It has been confirmed that premature birth can lead to immature lungs, low lung function, and immature immune system function, thereby increasing the risk of wheezing in children [11-14]. Enrico Lombard et al showed that GA and the development of the lung were closely related [15]. In this study, included new-borns were grouped and compared by GA, and the results confirmed that new-borns with a younger GA were at higher risk of early wheezing, which was consistent with the study of Unal et al. [16]. However, the incidences of early wheezing among different GA groups in this study were lower than those reported in the previous literature [17, 18], which might be related to the short follow-up and small sample size.
This study found that the incidence of persistent early wheezing among preterm infants (GA ≤ 32 weeks and 32 weeks < GA < 37 weeks) was significantly higher than that among full-term infants, which was consistent with previous literature reports [17]. In addition, this study also showed that the incidence of transient early wheezing among preterm infants with a GA ≤ 32 weeks was significantly greater than that among preterm infants with a GA > 32 weeks but < 37 weeks. However, there was no significant difference in the incidence of persistent early wheezing between the preterm infants with a GA ≤ 32 weeks and preterm infants with a GA > 32 weeks but < 37 weeks. The reasons might be as follows: first, the younger the gestational age of preterm infants was, the less mature their lungs were. Second, the respiratory system of the preterm infant gradually develops with age, resulting in a decrease in persistent early wheezing [19].
Birth weight is a well-established indicator of prenatal growth, intrauterine nutritional status and maternal health. It is a sensitive indicator of foetal respiratory and immune system development [20]. The Global Initiative for Asthma (GINA) also added low birth weight as a risk factor for persistent airflow limitation [2]. However, there was no significant correlation between birth weight and early wheezing in preterm and full-term infants in this study, which was inconsistent with the findings reported in the literature [21]. In the literature [21], the birth weight was used as the independent variable the analysis of relative factors of wheezing. However, the average birth weight of preterm infants in Group A was less than 2500 g in our study, which was not chosen as an independent variable. To reveal the relationship between premature birth and the symptom of wheezing, we set SGA and AGA as independent variables. On the other hand, some studies have shown that preterm infants with very low birth weight had a high incidence of impaired lung function, and the degree of impaired lung function was more severe in preterm infants with recurrent wheezing attacks [11, 22]. In our study, the results showed that SGA was a risk factor for early wheezing in preterm infants with a GA ≤ 32 weeks. This suggests that the lower the birth weight of a preterm infant at GA ≤ 32 weeks is, the more severe the impairment of lung function and the higher the risk of early wheezing will be. In summary, we speculated that the younger the gestational age and the lower the birth weight is, the higher the risk of early wheezing will be. However, the results will be further verified with a large sample size in the future.
One thing worth noting is that because this study was a retrospective study, most of the included neonates lacked lung function data. The relationship between early wheezing and lung function in preterm infants is expected to be further evaluated with a large sample in prospective studies in the future.
Sex was another risk factor for early wheezing in infants. In this study, we found that the proportion of males in the early wheezing group was significantly higher than that in the non-wheezing group among both preterm infants with a GA of > 32 weeks but < 37 weeks and full-term infants with a GA ≥ 37 weeks but < 42 weeks. Additionally, the results of the univariate analysis and multivariate analysis showed that male sex was a possible influencing factor and risk factor for early wheezing, respectively. This was in line with previous studies [17, 23]. However, this study did not find an association between sex and early wheezing among preterm infants with a GA ≤ 32 weeks.
A personal history of allergies was a risk factor for wheezing in children. We also found that new-borns with a personal history of allergies had a higher risk of early wheezing regardless of whether they were preterm infants with a GA > 32 weeks but < 37 weeks or full-term infants with a GA ≥ 37 weeks but < 42 weeks, which was consistent with previous studies [24]. However, the history of personal allergy did not show a significant correlation in the multivariate analysis of early wheezing in preterm infants with a GA > 32 weeks but < 37 weeks or full-term infants with a GA ≥ 37 weeks but < 42 weeks. The reasons might be as follows: first, the results related to a personal history of allergies suggest that a larger sample size is needed. Second, the parents might have recall bias regarding whether or not their children had a personal history of allergies. Third, some children might be too young for allergy symptoms. On the other hand, the effect of personal history of allergies was not significant for early wheezing among preterm infants with a GA ≤ 32 weeks, suggesting that a personal history of allergies might not be associated with early wheezing in preterm infants with a GA ≤ 32 weeks. This suggested that the early wheezing of preterm infants with a GA ≤ 32 weeks may be related to the immaturity of their respiratory system.
A family history of allergies was also an important risk factor for wheezing in children [25]. The results of this study showed that a family history of allergies was a risk factor for early wheezing in preterm infants with a GA > 32 weeks but < 37 weeks, which was consistent with previous findings [24]. However, there was no correlation between family history of allergies and early wheezing among preterm infants with a GA ≤ 32 weeks in this study, which was consistent with previous reports [17]. This suggested that a family history of allergies might not be associated with early wheezing in preterm infants with a GA ≤ 32 weeks. The above results indicated that the main cause of early wheezing in preterm infants with a GA ≤ 32 weeks might be the immature respiratory system, rather than a personal history of allergies or a family history of allergies.
Previous studies have shown that caesarean section delays and alters the development of intestinal flora in infants, thereby increasing susceptibility to wheezing [26]. However, whether caesarean section increases the risk of wheezing in children is controversial. Some studies have demonstrated that the risk of asthma in preterm infants delivered by caesarean section was higher than that in preterm infants delivered vaginally [27]. It has also been proposed that although the proportion of caesarean sections has increased, there is no correlation between caesarean section and the risk of wheezing [28]. The results of this study showed that there was no significant difference between caesarean section and children’s early wheezing. However, this did not indicate that caesarean section must not be a risk factor for early wheezing in children. Because the incidence of caesarean section in each group was greater in the early wheezing group than in the non-wheezing group, the failure to obtain statistically significant results might be related to the small sample size of cases.
Tobacco exposure increases the risk of wheezing by decreasing lung function and increasing airway hyperresponsiveness. A prospective birth cohort study showed that preterm infants whose mothers smoked during pregnancy had an increase in the number of wheezes and recurrent wheezing in early childhood [29]. Another study found that passive smoking was positively correlated with wheezing in preterm infants [16]. However, this study did not find a correlation between passive smoking and early wheezing in children in any group. Considering that with the long-term distribution of scientific information, an increasing number of parents were aware that smoking was harmful to their children's health, the amount and frequency of smoking have been reduced, and smoking has been increasing avoided at home. This reduced exposure of children to smoking exposure to some extent, thereby weakening the increased risk of early wheezing and its adverse effects by passive smoking.
It has been demonstrated that breastfeeding can reduce the risk of wheezing by preventing respiratory tract infection, promoting lung growth and development and supporting the maturation of the immune system. However, this study did not find that the feeding pattern was related to early wheezing in any group. This was inconsistent with the previous literature [30]. We speculated that this may be related to the improvement in the current processing of formula-based milk.
Some studies have shown that the use of invasive mechanical ventilation was associated with wheezing in preterm infants [16]. Preterm infants, especially those with bronchopulmonary dysplasia, required respiratory support due to immature lung development in the early postnatal period. While the use of mechanical ventilation plays a role in respiratory support, it might cause lung injury, leading to wheezing in children with bronchopulmonary dysplasia [31]. It has been found that preterm infants with a GA< 28 weeks are exposed to oxygen during the first 3 days of life or have frequent episodes of hypoxemia, which increases the risk of wheezing in children [32]. Although the rates of invasive mechanical ventilation use among preterm infants with a GA ≤ 32 weeks and a GA >32 but < 37 weeks was higher than that among infants in the non-wheezing group in this study, but this difference was not statistically significant. The reason might be related to the small sample size of cases using invasive mechanical ventilation.