Inflammation, sepsis severity and neurodevelopmental outcomes of late-onset sepsis in preterm neonates.

BACKGROUND: The aim of this study was to investigate the association between inflammatory biomarkers (C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6)) and sepsis severity (neonatal-Sequential-Organ-Failure-Assessment (nSOFA)) and neurodevelopmental outcomes at 2 years, among very preterm neonates. METHODS: Data on preterm neonates (gestational age <30 weeks) from 2016 until 2020 were reviewed. Outcomes of interest were NDI (no, mild, severe) and the motor and cognitive score on the Dutch-Bayley-Scales-of-Infant-and-Toddler-Development (Bayley-III-NL) assessed at the corrected age of 2 years. Logistic and linear regression analysis were used for categorical and continuous outcomes, respectively. All analyses were adjusted for gestational age, sex and birthweight-for-gestational-age SD-score. RESULTS: In total 410 patients were eligible for analysis. Maximum CRP concentrations were associated with lower motor and cognitive scores (effect estimate -0.03 points,(95% CI -0.07; -0.00) and -0.03 points,(95% CI -0.06; -0.004), respectively) and increased risk of severe NDI (odds ratio (OR) 1.01, (95% CI 1.00; 1.01)). High nSOFA scores (≥4) during sepsis episodes were associated with an increased risk of mild NDI (OR 2.01, (95% CI 1.34; 3.03)). There were no consistent associations between IL-6, PCT and the outcomes of interest. CONCLUSION: High CRP concentrations and sepsis severity in preterm neonates seem to be associated with neurodevelopmental outcomes in survivors at the age of 2 years. IMPACT STATEMENT: The level of inflammation and sepsis severity are associated with neurodevelopmental outcome in preterm neonates at 2 years of corrected age. Sepsis is a major health issue in preterm neonates and can lead to brain damage and impaired neurodevelopment. Biomarkers can be determined to assess the level of inflammation. However, the relation of inflammatory biomarkers with neurodevelopmental outcome is not known. The level of inflammation and sepsis severity are related to neurodevelopmental outcome in preterm neonates. Maximum CRP concentration and high nSOFA scores are associated with an increased risk of neurodevelopmental impairment in survivors at the corrected age of 2 years.

Early prediction of severe retinopathy of prematurity requiring laser treatment using physiological data.

BACKGROUND: Early risk stratification for developing retinopathy of prematurity (ROP) is essential for tailoring screening strategies and preventing abnormal retinal development. This study aims to examine the ability of physiological data during the first postnatal month to distinguish preterm infants with and without ROP requiring laser treatment. METHODS: In this cohort study, preterm infants with a gestational age <32 weeks and/or birth weight <1500 g, who were screened for ROP were included. Differences in the physiological data between the laser and non-laser group were identified, and tree-based classification models were trained and independently tested to predict ROP requiring laser treatment. RESULTS: In total, 208 preterm infants were included in the analysis of whom 30 infants (14%) required laser treatment. Significant differences were identified in the level of hypoxia and hyperoxia, oxygen requirement, and skewness of heart rate. The best model had a balanced accuracy of 0.81 (0.72-0.87), a sensitivity of 0.73 (0.64-0.81), and a specificity of 0.88 (0.80-0.93) and included the SpO2/FiO2 ratio and baseline demographics (including gestational age and birth weight). CONCLUSIONS: Routinely monitored physiological data from preterm infants in the first postnatal month are already predictive of later development of ROP requiring laser treatment, although validation is required in larger cohorts. IMPACT: Routinely monitored physiological data from the first postnatal month are predictive of later development of ROP requiring laser treatment, although model performance was not significantly better than baseline characteristics (gestational age, birth weight, sex, multiple birth, prenatal glucocorticosteroids, route of delivery, and Apgar scores) alone. A balanced accuracy of 0.81 (0.72-0.87), a sensitivity of 0.73 (0.64-0.81), and a specificity of 0.88 (0.80-0.93) was achieved with a model including the SpO2/FiO2 ratio and baseline characteristics. Physiological data have potential to play a significant role for future ROP prediction and provide opportunities for early interventions to protect infants from abnormal retinal development.

Oxygen saturation histogram classification system to evaluate response to doxapram treatment in preterm infants.

BACKGROUND: An oxygen saturation (SpO2) histogram classification system has been shown to enable quantification of SpO2 instability into five types, based on histogram distribution and time spent at SpO2 ≤ 80%. We aimed to investigate this classification system as a tool to describe response to doxapram treatment in infants with severe apnea of prematurity. METHODS: This retrospective study included 61 very-low-birth-weight infants who received doxapram. SpO2 histograms were generated over the 24-h before and after doxapram start. Therapy response was defined as a decrease of ≥1 histogram types after therapy start. RESULTS: The median (IQR) histogram type decreased from 4 (3-4) before to 3 (2-3) after therapy start (p < 0.001). The median (IQR) FiO2 remained constant before (27% [24-35%]) and after (26% [22-35%]) therapy. Thirty-six infants (59%) responded to therapy within 24 h. In 34/36 (94%) of the responders, invasive mechanical ventilation (IMV) was not required during the first 72 h of therapy, compared to 15/25 (60%) of non-responders (p = 0.002). Positive and negative predictive values of the 24-h response for no IMV requirement within 72 h were 0.46 and 0.94, respectively. CONCLUSIONS: Classification of SpO2 histograms provides an objective bedside measure to assess response to doxapram therapy and can serve as a tool to detect changes in oxygenation status around respiratory interventions. IMPACT: The SpO2 histogram classification system provides a tool for quantifying response to doxapram therapy. The classification system allowed estimation of the probability of invasive mechanical ventilation requirement, already within a few hours of treatment. The SpO2 histogram classification system allows an objective bedside assessment of the oxygenation status of the preterm infant, making it possible to assess the changes in oxygenation status in response to respiratory interventions.

Fatal Early-onset Sepsis Caused by Intrauterine Transmission of Serogroup Y Meningococcus.

Infections by meningococcal species are extremely rare in the first days of life. We present a fatal case of early-onset sepsis presenting at birth, caused by intrauterine transmission of serogroup Y N. meningitidis, evidenced clinically and histologically by corresponding chorioamnionitis and N. meningitidis-positive amniotic fluid. This case confirms a long-standing suspicion that N. meningitidis can be transmitted in utero.

Introducing heart rate variability monitoring combined with biomarker screening into a level IV NICU: a prospective implementation study.

The aim of this study was to investigate the association between the implementation of a local heart rate variability (HRV) monitoring guideline combined with determination of inflammatory biomarkers and mortality, measures of sepsis severity, frequency of sepsis testing, and antibiotic usage, among very preterm neonates. In January 2018, a guideline was implemented for early detection of late-onset neonatal sepsis using HRV monitoring combined with determination of inflammatory biomarkers. Data on all patients admitted with a gestational age at birth of < 32 weeks were reviewed in the period January 2016-June 2020 (n = 1,135; n = 515 pre-implementation, n = 620 post-implementation). Outcomes of interest were (sepsis-related) mortality, sepsis severity (neonatal sequential organ failure assessment (nSOFA)), sepsis testing, and antibiotic usage. Differences before and after implementation of the guideline were assessed using logistic and linear regression analysis for binary and continuous outcomes respectively. All analyses were adjusted for gestational age and sex. Mortality within 10 days of a sepsis episode occurred in 39 (10.3%) and 34 (7.6%) episodes in the pre- and post-implementation period respectively (P = 0.13). The nSOFA course during a sepsis episode was significantly lower in the post-implementation group (P = 0.01). We observed significantly more blood tests for determination of inflammatory biomarkers, but no statistically significant difference in number of blood cultures drawn and in antibiotic usage between the two periods.Conclusion: Implementing HRV monitoring with determination of inflammatory biomarkers might help identify patients with sepsis sooner, resulting in reduced sepsis severity, without an increased use of antibiotics or number of blood cultures.

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research.

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. IMPACT: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.

Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial).

BACKGROUND: Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies. METHODS: The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics. DISCUSSION: The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04152980 , Registered November 6th, 2019.

Zebrafish larvae as experimental model to expedite the search for new biomarkers and treatments for neonatal sepsis.

Neonatal sepsis is a major cause of death and disability in newborns. Commonly used biomarkers for diagnosis and evaluation of treatment response lack sufficient sensitivity or specificity. Additionally, new targets to treat the dysregulated immune response are needed, as are methods to effectively screen drugs for these targets. Available research methods have hitherto not yielded the breakthroughs required to significantly improve disease outcomes, we therefore describe the potential of zebrafish (Danio rerio) larvae as preclinical model for neonatal sepsis. In biomedical research, zebrafish larvae combine the complexity of a whole organism with the convenience and high-throughput potential of in vitro methods. This paper illustrates that zebrafish exhibit an immune system that is remarkably similar to humans, both in terms of types of immune cells and signaling pathways. Moreover, the developmental state of the larval immune system is highly similar to human neonates. We provide examples of zebrafish larvae being used to study infections with pathogens commonly causing neonatal sepsis and discuss known limitations. We believe this species could expedite research into immune regulation during neonatal sepsis and may hold keys for the discovery of new biomarkers and novel treatment targets as well as for screening of targeted drug therapies.

Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates.

BACKGROUND: Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. METHODS: The study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). RESULTS: A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. CONCLUSIONS: Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.

Using Classification Tree Analysis to Predict the Type of Infection in Preterm Neonates: Proof of Concept Study.

BACKGROUND: Late-onset neonatal sepsis is a major complication in preterm neonates. Early identification of the type of infection could help to improve therapy and outcome depending on the suspected microorganism by tailoring antibiotic treatment to the individual patient based on the predicted organism. Results of blood cultures may take up to 2 days or may remain negative in case of clinical sepsis. Chemical biomarkers may show different patterns in response to different type of microorganisms. OBJECTIVE: The aim of this study was to develop, as a proof of concept, a simple classification tree algorithm using readily available information from biomarkers to show that biomarkers can potentially be used in discriminating in the type of infection in preterm neonates suspected of late-onset neonatal sepsis. DERIVATION COHORT: A total of 509 suspected late-onset neonatal sepsis episodes in neonates born before less than 32 weeks of gestation were analyzed. To examine model performance, 70% of the original dataset was randomly selected as a derivation cohort (n = 356; training dataset). VALIDATION COHORT: The remaining 30% of the original dataset was used as a validation cohort (n = 153; test dataset). PREDICTION MODEL: A classification tree prediction algorithm was applied to predict type of infection (defined as no/Gram-positive/Gram-negative sepsis). RESULTS: Suspected late-onset neonatal sepsis episodes were classified as no sepsis (80.8% [n = 411]), Gram-positive sepsis (13.9% [n = 71]), and Gram-negative sepsis (5.3% [n = 27]). When the derived classification tree was applied to the test cohort, the overall accuracy was 87.6% (95% CI, 81.3-92.4; p = 0.008). The classification tree demonstrates that interleukin-6 is the most important differentiating biomarker and C-reactive protein and procalcitonin help to further differentiate. CONCLUSION: We have developed and internally validated a simple, clinically relevant model to discriminate patients with different types of infection at moment of onset. Further research is needed to prospectively validate this in a larger population and assess whether adaptive antibiotic regimens are feasible.

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Longitudinal growth during fetal life and infancy and cardiovascular outcomes at school-age.

OBJECTIVE: Low birth weight is associated with cardiovascular disease. We examined the effects of fetal and infant growth patterns on cardiovascular outcomes in children. METHODS: In a population-based prospective cohort study among 6239 children, we estimated fetal-femur length and weight by 20 and 30 weeks ultrasound, and child length and weight at birth, 0.5, 1, 2 and 6 years. We measured blood pressure (BP), carotid-femoral pulse wave velocity, aortic root diameter, left ventricular mass and fractional shortening at 6 years. We used regression analyses to identify longitudinal growth patterns associated with height-standardized vascular outcomes and body-surface-area-standardized cardiac outcomes. RESULTS: Younger gestational age and lower birth weight were associated with higher BP, smaller aortic root diameter and lower left ventricular mass in childhood (all P values <0.05). Children with decelerated or normal fetal growth followed by accelerated infant growth had higher BP, whereas those with decelerated growth during both fetal life and infancy had a relatively larger left ventricular mass. Longitudinal growth analyses showed that children with increased BP tended to be smaller during third trimester of fetal life, but of normal size during infancy, than children with normal BP. Children with increased aortic root diameter or left ventricular mass tended to be larger during fetal life, but of similar size during infancy. CONCLUSION: Specific fetal and infant growth patterns are associated with different cardiovascular outcomes in children. Further studies are needed to identify the underlying mechanisms and the long-term cardiovascular consequences.

International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents.

BACKGROUND: Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. METHODS AND RESULTS: Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5'-C-phosphate-G-3' methylation site) during prepuberty (P=2.86×10(-8)) and rs872256 during puberty (P=8.67×10(-9)). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5×10(-3). Using a P value threshold of <5×10(-3), we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms. CONCLUSIONS: Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects.

Fetal Smoke Exposure and Kidney Outcomes in School-Aged Children.

BACKGROUND: Fetal smoke exposure may result in developmental adaptations that permanently affect the developing kidney. In this study, the associations of maternal and paternal smoking during pregnancy with childhood kidney size and function were assessed. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: This study was conducted in a group of 5,622 children in Rotterdam, the Netherlands. PREDICTORS: Maternal and paternal smoking were assessed during pregnancy by questionnaires. OUTCOMES & MEASUREMENTS: At a median age of 6.0 (5th-95th percentile, 5.6-7.9) years, we measured childhood kidney volumes, estimated glomerular filtration rate (eGFR), and albumin-creatinine ratio. RESULTS: The confounder model, which included size at birth, shows that compared with children from mothers who did not smoke during pregnancy, those from mothers who continued smoking during pregnancy had smaller combined kidney volumes at the age of 6 years. The strongest effect estimate was observed for mothers who smoked 5 or more cigarettes per day during pregnancy (difference for combined kidney volume, -2.80 [95% CI, -5.15 to -0.45] cm(3)). Similarly, continued maternal smoking during pregnancy also was associated with a lower eGFR in childhood (difference, -2.25 [95% CI, -3.70 to -0.79] mL/min/1.73 m(2)). First-trimester-only smoking was associated with a higher risk of increased albumin-creatinine ratio (OR, 1.45; 95% CI, 1.05-2.01). Among mothers who did not smoke during pregnancy, paternal smoking was associated with smaller childhood combined kidney volume (difference, -1.78 [95% CI, -3.48 to -0.07] cm(3)), but not with childhood kidney function measures. LIMITATIONS: Smoking behavior was measured with questionnaires. Follow-up measurements were available for only 70% of the children. CONCLUSIONS: Continued maternal smoking during pregnancy is associated with smaller combined kidney volume and lower eGFR in school-aged children. Stronger effect estimates for maternal versus paternal smoking suggest that intrauterine adaptive responses may play a role as underlying mechanisms.

Dietary Intake, FTO Genetic Variants, and Adiposity: A Combined Analysis of Over 16,000 Children and Adolescents.

The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1-18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10(-4)), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10(-4)): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10(-10)) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Fetal and infant growth patterns and kidney function at school age.

Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm(3) [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m2 [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further.

Childhood kidney outcomes in relation to fetal blood flow and kidney size.

Impaired fetal abdominal blood flow may lead to smaller kidneys and subsequent impaired kidney function in later life. In a prospective cohort study among 923 pregnant women and their children, we measured fetal growth, kidney volumes, and umbilical and cerebral artery blood flow (median gestational age of 30.3 weeks; 95% range, 28.5-32.7 weeks). We used a higher umbilical/cerebral artery pulsatility index ratio as an indicator of preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs. At a median age of 5.9 years (95% range, 5.7-6.6 years), we measured childhood kidney volumes, creatinine and cystatin C blood levels, microalbuminuria, BP, and eGFR. A preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs associated only with a smaller combined kidney volume in childhood. Fetal combined kidney volume positively associated with childhood combined kidney volume and eGFR, and inversely associated with childhood creatinine and cystatin C levels (all P values <0.05), but did not associate with childhood microalbuminuria and BP. Children within the highest tertile of fetal umbilical/cerebral ratio and the lowest tertile of fetal combined kidney volume had the lowest eGFR (difference, -6.36 ml/min per 1.73 m(2); 95% confidence interval, -11.78 to -0.94 compared with children within the middle tertiles). These data suggest that impaired fetal blood to the abdominal organs and smaller fetal kidney size are associated with subclinical changes in kidney outcomes in school-aged children.

Kidney size and function in a multi-ethnic population-based cohort of school-age children.

BACKGROUND: Subclinical impaired kidney growth and function in childhood may lead to kidney diseases and high blood pressure in adulthood. We assessed the cross-sectional associations of childhood characteristics with kidney size and function in a multi-ethnic cohort. METHODS: This study was embedded in a population-based cohort study of 6,397 children with a median age of 6.0 years.Kidney volume, creatinine and cystatin C blood levels, microalbuminuria and blood pressure were measured, and glomerular filtration rate (GFR) was estimated. RESULTS: Childhood anthropometrics were positively associated with kidney volume, creatinine level and blood pressure (all p < 0.05). We observed ethnic differences in all kidney size and function measures (all p < 0.05). Children with smaller kidneys had higher creatinine and cystatin C blood levels, leading to a lower estimated GFR [difference 5.68 ml/min/1.73 m2 (95% confidence interval 5.14-6.12) per 1 standard deviation increase in kidney volume]. Larger kidney volume was associated with an increased risk of microalbuminuria. CONCLUSIONS: Childhood kidney volume and function are influenced by body mass index and ethnicity. Kidney volume is related with kidney function but not with blood pressure. These results may help to identify individuals at risk for kidney disease in an early stage.