Pulmonary development
The projects focus on lung development and the pathogenesis of chronic lung disease of the newborn (bronchopulmonary dysplasia). In particular the influence of prenatal inflammation (chorio-amnionitis) on surfactant metabolism and injury-repair in the lung is studied. Surfactant metabolism is studied in preterm infants with the use of stable isotopes. In addition broncho-alveolar lavages (BAL) are collected from these preterm infants for the analysis of cytokines and growth factors in relation to the development of chronic lung disease. These lung lavages are also used in an in vitro assay of injury-repair in cell culture. A ZonMw grant was received for the development of this assay into a model system for the study of neonatal chronic lung disease. Finally, we started large animal experiments in sheep in collaboration with prof. Jobe (Cincinnati, USA). These experiments were initiated by Dr. Boris Kramer, who was recruited from the University of Würzburg, Germany, to join our group both in research and in clinical Neonatology. He was a research fellow in the Division of Pulmonary Biology at Cincinnati Children's Hospital Medical Center in Ohio, USA, followed by a residency in Pediatrics and a fellowship in Neonatology at the University Children's Hospital Würzburg in Germany.
Dr. Kramer has developed a chorioamnionitis model in sheep, which will be established at the University of Maastricht. This model studies the effects of fetal inflammation on lung (and brain) development and showed that alveologenesis and vasculogenesis is disturbed with a resulting decresed surface area for gas exchange. This is part of the pathogenesis of chronic lung disease.
Cardiovascular development
Failure of ductus arteriosus (DA) closure after birth is a common complication of premature delivery. Significant progress in our understanding of the DA physiology and pathophysiology has been achieved with the use of mammalian models. However, these models are technically complex and experimental manipulations affect both the mother and the fetus. Therefore, there is a need for additional models, addressing these limitations. Our group has accumulated a broad experience in using the chicken embryo as a model in developmental vascular biology. Very recently, we have characterized the vascular reactivity of the chicken DA. We have found a high degree of similarity with the mammalian DA, particularly in the developmental response to O2. Our data support the concept that increasing O2 tension plays a critical role of in the closure of DA, also in non-mammalian species. In addition, we documented how the chicken DA preparation for its specific task of postnatal closure is reflected in critical maturational changes in reactivity. A patent DA complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease, necrotizing enterocolitis, and intraventricular hemorrhage. Understanding the basic mechanisms of either normal or altered functional and structural development of the DA, as well as inter-species differences in DA homeostasis, may provide insights into human patent DA pathophysiology and treatment.
Figure: Response of chicken ductus arteriosus (DA) to oxygen. Representative traces demonstrating oxygen-evoked contractions in the DA of 19- and 21-day-old embryos but not in the 15-day embryo (chicken incubation time: 21 days).
Furthermore, studies performed in La Paz, Bolivia (in collaboration with the University of Cambridge), showed that chronic hypoxia (high altitude) induced growth retardation and vascular anomalies such as a decrease in wall to lumen ratio in the aorta, suggesting a fetal cardiovascular adaptation to low oxygen.These studies with chronic instrumented chicken continue. A new collaboration on this project was started with the Catholic University in Leuven, Belgium.
In a clinical study newborns are now recruited to achieve endothelial function in Small for Gestational Age babies using laser Doppler technology compared to Appropriate for Gestational Age babies. Endothelial function is believed to predict cardiovascular disease in later life. The children are followed during the first 2 years of life and the longitudinal data on endothelial function are related to the changes in body composition.
Farmaceutical studies
Follow up of babies included in the CAP trial (caffeine forapnoe of prematurity) was performed. The 18 month follow-up was concluded. The neonatal outcome showed a surprising decrease in bronchopulmonary dysplasia in the caffeine group in comparison to placebo. (New England Journal of Medicine).
- Together with the Farmacy studies are conducted on farmacokinetics of antibiotics in newborns. This will lead to the PhD defense of Joyce Pullen in early 2007.
Brain development and pediatric neurology
- Studies on the behavioural effects of perinatal stress were continued and led to the thesis of Daniël van den Hove on "Prenatal stress and adult psychopathology" on April 27th, 2006. In adult male Spagne-Dowley rats, perinatal stress was associated with a clear increase in anxiety- and depression-related behaviour, with associated changes in corticosterone and brain pathology.
- Studies on rat perinatal hypoxia and especially the potential protective effect of conditioning by a previous fetal hypoxic period were started as a new PhD project in collaboration with NEURON.
Clinical research focused on the study of long-term outcomes related to age-dependent brain injury.
- Basic and clinical research and cerebral monitoring is continued in collaboration with the departments of (clinical) neurophysiology and the department of pediatrics of Maxima Medical Center in Eindhoven and Technical University Eindhoven.
- The study of the occurrence and impact of social problems on daily living of children with cerebral palsy. The development of a questionnaire to measure the quality of life is ongoing.
- Movement analysis in neonates with spina bifida aperta in collaboration with the neurology and pediatric departments of Groningen.
- Participation in the randomized controlled multicenter study "The effect of treatment of neonatal electrographic subclinical seizures in full-term asphyctic infants". Primary outcome is the occurrence of post neonatal epilepsy and neurodevelopmental outcome at 18 months of age.
Basic and Clinical Perinatology
"Aspects of fetal memory and maternal brain function in relation to the LCPUFA status" continued (grant from the Dutch Brain Foundation; project leaders Prof. Dr. J.G. Nijhuis en Prof. Dr G. Hornstra, PhD student Drs C. Dirix) completed its enrolment and the first result will follow soon.
The research project "perinatal audit of perinatal mortality in the first and second care level)" has published another paper in 2006 and in 2007 further publications can be expected (projectleaders: Prof. Dr. J.G. Nijhuis, and Dr. H.P. Oosterbaan, co-promoter dr L. Smits, PhD student: midwife P. de Reu).
The research project "Aspects of the influence of the term breech trial on breech deliveries in the Netherlands (project leaders Prof. Dr. J.G. Nijhuis, co-promoter Dr F.J.M.E. Roumen and Dr L. Smits, PhD student Drs. J. Molkenboer) have resulted in another publication in 2006, and an accepted manuscript, to be published in 2007. The thesis is expected to be defended in 2007.
The researchproject "home-deliveries: a randomised study" ("wat bevalt beter, thuis of in het ziekenhuis, een gerandomiseerde studie?") has been funded in 2005 by a grant of the "Profileringsfonds"(€120.000,--) and started enrolment in 2006. (Project leader Prof. Dr J.G. Nijhuis in close collaboration with Prof. Dr. J. Severens and Prof. Dr. F. van Merode).The project "Aspects of intra-uterine growth and further development in twins" published another article in 2006, and another is accepted and will be published in 2007. The thesis of M. Gielen will be defended in 2007.
In 2005, the department of Obstetrics and Gynaecology enlisted in the Dutch Obstetric Consortium with Dr. C. Willekes as Cluster Coordinator. All studies in this first Dutch initiative with collaboration of 10 perinatal centers and 40 non-academic clinics are funded by ZonMW. A large group of research nurses will ensure an optimal inclusion of patients. In this Consortium, Dr. C. Willekes is the Principal Investigator for the PPROMEXIL study (Premature Prelabour Rupture Of Membranes EXpectant management vs. Induction of Labour) with Drs. David van der Ham as PhD student. In case of premature prelabour rupture of the fetal membranes, either expectant management or induction of labour will be randomized in order to investigate with treatment modality will give the best neonatal outcome (most importantly neonatal infection).
Furthermore, the DIGITAT study (Disproportionate Intrauterine Growth Intervention Trial At Term), the HYPITAT study (HYpertension and Pre-eclampsia Intervention Trial At Term), the STAN study (The cost-effectiveness of ST-analysis of the fetal electro-cardiogram as compared to fetal blood sampling for intrapartum monitoring) are coordinated by Dr. C. Willekes and recruitment of patients is successfully underway.
Finally, Prof. Dr. J.G. Nijhuis and Dr. C. Willekes are projectleaders for the study" called "Aspects of 3D ultrasonography of the urogenital tract in the human fetus" with Drs. L. Duin as PhD student. Drs. Duin has started her research in 2005 and is anticipated to end her work in 2008. The first publication is recently accepted, a further three are anticipated in the course of 2007-2008.
Selected publications
Gyselaers WJ, Vereecken AJ, Nijhuis JG.
Community-based screening for Down syndrome in the first trimester using ultrasound and maternal serum biochemistry.
BJOG, 2006; 113: 362 (IF: 2,171)
Molkenboer JFM, Roumen FJME, Smits LJM, Nijhuis JG.
Birth weight and neurodevelopmental outcome of children at 2 years of age after planned vaginal delivery for breech presentation at term.
American Journal of Obstetrics and Gynecology 2006; 194: 624-629 (IF: 3.08)
Gyselaers WJA, Roets ERA, Holsbeke CDYJ van, Vereecken AJ, Herck EJH van, Straetmans DPL, Ombelet WUAM, Nijhuis JG.
Sequential triage in the first trimester may enhance advanced ultrasound scanning in population screening for trisomy 21.
Ultrasound Obstet Gynecol 2006; 27: 622-627 (IF: 2.43)
Research group
Prof.dr. C.E. Blanco, project leader
Prof.dr. L.J.I. Zimmermann
Prof.dr. J.S.H. Vles
Prof.dr. J.G. Nijhuis
Dr. E. Villamor
Dr. T. Mulder
Dr. A.W.D. Gavilanes
Dr. B.W.W. Kramer
Dr. J.F. van Iwaarden
Dr. C. Willekes
Dr. D.L.A. Van den Hove