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Eyes are examined on a baby
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The Sahlgrenska Center for Pediatric Ophthalmology Research

Research group
Active research
Project owner
Institute of Neuroscience and Physiology

Short description

The Sahlgrenska Center for Pediatric Ophthalmology Research at the Institute of Neuroscience and Physiology at the University of Gothenburg is a strategic research center focused on vascular and neural development research. Our center is based on partnerships between industry, clinical and experimental sciences as well as applied mathematics for development of prediction model.

The center

The center is focused on defining the underlying mechanisms of vascular and neural damage occurring after preterm birth and to develop strategies to better diagnose and possibly prevent these life-threatening complications.

Our studies suggest a number of ways to intervene medically in these disease processes. Studies on the disease mechanisms and the development of strategies to allow normal retinal and brain development may ultimately lead to significant reduction in the short and long-term morbidity of preterm infants.

Methods

Laboratory facilities at the Sahlgrenska Center of Pediatric Ophthalmologic Research include well-equipped analytical labs, (immunohistochemistry, western blots) and accredited clinical research lab for Pediatric studies (RIA, ELISA), molecular lab (RT-PCR, in-situ hybridisation) and image analysis (bright and fluorescence microscopy, stereology), biomarker discovery (Luminex multiplex system), advanced statistical prediction modelling, and bioinformatics. Excellent animal facilities with full surgical equipment are available at the Department of Physiology at Experimental Biomedicine. The laboratories has strong national and international network within Europe and USA.

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Our research is focused on defining the underlying mechanisms of vascular and neuronal damage occurring after preterm birth and to develop strategies to better diagnose and possibly prevent these life-threatening complications.
Photo: Pontus Andersson

Ongoing studies

Clinical studies

  • A clinical trial – Less is more (LIM) reducing the amount of blood taken for tests from extremely preterm infants
  • A clinical trial (Mega Donna Mega) to investigate the impact of AA/DHA on retinopathy, visual and neural development www.clinicaltrials.gov #NCT03201588
  • A clinical trial (Donna Mega) to investigate the impact of DHA/EPA on retinopathy, visual and neural development EudraCT no 2008-000046-31
  • A clinical trial (phase II study) with IGF-I/IGFBP-3 administration www.clinicaltrials.gov NCT 01096784
  • Further validation of WINROP® (national & international)
  • Ophthalmologic follow-up studies of infants with perinatal adverse history
  • Investigating the impact of postnatal serum IGF-I levels on preterm morbidity and postnatal growth
  • Effect of blood components importance for neuro- and angiogenesis in premature infants
  • Metabolic and Pharmacokinetic analysis of intravenous insulin administration to very preterm infants
  • Development of a digital e-health solution for ROP screening and diagnosis
  • Development of predictions models (DIGIROP-birth and DIGIROP-screen) for individualised risk for ROP needing treatment.

Experimental studies

  • Investigating the impact of chronic inflammation on ROP development in an experimental neonatal animal model
  • A proteomic and Luminex approach for identification of biomarkers in amnion, cord blood and serum that may predict an increased risk for ROP
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Photo: Johan Wingborg

Principal Investigator

Ann Hellström
MD, PhD, Professor

Group members

Chatarina Löfqvist, PhD, Associate Professor

Anna-Lena Hård, MD, PhD

Gunnel Hellgren, PhD, Associate Professor

Eva M. Andersson, PhD

Pia Lundgren, MD, PhD

Carola Pfeiffer Mosesson, RN, Monitor

Aldina Pivodic, PhD student

Anders Nilsson, PhD

Anna Thorell, MD

Karin Sävman, MD, PhD

Lena Jacobson, MD, PhD, Associate Professor

Svetlana Najm, MD

Hanna Danielsson, MD, PhD student

Dirk Wackernagel, MD, Senior Consultant

Anna-My Lund, PhD student, Registered Dietician

Ulrika Sjöbom, PhD student

William Hellström, PhD student

Prediction WINROP/DIGIROP-birth

WINROP® history

We have done extensive laboratory work showing that insulin like growth factor 1 (IGF-1) which mediates growth is a major factor in the development of ROP (Hellström A et al Proceedings of the National Academy of Sciences, 2001).

Based on that finding we developed and published an algorithm WINROP® based on serial neonatal measurements of body weight, which predicts ROP development. The original article including IGF measurements prompted an editorial in Archives of Ophthalmology “Screening for Retinopathy of Prematurity- The Promise of New Approaches”.

DIGIROP-birth

DIGIROP-birth is an individualized prediction model for the risk of ROP treatment developed by Aldina Pivodic. It is freely available at www.digirop.com.

Swedish National Patient Registry data from infants screened for ROP (2007–2018) were analyzed with Poisson regression for time-varying data (gestational age (GA), postnatal age, birth weight, sex and important interactions), to develop an individualized predictive model for ROP treatment, DIGIROP-Birth. The model was validated, internally, and externally (US and European cohorts), and compared to four published prediction models.

The studied outcome was ROP treatment. The measures are estimated momentary and cumulative risks, hazard ratios with 95% confidence intervals, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive (PPV) and negative predictive value (NPV).

Among 7,609 infants, GA 28.1 (SD 2.1) weeks, weight 1119 (SD 353) g, 3454 (45.4%) girls, 442 (5.8%) were treated for ROP, 142 (40.1%) of those born <24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8–12 (HR, 1.54/week; 95% CI, 1.39 to 1.70); thereafter, it decreased (HR, 0.70/week; 95% CI, 0.67 to 0.74). Validations of DIGIROP-Birth for GA 24–30 weeks showed high predictive ability for the model overall (AUC: internal 0.90, temporal 0.94, US external 0.87, European external 0.90), by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV and NPV were numerically at least as high as those obtained from CHOP-ROP, OMA-ROP, WINROP and CO-ROP, models requiring more complex data.

We validated an individualized prediction model, GA 24-30 weeks, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postconceptional age was a better predictive variable for the outcome. The model is generalizable, accessible through an application (www.digirop.com) and has at least as good test statistics as other models requiring longitudinal neonatal data not always available for ophthalmologists.   

The algorithm has now been further developed (web based, free of charge) and validated retrospectively on 50 children screened for ROP 2005-2007 at various Swedish neonatal wards in, Sweden. We found that WINROP® predicted early (mean 9 weeks before ROP needing treatment was detected by present screening routines) all infants who later developed proliferative ROP requiring treatment (sensitivity 100% and specificity 54%) (Löfqvist C et al Archives Ophthalmol 2009).

In order to make WINROP® rapid and robust as well as more equipment-free we have revised the algorithm using only serial weight measurements. With this approach WINROP® predicted early all infants who later developed proliferative ROP requiring treatment and correctly identified 75% of those who did not develop proliferative ROP (Hellström A et al Pediatrics 2009), and thus would not need any ophthalmologic screening. In addition, we have validated WINROP® in a preterm population in Boston (n=375) indicating a 100% sensitivity and a 76% specificity (Wu C et al Archives Ophthalmol 2009).

Applying these figures of reduced screening to the European preterm population the number of ophthalmological examinations could be safely reduced by 200,000 examinations/year, yet include 100% of infants requiring treatment for ROP. WINROP®  has been further validated in multiple clinical settings international, see PUB Med for scientific publications.

In order to establish this as the new standard of care worldwide WINROP® is now validated in Sweden, North America, Great Britain, Germany, Switzerland, Mexico, China, South Korea, Netherlands, India, Scotland, Canada and Brasil. WINROP® is now up and running in 62 countries, used by 400 caregivers in 236 different sites (2021).

The use of WINROP® for screening would identify early children at risk and could lead to early interventions.  Global health personnel could focus on the right patients at the right time. Thus, WINROP® (simple to perform with minimal training) would supply a decision making tool in ROP screening -an approach that is clearly cost effective and makes better use of resources.

Some of our collaborating partners:

  • Associate Professor David Ley, Ingrid Pupp Hansen MD, PhD and coworkers Neonatology Dep. University of Lund, Lund, Sweden.
  • Professor Lois Smith and coworkers, Children’s Hospital, Harvard Medical School, Boston, USA.
  • Professor Changlian Zhu, Zhengzhou University, China.
  • Fortes Filho JB, MD, PhD and coworkers, Departments of Ophthalmology and Pediatrics, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil.
  • Brian Fleck, MD PhD and coworkers, Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh, UK.
  • Professor Hans Ulrich Bucher, Dr. Veit Sturm, Dr Sandra Arri and coworkers, Departments of Neonatology & Ophthalmology, University Hospital of Zurich, University Hospital of Zurich, Switzerland.
  • Dr Consuelo Zepeda, Hospital Civil de Guadalajara El Carmen, Guadlajara Mexico.
  • Dr Anand Vinekar, Narayana Nethralaya Postgraduate Institute of Ophthalmology, Bangalore, India.
  • Dr Maria Marta Galan, La Plata Calleih, La Plata Argentina.
  • Dr Adam James, Paediatric Specialist Registrar, Coombe Womens and Infants University Hospital, Dublin, Irland.
  • Kerstin Albertsson Wikland, Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden

  • Helena Johansson McKillop Health Institute, Australian Catholic University, Melbourne, Australia.

  • Staffan Nilsson Department of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Sweden.

Commercial partner

Winrop application

If you want to apply for WINROP®, visit www.winrop.com 

WINROP® is free of charge.

Prevention IGF-I

We have previously demonstrated that low levels of serum IGF-1 and IGFBP-3 in children born preterm are strongly associated with ROP as well as other morbidities in preterm infants (e.g. poor growth, lung disease and poor brain development).

Based on these results we have clinically investigated the concept of restoring IGF-1/IGFBP-3 to in utero levels in premature infants. We have conducted and finalized a Phase I, pharmacokinetic study of intravenously administered rhIGF-I/rhIGFBP-3 complex (mecasermin rinfabate) to five very preterm children (GA 26-29 weeks). No side effects (b-glucose, heart rate, blood pressure) were seen and the dose and mode of delivery was established for Phase II study (Hellström A et al Ped Res 2009) (Ley D et al Ped Res 2013).

Carrying out this project is a major multi-disciplinary project with many participants, contributing with a broad range of competences, involved. For a successful implementation of the project, national and international experts in ophthalmology, neonatology, pharmacokinetics, pharmaceutics, GMP (Good Manufacturing Practice), GCP (Good Clinical Practice), GLP (Good Laboratory Practice) are needed. The Phase II study is an international multi-center trial with participation from the neonatal clinics in Lund and Stockholm.

The pharmaceutical company, Premacure AB, Uppsala, Sweden now acquired by Shire®, is coordinating all activities before, during and after the trial and is also in charge of obtaining all regulatory authorizations before the study can commence. Pharma Consulting Group AB (PCG), Uppsala, Sweden  has been contracted as independent monitor of the study. This will guarantee that the work is carried out in accordance with the regulatory provisions (GCP).

As we are focusing on factors that promote neural, vascular and metabolic development, our findings regarding ROP are likely to be applicable on several aspects of complications of premature birth and will hopefully provide benefits for the whole lifespan.

Prevention Fatty Acids

Extremely preterm (EPT) infants have a high incidence of neonatal morbidities including retinopathy of prematurity (ROP), a neurovascular disease with initial suppression of retinal blood-vessel growth, followed by pathologic neovascularization that can cause blindness. Treatment of severe ROP aims to cause regression of pathologic neovascularization and prevent retinal detachment by reducing the action of vascular endothelial growth factor (VEGF). Laser therapy is performed under general anesthesia and destroys the hypoxic VEGF producing peripheral retina. Anti-VEGF therapy comprises of intraocular injections, often repeated, of antibodies against VEGF. These substances enter the circulation and concerns for their effects on growing tissues have been raised. ROP correlates with reduced brain volumes and poor psychomotor development.

Infants born EPT, miss the third trimester transfer from the mother of the n-6 long chain polyunsaturated fatty acid (LCPUFA) arachidonic acid (AA) and the n-3 LCPUFA docosahexaenoic acid (DHA). AA and DHA are critical constituents of the retina and the brain and deficiencies associate with vascular complications of preterm birth. AA lipid fraction is two-fold higher in fetal than maternal blood throughout gestation while DHA fraction is similar to the maternal fraction until ~30 weeks gestational age (GA), then increases concomitant with rapid brain growth. Lipid emulsions currently used in parenteral nutrition contain insufficient or no AA and DHA. Breastmilk does not provide enough AA and DHA to fulfil the early requirements of EPT infants. Thus, EPT infants accumulate AA and DHA deficits during hospitalization.

Several studies suggest that low n-3 LCPUFAs are associated with ROP risk. Increased intake of n-3 protected against pathologic neovascularization in mouse oxygen induced retinopathy.

A few studies have been performed using enteral DHA supplementation early after birth to preterm infants. A reduction in stage 3 ROP was found in infants with birth weight 1000-1500g receiving enteral DHA for 14 days. The primary aim of this trial is to study the frequency of severe (stage 3 and/or type 1) ROP with and without AA:DHA supplementation. Secondary aims were to investigate the effects of AA:DHA supplementation on serum phospholipid fatty acid composition and rate of other complications of prematurity. This study adds to current knowledge by studying the effects of an enteral lipid supplement containing both AA and DHA to extremely preterm infants stratified into GA-based groups.

In this project outcomes will be neonatal morbidities, MRI at term, proteomics, metabolomics, nutritional impact on outcomes and long term follow-up at 2.5 and 5 years of age, www.clinicaltrials.gov # NCT03201588

  • Associate Professor David Ley, Ingrid Pupp Hansen MD, PhD and co-workers Neonatology Department, University of Lund, Lund, Sweden.
  • Boubou Hallberg MD, PhD, Dirk Wackernagel MD, Mireille Vanpee MD, PhD and co-workers Neonatology Department, The Karolinska University Hospital, Stockholm, Sweden.
  • Professor Lois Smith and co-workers, Children’s Hospital, Harvard Medical School, Boston, USA.
  • PREVENTROP partners
  • Professor Manon Benders and co-workers, Wilhelmina Children’s hospital of the University Medical Center in Utrecht, the Netherlands.

Commercial partners