News Forum

GPs with an interest in women's health review the latest papers of significance from research teams across the world.

HPV type specific risks of high-grade CIN
Diabetes and the prediction of adverse pregnancy outcomes
Detection of women at low and high risk of hip fractures
Prescribing HRT, tibolone and bisphosphonates
Breast cancer risk and intake of calcium and vitamin D
Loss of ovarian reserve after uterine artery embolisation
Liquid-based cytology versus the conventional method
HPV vaccine efficacy
Routine HPV vaccination on the NHS
Depression post-MI impacts more on women
Two-week rule for breast cancer
Low-fat foods may incease infertility risk

HPV type specific risks of high-grade CIN
Naucler P, Ryd W, Tornberg S et al. Br J Cancer 2007;97(1):129-32
At first glance, this Swedish paper simply appears to confirm the already-known fact that HPV 16 is one of the most carcinogenic subgroups of HPV. On further perusal, the paper proved very difficult, if not impossible, to follow for the average reader. The materials and methods section was particularly obscure, even though I read it several times.

It appears that this study is an offshoot of a multicentre one, started in 1987, in which the effect of HPV testing in cervical cancer screening was being studied. For this study, a cohort of 5,696 women aged 32-38 was formed. Unfortunately, I found it impossible to discover how many of these were HPV-positive. During a mean follow-up of 4.1 years, 148 of the women developed CIN 2+. Of these, 127 (85.8 per cent) had had a positive HPV test at baseline. The type with the highest population prevalence of infection was HPV 16 (2.5 per cent), which caused 33.1 per cent of the cases, followed by type 31 (1.4 per cent), causing 18.3 per cent of cases, type 45 (0.9 per cent) and type 18 (0.7 per cent). Thirteen per cent of women had more than one virus type. The authors point out that several types previously classified as high risk convey a lesser risk than HPV 16.

This study is particularly pertinent in view of the recent introduction of the vaccine against HPV, although very little mention was made of this. The current vaccine protects against HPV types 16, 18, 6 and 11, so according to the results of this study, would fail to protect a substantial number of women from subsequent development of cervical cancer.
- Dr Alison Glenesk is a GP with a special interest in women's health in Aberdeen, Scotland

Diabetes and the prediction of adverse pregnancy outcomes
Dodd JM, Crowther CA, Antoniou G et al. Aust N Z J Obstet Gynaecol 2007;47(4):307-12
The aim of this substantial study carried out in Australia was to assess different levels of blood glucose in predicting adverse pregnancy outcomes.

It is well established that diabetes and impaired glucose tolerance are associated with increased risk in pregnancy. The authors also state that there is uncertainty in the literature regarding screening for gestational diabetes and impaired glucose tolerance, and variable definitions of cut-off values.

They performed a retrospective cohort study, screening 16,975 women with a 50g glucose load, followed by a glucose tolerance test if that proved positive. Plasma glucose results were correlated with pregnancy outcomes.

Of this group, 1,804 women screened positive on the glucose challenge. With increasing plasma glucose concentrations, there was a significant increase in the risk of pre-eclampsia, caesarean section, shoulder dystocia and neonatal hypoglycaemia.

This study is interesting, if a little confusing for two reasons. First, there is no doubt that gestational diabetes is associated with adverse pregnancy outcomes, and screening does take place. Second, women who developed gestational diabetes in the study would have been treated, thus skewing the results. The question is, in the light of this study's results, should we now be actively screening for impaired glucose tolerance in pregnancy, as opposed to full-blown gestational diabetes? AG

Detection of women at low and high risk of hip fractures
Durosier C, Hans D, Krieg MA et al. Osteoporos Int 2007 doi: 10.1007/s00198-007-0414-0
This study from Australia attempted to refine the measurement of hip fracture risk if DXA scanning is unavailable. It suggests that combining clinical risk factors (CRF), such as BMI, fracture and fall history, diabetes, chair-test results and oestrogen treatment, with the heel stiffness index (HSI), as measured by quantitative ultrasound, might improve risk stratification.

Two white cohorts were pooled, giving a study population of 12,064 women aged 70-100. A risk score was constructed for each woman from the above variables. Using the composite score, 42 per cent of women not reporting a hip fracture were in the low-risk group at baseline, while 57 per cent of those who went on to sustain a fracture were in the high-risk group.

Using HSI alone, percentages were 38 per cent and 52 per cent, and for CRF, 34 per cent and 53 per cent. The combination method also helped to risk-stratify the intermediate group more accurately and the authors conclude that it improves risk assessment. Quite how useful this labour-intensive method is, however, in the absence of DXA scanning to inform decisions about treatment, is difficult to say. AG

Prescribing HRT, tibolone and bisphosphonates
Watson J, Wise L, Green J. Eur J Clin Pharmacol 2007 Jun 28; (Epub ahead of print)
Adverse publicity following the publication of the results of the randomised Women's Health Initiative (WHI) study and the observational Million Women Study has led to concerns about the safety of HRT among patients and health professionals. This study examined prescribing by GPs in the UK of HRT, tibolone and bisphosphonates to women aged 40 or more, between 1991 and 2005. Overall and age-specific prescribing prevalence were calculated for each therapy type.

Prescribing HRT to women aged 40 or more increased between 1991 and 1996 and remained fairly stable between 1997 and 2001. It has fallen by about 50 per cent since 2002, when the first WHI paper was published. Tibolone showed a similar pattern. Prescribing of bisphosphonates increased, particularly in women aged 70 or more.

It will be interesting to see if HRT prescriptions increase following further publication of WHI data in 2007, showing that HRT users aged 60 and less than 10 years past menopause have a lower risk of coronary disease.
- Miss Margaret Rees is reader in reproductive medicine and honorary consultant in medical gynaecology at John Radcliffe Hospital, Oxford

Breast cancer risk and intake of calcium and vitamin D
Lin J, Manson JE, Lee IM et al. Arch Intern Med 2007;167:1050-9
Vitamin D is a pro-steroid hormone with antiproliferative and pro-differentiation activity, which has led to interest in its possible role in cancer chemoprevention.

Cancer incidence and mortality have been positively correlated with latitude by geographic regions and are thought to be due to diminishing vitamin D synthesis from UV exposure at increasing latitudes.

Animal data suggest the potential anticarcinogenic effects of calcium and vitamin D on breast cancer development. However, epidemiological data relating calcium and vitamin D levels to breast cancer have been inconclusive. Total calcium and vitamin D intake was evaluated in relation to breast cancer incidence among 10,578 premenopausal and 20,909 postmenopausal women aged 45 or more who were free from cancer and CVD at baseline in the Women's Health Study. In an average of 10 years' follow-up, 276 premenopausal and 743 postmenopausal women were diagnosed with invasive breast cancer.

Higher intakes of total calcium and vitamin D were moderately associated with a lower risk of premenopausal breast cancer. However, intakes of both nutrients were not inversely associated with the risk of breast cancer among postmenopausal women. In contrast, the Iowa Women's Health Study of 34,321 postmenopausal women found that vitamin D intake of >800IU per day appears to be associated with a small decrease in risk of breast cancer among postmenopausal women.1

Vitamin D is an unusual nutrient, in that the primary natural source is UV sun exposure, rather than dietary intake, which may account for the discrepancies between the two studies. Further studies are needed, especially given recommendations to limit UV sun exposure to decrease risk of skin cancers.MR 1. Robien K, Cutler GJ, Lazovich D. Cancer causes control 2007;18(7):775-82

Loss of ovarian reserve after uterine artery embolisation
Hehenkamp WJ, Volkers NA, Broekmans FJ et al. Hum Reprod 2007; 22:1996-2005

Uterine artery embolisation (UAE) is used as an alternative to hysterectomy for symptomatic uterine fibroids, but there are concerns about premature ovarian failure after the procedure.

The authors investigated the occurrence of ovarian reserve reduction in a randomised trial comparing UAE and hysterectomy by measuring follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH) in 177 premenopausal women with menorrhagia due to uterine fibroids (UAE = 88, hysterectomy = 89).

At 24 months after treatment, the number of patients with FSH levels >40IU/L was 14/80 in the UAE group and 17/73 in the hysterectomy group. AMH levels remained significantly decreased during the follow-up period only in the UAE group compared to the expected AMH decrease due to ageing.

Thus both UAE and hysterectomy affect ovarian reserve. The effects of UAE on pregnancy and long-term outcomes in offspring are unknown. This study on ovarian reserve is another reason why UAE should only be offered to women who do not wish to have children. MR

Liquid-based cytology versus the conventional method
Ronco G, Cuzick J, Pierotti P et al. BMJ 2007;335:28-31; Davey E, d'Assuncao J, Irwig L et al. BMJ 2007;335:31-5
There are a flurry of papers about liquid-based cytology (LBC) and the separate issue of HPV vaccine, and the efficacy of both.

The UK cervical screening programme is one of the major triumphs of the NHS. It saves lives. Cervical cancer has a pre-invasive phase which may last for years and accounts for the success of screening for the disease.

For cervical screening to be cost-effective, at least 75 per cent of the female population must attend for regular smears. Since the advent of the cervical screening call/recall programmes in the UK in the late 1980s, the incidence of the disease has fallen by more than 40 per cent.

Deaths from cervical cancer have also decreased (in Scotland by 50 per cent) - partly because of increased early detection at the pre-invasive phase, partly because of advances in the treatment of established cervical cancer.

Interpreting papers from other countries, where the systems are so different, can be problematical. In the paper from Italy, by Ronco et al, only 49 per cent of the women screened had been for a smear in the past four years, whereas in the UK it is nearer 80 per cent. The paper from Australia, by Davey et al, had an inadequate smear rate in the conventional group of only 3.1 per cent - would that the UK rate (9.5 per cent) were that good.

The study looking at the accuracy of LBC versus conventional cytology was a randomised controlled trial with more than 45,000 women in Italy given a smear by the conventional method or by LBC.

LBC detected more grade I lesions than conventional cytology, especially in younger women aged 25-34, leading to a lower positive predictive value. For grade II or more, there was no statistically significant difference in sensitivity between the two, but LBC had a significant reduction in unsatisfactory smears (relative frequency 0.53 versus conventional).

In this split sample pairs prospective study, 55,000 women in Australia were given a conventional smear, then an LBC sample was taken. Critics could argue that there might be fewer cervical cells left for the LBC sample, or that this favours good LBC sampling by providing a cleaner surface.

The two methods agreed on 81 per cent of the cases. LBC was more likely to classify CIN I (OR 1.47), as in the study from Italy, but also had an increase in CIN II (OR 1.45) and less of an effect in CIN III (OR 1.15). The unsatisfactory rate was 1.8 per cent for LBC and 3.1 per cent for conventional cytology.

Is it a good thing to detect more CIN I in young women, when we know that about 60 per cent of women with mild dyskaryosis reported on cervical cytology will spontaneously clear the virus and subsequent smears will be normal? Will we cause more harm than good, making these women more anxious? These issues need to be addressed.
- Dr Sally Hope is a GP in Woodstock, Oxfordshire, and honorary research fellow in women's health, department of primary healthcare, University of Oxford

HPV vaccine efficacy
Paavonen J, Jenkins D, Bosch FX et al. Lancet 2007;369:2161-70
More than 18,000 women aged 15-25 were given three doses of HPV 16-18 vaccine or Hep A vaccine (both contain 0.5mg aluminium hydroxide), then smears at baseline and six-month intervals, with HPV DNA testing for 15 HPV oncogenic genotypes.

The mean follow-up was only 14.8 months, but the study is continuing. At present, there have been two cases of CIN II or worse in the vaccinated group and 21 in the controls.

Vaccine efficacy is estimated at 90.4 per cent. In total, 99.5 per cent of the women seroconverted for HPV 16 and 18 after the third dose. It also seems to provide some cross-protection on HPV 45 (59.9 per cent), HPV 31 (36.1 per cent) and HPV 52 (31.6 per cent). HPV 16 and 18 account for 70 per cent of all cervical cancers, so it is a real problem for the future of this vaccine: even if everybody were vaccinated, it would not prevent some oncogenic HPVs causing cancer, so everybody would still need smears.

There were no significant differences in safety between the two groups, but a slight increase in spontaneous miscarriage in the HPV group, which needs watching.

We await the government guidelines on HPV vaccine, but it sounds as though 12-year-old girls will be offered it. It will be a complicated message - they will still need smears when they become women. Should I buy three doses of vaccine as the best present a mother can give her teenage girls? From this evidence, they probably would derive some benefit, but it is too early to tell and by the time we know, it will be too late for them. SH

Routine HPV vaccination on the NHS
www.dh.gov.uk
The DoH has agreed in principle to accept advice from the Joint Committee on Vaccination and Immunisation, that routine vaccination against HPV should be introduced for girls aged 12-13 years. The decision is subject to independent peer review of the cost-benefit analysis, but the DoH says that routine vaccination could begin in autumn 2008. Funding for the programme will be considered within the context of the comprehensive spending review.

Depression post-MI impacts more on women
Norris CM, Hegadoren K, Pilote L. Eur J Cardiovasc Nurs 2007;6:92-8
Women are more likely than men to suffer depression after acute MI, according to a study in Canada. It involved 486 patients, including 102 women, who had been admitted to hospital for acute MI. Depression scores were found to worsen significantly in women from baseline to one year post-MI, while men reported an improvement at follow-up. Health-related quality of life scores were also worse in women at baseline and follow-up. The researchers say this suggests that women have more negative psychological responses post-MI, which affect their recovery.

Two-week rule for breast cancer
Potter S, Govindarajulu S, Shere M et al. BMJ 2007 Jul 13; (Epub ahead of print)
More than 90 per cent of urgent breast cancer referrals are diagnosed as benign disease, a UK study has found. Between 1999 and 2005, annual referrals to one breast centre in Bristol rose by 9 per cent; routine referrals fell by a quarter, while urgent referrals rose by 42 per cent. However, the percentage of urgent referrals diagnosed with cancer fell from 12.8 to 7.7 per cent, while cancer diagnoses among 'routine' referrals rose from 2.5 to 5.3 per cent. In 2005, more than one in four patients ultimately diagnosed with breast cancer were referred non-urgently. The researchers say that the system is failing patients and needs urgent review.

Low-fat foods may incease infertility risk
Chavarro JE, Rich-Edwards JW, Rosner B, Willett WC. Hum Reprod 2007;22:1340-7
Women trying to conceive should forget about low-fat foods, because they may increase the risk of infertility. In contrast, whole milk and ice cream can increase a woman's chances of pregnancy. A prospective study of 18,555 women aged 24-42 years found that those eating two or more servings of low-fat dairy foods daily increased their risk of anovulatory infertility by 85 per cent, compared with women who ate less than one serving per week. Women eating at least one serving of high-fat dairy food daily reduced their anovulatory infertility risk by more than a quarter, compared with those eating one or fewer high-fat portions per week.

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