Paths of Causal Influence from Prenatal Inflammation and Preterm Gestation to Childhood Asthma Symptoms

Introduction: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim of the present study was to investigate paths of assumed causality leading from fetal inflammatory response syndrome (FIRS) to asthma symptoms in formerly preterm infants.

Materials and Methods: This is a prospective cohort study, with demographic, antenatal, delivery and outcome data collected from 262 infants with less than 32 completed weeks of gestational age, in over a 10-year period. The primary outcome measure was the presence of symptoms of asthma beyond the age of 5 years.

Results: Our findings and a graphic representation of the path flows are depicted in Fig. 1. FIRS (OR: 4.7) and subsequent chronic lung disease (CLD) (OR: 7.7) and early childhood wheezing (ECW) (OR: 9.5) were the most important risk factors for development of asthma symptoms in children born with less than 32 weeks of gestational age. The path analysis showed that FIRS has a large direct (0.59), medium indirect (0.11) and large overall (0.70) effect on CLD; large negative direct effect on ECW (−0.34) and a large positive indirect effect (0.74), mediated by CLD. On the occurrence of asthma symptoms, FIRS has a medium negative direct effect (−0.18) and a medium positive indirect effect (0.26), mediated by CLD and ECW.

Discussion: Our study suggests that prenatal inflammation plays an important role in the development of chronic respiratory disturbances in preterm infants. We speculate that this influence is mainly related to structural and developmental lung abnormalities initiated in utero as a consequence of FIRS, resulting in CLD of prematurity, and overcoming the protective mechanisms of chorioamnionitis. The long term effect of fetal inflammation is actually mediated by CLD, leading to childhood wheezing and asthmatic phenotype.

Conclusion: The path analysis for presumed causal relationships in the development of asthma symptoms has provided additional insights toward understanding the complex pathogenetic mechanisms and identifying high-risk infants.

Fig. 1 Path diagram of causality of asthma symptoms in prematurely born including the presence of FIRS as an indirect variable. CLD, chronic lung disease; ECW, early childhood wheezing; FIRS, fetal inflammatory response syndrome; GA, gestation age; MV, mechanical ventilation.