Results
The analytical sample included 879 boys and 970 girls. By age seven years, 37.6% of children experienced one or more wheezing episodes (Table 1). EOT wheeze was the most common phenotype (20.5%); followed by LO (9.3%) and EOP (7.8%). Paediatrician-diagnosed LRTIs were common (46.8%). Every fifth mother reported smoking during pregnancy (19.6%) and 30.8% reported that their toddler had some exposure to tobacco smoke. Majority of children (80.8%) were breastfed; over a half (53.5%) for less than four months.
Table 1
Wheezing was linked to smoking during pregnancy (p=0.044), child’s SSE (p=0.008), LRTI (p<0.001), and lack/short duration of breastfeeding (p=0.035). Wheezing was more common among boys (p<0.001), Brno residents (p=0.031), second-born and higher birth-order children (p=0.044), and children of mothers with a history of asthma (p=0.028).
In bivariate models showing unadjusted relationships, the relative risk of wheezing vs. no wheezing was 54%-79% higher among children with high vs. low exposure to prenatal life events (Table 2). Relative risk ratios (RRR) for wheeze phenotypes were 1.54 (95% CI 1.16-2.05, p=0.003) for EOT; 1.72 (95% CI 1.13-2.63, p=0.012) for EOP; and 1.79 (95% CI 1.22-2.61, p=0.003) for LO. Increases in the relative risk of wheeze linked to postnatal life events were even higher. High vs. low exposure was associated with 57%-145% increases (EOT, RRR=2.11, 95% CI 1.58-2.82, p<0.001; EOP, RRR=2.45, 95% CI 1.55-3.90, p<0.001; LO, RRR=1.57, 95% CI 1.06-2.32, p=0.026).
Table 2
Multivariate Results
Adjusted Relationships between Perinatal Life Events and Wheeze.In Table 2, statistically significant differences in the likelihood of several wheeze phenotypes by high vs. low exposure to life events remain evident even after adjustment for covariates. Children with highprenatal exposure to life events have a 44% higher relative risk of EOT wheeze compared to counterparts with low exposure (RRR=1.44, 95% CI 1.06-1.95, p=0.020). Moreover, they have a 69% higher relative risk of LO wheeze (RRR=1.69, 95% CI 1.13-2.53, p=0.010). EOP wheeze approaches significance with RRR of 1.56 (95% CI 0.99-2.44, p=0.053). For postnatal life events, high vs. low exposure is related to a 74% increase in relative risk of EOT wheeze (RRR=1.74, 95% CI 1.28-2.36, p<0.001); the corresponding increase for EOP wheeze is 101% (RRR=2.01, 95% CI 1.23-3.26, p=0.005). These results support H1 and H2.
Figure 2 illustrates predicted probabilities of each wheeze phenotype based on marginal effects calculated for four categories of stress exposure, overall low stress (low prenatal/low postnatal life events); increasing stress (low prenatal/high postnatal life events); decreasing stress (high prenatal/low postnatal life events); and overall high stress (high prenatal/high postnatal life events). In all stress categories, the majority of children never wheeze, but the probability of staying wheeze-free throughout the observation period is considerably lower among children with overall high stress (51.9%) vs. children with overall low stress (72.2%). The predicted probability of EOT wheeze more than doubles among children in the overall high stress category (9.4%) compared to overall low stress category (4.5%) Predicted probabilities corresponding to overall low stress vs. overall high stress are 15.4% vs. 26.2%, respectively, for EOT wheeze and 8.0% vs. 12.5%, respectively, for LO wheeze.
Figure 2
Mediation between Prenatal Life Events and Wheeze. Models of mediators are displayed in Table 3. Unstandardized coefficients are reported for all types of models to facilitate interpretation. Higher prenatal life events predict higher postnatal life events (high vs. low prenatal life events, unstandardized coefficient b=0.77, 95% CI 0.49-1.06, p<0.001). Decomposition analysis reveals that postnatal life events partially mediate between prenatal life events on any wheeze vs. no wheeze (high vs. low prenatal events, direct effect odds ratio [OR]=1.51, 95% CI 1.18-1.93, p=0.001; indirect effect OR=1.13, 95% CI 1.06-1.21, p<0.001; total effect OR=1.71 95% CI 1.34-2.18, p<0.001), supporting H3a. Prenatal life events are unrelated to smoking during pregnancy, SSE, breastfeeding, LTRI, and allergy, ruling out mediation through these factors.
Table 3
Mediation between Postnatal Life Events and Wheeze. Children with higher exposure to postnatal life events are more commonly diagnosed with LRTI (Table 2) and LRTI mediates between postnatal life events and any wheeze (high vs. low postnatal events, direct effect OR=1.85, 95% CI 0.05-74.31, p=0.745; indirect effect OR=1.06, 95% CI 1.02-1.09, p=0.002; total effect OR 1.95, 95% CI 0.05-78.75, p=0.723). This result supports H4c. Postnatal life events are also linked to SSE, another significant mediator (direct effect OR=1.86, 95% CI 0.04-82.06, p=0.749; indirect effect OR=1.02, 95% CI 1.001-1.05, p=0.035). Mediation through breastfeeding is unsupported.
To illustrate multivariate results, Figure 3 displays estimated statistical effects for each pathway in the proposed conceptual model. It demonstrates the mediation of prenatal stress through postnatal stress, mediation of postnatal stress through respiratory infections, and mediation of postnatal stress through SSE.
Figure 3 here
Covariate Effects (results upon request). In the final multinomial logistic regression model of wheeze phenotypes, boys are more likely to develop early-onset wheeze compared to girls (EOT, RRR=1.60; 95% CI 1.25-2.04, p<.001; EOP, RRR=1.61; CI 1.13-2.31, p=0.009). EOP wheeze is related to maternal asthma history (RRR=3.08, 95% CI 1.44-6.58, p=0.004).