The effect of an isocaloric, protein- and mineral-enriched ('postdischarge') formula on growth, body composition and bone mineralization of late preterm infants.;Follow-up: The effect of an isocaloric, protein- and mineral-enriched (*postdischarge*) formula on growth, body composition and neurocognitive development of late preterm infants at the corrected age of 2 years.

Preterm infants are at risk long term for adverse (metabolic) effects, which
may be explained by the *fetal origins hypothesis* and the *catch up growth
hypothesis*. Prematurity and excessive growth during early childhood are risk
factors for the development of obesity, diabetes, hypertension and
cardiovascular disease in later life. Research mostly focuses on early preterm
born children (<32 weeks gestational age). Limited research has been performed
to look into the effects on late preterms (gestational age between 32 and 36
weeks) so far. Lapillonne et al. (JPeds 2013) state that late preterms require
special attention since they have unique and often unrecognized medical
vulnerabilities and nutritional needs. We think this assumption has yet to be
supported by evidence so the specific needs can be further explored and
specified.
Research among preterms in general, aims at an optimal balance between
sufficient growth on one side and risks associated with excessive (catch-up)
growth and fat accumulation on the other side. We hypothesize that an
isocaloric, protein- and nutrient-enriched (postdischarge) formula fed to late
preterm infants will promote both growth and a favorable body composition and
thereby diminish the previously mentioned health risks. For SGA born children
we expect this effect to be even more pronounced since both term and preterm
SGA infants seem to benefit from nutrient enriched formula. Male infants seem
to profit most from PDF feeding. With stratification for both gender and being
SGA or not, we hope to give more insight in those differences.

In the Netherlands, 6.4% of new-borns are born with a gestational age between
32 and 36 weeks (so called late preterms). Although this is a large group,
little is known about the exact needs of late preterms. As a consequence, there
is an enormous variety in Dutch nutrition-guidelines for late preterm infants
used in hospitals and after discharge.
The third trimester of pregnancy is considered not only a critical phase for
growth, but also for the programming of body functions. Evidence for subsequent
problems that preterms experience later in life is mainly derived from studies
in preterms born <32 weeks GA and a birth weight <1500g. Cardiovascular
disease, obesity, insulin resistance and increased blood pressure are a few of
the long term consequences associated with preterm birth. Adipose tissue and in
particular the distribution of it, may play an important role in the
development of metabolic complications.
Some studies have suggested that these long term consequences are also relevant
for late preterm infants. However, research mainly focused on conditions like
respiratory distress, hyperbilirubinemia, hypoglycaemia, etc.Several authors
underline the importance of expanding the knowledge about late preterm born
children. Since late preterms miss part of the vital intra-uterine period,
they could also be prone to develop nutritional deficits. Most of today*s
nutritional recommendations have been extrapolated from data for very low birth
weight (VLBW), very preterm (<32 weeks gestational age) and term infants.
Nutrition and growth is therefore an important field yet to be explored for the
late preterm group, especially with regard to long term outcomes.

Follow-up:
We would also like to refer to the above. Follow-up at the longer term is
important to be able to get insight in the effects of early nutrition on early
growth (pattern), vody composition and metabolic risk factors in late preterm
infants. Furthermore, at the age of 24 months it is possible to assess
neurocognitive develpoment of these children, and to compare this with term
born children (based on available norm values).
Even though late preterms are the majority of the whole group of preterm
children in the Netherlands, we know little about the consequences, especially
on the longer term. With this follow-up study we can contribute to the current
knowledge and understanding of the effects of nutrition on growth, body
composition and neurodevelopment in late preterm infants born in the
Netherlands.

The main objective is to compare growth and body composition of late preterm
infants at 6 months corrected age, fed either an isocaloric, protein- and
mineral-enriched ('postdischarge') formula (PDF) or standard term formula (TF)
between term age and 6 months corrected age.
The secondary objective is to compare cardio-metabolic risk factors, bone
mineral content (and associated serum bone markers) and endocrine parameters.

Overall, we will compare the formula fed infants with the infants fed human
milk.

Follow-up:
The main objective is to assess long-term effects of feeding an isocaloric
protein- and mineral-enriched formula compared to a standard term formula
between term age and 6 months corrected age, on growth, body composition,
neurodevelopment and cardiometabolic risks parameters of late preterm born
infants, at 24 months corrected age.

Double-blind randomized controlled multicentre trial.
- Intervention group: standard term formula (*Hero baby Standaard 1*)
- Intervention group: isocaloric, protein- en mineral-enriched
('postdischarge') formula (*Hero baby Prematuur 1*)
- *Control* group: human milk

Setting: VU University medical centre, Amsterdam, The Netherlands and
affiliated clinics between birth and discharge. Outpatient clinic of VU
University Medical Centre, between discharge and six months corrected age.

Follow-up:
Follow up of a double-blinded randomized controlled multicenter trial
(LEGO-study).

All infants will be fed human milk and/or protein and mineral enriched formula
from birth to term age. At term age, formula fed infants are randomized to PDF
or TF and are fed this diet until six months corrected age. Stratification for
gender and birth weight (p10) will be performed. Infants are fed
150-175 ml/kg/d according to the current guidelines and after discharge the
amount of formula per day is advised by the coordinating investigator.

Follow-up: not applicable

In the first week after birth a blood sample (3ml) will be taken, either
together with a routine clinical venepuncture or with placement of an
IV-cannula for parenteral nutrition. Subjects will visit the outpatient clinic
of the VU University medical center twice (around term age and corrected age 6
months). At both visits anthropometry, measurement of body composition in the
PEA-POD and a whole body DEXA-scan will be performed and a blood sample of
4.2ml will be taken. During the period from discharge until 6 months, parents
will keep a diary of the nutritional intake of their child.

Follow-up:
During the outpatient visit at 24 months corrected age, anthropometry, body
composition (using BOD POD, air-displacement plethysmography) and blood
pressure will be measured. Furthermore, a blood sample (3.7 ml) will be taken
and neurodevelopment will be assessed. Parents will be asked to fill in a
diary/questionnaire concerning the nutritional habits of their child.