Early Growth, Cardiovascular and Renal Development: The Generation R Study

__Abstract__ Cardiovascular disease is a major health problem in the adult general population. Epidemiological studies strongly suggest that early life events have an important role for the susceptibility to develop cardiovascular disease in later life. In the 1980’s, Barker and Osmond showed that areas of Britain with the highest neonatal mortality rates early in the 20th century also had the highest incidence of cardiovascular disease in adults, many decades later1. Birth weight is an important predictor of neonatal mortality. After these observations, many epidemiological studies consistently showed that low birth weight is associated with adult health outcomes such as cardiovascular disease, type 2 diabetes and kidney disease. It was also noted that the risk of cardiovascular disease was highest in subjects who show a postnatal catch-up growth after being born with a low birth weight6. These observations resulted in the “fetal origins of adult disease” hypothesis, also currently known as the “Developmental Origins of Health and Disease “ Hypothesis (DOHaD-hypothesis). This hypothesis states that a suboptimal fetal environment leads to developmental adaptations that permanently alter growth, physiology and metabolism, with long-term consequences for adult health. More recently, this hypothesis has been adapted to a more general “developmental plasticity hypothesis”, which proposes that an organism may develop in different ways, depending on the environment it is exposed to. Investigating specific adverse fetal exposures and early growth may provide new insights in mechanisms underlying the associations of low birth weight with adult disease. Different aspects of early development might be important in determining future risk of adult cardiovascular and renal diseases

A common genetic variant at 15q25 modifies the associations of maternal smoking during pregnancy with fetal growth: The generation r study

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

Genetic variants associated with adult blood pressure and kidney function do not affect fetal kidney volume. The Generation R Study

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

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

Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3

Objective: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m2" 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/heightx), 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/m3.1 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/m2 (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

Fetal and infant growth patterns and kidney function at school age

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

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Infant feeding patterns are associated with cardiovascular structures and function in childhood

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: 20.29 mm; 95% CI:20.55,20.03 mm), and less LV mass (b:21.46 g; 95% CI:22.41,20.52 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

Bone age assessment by dual-energy X-ray absorptiometry in children: An alternative for X-ray?

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