It has been confirmed that premature birth can cause immature lung, low lung function, 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 newborns were grouped and compared by GA, and the results confirmed that newborns with younger GA were at higher risk of early wheezing, which was consistent with the study of Unal et al [16]. However, the incidence of early wheezing in different GA groups in this study was lower than that reported in the previous literature [17, 18], considering that it might be related to the short follow-up and the small sample size.
This study showed that the incidence of early transient wheezing in preterm infants with GA ≦ 32 weeks was significantly greater than that of preterm infants with 32 weeks < GA < 37 weeks. However, there was no significant difference in the incidence of early persistent wheezing between the two groups. The reason for this result may be that the respiratory system of preterm infants gradually develops with age, resulting in a decrease in early persistent wheezing [19]. In addition, this study also found that the incidence of early persistent wheezing in preterm infants was significantly higher than that in full-term infants, which was consistent with previous literature reports [17].
Birth weight is a well-established indicator of prenatal growth, intrauterine nutritional status and maternal health. It is a sensitive indicator of fetal respiratory and immune system development [20]. Global Initiative for Asthma (GINA) also added low birth weight as a risk factor for persistent airflow limitation [2]. In this study, we found that the proportion of SGA infants was significantly higher in the early wheezing group than in normal group among preterm infants with GA ≤ 32 weeks. However, the relationship between them was analyzed by the binary logsitc method, and no significant difference was found. In addition, in preterm infants with 32 weeks < GA < 37 weeks and full-term infants with 37 weeks ≤ GA < 42 weeks, SGA was not found to be associated with early wheezing, which was inconsistent with that reported in the literature [21]. Therefore, the results will be further verified with a large sample size in the future.
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]. However, 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 demonstrated by a large sample of prospective studies in the future.
Gender 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 normal group in both preterm infants with 32 weeks < GA < 37 weeks and full-term infants with 37 weeks ≤ GA < 42 weeks. Meanwhile, the results of univariate analysis and multivariate analysis showed that male 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 gender and early wheezing in preterm infants with GA ≤ 32 weeks.
Personal history of allergy was a risk factor for wheezing in children2. We also found that newborns with a personal history of allergy had a higher risk of early wheezing whether they were preterm infants with 32 weeks < GA < 37 weeks or full-term infants with 37 weeks ≤ GA < 42 weeks, which was consistent with previous studies [24]. However, personal history of allergy did not show a significant difference in early wheezing in preterm infants with GA ≤ 32 weeks, suggesting that personal history of allergy might not be associated with early wheezing in preterm infants with GA ≤ 32 weeks. Family history of allergy was also an important risk factor for wheezing in children [25]. The result of this study showed that family history of allergy was a risk factor for early wheezing in preterm infants with 32 weeks < GA < 37 weeks, which was consistent with previous findings [24]. However, there was no correlation between family history of allergy and early wheezing of preterm infants with GA ≤ 32 weeks in this study, which was consistent with previous reports [17]. This suggested that a family history of allergy might not be associated with early wheezing in preterm infants with GA ≤ 32 weeks. The above results indicated that the main cause of early wheezing in preterm infants with GA ≤ 32 weeks might be immature respiratory system, rather than personal history of allergy and family history of allergy.
Previous studies have shown that cesarean section delays and alters the development of intestinal flora in infants, thereby increasing susceptibility to wheezing [26]. However, whether cesarean section increased the risk of wheezing in children was controversial. Some studies have demonstrated that the risk of asthma in preterm infants undergoing cesarean section was higher than that in spontaneous delivery [27]. It has also proposed that although the proportion of cesarean section has increased. There was no correlation between cesarean section and the risk of wheezing [28]. The result of this study showed that there was no significant difference between cesarean section and children’s early wheezing. However, this did not indicate that cesarean section must not be a risk factor for early wheezing in children. Because the incidence of cesarean section in each group was greater in early wheezing group than in normal group, the failure to obtain statistically significant results might be related to the small sample size of cases.
Tobacco exposure increased 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 of preterm infants [16]. However, this study did not find a correlation between passive smoking and early wheezing in children in each group. Considering that with the continuous popularization of popular science information, more and more parents were aware that smoking was harmful to their children's health, so the amount and frequency of smoking were reduced, as well as avoiding smoking at home. This reduced smoke exposure in children to some extent, thereby weakening the increased risk of early wheezing and its adverse effects by passive smoking.
It has been demonstrated that breast feeding 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 feeding pattern was related to early wheezing in each group. It was inconsistent with previous literature [30]. The reason might be related to the improvement of current process of formula 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 played 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 GA < 28 weeks of age are exposed to oxygen during the first 3 days of life or frequent episodes of hypoxemia, which increased the risk of wheezing in children [32]. Although the use rate of invasive mechanical ventilation in preterm infants with GA ≤ 32 weeks and 32 weeks < GA < 37 weeks was higher than that in normal group in this study, it was not statistically significant. The reason might be related to the small sample size of cases using invasive mechanical ventilation.