-1.27), reported Gita Mishra, PhD, of the University of Queensland in Brisbane, Australia, and co-authors in Thorax.

“Estrogen might influence the development of COPD in a complex way,” the group wrote. “In infancy and childhood, estrogen accelerates lung maturation and termination of lung growth. Girls with early menarche might experience insufficient lung growth in early life, lower lung function, and greater predisposition to COPD in later life.”

Other factors linked to risk of COPD included giving birth to three or more children compared with two (HR 1.14, 95% CI 1.12-1.17), and giving birth to four or more kids versus two (HR 1.34, 95% CI 1.28-1.40), in addition to experiencing multiple miscarriages (two vs zero: HR 1.28, 95% CI 1.24-1.32; three or more vs zero: HR 1.36, 95% CI 1.30-1.43), and experiencing stillbirth once (HR 1.38, 95% CI 1.25-1.53) or two or more times (HR 1.67, 95% CI 1.32-2.10) compared with never.

An association was also observed with age at natural menopause, with earlier ages linked to risk of COPD compared with older ages (<40 years vs 50-51: HR 1.69, 95% CI 1.63-1.75; ages 40-44 vs 50-51: HR 1.42, 95% CI 1.38-1.47).

Mishra and team pointed to the link between sex hormones and lung development, as well as lung diseases.

“Estrogen and progesterone are involved in formation and maintenance of a full complement of alveoli,” they wrote. “Female sex hormones may influence the development of COPD through the properties of modulating bronchodilation, inflammation, proliferation, and cigarette smoke metabolism.”

They noted that COPD and asthma have similar symptoms and inflammatory mechanisms. “Worsening asthma symptoms have been associated with estrogen changes through several female reproductive stages (e.g., menarche, pregnancy, and menopause),” they noted. “Similarly, in this study, the risk of COPD was associated with multiple female reproductive factors, indicating the role of estrogen changes in COPD development.”

Mishra explained that a key reason for this research was the already-documented gender disparities seen in COPD diagnosis rates, leading to the exploration of female sex hormones as a possible contributing factor.

“For the same amount of tobacco exposure, women are more likely to demonstrate severe airflow limitation at an earlier age compared with men,” she explained on the Thorax podcast. “The other thing also, which was interesting, is that if you look at non-smokers with COPD, they’re more likely to be women than men.”

Since the data are observational, some of the factors described, such as miscarriages, could instead be markers for COPD, rather than directly related, Mishra noted.

“What I always tell people is, ‘look, [the] COPD the we looked at happened a lot later in life. Miscarriages, experiencing stillbirth, menarche, and so forth, happens to us when we are much younger,'” she said. “We have plenty of time, hopefully, to be able to do something about it, whether it is being monitored carefully, talking to your GP [general practitioner] … So I do think that it’s important … for clinicians to collect female reproductive history just because it can tell us something about her health down the track.”

The researchers included participants from three cohorts — the Australian Longitudinal Study on Women’s Health 1946-1951 cohort, the U.K. Biobank, and the Swedish Women’s Lifestyle and Health Study — with data on reproductive factors and COPD.

A total of 283,070 women were included in the study analysis (mean age 54, 95.4% white), 3.8% of whom developed COPD over a median follow-up of 11 years. COPD patients were more likely to be older, and have 10 years or less of education, a 10 or more pack-year history of smoking, asthma, and a body mass index of 30 or higher.

Mishra and team explained that volunteer bias may have been introduced into the study, as patients who might be in poorer health may be less likely to participate in the study. Study patients also had a higher socioeconomic status and healthier lifestyle when compared with the general population, which could limit the study’s findings.

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