Women with a common womb condition are at risk of giving birth prematurely, The Daily Telegraph has reported. It says that research on more than 13,000 women with endometriosis shows that having the condition raised their risk of premature birth by around one-third. Endometriosis is a condition where the tissue lining the womb is found in other areas of the abdomen, often causing pain and infertility.

This was a large and well-conducted study that looked at almost 1.5 million births, comparing pregnancy and delivery outcomes in women diagnosed with endometriosis to those in women without the condition. Women with endometriosis were found to have an increased risk of premature birth as well as several other pregnancy-related complications, even after the influence of other factors believed to contribute to premature birth were taken into account.

 As the authors acknowledge, a possible source of error in their study is inaccuracy in the number of endometriosis cases, which were taken from hospital records only. Overall, this study’s findings highlight the importance of providing all pregnant women with appropriate support, care and monitoring. It is also another reminder that pregnant women or those trying to conceive should stay as healthy as possible, for example through eating well, remaining active, not smoking and avoiding alcohol.

Where did the story come from?

Olof Stephansson and colleagues from Karolinska University Hospital and Institute in Stockholm, Sweden, carried out this research. The study was funded by the Swedish Society of Medicine and was published in the peer-reviewed medical journal Human Reproduction.

What kind of scientific study was this?

This was a retrospective cohort study that compared the rates of premature birth and complications of pregnancy among women previously diagnosed with endometriosis and women who did not have the condition.

Endometriosis is relatively common gynaecological condition where endometrial tissue (the tissue that lines the uterus) is found outside the uterus and builds up in other areas around the pelvis and abdomen. It often causes painful periods, pain during intercourse and fertility problems.

The Swedish Medical Birth Register was used to identify single babies born between January 1992 and December 2006 (1,442,675 in total). Researchers linked the mothers of these babies to the Patient Register to identify those women who had been diagnosed with endometriosis at any time since 1964. This gave them a total of 13,090 single babies born during the 14-year period to 8,922 women diagnosed with endometriosis.

The authors used the Swedish Birth Register to obtain demographic data on the women and information on their age, BMI, smoking status and reproductive history (for example, previous children and use of fertility treatment). They also looked at the incidence of several complications during pregnancy, delivery and the period following birth, including premature birth, small-for-gestational-age (SGA), stillbirth, haemorrhage prior to birth, pre-eclampsia and the need for a caesarean section.

What were the results of the study?

Of the total 1,442,675 single births, 4,778 were stillborn (a rate of 3.3 per 1,000 births). Of the remaining live births, 71,689 were premature (born at less than 37 weeks), 883 of which were born to women with endometriosis (a rate of 6.78 per 100 births) and 70,806 to women without the condition (rate of 4.98 per 100 births).

Compared to women without the condition, those with endometriosis were of higher maternal age and were more likely to be having their first baby. After adjustment for age and other possible confounders (e.g. BMI, smoking status), there was a higher risk of premature birth among women with endometriosis (odds ratio 1.33, 95% confidence interval 1.23 to 1.44).  There was also a higher rate of premature birth among:

• women of low age (19 or under),
• women of high maternal age (35 or older),
• women with minimal education,
• women with high or low BMI,
• women who smoked, and
• women having their first baby.

Women with endometriosis also had a higher risk of pre-eclampsia, haemorrhage prior to birth and caesarean section. Fertility treatment had been used more often in women with endometriosis (11.9% against 1.4% in women without the condition). Risk of premature birth was increased among women with endometriosis regardless of whether they had used fertility treatment.

What interpretations did the researchers draw from these results?

The researchers concluded that endometriosis seems to be a risk factor for premature birth. Women with endometriosis may also be more likely to suffer from haemorrhage prior to birth or placental complications, to develop pre-eclampsia or to require a caesarean section.

What does the NHS Knowledge Service make of this study?

This was a large and well-conducted study that looked at almost 1.5 million Swedish births over a 14-year period. Having a diagnosis of endometriosis appeared to increase the risk of premature birth as well as several other pregnancy-related complications, even after adjustment for possible confounding factors such as maternal age, BMI, smoking status and previous births.

Women living with endometriosis can experience great physical and emotional distress, particularly when considering the difficulties that many experience when trying to conceive. The findings that other pregnancy-related complications are possibly associated with endometriosis may not come as a surprise to women with this challenging condition or to the medical professionals who treat it. As part of their review, the authors discussed the possible inflammatory and biochemical changes associated with birth and endometriosis and proposed factors that may be involved in the association between the two.

However, the authors acknowledge that there is a potential source of error in their results as diagnoses of endometriosis were only taken from hospital or outpatient records. As such, it is not known whether these were confirmed using biopsies and lab testing. There is also the possibility that a number of women with endometriosis may not be referred to hospital with their condition or may put up with symptoms and avoid consulting a doctor about them at all. On this basis, the number of cases of endometriosis in this population sample may not be entirely accurate.

It should be noted that premature birth was also independently associated with other risk factors, such as being a smoker, having a low (underweight) or high (obese) BMI, or being of high or low maternal age. The findings highlight the important need for pregnant women to receive dedicated support, care and monitoring and to maintain optimal health, for example through taking appropriate vitamin supplements, eating well, remaining active, not smoking and avoiding alcohol.

Links To The Headlines

Links To Science

Stephansson O, Kieler H, Granath F, and Falconer H. Endometriosis, assisted reproduction technology, and risk of adverse pregnancy outcome. Hum. Reprod. [Advance access publication] July 1, 2009

“Being married protects you against Alzheimer's in later life,” the Daily Mail reported. The newspaper said that researchers found that people who have a partner in middle age have half the risk of developing dementia compared to those who live alone. However, getting divorced or becoming widowed in middle age triples the risk of dementia.

It has often been suggested that marital status has an impact on health and quality of life. This study assessed the relationship between marital status in 2,000 middle-aged people (average age 50) and their cognitive impairment about 21 years later. It found that the risk of any cognitive impairment almost doubled if a person was alone in middle age compared to having a partner. Being without a partner in both middle age and later life further increased risk.

Cognitive function was not measured at the start of the study, so it is difficult to prove that marital status is related to cognitive impairment in later life. If the association does exist, the reasons behind it are difficult to establish. The risk of dementia is likely to be governed by a complex interaction of several factors, such as lifetime personal, social and intellectual interactions, health, lifestyle and medical and genetic factors.

Where did the story come from?

The research was carried out by Krister Håkansson from the Department of Psychology at Växjö University, Sweden, and colleagues from other institutions in Sweden and Finland.

The study was funded by Kuopio University Hospital, the Academy of Finland, a grant from the EU, the Swedish Council for Working Life and Social Research, the Finnish Cultural Foundation, the Foundation of Juho Vainio, the Gamla Tjänarinnor Foundation, the Helsingin Sanomain 100-vuotissäätiö and the Gun and Bertil Stohne Foundation.

The study was published in the peer-reviewed British Medical Journal.

What kind of scientific study was this?

This cohort study assessed whether being married in middle age is related to cognitive function in later life. It used participants from a previous study called the cardiovascular risk factors, aging and dementia (CAIDE) study. These people were recruited from four separate population samples in 1972, 1977, 1982 and 1987. The four samples were randomly selected from the population register of the Kuopio and Joensuu regions of eastern Finland and consisted of 30,078 adults aged 30 to 59 (average age 50.4 years). The sample was stratified so that there were at least 250 participants from each sex and from each of three 10-year age intervals. In 1998, 2,000 surviving members of this cohort were randomly selected to be interviewed again, 1,449 of whom (73%) chose to participate. By this time, they were aged between 65 and 70 and the average follow-up time was 20.9 years.

At the beginning of the study and then at follow-up, the researchers assessed the participants’ marital status and categorised them as single, married/cohabiting, divorced or widowed. They combined data on marital status at the two time points to create different categories of marital transition, for example whether participants were married at both times or married then widowed.

At follow-up, cognitive impairment was assessed using the mini-mental state examination (MMSE) for screening. The results of this were then used to decide whether further clinical examination and diagnostic testing (including brain imaging) were needed. Dementia was diagnosed using valid diagnostic criteria and defined as either mild cognitive impairment, Alzheimer’s disease or other forms of dementia. The researchers also used laboratory methods to investigate whether participants were carriers of the apolipoprotein E e4 allele (considered to be a risk factor for Alzheimer’s and vascular dementia). For the 551 selected participants who chose not to take part in the 1998 assessments, information on diagnoses of dementia was obtained from local hospitals and healthcare centres.

In their analyses, the researchers collapsed the middle-age marital status categories into the following: living with a partner/married, single, separated/divorced, or widowed. They combined marital status in middle-age and later life to give the following categories of marital transition: cohabiting with a partner on both occasions, cohabiting with a partner in middle age but not in later life, and living without a partner on both occasions. (The researchers said there were too few people were single in middle age but cohabiting in later life to be included in the analyses).

They assessed the relationship between marital status and cognitive impairment in later life, taking into account (adjusting for) other possible risk factors (assessed in middle age) of apolipoprotein E e4 allele status, education and occupation, sex and age, smoking, BMI, blood pressure, cholesterol, physical activity and depression.

What were the results of the study?

In the 1998 assessment, 294 of the 1,449 participants scored 24 or less on the MMSE (i.e. the cut-off below which they considered there to be evidence of cognitive impairment). Through further assessment and diagnostic testing, 82 were diagnosed with mild cognitive impairment, 48 with Alzheimer’s (or 52 if different diagnostic criteria were used) and nine with other types of dementia. When data from the hospital records of the 551 people who did not participate in the later assessment were included, overall 113 people were considered to have dementia (76 of whom had Alzheimer’s) and 1,887 were considered to be without dementia.

People without a partner (single/separated or widowed) in middle age were twice as likely to demonstrate cognitive impairment in later life compared to those who had a partner. When the researchers looked at the separate categories, they found that people who were widowed at middle age had more than twice the risk of any cognitive impairment, but the risk for those who were single/separated was not significant.

Those who were single/separated or widowed in middle age and were still in the same category at follow-up had almost three times the risk of cognitive impairment compared with married/cohabiting people.

Those who were widowed at both time points had seven times the risk of Alzheimer’s disease compared to married/cohabiting people (odds ratio 7.67, 95% confidence interval 1.6 to 40.0). The presence of the apolipoprotein E e4 allele further increased the risk of Alzheimer’s disease in people who were widowed at both time points.

What interpretations did the researchers draw from these results?

The authors concluded that living with a partner may have a protective effect against the development of cognitive impairment in later life. They say that social and genetic factors may explain the large increase in risk of Alzheimer’s disease for widowed people who are apolipoprotein E e4 carriers. They note that the increased risk among widowed people compared with single people indicates that social and other factors may be involved.

What does the NHS Knowledge Service make of this study?

This research assessed the relationship between marital status in middle age (average age 50) and cognitive impairment about 21 years later in 2,000 Finnish people. This study has strengths in being reportedly one of the first studies to have examined the effect of marital relationships and their long-term influence on dementia. It found that not having a partner in middle age doubled the risk of any cognitive impairment in later life compared to having a partner. Being without a partner in both middle age and later life further increased the risk. Specifically, people who were widowed seemed to have higher risk of cognitive impairment. A few points to note:

• The study only assessed cognitive impairment at follow-up. It is not clear whether any members of the sample already had cognitive impairment at the start of the study when marital status was assessed. Without taking into account cognitive impairment at the beginning of the study, it is difficult to conclude that marital status is responsible for impairment in later life.
• The marital status categories used in the study may have meant some relationships were misclassified. Personal relationships are not always easy to group according to a simple convention of married/cohabiting, single/separated or widowed. In addition, such categorisation is unable to take into account all the complexities and detail of the individuals’ situations, such as how long a relationship lasted, whether it was amicable and whether the person had a close, supporting network of family and friends.

The reasons behind the possible associations are not clear. The authors suggest a “brain reserve hypothesis”, the idea that various forms of social and intellectual interaction are protective against dementia. They discuss this theory in some depth. However, it is likely to be a complex relationship between several factors, such as personal, social and intellectual interactions and health, lifestyle, medical and genetic factors, that affect the risk of dementia.

Links To The Headlines

Solo life ups gene dementia risk. BBC News, July 03 2009

How being married can cut your risk of Alzheimer’s later in life. Daily Mail, 03 July 2009

Divorcees and widows 'face three times the risk of Alzheimer's'. The Daily Telegraph, 03 July 2009 

Links To Science

Last updated: 10.45 BST

The government yesterday announced important changes to the way it is managing the swine flu pandemic in the UK.

Andy Burnham, the health secretary, told parliament that the UK was formally moving from a “containment” to a “treatment” phase for swine flu.

This means intensive efforts to contain swine flu, via automatic school closures, for example, will end to free up capacity to treat the increasing numbers of people who are contracting swine flu each day.

There have been 7,447 cases confirmed in the UK since the outbreak started two months ago. Of these, over 100 have involved hospitalisation, and four people have died as a result of complications associated with swine flu.

"Cases are doubling every week and, on this trend, we could see over 100,000 cases per day by the end of August", said Burnham.

"Our national focus should be on treating the increasing numbers affected by swine flu... I can today tell the House we will move to this treatment phase across the UK" .

What are the practical implications?

The shift to a treatment phase has important practical implications for the public and the NHS. It means that as of today:

• GPs will be able to diagnose swine flu on the basis of patients’ symptoms rather than waiting for laboratory testing.
• The routine tracing of people who have come into contact with confirmed cases of swine flu will end.
• Schools and other institutions will close only if local circumstances warrant it, for example if a significant number of pupils or teachers are ill.

The way in which the antiviral medicines Tamiflu and Relenza are used and distributed will also change:

• The medicines will continue to be offered to all those who show symptoms of swine flu at their doctor's discretion.
• They will no longer be given to completely healthy people simply to slow the spread of swine flu.
• They will be used for prevention (prophylaxis) only on the advice of a doctor in high-risk groups. These include people with long-term conditions, those over 65, children under five and pregnant women.
• Individuals who require antivirals will be given a voucher reference entitling them to pick up the medication at a local collection point.

As part of the move to a treatment phase, the health secretary also announced the launch, "when it is needed", of a National Pandemic Flu Service.

This is a new telephone system that will support GPs in the diagnosis of swine flu and the distribution of antivirals. It will allow people with suspected swine flu to be diagnosed and given vouchers for antivirals via a dedicated call centre or online.

What should I do today if I think I have swine flu?

• First use the swine flu symptom checker.
• If you are then still concerned, stay at home and call your local GP. Use our service search to find contact details.
• If the GP confirms swine flu by telephone, you will be given a voucher reference entitling you to anti-viral medication.
• Give this to a healthy friend or relative and ask them to pick up antivirals for you from a designated local collection centre.

How dangerous is swine flu?

The vast majority of cases reported so far in this country have been mild. Only a small number have led to serious illness, and these have frequently been where patients have had underlying health problems.

There has been an argument put forward that the government should restrict antivirals to those groups who are most at risk of developing serious complications from swine flu. In other words, if people are otherwise healthy, then the NHS should let the virus run its course, treating it with paracetamol and bed rest as you would normal flu.

“A pioneering treatment for the UK's most common male cancer is more successful than surgery or radiotherapy,” The Daily Telegraph reported. The newspaper said that new research shows that intensive ultrasound therapy is as effective as traditional treatments (surgery or radiotherapy) but that side effects are dramatically reduced.

This research found reasonably favourable results from high-intensity focused ultrasound (HIFU) treatment in 172 men with localised prostate cancer (cancer that had not spread). It also found that there were relatively low rates of urinary incontinence and erectile dysfunction following treatment.

At present, treatment for localised prostate cancer is normally either radical (surgery or radiotherapy) or involves ‘watchful waiting’, where the cancer is monitored but not treated unless it develops. As such, minimally invasive alternatives like HIFU may be a preferable alternative. However, as with other newer alternative treatments for prostate cancer, available evidence is from small case series only and information on long-term outcomes is lacking. Further follow-up of men treated with HIFU and randomised controlled trials to directly compare the new treatment with surgery are needed.

Where did the story come from?

The research was carried out by Dr HU Ahmed and colleagues from University College London. Funding was provided by the Prostate Research Campaign UK and Prostate Cancer Research Centre UK. One of the authors received funding from and is a consultant for Negma Lerads, a manufacturer of a photodynamic agent used in prostate cancer therapy. The study was published in the peer-reviewed British Journal of Cancer.

What kind of scientific study was this?

This research examined the effectiveness of high-intensity focused ultrasound (HIFU) at treating men with localised prostate cancer. Men with localised prostate cancer normally have the options of radical treatment, such as surgery or radiotherapy, or monitoring, a process known as active surveillance or watchful waiting. However, the decision between doing nothing or having radical treatment is not an easy one.

HIFU is known as a minimally invasive therapy and, along with other alternatives such as radiofrequency ablation, cryosurgery and photodynamic therapy, offers a middle-ground approach. It has a potentially reduced risk of adverse effects compared to radical treatment and is more proactive than watchful waiting. However, these therapies are in various stages of research and development and their use in clinical practice is limited.

HIFU involves focussing high-energy ultrasound waves on the target cancerous tissues, which causes them to coagulate and die. The probe that emits the ultrasound waves is inserted into the rectum and a cooling balloon around the probe protects the surrounding healthy tissue. After the procedure, catheterisation is required for a period of time.

This case series reported on 172 men (average age 64 years) who received HIFU at two London centres between February 2005 and May 2007. The men had rejected surveillance and were either unable or did not wish to undergo surgery or radiotherapy. The men understood that HIFU was not a standard procedure and that knowledge of short- and medium-term outcomes was restricted to a few case series. Men were excluded if they had any specific symptoms that made HIFU inadvisable (contraindications), including a prostate volume greater than 40ml, calcification of the prostate or significant anorectal disease preventing probe insertion (for example, previous haemorrhoid removal or inflammatory bowel disease).

Some of the men who were included were pre-treated for three months with low-dose anti-androgen (anti-male hormone) treatment to reduce the size of their prostate. In procedures carried out earlier in the case series, standard urethral catheters were inserted for one to two weeks following HIFU. In later procedures, this was replaced with a suprapubic catheter.

Follow-up of the men was the same as that used for standard radical treatment. Serum PSA (prostate specific antigen, a prostate cancer marker that indicates disease activity) measurements were taken at six weeks and then every three months for the first year and every six months during subsequent years of follow-up. At one of the centres, patients also completed questionnaires that assessed any adverse effects they had experienced.

What were the results of the study?

Of the 172 men treated with HIFU, analysis was only possible in 136 cases as there was not complete data for risk stratification in the other 36 men. Of the 136 men analysed, 27.8% (38 men) were considered to have low-risk disease, 37.5% (51) had intermediate-risk disease and 34.6% (47) had high-risk disease. Following treatment, 78% of the men were discharged after an average of five hours. Average duration of follow-up was 346 days (range 135–759 days).

Adverse effects of HIFU were given as:

• Men who received post-treatment suprapubic catheterisation were significantly less likely to experience urethral stricture (narrowing of the urethra causing difficulty in passing urine) than men who received urethral catheterisation (19.4% against 40.4%).
• Antibiotics for suspected urinary tract infection were given to 23.8% of men.
• Epididymitis (infection and inflammation of a structure at the back of the testicle where sperm is stored) developed in 7.6% of men.
• Mild urinary incontinence occurred in 7% (12 out of 172) and one man needed to use pads for more severe incontinence.
• After one year, the majority of men (70%) were still able to achieve erection.
• There was no report of rectal problems following the procedure.

Overall, 78.3% of the men achieved a low PSA level one year after treatment (0.5 micrograms/ml or lower, and below 0.2 micrograms/ml in 57.8% of men) and 92.4% of men (159 out of 172) either achieved a low PSA level or had negative biopsy results, demonstrating no residual disease. Of the 13 men who were candidates for further treatment, eight received further HIFU, one had salvage radiotherapy and four were managed with active surveillance for low-risk disease.

What interpretations did the researchers draw from these results?

The authors concluded that, in the short term, good outcomes can be achieved following HIFU, with reasonably low levels of erectile dysfunction and urinary incontinence. However, longer-term outcomes need to be assessed.

What does the NHS Knowledge Service make of this study?

This case series has found reasonably favourable outcomes following HIFU treatment in 172 men with localised prostate cancer. This minimally invasive technique is an alternative for men who would otherwise only have the options of radical treatment (and its associated risks and adverse effects) or watchful waiting. However, as with most new techniques, it should be remembered that the evidence is limited to small case series only.

At present, the main limitation of this particular procedure is that there is little information available on longer-term outcomes. As the authors say, an international registry of all cases treated with HIFU would be helpful to document its success. However, it will be some time before this could become a standard treatment option and the outcomes of much larger numbers of men who have had this treatment are needed. The best-quality evidence would come from randomised controlled trials that compared HIFU to standard options (surgery, radiotherapy or watchful waiting) and other minimally invasive options. Headlines like “Prostate cancer treatment more successful than surgery” are not accurate at present.

Current NICE guidance advises that the evidence supports the safety and efficacy of HIFU for prostate cancer, provided that monitoring, audit and clinical governance of any procedures are carried out. It advises that longer-term effects on survival and quality of life are unknown, and that doctors should therefore ensure that patients understand these uncertainties and the alternative treatment options.

Links To The Headlines

Sound waves offer prostate hope. BBC News, July 2 2009

High hopes for HIFU: the ultrasound breakthrough in the battle against prostate cancer. Daily Mail, July 2 2009

Prostate cancer treatment 'more successful than surgery', claim British scientists. Daily Telegraph, July 2 2009

Ultrasound treatment HIFU offers new hope for prostate cancer patients. The Times, July 2 2009

Ultra-sound cancer cure. Daily Express, July 2 2009 

Links To Science

Ahmed HU, Zacharakis E, Dudderidge T et al. High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series. British Journal of Cancer, 2009; 101, 19–26

Scientists have unlocked “the secrets of schizophrenia”, according to The Independent. The newspaper says that research has identified thousands of tiny genetic variations which together could account for more than one-third of the inherited risk of schizophrenia.

Three international research teams have undertaken these complex and interlinked genetics studies, which have largely consistent findings. The studies have associated a number of gene variants with the risk of schizophrenia. Environmental factors are likely to also play a part and the variations identified in these three studies will not be responsible for all cases of schizophrenia. Equally, these associations do not necessarily mean that it would be possible to one day prevent the disease in people carrying these variants.

These findings further the understanding of the biology of schizophrenia and will undoubtedly prompt further research into how these gene variants may affect the physiological processes of schizophrenia. It is too soon to say how the findings will affect the diagnosis, prevention or treatment of this complex disorder, which is probably caused by both environmental and genetic factors. It is also likely that other gene variants, which are still to be identified, play a role in the disorder.

Where did the story come from?

These news reports are based on three related genome-wide association studies, published in the peer-reviewed medical journal Nature.

• The first study was carried out by the International Schizophrenia Consortium, a collection of researchers from the USA, Australia, UK and other European countries. Funding for this research came from a variety of sources.
• The second study was a genome-wide association study carried out by Jianxin Shi and colleagues from across the USA, UK and Australia, using the Molecular Genetics of Schizophrenia sample. This study was funded by the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression.
• The third study, the SGENE-plus, was carried out by Hreinn Stefansson and colleagues from a research consortium with members from countries across Europe, the UK, USA and China. This study was funded by EU grants. In a second aspect to this study, the researchers meta-analysed (pooled the results of) the other two studies above.

What kind of scientific study was this?

Schizophrenia is a complex disorder and both environmental and genetic factors are implicated in its development. All three of these studies were genome-wide association (GWA) studies, which looked for particular gene sequences (variants) that are associated with the condition.

This is done by comparing the genetics of people with a condition (in this case schizophrenia) with the genetics of people without it (control subjects). The variants that are more common in people with schizophrenia can be identified and their contribution to the risk of disease can be calculated.

These studies were necessarily complex and all three are linked, as the researchers used each other’s populations to confirm the findings of their own genome-wide association studies. It is common practice with genome-wide association studies to verify the results in a separate population of cases and controls.

The International Schizophrenia Consortium study

This first piece of research compared the gene sequences of 3,322 Europeans with schizophrenia with the genetics of 3,587 control subjects without the condition. The researchers undertook modelling to establish what contribution genetic variation made to the participants’ risk of schizophrenia. They also assessed whether the gene variants that they identified were common to the risk of bipolar disorder and some non-psychiatric diseases.

The Molecular Genetics of Schizophrenia (MGS) sample study

This second study was a GWA and meta-analysis. The case-control study aspect was in the MGS European-ancestry sample, which included 2,681 cases of schizophrenia and 2,653 controls, and an African-American sample with 1,286 case and 973 controls. In the meta-analysis aspect of this study, data on 8,008 cases and 19,077 controls were assessed.

The SGENE-plus study

This third study was an analysis of genome-wide associations performed on a sample of 2,663 cases and 13,498 controls from eight European locations. These were England, Finland (Helsinki), Finland (Kuusamo), Germany (Bonn), Germany (Munich), Iceland, Italy and Scotland. The researchers also combined their population with the populations of both studies above to strengthen their study and enable more accurate identification of gene variants.

What were the results of the study?

The International Schizophrenia Consortium study

The researchers found that the strongest association with schizophrenia was in a gene that coded for a protein called myosin, found on chromosome 22. The second-strongest association between variants and risk for schizophrenia was in a region of more than 450 gene variants, found across the major histocompatibility complex (MHC) region on chromosome 6p.

The researchers then confirmed some of their results using data on the participants in the other studies. Through their modelling, they concluded that common variation across multiple genes accounts for about one-third of the total increase in schizophrenia risk, although the influence could be much higher than estimated. They say that the many genes implicated in increasing schizophrenia risk also contribute to the risk of bipolar disorder.

The Molecular Genetics of Schizophrenia (MGS) sample study

The researchers did not find significant links with any gene variants in the case-control aspect of the research at the threshold of significance that they were using. They found a difference in the most common gene variants between people with European ancestry and those with African-American ancestry. When they combined the participants in their study with those in the other two studies, they confirmed the findings that gene variants on chromosome 6p were associated with schizophrenia risk.

The SGENE-plus study

The researchers found an association between a particular gene variant on chromosome 6p in the major histocompatibility complex (MHC) region and the risk of schizophrenia. When they added the participants from the other two studies, they found that four other gene variations, including two in the MHC region, were also significantly linked to schizophrenia risk.

What interpretations did the researchers draw from these results?

Researchers in the International Schizophrenia Consortium study concluded that their data supports the involvement of many genes in the risk for schizophrenia and that genes may explain about one-third of the heritability of the disorder. The risk of schizophrenia involved thousands of common variants, which each make a very small contribution to the risk.

The findings of this study, and those of the SGENE-plus study, implicate the MHC region in schizophrenia risk. This is consistent with the idea of an immune component to the disease as the MHC region has a role in immunity responses. However, while the authors say that the association with this region supports a role for infection in the causes of schizophrenia, it “does not provide strong evidence”.

The researchers in the MGS study concluded that they have identified a link between common gene variants on chromosome 6p and schizophrenia. They say that their study and the other studies suggest that these variants have small effects on the risk of schizophrenia. Larger samples may be useful to detect and understand the full range of rare and common gene variants that contribute to the risk of schizophrenia.

What does the NHS Knowledge Service make of this study?

The genome-wide association studies confirm what is already known about schizophrenia, that it is a complex disorder with complex causes and that individual gene variants play a small part individually in raising the risk. These studies have consistent findings and conclude that there are associations between schizophrenia and a number of gene variants, largely on chromosome 6 in the major histocompatibility region.

There are several important points to bear in mind when interpreting the results of these three genetics studies:

• Schizophrenia is a complex disorder. These three studies identified several gene variants that play a role in the risk of schizophrenia and it is likely that there are more which have yet to be identified.
• Our understanding of the biology and physiology behind the disorder may be furthered by the findings here, which will undoubtedly prompt further research.
• A better understanding of the biology of an illness raises hopes for better diagnosis, prevention and treatment of the disorder. However, these are still some way off.

The findings illustrate the complicated nature of the genetic component of schizophrenia. There is a complex inheritance pattern and many genetic and environmental factors play a part. Not everyone with the gene variants will develop schizophrenia.

Links To The Headlines

Unlocked: the secrets of schizophrenia. Independent, July 2 2009

Schizophrenia and manic depression: new link that could help millions. Daily Telegraph, July 2 2009

Schizophrenia genetically linked to other psychiatric disorders. Financial Times, July 2 2009

Gene clues to schizophrenia risk. BBC News, July 2 2009

Links To Science

The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature July 1 2009 (advanced online publication)

Shi J, Levinson DF, Duan J et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature, July 1 2009 (advanced online publication)

Stefansson H, Ophoff RA, Steinberg S et al. Common variants conferring risk of schizophrenia. Nature, July 1 2009 (advanced online publication)

Vegetarians are less likely to develop cancer than meat eaters, according to several newspapers. They have reported on a study which found that vegetarians are 45% less likely to develop cancer of the blood (such as leukaemias and lymphomas) and 12% less likely to develop cancer overall.

The findings come from the pooled results of two large studies, which looked at cancer rates and dietary habits in 61,566 people. Participants provided information on their diet at the start of the study and researchers followed them for up to 26 years to look at their development of cancer. Of 20 cancers examined, the risk of stomach, bladder and blood cancers was reduced in vegetarians, while eating fish but no meat decreased the risk of ovarian cancer.

However, the incidence of these four cancers across the whole sample was low (particularly for stomach and bladder cancer), which decreases the reliability of the risk figure calculated and the clinical relevance for the general public. The study has some other limitations, which mean its conclusion that “being a vegetarian decreases your risk of cancer” must be made with great caution if based solely on findings of this study.

Where did the story come from?

T J Kay of the University of Oxford and colleagues of other institutions in the UK and New Zealand carried out this research. The study was funded by Cancer Research UK. The principal author has declared that he is a member of the Vegetarian Society. The study was published in the peer-reviewed British Journal of Cancer.

What kind of scientific study was this?

This study examined cancer incidence among vegetarians, an area that has not previously been examined in depth. To do this, the authors pooled the results of two UK cohort studies: the Oxford Vegetarian Study and EPIC-Oxford cohort.

The Oxford Vegetarian Study recruited 11,140 participants from throughout the UK between 1980 and 1984. Vegetarians were recruited through media advertisements and told they could also invite their non-vegetarian friends and relatives to participate. At enrolment, participants completed a food frequency questionnaire and provided information on smoking status, alcohol use, exercise habits, social class, weight, height and reproductive status.

The EPIC-Oxford cohort recruited participants from the UK through GP practices and a mailed invitation, which specifically targeted vegetarians and vegans. A questionnaire was mailed directly to all members of the Vegetarian Society, Vegan Society and all surviving participants in the Oxford Vegetarian Study. Respondents could also recruit friends and relatives.

A total of 7,423 participants were recruited through GP practices and 58,042 through the postal method. The questionnaire included a food frequency questionnaire and collected the same additional lifestyle and health information as the Oxford Vegetarian Study.

Participants of both studies were followed up to the end of 2006 through records from the National Health Service Central Register, which provides information on diagnoses of cancer and all deaths. Participants who were originally in the Oxford Vegetarian Study and were later included in the EPIC-Oxford cohort contributed follow-up data to the Oxford Vegetarian Study until the date that they transferred.

Participants were excluded if they were not aged between 20 and 89 at the time of recruitment, if they had a malignancy (cancer) before the study or if they had no information for one or more of the factors, such as age, sex, smoking and dietary group. This left a total of 61,566 participants across both studies (15,571 men and 45,995 women). Of these, 2,842 contributed data to both studies.

The researchers calculated the risk of 20 cancers and an overall risk of cancer according to dietary categories. They also adjusted for other possible confounding risk factors. The dietary categories were: ‘meat eaters’, ‘fish eaters’ (who did not eat any meat), ‘vegetarian’ (who ate neither meat nor fish) or ‘unknown’ if this was not clear.

What were the results of the study?

One-third of participants were vegetarian and 75% were women. The overall sample contained a low number of current smokers. There were additional differences in other factors, such as BMI, alcohol use and reproductive status, between people of the different dietary categories.

The significant findings of the studies were:

• Being vegetarian decreased the risk of stomach cancer compared to being a meat eater (relative risk [RR] 0.36, 95% confidence interval [CI] 0.16 to 0.78). There was no significant difference in risk between fish eaters and meat eaters.
• Being a fish eater decreased the risk of ovarian cancer compared to being a meat eater (RR 0.37, 95% CI 0.18 to 0.77). There was no significant difference in risk between vegetarians and meat eaters.
• Being a vegetarian decreased the risk of bladder cancer compared to being a meat eater (RR 0.47, 95% CI 0.25 to 0.89). There was no significant difference in risk between fish eaters and meat eaters.
• Being a vegetarian decreased the risk of blood cancers compared to being a meat eater (RR 0.55, 95% CI 0.39 to 0.78). There was no significant difference in risk between fish eaters and meat eaters.
• Compared to eating meat, being a vegetarian or eating fish but no meat significantly decreased the risk of any malignancy overall (RR 0.88 and 0.82, respectively).

What interpretations did the researchers draw from these results?

The authors concluded that incidence of some cancers may be lower in vegetarians and fish eaters than in meat eaters.

What does the NHS Knowledge Service make of this study?

The pooled results of these two large cohort studies have demonstrated that being a vegetarian reduces the risk of certain cancers and cancer overall. However, there are some limitations to the design of this study which must be considered:

• This study has combined the results of two large cohort studies which assessed diet and then looked at cancer outcomes after several years of follow-up. However, the authors do not appear to have conducted a systematic review of other research in this area. This means that we cannot be sure that that they have examined other relevant trials that might potentially have different results to their own.
• Diet was assessed only once at the beginning of the study. It is not known for how long this dietary pattern had already existed at the time of enrolment (for example, a person could have been vegetarian for weeks or years) or whether this dietary pattern continued during follow-up. Additionally, the self-completed dietary questionnaires, which simply asked whether participants ever ate meat, fish, dairy or eggs, may have led to participants being wrongly categorised into different dietary groups.
• The study examined the risk of a number of cancers, not all of which were found to be significantly linked to diet. While vegetarianism significantly decreased the risk of four types of cancer, these were rare during the follow-up. There were only 49 cases of stomach cancer, 85 of bladder cancer, 140 of ovarian cancer and 257 of blood cancer in the total study group. This means that the absolute risk of this cancer for people of any dietary group is fairly low. Also, calculating a risk reduction by dietary group with such small numbers in each category means that the calculated risk figures may not be precise.
• Statistical adjustments were made to take into account the influence of several lifestyle factors, such as smoking. Again, these were assessed only once and were unlikely to have remained the same throughout follow-up. Each cancer also has a variety of other risk factors, including genetic, medical and lifestyle factors. These were not adjusted for in the risk analyses.
• It is difficult to know when the cancers seen actually developed. While the study found that there was a reduction in overall risk of cancer from being a vegetarian, this was no longer significant once the authors excluded people who had been diagnosed with cancer in the two years following recruitment (i.e. those who they considered may have already been developing cancer when the questionnaire was completed).
• The study’s participants are not necessarily representative of the general population. For example, one-third of participants were vegetarian, 75% of them were women and smoking rates were lower than in the general population.

Links To The Headlines

Being a vegetarian can cut your risk of cancer by a half, claim scientists. The Daily Telegraph, July 1 2009

Vegetarians 'avoid more cancers'. BBC News, July 1 2009

Vegetarians less likely to develop cancer than meat eaters, says study. The Guardian, July 1 2009

Vegetarians 'have lower cancer risk'. Daily Mirror, July 1 2009

Vegetarian diet 'can cut risk of cancer by 45 per cent'. Daily Mail, July 1 2009

Proof that vegetarians are less prone to cancer. Daily Express, July 1 2009

Links To Science

Key TJ, Appleby PN, Spencer EA et al. Cancer incidence in British vegetarians British Journal of Cancer, 2009; 101, 192–197

Researchers say that “statins cut the risk of heart attacks by 30% even in healthy people” and lower the chance of dying from any cause by 12%, the Daily Mail reported. It said that the drugs are currently only given to people who are at significant risk of heart attack or stroke. The latest review of the research has renewed the ongoing debate over whether everyone over 50 should be prescribed statins.

The news story is based on a large systematic review of 10 trials, which pooled the results of over 70,000 people. It found that, over an average 4.1 years, statins reduced the risk of death by any cause, as well as from heart attacks and strokes, in people who had not been diagnosed with cardiovascular disease but who had the risk factors for it.

As all these people had some degree of cardiovascular risk, such as high blood pressure, high cholesterol or diabetes, describing them as “healthy” does not clearly portray their risk status. However, these important findings indicate that a number of people could benefit from long-term statin use. As the authors say, identifying the people with risk factors could be a challenge and giving statins to everyone over a certain age would have significant cost and safety implications.

Where did the story come from?

The research was carried out by Dr JJ Brugts from the Department of Cardiology, Erasmus MC Thoraxcenter, Rotterdam, and colleagues from other international institutions. Several of the authors had affiliations with various pharmaceutical companies. The study was published in the peer-reviewed British Medical Journal.

What kind of scientific study was this?

This systematic review investigated whether statins reduce deaths from any cause and reduce the risk of major coronary and cerebrovascular events (such as heart attacks and strokes) in people who have cardiovascular risk factors but have not been diagnosed with cardiovascular disease. It also looked at whether gender, age (above or below 65) and diabetes have an effect.

The researchers carried out a search of several medical databases to identify trials that compared any statin with a control or placebo drug and their effects on “cardiovascular disease”, “coronary heart disease”, “cerebrovascular disease”, “myocardial infarction” or “cholesterol”. The trials were at least a year long and at least 80% of the participants had no existing cardiovascular disease. Following a quality assessment, 10 trials met the inclusion criteria.

The main outcome that the researchers examined in their analyses was death from any cause, followed by death from heart disease and stroke. Where data was available, they looked at these outcomes in several subgroups: men, women, the young, the elderly and people with diabetes. Where possible, results from the separate studies were pooled in meta-analysis.

What were the results of the study?

Of the 10 studies, two trials examined people with high cholesterol (one of which was in men only), one was in elderly people with cardiovascular risk factors, two were in people with high blood pressure and other risk factors, three were in people with diabetes, one was in people with low cholesterol and one was in people without vascular disease.

In total, the 10 studies included 70,388 participants who had been randomly allocated to receive a statin (35,138 participants) or a control pill (35,250). The number of participants in the trials ranged from 1,905 to 17,802. The average age of participants was 63 and the average length of follow-up was 4.1 years. Overall, 23% of the participants had diabetes. The different trials contained varying numbers of people with other risk factors, such as smoking, BMI, blood pressure and cholesterol.

During follow-up, 5.1% (1,725) of the statin group died compared with 5.7% (1,925) of the control group. Statin treatment significantly reduced the risk of death from any cause by 12% (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81 to 0.96). During this time, 4.1% of the statin group had a major coronary event, such as a heart attack, compared with 5.4% of the control group. In addition, 1.9% of the statin group had a major cerebrovascular event compared to 2.3% of the control group. Therefore, risk of any major coronary event, such as a heart attack, was 30% lower in the statin group (OR 0.70, 95% CI 0.61 to 0.81) and risk of stroke was 19% lower (OR 0.81, 95% CI 0.71 to 0.93).

Analysis of the subgroups (men, women, young, elderly and people with diabetes) showed that statins did not affect risk differently in any particular group.

What interpretations did the researchers draw from these results?

The researchers concluded that, in patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and significant reductions in the risk of major cardiovascular events, such as heart attack and stroke.

What does the NHS Knowledge Service make of this study?

This large and thorough review of 10 trials found that, over an average follow-up of 4.1 years, statins significantly reduced the risk of death from any cause as well as the risk of heart attacks and strokes in people without cardiovascular disease but who had risk factors.

These are important findings and they should be interpreted accurately:

• When combining the results of different trials, there is always some degree of limitation which arises from differences between the trials. These include different populations, different trial drugs, different concurrent use of other medications, different methods of assessing outcomes and different length of follow-up. In particular, the participants of the different trials are likely to have had a highly varied level of cardiovascular risk. As the authors acknowledge, in three of the trials that they included, a small proportion of the participants had existing cardiovascular disease.
• Although the majority of study participants did not have existing cardiovascular disease, they all had cardiovascular risk factors (which varied depending on the trial). Therefore, although some of the newspapers suggest that statins should be given to “all” or “healthy” people above a certain age, this is not strictly the case. If people have existing cardiovascular risk factors, it seems plausible that reduction of one of them, such as cholesterol, will influence risk in some way. How much risk is reduced may depend on the type of risk factors that people have, which this review was not able to examine.

These findings show that a number of people could benefit from long-term statin use. However, as the authors say, identifying people with risk factors could be a challenge. Administering statins to everyone over a certain age in a ‘cover all’ approach has significant cost and safety implications.

Links To The Headlines

Prescribe statins to those at risk at 40, study says. The Times, July 1 2009

Should all over-50s take anti-cholesterol drug? Statins even cut heart attack risk in the healthy. Daily Mail, July 1 2009

Statins 'cut risk of dying by more than a tenth'. The Daily Telegraph, July 1 2009

Statins 'slash risk of heart attacks by 30%'. Daily Express, July 1 2009

Links To Science

Brugts JJ, Yetgin T, Hoeks SE et al.The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ, 30 June 2009 

The Independent says that “the swine flu pandemic might not have happened had it not been for the accidental release of the same strain of influenza virus from a research laboratory in the late 1970s.” The news comes from a medical article which analysed the history of the influenza A H1N1 virus, including the recent development of swine flu seen around the world.

The reports say that the H1N1 influenza strain was responsible for a flu pandemic in 1977, but before this it had not been found in humans for more than 20 years. By looking at the genetic makeup of the 1977 virus, researchers have found that it was similar to a strain that was circulating in 1950. This 1950s strain would have been stored in labs and researchers have suggested that the re-emergence of the virus in 1977 “was probably an accidental release from a laboratory source”, possibly through laboratory workers becoming infected.

Professor John Oxford of the Royal London Hospital is reported as saying that the theory is “plausible”, but that “it may have been a good thing as it would have given many older people alive today some measure of immunity to the current pandemic.” The newspapers have concentrated on the possibility of an accidental reintroduction of the H1N1 virus during the 1970s. However, this is only one aspect of the complex history of the current pandemic swine flu virus discussed in the article. The current swine flu virus has developed over time by natural exchange of genetic material between human, bird and pig strains of the influenza virus. This review does not suggest that the current form was created in or leaked from a laboratory.

Where did the story come from?

The news story is based on a scientific article in the peer-reviewed New England Journal of Medicine by Dr Shanta M Zimmer and Dr Donald S Burke from the University of Pittsburgh. It was funded by the National Institute of General Medical Sciences in the US and the Bill and Melinda Gates Foundation.

What kind of scientific study was this?

The study was a narrative review which described the history of the current swine-origin influenza A virus (H1N1) strain, commonly known as swine flu. The authors discussed the evolutionary and epidemiologic events that led to the emergence of the swine flu strain that caused the current pandemic.

What were the results of the study?

The authors describe the first appearance of influenza in pigs in 1918, when there was a pandemic of human influenza A (H1N1). Pigs also developed respiratory symptoms resembling those of people with the virus, which led scientists to believe that the influenza virus was also infecting pigs.

The authors of this review describe various laboratory experiments in pigs and other animals that supported the theory that the influenza virus seen in pigs had come from the 1918 human pandemic strain. This includes a 1930s study that showed that human antibodies against the 1918 strain of human influenza A (H1N1) could prevent mice from being infected with swine influenza.

After 1918, the rapid changes in the human influenza virus meant that it became different to the influenza virus seen in pigs. The authors say that genetic studies of samples of the human H1N1 virus taken between 1918 and 2006 from 17 countries have shown that the virus gradually mutated over time, exchanging genetic material between different subtypes of the virus. However, it has not gained new genetic material from birds or other sources.

The disappearance of the human H1N1 virus
The authors say that from 1957, influenza A (H1N1) was no longer circulating in humans and that it was replaced by the H2N2 virus. This virus contained genetic material from both the H1N1 strain and a bird virus. The influenza A (H1N1) virus was not identified in humans again until 1977. The authors report that the reasons for this disappearance are not clear, but it may be because an increased immunity against the H1N1 strain, along with the immune reaction against the H2N2 strain, was enough to wipe out the H1N1 strain.

The authors describe evidence of sporadic transfers of swine flu infection to humans over the past 50 years. The first evidence of such transmission was documented in 1958. They say that swine influenza infection in humans may often go undetected because the symptoms were similar to those of human influenza. The sporadic cases of transmission were reported to be through work-related and environmental exposures, including family members of people in high-risk groups (such as those who worked with pigs).

The authors mention an outbreak of a new H1N1 strain of swine influenza in soldiers at an army base in New Jersey in 1976, which resulted in 230 confirmed cases and one death. The virus had a low person-to-person transmission rate and, although it spread within the army base due to close social contact, it did not spread outside the base. A mass immunisation programme against this outbreak immunised 40 million civilians.

The re-emergence of the human H1N1 virus
In 1977, the H1N1 virus also re-emerged in China, Hong Kong and the former Soviet Union. This virus had relatively mild effects and affected mainly young people. This strain was closely related to the strain that circulated in 1950, but not to those seen in 1947 and 1957.The authors say that this suggests that the strain had been “preserved since 1950” and that the re-emergence “was probably an accidental release from a laboratory source” that had managed to take hold due to the waning immunity to this strain in the population.

They say that since this time, the H1N1 virus has been circulating with another influenza A subtype (H3N2, the subtype that is more often dominant) during outbreaks of seasonal flu.
 
The authors discuss changes in the swine influenza virus since 1979. They report that, although swine influenza was detected in pigs in the US as early as 1930, it only spread to Europe in 1976 in a shipment of pigs from the US to Italy. A few years afterwards, the strain was replaced by another H1N1 strain, which was passed onto pigs from wild ducks. There were also reports of events occurring in China.

A new strain was also identified in North American pigs in 1998. This virus had a complex genetic makeup, with parts of its genetic sequence from the original H1N1 swine virus but other parts from bird influenza and human influenza viruses. As the genetic material was combined from three different sources, this was called a “triple reassortant” virus.

The first case of human infection with the triple reassortant virus occurred in Wisconsin in the US, where a 17-year-old became infected after being exposed to pigs at a slaughterhouse. Eleven further cases were reported between 2005 and 2009, with most of those infected having been exposed to pigs. However, the authors note that it is likely that more cases have occurred, as generally people with influenza symptoms do not have their virus isolated and tested to determine its origins.

The swine flu pandemic
The first two cases of the current strain of pandemic swine influenza (called the S-OIV strain) in the US were reported in April 2009. The US Centers for Disease Control and Prevention (CDC) found that these cases were caused by a swine virus that had not previously been identified in the US. Genetic analysis of the virus showed that it contained some genetic material from the triple reassortant swine virus and some from the Eurasian influenza A (H1N1) swine virus lineage.

The authors report that the newly emerged pandemic swine flu virus (S-OIV) has some weak genetic similarity with the circulating seasonal H1N1 virus within parts of their genetic makeup that are descended from the original 1918 strain. They say that how these two strains will compete is uncertain and that it is unknown whether immunity against the seasonal strain might offer some protection against the newly emerging virus.

What interpretations did the researchers draw from these results?

The authors conclude that the emergence of the swine flu pandemic highlights the importance of greater understanding and study of viruses that can affect both animals and humans. They also stress the “critical importance of international collaboration in efforts to predict and control future pandemic threats”.

What does the NHS Knowledge Service make of this study?

This review discusses the history of the influenza A (H1N1) viruses, leading up to the current swine flu pandemic. This history includes the original transmission of the H1N1 strain from humans to pigs during a 1918 pandemic, the divergence of the human and swine flu strains, the disappearance and re-emergence of the human H1N1 strain and genetic changes in the swine and human H1N1 strains.

The newspapers have concentrated on the probable reintroduction of the H1N1 strain into the human population from a laboratory during the 1970s. However, this was only one small aspect of the complex history of the swine flu virus, which has now become a pandemic.

The current swine flu virus has developed over time by natural exchange of genetic material between human, bird and pig strains of the influenza virus, and this review does not suggest that the current virus has been leaked from a laboratory.

Links To The Headlines

Did leak from a laboratory cause swine flu pandemic?. The Independent, June 30 2009

Swine flu lab accident may have caused pandemic? The Daily Telegraph, June 30 2009

Links To Science

Zimmer SM, Burke DS. Historical Perspective - Emergence of Influenza A (H1N1) Viruses. NEJM, June 29 2009 (online publication)

“Two or more abortions could more than double chances of a premature birth next time,” the Daily Mail has reported. Numerous news sources have reported on new research that has linked early pregnancy complications to problems later in pregnancy or in subsequent pregnancies.

This news story is based on a detailed review of a number of studies on pregnancy complications and outcomes. It looked at the link between different early pregnancy complications in a current or previous pregnancy, including prior miscarriage or termination, and adverse outcomes related to later pregnancy and birth. The review identified studies that noted several significant associations in early complications and later problems, in particular risk of premature delivery and low birth weight.

However, the authors note that there are a number of important limitations which must be taken into account when considering their findings. In particular, some figures quoted in the review come from individual studies of variable quality. Nevertheless, these findings indicate the importance of recognising any issues or complications of current and previous pregnancies so that all expectant mothers and their babies receive appropriate monitoring, care and support.

Where did the story come from?

This research was conducted by Dr Robert van Oppenraaij of Erasmus University Medical Centre in the Netherlands and colleagues of the European Society of Human Reproduction and Embryology (ESHRE) Special Interest Group for Early Pregnancy (SIGEP). No sources of funding were reported.

The study was published in the peer-reviewed medical journal Human Reproduction Update. The findings were presented by Dr van Oppenraaij at the 25th annual meeting of the ESHRE in Amsterdam.

What kind of scientific study was this?

This was a systematic review of literature which investigated the possible link between complications during early pregnancy and adverse pregnancy and birth outcomes.

The researchers searched the Medline and Cochrane literature databases for observational studies, which had examined any complications during the first 12 weeks (first trimester) of pregnancy. These included miscarriage or termination of a previous pregnancy and complications of the current pregnancy, including threatened miscarriage, morning sickness, crown-rump length discrepancy and apparent loss of a twin that was previously detected.

The authors looked for studies where data on these complications were combined with documentation of adverse outcomes in later pregnancy and birth. The outcomes they included in their search were numerous, including pre-eclampsia, placenta praevia (placenta positioned over the cervix), premature rupture of membranes, premature delivery and adverse outcomes in the newborn, such as death within 30 days of delivery.

From the studies, they extracted the risk figures for an adverse pregnancy outcome resulting from early pregnancy complications. The review examined each early pregnancy complication and its associated outcomes in depth and discussed possible reasons for this apparent link.

The researchers graded each link they found according to the consistency their finding had with the studies that provided the strongest level of evidence. This grading ranged from ‘A’ (consistent evidence from high-quality studies) to ‘D’ (inconsistent or inconclusive studies of any level). The review did not carry out statistical pooling of the results of the studies it identified, as the studies were reported to be too different to allow this approach. Odds ratios or relative risks of outcomes were reported from the “best and largest” individual studies.

The review provided a large number of detailed findings, a summary of which follows.

What were the results of the study?

The review found a significant increase (at least doubling) in the risk of the following outcomes after the associated complication in a previous pregnancy:

• Increased risk of infant death around the time of birth following a single miscarriage in a previous pregnancy.
• Increased risk of very premature delivery (birth at less than 34 weeks of pregnancy) following two or more previous miscarriages.
• Increased risk of very premature delivery following two or more previous terminations of pregnancy.
• Increased risk of placenta praevia, premature preterm rupture of membranes and low infant birth weight after recurrent miscarriage.

The review found a significant increase (at least doubling) in the risk of the following outcomes in a current pregnancy after the associated complication:

• Increased risk of low (less than 2.5kg) and very low (less than 1.5kg) birth weight after a threatened miscarriage.
• Increased risk of pregnancy-induced hypertension, pre-eclampsia, placental abruption, premature delivery, infant small for gestational age and low 5-minute Apgar score (a scoring system that assesses the immediate health and responsiveness of the newborn) after detection of an intrauterine haematoma.
• Increased risk of very premature delivery and intrauterine growth restriction after a crown-rump length discrepancy.
• Increased risk of very premature delivery and low and very low birth weight following a ‘vanishing twin phenomenon’.
• Increased risk of premature delivery (birth at less than 37 weeks), low birth weight and low 5-minute Apgar score in a pregnancy complicated by severe morning sickness (note that risk of miscarriage is significantly decreased in a pregnancy with morning sickness).

For a number of other specific outcomes, there was either no data about the association with early complications or no significant association.

What interpretations did the researchers draw from these results?

On the basis of their review, the authors conclude that specific events and complications during the first 12 weeks of pregnancy are predictors of subsequent adverse outcomes later in pregnancy and at the time of birth. However, they acknowledge that some of these associations are based on limited or small uncontrolled studies and that larger, population-based controlled studies will be needed to confirm these associations.

What does the NHS Knowledge Service make of this study?

This detailed review has identified a number of available studies which have examined the link between early pregnancy complications and adverse outcomes, both later in that same pregnancy and in future pregnancies.

The review identified studies that noted several significant associations. Although some of the associations are derived from large, high-quality studies, there are important limitations when considering certain pregnancy complications individually.

For example, termination of pregnancy may be carried out by either medical or surgical means at different times in a pregnancy and for various reasons (for example, due to an unwanted pregnancy or medical complications with the mother or developing foetus). This review considered all types of termination as a single risk factor and did not take into account how the range of reasons or methods involved may differently affect associated outcomes in a later pregnancy.

Equally, the main review only presented the overall relative risk figures (i.e. how many times more likely an event was) rather than the absolute size of the risk. From these figures we know how likely an outcome is following a particular complication compared to not having the complication, but the figure does not tell us how common that outcome will actually be among all pregnant women.

Absolute risk figures can be obtained by consulting the supplemental data provided alongside the main review and the individual studies themselves, but this data is too extensive to summarise here. Absolute risk figures were variable but, in general, they were still quite low. For example, incidence of low infant  birth weight was 9.4% in women who had had two or more miscarriages compared to 4.5% in women who had not, and 2.8% in women who had had a previous termination compared to 1.4% in women who had not had a termination.

There are several other points to note when interpreting this study:

• The studies included in the review are likely to be of variable quality and have different sizes, methods, assessment methods and the possibility of bias. The authors avoided combining them to give a pooled estimate of the risk of an outcome.
• The relative risk figures reported in the review were taken from a single study, which was the best and largest study identified. However, as the authors observe, the majority of studies from which these risk figures came were what they graded as B or C, i.e. evidence from moderate or poorer-quality studies or extrapolations of findings from studies of higher quality.
• There are various possible confounding factors linked to both early pregnancy and later pregnancy complications, which may or may not have been taken into account by the different studies when they were examining risk. These include maternal age, smoking, alcohol or drug abuse, socioeconomic status or medical comorbidity.
  As the authors say, larger, controlled studies using National Birth Registries are needed to further examine these associations.

Even though some of the associations are only supported by limited evidence and are not confirmed, they nevertheless indicate the importance of recognising any issues or complications that expectant mothers and their babies may face. This will enable them to receive appropriate monitoring, care and support.

As Dr van Oppenraaij said in the press conference, “While it is true that most conditions are difficult to prevent, with improved monitoring in high-risk pregnancies it is possible to reduce perinatal or postnatal foetal complications.”

Links To The Headlines

Early pregnancy problems warning. BBC News, June 28 2009

Problems in early pregnancy linked to more serious complications, says study. The Times, June 29 2008

Abortions double premature tot risk. Daily Mirror, June 29 2009

Two or more abortions could more than DOUBLE chances of a premature birth next time. Daily Mail June 29 2009

Links To Science

van Oppenraaij RHF, Jauniaux E, Christiansen OB et al. Predicting adverse obstetric outcomeafter early pregnancy events and complications: a review. Human Reproduction Update, March 7 2009 (advanced access publication)

Aneurysm screening is "set to save thousands of lives”, The Guardian has reported. The newspaper said that nearly 2,000 lives could be saved each year by a new screening programme for elderly men, which will look for weaknesses in the aorta, the body’s biggest artery. This national screening programme for abdominal aortic aneurysms (a potentially fatal swelling of the aorta) is being rolled out across England.

Two important studies, published in the British Medical Journal, have assessed the effectiveness and cost-effectiveness of the national screening programme. The programme was established based on the results of one of these studies: the Multicentre Aneurysm Screening Study. In a long-term follow-up of this pilot, a reduced rate of death from aneurysms was seen after 10 years. An economic analysis demonstrated that the programme is cost-effective. In other words, the benefits that the screening programme achieved are worth the cost.

A second, Danish study was based on a mathematical model of a hypothetical screening programme. It concluded that, based on UK thresholds of cost-effectiveness, ultrasound screening for abdominal aortic aneurysm is unlikely to be cost-effective.

Both studies acknowledged that a screening programme would reduce the number of deaths from aneurysms. Their discrepancies in terms of the cost-effectiveness results may be due to the costs used in the Danish model.

Where did the story come from?

The British Medical Journal has published two separate studies which assessed the clinical and financial effectiveness of abdominal aortic aneurysm screening programmes.

The first is a publication of the long-term results of a study conducted in the UK by Dr SG Thompson and colleagues on behalf of the Multicentre Aneurysm Screening Study Group (MASS). The MASS study, which began in 1997, was funded by the Medical Research Council.

In a second study, Danish researchers Lars Ehlers and colleagues from Aarhus University and other academic institutions across Denmark carried out a mathematical modelling exercise to determine the cost-effectiveness of screening men aged over 65 for aortic abdominal aneurysm. This study was funded by the Centre for Public Health in the Central Demark Region.

What kind of scientific study was this?

The aorta is a major blood vessel which originates in the heart and branches through the chest, abdomen and into the legs. At any point along its length, the vessel can balloon and dilate due to structural weakness. This is called an aortic aneurysm and, if it ruptures, can prove fatal.

The national aortic aneurysm screening programme, which has recently been rolled out across England, is largely based on the evidence from the MASS study. This study demonstrated a mortality benefit of ultrasound screening in men aged 65 to 74 in the UK. The longer-term results and an analysis of the cost-effectiveness of screening were presented in the most recent publication from this ongoing research.

The MASS study began in 1997 and enrolled 67,770 men, aged 65 to 74. The men were randomised to enter a control group or to receive an invitation for screening for abdominal aortic aneurysm. Early results showed that, of the 33,883 men invited, 27,204 (80%) attended screening. 1,344 aneurysms of 3cm or larger were detected. Men with aneurysms larger than 5.5cm were referred for surgery. Men with aneurysms of 3.0-4.4cm were re-scanned every year, while those with aneurysms 4.5 to 5.4cm were re-scanned every 3 months. Surgery was also offered if the aneurysm increased in size by 1cm or more in a single year, or if there were associated symptoms.

The men were followed up for an average of 10 years. The researches collected information from the UK Office for National Statistics on any aneurysm ruptures, deaths within 30 days of surgery for aortic aneurysm or deaths recorded as being due to a ruptured aortic aneurysm, abdominal aneurysm with or without mention of rupture or ruptured thoracoabdominal aneurysm.

The researchers used statistical methods to compare the deaths due to any cause and deaths due to abdominal aortic aneurysm between the screened and unscreened groups. The cost-effectiveness of the screening programme was also established by working out how much treatment cost in relation to the mortality benefits seen.

In the Danish study, researchers used a mathematical model to forecast the cost and benefits of screening a hypothetical cohort of men aged 65. The researchers used a hypothetical screening programme consisting of a mobile ultrasound team in a community setting.

The hypothetical population model took into account such factors as aneurysm prevalence and rates of screening attendance, which were based on estimates derived from a systematic review of relevant literature. For example, studies suggest that 4% of men over 65 have an abdominal aortic aneurysm larger than 3cm and that 77% of men invited will take up screening. Research also demonstrates the risk of rupture, aneurysm growth rate and the 30-day mortality for elective (non-emergency) and emergency surgery.

Estimates of long-term mortality figures after surgery for aneurysm were derived from a study of the Danish Vascular Registry. Costs of screening and surgery were taken from the literature and converted to 2007 pounds.

What were the results of the study?

Long-term follow-up of the men enrolled in the MASS study showed a mortality benefit in those invited for screening. Of the men invited for screening, 0.46% died due to abdominal aortic aneurysm, compared with 0.87% of men in the control group. These figures show that deaths were rare, but the group who received screening were 48% (1 - [0.46/0.87]) less likely to die from an abdominal aortic aneurysm.

As expected, more elective operations took place in the screened group than in the control group, which experienced more emergency surgeries than the screened group. However, there were no differences in mortality between the screened and unscreened groups receiving elective and emergency surgery.

The English study concluded that screening was cost-effective, at a cost of £9,400 per quality-adjusted life year (QALY) gained as a result. This figure is much lower than the £20,000 to £30,000 threshold used by the National Institute for Health and Clinical Excellence, which establishes guidelines for the use of treatments by the NHS. The Danish study estimated that abdominal aortic screening for men over 65 would cost £43,485 per QALY gained.

What interpretations did the researchers draw from these results?

In the MASS study, researchers concluded that the benefits of screening men aged 65 to 74 for abdominal aortic aneurysm are maintained for a period of up to 10 years and that the programme remains cost-effective over time. They say that to maximise the benefit from a screening programme, emphasis should be on achieving a high initial rate of attendance and good adherence to clinical follow-up, preventing delays in surgery and maintaining low operative mortality after surgery.

The Danish researchers concluded that, on the basis of acceptable thresholds of cost-effectiveness (£30,000 per QALY) in the UK, screening for aortic abdominal aneurysm is unlikely to be cost-effective. They say that further research is needed on long-term quality-of-life outcomes and costs.

What does the NHS Knowledge Service make of this study?

Both these studies are of interest given the introduction of England’s aortic abdominal aneurysm screening programme. They both highlight some important issues connected to this new programme and screening programmes in general.

The researchers of both studies highlight the possible limitations of their own work. The Danish researchers say that, while the type of model they used to estimate cost-effectiveness has strengths over and above the use of economic evaluations in primary studies, they were limited by having to rely on a combination of data from studies in different countries. Also, they only focused on men aged 65 at the start of screening.

The differences in the age groups of men in the MASS study and those in the Danish model may be one reason for the different conclusions about cost-effectiveness. They are also likely to have included different costs for elective and emergency surgery as MASS was UK-based and the Danish model used data from the Danish health system. Screening will also be sensitive to other costs, which can vary between countries.

The MASS researchers say that the cost-effectiveness of screening will improve over time because the main costs of the programme (screening and elective surgery for large aneurysms) occur early on. The Danish researchers point out that costlier elective surgery may increase the overall costs of screening.

An editorial that accompanies the publication of these two studies points out that the costs of screening in Denmark are higher than in the UK. Martin Buxton, the Professor of Health Economics who wrote this editorial, says that it is difficult to fully explain these different cost-effectiveness results without either access to more information about the Danish model or the chance to evaluate the inclusion of the new 10-year follow-up effectiveness data from the MASS study in the Danish model.

His conclusion is based on his appraisal of the available data and seems a sensible bottom line for policy makers: “The accumulated evidence suggests that a national screening programme in the UK is appropriate and likely to be cost-effective,” but with the proviso that “costs and outcomes need to be carefully monitored and the data need to be regularly re-analysed to ensure that both the effectiveness and cost-effectiveness remain acceptable in the context of changing practice.”

He says that “a UK screening programme will be acceptably cost-effective, providing that effectiveness can be maintained across the country and that the cost estimates remain relevant.”

Links To The Headlines

Screening 'could halve deaths from burst artery'. The Daily Telegraph, June 26 2009

Aneurysm screening study boost. BBC News, June 26 2009

Aneurysm screening set to save thousands of lives. The Guardian, June 26 2009

Links To Science

Thompson SG, Ashton HA, Gao L, Scott RAP. Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study BMJ 2009;338:b2307

Ehlers L, Overvad K, Sorensen J et al. Analysis of cost effectiveness of screening Danish men aged 65 for abdominal aortic aneurysm. BMJ 2009;338:b2243