Skin and Serum Carotenoids in Preterm Infants Fed on a Formula Supplemented With Carotenoids

Infants that are born prior to 37 weeks gestation often face complications resulting from
their prematurity. Preterm infants are susceptible to morbidities that are not common in
healthy term infants. Underdeveloped organs such as the lungs, eye, intestine, and brain
can reveal conditions unique to prematurity: chronic lung disease, bronchopulmonary
dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular
hemorrhage, etc. Infants in the NICU have increased inflammation and oxidative stress in
association with common diseases of prematurity and as well as the treatments used to combat
their illnesses (Gitto et al 2004; Ochoa et al 2003; Saugstad 2003).

According to the National Eye Institute (U.S. National Institutes of Health), retinopathy of
prematurity affects approximately 50% of preterm infants that are born weighing 1250 g or
less. While 90% of infants with ROP experience the milder form of the disease, which
requires little or no medical treatment, severe ROP can lead to serious visual impairments
or even blindness. This condition is of particular interest since Hylander et al. (Hylander
et al 2001) have reported that human milk feeding of preterm infants (<1500 g birth weight)
has been associated with a lower incidence of ROP and this association was proposed to be
driven by the antioxidant content of human milk. Human milk provides a variety of
antioxidants to the breastfed infant, including the carotenoids lutein, zeaxanthin,
lycopene, and beta-carotene. As discussed earlier, lutein and zeaxanthin are concentrated
to the eye and are thought to provide protection against both light-induced and metabolic
oxidative damage.

The retina and retinal vasculature are the last eye structures to develop in the human
fetus/neonate. Eyes of children with a history of ROP are reported to have retinal thinning
with diffuse hypopigmentation, mild linearization, or mild tortuosity of the major vessel
branch, mottled pigmentation of the macula, and other peripheral retinal anomalies
(Minicucci et al 1999). The lack of pigmentation in the retinal structure might be
explained by the deficit of lutein acquired by the fetus (by placental transfer during late
gestation) or by the neonate through the diet (by preterm infant formulas devoid of these
carotenoids). Preterm infants are at a nutritional disadvantage at birth as they have been
deprived of the period of maximal transfer of nutrients during the last few weeks of
pregnancy. Blood levels of beta-carotene have been associated with gestational age (Ostrea
et al 1986) and cord blood levels of beta-carotene (Herrera et al 2004; Kiely et al 1999;
Yeum et al 1998), lutein (Kiely et al 1999), and lycopene (Herrera et al 2004; Kiely et al
1999) were reported to be significantly lower than maternal levels. Stores of fat-soluble
antioxidant vitamins also could be compromised due to the minimal fat deposition in the
preterm infant.

It is therefore reasonable to suggest that providing preterm infants with a milk-based RTF
preterm infant formula with DHA and ARA supplemented with carotenoids, which are found in
human milk, would result in serum carotenoid levels more like the breastfed infant.
Further, increased dietary carotenoid intake by preterm infants might decrease the
prevalence of morbidities that are associated with prematurity, such as ROP, BPD, and IVH.

Inclusion Criteria:

- Birth weight 500-1500 g.

- Less than 33 weeks gestational age (GA) at birth. Maternal dates will be used to
estimate GA except in instances where a scan or the neonatologist's estimate differs
by two weeks or more. In this instance, the scan or neonatologist's estimate of GA
will be used. In the case where one neonatologist's estimate or scan confirms
maternal dates and the other estimate does not confirm maternal dates, use the
estimate of maternal dates.

- Randomization within 96 hours of initiation of enteral feeding of >/= 60mL/kg/d of HM
or formula

- Formula fed infants' feeding consists of no more than 20% from human milk.

- Enteral feeding initiated by 21 days of life (date of birth is Day 0 of life).

- Parent/LAR agrees to allow infants to receive the assigned SSC Advance or NeoSure
Advance formula in-hospital starting with the first enteral feed after randomization.
If mother is providing breast milk, formula will only be given if there is not
sufficient mother's milk.

- Parent/LAR signed the informed consent.

- SGA infants and infants with PDA are eligible to participate.

- Singleton or twin births only. For twins to be eligible, both must meet inclusion
criteria.

Exclusion Criteria:

- Serious congenital abnormalities that may affect growth and development.

- Grade III or IV IVH.

- Maternal incapacity: including maternal cocaine or alcohol abuse during pregnancy or
current, or if the mother or infant is currently receiving treatment consistent with
HIV therapy.

- History of major surgery (including surgery for NEC).

- Asphyxia (hypoxia and ischemia) as evident by severe and permanent neurological
damage.

- Confirmed NEC (modified Bell's stage II or III) or positive blood cultures at the
time of randomization

- Infants who are enrolled in this clinical study should be excluded from participation
in other concomitant studies. This exclusion criterion can be reviewed on a
case-by-case basis. For example, infants will not normally be excluded if only
demographic data are being collected or outcome measures on treatment modalities
common to current clinical practice are being gathered.