EPI-DAF

On the basis of international studies, a new guideline on perinatal treatment of spontaneous extreme preterm birth was implemented in The Netherlands in October 2010 (1). With this new national guideline the border of viability to support active treatment of extremely premature born children was lowered from 25 to 24 weeks’ gestation. Since the implementation in October 2010, the change in perinatal treatment has been evaluated in a small cohort (October 2010-October 2011). The survival rate of preterm infants of 24 and 25 weeks’ gestation has improved, but lower than other European countries (2). Of the children born at 24 and 25 weeks’ gestation and surviving to 2 years of age (24 week, 46% and 25 week, 65%), more than half had developed without disabilities (24 week, 60% and 25 week, 71%). Of all children, 25% (24 weeks) and 36% (25 weeks) survived to 2 years of age without disabilities (3). Limitations of the available Dutch evidence are related to the small sample size, the study period (first year after introduction of the guideline) and the retrospective character resulting in loss to follow-up. Outcome studies differ in survival rate, neonatal complications as well as in frequency of neurodevelopmental outcome, due to differences in national treatment policy, health care system, study period and cohort, and length of follow-up (4-8). Given the variability between countries, it is difficult to extrapolate international studies to The Netherlands (9). Hence, the availability of Dutch data on survival and outcome is important as this influence our antenatal counseling, resuscitation policies in the delivery room and NICU or revision of the perinatal guideline.

The national implementation of the 2010 guideline led to significantly more live-born infants born at 24 and 25 weeks’ gestation and improvement of survival. We hypothesize that neurodevelopmental outcome is within the range of variability of recent European studies (4, 5, 10, 11).

The aim is to collect prospectively the neurodevelopmental outcome at the corrected age of 24 months and 5½ years of extremely preterm infants below 27 weeks’ gestation born during a three-year period, between January 2018 and January 2021.

Multicenter study in all ten perinatal centers in the Netherlands. We will include all extremely preterm infants from 23 to 266 weeks’ gestation who attain the corrected age of 24 months or 5½ years in the period 1 January 2018 to 1 January 2021. The corresponding data of included children on birth, early neonatal morbidity and previous follow-up at 24 months if currently 5½ are retrieved from the national perinatal registry (Perined).

In general, the methodology follows the recommendation of the Dutch working group on follow-up of preterm infants (12). At the corrected age of 24 months assessment of Bayley Scale of Infant and Toddler Developmental (BSID III-NL, Dutch references), child behavior checklist, socio-economic status, neurology, gross motor function classification scale, visual and auditory acuity. At the corrected age of 5½ years assessment of the neurocognitive function (Wechsler Intelligence Scale for Children or Wechsler Preschool and Primary Scale of Intelligence, Dutch references), neurology, movement ABC and gross motor function classification scale, visual and auditory acuity.

1. Each perinatal center is responsible for uploading data of the neonatal registration form (revised LNR form, 2018) via the web-based entry module of Perined. Each perinatal center is responsible for uploading follow-up data (including socio-economic status, BSID

III-NL results, neurology, gross motor function classification, visual and auditory acuity etc.) via the web-based entry module of Perined.

2. Each perinatal center is responsible for inviting parents and their childr(en) for follow-up at the corrected age of 24 months and 5 ½ years, according to the recommendation of the Dutch working group on NICU follow-up. Loss to follow up will be registered.

3. Within each perinatal center three health care providers (pediatrician(-neonatologist), psychologist or physiotherapist) are asked for the study. One of them is denoted as primary investigator (PI) for the study. The local PI will co-author on future publications, as collaborator or study group, depending on journal requirements.

4. Perined supports the web-based entry module for data input/acquisition of the follow-up data at the corrected age of 24 months and 5½ years. In the case that data on follow-up are stored locally in one of the perinatal center, Perined supports the technical link between local data with the central database. To accomplish this linkage, local files will be transferred to the server of Perined.

5. In collaboration with each center and local PI’s, the PhD student supports in uploading follow-up data via the entry module. In addition, the PhD student reviews the corresponding historic neonatal data for consistency and edit missing data or errors via the entry module of Perined.

6. Perined provides one unique database with linked maternal and neonatal variables from all centers and coupled with the follow-up data at the corrected age of 24 months and 5½ years. This database is corrected for double admissions and forms the basis for the study. The study will be performed within Perined according to Perined regulations. Only anonymous data will be transferred outside Perined.

7. As handling of personal data has to comply with the Dutch personal data protection act, a non-disclosure agreement between PhD student and each perinatal center is advised. In addition, the PhD student is certified for good clinical practice or “Basiscursus regelgeving en organisatie van klinisch onderzoek" (BROK).

8. As all collected data is according to the recommendation of the Dutch working group on follow-up of preterm infants (Dutch Society of Pediatrics), this study is not subjected to the Dutch law “Medisch Wetenschappelijk Onderzoek met mensen” (WMO).

9. Informed consent of the parents is not necessary for the neonatal data. For the follow-up at the corrected age of 24 months and 5 ½ years, parents will be asked to give informed consent. This consent is necessary to include the follow-up data.

The primary outcome measure is a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death, as assessed at 24 months or 5 ½ years of corrected age. Neurodevelopmental impairment is internationally defined as no, mild, moderate and severe (4, 5, 10). 

Neurodevelopmental outcome assessment at corrected age of 24 months in the period 1 January 2018 to 1 January 2021 corresponds to infants born between 5 September 2015 and 2 October 2018, depending on gestational age. Neurodevelopmental outcome at corrected age of 5½ years in the period 1 January 2018 to 1 January 2021 corresponds to infants born between 5 March 2012 and 2 April 2015, depending on gestational age. From the national perinatal registry the estimated numbers of infants with 23 to 26 weeks’ gestation are 25, 250, 250 and 475, respectively (n= 1025) for both groups. The infants who will survive for primary outcome assessment will be approximately 10, 115, 200 and 400 (n=725). Taking loss-to follow-up into account (15-20%) we expect to include 600 children for follow up at 24 months as well as for follow-up at 5½ years.

In this observational study a formal sample size analysis is not easy to apply. The EXPRESS and EPICure-2 studies - with the same primary outcome measures on neurodevelopmental delay - included 456 and 576 children, respectively (4, 5). With the expectation of 600 children we assume that an appropriate comparison with international studies is feasible. Results will be presented as median with interquartile range, numbers with proportion (%), proportion with 95% confidence interval, or as odds ratios with 95% confidence interval. Group differences will be calculated using the χ2 test or Fisher exact test for dichotomous variables, and Mann-Whitney U test for continuous variables. One-year survival rate will be calculated by standard Kaplan-Meier survival analysis (95% confidence interval) and log rank test for significance. If appropriate, multiple cox regression analysis with calculation of hazard ratio and 95% confidence interval of confounders will calculated. A p-value <0.05 will be considered statistically significant. Data on neonatal variables and socio-economic status will be estimated for those formally followed up and those lost to follow-up. For neurodevelopmental impairment, percentages by week of gestation with 95% confidence intervals are presented. Using neonatal variables considered likely to influence outcome, predictor modeling (i.e. deep learning, machine learning) will be employed for the composite score on neurodevelopmental delay (none, mild, moderate, severe) in survivors to the corrected age of 24 months or 5 ½ years, respectively. Data will be analyzed in collaboration with the Department of Mathematics & Computer Science of the Eindhoven University of Technology.

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2. de Kluiver E, Offringa M, Walther FJ, Duvekot JJ, de Laat MW, Implementatiegroep Richtlijn Extreem Prematuren. Perinatal policy in cases of extreme prematurity; an investigation into the implementation of the guidelines. Ned Tijdschr Geneeskd. 2013;157(38):A6362.

3. Aarnoudse-Moens CSH, Rijken M, Swarte RM, Andriessen P, Ter Horst HJ, Mulder-de Tollenaer SM, et al. Two-year follow-up of infants born at 24 weeks gestation; first outcomes following implementation of the new 'guideline for perinatal policy in cases of extreme prematurity'. Ned Tijdschr Geneeskd. 2017;161(0):D1168.

4. Serenius F, Kallen K, Blennow M, Ewald U, Fellman V, Holmstrom G, et al. Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in sweden. JAMA. 2013 May 1;309(17):1810-20.

5. Moore T, Hennessy EM, Myles J, Johnson SJ, Draper ES, Costeloe KL, et al. Neurological and developmental outcome in extremely preterm children born in england in 1995 and 2006: The EPICure studies. BMJ. 2012 Dec 4;345:e7961.

6. Ancel PY, Goffinet F, EPIPAGE-2 Writing Group, Kuhn P, Langer B, Matis J, et al. Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in france in 2011: Results of the EPIPAGE-2 cohort study. JAMA Pediatr. 2015 Mar;169(3):230-8.

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12. Leden werkgroep Landelijke Neonatale Follow-up, (LNF). Aanbeveling landelijke neonatale follow-up- NICU follow-up&nbsp; . 2015 Januari,.

13. EXPRESS Group, Fellman V, Hellstrom-Westas L, Norman M, Westgren M, Kallen K, et al. One-year survival of extremely preterm infants after active perinatal care in sweden. JAMA. 2009 Jun 3;301(21):2225-33.