New research finds no association between breast pain and breast cancer

British Journal of General Practice | February 2022 | DOI: https://doi.org/10.3399/BJGP.2021.0475

Women with breast pain constitute more than 20% of breast clinic attendees. The aim of this prospective cohort study was to investigate breast cancer incidence in women presenting with breast pain and establish the health economics of referring women with breast pain to secondary care.

Of 10 830 women, 1972 (18%) were referred with breast pain, 6708 (62%) with lumps, 480 (4%) with nipple symptoms, 1670 (15%) with ‘other’ symptoms. Of the 1972 women with breast pain, breast cancer incidence was 0.4% compared with ∼5% in each of the three other clinical groups.

The study found that referring women with breast pain to a breast diagnostic clinic is an inefficient use of limited resources. Alternative management pathways could improve capacity and reduce financial burden.

Full paper: No association between breast pain and breast cancer: a prospective cohort study of 10 830 symptomatic women presenting to a breast cancer diagnostic clinic

See also: New research on breast pain ‘reassuring’ for patients, says College | RCGP

Association between use of macrolides in pregnancy and risk of major birth defects

Objective To examine the association between the use of macrolide antibiotics in pregnancy and the risk of major birth defects.

Design Nationwide, register based cohort study.

Setting Denmark, 1997-2016.

Participants Of 1 192 539 live birth pregnancies, pregnancies during which macrolides had been used (13 019) were compared with those during which penicillin (that is, phenoxymethylpenicillin) had been used (matched in a 1:1 ratio on propensity scores). Other comparative groups were pregnancies when macrolides had been used recently but before pregnancy (matched 1:1) and pregnancies where no antibiotics had been used (matched 1:4).

Main outcome measures Association with an outcome of any major birth defect and specific subgroups of birth defects were assessed by relative risk ratios and absolute risk differences.

Results In matched comparisons, 457 infants were born with major birth defects to women who had used macrolides during pregnancy (35.1 per 1000 pregnancies) compared with 481 infants (37.0 per 1000 pregnancies) to women who had used penicillin (relative risk ratio 0.95; 95% confidence interval 0.84 to 1.08), corresponding to an absolute risk difference of −1.8 (95% confidence interval −6.4 to 2.7) per 1000 pregnancies. The risk of major birth defects was not significantly increased for women who had used macrolides during pregnancy compared with those who had used macrolides recently but before becoming pregnant (relative risk ratio 1.00 (95% confidence interval 0.88 to 1.14); absolute risk difference −0.1 (95% confidence interval −4.8 to 4.7) per 1000 pregnancies) or compared with women who did not use any antibiotics (1.05 (0.95 to 1.17); 1.8 (−1.7 to 5.3) per 1000 pregnancies). For all three comparative group analyses and in the analyses of use of individual macrolides, no significant increased risk of specific subgroups of birth defects associated with the use of macrolides was found.

Conclusions In this nationwide cohort study, the use of macrolide antibiotics in pregnancy was not associated with an increased risk of major birth defects. Analyses of the associated risk of 12 specific subgroups of birth defects with the use of macrolides in pregnancy were not significant.

Reference: BMJ 2021;372:n107

Association of first trimester prescription opioid use with congenital malformations in the offspring

Objective To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure.

Design Population based cohort study.

Setting Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15).

Participants 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth.

Interventions Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester.

Main outcomes measures Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis.

Results 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14).

Conclusions Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.

Reference: BMJ 2021;372:n102

Associations of cereal grains intake with cardiovascular disease and mortality across 21 countries in Prospective Urban and Rural Epidemiology study

Objective To evaluate the association between intakes of refined grains, whole grains, and white rice with cardiovascular disease, total mortality, blood lipids, and blood pressure in the Prospective Urban and Rural Epidemiology (PURE) study.

Design Prospective cohort study.

Setting PURE study in 21 countries.

Participants 148 858 participants with median follow-up of 9.5 years.

Exposures Country specific validated food frequency questionnaires were used to assess intakes of refined grains, whole grains, and white rice.

Main outcome measure Composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, non-fatal myocardial infarction, stroke, or heart failure). Hazard ratios were estimated for associations of grain intakes with mortality, major cardiovascular events, and their composite by using multivariable Cox frailty models with random intercepts to account for clustering by centre.

Results Analyses were based on 137 130 participants after exclusion of those with baseline cardiovascular disease. During follow-up, 9.2% (n=12 668) of these participants had a composite outcome event. The highest category of intake of refined grains (≥350 g/day or about 7 servings/day) was associated with higher risk of total mortality (hazard ratio 1.27, 95% confidence interval 1.11 to 1.46; P for trend=0.004), major cardiovascular disease events (1.33, 1.16 to 1.52; P for trend<0.001), and their composite (1.28, 1.15 to 1.42; P for trend<0.001) compared with the lowest category of intake (<50 g/day). Higher intakes of refined grains were associated with higher systolic blood pressure. No significant associations were found between intakes of whole grains or white rice and health outcomes.

Conclusion High intake of refined grains was associated with higher risk of mortality and major cardiovascular disease events. Globally, lower consumption of refined grains should be considered.

Reference: BMJ 2021;372:m4948

Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study

Objective To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea.

Design Cohort study.

Setting A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019.

Participants 441 399 girls aged 11-14 years who had been vaccinated in 2017: 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV.

Main outcome measures Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV unvaccinated group, and adjusted relative risks were estimated using conditional logistic regression in the secondary analysis.

Results Among the 33 predefined serious adverse events, no associations were found with HPV vaccination in the cohort analysis, including Hashimoto’s thyroiditis (incidence rate per 100 000 person years: 52.7 v 36.3 for the vaccinated and unvaccinated groups; adjusted rate ratio 1.24, 95% confidence interval 0.78 to 1.94) and rheumatoid arthritis (incidence rate per 100 000 person years: 168.1 v 145.4 for the vaccinated and unvaccinated groups; 0.99, 0.79 to 1.25), with the exception of an increased risk observed for migraine (incidence rate per 100 000 person years: 1235.0 v 920.9 for the vaccinated and unvaccinated groups; 1.11, 1.02 to 1.22). Secondary analysis using self-controlled risk intervals confirmed no associations between HPV vaccination and serious adverse events, including migraine (adjusted relative risk 0.67, 95% confidence interval 0.58 to 0.78). Results were robust to varying follow-up periods and for vaccine subtypes.

Conclusions In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

Reference: BMJ 2021;372:m4931

Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study

Objective To determine the association between levels of low density lipoprotein cholesterol (LDL-C) and all cause mortality, and the concentration of LDL-C associated with the lowest risk of all cause mortality in the general population.

Design Prospective cohort study.

Setting Denmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years.

Participants Individuals randomly selected from the national Danish Civil Registration System.

Main outcome measures Baseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (cardiovascular, cancer, and other mortality).

Results Among 108 243 individuals aged 20-100, 11 376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted hazard ratio for all cause mortality was 1.25 (95% confidence interval 1.15 to 1.36) for individuals with LDL-C concentrations of less than 1.8 mmol/L (<70 mg/dL; 1st-5th centiles) and 1.15 (1.05 to 1.27) for LDL-C concentrations of more than 4.8 mmol/L (>189 mg/dL; 96th-100th centiles). The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction.

Conclusions In the general population, low and high levels of LDL-C were associated with an increased risk of all cause mortality, and the lowest risk of all cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL).

Reference: BMJ 2020;371:m4266

Clinical spectrum of coronavirus disease 2019 in Iceland: population based cohort study

Objective To characterise the symptoms of coronavirus disease 2019 (covid-19).

Design Population based cohort study.

Setting Iceland.

Participants All individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription polymerase chain reaction (RT-PCR) between 17 March and 30 April 2020. Cases were identified by three testing strategies: targeted testing guided by clinical suspicion, open invitation population screening based on self referral, and random population screening. All identified cases were enrolled in a telehealth monitoring service, and symptoms were systematically monitored from diagnosis to recovery.

Main outcome measures Occurrence of one or more of 19 predefined symptoms during follow-up.

Results Among 1564 people positive for SARS-CoV-2, the most common presenting symptoms were myalgia (55%), headache (51%), and non-productive cough (49%). At the time of diagnosis, 83 (5.3%) individuals reported no symptoms, of whom 49 (59%) remained asymptomatic during follow-up. At diagnosis, 216 (14%) and 349 (22%) people did not meet the case definition of the Centers for Disease Control and Prevention and the World Health Organization, respectively. Most (67%) of the SARS-CoV-2-positive patients had mild symptoms throughout the course of their disease.

Conclusion In the setting of broad access to RT-PCR testing, most SARS-CoV-2-positive people were found to have mild symptoms. Fever and dyspnoea were less common than previously reported. A substantial proportion of SARS-CoV-2-positive people did not meet recommended case definitions at the time of diagnosis.

Reference: BMJ 2020;371:m4529

Red meat intake and risk of coronary heart disease among US men: prospective cohort study

Objectives To study total, processed, and unprocessed red meat in relation to risk of coronary heart disease (CHD) and to estimate the effects of substituting other protein sources for red meat with CHD risk.

Design Prospective cohort study with repeated measures of diet and lifestyle factors.

Setting Health Professionals Follow-Up Study cohort, United States, 1986-2016.

Participants 43 272 men without cardiovascular disease or cancer at baseline.

Main outcome measures The primary outcome was total CHD, comprised of acute non-fatal myocardial infarction or fatal CHD. Cox models were used to estimate hazard ratios and 95% confidence intervals across categories of red meat consumption. Substitution analyses were conducted by comparing coefficients for red meat and the alternative food in models, including red meat and alternative foods as continuous variables.

Results During 1 023 872 person years of follow-up, 4456 incident CHD events were documented of which 1860 were fatal. After multivariate adjustment for dietary and non-dietary risk factors, total, unprocessed, and processed red meat intake were each associated with a modestly higher risk of CHD (hazard ratio for one serving per day increment: 1.12 (95% confidence interval 1.06 to 1.18) for total red meat, 1.11 (1.02 to 1.21) for unprocessed red meat, and 1.15 (1.06 to 1.25) for processed red meat). Compared with red meat, the intake of one serving per day of combined plant protein sources (nuts, legumes, and soy) was associated with a lower risk of CHD (0.86 (0.80 to 0.93) compared with total red meat, 0.87 (0.79 to 0.95) compared with unprocessed red meat, and 0.83 (0.76 to 0.91) compared with processed red meat). Substitutions of whole grains and dairy products for total red meat and eggs for processed red meat were also associated with lower CHD risk.

Conclusions Substituting high quality plant foods such as legumes, nuts, or soy for red meat might reduce the risk of CHD. Substituting whole grains and dairy products for total red meat, and eggs for processed red meat, might also reduce this risk.

Reference: BMJ 2020;371:m4141

Association Between Depressive Symptoms and Incident Cardiovascular Diseases

Question  Are depressive symptoms associated with incident cardiovascular diseases?

Findings  In a pooled analysis of individual-participant data from 563 255 participants in 22 prospective cohorts, depressive symptoms (assessed by the Center for Epidemiologic Studies Depression [CES-D] scale and other validated scales) were significantly associated with incident cardiovascular disease, including scores lower than the threshold typically indicative of depressive disorders (CES-D ≥16; hazard ratio per 1-SD higher log CES-D, 1.06).

Meaning  Depressive symptoms, even at levels lower than what is typically indicative of potential clinical depression, were associated with risk of incident cardiovascular disease although the magnitude of the association was modest.

Reference: JAMA. 2020;324(23):2396-2405.

First line drug treatment for hypertension and reductions in blood pressure according to age and ethnicity

Objective To study whether treatment recommendations based on age and ethnicity according to United Kingdom (UK) clinical guidelines for hypertension translate to blood pressure reductions in current routine clinical care.

Design Observational cohort study.

Setting UK primary care, from 1 January 2007 to 31 December 2017.

Participants New users of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), calcium channel blockers (CCB), and thiazides.

Main outcome measures Change in systolic blood pressure in new users of ACEI/ARB versus CCB, stratified by age (< v ≥55) and ethnicity (black v non-black), from baseline to 12, 26, and 52 week follow-up. Secondary analyses included comparisons of new users of CCB with those of thiazides. A negative outcome (herpes zoster) was used to detect residual confounding and a series of positive outcomes (expected drug effects) was used to determine whether the study design could identify expected associations.

Results During one year of follow-up, 87 440 new users of ACEI/ARB, 67 274 new users of CCB, and 22 040 new users of thiazides were included (median 4 (interquartile range 2-6) blood pressure measurements per user). For non-black people who did not have diabetes and who were younger than 55, CCB use was associated with a larger reduction in systolic blood pressure of 1.69 mm Hg (99% confidence interval −2.52 to −0.86) relative to ACEI/ARB use at 12 weeks, and a reduction of 0.40 mm Hg (−0.98 to 0.18) in those aged 55 and older. In subgroup analyses using six finer age categories of non-black people who did not have diabetes, CCB use versus ACEI/ARB use was associated with a larger reduction in systolic blood pressure only in people aged 75 and older. Among people who did not have diabetes, systolic blood pressure decreased more with CCB use than with ACEI/ARB use in black people (reduction difference 2.15 mm Hg (−6.17 to 1.87)); the corresponding reduction difference was 0.98 mm Hg (−1.49 to −0.47) in non-black people.

Conclusions Similar reductions in blood pressure were found to be associated with new use of CCB as with new use of ACEI/ARB in non-black people who did not have diabetes, both in those who were aged younger than 55 and those aged 55 and older. For black people without diabetes, CCB new use was associated with numerically greater reductions in blood pressure than ACEI/ARB compared with non-black people without diabetes, but the confidence intervals were overlapping for the two groups. These results suggest that the current UK algorithmic approach to first line antihypertensive treatment might not lead to greater reductions in blood pressure. Specific indications could be considered in treatment recommendations.

Reference: BMJ 2020;371:m4080