Hyper high haemoglobin content in red blood cells and erythropoietic transitions postnatally in infants of 22 to 26 weeks' gestation: a prospective cohort study.

OBJECTIVE: Blood cell populations, including red blood cells (RBC) unique to the extremely preterm (EPT) infant, are potentially lost due to frequent clinical blood sampling during neonatal intensive care. Currently, neonatal RBC population heterogeneity is not described by measurement of total haemoglobin or haematocrit. We therefore aimed to describe a subpopulation of large RBCs with hyper high haemoglobin content, >49 pg (Hyper-He) following EPT birth. DESIGN: Prospective observational cohort study. SETTING: Two Swedish study centres. PARTICIPANTS: Infants (n=62) born between gestational weeks 22+0 to 26+6. METHODS: Prospective data (n=280) were collected from March 2020 to September 2022 as part of an ongoing randomised controlled trial. Blood was sampled from the umbilical cord, at postnatal day 1-14, 1 month, 40 weeks' postmenstrual age and at 3 months' corrected age. RESULTS: At birth, there was a considerable inter-individual variation; Hyper-He ranging from 1.5% to 24.9% (median 7.0%). An inverse association with birth weight and gestational age was observed; Spearman's rho (CI) -0.38 (-0.63 to -0.07) and -0.39 (-0.65 to -0.05), respectively. Overall, Hyper-He rapidly decreased, only 0.6%-5.0% (median 2.2%) remaining 2 weeks postnatally. Adult levels (<1%) were reached at corresponding term age. CONCLUSION: Our results point to gestational age and birth weight-dependent properties of the RBC population. Future work needs to verify results by different measurement techniques and elucidate the potential role of differing properties between endogenous and transfused RBCs in relation to neonatal morbidities during this important time frame of child development. TRIAL REGISTRATION NUMBER: NCT04239690.

Modification of serum fatty acids in preterm infants by parenteral lipids and enteral docosahexaenoic acid/arachidonic acid: A secondary analysis of the Mega Donna Mega trial.

BACKGROUND & AIM: Preterm infants risk deficits of long-chain polyunsaturated fatty acids (LCPUFAs) that may contribute to morbidities and hamper neurodevelopment. We aimed to determine longitudinal serum fatty acid profiles in preterm infants and how the profiles are affected by enteral and parenteral lipid sources. METHODS: Cohort study analyzing fatty acid data from the Mega Donna Mega study, a randomized control trial with infants born <28 weeks of gestation (n = 204) receiving standard nutrition or daily enteral lipid supplementation with arachidonic acid (AA):docosahexaenoic acid (DHA) (100:50 mg/kg/day). Infants received an intravenous lipid emulsion containing olive oil:soybean oil (4:1). Infants were followed from birth to postmenstrual age 40 weeks. Levels of 31 different fatty acids from serum phospholipids were determined by GC-MS and reported in relative (mol%) and absolute concentration (µmol l-1) units. RESULTS: Higher parenteral lipid administration resulted in lower serum proportion of AA and DHA relative to other fatty acids during the first 13 weeks of life (p < 0.001 for the 25th vs the 75th percentile). The enteral AA:DHA supplement increased the target fatty acids with little impact on other fatty acids. The absolute concentration of total phospholipid fatty acids changed rapidly in the first weeks of life, peaking at day 3, median (Q1-Q3) 4452 (3645-5466) µmol l-1, and was positively correlated to the intake of parenteral lipids. Overall, infants displayed common fatty acid trajectories over the study period. However, remarkable differences in fatty acid patterns were observed depending on whether levels were expressed in relative or absolute units. For example, the relative levels of many LCPUFAs, including DHA and AA, declined rapidly after birth while their absolute concentrations increased in the first week of life. For DHA, absolute levels were significantly higher compared to cord blood from day 1 until postnatal week 16 (p < 0.001). For AA, absolute postnatal levels were lower compared to cord blood from week 4 throughout the study period (p < 0.05). CONCLUSIONS: Our data show that parenteral lipids aggravate the postnatal loss of LCPUFAs seen in preterm infants and that serum AA available for accretion is below that in utero. Further research is needed to establish optimal postnatal fatty acid supplementation and profiles in extremely preterm infants to promote development and long-term health. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, identifier: NCT03201588.

The Dietary Inflammatory Index Is Associated with Subclinical Mastitis in Lactating European Women.

Subclinical mastitis (SCM) is an inflammatory state of the lactating mammary gland, which is asymptomatic and may have negative consequences for child growth. The objectives of this study were to: (1) test the association between the dietary inflammatory index (DII®) and SCM and (2) assess the differences in nutrient intakes between women without SCM and those with SCM. One hundred and seventy-seven women with available data on human milk (HM) sodium potassium ratio (Na:K) and dietary intake data were included for analysis. Multivariable logistic regression was used to examine the association between nutrient intake and the DII score in relation to SCM. Women without SCM had a lower median DII score (0.60) than women with moderate (1.12) or severe (1.74) SCM (p < 0.01). A one-unit increase in DII was associated with about 41% increased odds of having SCM, adjusting for country and mode of delivery, p = 0.001. Women with SCM had lower mean intakes of several anti-inflammatory nutrients. We show for the first time exploratory evidence that SCM may be associated with a pro-inflammatory diet and women with SCM have lower intakes of several antioxidant and anti-inflammatory nutrients.

Human milk fatty acid composition and its association with maternal blood and adipose tissue fatty acid content in a cohort of women from Europe.

PURPOSE: Human milk (HM) composition is influenced by factors, like maternal diet and body stores, among other factors. For evaluating the influence of maternal fatty acid (FA) status on milk FA composition, the correlation between FA content in HM and in maternal plasma, erythrocytes, and adipose tissue was investigated. METHODS: 223 European women who delivered at term, provided HM samples over first four months of lactation. Venous blood and adipose tissue (only from mothers who consented and underwent a C-section delivery) were sampled at delivery. FAs were assessed in plasma, erythrocytes, adipose tissue, and HM. Evolution of HM FAs over lactation and correlations between FA content in milk and tissues and between mother's blood and cord blood were established. RESULTS: During lactation, arachidonic acid (ARA) and docosahexaenoic acid (DHA) significantly decreased, while linoleic acid (LA), alpha-linolenic acid (ALA), and eicosapentaenoic acid (EPA) remained stable. Positive correlations were observed between HM and adipose tissue for palmitic, stearic, oleic, and polyunsaturated fatty acids (PUFAs). Correlations were found between milk and plasma for oleic, LA, ARA, ALA, DHA, monounsaturated fatty acids (MUFAs), and PUFAs. No correlation was observed between erythrocytes and HM FAs. LA and ALA were more concentrated in maternal blood than in infant blood, contrary to ARA and DHA, supporting that biomagnification of LCPUFAs may have occurred during pregnancy. CONCLUSIONS: These data show that maternal adipose tissue rather than erythrocytes may serve as reservoir of PUFAs and LCPUFAs for human milk. Plasma also supplies PUFAs and LCPUFAs to maternal milk. If both, adipose tissue and plasma PUFAs, are reflection of dietary intake, it is necessary to provide PUFAs and LCPUFAs during pregnancy or even before conception and lactation to ensure availability for mothers and enough supply for the infant via HM.

High Rate of Cytomegalovirus Detection in Cholestatic Preterm Infants.

Objectives: To evaluate the prevalence of cytomegalovirus (CMV) infection in preterm infants with cholestasis. Study design: Preterm infants (<37 weeks gestational age) with cholestasis were tested for CMV DNA using Taqman PCR in blood cells from sedimented whole blood, plasma, and urine. Infants were regarded as positive for CMV if any sample was tested positive. Their mothers were tested for CMV serostatus simultaneously. A control group of non-cholestatic preterm infants, and their mothers, were tested at a similar age. Results: A total of 69 preterm infants with a median gestational age of 26 weeks and 5 days were included, 45 cholestatic and 24 non-cholestatic. Of the cholestatic infants, 31/45 (69%) were CMV positive vs. 3/24 (13%) of the non-cholestatic infants (p < 0.001). Cholestatic infants were equally preterm as the non-cholestatic ones, but were more severely ill. After adjusting for the risk factors necrotizing enterocolitis, prolonged parenteral nutrition, and gestational age, being CMV positive remained significantly associated with cholestasis in a multivariable logistic regression model. Characteristics of CMV-positive and -negative cholestatic infants showed differences only for necrotizing enterocolitis, occurring in 55% (17/31) of CMV positive vs. 21% (3/14) of CMV negative (p = 0.054), and mortality. Eight cholestatic CMV-positive infants died (26%) vs. none of the CMV-negative infants (p = 0.044). Conclusions: CMV DNA was detected in two out of three cholestatic preterm infants, by far more often than in the non-cholestatic control group. Cholestasis with simultaneous detection of CMV DNA may be associated with increased mortality.

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial.

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation.

BACKGROUND: The relationship between human milk oligosaccharides (HMOs) and infant growth and adiposity is not fully understood and comprehensive studies are missing from the current literature. METHODS: We screened and recruited 370 healthy, pregnant women and their infants from seven European countries. Breastmilk samples were collected using standardized procedures at six time points over 4 months, as were infant parameters. Correlations and associations between HMO area under the curve, anthropometric data, and fat mass at 4 months were tested. RESULTS: Lacto-N-neotetraose had a negative correlation with the change in length (rs = -0.18, P = 0.02). Sialyllacto-N-tetraose c (LSTc) had a positive correlation with weight for length (rs = 0.19, P = 0.015). Infants at the 25th upper percentile were fed milk higher in 3'-sialyllactose and LSTc (P = 0.017 and P = 0.006, respectively) compared to the lower 25th percentile of the weight-for-length z-score gain over 4 months of lactation. No significant associations between growth and body composition and Lewis or secretor-dependent HMOs like 2'-fucosyllactose were identified. CONCLUSIONS: Changes in the HMO composition of breastmilk during the first 4 months appear to have little influence on infant growth and body composition in this cohort of healthy mothers and infants. IMPACT: Modest associations exist between individual HMO and infant growth outcomes at least in healthy growing populations. Our study provides a comprehensive investigation of associations between all major HMO and infant growth and adiposity including several time points. Certain groups of HMOs, like the sialylated, may be associated with adiposity during the first months of lactation. HMO may modulate the risk of future metabolic disease. Future population studies need to address the role of specific groups of HMOs in the context of health and disease to understand the long-term impact.

A prospective case-control study on miRNA circulating levels in subjects born small for gestational age (SGA) evaluated from childhood into young adulthood.

OBJECTIVE: microRNAs (miRNAs) associated with metabolic risk have never been extensively investigated in SGA subjects. The aim of the current study was to evaluate miRNAs in SGA and AGA subjects and their relationships with the metabolic status and growth. DESIGN AND METHODS: A prospective longitudinal case-control study was performed in 23 SGA with postnatal catch-up growth and 27 AGA subjects evaluated at the age of 9 and 21 years. Circulating levels of miR-122-5p, miR-16-5p, miR-126-3p, and miR-486-5p were assessed by qPCR. RESULTS: SGA subjects were shorter both at 9 and at 21 years. No significant differences in insulin like growth factors and metabolic profile were found with the exception of basal glycemia at 9 years. miRNA levels did not differ between SGA and AGA subjects, at 9 and 21 years. miR-16-5p and miR-126-3p levels were higher at 9 than at 21 years. In SGA subjects, miR-122-5p at 9 years was inversely related to adiponectin levels at 21 years and miR-486-5p at 9 years was inversely related to whole-body insulin sensitivity at 9 years and directly related to Hb1Ac at 21 years. Regression analyses showed no predictive value of miRNAs for growth parameters in neither SGA nor AGA subjects. CONCLUSIONS: SGA with postnatal catch-up growth did not show any difference in metabolic risk markers or miRNA circulating levels compared to AGA controls in childhood and young adulthood. miR-122-5p during childhood could identify SGA subjects at higher risk of developing insulin resistance and, eventually, type 2 diabetes in adulthood but further studies are needed to confirm it.

Impact of maternal characteristics on human milk oligosaccharide composition over the first 4 months of lactation in a cohort of healthy European mothers.

Human milk oligosaccharide (HMO) composition varies among lactating mothers and changes during the course of lactation period. Interindividual variation is largely driven by fucosyltransferase (FUT2 and FUT3) polymorphisms resulting in 4 distinct milk groups. Little is known regarding whether maternal physiological status contributes to HMO variability. We characterized the trajectories of 20 major HMOs and explored whether maternal pre-pregnancy body mass index (ppBMI), mode of delivery, or parity may affect milk HMO composition. Using longitudinal breastmilk samples from healthy mothers (n = 290) across 7 European countries, we characterized HMO composion and employed mixed linear models to explore associations of maternal characteristics with individual HMOs. We observed HMO-specific temporal trajectories and milk group dependencies. We observed relatively small but significant differences in HMO concentrations based on maternal ppBMI, mode of delivery and parity. Our findings suggest that HMO composition to be regulated time-dependently by an enzyme as well as substrate availability and that ppBMI, mode of delivery, and parity may influence maternal physiology to affect glycosylation marginally within the initital period of lactation. Our observational study is the largest European standardized and longitudinal (up to 4 months) milk collection study assessing HMO concentrations and basic maternal characteristics. Time of lactation and milk groups had the biggest impact on HMO variation. Future studies need to elucidate these observations and assess the physiological significance for the breastfed infant.

Kidney volume, kidney function, and ambulatory blood pressure in children born extremely preterm with and without nephrocalcinosis.

BACKGROUND: Reduced kidney volume (KV) following prematurity is a proxy for reduced nephron number and is associated with the development of hypertension and end-stage renal disease in adults. We investigated whether extreme prematurity affects KV, function, and blood pressure in school-aged children and if nephrocalcinosis (NC) developed during the neonatal period had additional effects. METHODS: We investigated 60 children at a mean age of 7.7 years: 20 born extremely preterm (EPT < 28 weeks gestational age with NC (NC+)), 20 born EPT without NC (NC-), and 19 born as full-term infants (control). We measured KV by ultrasound, collected blood and urine samples to evaluate renal function, and measured office and 24-h ambulatory blood pressure (ABPM). RESULTS: Children born EPT had significantly smaller kidneys (EPT (NC+ NC-) vs control (estimated difference, 11.8 (CI - 21.51 to - 2.09 ml), p = 0.018) and lower but normal cystatin C-based glomerular filtration rate compared with control (estimated difference, - 10.11 (CI - 0.69 to - 19.5), p = 0.035). KV and function were not different between NC+ and NC- groups. Change in KV in relation to BSA (KV/BSA) from the neonatal period to school age showed significantly more EPT children with neonatal NC having a negative evolution of KV (p = 0.01). Blood pressure was normal and not different between the 3 groups. Fifty percent of EPT had a less than 10% day-to-night decline in ABPM. CONCLUSIONS: Kidney growth and volume is affected by EPT birth with NC being a potential aggravating factor. Circadian blood pressure regulation seems abnormal in EPT-born children.

Improved nutrition for extremely preterm infants - A population based observational study.

BACKGROUND AND AIMS: Extremely preterm (EPT) infants are at high risk for malnutrition due to immaturity and medical complications and they often accumulate nutritional deficits and experience growth faltering during treatment at neonatal intensive care units (NICUs). Enhanced intake of energy and protein during the first weeks of life improves weight gain and head circumference growth. The optimal nutritional strategy for these infants' health and long-term development remains unknown. Nutritional regiments have been identified as a potential area for improvement in Swedish NICUs. The aim of this study was to evaluate changes in nutritional intake over time during the first 56 postnatal days in EPT (<27 gestational weeks; n = 316) infants, who were treated in NICUs during 2004-2011 in Stockholm, using a population-based study approach. METHODS: Several different nutritional interventions were implemented over the 8-year period. Nutrition and growth data were obtained retrospectively from hospital records. All intakes of enteral and parenteral nutrients were retrieved daily during the first 28 postnatal days and on days 35, 42, 49 and 56. RESULTS: Energy intake (median) increased from 77 kcal/kg/d during the 2004-2005 period to 98 kcal/kg/d during the 2010-2011 period on days 4-6. Median protein intake increased from 2.4 g/kg/d during 2004-2005 to 3.6 g/kg/d during 2010-2011. Energy and protein intake during postnatal days 0-6 increased continuously over the 8 years and protein intake increased during all 56 postnatal days. Full enteral feeds were reached earlier and the proportion of enteral feeds during the first week was higher during 2008-2009 compared to all other years. A significant improvement in growth was primarily noted by comparing the 2004-2005 period to subsequent years. CONCLUSIONS: Neonatal nutrition improved significantly in Stockholm from 2004 to 2011. Above all, parenteral nutrition was initiated more promptly during the first week and was provided at higher quantities. However, many of the EPT infants born during the later years still did not reach the recommended macronutrient intake levels. A significant weight gain improvement was observed between 2004-2005 and 2006-2011.

High prevalence of cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal perforation: A retrospective observational study.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe, often fatal gastrointestinal emergency that predominantly affects preterm infants, and there is evidence that neonatal cytomegalovirus (CMV) infection may in some cases contribute to its pathogenesis. OBJECTIVES: This study aimed to evaluate the prevalence of CMV in infants with NEC. STUDY DESIGN: Seventy intestinal specimens from 61 infants with NEC, spontaneous intestinal perforation (SIP), or related surgical complications were collected at Karolinska University Hospital and Uppsala University Hospital, Sweden. Ten specimens from autopsied infants without bowel disease served as controls. Samples were analyzed for CMV immediate-early antigen (IEA), CMV late antigen (LA), 5-lipoxigenase (5LO) and CMV-DNA by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. In 10 index samples, CMV DNA was analyzed with Taqman PCR after laser capture microdissection (LCM) of cells positive for CMV IEA by IHC. RESULTS: CMV IEA was detected by IHC in 57 (81%) and CMV LA in 45 (64%) of 70 intestinal specimens from index cases; 2 (20%) of 10 control specimens were positive for both antigens. 5LO was detected in intestinal tissue section obtained from all examined index and controls. CMV DNA was detected in 4 of 10 samples (40%) after LCM. By ISH, all 13 IHC-IEA-positive samples were positive for CMV DNA; however, 3 of 5 IHC-IEA-negative samples (60%) were also positive. CONCLUSIONS: CMV-specific antigens and CMV DNA were highly prevalent in intestinal specimens from infants with NEC, SIP, and related surgical complications. Our findings provide further evidence that neonatal CMV infection contributes to the pathogenesis of these diseases and may affect patient outcome.

Cytomegalovirus infection and neonatal outcome in extremely preterm infants after freezing of maternal milk.

BACKGROUND: Cytomegalovirus (CMV) infection acquired from breast milk can cause serious illness in extremely preterm (EPT) infants (<28 weeks). Some neonatal centers freeze maternal milk (MM) to prevent CMV transmission; however, this practice is controversial. In this study, we assessed the CMV transmission rate and neonatal outcome in EPT infants after routine freezing of all MM. METHODS: EPT infants (n = 140) and their mothers were randomized to the intervention group (only freeze-thawed MM) or the control group (combined fresh and freeze-thawed MM). Freeze-thawed MM was frozen at -20°C for ≥3 days before thawing. Mothers had serological tests for CMV, and MM was analyzed for CMV by polymerase chain reaction and CMV culture. Infants underwent CMV screening with urine analysis by CMV-polymerase chain reaction and CMV culture until 12 weeks of age. RESULTS: Congenital CMV infection was detected in 2% of screened infants. The CMV transmission rate in infants fed with CMV-DNA positive milk was 8% (3 of 37) in the intervention group and 6% (2 of 33) in controls. All infants infected by CMV were asymptomatic. The final per-protocol analysis included 56 infants in the intervention group and 65 controls. Neonatal mortality was comparable between the groups (7% vs. 6%). Neonatal morbidity was similar, except for late onset Candida sepsis, which was more frequent in the controls (12% vs. 0%). CONCLUSIONS: Routine freezing of all MM did not affect the rate of CMV transmission but may help to prevent fungal sepsis in EPT infants. This observation merits further investigation.

Decreased heart rate variability in children born with low birth weight.

BACKGROUND: Low birth weight (LBW) is associated with cardiovascular morbidity in adulthood. Imbalance in the autonomic nervous system (ANS) has been implicated as a mechanism behind the developmental programming of cardiovascular function. We hypothesized that deviations in the ANS function are seen in children born with LBW. METHODS: Eighty-six children were included: 31 born preterm (<32 wk gestational age), 27 born at term but small for gestational age (SGA), and 28 born at term with normal birth weight (control). Twenty-four-hour Holter-electrocardiogram monitoring was performed at an average age of 9 y. Heart rate variability results were analyzed using frequency and time domain methods. RESULTS: All frequency components and both time domain parameters tested were significantly lower in the preterm and SGA children compared with controls. The low frequency/high frequency ratio was not significantly different between children born with LBW and controls. CONCLUSION: The autonomic control appears to be affected in children born with LBW despite gestational age at birth. Decreased total power, as an estimation of the ANS's global activity, rather than the balance between parasympathetic and sympathetic modulation might be an early marker of cardiovascular disease later on in life for LBW born children.

Leptin may enhance hepatic insulin sensitivity in children and women born small for gestational age.

OBJECTIVE: Children born small for gestational age (SGA) are at risk for developing type 2 diabetes. Lipodystrophy leads to early type 2 diabetes and leptin reverses the metabolic consequences of the disease. Low IGF-binding protein 1 (IGFBP1) can predict the development of type 2 diabetes. The aim of this study was to determine leptin, insulin, and IGFBP1 in children and adult women born preterm or SGA to evaluate the role of leptin as a compensatory mechanism in insulin resistance development. METHODS: Seventy-six children (8.5-10 years, 41 girls and 35 boys) and 45 women (23-30 years) were studied. The children comprised subjects born appropriate for gestational age (<30 gestational weeks) (n=22), born SGA at term (n=23), and full-term normal-weight controls (n=31). Among the women, the corresponding figures were, n=10, n=18, and n=17 respectively. Fasting levels of IGFBP1, leptin, insulin, and IGF1 were determined and total adiponectin only in women. RESULTS: In girls and women, term SGA subjects had higher leptin levels in relation to BMI SDS (P=0.042 and P=0.03 respectively). More than half of IGFBP1 variability was explained by leptin and insulin in children. In term SGA women, IGFBP1 level was lower compared with controls (P=0.012) and the regression line of IGFBP1 on insulin was suppressed below -1 s.d. of a reference material. CONCLUSION: Leptin levels were elevated in term SGA girls and women, in particular in adult women, but not found in preterm girls and women. IGFBP1 was lower in term SGA women. In children, leptin and insulin were strong suppressors of IGFBP1. We speculate that higher leptin levels could be a protective event to enhance hepatic insulin sensitivity.

Risk factors for acute respiratory morbidity in moderately preterm infants.

BACKGROUND: Infants born preterm account for a substantial part of neonatal morbidity, with acute respiratory disorders being a dominating clinical problem. Whereas focus in recent studies has been on extremely and very preterm infants, less is known about contemporary rates and risk factors for acute respiratory morbidity in moderately and late preterm infants. The objective of this population-based Swedish study was to establish rates for different acute respiratory diseases in moderately preterm infants, and to identify maternal, obstetric and neonatal risk factors for the two most common diagnoses, transient tachypnoea of the newborn (TTN) and respiratory distress syndrome (RDS). METHODS: The study included 4679 moderately preterm [gestational age (GA): 30 to 34 weeks], 15 036 late preterm infants (GA 35 to 36 weeks) and 451 479 term infants (GA: 37 to 41 weeks). All infants were born in 2004-2008. RESULTS: In moderately preterm infants, risk factors for TTN in multivariable analyses were multiparity, caesarean section before and after onset of labour, male sex, Apgar score 4-6 at 5 min and lower GA. Risk factors for RDS were multiparity, caesarean section before and after onset of labour, male sex, Apgar score <7 at 5 min and lower GA. Preterm rupture of membranes, antenatal corticosteroid treatment and being small for gestational age reduced the risk of RDS. CONCLUSION: We conclude that acute respiratory morbidity in moderately preterm infants is common and predicted by multiparity, caesarean section, low Apgar score and male sex.

The European database for subspecialist training in neonatology - transparency achieved.

BACKGROUND: The European Society for Neonatology (ESN) developed a curriculum for subspecialist training in Europe recommending standards for national neonatal training programmes. We speculate whether these official recommendations are widely accepted or used in practice. OBJECTIVES: To characterize the variation in national neonatal training programmes, to enhance transparency, and to compare them to the ESN Curriculum. METHODS: We constructed a database based on the backbone of the ESN Curriculum: (1) training - knowledge, (2) training - skills, (3) key competencies, (4) personal development, and (5) recording of progress. National neonatal representatives from all 30 member states of the Union of European Medical Specialties (UEMS) provided data on national training programmes. RESULTS: Although only one country (3%) based its neonatology training entirely on the ESN Curriculum, we found high levels of uniformity among the UEMS member countries regarding knowledge, skills, and key competencies needed to practice neonatology at a tertiary care level. Discrepancy was encountered on ethical and legal issues and on personal development of the trainees. Mentoring and professional evaluation was generally not implemented in the participating countries. CONCLUSIONS: There is an awareness and readiness to focus on educational demands for neonatal trainees. Further discussions about the overall educational goals of neonatal training and the essence of practicing neonatology in each country are needed. The ESN will undertake this process to provide an updated and effective syllabus aimed to harmonize care and outcomes for babies and their families across Europe.

Differences in insulin resistance markers between children born small for gestational age or born preterm appropriate for gestational age.

AIM: To evaluate the impact of prenatal or postnatal compromised environment on glucose homoeostasis in children born preterm and appropriate for gestational age or small for gestational age (SGA) at term. METHOD: Seventy-seven children (median 9.9 years, range 8.5-10) born at Karolinska Hospital were allocated to three groups: 21 subjects born before 30 weeks of gestational age (preterm), 26 SGA at term and 30 at term with appropriate birth weight (control). Anthropometric measurements were taken, and fasting blood samples for haemoglobin A1c, glucose, insulin, IGFBP-1, IGF-1 and lipid profile were taken. Glucose, insulin and IGFBP-1 samples were taken at 0, 30 and 120 min during an oral glucose tolerance test (OGTT). RESULTS: Subjects born preterm or SGA were shorter and thinner compared with Controls. After adjustment for body mass index (BMI), the SGA group had higher basal insulin levels (p = 0.029), higher homoeostasis model assessment-insulin resistance (p = 0.012) and lower whole-body insulin sensitivity index (p = 0.007) than Controls. IGFBP-1 decrease during OGTT was attenuated in the Preterm group compared with the Control (p = 0.045) and SGA groups (p = 0.007). CONCLUSION: The higher fasting insulin level in the SGA children, adjusted for BMI, could indicate peripheral insulin resistance. Preterm born children had reduced suppression of IGFBP-1 during OGTT, suggesting hepatic insulin resistance.

Neonatal morbidity in moderately preterm infants: a Swedish national population-based study.

OBJECTIVE: To determine the gestational age (GA)-specific risks for neonatal morbidity and use of interventions in infants born at 30 to 34 completed gestational weeks. STUDY DESIGN: A population-based Swedish study including 6674 infants born during 2004-2008. Risks for neonatal morbidity and use of interventions were investigated with respect to GA and birth weight standard deviation scores. RESULTS: Acute lung disorder was diagnosed in 28%, hypoglycemia in 16%, bacterial infection in 15% and hyperbilirubinemia in 59% of the infants. Thirty-eight percent had received antenatal steroid therapy, 43% nasal continuous positive airway pressure, 5.5% required mechanical ventilation, 5.2% were treated with surfactant, and 30% with antibiotic therapy. Neonatal morbidity rates increased with decreasing GA, with odds ratios for different outcomes ranging from 2.1 to 23 at 30 weeks compared with 34 weeks of GA. Low birth weight standard deviation scores was more common at lower GA and was associated with increased morbidity rates. CONCLUSIONS: Despite general advances in perinatal care, moderately preterm infants still have substantially increased risks for neonatal morbidity. Whereas the neonatal morbidity rate was similar to results of previous reports, management of respiratory problems differed markedly from other studies.

Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants.

OBJECTIVE: The objective of this study was to determine whether hyperglycemia during the first week of life in extremely preterm (EPT) infants was associated with increased mortality rates and with cerebral injury, as assessed with MRI of the brain, at term-equivalent age. METHODS: All 143 EPT infants (gestational ages of <27 weeks) who were born at Karolinska University Hospital between January 2004 and December 2006 and were alive at 24 hours were eligible. Of the 118 surviving infants, 24 were excluded for various reasons. MRI was performed for the 94 included survivors at term age, with a 1.5-T system, and scans were scored for gray matter/white matter (WM) abnormalities. Of the 25 infants who died before term age, 6 were excluded because of missing glucose documentation and the remaining 19 were included. Hyperglycemia was defined as plasma glucose levels of >8.3 mmol/L. RESULTS: Hyperglycemia occurring on the first day of life was identified as an independent risk factor for death (adjusted odds ratio: 3.7 [95% confidence interval: 1.3-10.6]; P = .01). Hyperglycemia occurring on the first day of life also was a risk factor for WM reduction, as determined through MRI, at term-equivalent age (adjusted odds ratio: 3.1 [95% confidence interval: 1.0-9.2]; P = .04). CONCLUSION: In this population-based cohort of EPT infants, hyperglycemia on the first day of life was associated with increased mortality rates and brain damage, as reflected by WM reduction at term age.