Background
Very preterm (VP) birth (i.e., before the 32 weeks of gestation) is a significant public health concern globally, and it is associated with high rates of mortality as well as short- and long-term morbidities [
1]. VP birth can result in neurodevelopmental, behavioural, and organ-specific health problems persisting throughout childhood and into adulthood [
2]. The sequelae of preterm birth can put a high burden on the family of the child, the health care system, and society [
1]. There is consistent evidence that mortality decreased over the decades into the 2000s, mainly in the group of extremely low birth weight / extremely preterm infants, and at gestational ages at the limit of viability [
3‐
7]. In the Netherlands, mortality of VP infants decreased from 25.4% to 1983 to 20.0% in 1995 [
8] and 18.1% in 2002 [
9]. The urgent question is whether this decrease in mortality might have led to a higher morbidity in the surviving infants.
Most studies conducted throughout different eras report an increase in infants surviving without major neonatal morbidities [
3‐
6]. Mixed outcome results were observed for single major morbidities like bronchopulmonary dysplasia (BPD), severe intraventricular haemorrhage (IVH), early and late-onset sepsis, severe retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) or patent ductus arteriosus [
3‐
7,
10,
11].
Introduction of new obstetric and neonatal/paediatric care practices in the 1990s [
3‐
5] that are nowadays considered as the most effective evidence-based practices [
12] might also explain improvements in neonatal morbidities of survivors. Antenatal corticosteroids given to women at risk of a VP delivery were implemented in order to promote foetal lung maturation. The use of antenatal corticosteroids has not only reduced mortality rates, but has also resulted in fewer neonates suffering from respiratory distress syndrome and IVH [
4]. Meanwhile, postnatal care introduced the use of nasal continuous positive airway pressure (CPAP), new ventilation techniques and most importantly, the intratracheal administration of surfactant [
4,
11]. In the 1990s, there was a trend in most national health care systems to establish and centralise neonatal intensive care units (NICUs), thereby providing professional and specialised care for VP-born infants [
4].
However, not only obstetric and neonatal care has changed, but there may also be changes in social conditions, such as higher educated mothers living in improved social circumstances and leading a healthier lifestyle (including fewer mothers smoking during pregnancy). Social factors have been found to be associated with both prenatal and neonatal morbidities as well as with infant outcome [
13,
14].
Evidence that neonatal morbidity still varies considerably across different regions in Europe [
15,
16] underlines the need to compare data at a national level, from cohorts recruited more than a decade apart. For this purpose, we have conducted a comparison of two community-based cohorts within only one country, namely the Netherlands: Project on Preterm and Small-for-gestational age infants (POPS, 1983) and Longitudinal Preterm Outcome Project (LOLLIPOP, 2002−03). Between 1983 and 2002−03, three new policies and acts have been passed and implemented in neonatal care in the Netherlands. First, new modalities such as antenatal corticosteroids, surfactant therapy, and high frequency ventilation were introduced [
17]. Second, the Act of the Dutch Ministry of Health [
18] has assigned 10 centres for neonatal intensive care treatment, while the Health Council [
19] has recommended obstetrical staff to transfer pregnant women with risk of premature birth to perinatal centres (centralisation). Third, the care of extremely preterm infants was conservative before the 2000s [
20] [
21] in terms that the obstetrical guidelines focused on the prolongation of pregnancy and not an increase of the number of live births. Intensive neonatal treatment for infants born < 26 weeks is only recommended in the Netherlands since 2005 [
21]. Because of considerable changes in neonatal care practices and national policies associated with improved survival, but still unclear improvement in neonatal morbidities of VP infants, there is a need for investigations to assess changes in neonatal outcomes and treatments throughout different eras. POPS and LOLLIPOP with community-based data from the same national background provide this opportunity. Therefore, this study aimed at identifying: (i) changes in neonatal morbidity, neonatal care practices, and the length of NICU and hospital stay of infants born VP between 1983 and 2003 in the Netherlands, and (ii) whether these changes are associated with sociodemographic and prenatal characteristics of the mother as well as with neonatal characteristics of the infant.
Discussion
The most important finding of this study was a significant decrease in the duration of NICU and hospital stay of VP-born infants in the Netherlands between 1983 and 2003. Additionally, changes in rates of neonatal morbidities and care practices were also observed: declined IVH- and sepsis-rates, and increased rates of apnoea and a more common use of CPAP and caffeine therapy in the 2000s,
Sociodemographic and prenatal characteristics
We observed a higher maternal age (30.5 vs. 27.2 years) and a higher parental education (41.9% vs. 25.4%) in LOLLIPOP, which can be explained by a general sociodemographic trend in Western Europe [
31,
32]. In the Netherlands maternal age at first childbirth increased from 28 years of age in 1970 to 30 years in 2000 and the rate of tertiary education rose from 22,2% (1990) to 32.1% in 2003. The decline of maternal smoking during pregnancy from 31.4% (POPS) to 20.5% (LOLLIPOP) could be expected, as the prevalence of daily smoking of Dutch adults decreased from 40% to 1983 to 26.7% in 2003 [
33]. Meanwhile, the general trend for total fertility rate increased from 1.47 to 1.75 between 1983 and 2003 in the Netherlands [
34]. In this study, we observed more primipara in LOLLIPOP.
Infant characteristics
In both cohorts, the prevalence of infants born before 26 weeks GA was under 2%. This phenomenon can be attributed to the fact that the policy on the treatment of VP infants was still conservative at the beginning of the 2000s in the Netherlands, with neonatal intensive care not routinely provided to infants born earlier than 26 weeks GA [
20]. The number of multiple births was higher in the LOLLIPOP cohort. This is in line with a general trend of increased rates of multiple births associated with the increased use of assisted reproductive technologies (where multiple embryos were implanted) [
4] and the increasing age of the mothers [
35]. We observed improved obstetrical outcomes of infants born in the 2000s in terms of the rate of PPROM, meconium-stained amniotic fluid and low APGAR score when compared to the POPS infants. This may be attributed to the improved pregnancy care. The incidence of caesarean sections increased over time, and fits into the international trends [
36].
Neonatal morbidity
Our study revealed that the incidence of severe IVH and sepsis decreased in VP survivors over the two decades examined. The diagnosis of apnoea increased significantly from 66.9% (in 1983) to 90.8% (in 2003). Changes in the rates of some neonatal morbidities can be attributed to new routine care practices established between 1983 and 2003. The routine antenatal administration of corticosteroids to mothers with a risk of premature delivery may have played an important role in reducing the IVH rates [
4]. Our analysis shows that the cohort difference disappeared after adjusting for infant characteristics. This result corresponds with the findings that infant characteristics such as the higher APGAR score, and the caesarean section can be associated with the decline in severe IVH rates [
37]. Our study has revealed that low GA was a stronger risk factor for severe IVH than the cohort itself. Nevertheless, previous studies from the Netherlands have not reported any improved incidence of severe IVH in surviving VP infants between the 1980s and the 1990s (incidence rate of severe IVH was approximately 8% in the 1990s) [
8,
38,
39].
We found an incidence of 27.7% of sepsis in 2003. This rate corresponds with results of other studies reporting late-onset sepsis incidence in the 2000s [
10,
40], but it seems to be high when compared with a population-based finding from Switzerland [
6]. Other authors reported a decrease in both early- and late-onset sepsis in the tertiary hospitals with NICU in the Netherlands between the 1980 and 2000 s which could be associated with group B Streptococcus prophylaxis by giving antibiotics to mothers with imminent preterm birth [
41]. In addition, better availability of alcohol-based hand rubs should have become more common by the 2000s. Although, the lack of a general protocol on hand hygiene caused differences in various NICUs how sufficiently hospital workers used hand hygiene before contacting VP infants [
42,
43].
The almost 100% occurrence of apnoea may be due to the increased use of CPAP instead of mechanical ventilation (see
Neonatal care practices section),but could also be due to an increased awareness of apnoeic events and of the necessity of them being treated. The use of an accurate automated computer algorithm for detecting apnoea is a more reliable measure than the medical record that was mainly used in the previous years [
44]. At the same time, the epidemiology of apnoea remains controversial [
45]. Due to the different definitions for BPD used in the cohorts (diagnosis at postnatal 28 days
versus 36 weeks postmenstrual age), this study could not analyse the collected BPD data. Only the duration of mechanical ventilation, as a possible factor affecting the BPD rates, was documented here, and it remained constant between 1983 and 2003. Anthony et al. [
8]. have reported an increase in mean ventilatory days in the Netherlands: from 8.6 days in 1983 (POPS) to 14.2 days in 1995. However, this result can neither confirm nor reject the findings of other studies conducted in Europe that have reported an incidence of BPD around 10–20% [
46] or exceeding 40% in the 2000s [
47,
48].
Neonatal care practices
There is good evidence that four neonatal care practices (namely birth in a tertiary centre with a NICU, the administration of antenatal corticosteroids, the prevention of hypothermia, and surfactant applied within 2 h after birth or early nasal CPAP) can result in survival with less severe morbidity for infants at high risk [
12]. One of the four basic neonatal care practices (i.e., CPAP) was added to our analysis. We have found an increased use of this type of respiratory support in the LOLLIPOP cohort (increase of almost 40%). More LOLLIPOP infants received mechanical ventilation as well, but the increased rate of mechanical ventilation was less than 10%. CPAP was introduced into the neonatal care practices in the 1970s [
49,
50], but it was still not used on a large scale in the 1980s when still mechanical ventilation was the primary treatment of respiratory failure of VPs [
51]. Between the 1980 and 2000 s, several studies found that bubble CPAP at the delivery room could both prevent mechanical ventilation and reduce ventilatory induced lung damage [
52,
53]. Additionally, the harmful effect of mechanical ventilation on neurodevelopment was meanwhile also reported [
54]. This evidence should have resulted in a leading role of CPAP in the neonatal routine care by the 2000s.
We observed an increased rate of use of caffeine therapy in LOLLIPOP indeed. While in the 1980s, both theophylline and caffeine were used for treating apnoeic events, the largest trial about the beneficial effect of caffeine therapy in preventing BPD and neurodevelopmental impairments at 18 months of age was published in 2006 [
55,
56]. As a RCT in 1992 reported that caffeine was more effective than theophylline in reducing apnoea [
57], we can assume that caffeine therapy increasingly became an important part of neonatal care practices by the 2000s.
Therapies accelerating lung maturation and supporting lung function were administered only in the LOLLIPOP (and not in the POPS) at a proportion of 53.4% for complete antenatal corticosteroid treatment and 37.8% for receiving surfactant therapy. The rate of the use of a surfactant therapy is in line with [
6] or below [
5,
10] the average proportion of other findings from the 2000s. Other studies have reported both complete and incomplete steroid treatments received by the mother [
10,
58] that can explain the lower proportion of full courses of antenatal corticosteroids administered in LOLLIPOP.
Length of hospital stay
This study shows a significant decline in the length of NICU and of total hospital stay after a VP birth in 2003. The EuroHOPE Study [
59] has compared the length of hospital stay of VP/VLBW infants from seven European countries between 2006 and 2008. Surviving infants spent between 46.2 and 61 days in the hospital until their first discharge. For the Netherlands, a median of 53.4 days is reported, which compares well with the 54 days observed here for the LOLLIPOP study (2003).
This difference in the length of NICU and hospital stay between the 1980s’ and the 2000s’ cohorts remained significant after an adjustment for neonatal morbidity and care practices. Thus, the study does not confirm that the length of the NICU and the hospital stay are closely connected to neonatal morbidity and care practices as analysed. The decline may be caused by the national protocols that were introduced between the two timepoints, e.g., new routines in the perinatal care and centralisation of neonatal institutions. In a European cross-country comparison, Maier et al. [
60]. revealed that the median hospital stay after a VP birth was 51 days (range: 41−71 days) in 2003 in the Eastern-Central region of the Netherlands. This was below the average hospital stay in the European regions investigated (median: 56 days, range: 41–77 days). The authors have argued that this result might be explained by not providing an active management for infants born at before 26 weeks GA.
Our findings show that neonatal morbidities and care practices studied in this paper cannot explain the differences between cohorts in length of NICU and hospital stay. At the same time, we have to emphasise the decreasing rate of severe IVH and sepsis over time. In this study, we were not able to analyse potential changes in the incidence of various neonatal morbidities. There is evidence that BPD, ROP and periventricular leukomalacia became less frequent in the 2000s [
40]. The more frequent use of CPAP and caffeine therapy could indicate a faster and more effective treatment of respiratory problems which could have resulted in fewer days spent in the hospital after birth. In the frame of this study, we cannot explain possible effects of other neonatal care practices such as feeding with human milk, community nursing, more discharges on partial tube feeds or the modification of discharge criteria. Additionally, specific maternal characteristics such as SES and maternal illness could have influenced preterm birth [
61] and thus the development of neonatal morbidities and the length of hospital stay.
Strengths, limitations, and implication for further research
As a strength, this study has compared data collected in the same country, with an identical population background, at two timepoints with a considerable difference of 20 years. The two cohorts represent a sizeable proportion of VP infants in the Netherlands in the respective years (POPS: 94%; LOLLIPOP: 25%). The study has also analysed data of VP infants who survived at least until 2 years of age. Finally, a rigorous protocol for the harmonisation of all variables selected for this study was followed. As a result of the harmonisation employed herein, only characteristics with identical definitions were considered eligible for analysis. The harmonisation we carried out forms a basis for undertaking further comparative analyses between POPS and LOLLIPOP that focus on the developmental outcomes of VP-born children in the future.
Among the limitations of our study are the differences of the two cohorts in terms of their research goals and the data collection methods followed. LOLLIPOP is a cohort with inclusion at age of 4 with retrospective data collection of perinatal and other follow-up data. This has resulted in missing data on the early life period. Due to different designs, in the strict harmonisation as used, several important characteristics had to be excluded from the analysis (e.g., BPD and maternal diabetes). Moreover, the cohorts did not provide detailed information about the administration protocol of some care practices (e.g., for starting and ending CPAP-therapy, nutrition of the infants or growth data at discharge). Some data not collected or lost during the harmonisation (e.g. sociodemographic status, maternal illness) could have influenced the results of this study. Missing values could have also influenced the results, although most of the variables included in this study comprised rates of missing data around 10–15% or below.On one hand, this comparison of both cohorts does not provide a whole picture of changes of the medical and social characteristics of the VPs over time. On the other hand, we analysed data on the basis of identical characteristic definitions between two studies with different study design. This could be a direction for future investigations, both for within-country and cross-country comparisons of characteristics, short-term or long-term morbidities of VPs. Our harmonised dataset from POPS and LOLLIPOP is a strong basis for future comparative analysis with regard to long-term health and development of the selected children.
Conclusions
This comparative study of two VP-born infant cohorts from 1983 and from 2003 in the same country has identified substantial changes in terms of the rates of IVH, sepsis, apnoea, the use of CPAP, the use of caffeine therapy, and the length of NICU and hospital stay. Studies investigating changes in neonatal morbidity with changes in neonatal care need to consider the sociodemographic changes of the populations over time. Although, we could not identify the effect of sociodemographic parameters on changes in neonatal morbidity and care practices, we cannot state that other potential sociodemographic parameters did not influence the improvements. We found that altered therapeutic approaches may have led to fewer cases of severe IVH and sepsis. Moreover, the improved neonatal care practices (including the use of antenatal corticosteroids, the use of surfactant therapy, and the improved respiratory support) may have contributed to the cost-reducing shortening of the length of NICU (− 50%) and total hospital (− 15%) stays.
Most remarkable is the fact that, despite a considerable increase in the survival rates from 1983 to 2003, the neonatal morbidities of the surviving infants investigated here have not increased. This is promising and may be due to changes implemented in the applied national protocols over the period of time studied.
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