In order to develop new, preventive and/or early supportive respiratory treatment strategies for extremely preterm newborns, registration and correlation of the clinical data on risk factors and clinical respiratory outcomes is necessary. We therefore studied the association between the method of delivery and respiratory outcomes in extremely preterm and ELBW infants, who were born between 2000–2003 in the MUMC+. A non-equal distribution of GA and birth weight SDS was found between VD infants and CS infants, with different risk profiles for preterm birth indication and respiratory outcomes. This finding was unexpected. However, the standardized operating procedures (SOPs) which were applied in the Netherlands during those years were different from the SOPs which are currently applied. Preterm CS with an indication of IUGR were almost never conducted below a GA of 28 weeks because of a ‘no, unless’-policy [37], resulting in most of the births < 28 weeks being VD.
Since preterm birth is directly associated with poorer neonatal outcomes, we were not surprised to find different incidences for PDA and IVH [38]. Furthermore, LBW correlates with a lower functional residual capacity (FRC) and causes a more compliant chest wall, leading to more difficulties in drawing the first breath [7]. This makes growth restriction an important confounder for respiratory outcomes. Therefore, as expected, these differences disappeared after correcting for the most important confounders: GA, birth weight SDS, antenatal steroids, fetal distress, 1-minute Apgar score and 5-minute Apgar score. An independent association was found between the method of delivery and surfactant, after adjusting for GA and birth weight SDS. This confirms the knowledge that CS may lead to a lower endogenous surfactant secretion due to lower catecholamine levels, causing these infants to be in need of exogenous surfactant therapy [11]. The higher catecholamine levels during fetal distress on the other hand, explain why this association disappears after correcting for fetal distress [39].
Surprisingly, no other independent associations were found between the delivery method and respiratory morbidity, invasive MV and CPAP. This is in contrast to the study by Werner et al. who did find an association between CS and RDS [40]. However, the latter study included a different patient group, namely preterms (25–34 weeks GA) who were small for GA (birth weight < 10th percentile of standard birth weight for their GA). In another study in preterms (≤ 30–36 weeks GA), a higher incidence of pneumothorax was reported in the CS group and preterms in this group were more in need of CPAP and MV [28]. The discrepancies in results between these studies and ours could be due to the different study populations. Still, our findings were consistent with Sangkomkamhang et al. [41], who reported no difference in the incidence of RDS, although they also included a different study population (infants born at GA ≤ 36 weeks). Since a difference in surfactant treatment was found between our two groups, we speculated that preventive treatment might have been applied more effectively in the CS group. This was tested by additionally adjusting for surfactant in all the models [Additional file 3], which should eliminate differences in RDS and pneumothorax diagnosis but not in BPD incidence [42]. However, an influence of surfactant on respiratory morbidity and respiratory support was not found. Another possible explanation was the lack of maternal medical information, which might contain confounders. No information about the onset of labor was taken into account, because this information was unavailable. The CS infants of the mothers who were already in labor are thought to have better respiratory outcomes due to a higher catecholamine release and a higher uterine tone because of present contractions. The surfactant system is activated during labor and an increase of cortisol and thyroid hormones as a reaction to the birth process promote the neonatal transition from fetal to extrauterine lung function [9, 43]. A large proportion of emergency CS in our cohort could have influenced the magnitude of our results. We therefore speculated that the birth process of the CS group in this study was more stimulating regarding the neonatal respiratory transition, than the birth of infants born by CS at a higher GA. This could then explain why there were less respiratory complications in our group than expected. To further investigate this, future studies should focus on respiratory outcomes after CS, adjusted for different GA groups.
One of the strengths of this study was that it was conducted in the only regional tertiary center in the Dutch province of Limburg, where care has been based on SOPs for attending policy. Multiple outcomes were documented in a database, combining several documents from the medical files of the patients, which improves the quality of the data. In order to reduce individual variation in care, the Netherlands have embraced SOPs very early [44]. Therefore, we rated the possibility of high variation in the clinical decision-making among the attending physicians neglectable. This was in particular highlighted in the SOP of surfactant treatment, in which precise cut offs for oxygen therapy mandating surfactant treatment are given. Furthermore, performing statistical corrections for potential confounders made our results more truthful. A limitation, however, was that data were collected retrospectively, leading to an inability to control exposure or outcome assessment and the need to rely on the accurate recordkeeping of others. Also, the 3-year interval of data collection and sample size were limitations. The diagnosis BPD has difficulties in itself, because the current definitions require a postmenstrual age of 36 weeks before classification can be done accurately [45]. The limitation of having an assessment at one time point is that infants who have died prior to this age, but who would have developed BPD later on, could not be included in the analyses. This may have led to seemingly better outcomes in BPD infants, because of missing recording of the outcomes of infants in the worst condition and clinical course. We have corrected for the problem of missing the recording of infants who were transferred or discharged before 36 weeks’ postmenstrual age, and who had thus not been diagnosed with BPD yet, by collecting data from medical records until the age of five. We, however, refrained from a combined outcome of death or BPD, which has been used to deal with this shortcoming [46].