Performance of six birth-weight and estimated-fetal-weight standards for predicting adverse perinatal outcome: a 10-year nationwide population-based study.

OBJECTIVE: To evaluate three birth-weight (BW) standards (Australian population-based, Fenton and INTERGROWTH-21st ) and three estimated-fetal-weight (EFW) standards (Hadlock, INTERGROWTH-21st and WHO) for classifying small-for-gestational age (SGA) and large-for-gestational age (LGA) and predicting adverse perinatal outcomes in preterm and term babies. METHODS: This was a nationwide population-based study conducted on a total of 2.4 million singleton births that occurred from 24 + 0 to 40 + 6 weeks' gestation between 2004 and 2013 in Australia. The performance of the growth charts was evaluated according to SGA and LGA classification, and relative risk (RR) and diagnostic accuracy based on the areas under the receiver-operating-characteristics curves (AUCs) for stillbirth, neonatal death, perinatal death, composite morbidity and a composite of perinatal death and morbidity outcomes. The analysis was stratified according to gestational age at delivery (< 37 + 0 vs ≥ 37 + 0 weeks). RESULTS: Following exclusions, 2 392 782 singleton births were analyzed. There were significant differences in the SGA and LGA classification and risk of adverse outcomes between the six BW and EFW standards evaluated. For the term group, compared with the other standards, the INTERGROWTH-21st BW and EFW standards classified half the number of SGA (< 10th centile) babies (3-4% vs 7-11%) and twice the number of LGA (> 90th centile) babies (24-25% vs 8-15%), resulting in a smaller cohort of term SGA at higher risk of adverse outcome and a larger LGA cohort at lower risk of adverse outcome. For term SGA (< 3rd centile) babies, the RR of perinatal death using the two INTERGROWTH-21st standards was up to 1.5-fold higher than those of the other standards (including the WHO-EFW and Hadlock-EFW), while the INTERGROWTH-21st -EFW standard indicated a 12-26% reduced risk of perinatal death for LGA cases across centile thresholds. Conversely, for the preterm group, the WHO-EFW and Hadlock-EFW standards identified a higher SGA classification rate than did the other standards (18-19% vs 10-11%) and a 20-65% increased risk of perinatal death in term LGA babies. All BW and EFW charts had similarly poor performance in predicting adverse outcomes, including the composite outcome (AUC range, 0.49-0.62) for both preterm (AUC range, 0.58-0.62) and term (AUC range, 0.49-0.50) cases and across centiles. Furthermore, specific centile thresholds for identifying adverse outcomes varied markedly by chart between BW and EFW standards. CONCLUSIONS: This study addresses the recurrent problem of identifying fetuses at risk of morbidity and perinatal mortality associated with growth disorders and provides new insights into the applicability of international growth standards. Our findings of marked variation in classification and the similarly poor performance of prescriptive international standards and the other commonly used standards raise questions about whether the prescriptive international standards that were constructed for universal adoption are indeed applicable to a multiethnic population such as that of Australia. Thus, caution is needed when adopting universal standards for clinical and epidemiological use. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

The familial aggregation of atopic diseases and depression or anxiety in children.

BACKGROUND: Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases has strong genetic and environmental components; therefore, it seems likely that there is a shared liability rather than causative risk. OBJECTIVE: To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety. METHODS: Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n = 14 197. Current and ever asthma, eczema, hay fever and food allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic (MZ) twins and same-sex dizygotic (DZ) twins for atopic disease in 1 twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth. RESULTS: Familial co-aggregation analysis found that if 1 twin had at least 1 current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations, suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates. CONCLUSIONS AND CLINICAL RELEVANCE: Atopic diseases and depression or anxiety tend to occur together in families; therefore, when treating for 1 disease, the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity, and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation.

Prenatal maternal psychosocial stress and offspring's asthma and allergic disease: A systematic review and meta-analysis.

BACKGROUND: Prenatal maternal stress may influence offspring's atopic risk through sustained cortisol secretion resulting from activation of the hypothalamic-pituitary axis (HPA), leading to Th2-biased cell differentiation in the foetus. We undertook a systematic review and meta-analysis investigating the relationship between prenatal maternal psychosocial stress and risk of asthma and allergy in the offspring. METHODS: We searched 11 electronic databases from 1960 to 2016, searched the grey literature and contacted experts in the field. Type of stress indicator included mood disorders, anxiety, exposure to violence, bereavement and socio-economic problems occurring during pregnancy, both objectively and subjectively measured. We included all possible asthma and IgE-mediated allergy outcomes. We conducted random-effects meta-analyses to synthesize the data. RESULTS: We identified 9779 papers of which 30 studies (enrolling >6 million participants) satisfied inclusion criteria. The quality of 25 studies was moderate, 4 were strong, and one was weak. Maternal exposure to any type of stressors was associated with an increased risk of offspring atopic eczema/dermatitis (OR 1.34, 95% CI 1.22-1.47), allergic rhinitis (OR 1.30, 95% CI 1.04-1.62), wheeze (OR 1.34, 95% CI 1.16-1.54) and asthma (OR 1.15, 95% CI 1.04-1.27). Exposure to anxiety and depression had strongest effect compared to other stressors. Exposure during the third trimester had the greatest impact compared to first and second trimesters. The increased risk was stronger for early-onset and persistent than for late-onset wheeze. Bereavement of a child (HR 1.28, 95% CI 1.10-1.48) or a spouse (HR 1.40, 95% CI 1.03-1.90) increased the risk of offspring asthma. CONCLUSIONS: Exposure to prenatal maternal psychosocial stress was associated with increased risk, albeit modestly, of asthma and allergy in the offspring. The pronounced risk during the third trimester may represent cumulative stress exposure throughout pregnancy rather than trimester-specific effect. Our findings may represent a causal effect or a result of inherent biases in studies, particularly residual confounding.

Omega-3 supplementation during the first 5 years of life and later academic performance: a randomised controlled trial.

BACKGROUND/OBJECTIVES: Consumption of oily fish more than once per week has been shown to improve cognitive outcomes in children. However, it is unknown whether similar benefits can be achieved by long-term omega-3 fatty acid supplementation. The objective was to investigate the effect of omega-3 fatty acid supplementation during the first 5 years of life on subsequent academic performance in children by conducting a secondary analysis of the CAPS (Childhood Asthma Prevention Study). SUBJECTS/METHODS: A total of 616 infants with a family history of asthma were randomised to receive tuna fish oil (high in long-chain omega-3 fatty acids, active) or Sunola oil (low in omega-3 fatty acids, control) from the time breastfeeding ceased or at the age of 6 months until the age of 5 years. Academic performance was measured by a nationally standardised assessment of literacy and numeracy (National Assessment Program Literacy and Numeracy (NAPLAN)) in school years 3, 5, 7 and 9. Plasma omega-3 fatty acid levels were measured at regular intervals until 8 years of age. Between-group differences in test scores, adjusted for maternal age, birth weight and maternal education, were estimated using mixed-model regression. RESULTS: Among 239 children, there were no significant differences in NAPLAN scores between active and control groups. However, at 8 years, the proportion of omega-3 fatty acid in plasma was positively associated with the NAPLAN score (0.13 s.d. unit increase in score per 1% absolute increase in plasma omega-3 fatty acid (95% CI 0.03, 0.23)). CONCLUSIONS: Our findings do not support the practice of supplementing omega-3 fatty acids in the diet of young children to improve academic outcomes. Further exploration is needed to understand the association between plasma omega-3 fatty acid levels at 8 years and academic performance.

Perinatal factors and respiratory health in children.

BACKGROUND: There is conflicting evidence regarding the associations between anthropometric birth measures and asthma and lung function in children, particularly for apparently healthy infants born at term. OBJECTIVE: Our objective was to elucidate these relationships paying particular attention to features of study design and analysis that may threaten the validity of previous studies in this field. METHODS: We analysed data from a cohort of children with a family history of asthma who were recruited antenatally. Anthropometric birth measures and potential confounders were recorded at birth and within the first year of life. Lung function and asthma outcomes were measured at 8 years of age. Airway hyperresponsiveness (AHR) was measured by methacholine challenge. The potential for a reversal paradox, due to inclusion of covariates on the causal pathway, was investigated. RESULTS: Four hundred and fifty (73% of the initial cohort) children were tested at age 8 years. Birth weight in the lowest tertile was associated with current asthma (OR 1.95, 95% CI 1.08, 3.54) and recent wheeze (OR 1.87, 95%CI 1.08, 3.24), but not with AHR (OR 1.37, 95% CI 0.68, 2.78). Birth weight was positively associated with lung function. Current height modified the relationship between birth length and lung function suggesting that post-natal growth has an effect on this relationship. CONCLUSIONS: Low birth weight is associated with a greater risk of current asthma and lower lung function at 8 years in children with a family history of asthma. Current height should be treated as an effect modifier when investigating the fetal origins hypothesis.

TGF-beta 1 dissociates human proximal tubule cell growth and Na(+)-H+ exchange activity.

Stimulation of proximal tubule cell (PTC) growth in a variety of physiological and pathological renal conditions is preceded by increased renal production of transforming growth factor-beta 1 (TGF-beta 1) and by augmented tubular sodium transport via activated sodium hydrogen exchange (NHE). Since TGF-beta 1 has been shown to be an important paracrine and autocrine regulator of PTC growth, the hypothesis that TGF-beta 1 modulates basal and mitogen-stimulated PTC growth via an effect on NHE activity was examined. Confluent, quiescent, human PTC were incubated for 24 hours in serum-free media containing vehicle (control) or 1 ng/ml TGF-beta 1, in the presence or absence of 100 ng/ml insulin-like growth factor-1 (IGF-I). Under basal conditions, TGF-beta 1 inhibited thymidine incorporation (73.5 +/- 7.3% of control, P < 0.05), but exerted no effect on cellular protein content (97.4 +/- 10.7% of control), an index of hypertrophy. There was no significant alteration of NHE activity, measured as ethylisopropylamiloride (EIPA)-sensitive H+ efflux (2.72 +/- 0.50 vs. control 3.26 +/- 0.68 mmol/liter/min) or 22Na+ influx (2.20 +/- 0.23 vs. control 2.19 +/- 0.19 nmol/mg protein/min). When co-incubated with IGF-I. TGF-beta 1 induced significant PTC hypertrophy (116.9 +/- 8.2% of control, P < 0.05), which was not seen with either agent alone. TGF-beta 1 counteracted the stimulatory effect of IGF-I on DNA synthesis (TGF-beta 1 + IGF-I 103.0 +/- 7.3% vs. IGF-I alone 181.2 +/- 30.3% of control, P < 0.05), but did not affect IGF-I-stimulated EIPA-sensitive 22Na+ influx (3.63 +/- 0.63 vs. IGF-I alone 3.67 +/- 0.50 nmol/mg protein/min, P = NS, both vs. control 2.19 +/- 0.19 nmol/mg protein/min, P < 0.05). Similar results were obtained when NHE activity was measured as EIPA-sensitive H+ efflux. Moreover, the kinetics of NHE activation by the combination of TGF-beta 1 and IGF-I (involving an increase in Vmax) were identical to that previously found for PTC exposed to IGF-I alone. The study demonstrates that TGF-beta 1 elicits distinct PTC growth responses in the presence and absence of IGF-I, without modification of NHE activity. The combination of predominant PTC hypertrophy and enhanced proximal tubule Na+ reabsorption found in many conditions that are associated with renal growth is likely to require the integrated actions of both TGF-beta 1 and IGF-I.

Insulin-like growth factor I stimulates apical sodium/hydrogen exchange in human proximal tubule cells.

To determine whether insulin-like growth factor I (IGF-I) stimulated apical sodium/hydrogen exchange (NHE), confluent primary human proximal tubule cells (PTC) were incubated for 48 h in serum-free media in the presence or absence of 100 ng/ml IGF-I. Cells incubated in IGF-I demonstrated significant increases in thymidine incorporation (181.2 +/- 30.3% of control values; n = 12, P = 0.01) and in resting intracellular pH (pHi) (7.52 +/- 0.08 vs. 7.30 +/- 0.06; n = 20, P < 0.05), as determined by 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein quantitative microspectrofluorometry. Following intracellular acid loading, ethylisopropylamiloride (EIPA)-inhibitable H+ efflux and 22Na+ influx after 1 min were both significantly enhanced in IGF-I-treated cells compared with controls (8.78 +/- 1.69 vs. 3.03 +/- 0.72 mM/min and 3.47 +/- 0.49 vs. 1.55 +/- 0.35 nmol x mg protein(-1) x min(-1), respectively). 22Na+ uptake studies in PTC grown on permeable supports demonstrated preferential stimulation of apical vs. basolateral NHE. The 50% inhibitory concentrations (IC50) in IGF-I-treated and control cells for EIPA (0.5 and 1.1 microM, respectively) and for HOE-694 (4.0 and 10.0 microM, respectively) were also consistent with predominant activation of apical, rather than basolateral, NHE activity. Kinetic analysis revealed an increase in maximal transport velocity (Vmax, 15.50 +/- 1.50 vs. 7.26 +/- 3.07 mM/min; n = 10, P < 0.05), without a significant change in antiporter affinity for extracellular Na+. Incubation of PTC with 100 ng/ml IGF-I produced an acute, reversible, and EIPA-inhibitable pHi increase of 0.05 +/- 0.01 pH units (n = 5, P < 0.05). The results suggest that IGF-I may contribute to the metachronous stimulation of apical NHE and PTC growth observed in many physiological and pathological conditions involving the human kidney.

Human renal fibroblasts modulate proximal tubule cell growth and transport via the IGF-I axis.

To determine the paracrine interactions involved in the tubulointerstitial response to progressive renal disease, the role of insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) in in vitro interactions between human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were studied in primary cell culture. PTC growth and transport were increased in the presence of CF-conditioned media (CF-CM), as shown by increased thymidine incorporation, cellular protein content and sodium-hydrogen exchange (NHE) activity, to 185 +/- 31% (P < 0.01), 150 +/- 18% (P < 0.05) and 195 +/- 27% (P < 0.01) of the control values, respectively. IGF-I was produced by cultured CF at a rate of 64.6 +/- 7.5 ng/mg protein/day. Exogenous IGF-I applied to PTC provoked similar enhancement of growth and NHE activity as CF-CM and the stimulatory effect of CF-CM was blocked by specific immunoneutralization of IGF-I receptors. These receptors were threefold more abundant on PTC basolateral versus apical membranes. IGF binding proteins (IGFBP)-2 and IGFBP-3 were secreted by CF at rates of 694 +/- 88 and 1769 +/- 45 ng/mg/day, with the release of IGFBP-3 being enhanced in the presence of PTC-CM (120.0 +/- 9.7% of control, P < 0.01). Moreover, the addition of CF-CM to PTC increased cell-associated IGFBP-3 on PTC surfaces, without changes in IGF-I receptor numbers or affinity and without changes in PTC mRNA for IGFBP-3. Des(1-3)IGF-I, an analog that binds to the IGF-I receptor but not to IGFBPs, provided a less potent stimulus for PTC growth compared with IGF-I, indicating that cell-associated IGFBP-3 facilitates the action of IGF-I on PTC. The results support important paracrine roles for both IGF-I and IGFBPs in the interstitial regulation of proximal tubule growth and transport.