NHLBI Workshop On Prenatal and Perinatal Determinants of Lung Health and Disease in Early Life

Purpose

Multiple influences on human lung growth and development occur, beginning with preconception exposures and continuing through conception and childhood into early adulthood.  Numerous environmental exposures (both positive and negative) accumulate along this pathway, and their sum determines lung health and disease. Many studies of perinatal and pediatric lung health and disease have focused on very premature neonates, a population most likely to have aberrant physiology, acute lung injury, or other medical comorbidities in addition to long-term lung disease. However, there is a great need to better delineate the normal trajectories of lung growth and development throughout the lifespan among most infants who are delivered at term or late preterm and to identify the environmental influences that may positively or negatively affect lung development. Although evidence suggests correlations between infant lung health and adult lung function, significant knowledge gaps exist regarding the influence of the preconception, perinatal, and postnatal periods on general lung health throughout life.

On October 1 and 2, 2015, the National Heart, Lung, and Blood Institute convened a group of extramural investigators to develop recommendations for the direction(s) of future research in prenatal and perinatal determinants of lung health and disease in early life and to identify opportunities for scientific advancement. Workshop participants were divided into working groups that focused on 4 areas of lung development research: (1) lung development and function in infants that influence the trajectory to health and disease; (2) pregnancy abnormalities that disturb lung development; (3) preconception, prenatal, and postnatal developmental programming; and (4) maternal, fetal, infant, and childhood environmental exposures. Each subgroup reviewed the current state of the science, identified gaps in knowledge, and offered specific recommendations for future research.

1. Lung Development and Function in Infants

Normal lung development consists of a series of carefully orchestrated events. Longitudinal studies of lung development and function indicate that, in most cases, an individual’s pulmonary function follows a predictable progression from birth through childhood and early adulthood until full maturation at age 22 years. Subsequent gradual age-related declines also generally follow a predictable pattern. Those individuals who begin in the lowest quartile of lung function as an infant are typically in the lowest quartile of lung function as an adult. Individuals in the lower quartile are most susceptible to lung-related disease later in life, probably because of a failure to achieve maximum adult airflow and vital capacity, resulting in premature loss of the physiological respiratory reserves. Lange et al reported that diminished airway function (a forced expiratory volume in the first second of expiration <80%predicted) after birth was associated with adult respiratory disease and that accelerated lung function decline (loss of forced expiratory volume in the first second of expiration) later in life was not a required feature of chronic obstructive pulmonary disease. However, multiple aspects of normal lung development, including developmental trajectories, are poorly understood and could be informed by well-designed longitudinal cohort studies.

   2.  Pregnancy Abnormalities That Disturb Lung Development

Although neonates born very preterm before 34 weeks have the highest likelihood of developing respiratory morbidity after birth, these very preterm infants represent only a small fraction of all babies cared for in neonatal intensive care units annually in the United States. Neonates born early term (37-38 weeks’ gestation) or late preterm (34-36weeks’ gestation) represent the largest proportion of babies in neonatal intensive care units. These infants have a significantly higher incidence of almost all adverse respiratory morbidities (including respiratory distress syndrome, transient tachypnea of the newborn, pneumonia, respiratory failure, need for surfactant, and mechanical ventilation) compared with those born at 39 weeks and beyond.

Recent efforts focused on obstetric quality improvement have resulted in a significant shift in delivery gestational age at or beyond 39 weeks’ gestation. Even so, many term and preterm neonates experience respiratory morbidities that are difficult to predict, and many may eventually develop respiratory morbidities later in childhood and as adults.

A significant challenge when investigating the effect of the prenatal period on fetal lung development is the inability to directly study the fetal human lung. Animal models in combination with surrogate markers of lung injury (eg, vascular endothelial growth factor and soluble fms-like tyrosine kinase-1) from maternal blood, amniotic fluid, and/or the placenta may provide viable alternative investigative strategies.

  3.  Developmental Programming and Lung Development

A unique steady-state microbiota exists in the lungs, and colonization of the airways provides crucial signals for local immune cell maturation. Microbial exposure from the interaction of the maternal-placental-fetal unit, the route of birth, or even intestinal microbiota can alter the collective genome of the lung microbiota and shape lung trajectory toward or away from disease later in life. The placenta is no longer considered a sterile organ, and the effect of maternal-fetal microbiomes on long-term respiratory outcomes is an area of ongoing investigation.

The balance of house keeping and pathogenic microorganisms, rather than the absolute presence of any microbes, is key in determining the development of disease. Although the modulation of inflammation at the maternal-fetal interface is likely an important driver of fetal outcomes, the mechanisms are largely unknown.

  4.  Environmental Interactions and Exposures

There are multiple opportunities during the antenatal and immediate postnatal periods for environmental exposures that may directly or indirectly influence lung health outcomes among infants born at any gestational age. These include maternal gestational diabetes mellitus, medication or drug exposure during pregnancy, peripartum infection, cesarean delivery (with possible resultant effect on the diversity of the lung microbiome), postnatal exposure to oxygen, and postnatal initiation of positive pressure ventilation. One well-studied exposure is cigarette smoke, which has significant effects on developing lungs. Antenatal exposure (irrespective of postnatal exposure) doubles the risk of childhood asthma, increases the risk for sudden infant death syndrome, thickens airways and vascularwalls, andmay permanently alter alveolar and airway geometry.

Epigenetic changes in gene expression can explain phenotypic variation caused by environmental factors. Therefore, epigenetic analysis may provide clues to the potential etiologies behind human disease, including lung disease. Both developmental (patterns of gene expression independent of the environment) and environmental (patterns of gene expression that vary depending on the environment) epigenetics can affect the regulation of transcription and can also affect non coding regions of the genome.While studies have suggested a role for epigenetics in nearly all disease processes, most research has demonstrated only association, not causation. Additional work is needed to determine the underpinnings of disease at the molecular level and the influence of environmental exposures on gene expression, which may lead to new therapeutic strategies.

Recommendations

There are multiple opportunities to address the specific research priorities outlined. It is clear that future investigations will need not only to examine abnormal lung development, but also to use developing technology and resources to better define normal.

Some proportion of future studies will need to use birth cohorts to capture the important influence of preconception and obstetric risk factors on lung health, development, and disease. It is imperative that these birth cohorts include well-characterized obstetrical data, with comprehensive plans for prospective follow-up. On the other hand, the importance of continued basic science, translational, and animal studies cannot be overemphasized, particularly as these data may provide more immediate answers regarding causality. Multidisciplinary approaches with obstetricians, neonatologists, pediatric and adult pulmonologists, epidemiologists, and basic scientists are essential for the comprehensive research needed to advance the understanding of lung development across a lifetime.

Workshop Co-Chairs

• Carol Blaisdell, MD, DLD, NHLBI NIH
• Cynthia Gyamfi-Bannerman, MD, MSc,Columbia University
• Alan H. Jobe, MD, PhD, Cincinnati Children's Hospital

Workshop Participants

• Philip L. Ballard, MD, University of California at San Francisco
• A. Sonia Buist, MD, Oregon Health and Sciences University, Portland
• Sean Fain, PhD, University of Wisconsin–Madison
• Tom Ferkol, MD, Washington University in St Louis, St Louis Missouri
• Henry L. Galan, MD, University of Colorado Hospital, Aurora
• Aaron Hamvas, MD, Northwestern University Feinberg School of Medicine
• Ann and Robert H. Lurie, Children’s Hospital of Chicago, Chicago, Illinois
• Suhas G. Kallapur, MD, University of Cincinnati School of Medicine, Cincinnati, Ohio
• S. Ananth Karumanchi, MD, Harvard Medical School, Boston, Massachusetts
• Robert H. Lane, MD Medical College of Wisconsin, Children’s Hospital of Wisconsin
• Augusto A. Litonjua, MD, Harvard Medical School, Boston, Massachusetts
• Cynthia McEvoy,MD, Oregon Health & Science University, Portland
• Sharon McGrath-Morrow, MD, Johns Hopkins Medical Institutions, Baltimore, Maryland
• Indira U. Mysorekar, PhD, Washington University School of Medicine, St Louis, Missouri
• George R. Saade, MD, University of Texas Medical Branch, Galveston
• Eliot R. Spindel, MD, Oregon Health & Science University, Beaverton
• Jeffrey A. Whitsett, MD, University of Cincinnati School of Medicine, Cincinnati, Ohio

Additional Contributions:

• Steven Abman, MD, Children’s Hospital Colorado, Pediatric Heart Lung Center Aurora
• Judy L. Aschner,MD, Children’s Hospital at Montefiore, Bronx, New York
• Roberta A. Ballard, MD, University of California at San Francisco
• Karen Mestan, MD, Northwestern University Feinberg School of Medicine
• Gloria Pryhuber, MD, University of Rochester Medical Center, Rochester, New York
• Deepa Rastogi, MD, Children’s Hospital at Montefiore, Bronx, New York
• Rita M. Ryan, MD, Medical University of South Carolina, Charleston
• Jack K. Sharp, MD