Multi-Center Study to Determine the Role of Fatty Acids in Serum in Preventing Retinopathy of Prematurity (MDM)

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.