21 February, 2012
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09 June, 2011
Predicting pre-eclampsia
Pre-eclampsia remains unpredictable, despite numerous biochemical and biophysical efforts to provide pointers. Working on history taking may prove of some value so North et al (BMJ 2011;342:d1875) embarked on an international study of over 3000 healthy nulliparous women which screened for pregnancy endpoints (the SCOPE study).
The women were interviewed at the start of the second trimester, routine biometry and Doppler studies were carried out around 20 weeks and the later development of pre-eclampsia tracked. It turned out that 5% did show signs and symptoms of pre-eclampsia with the following points on history indicating an increased risk: young maternal age, higher mean arterial blood pressure, raised BMI, family history of pre-eclampsia, family history of coronary heart disease, the woman having a low birth weight, vaginal bleeding for at least 5 days during early pregnancy or a duration of the sexual relationship of six months or less. The only protective predictor was a previous miscarriage of at least 10 weeks gestation with the same partner.
Adding the ultrasonic data did not improve the SCOPE prediction tool which raises the predictability of history taking to about 10%. Maybe adding the biochemical markers will increase the value of this interesting but inconclusive line of investigation.
The women were interviewed at the start of the second trimester, routine biometry and Doppler studies were carried out around 20 weeks and the later development of pre-eclampsia tracked. It turned out that 5% did show signs and symptoms of pre-eclampsia with the following points on history indicating an increased risk: young maternal age, higher mean arterial blood pressure, raised BMI, family history of pre-eclampsia, family history of coronary heart disease, the woman having a low birth weight, vaginal bleeding for at least 5 days during early pregnancy or a duration of the sexual relationship of six months or less. The only protective predictor was a previous miscarriage of at least 10 weeks gestation with the same partner.
Adding the ultrasonic data did not improve the SCOPE prediction tool which raises the predictability of history taking to about 10%. Maybe adding the biochemical markers will increase the value of this interesting but inconclusive line of investigation.
04 April, 2011
Nifedipine & preterm labour
The management of preterm labour involves the acute suppression of uterine contractions. By inhibiting the end-organ response it is presumed the initial stimulus will not remain operative or the incident producing it has passed. It is a conveniently uninvestigated aspect of preterm labour research – so are randomized trials using placebo controls which are scarce and nifedipine has never been subjected to this gold-standard form of investigation (Caritis AJOG 2011;204:95-6).
Most trials of uterine activity suppression test one drug against another and look at relative efficacy and side-effects rather than neonatal outcomes. However in the present ethical climate it may be that comparative efficiency is the best that can be hoped for and the best evidence comes from a meta-analysis by Conde-Anudelo et al (AJOG 2011;204:134 e 1-20).
Their work shows nifedipine to be superior to beta-adrenergics and magnesium sulphate for tocolysis of women in preterm labour, so if a decision is made on clinical grounds to suppress the myometrium then there is guidance in favour of nifedipine for the person in charge of the case.
Most trials of uterine activity suppression test one drug against another and look at relative efficacy and side-effects rather than neonatal outcomes. However in the present ethical climate it may be that comparative efficiency is the best that can be hoped for and the best evidence comes from a meta-analysis by Conde-Anudelo et al (AJOG 2011;204:134 e 1-20).
Their work shows nifedipine to be superior to beta-adrenergics and magnesium sulphate for tocolysis of women in preterm labour, so if a decision is made on clinical grounds to suppress the myometrium then there is guidance in favour of nifedipine for the person in charge of the case.
Hot flush treatment
There are limited non-hormonal treatments for women seeking relief from hot flushes. Peri- and postmenopausal women may not wish to take estrogens and selective serotonin reuptake inhibitors (SSRIs) offer a reasonably good option for decreasing the frequency, severity or bothersome effects of hot flushes.
A report by Freeman et al (JAMA 2011;305:267-74) indicates that the SSRI escitalopram is effective in controlling flushes in healthy menopausal women.
As usual in controlled trials for flushes about one third of volunteers had a 50% reduction in symptoms on the placebo but more than half had a similar beneficial effect from 10 – 20 mg per day of escitalopram over 8 weeks. The active substance had few side effects and it was convincing that 3 weeks after the trial ended those who took the escitalopram had the return of more hot flushes than those “coming off” the placebo.
For the record the participants had at least 4 flushes or night sweats a day before treatment and there were no racial differences between African-American and white women who were equally represented in the sample population. Estrogens are the treatment of choice for menopausal symptoms but escitalopram appears to be an option in reducing the frequency, severity and bother of menopausal vasomotor symptoms.
A report by Freeman et al (JAMA 2011;305:267-74) indicates that the SSRI escitalopram is effective in controlling flushes in healthy menopausal women.
As usual in controlled trials for flushes about one third of volunteers had a 50% reduction in symptoms on the placebo but more than half had a similar beneficial effect from 10 – 20 mg per day of escitalopram over 8 weeks. The active substance had few side effects and it was convincing that 3 weeks after the trial ended those who took the escitalopram had the return of more hot flushes than those “coming off” the placebo.
For the record the participants had at least 4 flushes or night sweats a day before treatment and there were no racial differences between African-American and white women who were equally represented in the sample population. Estrogens are the treatment of choice for menopausal symptoms but escitalopram appears to be an option in reducing the frequency, severity and bother of menopausal vasomotor symptoms.
04 January, 2010
Treatment of depression in pregnancy
Women during their childbearing years are susceptible to depression. In developed countries more than 10% of women take antidepressants during their reproductive life - most commonly selective serotonin reuptake inhibitors (SSRIs). The safety of these drugs in pregnancy is critical and a study by Pedersen et al from Denmark adds to prescribing principles (BMJ 2009; 339: b3569).
The researchers correlated congenital malformations with maternal antidepressant use in half a million children and found no overall increased risk. However the drugs were associated with septal defects of the heart. This was found for all SSRIs, especially when combinations were used or different drugs were prescribed serially. The absolute increase was from a background rate of 0.5% to 0.9% for single medications and 2% for multiple prescriptions.
This risk must be weighed against the dangers of not treating major depression or using psychotherapy. The American College of O&G has stated that women can continue or start SSRI antidepressants in pregnancy but should be appraised of the risks, however small (Chambers BMJ 2009; 339: b3525).
The researchers correlated congenital malformations with maternal antidepressant use in half a million children and found no overall increased risk. However the drugs were associated with septal defects of the heart. This was found for all SSRIs, especially when combinations were used or different drugs were prescribed serially. The absolute increase was from a background rate of 0.5% to 0.9% for single medications and 2% for multiple prescriptions.
This risk must be weighed against the dangers of not treating major depression or using psychotherapy. The American College of O&G has stated that women can continue or start SSRI antidepressants in pregnancy but should be appraised of the risks, however small (Chambers BMJ 2009; 339: b3525).
Preterm infants and infection
Preterm infants are at risk of a host of morbidities. Most obviously their immature respiratory and metabolic systems place them at a disadvantage while their fragile cardiovascular anatomy and physiology makes them prone to cerebral and gastro-intestinal incidents.
Also linked to poor outcomes, especially in very low-birth-weight infants of less than 1500g, is infection. About 20% of these babies will develop serious infections while in intensive care units. Nosocomial infections occurring after 3 days of age carry major risks of mortality or impaired neuro-development and the smallest are the most vulnerable. There are enormous short-term costs of hospital treatment plus the long-term financial implications of looking after mentally compromised survivors.
Hard on the heels of encouraging magnesium sulphate research to reduce cerebral palsy risk come data on the use of lactoferrin to lower the risk of neonatal infections. Lactoferrin is the major whey protein in human milk and has many functions in early immune processes (Kaufman JAMA 2009; 302:1467-8). Apart from antimicrobial activity, it promotes healthy gut flora and enhances the immature immune system. It is found in higher quantities in colostrum than mature milk, again suggesting a natural boost immediately after delivery.
Manzoni et al (JAMA 2009; 302: 1421-8) studied the administration of bovine lactoferrin, with or without an adjuvant against placebo to a series of very low-birth-weight infants and found some promising results. Subjects receiving the lactoferrin had bacterial and fungal sepsis rates of 6% whereas the placebo group rate was 17%.
The smaller the infant the greater the impact of the lactoferrin so another promising door appears to be opening in the care of preterm infants.
Also linked to poor outcomes, especially in very low-birth-weight infants of less than 1500g, is infection. About 20% of these babies will develop serious infections while in intensive care units. Nosocomial infections occurring after 3 days of age carry major risks of mortality or impaired neuro-development and the smallest are the most vulnerable. There are enormous short-term costs of hospital treatment plus the long-term financial implications of looking after mentally compromised survivors.
Hard on the heels of encouraging magnesium sulphate research to reduce cerebral palsy risk come data on the use of lactoferrin to lower the risk of neonatal infections. Lactoferrin is the major whey protein in human milk and has many functions in early immune processes (Kaufman JAMA 2009; 302:1467-8). Apart from antimicrobial activity, it promotes healthy gut flora and enhances the immature immune system. It is found in higher quantities in colostrum than mature milk, again suggesting a natural boost immediately after delivery.
Manzoni et al (JAMA 2009; 302: 1421-8) studied the administration of bovine lactoferrin, with or without an adjuvant against placebo to a series of very low-birth-weight infants and found some promising results. Subjects receiving the lactoferrin had bacterial and fungal sepsis rates of 6% whereas the placebo group rate was 17%.
The smaller the infant the greater the impact of the lactoferrin so another promising door appears to be opening in the care of preterm infants.
10 July, 2009
The screening process
The future of cervical screening is being carefully scrutinised. There is no doubt that cytology is one of the most valuable of all screening modalities, being able to detect pre-cancerous lesions while they are amenable to curative procedures that prevent more serious disease.
The profession and the public are analysing the role of all population screening strategies with the harms being objectively assessed as well as the benefits. There is a temptation to become caught up in the preventative fervour of prophylactic screening without looking at the downside implicit in all programmes. These negative aspects are derived from an over-reaction to minor deviations or difficult-to-interpret results, as well as the psychological and emotional fall-out generated by false positives. There is a spectrum of under-recognised harm from a pre-occupation with abnormal labels, through to the financial interests of business to grow the screening industry.
Health professionals exhort their patients to prevent disease and it is easy to slip into the simplistic mantra of early detection being the equivalent of prevention. Screening is no more preventative than insuring your home is preventative of its burning down. While reminding ourselves of the differences between screening and prevention, it is as well to remember the fundamentals of an effective screening test which should have the following characteristics (Clark Cancer Control 1995;2:485-92):
1. The disease sought should be an important health problem
2. A presymptomatic stage of the disease should exist
3. The natural history of the disease should be well understood
4. There should be an acceptable screening test available
5. Screening tests should be acceptable to the population being tested
6. Outcomes after presymptom diagnosis and treatment should be better than those after symptoms
7. Reduced morbidity/mortality should outweigh harms from false-positive tests
8. Benefits of the test should be achieved at acceptable risk
So does population based cervical cytology measure up to these ideals?
The massive reduction in deaths from cervical cancer in countries where programmes have been introduced does not preclude its re-evaluation as every intervention must be reconsidered in the present economic melt down. Fortunately cytology does hold up cost-effectively in developed countries like the United States where the burden of the disease has decreased by 75% but there are other strategies which need to be considered in developing countries where the costs of clinics, laboratories administration and personnel are prohibitive.
The role of HPV DNA testing in screening is starting to emerge. At present HPV tests are used to triage women with equivocal cytology who may or may not need colposcopy.
The next focus for HPV tests has been in women over the age of 30 years. These women are past the stage of self-limiting infections, and if they are HPV negative with normal cytology then they may constitute a group in whom fewer smears are necessary. Less frequent screening carries large financial implications.
Castle et al (Obstet Gynecol 2009;113:595-600) looked at the number of women who had oncogenic HPV positive tests in the general population of California and evaluated their cytology at the same time. Those between 30 and 34 years had 10% HPV oncogenic positive results but this dropped to around 5% in women older than 40 years. In the entire population the HPV positive rate was lower than anticipated thus not realising epidemiologists' fears of a sharply increased need for further investigation if widespread HPV screening is introduced. Conversely women with negative HPV tests plus negative cytology had a very low risk of incipient precancer and their screening can safely be extended beyond 3 years.
In some practices an “annual smear” has become traditional and women may be reluctant to give up their routine check-ups for fear of failing to detecting early disease. Cotesting with both cytology and HPV DNA may resolve this issue.
When to stop screening is an unsettled matter. There is no point in cytological screening in women who have had their cervix removed by hysterectomy for benign indications. Vault smears are not justified, but for older women with a cervix, when should screening end? Recommendations vary from country to country with 65 or 70 being the most frequently advised age on both sides of the Atlantic but this is in low-risk women who are asymptomatic. Certainly the latest data from Denmark (Rebolj et al (BMJ 2009; 338:b1354) indicates that negative smears in women in their fifties have the same predictive value as women in their thirties suggesting continued vigilance is a good idea.
Finally, Strander (BMJ 2009:338:b809) believes the story will unfold as the technology improves with computer generated risk factors guiding the frequency and duration of screening. Surely algorithms can be devised which include lifestyle considerations plus previous cytology and HPV results which would streamline services, save unnecessary retesting as well as indicating when to stop screening?
The profession and the public are analysing the role of all population screening strategies with the harms being objectively assessed as well as the benefits. There is a temptation to become caught up in the preventative fervour of prophylactic screening without looking at the downside implicit in all programmes. These negative aspects are derived from an over-reaction to minor deviations or difficult-to-interpret results, as well as the psychological and emotional fall-out generated by false positives. There is a spectrum of under-recognised harm from a pre-occupation with abnormal labels, through to the financial interests of business to grow the screening industry.
Health professionals exhort their patients to prevent disease and it is easy to slip into the simplistic mantra of early detection being the equivalent of prevention. Screening is no more preventative than insuring your home is preventative of its burning down. While reminding ourselves of the differences between screening and prevention, it is as well to remember the fundamentals of an effective screening test which should have the following characteristics (Clark Cancer Control 1995;2:485-92):
1. The disease sought should be an important health problem
2. A presymptomatic stage of the disease should exist
3. The natural history of the disease should be well understood
4. There should be an acceptable screening test available
5. Screening tests should be acceptable to the population being tested
6. Outcomes after presymptom diagnosis and treatment should be better than those after symptoms
7. Reduced morbidity/mortality should outweigh harms from false-positive tests
8. Benefits of the test should be achieved at acceptable risk
So does population based cervical cytology measure up to these ideals?
The massive reduction in deaths from cervical cancer in countries where programmes have been introduced does not preclude its re-evaluation as every intervention must be reconsidered in the present economic melt down. Fortunately cytology does hold up cost-effectively in developed countries like the United States where the burden of the disease has decreased by 75% but there are other strategies which need to be considered in developing countries where the costs of clinics, laboratories administration and personnel are prohibitive.
The role of HPV DNA testing in screening is starting to emerge. At present HPV tests are used to triage women with equivocal cytology who may or may not need colposcopy.
The next focus for HPV tests has been in women over the age of 30 years. These women are past the stage of self-limiting infections, and if they are HPV negative with normal cytology then they may constitute a group in whom fewer smears are necessary. Less frequent screening carries large financial implications.
Castle et al (Obstet Gynecol 2009;113:595-600) looked at the number of women who had oncogenic HPV positive tests in the general population of California and evaluated their cytology at the same time. Those between 30 and 34 years had 10% HPV oncogenic positive results but this dropped to around 5% in women older than 40 years. In the entire population the HPV positive rate was lower than anticipated thus not realising epidemiologists' fears of a sharply increased need for further investigation if widespread HPV screening is introduced. Conversely women with negative HPV tests plus negative cytology had a very low risk of incipient precancer and their screening can safely be extended beyond 3 years.
In some practices an “annual smear” has become traditional and women may be reluctant to give up their routine check-ups for fear of failing to detecting early disease. Cotesting with both cytology and HPV DNA may resolve this issue.
When to stop screening is an unsettled matter. There is no point in cytological screening in women who have had their cervix removed by hysterectomy for benign indications. Vault smears are not justified, but for older women with a cervix, when should screening end? Recommendations vary from country to country with 65 or 70 being the most frequently advised age on both sides of the Atlantic but this is in low-risk women who are asymptomatic. Certainly the latest data from Denmark (Rebolj et al (BMJ 2009; 338:b1354) indicates that negative smears in women in their fifties have the same predictive value as women in their thirties suggesting continued vigilance is a good idea.
Finally, Strander (BMJ 2009:338:b809) believes the story will unfold as the technology improves with computer generated risk factors guiding the frequency and duration of screening. Surely algorithms can be devised which include lifestyle considerations plus previous cytology and HPV results which would streamline services, save unnecessary retesting as well as indicating when to stop screening?
23 April, 2009
Breast Cancer Screening
The national routine breast screening programme in the UK has doubled the number of women screened in the last 10 years and it is now approaching 2 million per year. This is due to more women availing themselves of the service and an extension of the previously restricted age offer to 50 - 65 year-olds by a further 5 years. The latest data reveal twice the number of cases detected compared with a decade ago, with most being invasive and half being less that 1.5cm in size which are not detectable by hand (Mayor BMJ 2009;338:315).
The claim is made that the programme is serving an “increasing number of women's lives” but this is not a universally accepted point of view.
A spirited rebuttal to unconditional screening programmes is made by Gotzsche et al (BMJ 2009;338:446-8) in which the point is made that mammography has a downside - cost, discomfort, false-positive findings and over-treatment. The authors castigate programmes whose information leaflets fail to mention the harmful effects of screening and over-emphasize the benefits. They argue that choices about screening can only be made by healthy women if the cons as well as the pros are presented. They looked at 31 leaflets from publicly-funded programmes and found them all to be biased so they have produced their own evidence-based contribution (see www.bmj.com).
Women should not be coerced or made to feel guilty if they choose not to undergo screening - informed choice implies unbiased information.
While on the topic of screening for women, the latest figures of cervical screening in the UK are quoted by Kmietowicz (BMJ 2009;338:497). Since the national programme was introduced 30 years ago, the number of diagnoses of cervical cancer have halved. The disease has dropped from the 6th to the 13th most common cancer in women and mortality rates have plummeted. The only negative data show fewer young women are taking up screening invitations but, as a group, those under the age of 35 remain vulnerable.
The claim is made that the programme is serving an “increasing number of women's lives” but this is not a universally accepted point of view.
A spirited rebuttal to unconditional screening programmes is made by Gotzsche et al (BMJ 2009;338:446-8) in which the point is made that mammography has a downside - cost, discomfort, false-positive findings and over-treatment. The authors castigate programmes whose information leaflets fail to mention the harmful effects of screening and over-emphasize the benefits. They argue that choices about screening can only be made by healthy women if the cons as well as the pros are presented. They looked at 31 leaflets from publicly-funded programmes and found them all to be biased so they have produced their own evidence-based contribution (see www.bmj.com).
Women should not be coerced or made to feel guilty if they choose not to undergo screening - informed choice implies unbiased information.
While on the topic of screening for women, the latest figures of cervical screening in the UK are quoted by Kmietowicz (BMJ 2009;338:497). Since the national programme was introduced 30 years ago, the number of diagnoses of cervical cancer have halved. The disease has dropped from the 6th to the 13th most common cancer in women and mortality rates have plummeted. The only negative data show fewer young women are taking up screening invitations but, as a group, those under the age of 35 remain vulnerable.
11 March, 2009
Antioxidants and cancer prevention
Antioxidants are the hope of the healthy. Millions of people take supplements, usually vitamins or antioxidants, in the hope that these extras will prevent chronic conditions. The supplement industry is vast but many of the popular products so eagerly ingested lack scientific evidence of benefit.
The latest casualties are selenium and vitamin E for the prevention of cancer in men. In the largest randomised controlled trial ever undertaken, comprising over 35 000 people, these substances were no more effective than placebo in reducing the rates of prostate or any other cancers in middle-aged and elderly men. The trial was supposed to last 12 years but was stopped half-way when an interim audit shown no effect of each agent or a combination (Lippman et al JAMA 2009;301:39-51).
In a second smaller trial of 15 000 male doctors - also middle-aged - vitamins E and C were pitted against placebo and, again, after 8 years there was no decreased risk of any cancer found (Gazanio et al pp 52-62).
It seems clear that healthy men and women do not lower their chances of developing cancer by taking vitamins C, E or selenium. Half of all American adults take supplements. Will these definitive studies change their habits?
At the other end of the age spectrum, other additives have also not been faring very well. Theoretically, giving preterm infants high doses of polyunsaturated fatty acids in their diets could assist brain structure and function. Babies born before 33 completed weeks of gestation are at risk of developmental and behavioural problems, but it is unclear whether standard or high dose fatty acids in their early feeds will make any difference to long-term outcomes.
Makrides et al (JAMA 2009;301:175-82) supplemented the diet of the mothers whose expressed breast milk formed the bulk of the infant's nutrition. The intervention group took capsules containing tuna oil while the controls had a standard diet, resulting in the babies receiving either high or low doses of docosahexanoic acid (DHA) from birth to the date when they would have reached term in utero. Examining both groups at 18 months there was no difference in the neuro-developmental outcome between those receiving the DHA supplementation or not. However, the girls did better than the boys which may lead to even higher dose trials.
The latest casualties are selenium and vitamin E for the prevention of cancer in men. In the largest randomised controlled trial ever undertaken, comprising over 35 000 people, these substances were no more effective than placebo in reducing the rates of prostate or any other cancers in middle-aged and elderly men. The trial was supposed to last 12 years but was stopped half-way when an interim audit shown no effect of each agent or a combination (Lippman et al JAMA 2009;301:39-51).
In a second smaller trial of 15 000 male doctors - also middle-aged - vitamins E and C were pitted against placebo and, again, after 8 years there was no decreased risk of any cancer found (Gazanio et al pp 52-62).
It seems clear that healthy men and women do not lower their chances of developing cancer by taking vitamins C, E or selenium. Half of all American adults take supplements. Will these definitive studies change their habits?
At the other end of the age spectrum, other additives have also not been faring very well. Theoretically, giving preterm infants high doses of polyunsaturated fatty acids in their diets could assist brain structure and function. Babies born before 33 completed weeks of gestation are at risk of developmental and behavioural problems, but it is unclear whether standard or high dose fatty acids in their early feeds will make any difference to long-term outcomes.
Makrides et al (JAMA 2009;301:175-82) supplemented the diet of the mothers whose expressed breast milk formed the bulk of the infant's nutrition. The intervention group took capsules containing tuna oil while the controls had a standard diet, resulting in the babies receiving either high or low doses of docosahexanoic acid (DHA) from birth to the date when they would have reached term in utero. Examining both groups at 18 months there was no difference in the neuro-developmental outcome between those receiving the DHA supplementation or not. However, the girls did better than the boys which may lead to even higher dose trials.
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