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Purpose: Despite its promise to enhance patient outcomes and support clinical decision making, clinical use of artificial intelligence (AI) models at the bedside remains limited. Translation of advancements in AI research into tangible clinical benefits is necessary to improve neonatal and pediatric care for critically ill patients. This systematic review seeks to assess the maturity of AI models in neonatal and pediatric intensive care unit (NICU and PICU) treatment, and their risk of bias and objectives., Methods: We conducted a systematic search in Medline ALL, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar. Studies using AI models during NICU or PICU stay were eligible for inclusion. Study design, objective, dataset size, level of validation, risk of bias, and technological readiness of the models were extracted., Results: Out of the 1257 identified studies 262 were included. The majority of studies was conducted in the NICU (66%) and most had a high risk of bias (77%). An insufficient sample size was the main cause for this high risk of bias. No studies were identified that integrated an AI model in routine clinical practice and the majority of the studies remained in the prototyping and model development phase., Conclusion: The majority of AI models remain within the testing and prototyping phase and have a high risk of bias. Bridging the gap between designing and clinical implementation of AI models is needed to warrant safe and trustworthy AI models. Specific guidelines and approaches can help improve clinical outcome with usage of AI., (© 2024. The Author(s).)

Background: Preterm neonates are extensively monitored to require strict oxygen target attainment for optimal outcomes. In daily practice, detailed oxygenation data are hardly used and crucial patterns may be missed due to the snapshot presentations and subjective observations. This study aimed to develop a web-based dashboard with both detailed and summarized oxygenation data in real-time and to test its feasibility to support clinical decision making., Methods: Data from pulse oximeters and ventilators were synchronized and stored to enable real-time and retrospective trend visualizations in a web-based viewer. The dashboard was designed based on interviews with clinicians. A preliminary version was evaluated during daily clinical rounds. The routine evaluation of the respiratory condition of neonates (gestational age < 32 weeks) with respiratory support at the NICU was compared to an assessment with the assistance of the dashboard., Results: The web-based dashboard included data on the oxygen saturation (SpO 2 ), fraction of inspired oxygen (FiO 2 ), SpO 2 /FiO 2 ratio, and area < 80% and > 95% SpO 2 curve during time intervals that could be varied. The distribution of SpO 2 values was visualized as histograms. In 65% of the patient evaluations (n = 86) the level of hypoxia was assessed differently with the use of the dashboard. In 75% of the patients the dashboard was judged to provide added value for the clinicians in supporting clinical decisions., Conclusions: A web-based customized oxygenation dashboard for preterm neonates at the NICU was developed and found feasible during evaluation. More clear and objective information was found supportive for clinicians during the daily rounds in tailoring treatment strategies., (© 2024. The Author(s).)

Introduction: Sepsis is characterized by a dysregulated innate immune response. It is a leading cause of morbidity and mortality in newborns, in particular for newborns that are born premature. Although previous literature indicate that the pro-inflammatory response may be impaired in preterm newborns, serum levels of monocyte-derived cytokines, such as TNF-α and IL-6, vary highly between newborns and can reach adult-like concentrations during sepsis. These contradictory observations and the severe consequences of neonatal sepsis in preterm newborns highlight the need for a better understanding of the pro-inflammatory cytokine response of preterm newborns to improve sepsis-related outcomes., Methods and Results: Using an in vitro model with multiple read outs at the transcriptional and protein level, we consistently showed that the monocyte-derived cytokine response induced by sepsis-related bacteria is comparable between preterm newborns, term newborns and adults. We substantiated these findings by employing recombinant Toll-like receptor (TLR) ligands and showed that the activation of specific immune pathways, including the expression of TLRs, is also similar between preterm newborns, term newborns and adults. Importantly, we showed that at birth the production of TNF-α and IL-6 is highly variable between individuals and independent of gestational age., Discussion: These findings indicate that preterm newborns are equally capable of mounting a pro-inflammatory response against a broad range of bacterial pathogens that is comparable to term newborns and adults. Our results provide a better understanding of the pro-inflammatory response by preterm newborns and could guide the development of interventions that specifically modulate the pro-inflammatory response during sepsis in preterm newborns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jans, van Dun, Gorissen, Pieterman, Voskamp, Schoenmakers, Taal and Unger.)

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., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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 SpO 2 /FiO 2 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 SpO 2 /FiO 2 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., (© 2023. The Author(s).)

Background: An oxygen saturation (SpO 2 ) histogram classification system has been shown to enable quantification of SpO 2 instability into five types, based on histogram distribution and time spent at SpO 2  ≤ 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. SpO 2 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) FiO 2 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 SpO 2 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 SpO 2 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 SpO 2 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., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2022. The Author(s).)

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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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., (© 2021. The Author(s).)

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., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

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.

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., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

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.

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., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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., (Copyright © 2014 by the American Society of Nephrology.)

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., (Copyright © 2014 by the American Society of Nephrology.)

Objective: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m(2) " is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children., Methods: A GWAS of height-adjusted BMI (BMI[x] = weight/height(x) ), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed., Results: GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m(3.1) change per allele G (0.19, 0.38), P = 6 × 10(-9) ). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m(2) (0.15, 0.35), P = 6 × 10(-7) )]. Results were replicated in an independent sample, the Generation R study., Conclusions: Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits., (Copyright © 2014 The Obesity Society.)

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.

Objective: Fetal smoke exposure may influence growth and body composition later in life. We examined the associations of maternal and paternal smoking during pregnancy with total and abdominal fat distribution in school-age children., Methods: We performed a population-based prospective cohort study among 5243 children followed from early pregnancy onward in the Netherlands. Information about parental smoking was obtained by questionnaires during pregnancy. At the median age of 6.0 years (90% range: 5.7-7.4), we measured anthropometrics, total fat and android/gynoid fat ratio by dual-energy X-ray absorptiometry, and preperitoneal and subcutaneous abdominal fat were measured by ultrasound., Results: The associations of maternal smoking during pregnancy were only present among girls (P-value for sex interaction<0.05). Compared with girls from mothers who did not smoke during pregnancy, those from mothers who smoked during the first trimester only had a higher android/gynoid fat ratio (difference 0.23 (95% confidence interval (CI): 0.09-0.37) s.d. scores (SDS). Girls from mothers who continued smoking throughout pregnancy had a higher body mass index (difference: 0.24 (95% CI: 0.14-0.35) SDS), total fat mass (difference: 0.23 (95% CI: 0.14-0.33) SDS), android/gynoid fat ratio (difference: 0.34 (95% CI: 0.22-0.46) SDS), subcutaneous abdominal fat (difference: 0.22 (95% CI: 0.11-0.33) SDS) and preperitoneal abdominal fat (difference: 0.20 (95% CI: 0.08-0.31) SDS). Similar associations with body fat distribution outcomes were observed for paternal smoking during pregnancy. Both continued maternal and paternal smoking during pregnancy may be associated with an increased risk of childhood overweight. The corresponding odds ratios were 1.19 (95% CI: 0.98-1.46) and 1.32 (1.10-1.58), respectively., Conclusions: Maternal and paternal smoking during pregnancy are associated with an adverse body and abdominal fat distribution and increased risk of overweight in children. Similar effects of maternal and paternal smoking suggest that direct intrauterine mechanisms and common family-based lifestyle-related factors explain the associations.

Background: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes., Objective: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma., Methods: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110)., Results: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma., Conclusion: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The ability to taste 6-n-propylthiouracil (PROP) may be associated with body composition, but previous findings from observational studies are conflicting and cannot be interpreted causally. The aim of this study was to estimate the causal association between PROP taster status and body composition in a population-based cohort study., Methods: The study was embedded in a population-based prospective birth cohort study. The TAS2R38 genotype (rs713598) was used as an instrumental variable (IV) to obtain unbiased effect estimates of the relation between PROP taster status and body weight (n=3778). Adiposity measures included body mass index (BMI) and fat mass measured by dual- energy X-ray absorptiometry scan at the child's age of 6 years. Associations were investigated using both ordinary linear regression (OLS) and two-stage least squares regression (2SLS)., Results: Non-taster girls had higher BMI standard deviation scores (SDS) and higher body fat as compared with taster girls (results from linear regression BMI SDS: -0.09, P=0.023, body fat mass (%): -0.49, P=0.028). The TAS2R38 genotype predicted PROP phenotype (F=240), indicating a strong IV. The 2SLS effect estimates were imprecise but similar to the observational estimates (-0.08 for BMI SDS and -0.46 for body fat mass %) and were not significantly different from the OLS results (Hausman test: P>0.10). For boys there were no differences observed between tasters and non-tasters., Conclusions: Our findings suggest a causal relation between PROP taster status and body weight among 6-year-old girls; Mendelian randomization was consistent with conventional estimates. In contrast, body weight among boys appeared to be independent of the PROP taster status. Further research should focus on possible underlying pathways, such as dietary behavior.

Nutrition in infancy seems to be associated with cardiovascular disease and its risk factors in adulthood. These associations may be explained by cardiovascular developmental adaptations in childhood in response to specific infant feeding patterns. The aim of this study was to assess whether duration and exclusivity of breastfeeding and timing of introduction of solid foods affect cardiovascular development in childhood. In a population-based prospective cohort study from fetal life onward, information about duration and exclusivity of breastfeeding and timing of introduction of solid foods was obtained from delivery reports and questionnaires. Blood pressure, carotid-femoral pulse wave velocity (PWV), left atrial diameter (LAD), aortic root diameter (AOD), left ventricular (LV) mass, and fractional shortening (FS) were measured at a median age of 6.0 y (95% range: 5.6-7.4 y). Analyses were based on 5003 children. Age at introduction of solid foods was negatively associated with systolic and diastolic blood pressure at the age of 6 y. Compared with children who had ever been breast-fed, never-breast-fed children had a higher carotid-femoral PWV (β: 0.13 m/s; 95% CI: 0.03, 0.24 m/s), a smaller LAD (β: -0.29 mm; 95% CI: -0.55, -0.03 mm), and less LV mass (β:-1.46 g; 95% CI: -2.41, -0.52 g) at the age of 6 y. Among breast-fed children, duration and exclusivity were not associated with cardiovascular structures or function. Breastfeeding pattern and age at introduction of solid foods were not associated with AOD or FS. Feeding patterns in infancy may influence cardiovascular development in childhood. Further research is required to replicate these findings and to investigate whether these changes contribute to an increased risk of cardiovascular disease in later life.

Background: Foetal smoke exposure might lead to foetal developmental adaptations that permanently affect the cardiovascular system. We assessed the associations of both maternal and paternal smoking during pregnancy with childhood cardiovascular structures and function., Method: In a prospective cohort study among 5565 children, we examined whether maternal and paternal smoking during pregnancy are associated with blood pressure, carotid-femoral pulse wave velocity and left cardiac structures and function in 6-year-old children., Results: As compared with children from non-smoking mothers, children from mothers who smoked more than 10 cigarettes per day had a higher diastolic blood pressure [difference 1.43 mmHg (95% confidence interval: 0.22, 2.63)]. Maternal smoking during pregnancy was not associated with systolic blood pressure, childhood carotid-femoral pulse wave velocity or left cardiac structures. Maternal smoking of 10 or more cigarettes per day was associated with a higher fractional shortening in childhood [difference 1.01% (95% confidence interval: 0.18, 1.84)]. Among mothers who did not smoke during pregnancy, paternal smoking was associated with aortic root diameter but not with other cardiovascular outcomes., Conclusions: Maternal smoking during pregnancy is associated with higher diastolic blood pressure and fractional shortening, although the effect estimates are small. The stronger effect estimates for maternal smoking compared with paternal smoking might suggest that direct intrauterine adaptive responses are involved as underlying mechanisms.

Background: Maternal psychological distress during pregnancy might lead to higher fetal cortisol exposure, which subsequently leads to fetal cardiovascular developmental adaptations and cardiovascular dysfunction in later life., Aims: We examined whether maternal and paternal psychological distress was associated with the cardiovascular outcome measurements in school age children., Study Design and Subjects: In a population-based prospective cohort study among 4831 children, we assessed maternal and paternal psychological distress during pregnancy by questionnaire, using the Brief Symptom Inventory (see Fig. 1)., Outcome Measures: At the child age of six years, we performed blood pressure and carotid-femoral pulse wave velocity measurements, and M-mode measurements of left cardiac structures and fractional shortening., Results: We did not observe associations of high maternal and paternal psychological symptom scores with childhood blood pressure and carotid-femoral pulse wave velocity after adjustment for potential confounders. Maternal overall psychological symptoms were associated with a lower childhood left ventricular mass (difference -1.10 g (95% confidence interval -2.13 to -0.07) between mothers with high scores and normal scores), but not with other cardiac structures and fractional shortening. Paternal overall psychological symptoms showed a similar association with childhood left ventricular mass (difference -1.34 grams (95% confidence interval -3.69 to 1.02) between fathers with high scores and normal scores)., Conclusions: Our results do not support the hypothesis that maternal psychological distress affects cardiovascular development in early life. Similar associations of maternal and paternal psychological distress with left ventricular mass suggest that these associations could be due to unmeasured social and environmental factors, rather than direct intra-uterine effects., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Objective: The associations of size at birth, with infant growth of head circumference, length and weight, and fat mass and body mass index in preschool children were examined., Design and Methods: In a population-based prospective cohort study among 3,941 children, head circumference, length and weight until the age of 4 years were repeatedly measured. Catch-up and catch-down growth were defined as a change in standard deviation scores of >0.67 from birth to 2 years of age., Results: Although most children born small and large size for gestational age showed infant catch-up and catch-down growth, respectively, their mean head circumference, length and weight remained smaller and larger respectively, until the age of 4 years. Catch-up growth in children with a small and appropriate weight for gestational age and lack of catch-down growth in children born with a large weight for gestational age were associated with higher body mass index in preschool children. Children born with an appropriate weight for gestational age with catch-up growth and children born with a large weight for gestational without catch-down growth had increased risks of childhood overweight {odds ratios: 3.11 (95% confidence interval[95% CI] 2.37, 4.08) and 12.46 (95% CI: 6.07, 25.58) respectively}., Conclusions: Children born small, appropriate and large size for gestational age have different growth patterns in early childhood and persistent differences in their head circumference, length, and weight until the age of 4 years. Children born with an appropriate weight for gestational age with catch-up growth and large weight for gestational children without catch-down growth have an increased risk of overweight., (Copyright © 2013 The Obesity Society.)

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

Background: Smaller kidneys with reduced number of nephrons in early life lead to impaired kidney function and risk for hypertension and chronic kidney disease. These associations might be partly explained by common genetic variation., Aims: To assess the associations between common genetic variants, which have recently shown to be associated with blood pressure or kidney function, with fetal kidney volume., Study Design: A prospective population based cohort study in Rotterdam, The Netherlands., Subjects: 855 children, followed from early fetal life onwards (born 2003-2005)., Predictor: Common genetic variants previously associated with blood pressure or kidney function., Outcome Measures: Combined third trimester fetal kidney volume., Results: After taking into account multiple testing, only rs12940887 (near ZNF652) was significantly associated with fetal kidney volume (β: 0.88 (95% CI: 0.40; 1.37) cm(3) per minor allele, P-value<0.001), but the effect showed the opposite direction as expected. The remaining common genetic variants were not associated with fetal kidney volume. We also did not find associations of genetic variants previously shown to affect newborn kidney volume, with third trimester fetal kidney volume., Conclusions: Our results suggest that common genetic variants, associated with kidney function or disease and blood pressure, do not affect the third trimester fetal kidney volume. Further studies are needed to elucidate the mechanisms underlying the associations between small kidney size and increased risks of hypertension and impaired kidney function in adulthood., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.

Objective: The aim of the study was to validate dual-energy X-ray absorptiometry (DXA) as a method to assess bone age in children., Methods: Paired dual-energy X-ray absorptiometry (DXA) scans and X-rays of the left hand were performed in 95 children who attended the paediatric endocrinology outpatient clinic of University Hospital Rotterdam, the Netherlands. We compared bone age assessments by DXA scan with those performed by X-ray. Bone age assessment was performed by two blinded observers according to the reference method of Greulich and Pyle. Intra-observer and interobserver reproducibility were investigated using the intraclass correlation coefficient (ICC), and agreement was tested using Bland and Altman plots., Results: The intra-observer ICCs for both observers were 0.997 and 0.991 for X-ray and 0.993 and 0.987 for DXA assessments. The interobserver ICC was 0.993 and 0.991 for X-ray and DXA assessments, respectively. The mean difference between bone age assessed by X-ray and DXA was 0.11 years. The limits of agreement ranged from -0.82 to 1.05 years, which means that 95% of all differences between the methods were covered by this range., Conclusions: Results of bone age assessment by DXA scan are similar to those obtained by X-ray. The DXA method seems to be an alternative for assessing bone age in a paediatric hospital-based population.

Objective: Maternal smoking during pregnancy is associated with fetal growth retardation. We examined whether a common genetic variant at chromosome 15q25 (rs1051730), which is known to be involved in nicotine metabolism, modifies the associations of maternal smoking with fetal growth characteristics., Methods: This study was performed in 3,563 European mothers participating in a population-based prospective cohort study from early pregnancy onwards. Smoking was assessed by postal questionnaires and fetal growth characteristics were measured by ultrasound examinations in each trimester of pregnancy., Results: Among mothers who did not smoke during pregnancy (82.9%), maternal rs1051730 was not consistently associated with any fetal growth characteristic. Among mothers who continued smoking during pregnancy (17.1%), maternal rs1051730 was not associated with head circumference. The T-allele of maternal rs1051730 was associated with a smaller second and third trimester fetal femur length [differences -0.23 mm (95%CI -0.45 to -0.00) and -0.41 mm (95%CI -0.69 to -0.13), respectively] and a smaller birth length [difference -2.61 mm (95%CI -5.32 to 0.11)]. The maternal T-allele of rs1051730 was associated with a lower third trimester estimated fetal weight [difference -33 grams (95%CI -55 to -10)], and tended to be associated with birth weight [difference -38 grams (95%CI -89 to 13)]. This association persisted after adjustment for smoking quantity., Conclusions: Our results suggest that maternal rs1051730 genotype modifies the associations of maternal smoking during pregnancy with impaired fetal growth in length and weight. These results should be considered as hypothesis generating and indicate the need for large-scale genome wide association studies focusing on gene--fetal smoke exposure interactions.

An adverse fetal environment leads to smaller kidneys, with fewer nephrons, which might predispose an individual to the development of kidney disease and hypertension in adult life. In a prospective cohort study among 1,072 children followed from early fetal life onward, we examined whether maternal smoking during pregnancy, as a significant adverse fetal exposure, is associated with fetal (third trimester of pregnancy, n = 1,031) and infant kidney volume (2 years of age, n = 538) measured by ultrasound. Analyses were adjusted for various potential confounders. Among mothers who continued smoking, we observed dose-dependent associations between the number of cigarettes smoked during pregnancy and kidney volume in fetal life. Smoking less than five cigarettes per day was associated with larger fetal combined kidney volume, while smoking more than ten cigarettes per day tended to be associated with smaller fetal combined kidney volume (p for trend: 0.002). This pattern was not significant for kidney volume at the age of 2 years. Our results suggest that smoking during pregnancy might affect kidney development in fetal life with a dose-dependent relationship. Further studies are needed to assess the underlying mechanisms and whether these differences in fetal kidney volume have postnatal consequences for kidney function and blood pressure.

Context: A recent genome-wide association study identified variants near CCNL1/LEKR1 (rs900400) and in ADCY5 (rs9883204) to be associated with birth weight. We examined the associations of these variants with fetal growth characteristics in different trimesters, with a main interest in the timing of the associations and the affected body proportions., Methods: We used data from two prospective cohort studies from fetal life onward in The Netherlands and Australia. Repeated fetal ultrasound examinations were performed to measure head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW). Analyses were based on a total group of 3909 subjects., Results: The C-allele of rs900400 was associated in second trimester with smaller fetal HC and FL, and in third trimester with smaller HC, AC, FL, and EFW. For each C-allele, the combined effect estimate for EFW in third trimester was -18.6 g (95% confidence interval, -27.5, -9.7 g; P = 4.2 × 10(-5)). The C-allele of rs9883204 was not associated with fetal growth characteristics in second trimester but was associated with restriction of all growth characteristics, except HC, in third trimester and at birth. For each C-allele, the combined effect estimate was -16.9 g (95% confidence interval, -26.8, -7.0 g; P = 8.4 × 10(-4)) for EFW in third trimester. Both genetic variants were associated with lower birth and placenta weight., Conclusions: Our results suggest that a genetic variant of rs900400 leads to symmetric growth restriction from early pregnancy onward, whereas a genetic variant of rs9883204 leads to asymmetric growth restriction, characterized by a relatively larger HC, from third trimester.

Information about growth of kidney structures in early life is limited. In a population-based prospective cohort study, from foetal life onwards, we constructed reference curves for kidney growth from the third trimester of pregnancy until early childhood, using data from 1,158 healthy children. Kidney size, defined as length, width, depth and volume, was measured in the third trimester of pregnancy and at the postnatal ages of 6 months and 24 months. Analyses were based on more than 2,500 kidney measurements. In the third trimester of pregnancy and at 6 months of age all kidney measurements were larger in boys than in girls. At 24 months of age, these gender differences were only significant for left kidney structures and right kidney length. Both groups showed trends towards smaller left kidney measurements than right kidney measurements at all ages. Gender-specific reference curves based on post-conceptional and postnatal ages were constructed for left and right kidney length, width, depth and volume. We concluded that kidney size is influenced by age and gender. Left kidney size tended to be smaller than right kidney size, except for kidney length. The reference curves can be used for assessing kidney structures by ultrasound in foetal life and early childhood.

Objectives: To study whether the growth hormone (GH) response after the subcutaneous administration 50 microg of octreotide (acute octreotide test) has any predictive value for long-term IGF-I normalization with Sandostatin LAR., Design: Twenty four therapy-naive patients with active acromegaly were studied., Results: > 75% GH decrease in the acute octreotide test predicted long-term IGF-I normalization with Sandostatin LAR in 8/11 (73%) of patients. 3/13 (23%) patients with < 75% GH decrease in the acute octreotide test were long-term biochemically controlled with Sandostatin LAR. Using the > 75% GH reduction criterion, the sensitivity and specificity of this test for predicting long-term normalization of serum IGF-I with Sandostatin LAR treatment were 73% and 77%, respectively (positive and negative predictive values: 73% and 77%, respectively). 6/8 (75%) patients with GH suppression to levels < 1.1 microg/l and 9/16 (56%) patients with GH suppression to levels < 2 microg/l in the acute octreotide test showed normalization of serum IGF-I with long-term Sandostatin LAR treatment. The sensitivity and specificity of GH suppression < 1.1 microg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 55% and 85%, respectively (positive and negative predictive values: 75% and 69%, respectively). The sensitivity and specificity of GH suppression < 2 microg/l for predicting of the long-term normalization of serum IGF-I with Sandostatin LAR therapy were 82% and 46%, respectively (positive and negative predictive values: 56% and 75%, respectively)., Conclusion: The acute octreotide is not recommended for clinical decision making with regard to long-term treatment using the long-acting somatostatin analog Sandostatin LAR in acromegaly.