Effect of donor human milk on severe infections and mortality in VLBW infants, a double blind randomized controlled trial

Lack of enteral nutrition results in intestinal atrophy potentially causing
increased bacterial translocation, thereby making VLBW infants more prone to
sepsis. According to current feeding protocols in NICU*s, minimal enteral
feeding is initiated within 6 hours after birth. After premature delivery the
onset of lactation is often delayed and therefore VLBW infants are often being
fed with preterm formula during the first few days of life. Feeding VLBW
infants with own mother*s milk is to be preferred because it reduces the
incidence of sepsis and NEC. When own mother*s milk is not available during
this period, donor milk might be of benefit to these infants when compared to
formula. We hypothesize that feeding VLBW infants with a diet that is
completely based on human milk during the first 10 days of life will result in
a decrease in the incidence of serious infections, necrotizing enterocolitis
(NEC), and neonatal mortality.

Amendement ESS:
Both donor milk and milk of the own mother do not contain enough minerals for a
proper bone mineralization. Extra minerals are added to the milk by using
"breast milk fortifier" (BMF). BMF is not added to the milk directly after
birth: it is assumed that milk with BMF is tolerated less well by premature
infants. On the other hand: if administration of BMF is delayed too long, bone
mineralization will be impaired. It iscurrently unknown what is the optimal
timing to add BMF to breast milk: there are no large randomized controlled
trials on this subject. Therefore the moment at which BMF is administered for
the first time differs substantially between the Dutch NICU's. Since a few
years infants in the RUNMC (Nijmegen) receive BMF as soon as they're able to
tolerate 50 ml of enteral nutrition per day, on average on day 4 - 5 of life
("early supplementation"). Infants that participate in the Early Nutrition
Study receive BMF from the 10th of life onwards ("late supplementation"). In
this amendement the effects of both these regimens are evaluated.

Amendement Adrenocortical Function:
Preterm birth has been associated with increased risks of neonatal mortality
and adverse neurodevelopment, particularly in boys. Giving breast milk to
preterm infants seems to be associated with improvements in neurodevelopment
and cardiovascular parameters, again particularly in males. Among the
candidate mechanisms that may underlie these sex-specific associations are
variations in the adrenocortical function. Adrenocortical insufficiency is
common in the early neonatal course of preterm infants and is followed by a
rapid adaptation of the hypothalamus-pituitary-adrenal (HPA) axis by the end of
the second week, with the largest improvement in adrenocortical function being
observed in ill preterm infants.
Infants that participate in the Early Nutrition Study receive either donor milk
or formula as a complement to own mother's milk. This makes it possible to
assess a difference in production and metabolism of cortisol between infants
that are fed with human milk only and infants that are partly fed with formula.

Amendement Body Composition:
Premature infants have less lean tissue with a similar fat mass at term
equivalent age. The mechanisms responsible for this difference in body
composition are likely to be multifactorial. The pattern of body composition is
in part a consequence of the nutrition that preterm infants receive the first
period of life. We hypothesis that a diet completely consisting of human milk
during the first period of life have a beneficial effect on body composition in
preterm infants. Infants that participate in the Early Nutrition Study receive
either donor milk or formula as a complement to own mother's milk. This makes
it possible to assess a difference in body composition between infants that are
fed with human milk only and infants that are partly fed with formula.
Introduction of complementary foods is an important dietary change and
associated with major modifications in both macronutrient and micronutrient
intake. It is relevant to consider whether complementary feeding influences the
risk of obesity. Not only the composition but also timing of introduction of
complementary foods seems to have effect on long-term health. Infants who
received complementary foods before 15 weeks of life are heavier and their
percentage of body fat is greater at 7 years of age compared to those given
complementary feeding at 15 weeks or later. The long-term consequences of early
introduction of complementary feeding and their effect on body composition and
development of allergic diseases in preterm infants are unknown. In this study
these consequences and effects will be determined.

To determine whether (supplemental) human donor milk has beneficial effects (in
terms of reduction of infectious episodes and mortality) when compared to
(supplemental) preterm formula during the first 10 days of life in VLBW
infants.

Amendement ESS:
Evaluating the effect of "early" (day 4-5) administration of BMF or "late"
administration of BMF (day 10 of life) on bone mineralization and feeding
tolerance.

Amendement Adrenocortical Function:
To determine whether the production and metabolism of cortisol differs between
infants fed with a completely human milk based diet compared to infants
(partly) fed with formula and to assess whether this difference is sex-related.

Amendement Body Composition:
To determine whether body composition of infants with a completely human milk
based diet differs from that of infants (partly) fed with formula.
Additionally, to determine whether the timing of introduction and the
composition of complementary feeding is related to body composition and the
development of allergic diseases.

Double blind randomized controlled trial. The Early Supplementation Study (the
add-on study intended to be performed in the UMCN) is a unblinded study.

If own mother*s milk is not available in sufficient amounts, the intervention
group (group A) will receive additional donor milk and the placebo group (group
B) will receive additional standard preterm formula. Donor milk and formula
therefore serve as *add-on* therapy to own mother*s milk.

Amendement ESS:
No intervention. Infants from the RUNMC can be randomized to participate in
group C. This group will receive nutrition according to standard feeding
protocol in use at the RUNMC. The differance with the other participents from
the ENS is that group C will receive BMF as soon as they tolerate 50 ml of
enteral nutrition per day.

Amendement Adrenocortical function:
No additional intervention.

Amendement Body Composition:
No additional intervention.

The parameters used as endpoints (incidence of infection, morbidity, feeding
tolerance) are routinely assessed as part of standard care. For the
determination of fecal microbiota, stool samples will be collected from the
diaper. This is of no burden to the infant.
Administration of banked pasteurized human donor milk to VLWB infants has been
proven to be safe in respect to transmission of infectious disease. Quantity of
macronutrients will be guaranteed by near-infrared analysis of each milk
sample. The benefits of feeding children with their own mothers* milk are
clearly documented in literature. There are various reasons to hypothesize that
pasteurized donor milk exhibits similar effects. Therefore it is possible that
infants fed with donor milk will benefit from this intervention.

Amendement ESS:
To determine the bone density participants of the RUNMC and VUmc will be
subjected to a DXA scan at term corrected age. For this scan infants will be
placed on the scanning table (comparable to a Xray investigation) after they
have received nutrition. Usually the infants will fall asleep and will not
notice the research. The duration of the DXA scan is less then 15 minutes.
In the RUNMC Speed of Sound (ultrasound) measurements will be performed 7 times
to monitor bone mineralization. This procedure is not painful and will be
performed after routine nursing procedure so infants will not be disturbed/
woken up. In the VUmc SOS measurements are part of routine care.
Infants admitted to the NICU of the RUNMC will be subjected to a kidney
ultrasound to check for nephrocalcinosis. This procedure is not painful.

Amendement Adrenocortical Function:
At the age of 10 days, 30 days and 2 years urine cortisol will be measured.
Urine will be collected by absorbating gazes in the diaper. This is
non-invasive and not painful. The ALGO screening, as well as the non-invasive
monitoring of heart rate, respiratory rate, and transcutaneous saturation, are
part of standard care.

Amendement Body Composition:
At the age of 1,2 and 5 years body composition will be measured by using air
displacement plethysmography (ADP) systems: Pea Pod and Bod Pod and by using
Deuterium Dilution.
Measurements with Pea Pod and Bod Pod are non-invasive, not painfull and take
less than 10 minutes. Infants will be placed on the scanning table (< 2 years
of age) or on a chair (>2 years of age) and can move freely.
The use of Deuterium Dilution is save and non-invasive. Stable isotopes are
non-radioactive, not detrimental and are already naturally present in the human
body in small amounts. An amount of 3 ml / kilogram body weight of 2H2O will be
administered orally. Saliva samples can be easily collected by swabbing a dry
cotton rod in the child*s mouth for 2-5 minutes.