Cortisol and Cortisone in Early Childhood in Very-Low-Birthweight Infants and Term-Born Infants.

INTRODUCTION: Besides programming of the hypothalamic-pituitary-adrenal (HPA) axis, changes in the activity of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) could contribute to the later metabolic and cardiovascular consequences of preterm birth. OBJECTIVE: We compared serum cortisol, cortisone, and cortisol/cortisone ratio in early childhood in very-low-birthweight (VLBW) infants and term appropriate for gestational age (AGA) born infants. METHODS: We included 41 VLBW infants, participating in the randomized controlled Neonatal Insulin Replacement Therapy in Europe trial, and 64 term AGA-born infants. Cortisol and cortisone were measured in blood samples taken at 6 months and 2 years corrected age (VLBW children) and at 3 months and 1 and 2 years (term children). At 2 years of (corrected) age (HDL) cholesterol, triglycerides, glucose, and insulin were also measured. RESULTS: During the first 2 years of life, cortisol/cortisone ratio is higher in VLBW children compared to term children. In the total group of children, cortisol/cortisone ratio is positively related to triglycerides at 2 years of (corrected) age. In VLBW children, over the first 2 years of life both cortisol and cortisone are higher in the early-insulin group compared to the standard care group. CONCLUSIONS: In VLBW infants, lower 11ß-HSD2 activity probably contributes to the long-term metabolic and cardiovascular risks. In VLBW infants, early insulin treatment could affect programming of the HPA axis, resulting in higher cortisol and cortisone levels during early childhood.

Assessing bone development in preterm infants using quantitative ultrasonography showed a decline in the early postnatal period.

AIM: Preterm infants have an insufficient bone mineral store at birth and this study explored their bone development during the early postnatal period. METHODS: The metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT) were used to assess bone development in 277 preterm infants, admitted to the neonatal intensive care unit of the VU University Medical Center, Amsterdam, the Netherlands from 2007-2012. RESULTS: During the first nine postnatal weeks, the mcSOS declined from 10 to 38 m per second per week and the mcBTT declined from 20 to 71 nanoseconds per week. The pattern of change in both of these measurements showed a significant difference between infants born before 32 weeks of gestation (p = 0.048) and those born between 28 and 32 weeks of gestation (p = 0.008). There was a borderline significant difference in the pattern of change of the mcBTT in infants with a protein intake below 2 g/kg per day versus a higher intake (p = 0.050). CONCLUSION: The mcSOS and mcBTT of preterm infants showed a small to moderate decline during the early postnatal period. Future studies should explore the clinical relevance of this decline and develop interventions to halt it.

IGF-I and relation to growth in infancy and early childhood in very-low-birth-weight infants and term born infants.

BACKGROUND: In very-low-birth-weight infants IGF-I plays an important role in postnatal growth restriction and is probably also involved in growth restriction in childhood. We compared IGF-I and its relation to growth in early childhood in very-low-birth-weight infants and term appropriate for gestational age born infants. METHODS: We included 41 very-low-birth-weight and 64 term infants. Anthropometry was performed at all visits to the outpatient clinic. IGF-I and insulin were measured in blood samples taken at 6 months and 2 years corrected age (very-low-birth-weight children) and at 3 months, 1 and 2 years (term children). RESULTS: Over the first 2 years of life growth parameters are lower in very-low-birth-weight children compared to term children, but the difference in length decreases significantly. During the first 2 years of life IGF-I is higher in very-low-birth-weight children compared to term children. In both groups there is a significant relationship between IGF-I and (change in) length and weight over the first 2 years of life and between insulin and change in total body fat. CONCLUSIONS: Considering the relation of IGF-I to growth and the decrease in difference in length, higher IGF-I levels in very-low-birth-weight infants in early childhood probably have an important role in catch-up growth in length.

Salivary and serum cortisol and relation to blood pressure in infancy and early childhood in very-low-birth-weight infants.

BACKGROUND: Programming of the hypothalamic-pituitary-adrenal (HPA) axis possibly explains the relation between intrauterine growth restriction (IUGR) and/or preterm birth and elevated blood pressure in later life. Very-low-birth-weight infants (birth weight <1,500 g) have high prevalence of raised blood pressure, already in early childhood. We investigated cortisol levels, relation to blood pressure and reliability of salivary cortisol in infancy and early childhood in very-low-birth-weight infants. METHODS: We included 41 children, participating in the randomized controlled Neonatal Insulin Replacement Therapy in Europe (NIRTURE) trial. Serum and salivary samples for cortisol measurement (immunoassay) were taken simultaneously at 6 mo and separately at 2 y corrected age. Blood pressure was measured at 2 y corrected age. RESULTS: Serum cortisol was significantly correlated to systolic and diastolic blood pressure in boys and in the early-insulin treated group. At 2 y corrected age serum cortisol was significantly higher in the early-insulin group compared to the standard care group. At 6 mo corrected age salivary cortisol was significantly correlated to serum cortisol. CONCLUSION: In very-low-birth-weight boys, the positive correlation between cortisol and blood pressure is present at 2 y corrected age. Early insulin therapy could affect programming of the HPA axis. Salivary cortisol mirrors serum levels at 6 mo corrected age.

Components of the metabolic syndrome in early childhood in very-low-birth-weight infants and term small and appropriate for gestational age infants.

BACKGROUND: Term small-for-gestational-age (SGA) and preterm born infants have an increased prevalence of metabolic syndrome components already in childhood. Our recent study in 2-y-old very-low-birth-weight (VLBW) infants was limited by the absence of a control group of term born children. We compared the metabolic syndrome components in early childhood in VLBW and term SGA infants to term appropriate for gestational age (AGA) infants. METHODS: We included 38 VLBW children and 82 term born children (64 AGA/18 SGA). HDL cholesterol, triglycerides, glucose, and insulin were measured in blood samples taken at 1 y (term children) and 2 y (all children) of (corrected) age. RESULTS: At 2 y corrected age, VLBW children have lower BMI and higher glucose level compared to AGA children. SGA children have lower BMI at 1 and 2 y of age and a high prevalence of high triglyceride levels at 1 y of age compared to AGA children. Total body fat is a significant determinant of HDL cholesterol and triglycerides and birth weight is a significant determinant of glucose at 2 y corrected age. CONCLUSION: In early childhood, VLBW and term SGA children already have a high prevalence of some metabolic syndrome components compared to term AGA children.

Components of the metabolic syndrome in early childhood in very-low-birth-weight infants.

BACKGROUND/AIMS: Term small-for-gestational-age and preterm born infants have an increased prevalence of metabolic syndrome components already in childhood. Data in very-low-birth-weight (VLBW) children are limited. We investigated the prevalence of metabolic syndrome components in VLBW infants at 2 years of corrected age. METHODS: We included 38 children, participating in the Neonatal Insulin Replacement Therapy in Europe (NIRTURE) trial, a randomized controlled trial of early insulin therapy in VLBW infants. Metabolic syndrome components were defined as: body mass index SDS >2; blood pressure (systolic and/or diastolic) ≥ 90th percentile; triglycerides ≥ 0.98 mmol/l; high-density lipoprotein (HDL) cholesterol ≤ 1.03 mmol/l; glucose ≥ 5.6 mmol/l. RESULTS: Two children (5%) had three metabolic syndrome components, 13 children (34%) had two components, and 11 children (29%) one component. 63% had raised blood pressure (prevalence higher in boys), 32% low HDL, and 30% high triglycerides (prevalence lower in early insulin group). In children with body mass index SDS <0, insulin-treated children had higher HDL than children with standard care. Systolic blood pressure was correlated with growth between term and 2 years of corrected age. CONCLUSIONS: VLBW infants already have a high prevalence of metabolic syndrome components at 2 years of corrected age. Early insulin treatment could have long-term benefits for some of these components.

Urine gonadotropin and estradiol levels in female very-low-birth-weight infants.

BACKGROUND: The postnatal activation of the hypothalamic-pituitary-gonadal axis is more exaggerated in preterm than in full-term born infants and may be important for future reproductive function. AIM: The objective of this study was to investigate the postnatal activation of the hypothalamic-pituitary-gonadal axis in female very-low-birth-weight infants. STUDY DESIGN: We performed serial measurements of gonadotropin and estradiol levels in urine samples of female very-low-birth-weight infants collected at 1 and 4weeks postnatal age, at 32weeks postmenstrual age, at expected date of delivery and at the corrected age of three and six months. SUBJECTS: Twenty-two very-low-birth-weight infants (gestational age 25.4-30.1weeks), participating in the Neonatal Insulin Replacement Therapy in Europe trial, were included in this study. OUTCOME MEASURES: Gonadotropin and estradiol levels were measured in serial urine samples. RESULTS: Longitudinal analysis shows that after birth FSH and LH levels increase until 32weeks postmenstrual age (4weeks postnatal age) and then decrease until 3months corrected age (26weeks postnatal age). Estradiol levels decrease from 28weeks postmenstrual age (1week postnatal age) until 6months corrected age (39weeks postnatal age). CONCLUSIONS: Serial urine sampling for measurement of gonadotropin and estradiol levels provides an accurate description of the postnatal activation of the hypothalamic-pituitary-gonadal axis in very-low-birth-weight girls. Levels of FSH and LH peak at a mean postmenstrual age of 32weeks (postnatal age of 4weeks) whereas estradiol levels are highest shortly after birth.

Catch-up growth in children born growth restricted to mothers with hypertensive disorders of pregnancy.

BACKGROUND: In preterm hypertensive disorders of pregnancy, fetal growth restriction (FGR) occurs frequently. The timing and severity of FGR impacts childhood growth and is associated with metabolic changes later in life. AIM: To examine growth and the impact of FGR in early childhood. DESIGN: Prospective cohort study. PARTICIPANTS: Children (n=135) born to mothers who were admitted before 34 weeks' gestational age with a severe hypertensive disorder of pregnancy. OUTCOME MEASURES: Height, weight, body mass index (BMI), head circumference (HC), SD scores (SDS) at 3 months, and 1 and 4.5 years of age, and complete catch-up growth (height SDS-target height SDS >-1.6). RESULTS: Growth scores were lower compared to Dutch growth curves, except for BMI at 3 months and girls' HC at all ages. Mean height SDS increased over time from -1.4 to -0.5 at 4.5 years, with 94% having complete catch-up growth. Mean BMI SDS decreased from -0.2 at 3 months to -1.0 at 1 year, and was -0.8 at age 4.5. Mean HC SDS was stable over time and -0.3 at 4.5 years. The customised birth weight ratio, as a measure of the degree of FGR, was related to all growth SDS at 4.5 years, while gestational age at birth was not. CONCLUSIONS: Although the majority of children born growth restricted had catch-up growth of height within the normal range at 4.5 years of age, they were smaller, but especially lighter compared to Dutch growth charts. The degree of FGR was associated with all growth outcomes.

Outcome at 4.5 years of children born after expectant management of early-onset hypertensive disorders of pregnancy.

OBJECTIVE: The objective of the study was to describe neurodevelopmental outcome at the age of 4.5 years in 216 children, born after expectant management of severe early-onset hypertensive complications of pregnancy. STUDY DESIGN: This was a prospective follow-up study until age 4.5 years from maternal admission onward. Developmental outcome measurements included child intelligence quotient and behavioral, motor, and neurological outcome. Abnormal composite outcome (perinatal mortality or abnormal developmental outcome) was studied in relation to gestational age (GA), birthweight (BW), and perinatal variables. RESULTS: Fetal and neonatal mortality was 9% and 8%, respectively. Of the 178 survivors, 149 (84%) were seen for follow-up. Mean GA was 31.4 weeks and 90% were born growth restricted. Abnormal developmental outcome occurred in 20% and abnormal composite outcome in 37%. CONCLUSION: Perinatal mortality or abnormal child development occurs in one third of pregnancies with early-onset and severe hypertensive complications and is highest in the lowest GA and BW ranges.

Optimal growth and lower fat mass in preterm infants fed a protein-enriched postdischarge formula.

BACKGROUND AND OBJECTIVES: Postdischarge formulas with extra energy and protein improve short-term growth but may also influence long-term body composition in an unwanted manner. Energy- and protein-enriched formulas with an increased protein-to-energy ratio improves gain of lean mass. The objective of the study was to investigate whether feeding a nutrient-enriched formula without extra energy after term, usually 3 to 4 weeks after discharge, would influence growth and body composition in infancy. METHODS: In this randomized controlled trial preterm infants were fed fortified human milk or preterm formula until term. At term, 102 infants were randomized to a nutrient-enriched formula without extra energy or standard formula until 6 months corrected age. Twenty-six infants received unfortified human milk after term. At term and 6 months corrected age, anthropometry and a dual-energy x-ray absorptiometry (DEXA) scan were performed. Lean and fat mass (FM) were corrected for height. RESULTS: There were no differences in growth or body size between the feeding groups. Infants fed the enriched formula gained less FM and had lower FM corrected for body size at 6 months corrected age than infants fed standard formula. Infants fed human milk had lower lean mass and higher FM corrected for body size at 6 months corrected age than formula-fed infants. CONCLUSIONS: Feeding nutrient-enriched formula without extra energy after term does not change quantity of growth but does influence type of weight gain and body composition of preterm infants. Infants fed the nutrient-enriched formula had lower FM corrected for body size at 6 months corrected age than infants fed standard formula or human milk.

Whole body protein turnover and urea production of preterm small for gestational age infants fed fortified human milk or preterm formula.

OBJECTIVES: To investigate protein metabolism and urea production in preterm small for gestational age neonates fed a preterm formula or fortified human milk. METHODS: Ten preterm small for gestational age neonates were fed either their own mother's milk fortified with a powdered protein mineral supplement or a special preterm formula. Protein metabolism was determined using constant steady-state infusion of L-[ring-2H5]phenylalanine and L-[1-13C]valine. Urea production was determined from steady-state [13C]urea kinetics. RESULTS: Mean protein intake was 24% higher in the preterm formula group than in the fortified human milk group. No differences in protein turnover, synthesis and breakdown were observed between the two groups, but protein accretion was 71% to 79% higher in the preterm formula group than the fortified human milk group. Urea production rates were not different in the two groups. There was a strong negative correlation between urea production and protein accretion calculated from phenylalanine kinetics but not when calculated from valine kinetics. CONCLUSIONS: Preterm formula and fortified human milk appear equally well tolerated by preterm small for gestational age neonates, but protein accretion was higher in the preterm formula group. In preterm small for gestational age infants, both phenylalanine and valine kinetic methods can be used to accurately determine protein metabolism.

Neuromotor function and school performance in 7-year-old children born as high-risk preterm infants.

Neuromotor behavior was studied in 63 children at a mean age of 7 years. They were born at a gestational age less than 32 weeks and/or birthweight under 1500 g and were categorized according to their medical history in conformance with the Neonatal Medical Index (from category I to V, from few to serious complications). We included only children considered at high risk as categorized in III to V. The neuromotor behavior study focuses on different subcategories, such as hand function, quality of walking, posture, passive muscle tone, coordination, and diadochokinesia. Hand preference and/or lateralization, the presence of associated movements, and/or asymmetry were noted, as was school performance. Then gender, gestational age, birthweight, and dysmaturity were investigated as confounding factors. The outcome at 7 years was correlated with the Neonatal Medical Index and the neonatal brain ultrasonography classification. None of the children scored 100% on the combined subcategories. Nineteen children (30%) had an overall score between 75 and 99%. Significant relationships between all different subcategories were found. Lack of hand preference, poor lateralization, and male gender were related to poor overall outcome. Poor motor control was correlated to special schooling and education below age level. The Neonatal Medical Index proved to have a significant influence on total outcome and the subcategories at the age of 7 years, with the worst outcome in children formerly classified in category V. Neuromotor behavior at 7 years of age was not related to birthweight, gestational age, dysmaturity, and neonatal brain ultrasonography classification only.

The corticotrophin-releasing hormone test in preterm infants.

OBJECTIVE: The developing hypothalamic--pituitary--adrenal axis (HPAA) may be immature and not yet fully functional in preterm infants. This may result in an inappropriate adrenal response to stress. Little is known about the pituitary--adrenal response to corticotrophin-releasing hormone (CRH) stimulation during the early neonatal period in preterm infants born before 32 weeks of gestation. Therefore, in a first study we investigated the pituitary--adrenal response to 1 microg/kg CRH i.v. in 13 preterm infants born less-than-or-equal 32 weeks of gestation. In addition, in a randomized placebo-controlled study we compared the pituitary--adrenal response of 1 microg/kg CRH to placebo and stimulation with 2 microg/kg CRH. RESULTS: In the first study, the level of ACTH increased from 6.9 +/-2.1 to 11.6 +/- 5.1 pmol/l (P < 0.01) and cortisol increased from 350 plus minus 115 to 582 +/- 201 nmol/l (P < 0.05). Thirty-eight percent of the studied infants showed a maximal level of ACTH < 9 pmol/l, and 15% showed a maximal level of cortisol < 360 nmol/l. In the randomized study, infants in the 1 microg/kg and in the 2 microg/kg CRH group, but not in the placebo group, showed a significant increase in cortisol and ACTH after stimulation (P < 0.01). Stimulated levels of ACTH and cortisol were significantly higher in the 2 microg/kg group compared with the placebo and the 1 microg/kg group. No differences were found for plasma ACTH and cortisol levels in the 1 microg/kg group compared with the placebo group. Basal levels of cortisol and ACTH obtained from the first and from the randomized study correlated significantly (n = 29; r = 0.42, P < 0.03). In addition, in infants stimulated with 1 microg/kg CRH a lower cortisol response correlated with a longer stay in hospital (n = 13; r = --0.57, P < 0.05). CONCLUSIONS: In this study we show that a 1 microg/kg CRH stimulation test in preterm infants results more often in an inappropriate adrenal response while stimulation with 2 microg/kg CRH gives rise to an appropriate response in all studied infants. Furthermore, stimulation with 2 microg/kg CRH results in higher levels of ACTH and cortisol compared to placebo and 1 microg/kg CRH. We conclude that in preterm infants the ability of the pituitary to respond adequately to CRH stimulation depends on the dose of CRH used and may also be dependent on the maturity of the pituitary--adrenal axis.

Neonatal antibody titers against varicella-zoster virus in relation to gestational age, birth weight, and maternal titer.

OBJECTIVE: Varicella-zoster virus (VZV) can cause severe disease in premature neonates. The fetus receives protective maternal VZV-immunoglobulin G (IgG) mainly in the third trimester of pregnancy. Therefore, premature neonates are considered at risk for VZV infection. Administration of varicella-zoster immunoglobulin (VZIG) within 96 hours after exposure effectively prevents severe illness in susceptible patients. The objectives of this study were to define the major determinants of the neonatal VZV-IgG titer and to determine the half-life of transplacentally acquired VZV-IgG. Guidelines provided by the Centers for Disease Control and Prevention for the use of VZIG in (premature) neonates were evaluated. METHODS: VZV-IgG titers were measured in sera of 221 neonates and 43 mothers using a quantitative enzyme-linked immunosorbent assay. In 27 neonates, VZV-IgG titers were followed for up to 14 weeks. RESULTS: In a linear regression model, the maternal antibody titer was the major determinant of the neonatal titer (beta = 0.89); gestational age was only of minor importance (beta = 0.18). The median half-life of VZV-IgG in neonates was 25.5 days (range: 14.6-76.0 days). In the first weeks of life, major fluctuations of the VZV-IgG titer occurred in >50% of the neonates. The predictive value of Centers for Disease Control and Prevention guidelines for identification of neonates who should receive VZIG in case of exposure to VZV was poor: positive and negative predictive values were 0.80 and 0.43, respectively. CONCLUSIONS: The neonatal VZV-IgG titer is predominantly predicted by the maternal VZV-IgG titer, whereas birth weight and gestational age are much less predictive than previously reported.