Trajectories of HbA1c Levels in Children and Youth with Type 1 Diabetes

Purpose

To illustrate the distribution of Hemoglobin A1c (HbA1c) levels according to age and gender among children, adolescents and youth with type 1 diabetes (T1DM).

Methods

Consecutive HbA1c measurements of 349 patients, aged 2 to 30 years with T1DM were obtained from 1995 through 2010. Measurement from patients diagnosed with celiac disease (n = 20), eating disorders (n = 41) and hemoglobinopathy (n = 1) were excluded. The study sample comprised 4815 measurements of HbA1c from 287 patients. Regression percentiles of HbA1c were calculated as a function of age and gender by the quantile regression method using the SAS procedure QUANTREG.

Results

Crude percentiles of HbA1c as a function of age and gender, and the modeled curves produced using quantile regression showed good concordance. The curves show a decline in HbA1c levels from age 2 to 4 years at each percentile. Thereafter, there is a gradual increase during the prepubertal years with a peak at ages 12 to 14 years. HbA1c levels subsequently decline to the lowest values in the third decade. Curves of females and males followed closely, with females having HbA1c levels about 0.1% (1.1 mmol/mol) higher in the 25^th 50^th and 75^th percentiles.

Conclusion

We constructed age-specific distribution curves for HbA1c levels for patients with T1DM. These percentiles may be used to demonstrate the individual patient''s measurements longitudinally compared with age-matched patients.     

Incidence of Type 2 Diabetes in Pre-Diabetic Japanese Individuals Categorized by HbA1c Levels: A Historical Cohort Study

Objective

Reported incidence of type 2 diabetes estimated at the pre-diabetic stage differs widely (2.3–18.1% per year). Because clinicians need to know the risk of incident diabetes after a diagnosis of pre-diabetes, our objective was to estimate precise incidence of diabetes using baseline HbA_1c levels.

Methods

A historical cohort study using electronic medical record data obtained between January 2008 and December 2013. A total of 52,781 individuals with HbA_1c < 6.5% were assigned to one of six groups categorized by baseline HbA_1c level: ≤ 5.5% (n=34,616), 5.6–5.7% (n=9,388), 5.8–5.9% (n=4,664), 6.0–6.1% (n= 2,338), 6.2–6.3% (n=1,257), and 6.4% (n=518). Participants were tracked until a subsequent diagnosis of diabetes or end of follow-up during a period of 5 years.

Results

During the follow-up period (mean 3.7 years), 4,369 participants developed diabetes. The incidence of diabetes in the first year was 0.7, 1.5, 2.9, 9.2, 30.4, and 44.0% in the six HbA_1c groups, respectively. At five years the incidence was 3.6, 8.9, 13.8, 27.5, 51.6, and 67.8%, respectively (p < 0.0001 comparing the HbA_1c ≤5.5% group to the other groups). After adjustment for confounding factors, the hazard ratios compared with the HbA_1c ≤5.5% group were significantly elevated: 2.3 (95%CI 2.0–2.5), 3.4 (95%CI 2.9–3.7), 8.8 (95%CI 8.0–10.1), 26.3 (95%CI 23.3–30.1), and 48.7 (95%CI 40.8–58.1) in the five HbA_1c groups (p < 0.0001).

Conclusion

By fractionating baseline HbA_1c levels into narrower HbA_1c range groups, accuracy of estimating the incidence of type 2 diabetes in subsequent years was increased. The risk of developing diabetes increased with increasing HbA_1c levels, especially with the HbA_1c level ≥ 6.2% in the first follow-up year.     

The Impact of Diabetes Mellitus and Corresponding HbA1c Levels on the Future Risks of Cardiovascular Disease and Mortality: A Representative Cohort Study in Taiwan

Background

This study explored the relationship between the glycated hemoglobin (HbA1c) level in patients with or without diabetes mellitus and future risks of cardiovascular disease and death.

Methods

Based on a national representative cohort, a total of 5277 participants (7% with diabetes) were selected from Taiwan''s Triple High Survey in 2002. The comorbidities, medication usages, and outcomes of cardiovascular disease and death, were extracted from the Taiwan’s National Health Insurance Research Database and National Death Registry.

Results

After a median follow-up of 9.7 years, participants with diabetes had higher incidence of new onset cardiovascular disease (17.9 versus 3.16 cases per 1000 person-years) and death (20.1 versus 4.96 cases per 1000 person-years) than those without diabetes (all P < 0.001). Diabetes showed increased risk of all-cause death after adjusting for all confounders (adjusted hazard ratio [HR]: 2.29, 95% confidence interval [CI]: 1.52-3.45). Every 1% increment of HbA1c was positively associated with the risk of total cardiovascular disease (HR: 1.2, 95% CI: 1.08-1.34) and the risk of death (HR: 1.14, 95% CI: 1.03-1.26) for all participants. As compared to the reference group with HbA1c below 5.5%, participants with HbA1c levels ≥7.5% had significantly elevated future risks of total cardiovascular disease (HR: 1.82, 95% CI: 1.01-3.26) and all-cause death (HR: 2.45, 95% CI: 1.45-4.14).

Conclusions/Interpretation

Elevated HbA1C levels were associated with increased risks of cardiovascular disease and death, the suboptimal glycemic control with HbA1c level over 7.5% (58.5 mmol/mol) was strongly associated with increased risks of cardiovascular disease and all-cause death.     

Extreme Levels of HbA1c Increase Incident ESRD Risk in Chinese Patients with Type 2 Diabetes: Competing Risk Analysis in National Cohort of Taiwan Diabetes Study

Background

Whether HbA1c is a predictor of end-stage renal disease (ESRD) in type 2 diabetes patients remains unclear. This study evaluated relationship between HbA1c and ESRD in Chinese patients with type 2 diabetes.

Methods

Patients aged ≥ 30 years who were free of ESRD (n = 51 681) were included from National Diabetes Care Management Program from 2002–2003. Extended Cox proportional hazard model with competing risk of death served to evaluate association between HbA1c level and ESRD.

Results

A total of 2613 (5.06%) people developed ESRD during a follow-up period of 8.1 years. Overall incidence rate of ESRD was 6.26 per 1000 person-years. Patients with high levels of HbA1c had a high incidence rate of ESRD, from 4.29 for HbA1c of  6.0%–6.9% to 10.33 for HbA1c ≥ 10.0% per 1000 person-years. Patients with HbA1c < 6.0% particularly had a slightly higher ESRD incidence (4.34 per 1000 person-years) than those with HbA1c  of 6.0%–6.9%. A J-shaped relationship between HbA1c level and ESRD risk was observed. After adjustment, patients with HbA1c < 6.0% and ≥ 10.0% exhibited an increased risk of ESRD (HR: 1.99, 95% CI: 1.62–2.44; HR: 4.42, 95% CI: 3.80–5.14, respectively) compared with those with HbA1c of 6.0%–6.9%.

Conclusions

Diabetes care has focused on preventing hyperglycemia, but not hypoglycemia. Our study revealed that HbA1c level ≥ 7.0% was linked with increased ESRD risk in type 2 diabetes patients, and that HbA1c < 6.0% also had the potential to increase ESRD risk. Our study provides epidemiological evidence that appropriate glycemic control is essential for diabetes care to meet HbA1c targets and improve outcomes without increasing the risk to this population. Clinicians need to pay attention to HbA1c results on diabetic nephropathy.     

Association between Birth Interval and Cardiovascular Outcomes at 30 Years of Age: A Prospective Cohort Study from Brazil

Background

Birth interval is an important and potentially modifiable factor that is associated with child health. Whether an association exists with longer-term outcomes in adults is less well known.

Methods

Using the 1982 Pelotas (Brazil) Birth Cohort Study, the association of birth interval with markers of cardiovascular health at 30 years of age was examined. Multivariable linear regression was used with birth interval as a continuous variable and categorical variable, and effect modification by gender was explored.

Results

Birth interval and cardiovascular data were present for 2,239 individuals. With birth interval as a continuous variable, no association was found but stratification by gender tended to show stronger associations for girls. When compared to birth intervals of <18 months, as binary variable, longer intervals were associated with increases in height (1.6 cm; 95% CI: 0.5, 2.8) and lean mass (1.7 kg; 95% CI: 0.2, 3.2). No difference was seen with other cardiovascular outcomes.

Conclusions

An association was generally not found between birth interval and cardiovascular outcomes at 30 years of age, though some evidence existed for differences between males and females and for an association with height and lean mass for birth intervals of 18 months and longer.     

The relationship between maternal and offspring birth weights after maternal prenatal famine exposure: the Dutch Famine Birth Cohort Study

We examined the impact of famine-induced changes in maternal birth weight (MBW) on the association between MBW and offspring birth weight (OBW). Women born before, during, and after the Dutch Famine of 1944-1945 were interviewed at ages 41 to 46 years. Women (n = 582) and their children (n = 1,111) were included in the analysis if both mother and child were singleton and the child was not delivered preterm. Mean birth weight (BW) of women with first-trimester exposure (n = 110) was 154 g higher (p = 0.008), and mean BW of women with third-trimester exposure (n = 138) was 251 g lower (p < 0.001) than mean BW of unexposed women (n = 302). First-born offspring of women with first-trimester exposure were 72 g heavier (95% confidence interval [CI], -57 to 201; p = 0.27), and offspring of women with third-trimester exposure were 43 g lighter (95% CI, -170 to 79; p = 0.47) than offspring of unexposed women. Among unexposed women, each 100 g increase in MBW was associated with 25 g (95% CI, 12 to 37) increase in OBW (adjusted for maternal age, smoking, weight, and height and offspring sex). This association was attenuated in famine-exposed women (first-trimester change in OBW = 20 g per 100 g MBW; 95% CI, -1 to 41; third-trimester change in OBW = 14 g per 100 g MBW; 95% CI, -9 to 37). When MBW and trimester of maternal famine exposure were considered in a joint model, there was no independent effect of trimester of maternal famine exposure on OBW. Associations were less consistent for later-born offspring. We conclude that maternal prenatal famine exposure does not affect the association between maternal and offspring BW. Trimester of exposure was not a determinant of OBW, other than through its effect on MBW. Nevertheless, acute famine may impact on second-generation BW distributions indirectly, through its effect on the distribution of MBW.     

Effect of Antenatal Parasitic Infections on Anti-vaccine IgG Levels in Children: A Prospective Birth Cohort Study in Kenya

Background

Parasitic infections are prevalent among pregnant women in sub-Saharan Africa. We investigated whether prenatal exposure to malaria and/or helminths affects the pattern of infant immune responses to standard vaccinations against Haemophilus influenzae (Hib), diphtheria (DT), hepatitis B (Hep B) and tetanus toxoid (TT).

Methods and Findings

450 Kenyan women were tested for malaria, schistosomiasis, lymphatic filariasis (LF), and intestinal helminths during pregnancy. After three standard vaccinations at 6, 10 and 14 weeks, their newborns were followed biannually to age 36 months and tested for absolute levels of IgG against Hib, DT, Hep B, and TT at each time point. Newborns’ cord blood (CB) lymphocyte responses to malaria blood-stage antigens, soluble Schistosoma haematobium worm antigen (SWAP), and filaria antigen (BMA) were also assessed. Three immunophenotype categories were compared: i) tolerant (those having Plasmodium-, Schistosoma-, or Wuchereria-infected mothers but lacking respective Th1/Th2-type recall responses at birth to malaria antigens, SWAP, or BMA); ii) sensitized (those with infected/uninfected mothers and detectable Th1/Th2-type CB recall response to respective parasite antigen); or iii) unexposed (no evidence of maternal infection or CB recall response).Overall, 78.9% of mothers were infected with LF (44.7%), schistosomiasis (32.4%), malaria (27.6%) or hookworm (33.8%). Antenatal maternal malaria, LF, and hookworm were independently associated with significantly lower Hib-specific IgG. Presence of multiple maternal infections was associated with lower infant IgG levels against Hib and DT antigens post-vaccination. Post-vaccination IgG levels were also significantly associated with immunophenotype: malaria-tolerized infants had reduced response to DT, whereas filaria-tolerized infants showed reduced response to Hib.

Conclusions

There is an impaired ability to develop IgG antibody responses to key protective antigens of Hib and diphtheria in infants of mothers infected with malaria and/or helminths during pregnancy. These findings highlight the importance of control and prevention of parasitic infections among pregnant women.     

Fetal and Childhood Exposure to Phthalate Diesters and Cognitive Function in Children Up to 12 Years of Age: Taiwanese Maternal and Infant Cohort Study

Few studies have examined the association between environmental phthalate exposure and children’s neurocognitive development. This longitudinal study examined cognitive function in relation to pre-and postnatal phthalate exposure in children 2–12 years old. We recruited 430 pregnant women in their third trimester in Taichung, Taiwan from 2001–2002. A total of 110, 79, 76, and 73 children were followed up at ages 2, 5, 8, and 11, respectively. We evaluated the children’s cognitive function at four different time points using the Bayley and Wechsler tests for assessing neurocognitive functions and intelligence (IQ). Urine samples were collected from mothers during pregnancy and from children at each follow-up visit. They were analyzed for seven metabolite concentrations of widely used phthalate esters. These esters included monomethyl phthalate, monoethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, and three metabolites of di(2-ethylhexyl) phthalate, namely, mono-2-ethylhexyl phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. We constructed a linear mixed model to examine the relationships between the phthalate metabolite concentrations and the Bayley and IQ scores. We found significant inverse associations between the children’s levels of urinary mono(2-ethyl-5-oxohexyl) phthalate and the sum of the three metabolites of di(2-ethylhexyl) phthalate and their IQ scores (β = -1.818; 95% CI: -3.061, -0.574, p = 0.004 for mono(2-ethyl-5-oxohexyl) phthalate; β = -1.575; 95% CI: -3.037, -0.113, p = 0.035 for the sum of the three metabolites) after controlling for maternal phthalate levels and potential confounders. We did not observe significant associations between maternal phthalate exposure and the children’s IQ scores. Children’s but not prenatal phthalate exposure was associated with decreased cognitive development in the young children. Large-scale prospective cohort studies are needed to confirm these findings in the future.     

Urinary LTE4 Levels as a Diagnostic Marker for IgE-Mediated Asthma in Preschool Children: A Birth Cohort Study

Objectives

Leukotrienes play a central pathophysiological role in allergic asthma. The aim of this study was to investigate the utility of measuring urinary leukotriene E₄ (LTE₄) levels in the diagnosis of atopic diseases in early childhood.

Methods

Children aged 0 through 4 years from a birth cohort in the Prediction of Allergies in Taiwanese Children (PATCH) study were enrolled. Urinary LTE₄ levels were measured and its association between total serum IgE levels, allergen-specific IgE sensitization and atopic diseases were assessed.

Results

A total of 182 children were regular followed up at clinics for a four-year follow-up period. Urinary LTE₄ levels appeared to be elevated in children with total serum IgE levels exceeding 100 kU/L, allergen-specific IgE sensitization after 2 years of age. Elevation of urinary LTE₄ levels (≥500 pg/mg of creatinine) significantly discriminated high serum total IgE levels (≥100 kU/L) at age 2 (P = 0.027). A higher level of total serum IgE or urinary LTE₄ was significantly associated with the risk of developing allergic rhinitis and asthma at age 3. A significantly higher urinary LTE₄ level was found in children with a combination of IgE sensitization and asthma at age 4.

Conclusions

Urinary LTE₄ levels appear to be highly associated with IgE sensitization and its related allergic airway diseases after age 2. The measurement of urinary LTE₄ (≥500 pg/mg of creatinine) could not only be a non-invasive method for atopic predisposition but also potentially provide a strategy for the diagnosis and management of asthma in preschool children.     

Adiponectin and Leptin Trajectories in Mexican-American Children from Birth to 9 Years of Age

Objectives

To address molecular mechanisms underlying obesity development, we examined patterns of critical metabolism-related hormones, adiponectin and leptin (adipokines), over childhood.

Subjects and Design

Plasma adiponectin and leptin were measured in 80 Mexican-American children at birth and again at 2, 5, and 9 years from the ongoing prospective cohort followed by the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We used a mixture modeling approach to identify patterns in adipokine trajectories from birth to 9 years.

Results

Leptin was positively related to child body size within all ages, however adiponectin had inverse and weaker associations with BMI at 2, 5, and 9 years. Correlations between adipokine levels over the 0–2, 2–5, and 5–9-year periods increased for both leptin (r = 0.06, 0.31 and 0.62) and adiponectin (r = 0.25, 0.41 and 0.46). Our mixture modeling approach identified three trajectory clusters for both leptin (1L [slowly-rising], 2L [rapidly-rising], and 3L [stable]) and adiponectin (1A [steep-dropping and rebounding], 2A [moderately-dropping], and 3A [stable]). While leptin groups were most separated over the 2–9-year period, adiponectin trajectories displayed greatest heterogeneity from birth to 2 years. Children in the rapidly-rising 2L group had highest BMI and waist circumference at 9 years. Further, children with greater birth weight had increased odds of belonging to this high risk group (OR = 1.21 95% CI 1.03, 1.43, compared to stable group 3L). Children whose mothers consumed more sugar-sweetened beverages during pregnancy were at risk of being in the steep-dropping 1A group (OR = 1.08, 95% CI 1.01, 1.17, compared to stable group 3A).

Conclusion

Our results highlight developmental differences in leptin and adiponectin over the childhood period. Leptin closely reflects child body size however factors affecting adiponectin and long-term consequences of its changes over infancy need to be further explored.     

Recent HbA1c Values and Mortality Risk in Type 2 Diabetes. Population-Based Case-Control Study

This study aimed to evaluate mortality within 365 days of HbA1c values of <6.5% or >9.0% in participants with clinical type 2 diabetes mellitus. A matched nested case-control study was implemented, within a cohort of participants with type 2 diabetes from 2000 to 2008. Conditional logistic regression was used to model the odds ratio for mortality adjusting for comorbidity and drug utilisation. There were 97,450 participants with type 2 diabetes; 16,585 cases that died during follow up were matched to 16,585 controls. The most recent HbA1c value was <6.5% (48 mmol/mol) for 22.2% of cases and 24.2% of controls, the HbA1c was >9.0% for 9.0% of cases and 7.7% of controls. In a complete case analysis, the adjusted odds ratio (AOR) for mortality associated with most recent HbA1c <6.5% was 1.31 (95% confidence interval (CI): 1.21,1.42). After multiple imputation of missing HbA1c values the AOR was 1.20 (CI: 1.12,1.28). The complete case analysis gave an AOR for HbA1c >9.0% of 1.51 (CI: 1.33, 1.70), in the multiple imputation analysis this was 1.29 (1.17,1.41). The risk associated with HbA1c <6.5% was age dependent. In the multiple imputation analysis the AOR was 1.53 (CI: 0.84 to 2.79) at age<55 years but 1.04 (CI: 0.92, 1.17) at age 85 years and over. In non-randomised data, values of HbA1c that are either <6.5% or >9.0% may be associated with increased mortality within one year in clinical type 2 diabetes. Relative risks may be higher at younger ages.     

The Terneuzen Birth Cohort: BMI Changes between 2 and 6 Years Correlate Strongest with Adult Overweight

Background

Complications of overweight amplify with age, and irreversible damage already exists in young persons. Identifying the most sensitive age interval(s) for adult overweight is relevant for primary prevention. The aim of the study was to assess the relative contribution of body mass index (BMI) changes between 0 and 18 years to adult overweight, and to identify the earliest critical growth period.

Methods and Findings

Data from 762 subjects in the Terneuzen Birth Cohort with an average of 21 growth measurements per subject from birth until 18 years were used. The main outcome measure was the BMI standard deviation score (SDS) at young adulthood. For each subject BMI SDS was fitted by a piecewise linear model at eight different ages and correlated to adult BMI SDS. The age intervals in between are considered critical according to three criteria, tested by respectively Students'' t-tests, multiple linear regression analyses and Pearson''s correlation tests. In the age intervals 4 months(m) -1 year(y), 2–6 y, 6–10 y and 10–18 y the BMI SDS change differs between adults with and without overweight (P≤0.001). The age intervals 2–6 y and 10–18 y also meet the second criterion, implying that the BMI change during this period has a predictive value for adult BMI SDS in addition to BMI SDS at the end of the period. The largest rise in correlation between estimated BMI SDS and measured adult BMI SDS occurs during the period 2–6 y (from 0.36 to 0.63), which results in a high sensitivity (0.6) and specificity (0.8) by the age of 6 y.

Conclusions/Significance

The age interval from 2 y to 6 y is the earliest and most critical growth period for adult overweight. Therefore, primary prevention of adult overweight seems most likely to be successful if targeted at this specific age interval. By identifying those with an upwards centile crossing between 2 and 6 years, the development towards adult overweight might be reversed.     

Cancer Risk in Children and Adolescents with Birth Defects: A Population-Based Cohort Study

Objective

Birth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects.

Methods and Findings

This retrospective, statewide, population-based, cohort study was conducted in three US states (Utah, Arizona, Iowa). A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state’s births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold (95% CI, 2.3 to 3.7) in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus.

Conclusion

Children with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research.     

Variables Involved in the Discordance between HbA1c and Fructosamine: The Glycation Gap Revisited

Aims

Glycation gap (GG) is defined as the difference between the measured level of HbA1c and the level that would be predicted from its regression on the fructosamine level. The aims of the study were: 1) To determine the reproducibility and consistency of GC; 2) To discover factors related to GG value. Given that metformin might increase glucose transport through the erythrocyte membrane, this treatment was also considered in the analyses of the results.

Methods

GG was calculated in two blood samples separated 30.6 (SD 7.3) weeks, obtained in 508 type 2 diabetic patients. The following variables were considered: HbA1c, fructosamine, glucose, creatinine, hematological parameters and treatment with metformin. Multivariate and logistic regression analyses were performed to explore the variables independently related to CG.

Results

GG was reproducible and consistent over time. Creatinine, mean corpuscular hemoglobin concentration (MCHC), and glycemia (inverse relationship); and HbA1c and treatment with metformin (direct relationship) were independently related to GG. Patients treated with metformin showed higher HbA1c values, despite similar fructosamine concentrations, than patients not treated with the drug.

Conclusions

GG is independently related to serum levels of creatinine, MCHC and treatment with metformin. The spurious effect of metformin on Hb glycation could have serious clinical implications and should be considered when interpreting the results of clinical trials.     

Rotavirus Seasonality and Age Effects in a Birth Cohort Study of Southern India

Introduction

Understanding the temporal patterns in disease occurrence is valuable for formulating effective disease preventive programs. Cohort studies present a unique opportunity to explore complex interactions associated with emergence of seasonal patterns of infectious diseases.

Methods

We used data from 452 children participating in a birth cohort study to assess the seasonal patterns of rotavirus diarrhea by creating a weekly time series of rotavirus incidence and fitting a Poisson harmonic regression with biannual peaks. Age and cohort effects were adjusted for by including the weekly counts of number of children in the study and the median age of cohort in a given week. Weekly average temperature, humidity and an interaction term to reflect the joint effect of temperature and humidity were included to consider the effects of meteorological variables.

Results

In the overall rotavirus time series, two significant peaks within a single year were observed – one in winter and the other in summer. The effect of age was found to be the most significant contributor for rotavirus incidence, showing a strong negative association. Seasonality remained a significant factor, even after adjusting for meteorological parameters, and the age and cohort effects.

Conclusions

The methodology for assessing seasonality in cohort studies is not yet developed. This is the first attempt to explore seasonal patterns in a cohort study with a dynamic denominator and rapidly changing immune response on individual and group levels, and provides a highly promising approach for a better understanding of the seasonal patterns of infectious diseases, tracking emergence of pathogenic strains and evaluating the efficacy of intervention programs.     

Hemoglobin A1c Levels and Risk of Severe Hypoglycemia in Children and Young Adults with Type 1 Diabetes from Germany and Austria: A Trend Analysis in a Cohort of 37,539 Patients between 1995 and 2012

Background

Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years.

Methods and Findings

We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4±3.8 y, range 1–20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19–1.37) to 1.05 (1.00–1.09) and from 1.39 (1.23–1.56) to 1.01 (0.93–1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6–1.7, p<0.001) and 1.9% (0.8–2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%–6.9% (RR 0.96 and 0.90 each year) and 7.0%–7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study.

Conclusions

The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients. Please see later in the article for the Editors'' Summary     

Obesity and Life Expectancy with and without Diabetes in Adults Aged 55 Years and Older in the Netherlands: A Prospective Cohort Study

BackgroundOverweight and obesity are associated with increased risk of type 2 diabetes. Limited evidence exists regarding the effect of excess weight on years lived with and without diabetes. We aimed to determine the association of overweight and obesity with the number of years lived with and without diabetes in a middle-aged and elderly population.ConclusionsObesity in the middle aged and elderly is associated with a reduction in the number of years lived free of diabetes and an increase in the number of years lived with diabetes. Those extra years lived with morbidity might place a high toll on individuals and health care systems.     

Gestational Age and Neonatal Brain Microstructure in Term Born Infants: A Birth Cohort Study

Objective

Understanding healthy brain development in utero is crucial in order to detect abnormal developmental trajectories due to developmental disorders. However, in most studies neuroimaging was done after a significant postnatal period, and in those studies that performed neuroimaging on fetuses, the quality of data has been affected due to complications of scanning during pregnancy. To understand healthy brain development between 37–41 weeks of gestational age, our study assessed the in utero growth of the brain in healthy term born babies with DTI scanning soon after birth.

Methods

A cohort of 93 infants recruited from maternity hospitals in Singapore underwent diffusion tensor imaging between 5 to 17 days after birth. We did a cross-sectional examination of white matter microstructure of the brain among healthy term infants as a function of gestational age via voxel-based analysis on fractional anisotropy.

Results

Greater gestational age at birth in term infants was associated with larger fractional anisotropy values in early developing brain regions, when corrected for age at scan. Specifically, it was associated with a cluster located at the corpus callosum (corrected p<0.001), as well as another cluster spanning areas of the anterior corona radiata, anterior limb of internal capsule, and external capsule (corrected p<0.001).

Conclusions

Our findings show variation in brain maturation associated with gestational age amongst ‘term’ infants, with increased brain maturation when born with a relatively higher gestational age in comparison to those infants born with a relatively younger gestational age. Future studies should explore if these differences in brain maturation between 37 and 41 weeks of gestational age will persist over time due to development outside the womb.     

HbA1c Test as a Tool in the Diagnosis of Gestational Diabetes Mellitus

Aims

Gestational diabetes mellitus (GDM) is a prevalent and potentially serious condition which may put both mothers and neonates at risk. The current recommendation for diagnosis is the oral glucose tolerance test (OGTT). This study aimed to determine the usefulness of HbA1c test as a diagnostic tool for GDM as compared to the traditional criteria based on the OGTT.

Methods

This was a diagnostic test accuracy study. We performed OGTT and HbA1c test in women attending prenatal visits at a tertiary hospital. GDM was defined according to WHO1999 or ADA/WHO 2013 criteria. ROC curve was used to evaluate the diagnostic performance of HbA1c. Sensitivity, specificity and likelihood ratios for different HbA1c cut-off points were calculated.

Results

Of the 262 women in the third trimester of gestation enrolled in the study, 86 (33%) were diagnosed with GDM. Only five of these women presented HbA1c ≥48 mmol/mol (6.5%). This cut-off point presented 100% specificity but very low sensitivity (7%). Based on ROC curve, and considering OGTT as the reference criterion, HbA1c ≥40 mmol/mol (5.8%) showed adequate specificity in diagnosing GDM (94.9%) but low sensitivity (26.4%). Unlike, HbA1c values of 31 mmol/mol (5.0%) presented adequate sensitivity (89.7%) but low specificity (32.6%) to detect GDM. For women with HbA1c ≥40 mmol/mol (5.8%), the positive and negative likelihood ratios were 5.14 (95%CI 2.49–10.63) and 0.78 (0.68–0.88), respectively. The post-test probability of GDM was about 40%, representing a 4.0-fold increase in the mean pre-test probability. This cut-off point could eliminate the need for the unpleasant and laborious OGTT tests in almost one third of cases, as 38% of patients with GDM may be diagnosable by HbA1c test alone.

Conclusions

Our results show that combined HbA1c and OGTT measurements may be useful in diagnosing GDM.     

Birth Weight,Growth and Feeding Pattern in Early Infancy Predict Overweight/Obesity Status at Two Years of Age: A Birth Cohort Study of Chinese Infants

Objectives

To investigate the early determinants of overweight and obesity status at age two years.

Methods

A total of 1098 healthy neonates (563 boys and 535 girls) were involved in this community-based prospective study in China. Data on body weight and length were collected at birth, the 3^rd and 24^th month. A self-administered questionnaire was used to collect data on social demography and feeding patterns of children, etc. Three multivariable logistic regression models were employed to make various comparisons of weight status, i.e., model 1 (obesity vs. non-obesity), model 2 (combined overweight and obesity vs. normal weight, and model 3 (obesity, overweight and normal weight).

Results

Prevalences of overweight/obesity (95^th >BMI ≥85^th p and BMI ≥95^th p, referring to WHO BMI standards) at 2 years of age are 15.8%/11.2% for boys and 12.9%/9.0% for girls, respectively. Being born with macrosomia (OR: 1.80–1.88), relatively greater BMI increment in the first 3 months (OR: 1.15–1.16) and bottle emptying by encouragement at age two (OR: 1.30–1.57) were found in all three models to be significant risk factors for higher BMI status at 2 years. Pre-pregnancy maternal BMI (OR: 1.09–1.12), paternal BMI (OR: 1.06), and mixed breastfeeding (OR: 1.54–1.57) or formula feeding (OR: 1.90–1.93) in the first month were identified as significant in models 2 and 3. Child-initiated bottle emptying at age two was observed to increase the risk of obesity by 1.31 times but only in model 1.

Conclusion

Fetal and early postnatal growth and feeding pattern appear to have significant impacts on early childhood overweight and obesity status independent of parental BMI. Policy-based and multidisciplinary approaches to promote breastfeeding and enhancement of feeding skills of care takers may be promising intervention strategies.