Monique van de Lagemaat

Timing of nutritional interventions in very-low-birth-weight infants: optimal neurodevelopment compared with the onset of the metabolic syndrome

Recent nutritional research in very-low-birth-weight (VLBW) infants is focused on the prevention of protein malnutrition during the first postnatal weeks. At this early age, nutritional protein fortification depends on amino acid infusion via a central vein because of the immature gastrointestinal tract. In 2010 new guidelines on nutrition were proposed by the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition nutrition committee. In particular, the relative increase in the protein fraction in the nutrition of these infants aims to prevent early postnatal weight loss, to prevent morbidity, and to stimulate neurodevelopment. On the other hand, an increasing number of follow-up studies in VLBW infants indicate that, in particular, those infants who show rapid growth after preterm birth are at risk of metabolic consequences and cardiovascular disease later in life. In this review, we describe the quest to develop a customized diet that offers optimal nutrition at several time points of growth and development during the first year of life. This diet should prevent early malnutrition, enhance neurodevelopment, and limit the increase in total body fat during the first 6 mo. We question whether one type of early diet suffices for normal neurodevelopment with a normal body composition in later life or whether we need several types of diet at various stages of development.

Small-for-gestational-age preterm-born infants already have lower bone mass during early infancy☆☆☆★

BACKGROUND In preterm-born infants, low birth weight and diminished bone accretion deteriorate peak bone mass. Whether low birth weight is already associated with decreased bone mass during infancy is unknown. OBJECTIVE To study the effect of birth weight on bone accretion between term age (40 weeks postmenstrual age) and six months post-term in preterm-born infants. DESIGN In 139 preterm-born infants (51% male, gestational age 30.3±1.5 weeks, birth weight 1341±288g) weight and whole-body bone mineral content (BMC, gram) were measured at term age and six months post-term. At birth, infants were small-for-gestational-age (SGA, n=33, weight and/or length<-2 SDS) or appropriate-for-gestational-age (AGA, n=98, weight and length≥-2 SDS). RESULTS At term age and six months post-term, BMC adjusted for gender and gestational age was lower in SGA than AGA infants (term age: 38.1±9.5 versus 48.6±10.1g, β=-0.26, 95% CI -0.37; -0.16, p<0.001; six months: 130.1±25.7 versus 145.4±22.9g, β=-0.16, 95% CI -0.25; -0.08, p<0.001). At six months post-term, BMC remained lower in SGA infants after adjustment for actual weight and length. Between term age and six months post-term, BMC gain adjusted for gender and gestational age was lower in SGA than AGA infants (91.7±22.8 versus 98.2±20.7g; β=-0.12, 95% CI -0.24; -0.003, p=0.044). BMC gain remained lower in SGA infants after adjustment for weight and length gain. CONCLUSION The first six months post-term, SGA preterms have lower bone accretion, independent of body size, suggesting that prenatal conditions for bone accretion cannot be replicated postnatally.

Post term dietary-induced changes in DHA and AA status relate to gains in weight, length, and head circumference in preterm infants

Preterms need supplementation with docosahexaenoic (DHA) and arachidonic (AA) acids to prevent steep postnatal declines. Associations between growth and erythrocyte (RBC) DHA and AA were studied in 139 preterms (51% male, gestational age 30.3±1.5 weeks, birth weight 1341±288g) fed human milk with breast milk fortifier or preterm formula until term, followed by postdischarge formula (PDF; n=52, 0.4% DHA, 0.4% AA), term formula (TF; n=41, 0.2% DHA, 0.2% AA), or human milk (HM; n=46). At six months, PDF resulted in higher RBC-DHA than TF and HM, while RBC-AA was higher than TF, but similar to HM. There were no between-group differences in growth between term and six months. RHC-DHA related positively with gain in weight and length and negatively with gain in head circumference. RBC-AA related positively with gain in head circumference and negatively with gain in weight and length. In conclusion, PDF with higher DHA and AA than TF may promote postnatal growth of preterms.

Follow-up of a randomized trial on postdischarge nutrition in preterm-born children at age 8 y

Background: Early nutritional interventions may modulate health risks in preterm-born infants. Previously, we showed that preterm-born infants fed an isocaloric protein- and mineral-enriched postdischarge formula (PDF) from term age to 6-mo corrected age (CA) gained more lean mass than did those fed term formula (TF). Long-term follow-up of randomized nutritional trials is important to test the hypothesis that short-term positive effects on health are sustainable.Objective: The aim of this follow-up study was to compare body size, body composition, and metabolic health at age 8 y in preterm-born children who were randomly assigned to receive either PDF or TF from term age until 6-mo CA.Design: A total of 79 of 152 children (52%) from the original randomized controlled trial were enrolled for follow-up at age 8 y. Weight, height, and head circumference were measured by using standard methods. Body composition, including fat mass, lean mass, bone mineral content, and bone mineral density, was determined by dual-energy X-ray absorptiometry. Blood pressure was measured in the supine position by using an automatic device. Metabolic variables, including glucose, insulin, insulin-like growth factor I, triglycerides, cholesterol, cortisol, and leptin, were measured after an overnight fast. Nutritional habits at age 8 y were assessed by using a 3-d nutritional diary.Results: At age 8 y, no differences were found in body size, body composition, bone variables, and metabolic health variables when comparing children fed PDF with those fed TF. Adjustment for known and possible confounders did not change these results.Conclusions: In this follow-up study in preterm-born children, we showed that the favorable effects of PDF at 6-mo CA either were not maintained or could not be confirmed because of attrition at the age of 8 y. We suggest that future research should focus on nutritional interventions in the pre- and postdischarge period as a continuum rather than as separate entities. This trial was registered at www.trialregister.nl as NTR 2972 (follow-up study [STEP-2 (Study Towards the Effects of Post-discharge Nutrition 2)]) and NTR 55 [original randomized controlled trial (STEP)].

Higher Vitamin D Intake in Preterm Infants Fed an Isocaloric, Protein- and Mineral-Enriched Postdischarge Formula Is Associated with Increased Bone Accretion

During the first half of infancy, bone accretion in preterm infants fed an isocaloric, protein- and mineral-enriched postdischarge formula (PDF) is higher compared with those fed term formula (TF) or human milk (HM). This may be related to higher protein, calcium, phosphorus, and vitamin D intakes. This study investigated serum calcium, phosphate, and 25-hydroxyvitamin D [25(OH)D] in relation to bone mineral content (BMC) in PDF-, TF-, and HM-fed preterm infants between term age (40 wk postmenstrual age) and 6 mo corrected age (CA). Between term age and 6 mo CA, 52 preterm infants were fed PDF (per 100 mL: 67 kcal, 1.7 g protein, 65 mg calcium, 38 mg phosphorus, 56 IU vitamin D), 41 were fed TF (per 100 mL: 67 kcal, 1.47 g protein, 50 mg calcium, 30 mg phosphorus, 48 IU vitamin D), and 46 were fed HM. Serum calcium, phosphorus, and 25(OH)D were measured at term age and at 3 and 6 mo CA. BMC (g) was measured by whole-body dual-energy X-ray absorptiometry at term age and at 6 mo CA. Between term age and 6 mo CA, intakes of calcium, phosphorus, and vitamin D were significantly higher in PDF- compared with TF-fed infants, and PDF-fed infants reached significantly higher serum 25(OH)D concentrations at 6 mo CA (103 ± 24.3 vs. 92.8 ± 15.5 nmol/L, P = 0.003). Between term age and 6 mo CA, increases in serum 25(OH)D were associated with an increase in BMC (β = 0.001; 95% CI: 0.00, 0.003; P = 0.046). In conclusion, during the first 6 mo postterm, higher vitamin D intake and greater increase in serum 25(OH)D concentration in PDF-fed preterm infants were associated with increased bone accretion.

Birth weight and postnatal growth in preterm born children are associated with cortisol in early infancy, but not at age 8 years.

BACKGROUND Preterm birth has been associated with altered hypothalamic-pituitary-adrenal (HPA-) axis activity as well as cardiometabolic diseases and neurodevelopmental impairments later in life. We assessed cortisol from term age to age 8 y in children born preterm, to explore the development of HPA-axis activity in association with intrauterine and early-postnatal growth until 6 mo. corrected age. METHODS In 152 children born at a gestational age ≤32 wks. and/or with a birth weight ≤1,500g, random serum cortisol was assessed at term age (n=150), 3 mo. (n=145) and 6 mo. corrected age (n=144), and age 8 y (n=59). Salivary cortisol was assessed at age 8 y (n=75): prior to bedtime, at awakening, 15min after awakening, and before lunch. Cortisol was analyzed in association with birth weight-standard deviation score (SDS), being born small for gestational age (SGA), and combinations of intrauterine and postnatal growth: appropriate for gestational age (AGA) with or without growth restriction (AGA GR+ or AGA GR-) at 6 mo. corrected age, and SGA with or without catch-up growth (SGA CUG+ or SGA CUG-) at 6 mo. corrected age. Cross-sectional associations at all time points were analyzed using linear regression, and longitudinal associations were analyzed using generalized estimating equations. RESULTS Longitudinally, birth weight-SDS was associated with cortisol (β [95%CI]): lower cortisol over time was seen in infants with a birth weight ≤-2 SDS (-50.69 [-94.27; -7.11], p=0.02), infants born SGA (-29.70 [-60.58; 1.19], p=0.06), AGA GR+ infants (-55.10 [-106.02; -4.17], p=0.03) and SGA CUG- infants (-61.91 [-104.73; -19.10], p=0.01). In cross-sectional analyses at age 8 y, no associations were found between either serum or salivary cortisol and birth weight-SDS, SGA-status, or growth from birth to 6 mo. corrected age. CONCLUSION In children born preterm, poor intrauterine and postnatal growth were associated with lower cortisol in early infancy, but not at age 8 y. Even though HPA-axis activity no longer differed between groups at age 8 y, or differences could not be confirmed due to attrition, it is unknown whether the differences found in early infancy could attribute to increased health risks later in life.

Procollagen type I N‐terminal peptide in preterm infants is associated with growth during the first six months post‐term

To identify growth‐related collagen and bone parameters in small‐for‐gestational‐age (SGA) and appropriate‐for‐gestational‐age (AGA) preterm infants during the first six months post‐term. In SGA preterm infants, increased growth and decreased bone acquisition, which we demonstrated previously, may be reflected by these markers.

Spectroscopic detection of brain propylene glycol in neonates: Effects of different pharmaceutical formulations of phenobarbital: Brain Propylene Glycol in Neonates

The first choice for treatment of neonatal convulsions is intravenous phenobarbital, which contains propylene glycol (PG) as a solvent. Although PG is generally considered safe, the dosage can exceed safety thresholds in neonates. High PG levels can cause lactic acidosis.

Salt sensitivity of blood pressure at age 8 years in children born preterm

Preterm birth and low birth weight have been associated with an increased risk of hypertension; postnatal growth and dietary salt intake may contribute to these associations. In adults, the change of blood pressure (BP) in response to modifications in salt intake, i.e., salt sensitivity of BP, has been independently associated with cardiovascular disease. Little is known about salt sensitivity in children. We hypothesize that it may partly explain the association between preterm birth and higher BP in later life. We assessed salt sensitivity of BP at age 8 years in 63 preterm-born children, and explored its association with postnatal growth, sodium intake, and body composition from infancy onwards. BP was measured at baseline and after a 7-day high-salt diet. The difference in mean arterial pressure (MAP) was calculated; salt sensitivity was defined as an increase in MAP of ≥5%. Ten children (16%) showed salt sensitivity of BP, which was associated with neonatal growth restriction as well as with lower fat mass and BMI from infancy onwards. At age 8 years, children classified as salt sensitive had a lower weight-for-age SD-score (−1.5 ± 1.3 vs. −0.6 ± 1.1) and BMI (13.8 ± 1.7 vs. 15.5 ± 1.8 kg/m2) compared to their salt resistant counterparts. Sodium intake was not associated with (salt sensitivity of) BP. Salt sensitivity of BP was demonstrated in preterm-born children at age 8 years and may contribute to the development of cardiovascular disease at later age. Long-term follow-up studies are necessary to assess reproducibility of our findings and to explore clustering with other cardiovascular risk factors.

Leptin and IGF-1 in relation to body composition and bone mineralization of preterm-born children from infancy to 8 years

Preterm birth has been associated with altered body composition, especially increased fat mass (FM) and decreased bone mineralization, and leptin and IGF‐1 have been suggested to be involved in the regulation of both. We aimed to study the interplay between leptin, IGF‐1, FM and bone mineralization measured in infancy and childhood of children born preterm.