Persons with Down syndrome (DS) have an increased reported incidence of pulmonary hypertension (PH). A majority of those with PH have associations with congenital heart disease (CHD) or persistent pulmonary hypertension of the newborn (PPHN); however, there are likely multifactorial contributions that include respiratory comorbidities. PH appears to be most commonly identified early in life, although respiratory challenges may contribute to a later diagnosis or even a recurrence of previously resolved PH in this population. Currently there are few large-scale, prospective, lifetime cohort studies detailing the impact PH has on the population with DS. This review will attempt to summarize the epidemiology and characteristics of PH in this population. This article will additionally review current known and probable risk factors for developing PH, review pathophysiologic mechanisms of disease in the population with DS, and evaluate current screening and management recommendations while suggesting areas for additional or ongoing clinical, translational, and basic science research.

Bronchopulmonary dysplasia (BPD), a disorder characterized by arrested lung development, is a frequent cause of morbidity and mortality in premature infants. Parenchymal lung changes in BPD are relatively well-characterized and highly studied; however, there has been less emphasis placed on the role that airways disease plays in the pathophysiology of BPD. In preterm infants born between 22 and 32 weeks gestation, the conducting airways are fully formed but still immature and therefore susceptible to injury and further disruption of development. The arrest of maturation results in more compliant airways that are more susceptible to deformation and damage. Consequently, neonates with BPD are prone to developing airway pathology, particularly for patients who require intubation and positive-pressure ventilation. Airway pathology, which can be divided into large and small airways disease, results in increased respiratory morbidity in neonates with chronic lung disease of prematurity.

Maternal hypothalamic-pituitary-adrenal (HPA) axis disruption in pregnancy may contribute to the programming of childhood respiratory disease and may modify the effect of chemical toxins, like lead (Pb), on lung development. Child sex may further modify these effects. We sought to prospectively examine associations between maternal HPA axis disruption, prenatal Pb and childhood lung function and explore potential effect modification by maternal cortisol and child sex on the association between prenatal Pb and lung function outcomes. Analyses included 222 mothers and children enrolled in a longitudinal birth cohort study in Mexico City. Maternal diurnal salivary cortisol was assessed in pregnancy; cortisol awakening response (CAR) and diurnal slope were calculated. Blood Pb was measured during the second trimester of pregnancy. Post-bronchodilator lung function was tested at ages 8–11 years. Associations were modeled using generalized linear models with interaction terms, adjusting for covariates. A higher (flatter) diurnal slope was associated with lower FEV₁/FVC ratio (β: −0.433, 95%CI [−0.766, −0.101]). We did not find any main effect associations between prenatal Pb and lung function outcomes. We report an interaction between Pb and cortisol in relation to FEV₁/FVC and FEF_25–75% (p_interaction<0.05 for all). Higher prenatal Pb was associated with reduced FEV₁/FVC only in children whose mothers had a high CAR. Higher prenatal Pb was also associated with reduced FEV₁/FVC and FEF_25–75% in mothers with a flatter diurnal slope. A 3-way interaction between prenatal Pb, CAR and sex on FEV₁/FVC, indicated that boys born to women with high CAR and higher prenatal Pb levels had lower FEV₁/FVC ratios (p_interaction=0.067). Associations between prenatal Pb and childhood lung function were modified by disrupted maternal cortisol in pregnancy and child sex. These findings underscore the need to consider complex interactions to fully elucidate effects of prenatal Pb exposure on childhood lung function.