Introduction
An imbalance between proinflammatory and anti-inflammatory mediators during pregnancy may lead to aberrant inflammation and is associated with increased mortality and morbidity of the mother and offspring.1 2 The maternal environment during gestation influences the offspring health at birth and throughout the life course. A dysregulated inflammation can negatively affect birth outcomes, resulting in an increased risk for restricted foetal growth and preterm birth.3 There is evidence that bronchopulmonary dysplasia (BPD) is associated with an imbalance between proinflammatory and anti-inflammatory factors, with an overweight of proinflammatory mediators.4 5
Club cell secretory protein (CC16) is abundant in normal airway secretions and is thought to be important in protecting the lung from inflammatory insults and oxidative stress. CC16 concentration in amniotic fluid increases during pregnancy and reaches a plateau at 30 weeks.6 Infants born at lower gestations may have a relative CC16 deficiency and thereby an insufficient defence against inflammation. In infants born before 30 weeks, those who developed BPD had lower levels of CC16 in tracheal aspirate on day 1 and did not show the expected increase of CC16 in the trachea during the first week of life.7
Vascular endothelial growth factor (VEGF) regulates vasculogenesis and angiogenesis, which are important steps during embryogenesis. The vascular growth has been shown to be impaired in preterm born infants with BPD,8 and low VEGF levels in tracheal aspirate during the first week of life is associated with BPD.9 Also, later in life, children born extremely preterm had significantly impaired exercise capacity at the age of 19,10 which might be due to a lower lung function and/or an impaired vascular function.
The proinflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) are important mediators during inflammation by recruiting and activating inflammatory cells and by inducing pathways of lung injury.11 Both IL-1β and TNF-α have been implicated in the mechanisms of preterm parturition12 and were increased in tracheal aspirate in infants who developed early lung disease.13 14 For example, the proinflammatory cytokine IL-1 is associated with chorioamnionitis, preterm prelabour rupture of membranes and preterm birth, possibly due to the increased levels of IL-1 in amniotic fluid and increased infiltration of leucocytes in the chorion and amnion.15
Gastric fluid aspirated early after birth is a source of lung fluid swallowed by the fetus. In very preterm infants, low CC16 in gastric fluid at birth was associated with higher concentrations of the proinflammatory cytokines IL-1β and TNF-α, and of matrix metalloproteinase-9 (MMP-9), in the trachea within 24 hours, and with a more severe respiratory disease in the neonatal period.16 In 102 very preterm infants with respiratory distress syndrome, those who developed BPD had higher levels of proinflammatory cytokines and a lower level of the anti-inflammatory cytokine IL-10 in tracheal fluid aspirated early after birth.17 However, possible long-term childhood effects of this proinflammatory state in the newborn lung need to be further investigated.
We hypothesised that an inflammatory imbalance in the lung early after birth, quantified as low CC16 and high proinflammatory cytokines in tracheal aspirate, would be associated with persistent airway symptoms and lung function abnormalities that could be detected by lung function testing at school age.