Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile.

BACKGROUND: COX-2 and NSAIDS differ in their gastrointestinal (GI) and cardiovascular (CV) toxicity from pharmacological, clinical and epidemiologic point of views. OBJECTIVE: Describe the patterns of use of NSAIDS and COX-2 in The Health Improvement Network (THIN) database in UK and the PharMetrics database in USA. METHODS: We examined the experience of 10 distinct cohorts of new users of diclofenac, naproxen, ibuprofen, piroxicam, other NSAIDS, meloxicam, celecoxib, etoricoxib, rofecoxib and valdecoxib. The study period was 1 January 1995 through 2004 (31 March in UK and 28 February in USA). We collected information on covariates including history of upper GI disease, CV disease, hepatic disease, dosage, concomitant medication, and visits to a rheumatologist. RESULTS: We identified 486 076 unique patient-drug pairs in UK and 1 533 239 in USA. In UK population 78 201 (16%) were COX-2 users and in PharMetrics 324 206 (21%) were COX-2 users. Diclofenac and ibuprofen (NSAIDS), and celecoxib and rofecoxib (COX-2) were the agents prescribed most frequently. The duration of therapy was longer among celecoxib and rofecoxib users than among other users. More COX-2 users than NSAIDS users received concomitant gastroprotective agents (GPA), corticosteroids and anti-platelet therapy, and had a history of thromboembolic events and hypertension. PharMetrics patients were prescribed higher doses of NSAIDS and COX-2. The use of any single agent for more than 90 days was uncommon, but more frequent in PharMetrics. Switching was uncommon and was generally to a NSAID. DISCUSSION: Our results confirm some previous findings from other authors such as the presence of both GI and CV channelling to COX-2 agents but refute others, such as the frequency of drug switching between these agents. The typical use of COX-2 agents in practice is for shorter duration, and at lower doses, than was employed in randomized clinical trials. This difference may help clarify the apparent discrepancy with respect to CV toxicity between the results from clinical trials, which showed a higher CV risk with these drugs, and non-experimental epidemiologic studies, which showed lower or no increase in risk.

Performance profile of an outcome measure: morbidity assessment index for newborns.

OBJECTIVE: Few tools have been optimised for use over the entire spectrum of neonatal morbidity and standardised for use in perinatal population and community health studies. The objective of this study was to determine the performance profile of the recently developed morbidity assessment index for newborns (MAIN score). This score was designed as a discriminative index of morbidity for the entire population of babies delivered >28 weeks gestation without a major congenital anomaly. DESIGN AND SETTING: MAIN score items were extracted retrospectively from the health records of 2892 consecutively born babies delivered beyond 28 weeks gestation in Edmonton area hospitals between June and December of 1999. MAIN RESULTS: The mean MAIN score in the general newborn population was 70.3 (95% confidence intervals 64.2 to 76.4). With the MAIN score tool, 84.6% of newborns scored from 0 to 150 (no/minimal morbidity), 11.3% from 151 to 500 (mild), 3.1% from 501 to 800 (moderate), and 1% had >800 (severe) score. The MAIN score tool was sufficiently sensitive to detect significant effects of low gestational age, low birth weight, male sex, caesarean delivery, tertiary hospital delivery, twins/triplets, non-vertex presentation, prenatal illicit drug use, and medical complications of pregnancy. CONCLUSION: The MAIN score fulfills the need for a simple, universal, yet sensitive and robust tool to provide a numerical index of early neonatal outcomes of prenatal care and adverse prenatal exposures in babies delivered beyond 28 weeks gestation. The performance of the MAIN score agrees well with the current medical awareness regarding the impact of adverse prenatal exposures on newborn morbidity.

Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus.

OBJECTIVE: Childhood obesity has contributed to an increased incidence of type 2 diabetes mellitus and metabolic syndrome (MS) among children. Intrauterine exposure to diabetes and size at birth are risk factors for type 2 diabetes mellitus, but their association with MS in childhood has not been demonstrated. We examined the development of MS among large-for-gestational-age (LGA) and appropriate-for-gestational age (AGA) children. STUDY DESIGN: The major components of MS (obesity, hypertension, dyslipidemia, and glucose intolerance) were evaluated in a longitudinal cohort study of children at age 6, 7, 9, and 11 years who were LGA (n = 84) or AGA (n = 95) offspring of mothers with or without gestational diabetes mellitus (GDM). The cohort consisted of 4 groups, ie, LGA offspring of control mothers, LGA offspring of mothers with GDM, AGA offspring of control mothers, and AGA offspring of mothers with GDM. Biometric and anthropometric measurements were obtained at 6, 7, 9, and 11 years. Biochemical testing included measurements of postprandial glucose and insulin levels and high-density lipoprotein (HDL) cholesterol levels at 6 and 7 years and of fasting glucose, insulin, triglyceride, and HDL cholesterol levels at 9 and 11 years. We defined the components of MS as (1) obesity (BMI >85th percentile for age), (2) diastolic or systolic blood pressure >95th percentile for age, (3) postprandial glucose level >140 mg/dL or fasting glucose level >110 mg/dL, (4) triglyceride level >95th percentile for age, and (5) HDL level <5th percentile for age. RESULTS: There were no differences in baseline characteristics (gender, race, socioeconomic status, and maternal weight gain during pregnancy) for the 4 groups except for birth weight, but there was a trend toward a higher prevalence of maternal obesity before pregnancy in the LGA/GDM group. Obesity (BMI >85th percentile) at 11 years was present in 25% to 35% of the children, but rates were not different between LGA and AGA offspring. There was a trend toward a higher incidence of insulin resistance, defined as a fasting glucose/insulin ratio of <7, in the LGA/GDM group at 11 years. Analysis of insulin resistance at 11 years in a multivariate logistic regression revealed that childhood obesity and the combination of LGA status and maternal GDM were associated with insulin resistance, with odds ratios of 4.3 (95% confidence interval [CI]: 1.5-11.9) and 10.4 (95% CI: 1.5-74.4), respectively. The prevalence at any time of > or =2 components of MS was 50% for the LGA/GDM group, which was significantly higher than values for the LGA/control group (29%), AGA/GDM group (21%), and AGA/control group (18%). The prevalence of > or =3 components of MS at age 11 was 15% for the LGA/GDM group, compared with 3.0% to 5.3% for the other groups. Cox regression analysis was performed to determine the independent hazard (risk) of developing MS attributable to birth weight, gender, maternal prepregnancy obesity, and GDM. For Cox analyses, we defined MS as > or =2 of the following 4 components: obesity, hypertension (systolic or diastolic), glucose intolerance, and dyslipidemia (elevated triglyceride levels or low HDL levels). LGA status and maternal obesity increased the risk of MS approximately twofold, with hazard ratios of 2.19 (95% CI: 1.25-3.82) and 1.81 (95% CI: 1.03-3.19), respectively. GDM and gender were not independently significant. To determine the cumulative hazard of developing MS with time, we plotted the risk according to LGA or AGA category for the control and GDM groups from 6 years to 11 years, with Cox regression analyses. The risk of developing MS with time was not significantly different between LGA and AGA offspring in the control group but was significantly different between LGA and AGA offspring in the GDM group, with a 3.6-fold greater risk among LGA children by 11 years. CONCLUSIONS: We showed that LGA offspring of diabetic mothers were at significant risk of developing MS in childhood. The prevalence of MS in the other groups was similar to the prevalence (4.8%) among white adolescents in the 1988-1994 National Health and Nutrition Examination Survey. This effect of LGA with maternal GDM on childhood MS was previously demonstrated for Pima Indian children but not the general population. We also found that children exposed to maternal obesity were at increased risk of developing MS, which suggests that obese mothers who do not fulfill the clinical criteria for GDM may still have metabolic factors that affect fetal growth and postnatal outcomes. Children who are LGA at birth and exposed to an intrauterine environment of either diabetes or maternal obesity are at increased risk of developing MS. Given the increased obesity prevalence, these findings have implications for perpetuating the cycle of obesity, insulin resistance, and their consequences in subsequent generations.

Insulin resistance syndrome in women with prior history of gestational diabetes mellitus.

The purpose of this study was to determine the prevalence of insulin resistance syndrome (IRS) and the risk factors for developing IRS among women with a history of gestational diabetes mellitus (GDM), compared with controls over 11 postdelivery years. Assessments of 106 women with a prior history of GDM and 101 controls were done on six occasions from 4-11 yr after delivery. Tests included glucose, insulin, lipids, blood pressure, and body measurements. The risk of IRS was analyzed by Cox regression. The results were that 27.2% of GDM and 8.2% of controls developed IRS by 11 yr after delivery. The hazard of developing IRS was 5.6 times (95% confidence interval = 2.6-12.3) among women with prepregnant obesity (body mass index >27.3 kg/m(2)), compared with women without prepregnant obesity and 4.4 times (95% confidence interval = 1.7-11.1) in women with a history of GDM, compared with controls. At 11 yr after delivery, the cumulative hazard for developing IRS in the next 2 yr was 26 times higher among GDM with prepregnant obesity, compared with controls without prepregnant obesity. We concluded that obesity and GDM in a prior pregnancy are significant risk factors for developing IRS over time. Early detection of markers of IRS is vital for possible prevention of type 2 diabetes and cardiovascular adverse events in women.