Respiratory morbidity through the first decade of life in a national cohort of children born extremely preterm

Since the early 1990s increasing numbers of infants born extremely preterm (EP) in high-income countries have survived [1, 2]. Birth at this stage of pregnancy interrupts important developmental processes, and requires gas exchange to take place in foetal lungs, often leading to the syndrome of bronchopulmonary dysplasia (BPD) [3]. The life-long health consequences of EP birth and BPD are unknown, but there are concerns of severe future morbidities, such as chronic obstructive pulmonary disease [4], metabolic syndrome [5], cardiovascular diseases and even early death [6, 7]. Continued health surveillance is therefore important in this group, particularly for those born at less than 26 weeks gestational age (GA), as their high survival rates are fairly recent history.

Health problems may be reflected in utilisation of health care services. Children born EP more often experience repeated hospital admissions during early childhood than children born at term [8]. Most published data on later outcome pertain to groups born in the pre-surfactant era, and there is a need for population based knowledge on health issues among EP-born survivors exposed to the advanced treatment facilities of the late 1990s and 2000s. Such data are of interest to a growing part of health care professionals, administrators, politicians, the EP-born individuals themselves and their families.

We have previously published data on morbidities and hospital admissions during the first five years of life in a national cohort of EP-born children [9, 10]. The aims of the present study were to investigate frequencies and causes of hospital admissions, general health issues and early predictors of health at five to 11 years of age in that same cohort, with a particular focus on respiratory outcomes.

Questionnaires were returned for 232 (62%) of the 372 surviving children at 11 years of age. Corresponding figures at two and five years of age were 265 (71%) and 284 (76%), respectively. The ISAAC questionnaire was completed for 192 of the children at both five and 11 years of age. Table 1 accounts for differences between participants and non-participants at 11 years of age. The median GA, proportion of mothers with higher education, and proportion of infants who received surfactant and had BPD were higher among the participants, while proportions of mothers who smoked during pregnancy or had chorioamnionitis, and of boys, retinopathy of prematurity or major neurosensory disability at five years of age were lower.

On average, 1.6 term-born subjects had to be approached to recruit one consenting match for each of the 61 eligible subjects born EP within Western Norway Regional Health Authority. Questionnaires were returned for 57 (93%) of the control children.

At 5–11 years of age, the admission rate for the EP-born children was twice that of term-born controls, but occurred mainly for children with neurosensory disabilities and for surgical reasons, such as adeno-tonsillectomy or insertion of ear ventilatory tubes. Admissions for respiratory causes were rare, and neither BPD nor GA below 26 weeks at birth was associated with increased risk. Compared to the period 2–5 years of age, hospital admissions as well as respiratory morbidity had decreased, but admission rates, respiratory symptoms, current asthma, and use of asthma medication was still more common than in the control group. Statistical associations between most tested perinatal variables and the measures of morbidity during the study period were weak, evidenced by lack of significance after Bonferroni adjustments.

The strengths of this study were primarily the nationwide and population-based recruitment base and the longitudinal follow-up design that facilitated age-related assessments from early to mid-childhood in a country with free and unlimited access to health care for children. Although follow-up was not complete, important background information was available for all EP-born children, allowing proper assessment of representativeness. Thus, the number of stillbirths, postnatal deaths and perinatal differences between participants and non-participants could be completely accounted for. Participants tended to have less disabilities and a higher GA than those lost to follow-up, but a higher fraction had BPD. The number of eligible participants (n = 372) reflects the occurrence rate of EP deliveries, and was comparable to most similar studies [15, 16]. The 62% follow-up rate was disappointingly low when compared to previous follow-ups of this cohort, but reflects recent tendencies of increasing attrition rates in this type of research, in Norway [17], as well as internationally [16, 18]. Estimating GA was based on ultrasound at 17–18 weeks, performed within the frames of the established national free and all-encompassing program for antenatal care. Multiple perinatal variables were assessed for potential associations with the outcomes in regression models that utilised a dataset with limited numbers of participants. Thus, in order to prevent type I statistical errors, Bonferroni corrected p-values were reported. Regrettably, we were unable to recruit term-born control subjects for the complete cohort; however, individually matched term-controls were recruited based on the “next-born-subject” principle for a regional subsample representing 20% of the national population. Thus, the control group was considered unbiased and demographically representative for the complete cohort. Nevertheless, the small size of the control group reduced statistical power in the comparative analyses, and increased the risk of making type II errors, particularly as most outcome events were relatively rare.

Significantly more EP than term-born control children were admitted during the study period, which is in agreement with some [19, 20], but not all [21] previous studies. Admissions for respiratory diseases were quite uncommon, which is in agreement with a previous report [22], as was our finding that neither BPD [20] nor home oxygen treatment [23] were associated with admissions during 5-11 years of age. The data fit lung function findings that have previously been reported for this cohort when they were 11 years of age, in that neonatal BPD did not predict later airway obstruction [12]. Overall, these findings suggest that effects of extremely low GAs, BPD and duration of oxygen treatment have become less important for later pulmonary health as treatment of EP-born infants has improved.

At 11 years of age, 30% of the EP-born participants had ever been diagnosed with asthma, which was low compared to published rates of 37–46% among extremely low birth weight children at age 8–14 years [19, 24]. Regarding current wheezing, wheeze on exercise and current asthma, our findings were nearly identical to those of children of similar age born at GA below 26  weeks in the EPICure study [16], while current use of asthma medication was slightly less common (15% versus 25%). Our 16% rate of current asthma was lower than rates reported for somewhat younger [25, 26] and slightly older [21] extremely low birth weight children and for very low birth weight children of similar ages [27, 28]. However, comparing the prevalence of asthma between studies [16, 21, 25‐28] is complicated due to lack of common diagnostic standards. Asthma is common also in the general paediatric population, and in a cohort of 10 year old children with BWs over 2000 grams born in Oslo in 1992 and 1993, 16.1% had ever been diagnosed with asthma, and 11.1% had current asthma [29]. In the present cohort, parental asthma was a strong predictor of asthma and wheezing when assessed at 11 years of age, but not at five years of age [10]. Thus, one may speculate that the occurrence of respiratory illness induced primarily by preterm birth decreases with age, while the relative importance of causes that are commonly implicated in unselected childhood populations (e.g. genetic determinants) increases with age.

For the children with neonatal BPD in this EP-born cohort, the rates for ‘asthma ever’ (35%) was similar to previous reports of 19–52% [18, 19, 30], while the rate of current asthma (20%) was in the lower end of reports ranging from 19% to 37% [16, 22, 31]. Current asthma at 11 years of age was not influenced by neonatal BPD, as was also observed by others [16, 18, 31, 32]. However, more children with BPD used asthma medication, both in this and other studies [18, 33], suggesting that they nevertheless might have more respiratory symptoms.

As regards development from the period 0–5 years of age to 5–11 years of age, the admission rates had declined significantly, but were still higher in the EP than term-born children, corresponding to Norwegian registry data comparing admissions between very preterm children and term-born children at similar ages [34]. Using The International Study of Asthma and Allergies in Childhood questionnaire, we found a significant reduction in respiratory symptoms from five to 11 years of age. This was encouraging, particularly as a large population based study of Western European children that utilised the same questionnaire reported a higher prevalence of current wheezing at age 13–14 years of age compared to 6–7 years of age (14.3% versus 9.6%) [14].

In conclusion, respiratory morbidity reflected by hospital admissions and respiratory symptoms as reported by parents in validated questionnaires, were clearly less pronounced in mid-childhood than in early childhood in this nationwide cohort of EP-born children, but still more common than in a regionally recruited group of term-born children. There were few convincing associations between perinatal variables and measures of morbidity. Notably, children with low GA and a history of neonatal BPD did surprisingly well, and these variables did not influence admission rates or occurrence of current asthma in adjusted analyses.