A systematic assessment of the association between frequently prescribed medicines and the risk of common cancers: a series of nested case-control studies.

BACKGROUND: Studies systematically screening medications have successfully identified prescription medicines associated with cancer risk. However, adjustment for confounding factors in these studies has been limited. We therefore investigated the association between frequently prescribed medicines and the risk of common cancers adjusting for a range of confounders. METHODS: A series of nested case-control studies were undertaken using the Primary Care Clinical Informatics Unit Research (PCCIUR) database containing general practice (GP) records from Scotland. Cancer cases at 22 cancer sites, diagnosed between 1999 and 2011, were identified from GP records and matched with up to five controls (based on age, gender, GP practice and date of registration). Odds ratios (OR) and 95% confidence intervals (CI) comparing any versus no prescriptions for each of the most commonly prescribed medicines, identified from prescription records, were calculated using conditional logistic regression, adjusting for comorbidities. Additional analyses adjusted for smoking use. An association was considered a signal based upon the magnitude of its adjusted OR, p-value and evidence of an exposure-response relationship. Supplementary analyses were undertaken comparing 6 or more prescriptions versus less than 6 for each medicine. RESULTS: Overall, 62,109 cases and 276,580 controls were included in the analyses and a total of 5622 medication-cancer associations were studied across the 22 cancer sites. After adjusting for comorbidities 2060 medicine-cancer associations for any prescription had adjusted ORs greater than 1.25 (or less than 0.8), 214 had a corresponding p-value less than or equal to 0.01 and 118 had evidence of an exposure-dose relationship hence meeting the criteria for a signal. Seventy-seven signals were identified after additionally adjusting for smoking. Based upon an exposure of 6 or more prescriptions, there were 118 signals after adjusting for comorbidities and 82 after additionally adjusting for smoking. CONCLUSIONS: In this study a number of novel associations between medicine and cancer were identified which require further clinical and epidemiological investigation. The majority of medicines were not associated with an altered cancer risk and many identified signals reflected known associations between medicine and cancer.

The effect of medications associated with drug-induced pancreatitis on pancreatic cancer risk: A nested case-control study of routine Scottish data.

BACKGROUND: Inflammation plays a role in pancreatic cancer. Many medications cause pancreatic inflammation, with some leading to a diagnosis of drug-induced pancreatitis (DIP), but few studies have examined these medications and pancreatic cancer risk. We therefore investigated the associations between pancreatic cancer risk and commonly-prescribed medicines for which there is strongest evidence of DIP. METHODS: A nested case-control study was undertaken using the Primary Care Clinical Informatics Unit Research database containing general practice (GP) records from Scotland. Pancreatic cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls (based on age, gender, GP practice and date of registration). Medicines in the highest category of evidence for DIP, based on a recent systematic review, and used by more than 2 % of controls were identified. Odds ratios (OR) and 95 % confidence intervals (CI) for associations with pancreatic cancer were calculated using conditional logistic regression after adjusting for comorbidities. RESULTS: There were 1,069 cases and 4,729 controls. Thirteen medicines in the highest category of evidence for DIP were investigated. There was little evidence of an association between any of these medications and pancreatic cancer risk apart from metronidazole (adjusted OR 1.69, 95 % CI 1.18, 2.41) and ranitidine (adjusted OR 1.37, 95 %CI 1.10, 1.70). However, no definitive exposure-response relationships between these medicines and cancer risk were observed. CONCLUSIONS: There is little evidence that commonly-prescribed medicines associated with inflammation of the pancreas are also associated with pancreatic cancer. These findings should provide reassurance to patients and prescribing clinicians.

Dietary Patterns and Retinal Vessel Caliber in the Irish Nun Eye Study.

BACKGROUND: Retinal vessel abnormalities are associated with cardiovascular disease risk. Widening of retinal venules is associated with increased risk of stroke while narrowing of retinal arterioles independently predicts incident hypertension, coronary heart disease and diabetes. Dietary factors are known to play an important role in cardiovascular health. However, few studies have examined the association between dietary patterns (DPs) and retinal microvascular health. OBJECTIVE: To examine the association between 'a posteriori'-derived DPs and retinal vascular caliber (RVC) in older women with a restricted lifestyle. METHODS: This was a cross-sectional study of 1233 participants (mean age: 76.3 years) from the Irish Nun Eye Study (INES). Computer-assisted software was used to measure RVC from digital eye images using standardized protocols. Dietary intake was assessed using a food frequency questionnaire (FFQ). DP analysis was performed using principal component analysis from completed FFQs. Regression models were used to assess associations between DPs and retinal vessel diameters, adjusting for age, body mass index, refraction, hypertension, diabetes mellitus, ischemic heart disease, cerebrovascular accident and fellow eye RVC. RESULTS: Two DPs were identified: a 'healthy' pattern with high factor loadings for fruit, vegetables, wholegrains and oily fish and an 'unhealthy' pattern with high factor loadings for sugar and sweets, chips, high fat dairy products and French fries. Adjusted linear regression analysis revealed that those who adhered most closely to the unhealthy DP had wider central retinal venular equivalent (CRVE) (p=0.03) and narrower central retinal arteriolar equivalent (CRAE) (p=0.01) compared to the least unhealthy DP. No independent relationship was observed between the healthy DP and RVC. CONCLUSION: In this cohort of older women with a restricted lifestyle, an unhealthy DP was independently associated with an unfavorable retinal profile, namely a widening of retinal venules and narrowing of retinal arterioles.

Proton pump inhibitor and histamine-2 receptor antagonist use and risk of liver cancer in two population-based studies.

BACKGROUND: Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are commonly used. PPIs have been shown to promote liver cancer in rats; however, only one study has examined the association in humans. AIMS: To investigate PPIs and H2RAs and risk of primary liver cancer in two large independent study populations. METHODS: We conducted a nested case-control study within the Primary Care Clinical Informatics Unit (PCCIU) database in which up to five controls were matched to cases with primary liver cancer, recorded by General Practitioners. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations with prescribed PPIs and H2RAs were calculated using conditional logistic regression. We also conducted a prospective cohort study within the UK Biobank using self-reported medication use and cancer-registry recorded primary liver cancer. Hazard ratios (HRs) and 95% CIs were calculated using Cox regression. RESULTS: In the PCCIU case-control analysis, 434 liver cancer cases were matched to 2103 controls. In the UK Biobank cohort, 182 of 475 768 participants developed liver cancer. In both, ever use of PPIs was associated with increased liver cancer risk (adjusted OR 1.80, 95% CI 1.34, 2.41 and adjusted HR 1.99, 95% CI 1.34, 2.94 respectively). There was little evidence of association with H2RA use (adjusted OR 1.21, 95% CI 0.84, 1.76 and adjusted HR 1.70, 95% CI 0.82, 3.53 respectively). CONCLUSIONS: We found some evidence that PPI use was associated with liver cancer. Whether this association is causal or reflects residual confounding or reverse causation requires additional research.

Angiotensin receptor blocker use and gastro-oesophageal cancer survival: a population-based cohort study.

BACKGROUND: Angiotensin receptor blockers (ARBs; including candesartan, losartan, olmesartan and valsartan) are widely used to treat hypertension, heart failure and diabetic neuropathy. There is considerable pre-clinical evidence that ARBs can reduce cancer progression, particularly for gastric cancer. Despite this, epidemiological studies have yet to assess the impact of ARB use on gastro-oesophageal cancer survival. AIM: To investigate the association between post-diagnosis ARB use and gastro-oesophageal cancer survival. METHODS: We selected a cohort of patients with newly-diagnosed gastro-oesophageal cancer between 1998 and 2012 from English cancer registries. We linked to prescription and clinical records from the Clinical Practice Research Datalink, and to death records from the Office for National Statistics. We used time-dependant Cox-regression models to calculate hazard ratios (HRs) comparing gastro-oesophageal cancer-specific mortality between post-diagnosis ARB users and non-users, after adjusting for demographics, comorbidities and post-diagnosis aspirin or statin use. RESULTS: Our cohort included 5124 gastro-oesophageal cancer patients, of which 360 used ARBs, and 3345 died due to their gastro-oesophageal cancer during follow-up. After adjustment, ARB users had moderately lower risk of gastro-oesophageal cancer mortality than the non-users (HR = 0.83, 95% CI 0.71-0.98). There was evidence of a dose-response relationship with the lowest HRs observed among patients receiving at least 2 years of prescriptions (HR = 0.42, 95% CI 0.25-0.72). CONCLUSIONS: In this large population-based gastro-oesophageal cancer cohort, we found moderately reduced cancer-specific mortality among ARB users. However, confirmation in further independent epidemiological studies with sufficient staging information is required.

Post-diagnostic oral bisphosphonate use and colorectal cancer mortality: a population-based cohort study within the UK Clinical Practice Research Datalink.

BACKGROUND: We conducted the first study to investigate post-diagnostic oral bisphosphonates use and colorectal cancer-specific mortality. METHODS: Colorectal cancer patients were identified from the National Cancer Data Repository (1998-2007) and linked to the UK Clinical Practice Research Datalink, providing prescription records, and Office of National Statistics mortality data. Time-dependent Cox regression models investigated colorectal cancer-specific mortality in post-diagnostic bisphosphonate users. RESULTS: Overall, in 4791 colorectal cancer patients, there was no evidence of an association between bisphosphonate use and colorectal cancer-specific mortality (adjusted hazard ratio=1.11; 95% confidence interval 0.80, 1.54) or with drug frequency or type. CONCLUSIONS: In this novel population-based cohort study, post-diagnostic bisphosphonate use was not associated with longer rates of colorectal cancer survival.

The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink.

PURPOSE: Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality. METHODS: Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality. RESULTS: Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses. CONCLUSIONS: There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

Increase in the pharmacological management of Type 2 diabetes with pay-for-performance in primary care in the UK.

AIMS: To determine whether the financial incentives for tight glycaemic control, introduced in the UK as part of a pay-for-performance scheme in 2004, increased the rate at which people with newly diagnosed Type 2 diabetes were started on anti-diabetic medication. METHODS: A secondary analysis of data from the General Practice Research Database for the years 1999-2008 was performed using an interrupted time series analysis of the treatment patterns for people newly diagnosed with Type 2 diabetes (n = 21 197). RESULTS: Overall, the proportion of people with newly diagnosed diabetes managed without medication 12 months after diagnosis was 47% and after 24 months it was 40%. The annual rate of initiation of pharmacological treatment within 12 months of diagnosis was decreasing before the introduction of the pay-for-performance scheme by 1.2% per year (95% CI -2.0, -0.5%) and increased after the introduction of the scheme by 1.9% per year (95% CI 1.1, 2.7%). The equivalent figures for treatment within 24 months of diagnosis were -1.4% (95% CI -2.1, -0.8%) before the scheme was introduced and 1.6% (95% CI 0.8, 2.3%) after the scheme was introduced. CONCLUSION: The present study suggests that the introduction of financial incentives in 2004 has effected a change in the management of people newly diagnosed with diabetes. We conclude that a greater proportion of people with newly diagnosed diabetes are being initiated on medication within 1 and 2 years of diagnosis as a result of the introduction of financial incentives for tight glycaemic control.

Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested case-control study.

BACKGROUND: Beta-blockers have potential antiangiogenic and antimigratory activity. Studies have demonstrated a survival benefit in patients with malignant melanoma treated with beta-blockers. OBJECTIVES: To investigate the association between postdiagnostic beta-blocker usage and risk of melanoma-specific mortality in a population-based cohort of patients with malignant melanoma. METHODS: Patients with incident malignant melanoma diagnosed between 1998 and 2010 were identified within the U.K. Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with malignant melanoma with a melanoma-specific death (cases) recorded by the Office of National Statistics were matched on year of diagnosis, age and sex to four malignant melanoma controls (who lived at least as long after diagnosis as their matched case). A nested case-control approach was used to investigate the association between postdiagnostic beta-blocker usage and melanoma-specific death and all-cause mortality. Conditional logistic regression was applied to generate odds ratios (ORs) and 95% confidence intervals (CIs) for beta-blocker use determined from general practitioner prescribing. RESULTS: Beta-blocker medications were prescribed after malignant melanoma diagnosis to 20·2% of 242 patients who died from malignant melanoma (cases) and 20·3% of 886 matched controls. Consequently, there was no association between beta-blocker use postdiagnosis and cancer-specific death (OR 0·99, 95% CI 0·68-1·42), which did not markedly alter after adjustment for confounders including stage (OR 0·87, 95% CI 0·56-1·34). No significant associations were detected for individual beta-blocker types, by defined daily doses of use or for all-cause mortality. CONCLUSIONS: Contrary to some previous studies, beta-blocker use after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in this U.K. population-based study.

Inflammatory and immunological biomarkers are not related to survival in adults with Cystic Fibrosis.

BACKGROUND: Chronic Pseudomonas aeruginosa pulmonary infection is associated with a decline in lung function and reduced survival in people with Cystic Fibrosis (CF). Damaging inflammatory and immunological mediators released in the lungs can be used as markers of chronic infection, inflammation and lung tissue damage. METHODS: Clinical samples were collected from CF patients and healthy controls. Serum IgG and IgA anti-Pseudomonas antibodies, sputum IL-8 and TNFα, plasma IL-6 and urine TNFr1 were measured by ELISA. Sputum neutrophil elastase (NE), cathepsin S and cathepsin B were measured by spectrophotometric and fluorogenic assays. The relationship between IgG and IgA, inflammatory mediators and long-term survival was determined. RESULTS: IgG and IL-6 positively correlated with mortality. However, multivariate analysis demonstrated that after adjusting for FEV(1), IgG was not independently related to mortality. A relationship was observed between IgG and IL-6, TNFα, TNFr1 and between IgA and IL8, cathepsin S and cathepsin B. CONCLUSIONS: These data indicate that biomarkers of inflammation are not independent predictors of survival in people with CF.

Chronic kidney disease and diabetes in the national health service: a cross-sectional survey of the U.K. national diabetes audit.

AIMS: We investigated the prevalence of chronic kidney disease and attainment of therapeutic targets for HbA1c and blood pressure in a large U.K.-based diabetes population. METHODS: The U.K. National Diabetes Audit provided data from 1 January 2007 to 31 March 2008. Inclusion criteria were a documented urinary albumin:creatinine ratio and serum creatinine. Patients were stratified according to chronic kidney disease stage and albuminuria status. Chronic kidney disease was defined as an estimated glomerular filtration rate < 60 ml min(-1) 1.73 m(-2) , albuminuria or both. The proportions of patients achieving nationally defined glycaemic and systolic blood pressure targets were determined. RESULTS: The cohort comprised 1,423,669 patients, of whom 868,616 (61%) met inclusion criteria. Of the patients analysed, 92.2% had Type 2 diabetes. A higher proportion of people with Type 2 diabetes (42.3%) had renal dysfunction compared with those with Type 1 diabetes (32.4%). Achievement of systolic blood pressure and HbA1c targets was poor. Among people with Type 1 diabetes, 67.8% failed to achieve an HbA1c < 58 mmol/mol (7.5%). Of all people with diabetes, 37.8% failed to achieve a systolic blood pressure < 140 mmHg. Blood pressure control was poor in advanced chronic kidney disease. For example, mean (standard deviation) systolic blood pressure rose from 128.6 (15.4) mmHg among people with Type 1 diabetes and normal renal function to 141.0 (23.6) mmHg in those with chronic kidney disease stage 5 and macroalbuminuria. CONCLUSIONS: The high prevalence of chronic kidney disease and poor attainment of treatment targets highlights a large subset of the diabetes population at increased risk of cardiovascular mortality or progressive kidney disease.

General practice-recorded depression and antidepressant use in young people with newly diagnosed Type 1 diabetes: a cohort study using the Clinical Practice Research Datalink.

AIMS: To investigate whether young people with Type 1 diabetes have an increased rate of depression and antidepressant use and whether their risk varies by age group, time from diabetes diagnosis, calendar period of diagnosis or complications status. METHODS: A cohort of incident cases of patients with Type 1 diabetes diagnosed before 35 years of age (n = 5548) was identified within the Clinical Practice Research Datalink and individually age and sex matched with up to two control subjects without diabetes (n = 10 657). Patients with depression were identified through general practice-recorded depression codes and antidepressant prescriptions. Cox regression models gave hazard ratios for depression in people with Type 1 diabetes compared with control subjects. RESULTS: People with Type 1 diabetes were twice as likely to have a record of antidepressant use and general practice-diagnosed depression as their matched control subjects (hazard ratio 2.08, 95% CI 1.73-2.50, P < 0.001). These associations varied by time from diagnosis, with marked increases observed within the first 5 years of diagnosis (hazard ratio 2.14, 95% CI 1.51-3.03, P < 0.001), and by age at diabetes diagnosis, with excesses noted even in the 10- to 19-year age group (hazard ratio 1.45, 95% CI 1.06-1.98, P = 0.02). CONCLUSIONS: This population-based study shows that people with Type 1 diabetes have higher rates of general practice-recorded depression and antidepressant use. The excess is present within 5 years of diabetes diagnosis, suggesting psychological input for patients is warranted in the early years of their condition.

ß-Blocker usage and colorectal cancer mortality: a nested case-control study in the UK Clinical Practice Research Datalink cohort.

BACKGROUND: Epidemiological and laboratory studies suggest that ß-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic ß-blocker usage on colorectal cancer-specific mortality in a large population-based colorectal cancer patient cohort. PATIENTS AND METHODS: A nested case-control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to ß-blocker usage (data from GP-prescribing records). RESULTS: Post-diagnostic ß-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78-1.02). Similar associations were found when analysing drug frequency, ß-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in ß-blocker users (adjusted OR = 0.88; 95% CI 0.77-1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40-0.97; P = 0.04). CONCLUSIONS: In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic ß-blocker use and colorectal cancer-specific mortality. CLINICAL TRIALS NUMBER: NCT00888797.

Non-steroidal anti-inflammatory drug use and brain tumour risk: a case-control study within the Clinical Practice Research Datalink.

PURPOSE: The aetiology of primary brain tumours is largely unknown; the role of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin use and glioma risk has been inconclusive, but few population-based studies with reliable prescribing data have been conducted, and the association with meningioma risk has yet to be assessed. METHODS: The UK Clinical Practice Research Datalink was used to assess the association between aspirin and non-aspirin NSAID use and primary brain tumour risk using a nested case-control study design. Conditional logistic regression analysis was performed on 5,052 brain tumour patients aged 16 years and over, diagnosed between 1987 and 2009 and 42,678 controls matched on year of birth, gender and general practice, adjusting for history of allergy and hormone replacement therapy use in the glioma and meningioma models, respectively. RESULTS: In conditional logistic regression analysis, excluding drug use in the year preceding the index date, there was no association with non-aspirin NSAID use (OR 0.96, 95 % CI 0.81-1.13) or glioma risk comparing the highest category of daily defined dose to non-users; however, non-aspirin NSAID use was positively associated with meningioma risk (OR 1.35, 95 % CI 1.06-1.71). No association was seen with high- or low-dose aspirin use irrespective of histology. CONCLUSIONS: This large nested case-control study finds no association between aspirin or non-aspirin NSAID use and risk of glioma but a slight increased risk with non-aspirin NSAIDs and meningioma.

Obesity and kidney disease in type 1 and 2 diabetes: an analysis of the National Diabetes Audit.

BACKGROUND: Obesity is increasingly prevalent in many countries. Obesity is a major risk factor for the development of type 2 diabetes but its relationship with diabetic kidney disease (DKD) remains unclear. Some studies have suggested that the metabolic syndrome (including obesity) may be associated with DKD in type 1 diabetes. AIM: To investigate the association between obesity and DKD. DESIGN: Retrospective cross-sectional study. METHODS: National Diabetes Audit data were available for the 2007-08 cycle. Type 1 and 2 diabetes patients with both a valid serum creatinine and urinary albumin:creatinine ratio were included. DKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), albuminuria or both. Logistic regression was used to analyse associations of obesity (body mass index ≥30 kg/m(2)) and other variables including year of birth, year of diagnosis, ethnicity and stage of kidney disease. RESULTS: A total of 58 791 type 1 and 733 769 type 2 diabetes patients were included in the analysis. After adjustment, when compared with type 1 diabetes patients with normal renal function those with DKD were up to twice as likely to be obese. Type 2 DKD patients were also more likely to be obese. For example, type 2 diabetes patients with an eGFR <15 ml/min/1.73 m(2) and normoalbuminuria, microalbuminuria or macroalbuminuria were all more likely to be obese; odds ratios (95% CI) 1.65 (1.3-2.1), 1.56 (1.28-1.92) and 1.27 (1.05-1.54), respectively. CONCLUSION: This study has highlighted a strong association between obesity and kidney disease in type 1 diabetes and confirmed their association in type 2 diabetes.

The impact of body mass index on maternal and neonatal outcomes: a retrospective study in a UK obstetric population, 2004-2011.

OBJECTIVE: To assess the prevalence of overweight and obesity, and the impact of body mass index (BMI) on maternal and neonatal outcomes, in a UK obstetric population. DESIGN: Retrospective study. SETTING: A tertiary referral unit in Northern Ireland. POPULATION: A total of 30 298 singleton pregnancies over an 8-year period, 2004-2011. METHODS: Women were categorised according to World Health Organization classification: underweight (BMI < 18.50 kg/m(2)); normal weight (BMI 18.50-24.99 kg/m(2); reference group); overweight (BMI 25.00-29.99 kg/m(2)); obese class I (BMI 30.00-34.99 kg/m(2)); obese class II (BMI 35-39.99 kg/m(2)); and obese class III (BMI ≥ 40 kg/m(2)). Maternal and neonatal outcomes were examined using logistic regression, adjusted for confounding variables. MAIN OUTCOME MEASURES: Maternal and neonatal outcomes. RESULTS: Compared with women of normal weight, women who were overweight or obese class I were at significantly increased risk of hypertensive disorders of pregnancy (OR 1.9, 99% CI 1.7-2.3; OR 3.5, 99% CI 2.9-4.2); gestational diabetes mellitus (OR 1.7, 99% CI 1.3-2.3; OR 3.7, 99% CI 2.8-5.0); induction of labour (OR 1.2, 99% CI 1.1-1.3; OR 1.3, 99% CI 1.2-1.5); caesarean section (OR 1.4, 99% CI 1.3-1.5; OR 1.8, 99% CI 1.6-2.0); postpartum haemorrhage (OR 1.4, 99% CI 1.3-1.5; OR 1.8, 1.6-2.0); and macrosomia (OR 1.5, 99% CI 1.3-1.6; OR 1.9, 99% CI 1.6-2.2), with the risks increasing for obese classes II and III. Women in obese class III were at increased risk of preterm delivery (OR 1.6, 99% CI 1.1-2.5), stillbirth (OR 3.0, 99% CI 1.0-9.3), postnatal stay > 5 days (OR 2.1, 99% CI 1.5-3.1), and infant requiring admission to a neonatal unit (OR 1.6, 99% CI 1.0-2.6). CONCLUSIONS: By categorising women into overweight and obesity subclassifications (classes I -III), this study clearly demonstrates an increasing risk of adverse outcomes across BMI categories, with women who are overweight also at significant risk.

Adiponectin multimers, body weight and markers of cardiovascular risk in adolescence: Northern Ireland Young Hearts Project.

BACKGROUND: Research examining the relationship between adiponectin (AN) isoforms, body weight and cardiovascular (CV) risk factors is limited, particularly in younger populations. OBJECTIVES: To investigate the inter-relationships between AN isoforms and CV risk factors, and their dependence on body weight status, in adolescents. DESIGN: Blood samples from 92 obese, 92 overweight and 92 normal weight age- and sex-matched adolescents were analysed for traditional cardiovascular disease (CVD) risk biomarkers and also total, high molecular weight (HMW), medium and low molecular weight (LMW) AN. RESULTS: A significant inverse association was observed between total and HMW AN and waist-hip ratio (P=0.015, P=0.006, respectively), triglycerides (P=0.003, P=0.003, respectively) and systolic blood pressure (P=0.012, P=0.024, respectively) and a significant positive association with high-density lipoprotein (P<0.001, P<0.001, respectively) in multi-adjusted analyses. There was no evidence of a relationship between multimeric AN and high-sensitivity C-reactive protein. There was also little evidence of a relationship between LMW AN and CVD risk factors. There was a strong, body mass index (BMI)-independent, association between AN, CVD biomarkers and the hypertriglyceridemic waist phenotype. CONCLUSION: Prominent, BMI-independent associations between total and HMW AN, but not LMW AN, and CVD risk factors were already evident in this young population. This research in adolescents supports the contention that AN subfractions may have different biological actions. These associations in apparently healthy adolescents suggest an important role for AN and its subfractions in the pathogenesis of metabolic syndrome traits and indicate that the potential for total or HMW AN to act as early universal biomarkers of CV risk warrants further study.

Do perinatal and early life exposures influence the risk of malignant melanoma? A Northern Ireland birth cohort analysis.

AIM: Intrauterine, early life and maternal exposures may have important consequences for cancer development in later life. The aim of this study was to examine perinatal and birth characteristics with respect to Cutaneous malignant melanoma (CMM) risk. METHODS: The Northern Ireland Child Health System database was used to examine gestational age adjusted birth weight, infant feeding practices, parental age and socioeconomic factors at birth in relation to CMM risk amongst 447,663 infants delivered between January 1971 and December 1986. Follow-up of histologically verified CMM cases was undertaken from the beginning of 1993 to 31st December 2007. Multivariable adjusted unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) of CMM risk. RESULTS: A total of 276 CMM cases and 440,336 controls contributed to the final analysis. In reference to normal (gestational age-adjusted) weight babies, those heaviest at birth were twice as likely to develop CMM OR 2.4 (95% CI 1.1-5.1). Inverse associations with CMM risk were observed with younger (<25 years) parental age at birth and both a higher birth order and greater household density OR 0.61 (95% CI 0.37-0.99) and OR 0.56 (95% CI 0.30-1.0) respectively. CONCLUSION: This large study of early onset melanoma supports a positive association with higher birth weight (imperatively gestational age adjusted) and CMM risk which may be related to factors which drive intrauterine foetal growth. Strong inverse associations observed with higher birth order and household density suggest that early-life immune modulation may confer protection; findings which warrant further investigation in prospective analyses.

A meta-analysis of the association between pre-eclampsia and childhood-onset Type 1 diabetes mellitus.

AIMS: To review and synthesize the evidence for an increased risk of childhood Type 1 diabetes mellitus in children born to mothers diagnosed with pre-eclampsia during pregnancy. METHODS: A comprehensive search of the published literature was performed in MEDLINE, Web of Science and EMBASE limited to studies published before August 2010. Crude odds ratios and 95% confidence intervals were calculated from the data reported in each study. Meta-analysis techniques were then used to derive a combined odds ratio and investigate heterogeneity. Sensitivity analyses were conducted by study design, ascertainment of pre-eclampsia and study quality. RESULTS: Data were available from 16 studies including 8315 children with Type 1 diabetes. Overall, there was little evidence of an increase in the risk of Type 1 diabetes in children born to mothers who had pre-eclampsia during pregnancy (OR = 1.10, 95% CI 0.96-1.27; P = 0.17). This association did not vary much between studies (I(2) = 28%, P for heterogeneity =0.14). The association was similar in three cohort studies (OR = 1.05, 95% CI 0.77-1.44; P = 0.75) and in seven studies with a low risk of bias (OR = 1.13, 95% CI 0.91-1.40; P = 0.27), but was more marked in 13 studies which ascertained pre-eclampsia from obstetrical records or birth registry data (OR = 1.18, 95% CI 1.03-1.36; P = 0.02). CONCLUSIONS: This analysis demonstrates little evidence of any substantial increase in childhood Type 1 diabetes risk after pregnancy complicated by pre-eclampsia.