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ObjectiveTo investigate the association between proportionality of fetal and placental growth measured at birth and the risk for congenital cerebral palsy (CP).Study designWe identified all live-born singletons born in Denmark between 1995 and 2003 and followed them from 1 year of age until December 31st, 2008. Information on four indices of fetal growth: ponderal index, head circumference/ abdominal circumference ratio, cephalization index and birth weight/ placenta weight ratio was collected. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). All measurements were evaluated as gestational age and sex specific z-scores and in z-score percentile groups, adjusted for potential confounders, and stratified on gestational age groups (

BackgroundCerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child.MethodsLiveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008. Redemption of antibiotics from the National Register of Medicinal Product Statistics and maternal infections reported by the National Hospital Register were used as markers of maternal infection during pregnancy. CP diagnoses were obtained from the Danish Cerebral Palsy Registry. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard models.ResultsOf the 440 564 singletons with follow-up data, 840 were diagnosed with congenital CP. Maternal genito-urinary tract infections (HR 2.1, 95% CI 1.4, 3.2) were associated with CP in all births, in term births (HR 1.9, 95% CI 1.1, 3.2), in children with spastic CP (HR 2.1, 95% CI 1.4, 3.3), and among first-born children (HR 1.9, 95% CI 1.4, 3.3). Overall, we found associations between redeemed nitrofurantoin (HR 1.7, 95% CI 1.1, 2.8) and CP. Among trimester-specific exposures, CP risk was associated with prescriptions redeemed in the first trimester for any antibacterials, beta-lactam antibacterials, and nitrofurantoin, an antibiotic commonly used to treat lower urinary tract infection, and genito-urinary tract infections in the third trimester.ConclusionGenito-urinary tract infections and antibiotic use during pregnancy were associated with increased risks of CP, indicating that some maternal infections or causes of maternal infections present in prenatal life may be part of a causal pathway leading to CP.

Background and aimMaternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes.Methods/principal findingsThe study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34-1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13-1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21-1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03-1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96-1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06-1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy.ConclusionsThese findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring.

PurposeSeveral observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients. However, patients with higher serum parathyroid hormone, a surrogate of higher death risk, are usually given higher VDRA doses, which can lead to confounding by indication and attenuate the expected survival advantage of high VDRA doses.MethodsWe examined mortality-predictability of low (>1 but

Blacks have high rates of chronic kidney disease, are overrepresented among the US dialysis patients, have higher parathyroid hormone levels, but greater survival compared to nonblacks. We hypothesized that mineral and bone disorders (MBDs) have a bearing on survival advantages of black hemodialysis patients. In 139,328 thrice-weekly treated hemodialysis patients, including 32% blacks, in a large dialysis organization, where most laboratory values were measured monthly for up to 60 months (July 2001 to June 2006), we examined differences across races in measures of MBDs and survival predictabilities of these markers and administered the active vitamin D medication paricalcitol. Across each age increment, blacks had higher serum calcium and parathyroid hormone (PTH) levels and almost the same serum phosphorus and alkaline phosphatase levels and were more likely to receive injectable active vitamin D in the dialysis clinic, mostly paricalcitol, at higher doses than nonblacks. Racial differences existed in mortality predictabilities of different ranges of serum calcium, phosphorus, and PTH but not alkaline phosphatase. Blacks who received the highest dose of paricalcitol (>10 µg/week) had a demonstrable survival advantage over nonblacks (case-mix-adjusted death hazard ratio = 0.87, 95% confidence level 0.83-0.91) compared with those who received lower doses (

BackgroundThe outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictability of time-averaged calcium values to reflect the 'cumulative' effect of calcium burden over time.MethodsWe employed a Cox model using up-to-5-year (7/2001-6/2006) time-averaged values to examine the mortality-predictability of cumulative serum calcium levels in 107,200 hemodialysis patients prior to the use of calcimimetics, but during the time where other calcium-lowering interventions, including lower dialysate calcium, were employed.ResultsBoth low (10.0 mg/dl) calcium levels were associated with increased mortality (reference: 9.0 to 3.5 mg/dl) and PTH levels (>150 pg/ml). Higher paricalcitol doses shifted the calcium range associated with the greatest survival to the right, i.e. from 9.0 to

BackgroundThe association of survival with characteristics of thrice-weekly hemodialysis (HD) treatment, including dose or duration of treatment, has not been completely elucidated, especially in different race and sex categories.Study designWe examined associations of time-averaged and quarterly varying (time-dependent) delivered HD dose and treatment time and 5-year (July 2001-June 2006) survival.Setting & participants88,153 thrice-weekly-treated HD patients from DaVita dialysis clinics.PredictorsHD treatment dose (single-pool Kt/V) and treatment time.Outcomes & other measurements5-Year mortality.ResultsThrice-weekly treatment time < 3 hours (but > or = 2.5 hours) per HD session compared with > or = 3.5 hours (but < 5 hours) was associated with increased death risk independent of Kt/V dose. The greatest survival gain of higher HD dose was associated with a Kt/V approaching the 1.6-1.8 range, beyond which survival gain was minimal, nonexistent, or even tended to reverse in African American men and those with 4-5 hours of HD treatment. In non-Hispanic white women, Kt/V > 1.8 continued to show survival advantage trends, especially in time-dependent models.LimitationsOur results may incorporate uncontrolled confounding. Achieved Kt/V may have different associations than targeted Kt/V.ConclusionsHD treatment dose and time appear to have different associations with survival in different sex or race groups. Randomized controlled trials may be warranted to examine these associations across different racial and demographic groups.

BackgroundIdentification of predictors of hyporesponsiveness to erythropoietin-stimulating agents (ESAs) in hemodialysis (HD) patients may help improve anemia management and reduce hemoglobin level variability.Study designWe conducted repeated-measure and logistic regression analyses in a retrospective cohort of long-term HD patients to examine the association of iron markers and measures of renal osteodystrophy with ESA responsiveness. The ESA response coefficient at the individual level, ie, the least confounded dose-response association, was separated from the population level, assumed to represent confounding by medical indication.Setting/participantsThe national database of a large dialysis organization (DaVita Inc, El Segundo, CA) with 38,328 surviving prevalent HD patients during 12 months who received ESA for at least 3 consecutive calendar quarters was examined.PredictorsSerum levels of ferritin, iron saturation ratio, intact parathyroid hormone, and alkaline phosphatase. OUTCOMES/OTHER MEASUREMENTS: The main outcome was case-mix-adjusted hemoglobin response to quarterly averaged ESA dose at the individual level. The odds ratio (OR) of the greatest versus poorest ESA-response quartile at the patient level was calculated. OR less than 1.0 indicated ESA hyporesponsiveness, and OR greater than 1.0, enhanced responsiveness.ResultsMean ESA-response coefficients of the least to most responsive quartiles were 0.301 +/- 0.033 (SD), 0.344 +/- 0.004, 0.357 +/- 0.004, and 0.389 +/- 0.026 g/dL greater hemoglobin level per 1,000 U/wk greater ESA dose in each quarter, respectively. The ORs of greatest versus poorest ESA responsiveness at the patient level were serum ferritin level less than 200 ng/mL (0.77; 95% confidence interval [CI], 0.70 to 0.86; reference, 200 to 500 ng/mL), iron saturation ratio less than 20% (0.54; 95% CI, 0.49 to 0.59; reference, 20% to 30%), intact parathyroid hormone level of 600 pg/mL or greater (0.54; 95% CI, 0.49 to 0.60; reference, 150 to 300 pg/mL), and alkaline phosphatase level of 160 IU/L or greater (0.64; 95% CI, 0.58 to 0.70; reference, 80 to 120 IU/L). Lower estimated dietary protein intake and serum levels of nutritional markers were also associated with greater risk of ESA hyporesponsiveness.LimitationsOur results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different associations than targeted hemoglobin level.ConclusionsIn long-term HD patients, low iron stores, hyperparathyroidism, and high-turnover bone disease are associated with significant ESA hyporesponsiveness. Prospective studies are needed to verify these associations.

Patients with chronic kidney disease (CKD), especially those requiring maintenance hemodialysis treatments, may lose up to 3 g of iron each year because of frequent blood losses. Higher doses of erythropoiesis-stimulating agents (ESAs) may worsen iron depletion and lead to an increased platelet count (thrombocytosis), ESA hyporesponsiveness, and hemoglobin variability. Hence, ESA therapy requires concurrent iron supplementation. Traditional iron markers such as serum ferritin and transferrin saturation ratio (TSAT) (ie, serum iron divided by total iron-binding capacity [TIBC]), may be confounded by non-iron-related conditions. Whereas serum ferritin

Background The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates. Methods and findings We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available. Conclusions In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated., Author(s): Jessica E. Miller 1,2,*, Raphael Goldacre 3, Hannah C. Moore 4, Justin Zeltzer 5, Marian Knight 6, Carole Morris 7, Sian Nowell 7, Rachael Wood 7, Kim W. Carter [...]

Aims: Public health responses to reduce SARS‐CoV‐2 transmission have profoundly affected the epidemiology and management of other infections. We examined the impact of COVID‐19 restrictions on antibiotic dispensing in Australia. Methods: We used national claims data to investigate antibiotic dispensing trends from November 2015 to October 2020 and whether changes reflected reductions in primary care consultations. We used interrupted time series analysis to quantify changes in monthly antibiotic dispensing and face‐to‐face and telehealth GP consultations and examined changes by recipient age, pharmacy State and prescriber specialty. Results: Over the study period, an estimated 19 921 370 people had 125 495 137 antibiotic dispensings, 71% prescribed by GPs. Following COVID‐19 restrictions, we observed a sustained 36% (95% CI: 33–40%) reduction in antibiotic dispensings from April 2020. Antibiotics recommended for managing respiratory tract infections showed large reductions (range 51–69%), whereas those recommended for non‐respiratory infections were unchanged. Dispensings prescribed by GPs decreased from 63.5 per 1000 population for April–October 2019 to 37.0 per 1000 for April–October 2020. Total GP consultation rates remained stable, but from April 2020, 31% of consultations were telehealth. Conclusion: In a setting with a low COVID‐19 incidence, restrictions were associated with a substantial reduction in community dispensings of antibiotics primarily used to treat respiratory infections, coincident with reported reductions in respiratory viral infections. Our findings are informative for post‐pandemic antimicrobial stewardship and highlight the potential to reduce inappropriate prescribing by GPs and specialists for respiratory viral infections. [ABSTRACT FROM AUTHOR]

Objective: Obesity is an established risk factor for severe coronavirus disease 2019 (COVID-19), but the contribution of overweight and/or diabetes remains unclear. In a multicenter, international study, we investigated if overweight, obesity, and diabetes were independently associated with COVID-19 severity and whether the BMI-associated risk was increased among those with diabetes.Research Design and Methods: We retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modeling the odds of each outcome (supplemental oxygen/noninvasive ventilatory support, invasive mechanical ventilatory support, and in-hospital mortality) by BMI category (reference, overweight, obese), adjusting for age, sex, and prespecified comorbidities. Subgroup analysis was performed on patients with preexisting diabetes. Site-specific estimates were combined in a meta-analysis.Results: Among 7,244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/noninvasive ventilatory support (random effects adjusted odds ratio [aOR], 1.44; 95% CI 1.15-1.80) and invasive mechanical ventilatory support (aOR, 1.22; 95% CI 1.03-1.46). There was no association between overweight and in-hospital mortality (aOR, 0.88; 95% CI 0.74-1.04). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity.Conclusions: In adults hospitalized with COVID-19, overweight, obesity, and diabetes were associated with increased odds of requiring respiratory support but were not associated with death. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk. [ABSTRACT FROM AUTHOR]