Contemporary Hormonal Contraception and the Risk of Breast Cancer

BACKGROUND

Little is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer.

METHODS

We assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast-cancer diagnoses, and potential confounders.

RESULTS

Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen–progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year.

CONCLUSIONS

The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.)

Reference: N Engl J Med 2017; 377:2228-2239December 7, 2017

 

 

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Development and validation of QDiabetes-2018 risk prediction algorithm to estimate future risk of type 2 diabetes

Objectives To derive and validate updated QDiabetes-2018 prediction algorithms to estimate the 10 year risk of type 2 diabetes in men and women, taking account of potential new risk factors, and to compare their performance with current approaches.

Design Prospective open cohort study.

Setting Routinely collected data from 1457 general practices in England contributing to the QResearch database: 1094 were used to develop the scores and a separate set of 363 were used to validate the scores.

Participants 11.5 million people aged 25-84 and free of diabetes at baseline: 8.87 million in the derivation cohort and 2.63 million in the validation cohort.

Methods Cox proportional hazards models were used in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years. Risk factors considered included those already in QDiabetes (age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids) and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, gestational diabetes, and polycystic ovary syndrome. Additional models included fasting blood glucose and glycated haemoglobin (HBA1c). Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status.

Main outcome measure Incident type 2 diabetes recorded on the general practice record.

Results In the derivation cohort, 178 314 incident cases of type 2 diabetes were identified during follow-up arising from 42.72 million person years of observation. In the validation cohort, 62 326 incident cases of type 2 diabetes were identified from 14.32 million person years of observation. All new risk factors considered met our model inclusion criteria. Model A included age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids, and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, and gestational diabetes and polycystic ovary syndrome in women. Model B included the same variables as model A plus fasting blood glucose. Model C included HBA1c instead of fasting blood glucose. All three models had good calibration and high levels of explained variation and discrimination. In women, model B explained 63.3% of the variation in time to diagnosis of type 2 diabetes (R2), the D statistic was 2.69 and the Harrell’s C statistic value was 0.89. The corresponding values for men were 58.4%, 2.42, and 0.87. Model B also had the highest sensitivity compared with current recommended practice in the National Health Service based on bands of either fasting blood glucose or HBA1c. However, only 16% of patients had complete data for blood glucose measurements, smoking, and body mass index.

Conclusions Three updated QDiabetes risk models to quantify the absolute risk of type 2 diabetes were developed and validated: model A does not require a blood test and can be used to identify patients for fasting blood glucose (model B) or HBA1c (model C) testing. Model B had the best performance for predicting 10 year risk of type 2 diabetes to identify those who need interventions and more intensive follow-up, improving on current approaches. Additional external validation of models B and C in datasets with more completely collected data on blood glucose would be valuable before the models are used in clinical practice.

Reference: BMJ 2017;359:j5019

Incidence, clinical management, and mortality risk following self harm among children and adolescents: cohort study in primary care

Objectives To examine temporal trends in sex and age specific incidence of self harm in children and adolescents, clinical management patterns, and risk of cause specific mortality following an index self harm episode at a young age.

Design Population based cohort study.

Setting UK Clinical Practice Research Datalink—electronic health records from 674 general practices, with practice level deprivation measured ecologically using the index of multiple deprivation. Patients from eligible English practices were linked to hospital episode statistics (HES) and Office for National Statistics (ONS) mortality records.

Participants For the descriptive analytical phases we examined data pertaining to 16 912 patients aged 10-19 who harmed themselves during 2001-14. For analysis of cause specific mortality following self harm, 8638 patients eligible for HES and ONS linkage were matched by age, sex, and general practice with up to 20 unaffected children and adolescents (n=170 274).

Main outcome measures In the first phase, temporal trends in sex and age specific annual incidence were examined. In the second phase, clinical management was assessed according to the likelihood of referral to mental health services and psychotropic drug prescribing. In the third phase, relative risks of all cause mortality, unnatural death (including suicide and accidental death), and fatal acute alcohol or drug poisoning were estimated as hazard ratios derived from stratified Cox proportional hazards models for the self harm cohort versus the matched unaffected comparison cohort.

Results The annual incidence of self harm was observed to increase in girls (37.4 per 10 000) compared with boys (12.3 per 10 000), and a sharp 68% increase occurred among girls aged 13-16, from 45.9 per 10 000 in 2011 to 77.0 per 10 000 in 2014. Referrals within 12 months of the index self harm episode were 23% less likely for young patients registered at the most socially deprived practices, even though incidences were considerably higher in these localities. Children and adolescents who harmed themselves were approximately nine times more likely to die unnaturally during follow-up, with especially noticeable increases in risks of suicide (deprivation adjusted hazard ratio 17.5, 95% confidence interval 7.6 to 40.5) and fatal acute alcohol or drug poisoning (34.3, 10.2 to 115.7).

Conclusions Gaining a better understanding of the mechanisms responsible for the recent apparent increase in the incidence of self harm among early-mid teenage girls, and coordinated initiatives to tackle health inequalities in the provision of services to distressed children and adolescents, represent urgent priorities for multiple public agencies.

Reference: BMJ 2017;359:j4351

Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study

Objective To determine whether nutritional supplementation during pregnancy is associated with a reduced risk of autism spectrum disorder (ASD) with and without intellectual disability in offspring.

Design Observational prospective cohort study using multivariable logistic regression, sibling controls, and propensity score matching.

Setting Stockholm County, Sweden.

Participants 273 107 mother-child pairs identified through population registers. The study sample was restricted to children who were aged 4 to 15 years by the end of follow-up on 31 December 2011 and were born between 1996 and 2007.

Exposures Multivitamin, iron, and folic acid supplement use was reported at the first antenatal visit.

Main outcome measure Diagnosis of ASD with and without intellectual disability in children determined from register data up to 31 December 2011.

Results Prevalence of ASD with intellectual disability was 0.26% (158 cases in 61 934) in the maternal multivitamin use group and 0.48% (430 cases in 90 480) in the no nutritional supplementation use group. Maternal multivitamin use with or without additional iron or folic acid, or both was associated with lower odds of ASD with intellectual disability in the child compared with mothers who did not use multivitamins, iron, and folic acid (odds ratio 0.69, 95% confidence interval 0.57 to 0.84). Similar estimates were found in propensity score matched (0.68, 0.54 to 0.86) and sibling control (0.77, 0.52 to 1.15) matched analyses, though the confidence interval for the latter association included 1.0 and was therefore not statistically significant. There was no consistent evidence that either iron or folic acid use were inversely associated with ASD prevalence.

Conclusions Maternal multivitamin supplementation during pregnancy may be inversely associated with ASD with intellectual disability in offspring. Further scrutiny of maternal nutrition and its role in the cause of autism is recommended.

Reference: BMJ 2017;359:j4273

Development and validation of QMortality risk prediction algorithm to estimate short term risk of death and assess frailty: cohort study

Objectives To derive and validate a risk prediction equation to estimate the short term risk of death, and to develop a classification method for frailty based on risk of death and risk of unplanned hospital admission.

Design Prospective open cohort study.

Participants Routinely collected data from 1436 general practices contributing data to QResearch in England between 2012 and 2016. 1079 practices were used to develop the scores and a separate set of 357 practices to validate the scores. 1.47 million patients aged 65-100 years were in the derivation cohort and 0.50 million patients in the validation cohort.

Methods Cox proportional hazards models in the derivation cohort were used to derive separate risk equations in men and women for evaluation of the risk of death at one year. Risk factors considered were age, sex, ethnicity, deprivation, smoking status, alcohol intake, body mass index, medical conditions, specific drugs, social factors, and results of recent investigations. Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for each age and ethnic group. The new mortality equation was used in conjunction with the existing QAdmissions equation (which predicts risk of unplanned hospital admission) to classify patients into frailty groups.

Main outcome measure The primary outcome was all cause mortality.

Results During follow-up 180 132 deaths were identified in the derivation cohort arising from 4.39 million person years of observation. The final model included terms for age, body mass index, Townsend score, ethnic group, smoking status, alcohol intake, unplanned hospital admissions in the past 12 months, atrial fibrillation, antipsychotics, cancer, asthma or chronic obstructive pulmonary disease, living in a care home, congestive heart failure, corticosteroids, cardiovascular disease, dementia, epilepsy, learning disability, leg ulcer, chronic liver disease or pancreatitis, Parkinson’s disease, poor mobility, rheumatoid arthritis, chronic kidney disease, type 1 diabetes, type 2 diabetes, venous thromboembolism, anaemia, abnormal liver function test result, high platelet count, visited doctor in the past year with either appetite loss, unexpected weight loss, or breathlessness. The model had good calibration and high levels of explained variation and discrimination. In women, the equation explained 55.6% of the variation in time to death (R2), and had very good discrimination—the D statistic was 2.29, and Harrell’s C statistic value was 0.85. The corresponding values for men were 53.1%, 2.18, and 0.84. By combining predicted risks of mortality and unplanned hospital admissions, 2.7% of patients (n=13 665) were classified as severely frail, 9.4% (n=46 770) as moderately frail, 43.1% (n=215 253) as mildly frail, and 44.8% (n=223 790) as fit.

Conclusions We have developed new equations to predict the short term risk of death in men and women aged 65 or more, taking account of demographic, social, and clinical variables. The equations had good performance on a separate validation cohort. The QMortality equations can be used in conjunction with the QAdmissions equations, to classify patients into four frailty groups (known as QFrailty categories) to enable patients to be identified for further assessment or interventions.

Reference: BMJ 2017;358:j4208

Trends for prevalence and incidence of resistant hypertension: population based cohort study in the UK 1995-2015

Objective To estimate the incidence and prevalence of resistant hypertension among a UK population treated for hypertension from 1995 to 2015.

Design Cohort study.

Setting Electronic health records from the UK Clinical Practice Research Datalink in primary care.

Participants 1 317 290 users of antihypertensive drugs with a diagnosis of hypertension.

Main outcome measures Resistant hypertension was defined as concurrent use of three antihypertensive drugs inclusive of a diuretic, uncontrolled hypertension (≥140/90 mm Hg), and adherence to the prescribed drug regimen, or concurrent use of four antihypertensive drugs inclusive of a diuretic and adherence to the prescribed drug regimen. To determine incidence, the numerator was new cases of resistant hypertension and the denominator was person years of those with treated hypertension and at risk of developing resistant hypertension. To determine prevalence, the numerator was total number of cases with resistant hypertension and the denominator was those with treated hypertension. Prevalence and incidence were age standardised to the 2015 hypertensive population.

Results The age standardised incidence of resistant hypertension increased from 0.93 cases per 100 person years (95% confidence interval 0.87 to 1.00) in 1996 to a peak level of 2.07 cases per 100 person years (2.03 to 2.12) in 2004. Incidence then decreased to 0.42 cases per 100 person years (0.40 to 0.44) in 2015. Age standardised prevalence increased from 1.75% (95% confidence interval 1.66% to 1.83%) in 1995 to a peak of 7.76% (7.70% to 7.83%) in 2007. Prevalence then plateaued and subsequently declined to 6.46% (6.38% to 6.54%) in 2015. Compared with patients aged 65-69 years, those aged 80 or more years were more likely to have prevalent resistant hypertension throughout the study period.

Conclusions Prevalent resistant hypertension has plateaued and decreased in recent years, consistent with a decrease in incidence from 2004 onwards. Despite this, resistant hypertension is common in the UK hypertensive population. Given the importance of hypertension as a modifiable risk factor for cardiovascular disease, reducing uncontrolled hypertension should remain a population health focus.

Reference: BMJ 2017;358:j3984

Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study

Objective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders.

Design Population based cohort study.

Setting Danish national registers.

Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk.

Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).

Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models.

Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.

Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.

Reference: BMJ 2017;358:j3668