Multi-Center Study to Determine the Role of Fatty Acids in Serum in Preventing Retinopathy of Prematurity (MDM)
Condition: Ophthalmological Disorder
MeSH terms: Retinal Diseases; Retinopathy of Prematurity; Eye Diseases; Premature Birth
Study type: Interventional

Summary: 
      The study is a Randomized Intervention, Multi-Center Study to Determine the Role of Fatty
      Acids in Serum and Breast Milk in preventing Retinopathy of Prematurity Subjects who meet all
      inclusion and none of the exclusion criteria will be enrolled into the study. Upon entry into
      the study, subjects will be randomized and given a unique subject number.

      A randomized intervention study of 105+105 (number based on power analysis regarding up to
      date ROP frequency, see 5.1 and 11.1) infants without major malformations born with a
      gestational age less than 28 weeks + 0 days will be performed.
    

Detailed description: 
      Every year around 10-12 % of all infants in Europe and the USA are born prematurely which
      results in 950000 preterm infants per year (500000 in Europe and 450000 in USA). Direct
      complications of preterm birth account for one million deaths each year worldwide, and
      preterm birth is a risk factor in over 50% of all neonatal deaths. In addition, preterm birth
      can result in a range of long-term complications in survivors, with the frequency and
      severity of adverse outcomes rising with decreasing gestational age and decreasing quality of
      care. The annual costs, beside patient suffering and parental emotional stress, of preterm
      care in USA amounts to 26,2 billion United States dollar in terms of immediate neonatal
      intensive care, subsequent long-term complex health care needs, as well as lost economic
      productivity.

      Possible problems that may occur after a preterm birth are:

      Organ disorders (intestine, heart, lung - BPD and asthma), ears (hearing problems), eyes (ROP
      and visual problems).

      Feeding problems and failure to thrive, Poor general growth,Physical disabilities such as
      cerebral palsy,Cognitive impairment,Learning disability or behavioral problems such as
      attention deficit (ADD) or autism spectrum disorders. Of infants born extremely prematurely,
      i.e. at less than 28 weeks gestation or with extremely low birth weight (<1000 g), 20 - 30%
      may show developmental disorders requiring treatment (3, 4). Impaired cognitive development
      and abnormal behavior may cause problems at school; in some countries the percentage of
      learning difficulties in the preterm population is as high as 25%.

      Much has been done to improve neonatal care e.g. target levels for oxygen saturation has been
      an issue for extensive discussions and clinical trials. In fact, the optimal oxygen
      saturation level for preterm infants has been called "a moving target", fluctuating almost as
      much as our patients oxygen saturation levels. Reaching a consensus on what these levels
      should be is still a work in progress. Nutrient delivery is another important and central
      area of neonatal care which is closely associated with morbidity outcome, and is in need of
      evidence-based guidelines. The project therefore aims to improve nutrient delivery to prevent
      or reduce the development of preterm disabilities.

      There is a long tradition in neonatology to develop national and in some cases local
      guidelines for care in each individual Neonatal Intensive Care Unit (NICU). This has resulted
      in a wide range of treatment approaches and experience-based strategies. These approaches may
      differ between countries and hospitals and even between neonatologists at the same hospital.
      There is, for example, a fragmented approach and incomplete compliance to guidelines for
      nutrient delivery, one important medical parameter tightly associated with neonatal
      morbidities. Although over 3000 randomized controlled trials have been reported in the field
      of neonatology, few interventions have yet been subjected to unbiased evaluation.

      Available nutritional fatty acid guidelines are not evidence-based and neither optimal
      composition nor amounts needed to meet the demands of these immature infants are known. What
      is known is that most infants born extremely preterm develop a large energy deficit resulting
      in poor neonatal growth. Many experience moderate hyperglycemia associated with lipid
      infusion. Hyperglycemia is a strong risk factor for preterm mortality as well as for ROP and
      other disorders of prematurity. With commonly used lipid solutions, preterm new-borns
      experience a rapid decline in blood fatty acid proportions of the long chain polyunsaturated
      fatty acids (LCPUFA), Arachidonic acid (AA) and DHA, as compared to the intra-uterine
      situation.

      In Sweden, approximately 300 infants are born extremely preterm i.e. before 28 gestational
      weeks yearly. With modern neonatal care, infants born as early as at 23-24 weeks of
      gestation, in the second trimester of gestation, have more than 50% chance of survival. The
      third trimester is a period of intense growth and differentiation of the central nervous
      system (CNS) of which the retina is a part, with rapid formation of synapses and dendritic
      spines and development of retinal photoreceptor cells. During this fetal time period AA and
      DHA are selectively transferred from the mother to her fetus and blood fractions of DHA
      increase above maternal values. AA fractions are high, twice those of the mother, from at
      least 24 weeks of gestation. After very preterm birth, the fractions of AA and DHA fall. In
      utero glucose, not lipid is the main source of energy and the LCPUFAs transferred during the
      third trimester play important structural and functional roles in membranes of the central
      nervous system and most other organs.

      DHA, which is an omega-3 LCPUFA is derived from algae and oily fish is the pre-dominant fatty
      acid of membrane phospholipids in the brain grey matter and the retina, especially its rod
      outer segments. DHA is not merely a structural component of cell membranes but essential for
      proper function of membranes. Since the capacity to synthesize DHA is limited in humans and
      especially in infants, it needs to be provided in the diet. Dietary DHA is needed for optimal
      functional maturation of the retina and visual cortex, it is a major component at the
      synaptic site, modulating the uptake and release of neurotransmitters. Absolute accretion of
      DHA in the brain is greater before than after term and DHA is also accumulated in adipose
      tissue. In addition, omega-3 LCPUFA has the potential to reduce oxidative stress, deranged
      glucose metabolism and inflammation.

      While many studies have focused on DHA and its role in fetal and neonatal development, few
      studies have addressed the role of the omega-6 LCPUFA AA during fetal life and after preterm
      birth. Like DHA, AA is an important component of cell membranes. Altered cell membrane
      composition results in altered cell function. AA is abundant in the vascular endothelium and
      in glia where it plays different roles than DHA which is especially abundant in retinal rod
      outer segments and in synapses and brain grey matter. In the retina AA metabolites contribute
      to neurovascular coupling i.e. modulation of blood flow with neuronal activity. Metabolites
      of AA both stimulate and inhibit inflammation and angiogenesis. In addition, AA is involved
      in blood vessel tonus control with AA derivatives mediating both vessel relaxation and
      contraction. Low AA concentrations are associated with late onset sepsis in preterm infants.
      Improved development of very preterm infants fed twice as much AA as DHA than of infants fed
      equal amounts of AA and DHA was recently reported.

      After extremely preterm birth energy expenditures increase, oral intake often takes some
      weeks to establish and total parenteral nutrition (TPN) is invariably required during the
      initial postnatal weeks. After birth lipids are the main source of energy, initially as
      integral part of administered TPN.

      Preterm infants treated with soy and olive oil based parenteral lipid solutions (Intralipid
      and Clinoleic) have low levels of LCPUFAs and increased supply of DHA has been recommended.
      It has been demonstrated that low DHA levels are associated with compromised fetal insulin
      sensitivity and insulin resistance in preterm infants is common and strongly associated with
      neonatal morbidity. Few studies have examined associations between low AA and preterm
      neonatal morbidities.

      One of the most severe morbidities affecting preterm infants is sight threatening ROP, a
      disorder characterized by reduced retinal vascularization followed by pathologic
      neovascularization which can lead to retinal detachment and blindness similar to diabetic
      retinopathy. ROP develops during the neonatal period and outcome is available around term age
      (40 postmenstrual weeks), which makes it a useful marker for short term outcome of
      neurovascular development in interventional studies.

      In animal studies, a diet rich in omega-3 LCPUFAs reduced pathologic retinal
      neovascularization in oxygen induced retinopathy, through reduction of inflammatory mediators
      and attenuation of endothelial cell activation.

      In two recent studies, the frequencies of ROP needing treatment as well as cholestasis were
      significantly reduced when a solution containing fish oil (SMOFlipid) was provided compared
      to Clinoleic in preterm infants with birth weight 1250 grams. In addition, ROP frequency was
      reduced in infants receiving SMOFlipid as compared to those receiving Intralipid. No
      randomized controlled trial comparing convention-al fatty acid administration without and
      with supplementation of AA and DHA from birth with regard to ROP has been published.
    

Intervention name(s): Formulaid
Intervention type(s): Dietary Supplement
Intervention description(s): Arachidonic acids (AA) Docosahexaenoic Acids(DHA) 2:1
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A randomized intervention study of 105+105 (number based on power analysis regarding up to date ROP frequency, see 5.1 and 11.1) infants without major malformations born with a gestational age less than 28 weeks + 0 days will be performed.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Retinopathy of Prematurity