This study reports on mortality and outcome at two years of age in extremely preterm infants in a Swiss cohort born after 2000, based on a nationwide prospective registry and follow-up program. Thereby it provides representative outcome information on a national level over a nine-year period. To the best of our knowledge, these data represent one of the largest datasets on a recent birth cohort.
The incidence of severe ND was 11%, while 24% of infants survived with moderate ND. The overall rate of any ND was moderately higher than reported in a similar cohort born in 2005 in Victoria, Australia
. Mortality depended strongly on gestational age and decreased from 70% at 24 weeks to 17% at 27 weeks. The observed mortality rates were slightly higher compared to a U.S. cohort
 and a recent Australian cohort
, but similar to European data
. We observed a significant decrease in mortality and severe ND over the study period with a parallel increase in survival without moderate or severe neurodevelopmental disability. This trend is supported by the observed overall decrease in major neonatal morbidities in preterm infants during the last decade in Switzerland
. However, some caution is required when interpreting the observed trend since implementation of BSID-II increased between 2000 and 2005 in the participating centres. We therefore adjusted analyses using random multilevel clustering for each centre in order to account for the effect of centre-to-centre differences. Since this is a purely observational cohort on neonatal morbidities and outcomes, it is not possible at this stage to identify specific changes in management that potentially could have led to improved outcomes over time. Theoretically, a variety of factors such as improved prenatal care, early start of CPAP, optimal feeding and strategies to reduce nosocomial infection may contribute to improved outcomes. The publication of the Swiss guidelines
 for the care of infants between 22 and 26 gestational weeks in 2002 may have affected the decision to provide palliative versus intensive care in infants below 26 weeks GA. Therefore, this study was based only on infants born after at least 24 0/7 weeks PMA and we performed sensitivity analyses excluding infants that died in delivery room. The sensitivity analyses confirmed the main results.
At birth, death and severe ND were mainly predicted by low gestational age and low birth weight, while antenatal corticosteroids to induce fetal lung maturation had a strong protective effect. Male sex increased the risk of adverse outcome, but it played a minor role compared to previous reports
[12, 13]. Surprisingly, outborn and multiple birth status did not affect outcome prediction in our cohort, but the rate of outborns was small. In the past, the majority of publications reporting on neonatal outcomes used both gestational age and birth weight as covariates, despite the strong collinearity between these. We think our model is more accurate, since birth weight is not an independent variable, but a result of gestational age and intrauterine growth (z-score of birth weight). Multivariate analyses confirmed that the z-score of birth weight was strongly associated with outcomes. Whether caesarean delivery has a protective effect is debated in the literature
[33, 34]. In our study, delivery by caesarean delivery showed a protective benefit in the univariate risk analysis, but this effect disappeared in the sensitivity analyses, suggesting the association was strongly confounded by the antenatal decision to treat a child in a palliative way and thus avoiding caesarean delivery. Additional multivariate analyses including delivery mode as a covariate resulted highly similar to the main models and caesarean delivery was not significantly associated with any of the outcomes (data not shown).
Long-term outcome in children surviving to 360/7 weeks PMA was only weakly influenced by the main perinatal factors gestational age, intrauterine growth, sex and lung maturation. Instead, the major neonatal morbidities such as BPD, ROP, major brain injury and NEC or sepsis played a major role. Our results are in agreement with a previous study reporting that the prognosis for very preterm infants changes during the course of early postnatal life depending on the incidence of neonatal morbidities
. Our findings confirm that antenatal corticosteroids improve survival without increasing morbidity in the survivors
. NEC and sepsis were strongly associated with outcomes in univariate analyses, which is in agreement with previous studies
[10, 22]. However, in multivariate models, BPD was the single strongest predictor of adverse outcome, while ROP, followed by BPD, was the strongest predictor of unfavourable outcome. Interestingly, further analyses revealed that sepsis was one of the strongest risk factors for BPD (multivariate p = 0.006), together with low gestational age, intrauterine growth restriction and absence of antenatal corticosteroids. This indicates that while BPD in our model is the better predictor of adverse outcome, sepsis represents one of the main causative factors leading to BPD. It is important but often difficult to distinguish whether a covariate is a marker of disease severity or actually a factor causing poor outcome. Mechanical ventilation and sepsis are known to cause direct damage to the lungs and, indirectly, to the brain
Several limitations of this study need to be mentioned. Nineteen percent of surviving infants did not receive BSID-II testing and were excluded from the logistic regression analyses. Even if our follow-up rate of 81% is comparable to published studies
, the infants lost from follow-up displayed a higher GA and a lower BPD rate than the study group. We cannot exclude that the loss from follow-up of these infants may have led to a slight underestimation of the overall outcome. We decided a priori to predict outcome at two time points, once at time of birth and once at 36 weeks gestational age. The selection of these two time points makes sense from a clinical point of view, since outcome prediction is most important pre-delivery and when approaching discharge. However, this model does not allow assessing the impact of the main postnatal morbidities on early neonatal mortality. Since data on chorioamnionitis and postnatal corticosteroids therapy were not prospectively recorded, we cannot comment on the impact of these two factors
[39, 40] on outcome. Finally, outcome assessment at two years of age may both over - and underestimate long-term cognitive and motor neurodevelopment
The strengths of this study include the fact that it is based on a large national prospective database. The definition of neurodevelopmental outcomes was based on a recent consensus definition. The definition of severe ND required extremely low cognitive or motor performances, i.e. <−3SD, and/or severe neurosensory disabilities, thus identifying severely disabled children. In comparison, the definition of neurodevelopmental disability used in several previous studies overlaps with our definition of severe and moderate ND
[11, 22, 42]. The uni- and multivariate statistical models were highly similar, confirming the independent contribution of the major risk factors on outcome.