These snippets are extracts from a monthly service called the Journal Article Summary Service. It is a service that summarises all that is new in obstetrics and gynaecology over the preceding month. If you would like to know the details of how to subscribe, please email the editor Athol Kent at firstname.lastname@example.org or visit the website www.getjass.com.
Are we at the stage where we should recommend hormonal prevention to postmenopausal women who are at a raised risk of breast cancer?
Certainly women carrying the BRCA1 and BRCA2 mutations should take action against their extremely high-risk predicament but what about others with lesser but still above average chances of malignancy?
It is known that those with a family history, especially with first-degree relatives who had early onset disease, or a background of atypical hyperplasia, or with very dense breast tissue, are at heightened risk. Both tamoxifen and raloxifene do reduce the risk of developing breast cancer so there is logic in recommending their use in women who wish to lower their odds of the malignancy. This view has been put forward by the influential United States Preventive Services Task Force panel, whose systematic review found that the reduced risk of hormone-receptor-positive cancers offered by the use of these selective estrogen receptor modulators carries more benefit than harm (McCarthy BMJ 2013;346:f2499).
Doctors should use risk assessment tools (like www.cancer.gov/bcrisktool) to calculate any woman's risk and if she is between 40 and 70 years old and has an estimated risk of greater than 3% in the next 5 years, then discuss prophylactic tamoxifen or raloxifene use with her provided a history of thromboembolic events has been excluded.
The recommendations are preliminary but raise the issue of those wanting to ‘be on the safe side’ now adding hormones to their exercise, weight-watching, alcohol moderation and lifestyle modifications to reduce their breast cancer risk.
Genomics and breast cancer
Genomics have a role to play in defining a woman's potential risk of breast cancer and may be helpful in monitoring the success of its treatment. All tumours shed cells or their breakdown products into the bloodstream of their hosts and some of these circulating DNA fragments can be detected by sophisticated genomic sequencing technologies. Once these biomarkers are identified it is possible to measure their levels to monitor spread or remission in women with metastatic breast cancer. At present Cancer Antigen 15-3 measurements and radiographic imaging are the best indicators of progression or quiescence of the disease but both have considerable limitations.
Now Dawson et al. from the UK (NEJM 2013;368:1199–209) have analysed circulating tumour DNA in breast cancer survivors who have metastases and this may open the door to more nuanced therapies, logical investigations and accurate prognostications. The proof-of-concept work has been done—now the technology must be refined and its clinical application proven so that the residual burden of disease can be calculated, responses to treatment assessed and future therapies planned.
Valproate in pregnancy
Valproate is an effective treatment for epileptic seizures as well as for pain and bipolar disorders. However, it is known to be teratogenic with a risk of around 10% in exposed infants who can suffer from congenital malformations such as spina bifida, atrial septal defects, cleft palate, hypospadias, polydactyly and craniosynostosis. It has also been shown to be associated with lowered IQs, learning delays and more subtle manifestations of social dysfunction (Meador and Loring JAMA 2013;309:1730–1).
Now a study from Denmark by Christensen et al. (JAMA 2013;309:1696–703) suggests that maternal valproate ingestion may increase an infant's chances of suffering from autism spectrum disorders (ASD). These range from the severest form of childhood autism (which appears before the age of 3 years), through Asperger syndrome to other developmental disorders. The researchers followed up all Danish children born between 1996 and 2006 for a period of 8 years and noted those with ASD and traced any exposure to valproate and other anti-epileptic drugs. The overall absolute rate of ASD in the entire population was 2.5%, which rose to 4.5% in those exposed to valproate (Figure 1).
This excess risk remained after adjusting for maternal epilepsy so it appears to be a medication-related effect persuading the authors to appeal for alternative forms of seizure control in women of childbearing age or for careful weighing of the risks when it is the only option available.
Vitamin D and pregnancy
There is much controversy about whether all women should receive vitamin D supplementation in pregnancy. At a simplistic level it can be argued that low levels of vitamin D are associated with poor outcomes so all women should comply with calls for supplements for all. At a scientific level numerous studies show highly variable serum levels of 25-hydroxyvitamin D in large affluent populations where the incidences of small babies, preterm deliveries and adverse results are low. There are no large randomised trials across populations that show clear benefit (Lucas et al. BMJ 2013;346:f1675).
Low vitamin D levels may be markers of low socio-economic status, poor nutrition or unhealthy lifestyles. Until these associations are established or ruled out it might be wisest to focus on education, breastfeeding and contraception to raise maternal and fetal outcomes rather than emphasising supplementation as the solution.
Active management of the third stage
The active management of the third stage of labour has saved countless women's lives. An oxytocic injected at delivery, early clamping of the cord and controlled cord traction are the time-honoured steps in preventing postpartum haemorrhage. But as science has looked more closely at each step in the process, so have the benefits of each become questioned. There is no doubt that a uterotonic agent is essential—but which one and what route of administration? At present it seems there are advantages of parenteral oxytocin over oral misoprostol but there are cogent arguments for the latter's use in deprived regions.
Early cord clamping has been shown NOT to be in the baby's interests in both developed and developing countries and simply should NOT be part of the optimal process of childbirth.
Which leaves controlled cord traction. It does speed up the third stage but does it lead to fewer postpartum haemorrhages? No, is the short answer in developing and now, it appears, in developed nations. A trial of controlled traction versus waiting for spontaneous separation before facilitating placental extraction conducted in France showed no difference in blood loss or rates of postpartum haemorrhage (Deneux-Tharaux et al. BMJ 2013;346:f1541). The process did take longer but speed may not be in the mother's or baby's interests and the chances of uterine inversion are reduced without controlled cord traction. This needs to be weighed against expeditiousness and maternal comfort, which was greater with controlled cord traction. These data reiterate that tradition and dogma must continually be challenged—no matter how ‘obviously superior’ they appear to be.
The cost of dementia
Dementia is defined as a chronic disease of ageing with cognitive decline that interferes with independent functioning. There are few predictive factors or preventive measures available so as populations age the burden of dementia will increase on more individuals, their families, their communities and the state. The cost to the individual of dementia is impossible to quantify, and never will be calculable. Neither will it be to their partners nor family who ‘lose’ a loved one and are faced with caring for a person who ‘used to be someone else’ with all the emotional, societal and financial demands such care requires.
But in developed countries where the mean life expectancy has reached 80 years and with dementia rates at 15% in 70-year-olds and increasing with age, the looming scenario needs to be faced financially. To assist with calculations Hurd et al. (NEJM 2013;368:1326–34) looked at what it costs to care for a person with dementia for a year in the USA. They came up with a figure of $50 000 or a total figure for the country of $200 billion per annum. They predict that this amount will rise by 80% in the next 30 years.
Women outlive men by approximately 5 years. The same means of reducing the risk of breast cancer risk are those that will reduce the likelihood of dementia, namely exercise, weight control with a Mediterranean diet, exercise, not smoking or drinking excessively and possibly hormone therapy. Retaining sharpness through using mental processes is also protective. Now is the time to encourage as many of these preventive measures as possible.
Why hasn't the polypill caught on?
Since cardiovascular disease is the premier cause of death across the world, why is there not a pill that reduces a person's risk of a cardiac event? An antihypertensive, a statin and some aspirin combined in a single pill and taken by everyone over the age of 55 years would surely be in everyone's interests? The concept of a polypill is 12 years old yet it has not taken off.
The drugs are not expensive and would pay for themselves in therapeutic costs saved, they have few adverse effects and the clinical trial results are promising—so why the inertia?
Smith et al. (JAMA 2013;309:1595–6) suggest several reasons. The reluctance of regulators to sanction a polypill for primary prophylaxis is understandable. They would require large trials over many years to agree that otherwise healthy citizens should be given medication that is not entirely harmless—however large the population benefit. Second, the public would need convincing and given the scepticism over vaccines, would adults participate in large enough numbers to make a difference? Third, who would be responsible for an abreaction to one of the polypill's components? Could supporting medical groups or manufacturers be sued? Fourth, there is no coherent business model making it worth someone's financial while to manufacture, distribute and monitor a population-sized endeavour. Surely if there were money to be made the pharmaceutical giants would be queuing up to participate?
The true reason is probably that those who are motivated to choose healthy lifestyles are the most likely people to take a polypill—and those with unhealthy habits and most likely to derive benefit, will not. It is therefore a project that is attractive, but doomed at the same time or, put more prosaically, ‘My heart is in it but my wallet isn't’.