The Division of Lung Diseases (DLD) at the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) hosted a two-day virtual workshop titled “Maternal and Perinatal Nutritional Programming of Lung Health in Childhood and Early Adulthood: Research Gaps and Opportunities” on October 24-25, 2024. Attendees included basic scientists, maternal-fetal medicine (MFM) experts, neonatologists, pulmonologists, nutrition experts, nurses, implementation scientists, and other multidisciplinary researchers. Presenters discussed the role of maternal and perinatal nutrition on lung health across the lifespan to identify critical research gaps, challenges, and opportunities to promote health, as well as disease prevention and management.

Workshop Objectives

• Examine the impact of maternal nutrition, dietary and sleep patterns, and infant nutrition and feeding schedules on lung development, including the fetal and postnatal lung clock, especially in preterm infants.
• Assess circadian signals in human milk and their impact on lung development and predisposition to childhood and adult chronic lung disease.
• Discuss the influence and timing of maternal and infant diet on the infant gut microbiome and predisposition to childhood and adult chronic lung disease.
• Review the impact of macro- and micro-nutrient intake and the feeding practices in preterm infants, especially those with bronchopulmonary dysplasia (BPD), during hospitalization and post-discharge on childhood and adult respiratory outcomes.
• Discuss implementation approaches including food as medicine, for nutritional interventions to optimize early lung health through nutrition.

Agenda

The agenda for this workshop can be viewed here.

Videocast

• DAY 1: Thursday, October 24, 2024 from 11 AM – 5:45 PM ET
• DAY 2: Friday, October 25, 2024 from 11 AM – 3 PM ET

Background

Chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are serious global health issues with rates continuing to increase. Chronic respiratory disease has its origins in the fetal period and early childhood when lungs are developing. Lung development begins in the third week of gestation and continues through adolescence to 22 years of age. After this point, lung function begins to decline at a steady rate over the lifespan. However, several factors alter the trajectory of lung function, including poor gestational growth and nutrition, that contribute to increased respiratory morbidity and mortality. Maternal undernutrition and poor diet quality can significantly impact lung development during periconception and gestation, leading to poor lung function trajectories and lung health . Additionally, prenatal and postnatal lung health are vulnerable to the influence of social determinants of health (SDOH), highlighting an urgent need to prioritize research in this area to address disparities in lung health.

Summary

Keynote Address

The keynote address focused on the intersection of nutrition with lung development, health, and disease. The concept of the Developmental Origins of Health and Disease (DOHAD) states that environmental exposures early in life can influence health and vulnerability to disease in later life. Lung development and growth are highly susceptible to injury during early life, and there exists some evidence that origins of respiratory health can span generations. Asthma and the preclinical phase of COPD can start early in life, highlighting the need to focus on prevention and early diagnosis of disease. Childhood risk factors such as bronchitis, allergies, pneumonia, and preterm birth are important to the risk of chronic lung disease in adults. Adverse exposures during pregnancy can also lead to dysfunction during the gestational period, even extending through generations. The keynote speakers highlighted the importance of addressing causal risk factors, increasing health education and awareness of chronic respiratory diseases, strengthening evidence-based guidelines, and improving risk prediction and early detection tools. The five sessions that followed the Keynote Address included: 1) Prenatal nutrition and lung disease, 2) Perinatal and postnatal nutrition and lung disease,3) Biomarkers and mediators of lung disease, 4) Links between nutrition, prematurity, and bronchopulmonary dysplasia with childhood and adult lung function; and 5) Food is medicine programs for lung health and disease.

Prenatal Nutrition and Lung Disease

Discussions on prenatal nutrition and lung disease highlighted the importance of the preconception and gestational periods on infant and childhood lung health. Asthma is one of the most common diseases in children, stemming from both genetic and environmental influences. Exposures during the prenatal period , including diet and nutrition, during pregnancy, strongly impacts the risk of developing asthma, and wheeze during infancy and COPD later in life. The level of impact varies based on the gestational age at exposure. Lessons and data from the Dutch Hunger Winter of 1944-45 indicated that children exposed to famine had significant risk of disease later on in life, with increased risk of obstructive lung disease among women and infants exposed during mid-gestation – highlighting the importance of nutrition during pregnancy. Maternal diets low in antioxidants and omega-3 polyunsaturated fatty acids (PUFAs), and high in saturated fats, processed sugars, and pro-inflammatory foods can contribute to childhood asthma and respiratory diseases during infancy and childhood. Nutrients such as Vitamin C, Vitamin D, and omega-3 PUFAs, decreased risk of persistent wheeze or asthma and protect against infections such as respiratory syncytial virus (RSV). Dietary and other lifestyle factors (e.g., sleep) at preconception or pre-pubescent periods of parents can impact lung development and growth of offspring. Overall, although there are clear indications of nutrition influencing infant lung health and development, more research is needed on the biological pathways and mechanisms to fully understand the impact of prenatal nutrition.

Perinatal and Postnatal Nutrition and Lung Disease

Maternal nutrition and infant diet diversity during the perinatal and postnatal significantly affects lung growth. Better maternal diet index scores have demonstrated reduced asthma and wheeze risk in infants, with ultra-processed foods and more advanced glycation end products resulting in increased risk of asthma and wheeze. Vitamins A, D, and E have demonstrated positive effects on respiratory tract growth, injury attenuation, and protection from some toxicities, however, these findings require further investigation. Additionally, cultural considerations should be included in designing diets and dietary interventions. Circadian rhythms in both pregnant people and infants were discussed as key influences on health. Disruption of circadian rhythms, or chrono disruption, has been indicated in pregnancy complications such as eclampsia, miscarriage, and gestational diabetes, in addition to influencing fetal lung growth and development. Infant circadian rhythms begin to form around 18-24 weeks gestation. Biomarkers in human milk may also impact infant lung health and development throughout the lifespan. More research is needed to fully investigate the circadian mechanisms that influence lung injury, inflammation, and repair.

Biomarkers and Mediators of Lung Disease

The third session of the workshop centered on biomarkers, including the microbiome, and metabolomics, to understand the interplay between diet and lung diseases. DNA methylation (DNAm) can have either harmful or helpful health impacts, and certain nutrients can influence overall lung function and health over the lifespan. For example, higher omega-3 PUFAs such as docosahexaenoic acid (DHA) have beneficial associations with lung function and for mitigating the effects of COPD. The gut microbiome can also play a significant factor in nutrition and asthma in children, with early childhood dysfunction leading to allergy and airway disease later in life. The benefits of using biomarkers to stratify risk and multi-omic approaches for nutrition and overall health were also discussed as avenues for improved precision medicine efforts. Speakers described the influence of nutrients and the microbiome on lung health, however, they noted the need to better understand the mechanisms between nutrition and DNAm, as well as the impacts of differences between sex, smoking status, and health disparities on improved lung health and function. While specific nutrients are important, it was also emphasized that metabolites and nutrients do not exist in isolation, therefore an individual’s entire nutritional profile and metabolome must be considered.

Links Between Nutrition, Prematurity, and BPD with Childhood and Adult Lung Function

Factors that contribute to chronic lung diseases begin in early childhood and are critical influences on chronic lung disease in adulthood, with preterm birth (PTB) and BPD presenting considerable risk. PTB is one of the earliest adverse exposures for infants, with mechanical interventions to assist preterm neonates potentially causing even further damage. Additionally, preterm infants tend to diverge further from other children in regards to lung function trajectories. Nutrition is a key factor impacting alveolar growth and development, which in turn can impact susceptibility to BPD, COPD, and other infections such as RSV. Cellular senescence is another marker describing the potential mechanisms contributing to impaired lung function trajectory and chronic lung function. PTB and nutrition may also influence acquired dysanapsis which describes disproportionate growth of airways and alveoli due to external forces, as opposed to intrinsic dysanapsis which is due to genetics. This disproportionate growth of airways and alveoli can lead to increased risk of chronic lung diseases and lowered lung trajectories. Further investigation is needed to fully understand the causes of dysanapsis and decreased lung function trajectories, as well as the linkage between PTB, sex, nutrition, and genetic factors with lung development and health across the lifespan. The role of senescence in human lung development also requires further study. International data sharing and cooperation efforts, such as the Prematurity’s Effects on the Lungs in Children and Adults (PELICAN) initiative, were discussed as methods to enable greater access to data sets, harmonize data, and share frameworks through which to identify risk factors and solutions.

For patients with bronchopulmonary disease (BPD) or cystic fibrosis (CF), nutrition can significantly influence lung growth and function. Optimal nutrition in patients with and without BPD and CF has the potential to slow decline of lung function and contribute to good weight gain and linear growth in infants, leading to improved pulmonary function. Vitamins A, D, and E, have demonstrated positive effects on respiratory tract growth and injury.

Food Is Medicine Programs for Lung Health and Disease

Nutrition security and food security as keys to ensure appropriate access to adequate amounts and quality of food. Adequate nutrition plays a role in overall health, preventing diseases, and ensuring appropriate development. It is important to consider how to implement interventions and innovations in a way that facilitates uptake and result in positive outcomes. Implementation science (IS) involves examining methods of implementation through the lenses of feasibility, acceptability, accessibility, cost, effectiveness, fidelity, cultural and regional context, and sustainability. IS must also include de-implementation approaches, or the process of removing interventions that are not effective. The idea of Food is Medicine is one example of implementation science within nutrition by facilitating access to nutritious foods through medically tailored meals, groceries, and programs. Examples of FIM were discussed including the Oregon Double Up Food Bucks initiative, in which SNAP recipients received double the amount of available dollars to use on fruits, vegetables, herbs, and other healthy foods.

Research Gaps and Opportunities:

• Develop evidence-based guidelines and recommendations for nutrition, circadian rhythm adjustments, microbiome work, implementation, and other strategies to improve lung development and health.
• Conduct longitudinal studies on nutrition and lung health, spanning across pre-conception and gestational periods, post-natal, and following through childhood.
• Investigate biological pathways and mechanisms of disease to fully understand how nutrition affects lung development, growth, and health.
• Include greater diversity in cohorts and consideration of SDOH and health disparities.
• Build a multidisciplinary workforce that represents the general population and informs interventions to improve nutrition and lung health.
• Investigate biomarkers to stratify risk and enable earlier detection of chronic lung diseases, even among prior generations such as grandparents.
• Leverage artificial intelligence (AI), machine learning (ML), and other technologies to improve precision medicine and nutrition, and understand the interplay of nutrients, transcription factors, drugs, genomics, environmental exposures, and infections on lung health and trajectories.
• Gather data within diverse communities and recognize that low- and middle-income countries (LMICs) have larger burdens of disease, therefore requiring further study and engagement with communities to improve lung health.
• Understand the role of improved maternal and infant nutrition on the potential to prevent or mitigate lung function decline and “catch-up” to standard trajectories.
• Investigate methods and approaches to meet people where they are and break down barriers to improve nutrition across populations and communities.
• Discuss implementation approaches for nutritional interventions to optimize early lung health through nutrition.

Conclusion

Throughout the workshop, speakers highlighted the impacts of adequate nutrition on lung health and development from preconception through gestation, postpartum, and throughout the lifespan. The positive and potentially protective effects of several nutrients were discussed, although speakers noted that nutrients do not exist in isolation and should be considered alongside exposure to other nutrients and factors. Key topics included the importance of the maternal diet index, infant diet diversity, circadian rhythms, addressing disparities in access to nutritious foods, and pregnancy complications (e.g., preterm birth, gestational diabetes, preeclampsia) on lung development, growth, and function trajectories. Nutrition can influence lung development, health, and progression of chronic lung diseases, however, the extent and mechanisms behind its influence require further investigation to develop evidence-based guidelines and recommendations.

Disclaimer: The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop. The summary does not represent a consensus opinion or directive made to or by NHLBI or NIH.

Participants

Workshop Co-Chairs

• Augusto A. Litonjua, MD, MPH, University of Rochester
• Cynthia McEvoy, MD, MCR, Oregon Health & Science University

Workshop Organizers

• Shilpy Dixit, PhD, National Center on Sleep Disorders Research
• Qing Lu, PhD, DVM, National Heart, Lung, and Blood Institute
• Gustavo Matute-Bello, MD, National Heart, Lung, and Blood Institute
• Charlotte Pratt, PhD, National Heart, Lung, and Blood Institute (Co-Chair)
• Beena G. Sood, MD, MS, National Heart, Lung, and Blood Institute (Co-Chair)
• Debbie Vitalis, PhD, National Heart, Lung, and Blood Institute

Speakers and Moderators

• Rodney D. Britt, Jr., PhD, ATSF, Nationwide Children’s Hospital, Ohio State University
• Dinh Bui, PhD, MPH, BPharm, University of Melbourne
• Kecia N. Carroll, MD, MPH, Icahn School of Medicine at Mount Sinai
• Dawn L. DeMeo, MD, MPH, Harvard Medical School, Brigham and Women’s Hospital
• Shyamali Dharmage, MBBS, MD, PhD, MSc, FCCPSL, FThorSoc, FERS, The University of Melbourne
• Liesbeth Duijts, MD, PhD, University Medical Center Rotterdam
• Erick Forno, MD, MPH, ATSF, Indiana University School of Medicine
• Jennifer Hahn-Holbrook, PhD, University of California Merced, LATCH Lab
• Nur Sabrina Idrose, BBioMed, PhD, MSc, University of Melbourne
• Rachel Kelly, PhD, Harvard Medical School
• Augusto A. Litonjua, MD, MPH, University of Rochester
• Susan Lynch, PhD, University of California San Francisco
• Nicole Marshall, MD, MCR, IBCLC, FACOG, FABM, Oregon Health & Science University
• Gustavo Matute-Bello, MD, National Heart, Lung, and Blood Institute
• Katie McDonald, PhD, RDN, CSP, ACFDC, Pediatric CF Center, Primary Children’s Hospital
• Cynthia McEvoy, MD, MCR, Oregon Health & Science University
• Sharon McGrath-Morrow, MD, MBA, Children’s Hospital of Philadelphia, University of Pennsylvania
• Audrey Miller, MD, Nationwide Children’s Hospital, Ohio State University
• Bonnie Patchen, PhD, RD, Brigham and Women’s Hospital
• Y.S. Prakash, MD, PhD, Mayo Clinic
• Charlotte Pratt, PhD, National Heart, Lung, and Blood Institute
• Shaon Sengupta, Md, MPH, FAAP, University of Pennsylvania
• Shannon Simpson, PhD, BMedSci (hons), The Kids Research Institute Australia
• Beena G. Sood, MD, MS, National Heart, Lung, and Blood Institute
• Padmaja Subbarao, MD, MSc, FRCP, The Hospital for Sick Children
• Judith Ann Tate, RN, ATS-F, FAAN, Ohio State University
• Carina Venter, PhD, RD, Children’s Hospital Colorado, University of Colorado-Denver School of Medicine
• Debbie Vitalis, PhD, National Heart, Lung, and Blood Institute