Drop the C-word to reduce anxiety and overtreatment, say experts

Renaming low risk conditions labelled as cancer

Removing the cancer label in low risk conditions that are unlikely to cause harm if left untreated may help reduce overdiagnosis and overtreatment, argue The BMJ


Evidence is mounting that disease labels affect people’s psychological responses and their decisions about management options. The use of more medicalised labels can increase both concern about illness and desire for more invasive treatment. For low risk lesions where there is evidence of overdiagnosis and previous calls to replace the term cancer, we consider the potential implications of removing the cancer label and how this may be achieved.

Our changing understanding of the prognosis of cancers

Some cancers are non-growing or so slow growing that they will never cause harm if left undetected. A prime example is low risk papillary thyroid cancer. Autopsy studies show a large reservoir of undetected papillary thyroid cancer that never causes harm, and the incidence of thyroid cancer has risen substantially in many developed countries. This rise has been predominantly driven by an increase in small papillary thyroid cancers, with mortality remaining largely unchanged. These small papillary thyroid cancers are increasingly being detected because of new technologies, increased access to health services, and thyroid cancer screening. Studies show that rates of metastases, progression to clinical disease, and tumour growth in patients with small papillary thyroid cancer who receive immediate surgery are comparable with those in patients who follow active surveillance.

Likewise, for both low risk ductal carcinoma in situ (DCIS) and localised prostate cancer, detection strategies have become controversial as long term outcomes for both conditions have been shown to be excellent and there is evidence and concern about overdiagnosis and overtreament. Given the potential harms of overtreatment of DCIS, active surveillance is now being trialled internationally as an alternative approach. …

continue reading Renaming low risk conditions labelled as cancer on The BMJ, 12 August 2018. Image  credit @bmj_company.

Is early detection always the best medicine ?

The Recommended Dose, with Alexandra Barratt

Hosted by acclaimed journalist and health researcher Dr Ray Moynihan, The Recommended Dose tackles the big questions in health and explores the insights, evidence and ideas of extraordinary researchers, thinkers, writers and health professionals from around the globe. The series is produced by Cochrane Australia and co-published with the BMJ.

Press Play > to listen to the recording.

Dr Ray Moynihan’s guest has led something of a double life, using both medicine and the media to explore and promote the critical role of evidence in healthcare. Now based at the University of Sydney, Alexandra Barratt‘s journey from clinician to journalist to global advocate for evidence based medicine and shared decision-making is a fascinating one.

Here Alexandra talks with Ray about her varied career and the reasons she’s ended up challenging conventional wisdom. She also talks about her research into the pros and cons of breast cancer screening and questions the widely-accepted idea that early detection is always the best medicine.

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Fetal air pollution exposure linked to low birth weight

Globally, two billion children (90% of all children) are exposed to air pollution above WHO guidelines

New UK research links toxic air to low birth weight that can cause lifelong damage to health, raising fears that millions of babies worldwide are being harmed.

What is already known on this topic

  • Road traffic pollution comprises not only air pollutants such as NO2 and particulate matter, but also noise
  • There is a large body of research demonstrating associations between maternal exposure to ambient air pollution during pregnancy and reduced birth weight, low birth weight (LBW), or small for gestational age (SGA)
  • The relation between road traffic noise and birth weight is unclear, and research examining traffic related air pollutant and noise coexposures together is very limited, so the extent to which observed air pollution associations might be attributable to road traffic noise is poorly understood

What this study adds

  • There is an increased risk of LBW specifically in relation to the air pollution profile of London
  • Exposure to local air pollution from road traffic is associated with increased risk of LBW in London, but there is little evidence for an independent exposure-response effect of traffic related noise on birth weight
  • Reducing exposure to traffic related air pollution could reduce the burden of LBW, SGA, and subsequent morbidity, and ultimately give babies in urban environments a healthier start in life

2017 Study Abstract

To investigate the relation between exposure to both air and noise pollution from road traffic and birth weight outcomes.

Retrospective population based cohort study.

Greater London and surrounding counties up to the M25 motorway (2317 km2), UK, from 2006 to 2010.

540 365 singleton term live births.

Main outcome measures
Term low birth weight (LBW), small for gestational age (SGA) at term, and term birth weight.

Average air pollutant exposures across pregnancy were 41 μg/m3 nitrogen dioxide (NO2), 73 μg/m3 nitrogen oxides (NOx), 14 μg/m3 particulate matter with aerodynamic diameter <2.5 μm (PM2.5), 23 μg/m3 particulate matter with aerodynamic diameter <10 μm (PM10), and 32 μg/m3 ozone (O3). Average daytime (LAeq,16hr) and night-time (Lnight) road traffic A-weighted noise levels were 58 dB and 53 dB respectively. Interquartile range increases in NO2, NOx, PM2.5, PM10, and source specific PM2.5 from traffic exhaust (PM2.5 traffic exhaust) and traffic non-exhaust (brake or tyre wear and resuspension) (PM2.5 traffic non-exhaust) were associated with 2% to 6% increased odds of term LBW, and 1% to 3% increased odds of term SGA. Air pollutant associations were robust to adjustment for road traffic noise. Trends of decreasing birth weight across increasing road traffic noise categories were observed, but were strongly attenuated when adjusted for primary traffic related air pollutants. Only PM2.5 traffic exhaust and PM2.5 were consistently associated with increased risk of term LBW after adjustment for each of the other air pollutants. It was estimated that 3% of term LBW cases in London are directly attributable to residential exposure to PM2.5>13.8 μg/m3during pregnancy.

The findings suggest that air pollution from road traffic in London is adversely affecting fetal growth. The results suggest little evidence for an independent exposure-response effect of traffic related noise on birth weight outcomes.

More Information
  • Impact of London’s road traffic air and noise pollution on birth weight: retrospective population based cohort study, BMJ 2017;359:j5299, 05 December 2017.
  • Air pollution harm to unborn babies may be global health catastrophe, warn doctors, theguardian, 05 December 2017.
  • Featured image Raivenne-lations.

Potential inverse association between maternal multivitamin supplement use and ASD in offspring

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

What is already known on this topic

Evidence from observational studies is inconsistent about whether maternal supplementation with multivitamins, iron, or folic acid is protective against autism spectrum disorder (ASD) in offspring
Although the cause of autism spectrum disorder may differ by presence of intellectual disability, few studies have examined relations between nutritional supplements and ASD based on level of cognitive function

What this study adds

This population based study of a large cohort in Stockholm supported a possible inverse association between maternal use of multivitamin supplements in early pregnancy and ASD with intellectual disability in offspring compared with no maternal use of multivitamins, iron, or folic acid

2017 Study Abstract

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.

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

Stockholm County, Sweden.

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.

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.

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.

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.

  • Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study, BMJ 2017;359:j4273, 04 October 2017.
  • Featured image credit @bmj_latest.

Epilepsy drug warnings DO NOT reach enough women, 2017 survey finds

Almost 70% of women surveyed about a powerful epilepsy drug have not received new safety warnings about the dangers of taking it during pregnancy

Two thirds of women who take the antiepileptic drug sodium valproate said they had not received new safety warnings about the dangers of taking it during pregnancy, a survey carried out by epilepsy charities has found. A similar survey last year found that half of women taking the drug were unaware it could harm their fetus.

The new results are to be presented at a public hearing on the safety of valproate drugs organised by the European Medicines Agency on 26 September in London. …

… continue reading Women still not being told about pregnancy risks of valproate on The BMJ doi.org/10.1136/bmj.j4426, published 22 September 2017.
Featured image credit @bmj_latest.

FDA’s new drug approvals : is there evidence that the public is happy to sacrifice safety for speed ?

Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study

Most drugs today qualify for one of the FDA’s expedited pathways. But what is the evidence that the public is on board with the notion of sacrificing safety for speed?

What is already known on this topic
  • Recent legislation in America opens the possibility for the expansion and increased use of FDA expedited drug development and review pathways designed to respond to public health priorities
  • Evidence on whether drugs approved through expedited regulatory pathways carry higher levels of safety risks that are unknown at the time of approval is conflicting
  • Some studies suggest that the review process does not impact the quality of the safety assessment, whereas others show a difference
What this study adds
  • In this analysis concerning more than 15 years of comprehensive data, expedited pathway drugs had a 38% higher rate of safety related label changes than drugs approved through non-expedited pathways
  • As policymakers continue to expand expedited regulatory pathways, physicians and patients should be aware of the potential safety trade-offs involved in these pathways

2017 Study Abstract

To determine if drugs approved through the Food and Drug Administration’s expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways.

Retrospective cohort study.

FDA public records, January 1997 to April 2016.

382 FDA approved drugs.

Main outcome measures
The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug’s time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other.

Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.

Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates.

More Information

  • Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study, BMJ 2017;358:j3837, 07 September 2017.
  • Speed vs safety in the FDA’s new drug approvals—speed wins, again, blogs.bmj, September 12, 2017.
  • Featured image credit stickergiant.

Antidepressant use during pregnancy and psychiatric disorders in offspring

Danish nationwide register based cohort study, 2017

What is already known on this topic

  • Several studies have linked selective serotonin reuptake inhibitor use during pregnancy to autism spectrum disorder in offspring, although results have been conflicting
  • The potential explanation for this association is that selective serotonin reuptake inhibitors cross the placental barrier and affect the development of the fetal brain
  • If this holds true, in utero exposure to selective serotonin reuptake inhibitor and other classes of antidepressants may increase risk for various psychiatric disorders besides autism spectrum disorder

What this study adds

  • Antidepressant use during pregnancy was associated with increased risk for various diagnostic groups of psychiatric disorders in offspring
  • The observed associations may be attributable to the severity of underlying maternal psychiatric disorders in combination with in utero antidepressant exposure

Study Abstract

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

Population based cohort study.

Danish national registers.

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.

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.

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.

  • Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study, BMJ 2017;358:j3668, 06 September 2017.
  • Characteristics of study population according to maternal antidepressant use before and during pregnancy. Values are numbers (percentages) unless stated otherwise, featured image credit bmj.

Breast feeding associated with a lower risk of endometriosis

History of breast feeding and risk of incident endometriosis: prospective cohort study

2017 Study Abstract

To investigate the association between lifetime breast feeding, exclusive breast feeding, postpartum amenorrhea, and incidence of endometriosis among parous women.

Prospective cohort study.

Nurses’ Health Study II, 1989-2011.

72 394women who reported having one or more pregnancies that lasted at least six months, 3296 of whom had laparoscopically confirmed endometriosis. For each pregnancy, women reported duration of total breast feeding, exclusive breast feeding, and postpartum amenorrhea.

Main outcome measures
Incident self reported laparoscopically confirmed endometriosis (96% concordance with medical record) in parous women. Multivariable Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for diagnosis of endometriosis.

Duration of total and exclusive breast feeding was significantly associated with decreased risk of endometriosis. Among women who reported a lifetime total length of breast feeding of less than one month, there were 453 endometriosis cases/100 000 person years compared with 184 cases/100 000 person years in women who reported a lifetime total of ≥36 months of breast feeding. For every additional three months of total breast feeding per pregnancy, women experienced an 8% lower risk of endometriosis (hazard ratio 0.92, 95% confidence interval 0.90 to 0.94; P<0.001 for trend) and a 14% lower risk for every additional three months of exclusive breast feeding per pregnancy (0.86, 0.81 to 0.90; P<0.001 for trend). Women who breastfed for ≥36 months in total across their reproductive lifetime had a 40% reduced risk of endometriosis compared with women who never breast fed (0.60, 0.50 to 0.72). The protective association with breast feeding was strongest among women who gave birth within the past five years (P=0.04 for interaction). The association with total breast feeding and exclusive breast feeding on endometriosis was partially influenced by postpartum amenorrhea (% mediated was 34% (95% confidence interval 15% to 59%) for total breast feeding and 57% (27% to 82%) for exclusive breast feeding).

Among women who experienced at least one pregnancy that lasted at least six months, breast feeding was inversely associated with risk of incident endometriosis. This association was partially, but not fully, influenced by postpartum amenorrhea, suggesting that breast feeding could influence the risk of endometriosis both through amenorrhea and other mechanisms. Given the chronic and incurable nature of endometriosis, breast feeding should be further investigated as an important modifiable behavior to mitigate risk for pregnant women.

  • History of breast feeding and risk of incident endometriosis: prospective cohort study, BMJ 2017;358:j3778, 29 August 2017.
  • Featured image credit @bmj_latest, 2 sept. 2017.

Should doctors prescribe physical activity ?

An Intervention to Increase Exercise Habits and Healthy Eating

About a quarter of men and a third of women in the United Kingdom describe themselves as physically inactive. The UK medical royal colleges and others have called for healthcare professionals to help tackle the problem, urging primary care professionals to lead the fight and to “question patients about their physical activity and exercise habits at every meeting.”

2017 Study Abstract

A healthy lifestyle is associated with improved quality of life among cancer survivors, yet adherence to health behavior recommendations is low.

This pilot trial developed and tested the feasibility of a tailored eHealth program to increase fruit and vegetable consumption and physical activity among older, long-term cancer survivors.

American Cancer Society (ACS) guidelines for cancer survivors were translated into an interactive, tailored health behavior program on the basis of Social Cognitive Theory. Patients (N=86) with a history of breast (n=83) or prostate cancer (n=3) and less than 5 years from active treatment were randomized 1:1 to receive either provider advice, brief counseling, and the eHealth program (intervention) or advice and counseling alone (control). Primary outcomes were self-reported fruit and vegetable intake and physical activity.

About half (52.7%, 86/163) of the eligible patients consented to participate. The most common refusal reasons were lack of perceived time for the study (32/163) and lack of interest in changing health behaviors (29/163). Furthermore, 72% (23/32) of the intervention group reported using the program and most would recommend it to others (56%, 14/25). Qualitative results indicated that the intervention was highly acceptable for survivors. For behavioral outcomes, the intervention group reported increased fruit and vegetable consumption. Self-reported physical activity declined in both groups.

The brief intervention showed promising results for increasing fruit and vegetable intake. Results and participant feedback suggest that providing the intervention in a mobile format with greater frequency of contact and more indepth information would strengthen treatment effects.

Correction of a pathogenic gene mutation in human embryos

Gene editing technique successfully corrects mutation in human embryos

Researchers in the United States have successfully used a gene editing technique in early stage human embryos to correct a mutation that causes hypertrophic cardiomyopathy.

The embryos in the study were not allowed to develop for more than a few days and were never intended to be implanted into a womb. Further research is needed to establish the safety of the method before it can be adopted clinically. However, if the technique proves to be safe, it could potentially be used for other genetic disorders such as cystic fibrosis or Huntington’s disease.

2017 Study Abstract

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

Sources and Press Releases
  • Correction of a pathogenic gene mutation in human embryos, nature, doi:10.1038/nature23305, 02 August 2017.
  • Gene editing technique successfully corrects mutation in human embryos, BMJ 2017;358:j3726, 03 August 2017.
  • Featured image Schematic of MYBPC3∆GAGT gene targeting by injection of CRISPR–Cas9 into human zygotes at the S-phase of the cell cycle. MII oocytes were fertilized by sperm from a heterozygous patient with equal numbers of mutant and wild-type (WT) spermatozoa. CRISPR–Cas9 was then injected into one-cell zygotes. Embryos at the 4–8-cell stage were collected for genetic analysis. Injection during S-phase resulted in mosaic embryos consisting of non-targeted mutant, targeted NHEJ-repaired and targeted HDR-repaired blastomeres. credit nature.
  • Brave New World? Not Even Close, scientificamerican, August 2, 2017.
  • Deadly gene mutations removed from human embryos in landmark study, theguardian, August 2, 2017.
  • Embryo editing technique is ‘ethically dubious’, fertility expert warns, christian, August 8, 2017.