New fears raised over hormone therapy cancer risk

Medical Tribune September 2009 P3

A new study of almost a million people has strengthened the link between postmenopausal hormone therapy and the risk of developing ovarian cancer.

Danish researchers reviewed registry data from 909,946 women aged 50 to 79, over an average of 8 years of follow up. They found that hormone therapy users had an incidence rate ratio of 1.38 (95 percent CI 1.26 – 1.51) for all ovarian cancers, compared to women who had never used therapy. Cancer risk was increased “regardless of the duration of use, the formulation, estrogen dose, regimen, progestin type and route of administration,” the authors wrote.

“Thus the risk of ovarian cancer is one of several factors to take into account when assessing the risks and benefits of hormone use,” they concluded.

[JAMA 2009 Jul 15;302(3):298-305]

Fears allayed over menopausal memory loss

Medical Tribune August 2009 P8

David Brill

Women who experience memory loss as they approach the menopause can be reassured that the problem is only temporary, say US researchers.

In a recent study of over 2,000 women, they found that verbal memory and processing speed appear to drop during perimenopause, but typically return to normal upon reaching postmenopause.

The findings confirm a problem which is reported by up to 60 percent of women but has been addressed by very few quantitative studies, say the authors. [Neurology 2009;72:1850-7]

Lead author of the Study of Women’s Health Across the Nation (SWAN) report, Dr. Gail Greendale, said that physicians can now use the findings to reassure concerned women and “validate their experience.”

“Women who are experiencing memory difficulties during the menopause transition often find this experience frightening. They do not know what to expect and worry that their memory will worsen over time,” said Greendale, of the David Geffen School of Medicine at the University of California, Los Angeles, US.

“The SWAN results provide women with a frame of reference … and show that the memory problems are temporary. Also, if women are having memory problems of a greater degree than that which we observed, then their physician should not ascribe the problem to menopause and should dig deeper,” she said.

The SWAN study involved 2,362 women with a mean age of 45.9. They were classified as premenopausal, perimenopausal or postmenopausal, and followed for 4 years with regular testing in domains of processing speed, verbal memory and working memory.

The decline in cognition over the menopause transition was particularly marked for processing speed: pre- and postmenopausal women showed significant improvements with repeated testing, whereas late perimenopausal women scored worse over time. A similar effect was seen for verbal memory, but there was no difference in working memory between groups.

The paper also points to cognitive benefits of early initiation of hormone therapy: women who had already begun therapy before their final menstruation scored 4 to 6 percent higher on tests than those with no prior therapy.

Estrogen has a range of effects on the brain and is thought to influence mood, higher cognitive function and motor skills. Estrogen receptor density is particularly high in the prefrontal cortex and hippocampus – hence it has been postulated that the fluctuation in estrogen levels during perimenopause could adversely influence brain function. [J Appl Physiol 2001;91:2785-801]

Only two previous longitudinal studies however have measured cognitive performance over the menopause transition, according to Greendale and colleagues. The more recent of the two, a study of 694 women from a rural community in Taiwan, found that verbal memory declined during the menopause transition. The other study found no cognitive effects of the transition on working memory or perceptual speed. [Maturitas 2006;53:447-53; Neurology 2003;61:801-6]

Fertility preservation guidelines overlooked by oncologists

Medical Tribune July 2009 P4
David Brill

The majority of US oncologists do not follow recommendations on discussing fertility preservation with cancer patients, a survey shows.

Although seventy nine percent of respondents reported broaching the subject with patients, less than 25 percent referred them to a specialist or provided educational materials.

Just 38 percent were even aware of the existence of the guidelines, issued by ASCO in 2006. [J Clin Oncol 2006 Jun 20;24(18):2917-31]

The findings could prompt the development of new training programs for physicians and nurses, said study author Dr. Gwendolyn Quinn of the H. Lee Moffitt Cancer Center and Research Institute, Miami, US.

“We send patients to get wigs before they lose their hair during chemotherapy. We give medications to prevent nausea. Discussing fertility preservation should be something else that we do early in a patient’s care, rather than waiting until infertility occurs,” she said.

The survey was mailed to 1,979 oncologists – 613 of whom completed it. Those working in gynecological oncology and hematological/medical oncology were the most comfortable with having fertility preservation conversations. Physicians’ views of fertility preservation were also a key factor: those with a favorable attitude towards preservation were nearly five times as likely to discuss the options.

The main reason given for avoiding the discussion was that patients were too ill to delay treatment. Of greater concern, however, was physicians who skipped it because they did not believe that the patient was going to survive their cancer, said Quinn.

“It’s the patient’s right. It’s their choice. They may never pursue it, and some of them can’t afford it, but just to be given that information is important, and it’s perhaps not the role of the physician to make decisions. The guidelines say all patients – they don’t specify the healthiest of patients or the ones most likely to survive,” she said.

Even those who do not survive may wish to review their options for “posthumous parenting,” she added, noting that many US couples cryopreserve embryos or sperm for this purpose before beginning treatment.

Quinn acknowledged, however, that there can be many barriers to discussing fertility preservation, including financial constraints for the patient, or a lack of physician resources in certain geographic areas.

“It’s important to bring it up very near to the time of diagnosis, but we understand that it’s an emotional time,” she said. Future training could move the emphasis towards nurses, who may be better placed to have an in-depth discussion with the patient, she added.

Dieticians call for action on overweight mothers-to-be

Medical Tribune July 2009 P16

David Brill

Overweight women should receive nutrition counseling before, during and after pregnancy, leading US dietitians have advised.

With the global obesity epidemic showing no signs of slowdown, the health of mothers and babies alike is at risk unless eating habits improve, cautions a recent joint statement from the American Dietetic Association (ADA) and the American Society of Nutrition (ASN).

Studies show that obese mothers are more likely to experience preeclampsia, gestational diabetes mellitus (GDM), gestational hypertension, postpartum anemia and cesarean delivery than women of normal weight. Their offspring, meanwhile, face an increased risk of birth defects, fetal macrosomia, childhood obesity and even perinatal death.

Ms. Ximena Jimenez, a consultant dietitian and national ADA spokesperson, said that healthcare professionals across the spectrum should work together to promote healthy eating and physical activity in women who are pregnant or planning to conceive. Physicians, for example, can play “a big role” in reinforcing the advice given by dietitians and other specialists, she said.

“A lot of the time it takes more than one type of counseling to get these women to change their lifestyle. I would encourage any healthcare professional to encourage these women to seek nutrition counseling,” she said.

“The principles are that you want them to increase whole grains and decrease refined carbohydrates like cakes, pastries and white breads. We also want them to replace saturated fat with healthy fats like omega-3 fats or fats from olive oil, canola oil or avocado, and also to increase their intake of fruits and vegetables. We also want them to be physically active,” she added.

Some 52 percent of women aged 20 to 39 in the US are overweight or obese (BMI 25 or above), according to data from the National Health and Nutrition Examination Survey of 2003-2004. Twenty-nine percent are obese (BMI 30 or above) and 8 percent are extremely obese (BMI 40 or above). Among adolescent girls aged 12 to 19, almost 32 percent are overweight or at risk of being overweight. [JAMA 2006 Apr 5;295(13):1549-55]

Despite the scale of the task, Jimenez remains optimistic that overweight women can be successfully counseled.

“I think it’s a very realistic target. There has to be promotion of healthy eating among women,” she said. “Imagine the benefits. As a society we are all going to benefit because we are going to have healthy women and healthy children.”

Jimenez highlighted studies showing the success of dietary interventions in overweight mothers, such as the Nurses’ Health Study, which found that risk of GDM was approximately halved by following a low-glycemic, high-cereal fiber diet. [Diabetes Care 2006 Oct;29(10):2223-30] The risk of preeclampsia can also be halved by taking calcium supplements, a meta-analysis of 12 studies shows. [Cochrane Database Syst Rev 2006 Jul 19;3:CD001059]

The new ADA / ASN position statement also reviews the literature on the prevalence of various pregnancy outcomes for overweight mothers and their babies. [J Am Diet Assoc 2009 May;109(5):918-27]

The risk of developing GDM, for example, is reported to double in overweight women, and increase over eightfold in the extremely obese. [Diabetes Care 2007 Aug;30(8):2070-6] Preeclampsia risk is around three times higher in pregnant women who are obese than those of normal weight. [Obstet Gynecol 2007 Feb;109:419-33]

The offspring of obese mothers are around twice as likely to have neural tube defects such as spina bifida, according to the US National Birth Defects Prevention Study. [Arch Pediatr Adolesc Med 2007 Aug;161(8):745-50] Oral clefts, hydrocephaly and cardiac abnormalities were also found to be more common in these infants than those born to normal-weight mothers.

Age no barrier to continued cervical screening

Medical Tribune June 2009 P9

David Brill

Cervical cancer screening should not stop at age 50, even in women who have had several all-clears in the past, new evidence suggests.

An analysis of national data from the Netherlands found that older women were just as likely to develop cancer after three negative smear tests as younger women.

Previous studies had found that pre-invasive disease is rare in well-screened over-50s, prompting calls for screening to be stopped at this age.

The Dutch study, however, focused instead on the incidence of full-blown cancers. It included data from 445,382 women aged 30 to 44 at the time of their third negative smear, and 218,847 women aged 45 to 54. [BMJ 2009 Apr 24;338:b1354]

After 10 years of follow-up the cumulative incidence of cancer was similarly low: 41 per 100,000 in the younger age group, and 36 per 100,000 in the older age group (P=0.48).

The findings suggest that age should not be the decisive factor for early cessation of screening in well-screened women, said lead author Dr. Matejka Rebolj. They do not, however, provide a definitive answer as to whether it will ultimately prove worthwhile to continue universal screening after three negative tests.

“We cannot really say with these data whether you should continue screening or not. However we can say that if you’re screening younger women, then in order to make your policy consistent you should continue screening women above the age of 50,” said Rebolj, a postdoctoral researcher at the University of Copenhagen, Denmark.

“The next logical step would be to do a proper cost-effectiveness analysis to determine whether this low absolute level of risk does warrant further screening. Until then we should encourage women to continue screening at the regular interval recommended in each particular country.”

Singapore oncologist Dr. Francis Chin praised the quality of the data, and said that the findings support Singapore’s policy of continuing screening up to age 69.

“This study confirms the importance of screening in the age group over 50 years old, because the risk of cervical cancer after several negative smears is similar in older versus younger patients,” said Chin, consultant radiation oncologist at the National Cancer Centre Singapore.

“The predilection of doctors has always been that screening and early detection is better than treating cancer in the later stages. These data confirm and validate this policy,” he said.

Singapore’s Health Promotion Board (HPB) agreed that the study supports the current guidelines of its CervicalScreen Singapore initiative, implemented in 2004. The program, which promotes screening every 3 years, will continue to focus on increasing its coverage of eligible women, said Dr. Shyamala Thilagaratnam, director, Healthy Ageing Division, HPB.

Several previous studies have proposed that cervical screening should stop at 50, notably a 1997 paper which found that only 1 percent of 23,440 previously screened over-50s had significant cytological abnormalities. The authors concluded that ending screening in this group could reduce anxiety and enable better allocation of resources to targeting higher-risk women. [Br J Obstet Gynaecol 1997 May;104(5):586-9]

The case against this argument, however, could be furthered strengthened by another recent paper, supporting the findings of the Dutch study. UK researchers, reviewing National Health Service screening records for 2 million women, found that two thirds of all the lesions detected in over-50s were found in women who had had previously had negative smears results. Discontinuation of screening would therefore lead to the majority of important abnormalities being missed, the researchers say. [Br J Cancer 2009 May 5; Epub ahead of print]

Singapore physician Dr. Siew Wei Fong concurred with the conclusion that screening should continue beyond the age of 50, in light of the recent evidence. She added that she does not expect any change in screening practices at the Singapore Polyclinics, where she is senior family physician.

Smokers more likely to drop oral contraceptives

Medical Tribune June 2009 P12
David Brill

Young women who smoke are more likely to stop taking oral contraceptives (OCs), a recent study suggests.

After 6 months of follow-up, only 26 percent of smokers were still taking OCs, compared to 46 percent of non-smokers (P<0.0001).

The study included 1,598 inner-city women aged under 25 – 198 of whom were smokers. After adjustment for confounding factors, smokers were 40 percent less likely to still be taking OCs (odds ratio 0.6; 95 percent CI, 0.4 – 1.0). [Contraception 2009 May;79(5):375-8]

“The take-home message is that smokers may be risk takers and thus more likely to discontinue contraceptives,” said lead author Dr. Carolyn Westhoff, professor of obstetrics and gynecology at Columbia University, New York, US.

The findings also serve as a reminder of the need to promote the right public health messages about smoking and OC use, say the researchers. Smoking while taking OCs is widely considered to be dangerous, but evidence so far is only conclusive for women over 35.

“The public health message and package labeling that birth control pills and smoking are incompatible is a bit over-simplified. While smoking is always a bad thing, the adverse interaction with OCs doesn't apply to our youngest patients,” said Westhoff. Pushing the same message to younger women could encourage them to quit OCs rather than quit smoking, she noted.

Study subjects were enrolled at three publicly funded family planning clinics. They reported smoking status at baseline, and OC continuation at 3 and 6 months. Twelve percent of the cohort were smokers.

“Whether public health messages or clinician messages about the risk of smoking and OC use are driving the excessive discontinuation rates seen in this study deserves further study,” the researchers wrote.

“In the meanwhile, these data indicate that young smokers may be a high-risk group for premature discontinuation of OCs. Clinicians need to clarify the appropriate health messages and find ways to support young smokers in avoiding pregnancy.”

The study is a secondary analysis of a previously published trial, which found that initiating OCs in the clinic, under observation, improved short-term compliance compared to a conventional, delayed start. [Obstet Gynecol 2007 Jun;109(6):1270-6]

Vaccinate the young against HPV, says Nobel Laureate

Medical Tribune May 2009 SFIII

David Brill

Countries should “seriously consider” offering widespread human papillomavirus (HPV) vaccinations, according to the Nobel Prize-winning scientist who first linked the virus to cervical cancer.

Professor Harald zur Hausen, addressing the media on a recent visit to Singapore, said that boys and girls alike would benefit from the vaccine, but stressed that it should be given prior to the onset of sexual activity.

For older women who are already sexually active, it should be a personal decision whether or not to be vaccinated, he said.

zur Hausen also rejected the argument that effective screening programs can be superior to widespread vaccination.

“I think that’s a mistake because screening and vaccination do something different,” he said. “In screening you discover lesions which need to be removed. In vaccination you prevent the lesions, and therefore you don’t [need] surgical intervention.”

Vaccination has been shown to be safe and highly effective for preventing HPV infections but opinions remain divided about who, when and how to vaccinate. Australia, for example, has approved vaccination of women aged 10 to 45, whereas the US FDA limits approval to 9 to 26 year-olds.

“It would really be something which one should seriously consider – to vaccinate everyone,” said zur Hausen, winner of the 2008 Nobel Prize in Physiology or Medicine.

“[But] let me be quite clear about it – the vaccine is really only protective in preventing the infection. If there has [already] been an infection the vaccine has no effect whatsoever.

“Up to the onset of sexual activity, yes, you can clearly say it’s worthwhile. But subsequently it’s more difficult to make a statement along those lines.”

Neither of the HPV vaccines is presently approved for use in males, but zur Hausen outlined several supporting arguments. Firstly, it would protect women from cervical cancer by reducing HPV transmission. Secondly, men themselves would gain protection from genital warts and other HPV-positive cancers, including anal and oropharyngeal cancers. Upcoming data from the first clinical studies in boys “look very promising,” he said.

zur Hausen also called for reductions in the price of HPV vaccines, which are presently “unaffordable” for parts of the developing world. This would pave the way for global vaccination programs, offering “the theoretical chance to eradicate some of these infections which lead to cervical cancer.”

Professor zur Hausen delivered the 6th Humphrey Oei Distinguished Lecture at the National Cancer Center, Singapore, and the second opening lecture at the Asian Oncology Summit 2009.

Singapore to wait and see on HPV vaccination

Medical Tribune May 2009 SFIII
David Brill

Singapore will not rush to make human papillomavirus (HPV) vaccination part of its national immunization program.

Insteady, the city-state will await the outcomes of vaccination programs in other countries before making its own decision, said Dr. Balaji Sadasivan, senior minister of state, Ministry of Foreign Affairs.

In the meantime, the nation will continue strengthening its Pap smear screening coverage. The HPV vaccine will remain available on an optional basis, giving individual parents the right to choose whether to vaccinate their daughters.

“As a country with a lower incidence of cervical cancer, the risk-benefit ratio will be lower in Singapore. We should therefore be cautious in making any national recommendation with regard to vaccination,” said Balaji at the recent Asian Oncology Summit 2009.

“If we put it in our national immunization program almost every young girl will get vaccinated. That’s a very, very major step, and sometimes … it’s not necessarily the wisest thing to be the first to try something out because you’re basically the guinea pig. It may just be safer to wait and see how other countries proceed with this.”

Balaji singled out the UK in particular as one “for us to watch,” following the September 2008 introduction of a national HPV immunization program for girls aged 12 to 13. “If it turns out to be safe to do it on a national scale then I think it would make sense for us to consider doing the same thing,” he said, adding that it would be “a few years” before any conclusions could be made.

Balaji also expressed clinical concerns about the vaccine, notably that it remains unclear whether immunity is long-lasting. It is also unknown whether other strains of HPV could become dominant if current strains are contained.

“From an ethical standpoint, there is also the issue of consent, which has to be viewed in the local context, where the community’s moral viewpoint is that offering such a vaccination program sends out the wrong message – that teenage sex is condoned by the community,” he said.

“Pap smear screening is one of the most effective ways of reducing the risk of cervical cancer, and we have pretty good coverage of about 60 to 70 percent. We should continue to build on that program and not neglect [it] because of the possibility of vaccination. That is a reasonable alternative while waiting to have better data,” he concluded.

Dr. Balaji delivered the opening address at the Asian Oncology Summit 2009, and spoke directly with the media.

Folic acid-vitamin combo cuts AMD risk in women

Medical Tribune May 2009 P11
David Brill

Taking folic acid with vitamins B6 and B12 could help to prevent age-related macular degeneration (AMD) in women at high risk of cardiovascular disease (CVD).

Women who took daily supplements for 7 years reduced their relative risk of AMD by around a third, a recent trial reported.

The analysis included 5,205 women aged over 40 who had a history of CVD and a minimum of three CVD risk factors but no AMD at baseline. There were 55 cases of AMD in the treatment group and 82 in the placebo group at trial’s end. [Arch Intern Med 2009 Feb 23;169:335-41]

Lead author Dr. William Christen, an associate professor at Brigham and Women’s Hospital and Harvard Medical School, US, said that the intervention is safe and inexpensive and could, theoretically, be applied on a wide scale. However, he stressed the need for more research before making any specific recommendations.

“This is the first trial to suggest a possible benefit so I think it’s important at this point to corroborate the findings in other populations,” he said.

“Other than avoiding cigarette smoking we have no means to prevent the early stages of AMD so these findings, if they’re corroborated … will be particularly important from a public health perspective.”

AMD is the leading cause of blindness in European and US over-60s and is thought to be on the rise in Asia.

The Singapore Malay Eye Study found that in its early stages the condition affects 3.5 percent of Malays aged 40 to 80 – a comparable figure to that reported in the Australia. The prevalence of late-stage AMD among Malays was 0.34 percent. [Ophthalmology 2008;115(10):1735-41]

For elderly Singaporeans in general the prevalence of AMD could be as high as 27 percent, according to a study of 574 over-60s. Awareness of the condition however seems to be low – for every AMD patient with a confirmed diagnosis there were 154 who did not know they had the condition. [Singapore Med J 1997;38(4):149-55]

Vitamins are not currently recommended for primary AMD prevention but have been shown to delay progression in those who already have intermediate-stage disease. A combination of high-dose antioxidants (vitamins C, E and beta carotene) and zinc reduced the odds of developing advanced AMD by 28 percent, as compared to placebo, in a trial of 3,640 patients with an average of 6.3 years of follow up. [Arch Ophthalmol 2001 Oct;119(10):1417-36]

Christen et al. randomized participants to placebo or a regimen of 2.5 mg/day folic acid, 50 mg/day vitamin B6 and 1 mg/day vitamin B12 – higher dosages than typically given over the counter. The relative risk in the treatment group was 0.66 for AMD (95 percent CI 0.47-0.93; P=0.02) and 0.59 for visually significant AMD (95 percent CI 0.36-0.95; P=0.03). Mean follow-up was 7.3 years.

The study could also provide important new insights into the much-debated role of homocysteine in vascular disease. The marker has been strongly linked to atherosclerosis, CVD and AMD, but trials have yet to show that homocysteine-lowering therapies, notably folic acid and B vitamins, significantly improve outcomes.

“If these findings are real for AMD then one possible explanation would be … that there may be a difference between small vessel and large vessel disease in the response to homocysteine lowering. At this point we can only speculate,” said Christen.

Caffeine in pregnancy restricts fetal growth, study warns

Medical Tribune February 2009 P6

David Brill

Consuming caffeine during pregnancy can significantly increase the risk of fetal growth restriction, according to one of the largest and most comprehensive studies to weigh in on a notoriously inconclusive debate.

Pregnant women are typically advised to reduce their caffeine intake as a sensible precaution, but research findings have been inconsistent and a definitive link to birth defects has remained elusive.

The new study, which claims to be the first to give a “true picture” of caffeine intake in pregnancy, found that the association was significant at all levels of consumption and continued throughout pregnancy.

The size of the effect is similar to that seen for alcohol consumption, the UK researchers reported in the British Medical Journal. [2008 337:a2332] They recruited 2,635 low-risk women at 8 to 12 weeks of pregnancy and followed them up until birth.

An intake of more than 200 mg/day of caffeine was linked to an average birth weight reduction of up to 70g (P = 0.004) and increased the odds ratio for having a growth restricted baby to 1.5, as compared to an intake of below 100 mg/day (P = 0.02).

Dr. Shephali Tagore, an associate consultant in the department of maternal fetal medicine at KK Women’s and Children’s Hospital, Singapore, said the study confirms that the advice to reduce caffeine intake before and during pregnancy is appropriate.

“While previous studies have suggested a risk, this study group has objectively quantified caffeine from all known sources. This is a major strength of the study. They have found a dose-response relationship, showing that increasing caffeine intake was associated with increasing risk of fetal growth restriction,” she said.

Tagore added, however, that it is difficult to draw firm conclusions from the paper since there was no control group of women who did not consume any caffeine during pregnancy,

Previous studies have overestimated the impact of tea and coffee and relied too heavily on retrospective recall of caffeine consumption, according to the authors, who took a more thorough approach by using a comprehensive questionnaire which was validated against food diaries and saliva samples.

They found that only 14 percent of the women’s caffeine intake came from coffee. Tea was the major source, comprising 62 percent of intake, with cola drinks and chocolate contributing 12 and 8 percent respectively.

“We believe that, for the first time, this reflects a true picture of total caffeine intake by women during pregnancy,” they wrote. “Our findings emphasize the weakness of studies where caffeine intake was equated to that of coffee alone.”

Caffeine is absorbed rapidly and can cross the placenta freely. The main enzyme for breaking down the compound, however, is not found in the placenta or fetus so exposure depends largely on maternal metabolism.

To investigate whether individual metabolic differences affected fetal growth the researchers also measured the half-life of caffeine in the women’s saliva. The association with fetal growth restriction was strongest in women who had the fastest caffeine clearance but this result did not reach significance (P=0.06).

Caffeine consumption has also been linked to miscarriage. A study published last year found that an intake above 200mg/day more than doubled the risk. [Am J Obstet Gynecol 2008 Mar;198(3):279.e1-8]

Another recent study found that injecting the caffeine equivalent of two cups of coffee into pregnant mice decreased cardiac function and stunted development of the cardiac ventricles in their offspring. [FASEB J 2008 Dec 16 Epub ahead of print]

Simple strategy effective in postpartum depression screening

Medical Tribune February 2009 P16
David Brill

Combining two existing screening tools could be a straightforward, time-saving and effective way to detect postpartum depression (PPD) in primary care, US research has shown.

The first screening stage, comprising two simple yes/no questions, was 100 percent sensitive at detecting PPD, according to the Annals of Family Medicine study. [2009; 7:63-70]

Patients with a positive result on the two-question screen should then progress onto the nine-item Patient Questionnaire (PHQ-9), say the University of Minnesota researchers, who report that this second stage was 92 percent specific. They tested the two-tiered strategy in 506 women who brought their newborn infants for well-child visits at pediatric and family medicine clinics over the course of 9 months.

The screening tools have already been incorporated into routine practice at several Minnesota clinics and are soon to be implemented in three large hospitals, according to Dr. Dwenda Gjerdingen, who led the study.

“We find them easy to administer, patients find them easy to complete, and they give us a good sense of where the patient is at in terms of their mental health,” she said.

“You want your initial screen to be highly sensitive, which this one is: the two-question screen does not miss depressed patients. Then the PHQ-9 is a very specific test so when depressed people complete it and it turns out to be positive, it is likely to be a true positive and not a false positive.”

The two-question screen focuses on the main symptoms of depression: diminished mood and loss of pleasure in activities.

Despite the common nature of PPD – the condition affects around 22 percent of new mothers and is the most common complication of childbirth – less than half of mothers are presently being screened, the authors wrote. The condition not only affects the mother’s wellbeing but can also harm the cognitive development of the infant. [Arch Womens Ment Health 2003 Nov;6(4):263-74]

The results of the new strategy were validated against the Structured Clinical Interview from the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV. Forty-five (8.9 percent) of the women were found to have major depression.

Gjerdingen noted that the PHQ-9 still missed a few depressed patients, so suspicion should be retained in those who achieve a negative result having scored positively on the initial two-question screen. These women should be advised to see their doctor if they experience a dip in mood, she said.

Both the two-question screen and the PHQ-9 are already used in general depression but had yet to be validated in PPD. Other potential screening options for PPD are available but typically take longer to complete, Gjerdingen said.

Asian women less aware of long-term risks after gestational diabetes

Medical Tribune November 2008 P6
David Brill

Asian-born women who experience gestational diabetes mellitus (GDM) during pregnancy may be less acutely aware of their subsequent risk of developing diabetes, according to an Australian study.

A large postal survey of women with a history of GDM revealed that 92.3 percent knew that the condition predisposes to later development of type 2 diabetes.

Less than 30 percent of the 1,176 respondents, however, considered themselves to be at high or very high risk.

Risk perception was particularly low among Asian-born women, with just 15.5 percent believing themselves to be at high risk – a significantly lower proportion than Australian-born women (P=0.013).

“This is of some concern considering that evidence suggests that this may be in fact the highest-risk group,” said Ms. Melinda Morrison, a pediatric diabetes dietician who presented the study findings.

“We’re talking about Asian women in Australia so it may be down to how the messages are getting through, as well as possible cultural differences,” she said.

She added, however, that the data have yet to be fully analyzed so it is difficult to speculate on possible explanations for the finding at this point.

American Diabetes Association guidelines identify Asians as a high-risk population for GDM. [Diabetes Care 2000 Jan;23 Suppl 1:S77-9] A study of 2,797 Asian pregnancies found that the incidence of GDM was 10.6 percent for Vietnamese women, 9.2 percent for Chinese women and 8.6 percent for Filipino women. [Diabetes Care 2001 May;24(5):955-6]

GDM affects between 3 and 8 percent of pregnancies in Australia, according to Morrison, who is based at the New South Wales section of the charity Diabetes Australia.

With these women at substantially higher risk for developing diabetes this group represents an important target for disease prevention through lifestyle modification, she said.

“Often these women really only have contact with their GP after pregnancy and are no longer in the system of diabetes care necessarily, so it is over to the GP to help them make those changes and raise that awareness,” she said.

Hormone patch improves schizophrenia symptoms

Medical Tribune October 2008 P5
David Brill

Estrogen – often blamed when women behave irrationally or emotionally – could in fact turn out to be an effective treatment for those with mental illness.

Researchers from Australia have shown that estradiol, delivered in the form of skin patches, can alleviate psychotic symptoms in schizophrenic women of childbearing age.

In a randomized trial with 102 participants, those given the patches alongside their regular medications showed significant reductions in both positive and general psychopathological symptoms compared to those on placebo. In many cases the effects were rapid, with hallucinations improving within 2 or 3 days of starting treatment. Improvements in memory and the ability to think clearly about complex issues were also commonly reported following treatment.

Professor Jayashri Kulkarni, who led the study, said that the benefits of hormone therapy might extend to other mental illnesses such as postnatal depression.

She added that further research into the role of estrogen for treating schizophrenia is still needed, but suggested that the hormone could already be used for certain women who have reached a plateau with antipsychotic drugs.

“Even as the data stand there is enough to suggest that for women who have tried standard treatments and haven’t made a brilliant recovery, it is possible and useful for clinicians in everyday practice to think about using a hormonal approach,” said Kulkarni, who is director of the Alfred Psychiatry Research Centre at The Alfred and Monash University in Melbourne. She added, however, that close monitoring for the long-term side effects of estrogen therapy would be needed in such cases.

Participants in the trial were assigned in a double-blind fashion to receive transdermal patches – containing either placebo or 100 μg estradiol – alongside their regular antipsychotics. [Arch Gen Psychiatry 2008 Aug;65(8):955-60]

The trial lasted for 28 days. No notable differences in adverse effects were recorded between the estradiol and placebo groups. Outcomes were assessed using the Positive and Negative Syndrome Scale (PANSS).

The mechanisms for the estrogen effect are unclear, but the researchers suggest that the hormone could rapidly enhance blood flow to the brain and improve cerebral glucose metabolism. Alternatively the effect may be mediated through modulation of the dopamine or serotonin neurotransmitter systems, or through the remodeling of neural pathways, they wrote.

“The other thing that was really interesting was that we didn’t have much problem recruiting for the study,” Kulkarni added.

“Many women patients have intuitively noted a change in their body menstrual cycle and associated that with changes in their mental state, so when we offered something
that seemed to fit with that sort of intuition it was really taken up very well by the patients,” she said.

The benefits of combining women’s and children’s healthcare

Medical Tribune August 2008 P2-3

Associate Professor Tay Eng-Hseon reflects on the advantages offered by centers such as KK Women’s and Children’s Hospital, Singapore

A mother and her child share a special relationship that begins even before birth. Having a combined hospital to attend to both of their needs provides continuity of care for the new family, and can help to develop and strengthen this bond. The ability to deliver specialist pediatric care on-site removes the potential need to separate a mother from her newborn baby within moments of delivery, enabling the family unit to remain intact within the same hospital. And as the child continues to grow, mothers can enjoy the convenience of having their own health needs attended to at the same place as those of their children. Joint visits such as this can help to reinforce the social support network and cohesion within a family.

Combining women’s and children’s healthcare is also beneficial from a medical standpoint as well as a social one. Delivery of crossover services becomes quicker, easier and more efficient within a single site. Many times at KK Women’s and Children’s Hospital (KKH) we have witnessed a neonatologist supervise the birth of a child before handing over to the pediatric urologist or cardiac surgeon, thereby allowing treatment to continue promptly without interruption or the need for further travel, with the associated delays and costs that this entails.

KKH treats a more specific section of the community than a general hospital, and this has proved to be beneficial from a practical point of view as well. With the field of potential patients narrowed we can reduce the range of equipment that we need, keep a more specific selection of drugs at the pharmacy, and standardize the hospital wards to a greater degree. We can also provide more specialized training for physicians, who can gain hands-on experience of a wide spectrum of conditions within their discipline.

Specializing in this way also has benefits for research, enabling a greater focus which in turn improves the ease of execution. Consequently KKH has participated in several large-scale international trials, including those of the rotavirus and cervical cancer vaccines. Entry into trials such as these can be competitive, but the ability to accrue large numbers of subjects quickly and easily has enabled our hospital to stay ahead of the competition. Furthermore we can provide a different patient perspective to centers in Europe and the US, and for these particular studies KKH was the main provider of Asian subjects.

Until 1997, pediatric hospital care in Singapore was spread between Tan Tock Seng, Singapore General and National University Hospitals. The visionary decision to consolidate these services into KKH – previously a dedicated women’s hospital – has enabled the hospital to expand into new areas and provide further dimensions of care to its patients. Examples include the development of highly specialized breast surgery and plastic and reconstructive surgery teams, and the opening of the Women Wellness Centre and Department of Child Development. Promoting mental health within the same vicinity as physical health also has the added benefit of reducing the stigma that can be associated with conventional psychiatric settings.

In a large specialist center such as KKH, the progression to higher-level services is a natural one, and it would not be surprising to see the private sector develop along these lines in future. High-end secondary and tertiary care such as this can only be feasible when there is access to a high volume of primary care patients, however, otherwise the demand will not match the capacity for supply and an expensive excess will develop.

In Singapore, patients from all corners of the country can reach the hospital within 30 minutes, making the concentration of care into one specialist centre very feasible. By virtue of its size and position within a dense population, KKH delivers a third of the 38,000-odd babies born each year in Singapore and provides care for around 80 percent of the country’s children. This model of centralized combined healthcare might not be feasible in all countries, however, and smaller hospitals in more sparsely-populated areas may not be able to match the volume of patients needed to sustain a dedicated center.

By focusing and centralizing our services we have been able to enhance our international reputation and provide regional leadership, and over the years we have attracted many foreign doctors on training fellowships. Other countries have begun looking into our model of hospital structure, and there has been a lot of interest from China in particular. For now women’s and children’s hospitals remain a rarity within Asia but, as KKH demonstrates, this system can provide many important benefits to both doctors and patients at all levels of care.

Heel ultrasound predicts osteoporotic fracture risk

Medical Tribune August 2008 P5
David Brill

A simple formula combining clinical information with quantitative ultrasound data from the heel can be used to predict whether a woman is at risk for osteoporotic fractures, a study has shown.

The prediction rule, which assigns patients a risk score from 0 to 14, was tested in 6,174 Swiss women aged 70 to 85 who were followed up for 2.8 years.

Rates of osteoporotic fracture were 6.1 percent among women defined as high-risk and 1.8 for those defined as low-risk, when using a cut-off score of 4.5. The sensitivity of the formula using this score was 90 percent.

“The whole idea of this study was to end up with a tool that can be used by primary care physicians on a daily basis,” said Dr. Idris Guessous, lead author of the study which was published in Radiology.

Ultrasound is inexpensive and portable, he added, and could be used as a diagnostic screening tool in countries where costly bone mineral density (BMD) scans are not available. Resource-permitting, the two modalities could be used in combination for select high-risk women he said.

Dr. Lau Tang Ching – consultant rheumatologist at Tan Tock Seng Hospital, Singapore – said that ultrasound could be useful for assessing nursing home patients who would have difficulty visiting hospital for a BMD scan.

He added, however, that he would like to have seen the authors report the continuous score spectrum for fracture risk prediction, rather than using the single cut-off point of 4.5.

“It would also be good if the test characteristics of the ultrasound machine were compared with dual X-ray absorptiometry BMD or with other well established predictors of low BMD such as the Osteoporosis Self-Assessment Test,” said Lau.

The researchers used a quantitative ultrasound device which requires an operator to position the subject’s foot in a water bath. The measurement procedure is otherwise automatic.

“What is really specific to this study is the way that clinical risk factors – history of fractures or recent fall – are combined with this ultrasound technique, so there are two domains that are included in the score,” said Guessous, who is a senior research fellow at Lausanne University Hospital in Switzerland.

“I stress this point because this score may not only highlight the quality of the bone itself, which is a major risk factor for fractures, but it also highlights the risk of fall for a woman.

“Depending on which factors the woman is at risk for you may better target your intervention, so eventually women who are at more risk of falling than having a bad quality of bone may end up having other interventions like hip protectors or rebalancing techniques, than just receiving bisphosphonate drugs,” he said.

Diagnosing and managing osteoporosis in primary care

Medical Tribune August 2008 P15-16

Osteoporosis affects around a third of women aged 60 – 70 and two thirds of those aged 80 and above. The condition also affects men – approximately one in five of whom will suffer an osteoporosis-related fracture above the age of 50. Osteoporosis carries a significant burden in terms of hospitalization for fractures, and patients will typically experience increased morbidity, disability, and a reduction in independence.

Diagnosis

Osteoporosis is a silent epidemic, and overt signs are usually absent until a patient presents with a fracture. This is likely to be a fragility fracture caused by relatively low trauma – a sign that the bones have become weakened. Compression fractures of the vertebrae are a common presentation, while other types include Colles’ fractures of the wrist and hip fractures, both of which typically result from a fall.

There are several risk factors for osteoporosis that general practitioners (GPs) should be aware of, such as increasing age, frailty, a personal history of fractures and a family history of fractures (particularly on the maternal side). Loss of height is also common among patients, and suggests that the vertebrae are collapsing. Back pain may also be present – often signifying that the patient has an undiagnosed compression fracture.

It should also be noted that osteoporosis in men tends to have a later age of onset than in women. Consequently mortality from fractures is twice as high for men, so it is important that GPs retain a high suspicion for osteoporosis among their elderly male patients.

GPs can also encourage their elderly patients to use the Osteoporosis Self-Assessment Tool for Asians, which is applicable for post-menopausal women of Asian descent. This can help to identify patients at high risk, who can then visit their doctor for screening and further assessment.

The gold standard for diagnosis of osteoporosis is a bone mineral density (BMD) scan using dual energy x-ray absorptiometry, with osteoporosis defined as a T-score of minus 2.5 or lower. In the absence of any other cause, a fragility fracture can also be considered as a diagnosis for osteoporosis. Patients should also receive the relevant x-rays to fully document their fractures. It can be challenging for GPs to pinpoint osteoporosis in patients who have not experienced a fracture, as some patients might find the cost of the tests prohibitive. Access to BMD scanners can sometimes be problematic

Practice Guidelines

The Ministry of Health (MOH) in Singapore is currently revising its guidelines for osteoporosis, which were last published in 2002. The new version is expected to be available later this year. The Academy of Medicine of Malaysia also has its own guidelines for osteoporosis, the second edition of which was released in 2002.

Various guidelines and recommendations are also available from the International Osteoporosis Foundation (IOF) website, including IOF-endorsed guidelines published in 2008 by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). This comprehensive 30-page document covers the diagnosis and management of the condition in postmenopausal women.

Recommendations and other helpful documents for the secondary prevention of osteoporosis are available from the National Institute for Health and Clinical Excellence (NICE), UK.

Treatment

There are many factors to consider when treating osteoporosis, and it is important to decide carefully on an appropriate strategy for each patient before proceeding with treatment.
Drug treatments are available but the cumulative costs can be formidable. The first decision physicians should take after making a definite diagnosis of osteoporosis, therefore, is whether or not to treat the patient. This decision should be based on the patient’s 10-year fracture risk, which can be calculated using IOF guidelines. A 65-year old at low fracture risk, for example, might not warrant the same treatment approach as a high-risk 85-year-old. In some cases it may be best to postpone treatment following diagnosis, monitor the patient closely and review the decision at a later stage.

Before initiating drug therapy it is important to obtain a BMD scan. This will provide a baseline value for comparisons, so that the long-term efficacy of therapy can be monitored.

Bisphosphonates, such as alendronate and risedronate, are the first-line therapy for patients who do merit drug treatment. Doctors should make their patients aware that these drugs must be taken according to certain instructions. Tablets should be taken on an empty stomach first thing in the morning, and the patient should refrain from eating for an hour afterwards or consuming any caffeine-containing drinks or milk products in this time. Failure to do so can render the tablet ineffective – which may be an explanation in cases where BMD is not improving. Elderly patients may also forget to take the drugs, or take them but forget that they have done so and lie down shortly after, which can cause painful esophagitis.

Other drug treatments include strontium ranelate, raloxifene and parathyroid hormone injections (such as teriparatide).. Annual injections of zoledronic acid, a form of bisphosphonate, have also been shown to reduce the risk of fractures and the data in support of this option are promising. The injection can be expensive, however, and some patients might prefer treatments that spread the cost out over the year.

GPs should prescribe calcium supplements for patients who are deficient, which can be a common problem in Asian countries where dairy consumption is low. The recommended intake at different ages can be found in the guidelines. Boosting calcium levels can also serve as a prevention strategy, and GPs should also encourage the use of supplements in non-osteoporotic elderly patients who are at high risk.

Lifestyle management is also a key aspect of treating osteoporosis in the primary care setting. Ill-health can lower general nutrition, leading to further reductions in calcium levels, so a healthy diet should be promoted for all cases. Osteoporotic patients should be advised not to drink or smoke, and should also be encouraged to perform weight-bearing exercises at least three times per week for 50 – 60 minutes at a time in order to improve strength and co-ordination and reduce bone loss.

Disease management tools

Elderly patients living in the community have a roughly 30 percent chance of falling in a year, and fall prevention strategies are an important tool for reducing the risk of fractures among those with osteoporosis.

Falls typically result from a combination of several underlying causes. Risk factors such as poor gait, eyesight, and neurological comorbidities should be addressed where possible, which may require collaboration between different medical disciplines. Psychologically-altering medications such as antipsychotics and sleeping tablets can also increase the risk of falls, and may need to be adjusted accordingly.

Physicians may also need to consult with occupational therapists and physiotherapists, and in some cases might choose to encourage patients to make modifications to their home environment. Suggestions can include improving lighting, anchoring carpets and rugs, securing loose wires and applying non-slip mats to stairs and bathroom floors.

Further information on osteoporosis and home care solutions can usually be obtained from specialist centers and clinics, and GPs should refer their patients onwards for further advice and treatment where appropriate.

Conclusion

Managing osteoporosis in the primary care setting begins with an accurate diagnosis. GPs should remain vigilant for patients who have a history of fragility fractures or falls, and remember that men are also at risk for the condition. Once osteoporosis is identified, doctors should choose carefully from the range of available treatment options and select the strategy that is best suited to the patient.

Oral estrogen linked to venous thromboembolism

Medical Tribune July 2008 P3

Taking oral estrogen more than doubles the risk of venous thromboembolism (VT), according to a meta-analysis comprised of nine randomized controlled trials and eight observational studies.

The odds ratio for developing a clot among
current users of oral therapy was 2.5 compared
to non-users. This risk was highest in the first year of treatment, during which the odds ratio for developing VT was four. Conversely there was no significant elevated risk associated with estrogen given by transdermal patch.

The authors concluded that using this method of delivery could improve the safety and benefits of hormone replacement therapy. [BMJ 2008 May 31;336(7655):1227-31]

Breast cancer recurrence stressful for docs and patients alike

Medical Tribune July 2008 P4
David Brill

Telling a patient that her breast cancer has returned is traumatic for doctors too, according to a Singapore survey.

Nineteen out of 20 physicians interviewed said that breaking this news was harder than delivering the initial diagnosis of cancer, while half described this as the most stressful part of their job.

The study, designed to explore patient-doctor relationships, also revealed that trust between the two parties can be eroded when breast cancer recurs.

“Patients start asking themselves what’s gone wrong: ‘I trusted this doctor, why has it recurred?’” said Dr. Wee Siew Bock, a consultant breast surgeon at Mount Elizabeth Medical Centre, Singapore, who participated in the survey.

“Almost one in three doctors feels that when [recurrence] happens the patient will lose a bit of
trust in them. And I think that doctors in general see it more like an issue of failure – not because you have failed to treat the patient adequately but because you have not been able to meet the expectations of the patient, which is cancer-free survival after the first episode,” said Wee.

The patient arm of the survey comprised 68 Singapore residents who were assessed by questionnaire. The physician group – made up of nine breast cancer surgeons and 11 oncologists – was interviewed face-to-face.

The study also found that while 84 percent of patients said that they trusted their doctor to
recommend the best available treatment, 79 percent admitted to wishing that they had been given a more detailed explanation of why that treatment was chosen.

These findings underscore the need to empathize with patients when breaking the news of a recurrence, according to Wee, who presented the results at the recent inaugural Breast Cancer Survivors’ Conference.

“I think that being able to make the patient understand her condition better means that you
are likely to get a more engaged patient when it comes to treatment. And a patient who is more
engaged is likely to be more positive and generally able to handle and cope with their illness a lot
better,” he said.

Wee also advised doctors to consider the importance of a patient’s support network, and to try
to encourage family members or friends to accompany the patient for consultations.

“It’s exceptionally traumatic if the patient just breaks down and falls apart in front of you and there’s nobody to support them, because at the end of the day you’re still the doctor … you have been delivering good news all along, now you tell her the bad news. I don’t think she will turn to you for support,” he concluded.

The survey was jointly commissioned by the Breast Cancer Foundation and AstraZeneca Oncology, and was conducted by German market research company, GfK.


Tips for communicating bad news to patients

Dr. Wee Siew Bock, consultant breast surgeon at Mount Elizabeth Medical Centre, Singapore, offers tips on breaking bad news to patients.

1. Be patient with your patients: “The most important thing is to sit down and listen … giving the patient time to express her fears and concerns will actually go a long way in helping you communicate better.”

2. Speak the same language: “One of the things that we must try to do is use more lay terms. Sometimes even using the dialects or languages that the patient is conversant in helps a lot.”

3. Be creative: “Sometimes I feel that using little analogies is very useful. It helps the patient … grasp the situation a bit better.”

4. Wait for the right moment: “It might be easier to get the message across with another relative of the patient around. Usually this happens with older women: if you have the younger relatives around, they can explain it better.”

5. Do your research: “I find it may be useful to just review the patient’s medical history: how she was when you first diagnosed her a few years ago, who came with her, how she coped – just to try to refresh how it was that she handled that situation. That gives you an additional dimension to how to break this bad news to that patient.”

Mixed fortunes for ultrasound breast cancer screening

Medical Tribune July 2008 SFIV
David Brill

Adding ultrasound to standard mammography for breast screening will identify more cancers but also lead to more false alarms, according to research published in the Journal of the American Medical Association.

The study, conducted by the American College of Radiology Imaging Network, found that a combined protocol would yield an extra 4.2 cancers for every 1,000 women screened compared to mammography alone (95 percent confidence interval 1.1 – 7.2; P=0.003). Combining ultrasound with mammography, however, increased the false positive rate from 4.4 percent to 10.4 percent. [JAMA 2008 May 14;299(18):2151-63]

Dr. James Khoo, head of the department of oncologic imaging at the National Cancer Centre Singapore, said that this increase was a concern.

“From mammography alone you would be doing a certain number of biopsies, but if you add ultrasound the number of biopsies would increase significantly and the vast majority would be benign results,” he said.

Khoo added that being recalled for extra tests is “a very fearful experience” for most women, and that feelings of anxiety can persist for a long time even once a lesion is identified as benign.

The study analysis comprised 2,637 women at high risk for breast cancer, who were followed up for 12 months. Of these 275 were recommended for an unnecessary biopsy after combined screening, compared to 116 who were screened with mammography alone.

Although combined screening increased the diagnostic yield in the study it did not detect all cancers: eight women out of 40 who were ultimately diagnosed with cancer had lesions that were not detected on either modality.

Previous research suggested that women at high risk for breast cancer should be monitored using mammography and magnetic resonance imaging (MRI). [J Clin Oncol 2005 Nov 20;23(33):8469-76]

Although unlikely to replace MRI in these patients, ultrasound could be used in addition or as an alternative when MRI is contraindicated, said Khoo.

Ultrasound is well tolerated, relatively inexpensive and widely available, and has the potential to detect small node-negative cancers which can be missed by mammography. However the technology is hindered by high inter-observer variability and a low sensitivity for detecting microcalcifications, such as those seen in ductal carcinoma in situ.

In an accompanying comment in the journal, Christiane Kuhl from the University of Bonn in Germany wrote that: “Individualized screening schemes tailored to the individual risk and to the personal preferences of a woman may be the way to consider how to screen for breast cancer.

“Whether in the long run, ultrasound or breast MRI will be more appropriate for this purpose remains to be seen,” she concluded