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Changing Dutch approach and trends in short-term outcome of periviable preterms
  1. Maria J Zegers1,
  2. Chantal W P M Hukkelhoven2,
  3. Cuno S P M Uiterwaal3,
  4. Louis A A Kollée1,
  5. Floris Groenendaal4
  1. 1Department of Neonatology, Radboud University Medical Centre, Nijmegen, The Netherlands
  2. 2The Netherlands Perinatal Registry, Utrecht, The Netherlands
  3. 3Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands
  4. 4Wilhelmina Children's Hospital, Utrecht, The Netherlands
  1. Correspondence to Chantal W P M Hukkelhoven, The Netherlands Perinatal Registry, Postbus 8588, Utrecht 3503 RN, The Netherlands; chukkelhoven{at}perinatreg.nl

Abstract

Background In 2006, the Dutch guideline for active treatment of extremely preterm neonates advised to lower the gestational age threshold for active intervention from 26 0/7 to 25 0/7 weeks gestation.

Objective To evaluate the association between the guideline modification and early neonatal outcome.

Design National cohort study, using prospectively collected data from The Netherlands Perinatal Registry.

Patients The study population consisted of 9713 infants with a gestational age between 24 0/7 and 29 6/7 weeks, born between 2000 and 2011. Three gestational age subgroups were analysed: 24 0/7 to 24 6/7 weeks (n=269), 25 0/7 to 25 6/7 weeks (n=852) and 26 0/7 to 29 6/7 weeks (n=8592).

Main outcome measures Neonatal intensive care unit (NICU) admission, live births, neonatal in-hospital mortality, morbidity and favourable outcome (no mortality or morbidity) before (2000–2005; period 1) and after (2007–2011; period 2) introduction of the modified guideline, using χ2 tests and univariable and multivariable logistic regression analyses.

Results In the second period, the proportion of live births and NICU admissions increased and the proportion of neonatal and in-hospital mortality decreased significantly in all subgroups. Morbidity in surviving infants of 25 weeks increased significantly, although the association between guideline modification and morbidity became non-significant after case-mix adjustment. Overall, favourable outcome did not change significantly after guideline modification in all subgroups when adjusted for variation in case-mix.

Conclusions Overall, the trend in mortality gradually declined at all gestational ages, starting before 2006. This suggests that the guideline modification was a formalisation of already existing daily practice.

  • Epidemiology
  • Neonatology
  • Mortality

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What is already known on this topic

  • Mortality, short-term and long-term morbidity are high in extremely preterm infants.

  • Dutch neonatal policy was restricted before 2006 in extremely preterm infants born before 26 0/7 weeks, resulting in higher mortality compared with other European countries.

  • In 2006, the restricted Dutch neonatal guideline was modified into a more active treatment for infants born between 25 0/7 and 25 6/7 weeks gestation.

What this study adds

  • After the guideline modification in 2006, the percentage of neonatal intensive care unit (NICU) admissions increased significantly in infants born at 24 0/7 to 29 6/7 weeks gestation.

  • A declining mortality trend exists in infants born at 24 0/7 to 29 6/7 weeks gestation, which started before the guideline of 2006.

  • Morbidity did increase in survivors born between 25 0/7 and 25 6/7 weeks gestation, although this became non-significant after case-mix adjustment.

Introduction

Until 2006, the Dutch guideline for active treatment of extremely preterm births has been very restrictive because of serious short-term morbidity and adverse neurological and cognitive long-term outcomes.1–5 Briefly, infants born between 22 0/7 and 25 6/7 weeks were not admitted to a neonatal intensive care unit (NICU) unless they were considered viable. Compared with other countries, infants born ≤26 0/7 weeks gestation had a higher neonatal mortality, while no differences in either treatment guidelines or mortality existed for infants born at 27 0/7and 32 6/7 weeks gestation.5–8

In 2006, the restrictive Dutch guideline was modified to include active treatment of newborns between 25 0/7 and 25 6/7 weeks gestation unless strong reasons to withhold or withdraw treatment are present.9 To investigate whether the modified guideline has influenced early neonatal outcome of very preterm infants, we studied trends and changes in NICU admission, mortality and morbidity in two periods, that is, before and after the guideline modification (2000–2005 and 2007–2011). It should be mentioned that the 2006 guideline was modified again in 2010 by advising active treatment of neonates born at 24 0/7 to 24 6/7 weeks gestational age.10

Methods

Data sources

Data from the Netherlands Perinatal Registry (PRN) were used. This registry contains linked and validated population-based information concerning pregnancy, delivery, (re)admissions and pregnancy outcomes.11 Data are registered by midwives (LVR1-registration), obstetricians (LVR2-registration), general practitioners (LVRH-registration) and paediatricians/neonatologists (LNR-registration). The PRN covers approximately 95% of all births ≥16.0 weeks gestation in the Netherlands.11 For this study, data were retrieved from two different databases of the PRN registry. The first contains information registered by paediatricians and neonatologists only (LNR). The other database contains information on LVR1, LVR2, LVRH and the first admission at the paediatric department or NICU. All 10 perinatal centres with a level III NICU facility delivered data for this registry.

Study population

From the LNR, we selected all live-born infants with a gestational age of 24 0/7–29 6/7 weeks and weighing ≥500 g, born between 1 January 2000 and 31 December 2011. Infants born before 24 0/7 weeks gestation or infants with a birth weight ≤500 g were excluded since they were not treated actively until October 2010 unless apparently viable.9 Furthermore, infants with severe congenital malformations, chromosomal abnormalities or Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes Simplex, Enterovirus and Syphilis infections were excluded as they carry a high risk of adverse outcome irrespective of treatment (n=276 (5%) before and n=274 (6%) after the guideline modification). To evaluate live births, all infants with a gestational age of 24 0/7 to 29 6/7 weeks were selected from the linked database LVR1/LVR2/LVRH/LNR.

Outcome measurements and characteristics

Five outcome measurements were analysed, that is, live births (percentage of total births), neonatal (during the first 28 days of life) and in-hospital (including after 28 days) mortality in NICU admissions, morbidity and favourable outcome (survival without morbidity) in NICU survivors. All outcome measurements were determined using the LNR data set, except the number of live births.

Morbidity was defined as a composite variable of at least one of the following neonatal complications: chronic lung disease defined as oxygen needed at 36 weeks postmenstrual age (CLD),12 intraventricular haemorrhage grade III and IV defined by Papile's classification (IVH-III/IV),13 posthaemorrhagic ventricle dilatation, periventricular leukomalacia grade II and III defined by de Vries’ classification (cPLV-II/III),14 surgery for retinopathy of prematurity (ROP)15 and perforated necrotising enterocolitis.

Statistical analyses

Three subgroups were defined, consisting of infants with a gestational age of 24 0/7 to 24 6/7 (‘24 weeks’), 25 0/7 to 25 6/7 (‘25 weeks’) and 26 0/7 to 29 6/7 ('26+ weeks’). Infants born before 24 0/7 weeks gestational age were not included because in the Netherlands they were not treated actively until October 2010.16 Therefore, the perinatal guideline is not applicable for these infants. Furthermore, infants born at a gestational age of >29 6/7 weeks were not included since in the Netherlands a part of these infants are born in hospitals with a level II neonatal facility. Maternal and neonatal characteristics were compared between the three subgroups, before (2000–2005; period 1) and after (2007–2011; period 2) the guideline modification, using χ2 statistics and Student's t test where appropriate.

To compare the outcomes before and after the guideline modification for each subgroup, we used contingency tables with χ2 statistics, Fisher's exact test and univariable and multivariable logistic regression analyses. Case-mix correction for temporal variation was performed for variables with a proven effect on neonatal outcome in the literature (sex, small-for-gestational age (<10th weight percentile), maternal socio-economic status (based on four-digit postal code),17 multiple birth and being born in a level III perinatal centre—‘inborn’)). The logistic regression analysis was performed separately in all three gestational age subgroups. Furthermore, trends in outcomes were evaluated over the whole study period. p-Values <0.05 were considered statistically significant. Calculations were performed using a statistical software package (SAS V.9.2; SAS Institute, Cary, North Carolina, USA).

Results

Study population

The LNR study population (live born, admitted to an NICU, 24 0/7 to 29 6/7 weeks, ≥500 g, without congenital malformations) consisted of 10 528 infants with 5254 and 4459 infants born before and after the guideline modification, respectively. The LVR1/LVR2/LVRH/LNR study population (stillborn and live born, 24 0/7 to 29 6/7 weeks) consisted of 15 186 infants with 8055 and 5947 infants born before and after the guideline modification, respectively. Table 1 shows the maternal and neonatal baseline characteristics of the subgroups in both periods based on the LNR. Frequencies of most maternal and neonatal characteristics were similar before and after the guideline modification. Remarkable was the increased proportion of very preterm infants born in a centre with an NICU facility after the guideline modification (table 1).

Table 1

Maternal and neonatal characteristics before and after guideline modification

NICU admissions

The proportion of NICU admissions in the total study population increased strongly after the guideline modification from 8.5% to 30.2% at 24 weeks, from 39.1% to 68.4% at 25 weeks and from 76.7% to 82.4% at 26+ weeks (p<0.05).

Live-born infants

The number of live-born infants was significantly higher in period 2 compared with period 1. It increased from 47.5% to 58.3%, from 57.6% to 70.3% and from 79.7% to 84.1% at 24, 25 and 26+ weeks, respectively (p<0.0001) (table 2).

Table 2

Outcome measures before and after guideline modification

Mortality

Neonatal and in-hospital mortality were significantly lower in all subgroups in period 2 (table 2).

Table 3 shows the unadjusted and adjusted association between the two study periods and mortality and morbidity. Mortality occurred approximately five times less at 24 weeks, about three times less at 25 weeks and approximately two times less at 26+ weeks after case-mix adjustment (table 3).

Table 3

Association between the two study periods and mortality and morbidity

Neonatal morbidity

Neonatal morbidity in surviving infants after NICU admission significantly increased after the guideline modification from 37.7% to 46.6% at 25 weeks (p<0.05; table 2). However, after adjustment for case-mix, the ORs remained similar but became non-significant (table 3). Overall, after the guideline modification, outcome was not significantly more favourable for all gestational ages after case-mix adjustment (table 3).

Trends

Figure 1A, B shows the trends in in-hospital mortality and neonatal morbidity. The year in which the guideline was modified is marked (2006). In the second time period, in-hospital mortality declined in all subgroups. At 24 weeks, it has a peak incidence between 2005 and 2007 but shows a steep decline thereafter. Morbidity slightly increased at 24 weeks after 2006. At 25 weeks, morbidity increased slowly in the second time period. It remained stable at 26+ weeks. Trends in in-hospital mortality and neonatal morbidity per gestational age before and after the guideline modification are shown in figure 2A. In general, mortality and morbidity were both lower in period 2 and declined per week gestational age. Figure 2B shows trends in favourable outcome, which was higher after the guideline modification in all subgroups and increased per week gestational age.

Figure 1

(A) In-hospital mortality in neonatal intensive care unit (NICU) admissions over the years 2000–2011. (B) Morbidity in survivors after NICU admission over the years 2000–2011.

Figure 2

(A) In-hospital mortality in neonatal intensive care unit (NICU) admissions and morbidity in survivors after NICU admission per gestational age (weeks) before (2000–2005) and after (2007–2011) the guideline modification. (B) Favourable outcome in NICU admissions per gestational age (weeks) before (2000–2005) and after (2007–2011) the guideline modification.

Discussion

We evaluated early neonatal outcome in an 11-year period in the Netherlands and focused on the modification of the Dutch perinatal and neonatal guideline in 2006, recommending active treatment of neonates born at a gestational age of 25 0/7 weeks or more. We demonstrated that, after the guideline modification, the proportion of neonatal and in-hospital mortality decreased not only at 25 weeks, but also at 24 and 26+ weeks gestational age. However, increased survival at preterm age comes at a price: serious morbidity in survivors born at 24 and 25 weeks increased with potential negative effects on long-term neurodevelopmental outcome. Overall, after correction for case-mix, no significant changes on morbidity or favourable outcome could be demonstrated.

Perinatal mortality as well as neonatal treatment decision-making guidelines in extremely preterm infants in the Netherlands has been the subject of much debate.6–8 ,18–20 In 1967, the Netherlands had the lowest perinatal mortality in Europe. However, two decades later, the decline in perinatal mortality seemed to develop slower than in other European countries. The PERISTAT report in 2004 mentioned that the Netherlands had one of the highest perinatal mortality rates in Europe: 7.1 per 1000 births, which was the 15th highest perinatal mortality rate in 22 countries (range 4.2–9.4 per 1000 births). In 2010, perinatal mortality decreased to 5.1 per 1000 births (range 2.3–8.4 per 1000 births). However, this was still 13th rank. Remarkably, neonatal mortality did not show a declining trend.21–23 Many hypotheses and studies, considering registration of newborns, the percentage of non-Western immigrants, maternal age and smoking habits, appeared to clarify differences between the Netherlands and other European countries. However, these factors cannot fully explain the differences in perinatal mortality.24–27 Perinatal care is considered to be an important factor since the Dutch treatment guideline concerning extremely preterm births (22 0/7 to 25 6/7 weeks) was, until recently, very restrictive in comparison to surrounding countries, based on the high neurological and cognitive morbidity in short-term and long-term follow-up studies.1–4 ,24 ,28–31 This resulted in a higher mortality rate in extremely preterm infants compared with countries with a less restrictive policy.

In this study, the number of live-born infants increased after modification of the guideline in 2006. In addition, the proportion of infants born in a perinatal centre was higher at all gestational ages after the guideline modification. Neonatal and in-hospital mortality rate as well as the mortality risk significantly decreased after the guideline modification in all subgroups. Mortality proportions in this study are similar to those in other European countries and Canada, which have a more active treatment approach. Our mortality rate was comparable to the EPICure II study and other studies in countries with an active treatment approach in extreme prematurity.2 ,5 ,10 ,32–37 Explanations for the improved mortality figures may be technological (more lung protective ventilation strategies, early caesarean section), pharmacological (systematic antenatal corticoid and surfactant administration) and organisational (early prenatal transfer and centralised management).1 ,33 ,36 ,38

Moreover, the decreasing mortality over the years 2000–2005 suggests also an effect of general improvements in perinatal and obstetric care. By applying a case-mix correction for being inborn, we tried to minimise the influence of prenatal care including intrauterine referral policy and show the effect of treatment policy when admitted to an NICU more clearly. In spite of the fact that the guideline modification focused only on children born at 25 weeks gestation, mortality decreased in all gestational age subgroups. As mentioned, the 2006 guideline was later replaced by the Dutch 2010 guideline, advising active treatment of neonates born at 24 0/7 to 24 6/7 weeks gestational age,10 which might have influenced our overall figures in the period 2006–2011. Interestingly, mortality also decreased at 24 weeks, which may have contributed to the 2010 guideline. However, no conclusion can be drawn regarding the trend after 2010 because of the small number of included infants after this guideline adaption. Mortality results at 24 weeks were also comparable to the EPICure II study.29 This supports the contributing factor of improved perinatal care in the survival of extremely preterm infants.

Overall, there is a declining trend on neonatal mortality in all extremely preterm infants, starting years before the guideline modification, suggesting that 2006 was a transition period and a formalisation of neonatal policy what was already existing daily practice. Decreased total birth rate does not explain these results because the percentage of infants born <32 weeks gestational age did not decrease in the last years (total birth rate in the Netherlands decreased from 191.385 in 2000 to 178.723 in 2011, with no difference in percentage of infants born <32 weeks gestational age (1.4%)).39

A higher survival of extremely preterm children could be accompanied by short-term morbidity and long-term handicaps,1–4 ,28–30 although other recent studies do not support this.29 ,32–34

Our results suggest a higher morbidity at 24 and 25 weeks; however, this became non-significant after case-mix adjustment. The results even suggest a better favourable outcome after the guideline modification, although this was also non-significant.

Strengths and limitations of this study

The major strength of this study is the use of a large national population-based cohort using validated and detailed population information. However, this study has several limitations too.

First, no data were reported for later psychomotor development, which is known to be higher in preterm neonates.30 ,31 However, this study analysed serious short-term morbidity, which is known to be related to neurodevelopmental impairments.

Second, outcomes were not adjusted for some maternal and neonatal characteristics and pregnancy parameters. Most detailed information about infants admitted to the NICU is obtained from the LNR (paediatric) database. However, this database did not register detailed maternal characteristics before 2008 and no pregnancy parameters after 2008. Third, some level I–II paediatric units did not contribute to the national database. This may have resulted in under-reporting of CLD and ROP.

Future detailed monitoring of the registered data could improve the quality of these data. Furthermore, the effects of adjusted gynaecological policy, like more and early referral to a perinatal centre, active inhibition of labour at very preterm age and more active maternal administration of corticosteroids, cannot be evaluated in this study. These factors can interact with the neonatal policy and explain improved mortality rates.

Finally, the data from the three registries were linked and validated with a probabilistic linkage technique.40 However, because of registration errors (eg, typing errors) and because only few linkage variables are available in the LNR for about 8% of the neonates registered in the LNR, no accessory LVR1, LVR2 or LVRH record could be found. Therefore, we were not able to validly analyse the number of live-born infants who were not admitted to the NICU, but died in the delivery room.

In conclusion, this study confirmed that the modified Dutch guideline for more active treatment of infants born after 25 0/7 weeks gestation in 2006 was accompanied by significantly more live-born infants and NICU admissions and a decrease of neonatal and in-hospital mortality of extremely preterm babies. However, this was accompanied by more severe neonatal morbidity with a major risk of long-term health problems, although this was non-significant. Long-term follow-up is, therefore, necessary to evaluate the effects of active treatment at the lower limit of viability.

References

Footnotes

  • Contributors All authors were involved in development of the hypothesis, interpretation of the results and production of the manuscript. MJZ and CWPMH were responsible for the data analyses. FG, CWPMH, CSPMU and LAAK revised the article. All authors have approved the final version.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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