Tot eind september werden 375 vrouwen geregistreerd en 332 vrouwen gerandomiseerd. 175 vrouwen werden in Nederlandse centra geincludeerd.
Inclusie is gering vertraagd doordat een van de Nederlandse centra (Zwolle) wegens vertrek van de hoofdonderzoeker, tijdelijk niet includeerde. Per 1-10 zal inclusie dar weer hervat worden. Voorts is het Academisch Ziekenhuis Groningen, na een wat lange voorbereiding, nu in staat om te participeren. We gaan er van uit dat de voortgang van de studie het komende jaar weer het eerdere tempo zal oppakken.
De gemiddelde zwangerschapsduur bij randomisatie is 29 weken (SD 1.5). Verlenging van de zwangerschap na inclusie is gemiddeld 1.5 weken. Gemiddeld geboortegewicht is 965 gram (SD 274). Dit betekent dat voldoende vrouwen bij een zeer vroege zwangerschapsduur zijn geïncludeerd. Dit is van belang aangezien, als een verschil in uitkomst tussen de randomisatie groepen optreedt, dit naar verwachting het meest uitgesproken zal zijn bij de meest premature kinderen.
Follow up met Bayley III werd vorig jaar georganiseerd en kinderartsen of psychologen van alle centra zijn inmiddels getraind om de Bayley III uit te voeren. Kinderen geboren tijdens het eerste studie jaar werden inmiddels getest met slechts zeer geringe uitval.
Nog niet bekend
Optimal management of severe early fetal growth restriction is one of the greatest challenges in Obstetrics. In case of abnormal fetal monitoring obstetricians are often uncertain when to deliver these babies and how to balance between the complications of extreme preterm delivery and the risks of prolonged intrauterine exposure to malnutrition, hypoxia and antepartum death.
Prospective observational research by the study group and others has provided evidence that Doppler measurement of the fetal ductus venosus (DV) may be the best parameter to guide timing of delivery in these pregnancies. However this hypothesis needs further evidence. The objective of this multi-centre randomised protocol, approved by the editorial board of the Lancet, is to determine which technique results in optimal timing of delivery of early preterm growth restricted infants: DV measurement (two different cut-offs - 1. mild or 2.severe abnormality) and 3. traditional monitoring based on cardiotocography with measurement of short term variation (STV) will be compared. Criteria for inclusion aim at selecting a group of early and severe growth restricted fetuses with a gestational age between 26 and 32 weeks. Randomisation will assign fetuses to the three branches. The primary outcome is normal neurological outcome at 2 years, corrected for gestational age at delivery, without minor or major sequelae, examined by Griffith`s Mental Developmental Scale. Two years is the earliest age to evaluate infant development. Composite adverse infant outcome, defined by major neonatal morbidity and mortality until discharge, is an intermediate endpoint, which will be used for safety monitoring and for an interim report.
The hypothesis of the study is that among preterm growth-restricted infants timing delivery when the fetal DV is just marginally or severely abnormal, i.e. before the onset of severe fetal hypoxemia, increases the rate of normal infant neurological outcome compared with timing of delivery based on severe changes in fetal heart STV (control group).
570 women should be randomised to detect a difference of 50% normal neurological outcome in the control group to 66.6% in any of the DV groups (OR 2.0) with alpha 0.05 and beta 0.8, allowing for 20% mortality. Based on estimates by the participating centres (236 inclusions/year), the study group expects to complete the randomisation within three years.
Twenty European perinatal centres are participating. Five are Dutch centres and so 1/4 of all patients will be recruited in the Netherlands. All participants have extensive experience in fetal Doppler and monitoring and all are convinced that a randomised trial should be performed before wide scale application of DV Doppler measurement can be advised for fetal monitoring. This study will enable development of guidelines concerning timing of delivery in early preterm fetal growth restriction, which is of importance for all obstetric high care centres, which treat this condition, both in the Netherlands and abroad. Implementation of results of the trial will be facilitated by the fact that the study is performed in a large number of university clinics all over Europe and that treatment of early preterm fetal growth restriction is generally limited to such clinics.
Centres from each European country have applied locally for funding and medical ethical approval. Most participants will start inclusion during the first half of 2005. We request financial support to perform this important study in the Netherlands and for data management of the complete study to ascertain quality of data acquisition. Duration of the complete study will be 5 years (3 years randomisation and 2 years follow-up). Three years after start of the study the intermediate endpoint can be reported. Results of the study will be published anonymously on behalf of the study group.