Ronald N. Goldberg

10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.

BACKGROUND In the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term. METHODS All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years (IQR 5.5-5.8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727. FINDINGS During the 10.0-year (IQR 9.0-10.5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years (95% CI 4.1-5.7) in the intensive lifestyle intervention group, 7.8 (6.8-8.8) in the metformin group, and 11.0 (9.8-12.3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo. INTERPRETATION During follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network

OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified. CONCLUSION: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.

Early Onset Neonatal Sepsis: The Burden of Group B Streptococcal and E. coli Disease Continues

BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.

Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated With Increased Rates of Necrotizing Enterocolitis and Death for Extremely Low Birth Weight Infants

OBJECTIVES. Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results. METHODS. We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death. RESULTS. Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. CONCLUSION. Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.

Neonatal Candidiasis Among Extremely Low Birth Weight Infants: Risk Factors, Mortality Rates, and Neurodevelopmental Outcomes at 18 to 22 Months

BACKGROUND. Neonatal candidiasis is associated with substantial morbidity and mortality rates. Neurodevelopmental follow-up data for a large multicenter cohort have not been reported. METHODS. Data were collected prospectively for neonates born at <1000 g at National Institute of Child Health and Human Development-sponsored Neonatal Research Network sites between September 1, 1998, and December 31, 2001. Uniform follow-up evaluations, including assessments of mental and motor development with the Bayley Scales of Infant Development II, were completed for all survivors at corrected ages of 18 to 22 months. We evaluated risk factors for the development of neonatal candidiasis, responses to antifungal therapy, and the association between candidiasis and subsequent morbidity and death. RESULTS. The cohort consisted of 4579 infants; 320 of 4579 (7%) developed candidiasis; 307 of 320 had Candida isolated from blood, 27 of 320 had Candida isolated from cerebrospinal fluid, and 13 (48%) of 27 of those with meningitis had negative blood cultures. In multivariate analysis of risk factors on day of life 3, birth weight, cephalosporins, gender, and lack of enteral feeding were associated with development of candidiasis. After diagnosis, most neonates had multiple positive cultures despite antifungal therapy, and 10% of neonates had candidemia for ≥14 days. Death or neurodevelopmental impairment (NDI) was observed for 73% of extremely low birth weight infants who developed candidiasis. Death and NDI rates were greater for infants who had delayed removal or replacement of central catheters (>1 day after initiation of antifungal therapy), compared with infants whose catheters were removed or replaced promptly. CONCLUSIONS. Blood cultures were negative for approximately one half of the infants with Candida meningitis. Persistent candidiasis was common. Delayed catheter removal was associated with increased death and NDI rates.

Prevention Conference VI: Diabetes and Cardiovascular Disease Writing Group IV: Lifestyle and Medical Management of Risk Factors

In patients with diabetes, a high priority must be given to modification of the major risk factors for cardiovascular disease (CVD). There is growing evidence that control of these risk factors will reduce the likelihood of developing CVD and its complications in patients with diabetes.1 In clinical management of patients with diabetes, attention must be given to the following risk factors: smoking, hypertension, prothrombotic state, low-density lipoprotein (LDL) cholesterol and diabetic dyslipidemia, hyperglycemia, overweight/obesity, physical inactivity, and adverse nutrition. Specific considerations of Writing Group IV will be reviewed. They will be discussed in light of current recommendations for management of risk factors in diabetes as presented by the American Diabetes Association (ADA), the American Heart Association (AHA), and the national education programs sponsored by the National Heart, Lung, and Blood Institute (NHLBI).2–11⇓⇓⇓⇓⇓⇓⇓⇓⇓ These recommendations are summarized in the Table. View this table: Table 1107395. Goals for Risk Factor Management in Patients With Diabetes In addition to being a cause of many forms of cancer and chronic lung disease, cigarette smoking is a major cardiovascular risk factor. When a smoking patient also has diabetes, this patient is doubly at risk for CVD. Thus, every effort must be made to convince patients with diabetes who smoke to give up the smoking habit. This need is strongly reinforced by a position statement from the ADA.10 Elevated blood pressure is a major independent risk factor for multiple cardiovascular end points: coronary heart disease (CHD), stroke, chronic renal failure, and heart failure.11 Patients with diabetes have an increased prevalence of hypertension.12 Multiple factors undoubtedly contribute to hypertension in patients with diabetes, eg, obesity, insulin resistance, hyperinsulinemia, and renal disease. Systolic hypertension appears to be the main blood pressure–related risk factor in patients with diabetes.13 …

Very low birth weight preterm infants with early onset neonatal sepsis: The predominance of Gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003

Background: Early onset neonatal sepsis (EOS, occurring in the first 72 hours of life) remains an important cause of illness and death among very low birth weight (VLBW) preterm infants. We previously reported a change in the distribution of pathogens associated with EOS from predominantly Gram-positive to primarily Gram-negative organisms. Objective: To compare rates of EOS and pathogens associated with infection among VLBW infants born at centers of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network during 3 time periods: 1991–1993; 1998–2000; and 2002–2003. Study Design: Prospectively collected data from the NICHD Neonatal Research Network VLBW registry were retrospectively reviewed. Rates of blood culture confirmed EOS, selected maternal and infant variables and pathogens associated with infection were compared between 2002–2003 and 2 previously published cohorts. Results: During the past 13 years, overall rates of EOS have remained stable (15–19 per 1000 live births of infants 401–1500 g). More than one-half of early infections in the 2002–2003 cohort were caused by Gram-negative organisms (53%), with Escherichia coli the most common organism (41%). Rates of group B streptococcal infections remain low (1.8 per 1000 live births). Between 1991–1993 and 1998–2000, there was a significant increase in rates of E. coli infections; but in 2002–2003, there was no significant change (7.0 per 1000 live births). Infants with EOS continue to be at significantly increased risk for death compared with uninfected infants. Conclusion: EOS remains an uncommon but important cause of morbidity and mortality among VLBW infants. Gram-negative organisms continue to be the predominant pathogens associated with EOS.

A cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity.

Abstract Background. Retinopathy of prematurity is a disease affecting the blood vessels of the retina in premature infants that may result in scarring, retinal detachment, and loss of vision. An association between this condition and the exposure of premature infants to supplemental oxygen has been postulated, but the relation between retinopathy of prematurity and blood oxygen levels has not been defined. The purpose of this study of a cohort of preterm infants was to correlate the incidence and severity of retinopathy of prematurity with the duration of exposure to different ranges of oxygen tension as measured by transcutaneous monitoring (tcPO2). Methods. One hundred one premature infants (birth weight, 500 to 1300 g) requiring supplemental oxygen had continuous monitoring of tcPO2. The number of hours during which the tcPO2 was 80 mm Hg or higher was tabulated for each infant during the first four weeks of life. Results. There was a significant association between the amount of time that the tcPO2 w...

The Association of Third-Generation Cephalosporin Use and Invasive Candidiasis in Extremely Low Birth-Weight Infants

OBJECTIVES. Previous studies have shown that incidence of invasive candidiasis varies substantially among centers, and previous use of broad-spectrum antibiotics is a risk factor for candidiasis in extremely low birth-weight infants. Differences in center practices, such as antibiotic strategies and the effects of these strategies on center incidence of candidiasis, are not reflected in assessments of an individuals risk of candidiasis. We evaluated the relationship between empirical antibiotic practices for extremely low birth-weight infants and center incidence of candidiasis. METHODS. We studied a cohort of extremely low birth-weight infants who survived ≥72 hours and were admitted to 1 of 12 tertiary centers between 1998 and 2001. Multivariable logistic regression was used to validate previous broad-spectrum antibiotics use as a risk factor for subsequent candidiasis in individual infants. We calculated correlation coefficients to assess the relationship between center incidence of candidiasis with antibiotic practice patterns. RESULTS. There were 3702 infants from 12 centers included, and 284 (7.7%) developed invasive candidiasis. Broad-spectrum antibiotics use was associated with candidiasis for individual infants. Center candidiasis incidence ranged from 2.4% to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant. CONCLUSIONS. Center incidences of invasive candidiasis differ substantially, and antibiotic practice differences are possible contributors to center variation in candidiasis risk.

Neonatal candidiasis: epidemiology, risk factors, and clinical judgment.

OBJECTIVE: Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (<1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis. METHODS: The study involved a prospective observational cohort of infants ≤1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis. RESULTS: Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from ≥1 of these sources: blood (n = 96); cerebrospinal fluid (n = 9); urine obtained by catheterization (n = 52); or other sterile body fluid (n = 10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled ≥50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. CONCLUSION: Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.