Adverse Pregnancy Outcomes and Future Maternal COPD Risk

Technical Summary: Adverse Pregnancy Outcomes and Future Maternal COPD Risk

Problem Statement
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of global mortality, with a rising prevalence and mortality rate among women that often surpasses that of men. Despite this, sex-specific risk factors for COPD remain poorly understood. While smoking is a primary driver, many women with COPD are never-smokers, suggesting other biological and environmental determinants. Previous research has established that Adverse Pregnancy Outcomes (APOs)—including hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM), preterm delivery, and abnormal fetal growth—are strong predictors of future maternal cardiovascular disease. Given the shared biological pathways between cardiovascular disease and COPD (such as systemic inflammation and oxidative stress), the authors hypothesized that APOs might also serve as early indicators of long-term respiratory vulnerability, specifically the risk of developing incident COPD later in life. Prior to this study, the relationship between APOs and future COPD risk had not been systematically investigated in a large national cohort.

Methodology
This study is a secondary analysis of the Women's Health Initiative Observational Study (WHI-OS).

• Cohort: The analysis included 25,541 postmenopausal women aged 50–79 years, enrolled between 1993 and 1998, and followed through 2024. Participants were required to have a history of at least one pregnancy and no prior diagnosis of COPD at enrollment.
• Exposure Assessment: Data on APOs were collected retrospectively in 2017 via a follow-up questionnaire. APOs were defined as a history of:
  • Hypertensive disorders of pregnancy (HDP: gestational hypertension and/or pre-eclampsia).
  • Gestational diabetes (GDM).
  • Large for gestational age (LGA) infant (birth weight >9 lb 14 oz).
  • Small for gestational age (SGA) infant (birth weight <5.5 lbs).
  • Preterm delivery (born at least 3 weeks early).
  • The study also analyzed the cumulative effect of having two or more different types of APOs.
• Outcome Assessment: The primary outcome was incident self-reported COPD (emphysema or chronic bronchitis). Participants were queried annually for the first 8 years and from 2010 onward. Incident COPD was defined as a positive response to the COPD question in follow-up questionnaires but a negative response at baseline.
• Statistical Analysis: The authors employed adjusted cause-specific proportional hazard models to evaluate associations between APOs and incident COPD. Models were adjusted for age, smoking history (pack-years and secondhand smoke), asthma history, race/ethnicity, education, income, geographic region, personal history of prematurity/low birth weight, and parity. To handle missing data, multiple imputation (20 datasets) was used. Interval censoring was applied to account for the unknown exact timing of COPD onset between follow-up intervals.

Key Results

• Prevalence: Among the 25,541 participants, 7,226 (28.3%) reported at least one APO. Preterm delivery was the most common APO (50.6% of those with APOs), followed by SGA (42.5%) and HDP (21.8%). Over the follow-up period, 4,205 women (16.5%) reported incident COPD.
• Primary Association: A history of any APO was significantly associated with an increased risk of future COPD. The adjusted hazard ratio (aHR) was 1.15 (95% CI 1.07–1.22).
• Specific APOs: Independent associations were found for specific APOs:
  • HDP: aHR 1.27 (95% CI 1.13–1.42).
  • SGA: aHR 1.11 (95% CI 1.02–1.21).
  • Preterm delivery: aHR 1.11 (95% CI 1.02–1.21).
  • No significant independent associations were found for GDM or LGA infants.
• Cumulative Effect: Women with two or more different types of APOs had a significantly elevated risk of incident COPD (aHR 1.12, 95% CI 1.02–1.23).
• Stratification and Interaction: The association between APOs and COPD was generally significant only after 10 years of follow-up. Interaction analyses showed that the association did not significantly differ by lactation status, race, ethnicity, or smoking pack-years.

Significance and Claims
The authors claim this is the first national cohort study to link APOs with higher maternal COPD risk. The study suggests that abnormal pregnancy may serve as an early indicator of long-term respiratory vulnerability, potentially acting as a "stress test" for future pulmonary health similar to its established role in predicting cardiovascular disease.

The findings imply that the biological mechanisms underlying APOs—such as systemic inflammation, immune dysregulation, and oxidative stress—may persist postpartum and contribute to the development of COPD decades later. The authors posit that integrating obstetric history into pulmonary risk assessments could facilitate the earlier identification of women at risk for COPD, particularly those who are never-smokers or have other risk factors.

Limitations Noted
The paper acknowledges several limitations, including the reliance on self-reported data for both APOs and COPD (introducing potential recall bias and misclassification), the retrospective collection of obstetric history long after the events occurred, the lack of spirometry confirmation for COPD diagnoses, and the predominantly White composition of the cohort, which may limit generalizability to more diverse populations. The authors also note the possibility of residual confounding regarding environmental exposures and socioeconomic status.