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BBC News has reported that doctors should check ill children for leg pain, confusion, stiff neck and sensitivity to light, as they are "red flag" symptoms for meningitis.

The news is based on research that compared children’s early symptoms of meningococcal disease to the symptoms seen in a group of children with only minor infections. Meningococcal disease is a type of bacterial infection that can cause serious problems such as septicaemia. The research found that headache and paleness, which are often suggested as possible early warnings signs, were just as frequent in children who had minor infections. However, confusion, sensitivity to light, neck pain/stiffness and leg pain were all stronger indicators of meningococcal disease. Although the development of a rash is an important sign, it typically appears at a later stage of infection.
 
It should also be noted that the research was intended for informing doctors rather than parents, and parents should not be worried about this news. The study’s results will also need further verification as it had some limitations, such as parents possibly recalling their children’s symptoms incorrectly.

Parents and carers who are worried about any symptoms in babies or young children, especially if they have a high temperature (fever), should always contact their doctor. Meningococcal disease is a very serious illness but if treated quickly, most children make a full recovery.

 

Where did the story come from?

The study was carried out by researchers from Oxford University and Oregon Health and Science University using data collected from GP surgeries in Oxfordshire and Somerset. The study was published in the peer-reviewed British Journal of General Practice.

The Daily Telegraph and the BBC have reported the study accurately. Both of them reported comments from independent experts who warned against parents ignoring other symptoms.

 

What kind of research was this?

This was a non-randomised comparative study, which looked at the frequency of certain classic and “red flag” symptoms associated with meningococcal disease, the diseases caused by Neisseria meningitidis bacteria. It analysed these symptoms by gathering cross-sectional data on the symptoms of children visiting GPs with minor infections (the control group) and comparing it to previously-published data on the pre-hospital symptoms seen in children with diagnosed meningococcal disease (the case group).

The authors say that it can be challenging for doctors in primary care to identify which children have serious infections among the many who present with febrile illnesses. It is also a worry for parents. They also point out that about half of children with meningococcal disease are not identified in the first consultation in primary care (usually with a GP).

One reason is because “classic” symptoms, such as neck stiffness, sensitivity to light and rash, may not appear until later in the course of the illness. They say that several possible “red flag” features that occur at an earlier stage of meningococcal disease have been proposed as potential aids for early detection. These are leg pain, cold hands and feet and pale colour.

 

What did the research involve?

To gather control group data for the study, the authors recruited 1,212 children who had visited 15 GP surgeries with some form of acute illness.  They collected information about the frequency of symptoms among the children presenting to the GP by giving their parents a symptom checklist to complete.

Within this group, 407 children were reported to have both fever and a minor infection, making them suitable for comparison against children with meningococcal disease. They had a typical range of minor infections. This control group had an average age of 3 years and 6 months. Half of them were aged between 22 to 79 months. There were few teenagers.

The researchers then looked at the incidence of various symptoms within the meningococcal disease group and the control group with general minor infections. The symptoms they were interested in included:

• sensitivity or fear of light (photophobia)
• neck pain or stiffness
• headache
• leg pain
• cold hands or feet
• pale colour
• confusion
• drowsiness or feeling very sleepy
• rash or new spots on skin
• nausea or vomiting
• feeling irritable or miserable
• general aching
• difficult/laboured breathing

The researchers compared the frequency of symptoms obtained from the children seen in GP surgeries with previously published data on the frequency of the same symptoms in children with diagnosed meningococcal disease. They used standard statistical methods to compare the frequency of different symptoms and to calculate their diagnostic value.

 

What were the basic results?

The researchers had parental report data on 407 children who were identified as having a fever and a minor infection, and 345 children who developed meningococcal disease.

The researchers looked at the specificity of each symptom – testing positive for a symptom with a high specificity tends to confirm the diagnosis. They found that four symptoms were “highly specific” for meningococcal disease.

However, a more clinically-relevant measure would be the ‘likelihood ratio’ of a positive result (LR+), a value that indicates the chance that the presence of a specific symptom is caused by meningococcal disease. The researchers suggest that a LR+ of more than 5.0 is important as it indicates a high chance of having the disease in those who have that symptom. They found that:

• confusion had an LR+ value of 24.2 (95% confidence interval [CI] 11.5 to 51.3)
• sensitivity to light had an LR+ value of LR+ 6.5  (95% CI 3.8 to 11)
• leg pain had an LR+ value of LR+ 7.6  (95% CI 4.9 to 11.9)
• neck pain had an LR+ value of LR+ 5.3 (95% CI 3.5 to 8.3)

They also identified symptoms that offered a “likelihood ratio” of a negative result (LR-) of 0.3 or less, a score that would suggest that meningococcal disease was unlikely if an individual did not have the symptom. These were:

• drowsiness (LR- 0.2, 95% CI 0.2 to 0.3)
• rash (LR- 0.3, 95% CI 0.2 to 0.3)

They found that the two groups had a similar incidence of headache (LR+ 1.0, 95% CI 0.8 to 1.3) and of pale colour (LR+ 0.3, 95% CI 0.2 to 0.5). Cold hands and feet had a “small positive likelihood ratio” (LR+ 2.3, 95% CI 1.9 to 3.0) Rash (LR+ 5.5, 95% CI 4.3-7.1) was also found to have a positive LR above 5, but also had a low LR- score.

 

How did the researchers interpret the results?

The authors say that of the symptoms studied, the only ones that can be considered early “red flag” signs of potential meningococcal disease are confusion, leg pain, sensitivity to light, and neck pain/stiffness. Headache and pale colour were less frequent among children with meningococcal disease than those with minor infections. Cold hands and feet offered only “limited discrimination” between meningococcal disease and minor infection.

The authors say the findings should be used as evidence to support or modify methods by which doctors diagnose meningococcal disease and assess children with acute infections.

 

Conclusion

The study’s results confirm that four of the “classic” symptoms of meningococcal disease – leg pain, confusion, neck pain and sensitivity to light – are very rare in children with minor febrile illnesses compared to those with meningococcal disease. However it also found that two symptoms which are often described as early warning signs or symptoms – pale skin and headache – are equally likely to indicate a minor illness. Cold hands and feet were only slightly more likely in children with meningococcal disease.

Meningococcal disease can be a very serious illness. Unfortunately, it can be difficult to differentiate it from a relatively minor infections, particularly in its early stages or in younger children. Refining the clinical methods for diagnosing early meningitis would be invaluable. This study has suggested that certain symptoms may be good indicators of meningococcal disease in children. However, the study was relatively small and has a number of limitations, some of which the authors mention.

• Gauging the incidence of the symptoms depended on accurate parental recall of their children’s illness. However, there may have been some inaccuracy in the information provided by the parents of children with meningococcal disease, given the worrying nature of the infection and the practice of questioning parents in the later stages of the disease.
• Also, it is possible that children recruited from the GP surgeries were not representative of children across the UK.
• There were also few children aged 15-16 years, so it is not possible to say anything about symptom frequencies in young people.
• It may be hard for younger children to articulate certain symptoms of their illness, particularly if their illness is severe or if they are in distress: for instance, a child may not be able to differentiate between the two symptoms of light hurting their eyes and having a headache.
• It is important to consider the implications of combinations of symptoms, and how possessing or lacking different symptoms may affect diagnosis.

The early symptoms of meningococcal disease are similar to those of many other conditions, and include severe headache, fever, nausea and vomiting. Parents who are worried about any symptoms in a baby or young child should always seek medical advice.

Links To The Headlines

Doctors offered meningitis ‘red flag’ advice. BBC News, February 26 2011

Meningitis early-warning signs questioned. The Daily Telegraph, February 25 2011

Links To Science

Haj-Hassan TA, Thompson MJ, Mayon-White RT et al. Which early ‘red flag’ symptoms identify children with meningococcal disease in primary care? British Journal of General Practice, March 2011 Vol 61, No 584 [Awaiting publication]

“Scientists are a step closer to beating cancer after discovering how a rare type of the disease can heal itself,” reported the Daily Express. It said that this finding “could pave the way for new drugs to treat a range of tumours, including breast and bowel cancer”.

This story is based on research which identified the mutated gene that is responsible for a very rare skin cancer condition called multiple self-healing squamous epithelioma (MSSE). People with this condition have multiple skin tumours that grow rapidly for a few weeks before spontaneously healing, leaving only a scar. Now that researchers have identified the gene responsible, called TGFBR1, this will help them go on investigate how the tumours heal.

Study of this rare condition may help scientists to better understand how tumours can form, and how they resolve themselves. However, there is much more research to be done. Whether this will lead directly to new treatments for other kinds of more common tumours remains to be seen.

 

Where did the story come from?

The study was carried out by researchers from the University of Dundee College of Medicine and other international research institutions. Cancer Research UK and the Biomedical Research Council (A*STAR) of Singapore funded the research. The study was published in the peer-reviewed journal: Nature Genetics.

The Daily Telegraph and the Daily Express both covered this story.

 

What kind of research was this?

The aim of this genetics study was to identify the gene that causes a rare skin cancer condition called multiple self-healing squamous epithelioma (MSSE), or Ferguson-Smith disease. In this disease, multiple skin tumours form and grow rapidly for a few weeks but then spontaneously heal, leaving just scars. Previous studies have shown that this disease runs in families, and is caused by a mutation in a single gene located on the long arm of chromosome 9. However, the mutated gene had not yet been identified.

The methods used in this study are typical for this type of research. It is important to point out that most cancers are not caused by a mutation in a single gene but by a complex interplay of genetic and environmental factors. However, identifying the genes that cause these rarer cancers may potentially help researchers to understand more about the cancers with more complex causes.

 

What did the research involve?

The researchers used DNA from 143 individuals from 22 families affected by multiple self-healing squamous epithelioma (MSSE). At least half of these families were of Scottish ancestry.

To narrow down the genes that may be responsible for the cancer, the researchers used high-throughput techniques to ‘capture’ and sequence the 152 genes located in the region of DNA on chromosome 9 where the mutation was known to lie. They did this using DNA from 10 individuals: four affected pairs of parents and children from four unrelated families, and one parent-child pair from an unaffected control family. They then looked for mutations in the DNA that occurred in the affected parents and children (but not in the controls) and that would be expected to affect the protein that was encoded by the gene. The mutation causing the disease is dominant, which means that a person only needs to carry one mutated copy of the gene to be affected. Therefore, the researchers also knew they were looking for a mutation that affected only one of the two copies of the gene carried by each person.

The researchers found a mutation in a gene that fulfilled these criteria. They went on to sequence this gene in all the 22 available families with MSSE, to see if other individuals with the disease carried mutations in the same gene. They also sequenced the gene in 80 unrelated healthy Scottish individuals to make sure that mutations in this gene did not occur in healthy people.

The researchers then tested thin slices of MSSE tumours and normal skin to see whether the protein encoded by this gene was present.

 

What were the basic results?

Using high-throughput sequencing of the candidate region of chromosome 9, the researchers identified three different mutations in the transforming growth factor beta receptor 1 (TGFBR1) gene in individuals from three unrelated families affected by MSSE.

When they went on to sequence this gene in 22 families with MSSE, they found mutations in the TGFBR1 gene in 18 of the families. They sequenced 67 people with MSSE from these 18 families, and found that they all carried mutations in the TGFBR1 gene. They detected no TGFBR1 mutations in 80 unrelated healthy individuals from the Scottish population. The TGFBR1 protein was found in both normal skin and MSSE skin tumours.

The mutations identified would cause various changes to the TGFBR1 protein encoded by the gene, for example, changing one or more of the protein’s amino acids, or causing the protein to be shorter than normal. The TGFBR1 protein encoded by this gene sits in the membrane of the cells and binds to the signalling molecule TGF-?. Previous studies have found that TGF-? plays a role in cell growth and division, and that its effects on tumours can vary depending on their stage. TGF-? signalling normally restricts cell growth. It can also protect against early stage cancer formation in mice, but it can increase the aggressiveness of later-stage tumours.

 

How did the researchers interpret the results?

The researchers conclude that their results “show another link between TGFBR1 and cancer and provide compelling evidence that mutations in TGFBR1 cause the self-healing skin tumors of MSSE”. They say that in light of this discovery, they can now better study why these tumours spontaneously heal themselves.

 

Conclusion

This study has identified the genetic mutation that causes the rare and unusual skin cancer condition, multiple self-healing squamous epithelioma or Ferguson-Smith disease. This condition is rare and unusual in that the skin tumours spontaneously get better, leaving just scarring.

Most cancers are not caused by a mutation in a single gene. They are the result of a complex interplay of genetic and environmental factors. However, better understanding of rare tumour causing conditions caused by a single gene may help to understand the biology of other tumours better and, in this case, how they might heal themselves. A lot more research will be needed before researchers can fully understand the processes underlying this condition, and to determine their similarity to the processes leading to the formation of other skin cancers or other kinds of tumour.

At this stage, it is too early to say whether these findings will lead directly to new treatments for skin cancers or other kinds of tumours.

Links To The Headlines

Scientists discover cause of rare skin cancer that heals itself. The Daily Telegraph, February 28 2011

How the discovery of a faulty gene may be key to beating cancer. Daily Express, February 28 2011

Links To Science

Goudie DR, D’Alessandro M, Merriman B, et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nature Genetics 2011

Press release: Scientists discover cause of rare skin cancer that heals itself. Cancer research UK

“Hot flushes may be a blessing,” according to The Daily Telegraph. The newspaper reported that women who experience the menopausal symptom may have a reduced risk of heart attack and stroke.

The news is based on research that assessed menopausal symptoms, such as hot flushes and night sweats, in 60,027 US women with an average age of 63 years. The researchers followed the women for an average of 9.7 years to assess whether their symptoms were linked to their risk of heart attacks and strokes (cardiovascular events), or death due to any cause. However, the study did not provide conclusive answers on the matter, and found that the symptoms assessed were associated with either decreased or increased risk, depending on when they first occurred.

The results also conflict with some previous studies, which means that it is currently not clear whether hot flushes are an indicator of cardiovascular risk. As such, it is inappropriate at the moment to tell women who experience hot flushes that these symptoms are “a blessing” or that they have a “lower risk of heart attacks”.

 

Where did the story come from?

The study was carried out by researchers from several academic institutions in the US and was funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health and the US Department of Health and Human Services. The study was published in Menopause, the peer-reviewed journal of The North American Menopause Society.

In general, the newspapers over-simplified the findings of this study. The study has not been able to conclusively determine the predictive role that hot flushes and other “vasomotor symptoms” may have for cardiovascular disease events. Previous studies have showed them to indicate an increased risk. The current study found them to be associated with either a decreased or increased risk, depending on when the symptoms were experienced. Much further study is needed.

 

What kind of research was this?

This cohort study investigated the emerging theory that women with menopausal vasomotor symptoms (i.e. flushing) have increased cardiovascular risk. Previous studies have shown women who experience flushing to have higher blood pressure, cholesterol and body mass index (BMI), all of which are associated with an increased cardiovascular risk. The researchers also say that two major clinical trials – the Women’s Health Initiative (WHI) Hormone Therapy Clinical Trials and the Heart and Estrogen/Progestin Replacement Study – have reported an elevated risk of coronary heart disease among women who experienced hot flushes.

To gain a better understanding of the association, the researchers examined data from the ongoing WHI Observational Study (WHI-OS). This cohort study, they say, includes a larger, more-representative population of women who experience hot flushes than the WHI hormone therapy clinical trials, which excluded women with more significant vasomotor symptoms.

The objective of the current study was to investigate whether vasomotor symptoms predicted the
development of cardiovascular disease events (such as heart attack or stroke), or death from any cause. The researchers also looked at whether there is a difference between women who experience hot flushes at the start of their menopause and women who developed them later on.

 

What did the research involve?

From 1994 to 1998, the WHI-OS study enrolled 93,676 women from across 40 US clinical centres. Eligible participants were postmenopausal women aged 50-79 years old, with menopause defined as either no periods for at least 12 months if participants were aged 50-54, or no periods for at least 6 months if they were 55 or over.

At the start of the study, participants completed questionnaires about their lifestyle, demographic details and medical conditions, and had body measurements and blood pressure taken. The questionnaires specifically asked:

• whether they had ever been told by a doctor that they had high blood pressure, diabetes or high blood glucose
• if they had high cholesterol requiring pills
• if they had a family history of heart attack at a young age (over 55 years of age) in a first-degree relative

In addition, women gave details about their use of any hormone therapy (HT), and were classified as never, past or current users of HT.

Women were asked questions to assess if they had ever had vasomotor symptoms and, if so, when they first and last experienced them. They were also asked at the start of the study about the presence of vasomotor symptoms such as hot flushes or night sweats during the four weeks preceding their enrolment in the study. If symptoms were present, they were asked to rate them as mild (symptom did not interfere with usual activities), moderate (some interference with usual activities) or severe (so bothersome that usual activities could not be performed). Women were considered to have had vasomotor symptoms at the onset of menopause if their age when they first had hot flushes or night sweats was less than or equal to their age at menopause.

The study’s outcomes of interest were major coronary heart disease events (fatal or non-fatal heart attacks), any cardiovascular disease events (fatal or non-fatal heart attacks or strokes), and death from any cause. Analyses took into account various potential factors (confounders) that could affect the risk of cardiovascular disease (such as smoking, age and blood pressure).

Of the 93,676 postmenopausal women initially enrolled, 78,249 had no prior history of cardiovascular disease or cancer. Of these, 77,631 (99.2%) reported information on vasomotor symptoms at the start of the study and 60,773 (77.7%) reported information on vasomotor symptoms at the onset of menopause. The study’s analysis only included the 60,027 women who fulfilled all of these criteria.

 

What were the basic results?

The average age of women in this study was 63.3 years old, and they had gone through the menopause an average of 14.4 before enrolment in the study. The average (median) follow-up time of these women was 9.7 years. Of the women included, 4.3% withdrew before the end of follow-up and 6.7% died.

Of the 60,027 women analysed:

• 31.3% (18,799) had never experienced vasomotor symptoms
• 41.2% (24,753) had experienced them at the start of their menopause but they were gone by study enrolment (referred to as early symptoms)
• 25.1% (15,084) had had vasomotor symptoms persistently since menopause, both at start of menopause and at enrolment (referred to as persistent symptoms)
• 2.3% (1,391) did not have symptoms at start of menopause but had them at the time of enrolment (referred to as late symptoms)

Overall, the researchers reported that there was no association between having experienced vasomotor symptoms and the risk of any cardiovascular outcomes or death from any cause. However, results of these overall statistical analyses were not shown in the paper.

The researchers then separately analysed the three different groups who had vasomotor symptoms at different times. They found that, compared to women who had never experienced these symptoms:

• Women who experienced early symptoms had a significantly reduced risk of any cardiovascular disease event (fatal or non-fatal heart attack or stroke, hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.81 to 0.97), stroke (HR 0.83, 95% CI 0.72 to 0.96), or death from any cause (HR 0.92, 95% CI 0.85 to 0.99). There was no significant association with major coronary heart disease events.
• For women with persistent vasomotor symptoms, there was no significant association with any of the outcomes.
• Women who experienced late symptoms had an increased risk of major coronary heart disease events (HR 1.32, 95% CI 1.01 to 1.71), a borderline increased risk of any cardiovascular disease event (HR 1.23, 95% CI 1.00 to 1.52), and an increased risk of death from any cause (HR 1.29, 95% CI 1.08 to 1.54). There was no significant association with stroke.

 

How did the researchers interpret the results?

The researchers concluded that early vasomotor symptoms were not associated with increased cardiovascular risk, but with decreased risk of stroke, total cardiovascular events, and death from any cause. However, late vasomotor symptoms were associated with increased coronary heart disease risk and death from any cause.

As such, they say that the value of vasomotor symptoms for predicting cardiovascular disease events may vary depending on the stage of menopause at which they first occurred. They say there is a need for further research to examine the mechanisms underlying these associations.

 

Conclusion

This research has attempted to determine whether menopausal symptoms, such as flushing and hot sweats, can predict heart attacks and strokes (cardiovascular events) and death. However, the research does not provide conclusive answers.

Previous studies have shown hot flushes to indicate increased risk of cardiovascular disease, but the current study found these symptoms to be associated with either a decreased or increased risk, depending on when they were experienced. However, when the research considered the experience of hot flushes at any time during menopause, it found no association with the risk of cardiovascular disease events. How this seemingly complex relationship works was not examined by this research and, as the authors say, much further study is required.

This study had strengths in that it included a large sample of women who did not have cardiovascular disease at start of the study. It followed them for almost 10 years. The study had a low drop-out rate, it objectively assessed a large amount of health and lifestyle data, and accounted for a large number of potential confounders.

Among the study’s limitations are its retrospective assessment of symptoms that occurred before enrolment in the study, which may potentially have been inaccurately recalled by the participants. Another limitation, acknowledged by the authors, is the difficulty in picking apart the relationship between vasomotor symptoms and use of hormone therapy, although they attempted to do this by adjusting for hormone therapy use in their analyses.

In isolation, the findings of this research suggest a potentially complex relationship between vasomotor symptoms and risk of cardiovascular disease. The results also seem to differ from  other studies in this area: as such the link between vasomotor symptoms and cardiovascular risk are unclear and still require further research. In this context it is inappropriate at the current time to tell women who experience hot flushes that they are ‘a blessing’ or ‘lower risk of heart attacks’, as some newspapers have done.

Not smoking and maintaining a healthy weight through a balanced diet and regular exercise are the best ways to maintain good cardiovascular health.

Links To The Headlines

Hot flushes may be a blessing. The Daily Telegraph, February 25 2011

Hot flushes linked to lower heart attack risk. The Independent, February 25 2011

Women’s hot flushes may have silver lining: Menopause link to lower risk of heart attacks. Daily Mail, February 25 2011

Links To Science

Szmuilowicz ED, Manson JE, Rossouw JE et al. Vasomotor symptoms and cardiovascular events in postmenopausal women. Menopause: The Journal of The North American Menopause Society Vol. 18, No. 6

“Stress and tension does not prevent women undergoing infertility treatment from becoming pregnant,” reported The Daily Telegraph.

This news story is based on a review of previous studies, which investigated whether anxiety or depression affect the chances of becoming pregnant after a single cycle of fertility treatment, such as IVF. The review identified 14 studies in 3,583 women from 10 different countries, and combined their results to investigate this question.

The results showed that women who became pregnant after the treatment cycle did not differ significantly in levels of anxiety or depression before their treatment than women who did not become pregnant.

This is a well-conducted review , which provides a reliable summary of the existing studies on this question. The researchers’ conclusions were appropriate, and the review should reassure women and doctors that the emotional distress of fertility problems or other life events should not damage the chance of becoming pregnant through fertility treatment.

 

Where did the story come from?

The study was carried out by researchers from Cardiff University and the University of Thessaloniki, Greece. The research did not receive funding. The study was published in the peer-reviewed British Medical Journal. The BBC, Telegraph and Mail accurately reflected the findings of this review.

 

What kind of research was this?

This systematic review and meta-analysis investigated whether emotional distress in women receiving fertility treatment affected their chances of a successful pregnancy.

A systematic review, which searches the global literature on a particular subject, is the best way of identifying all relevant studies that have investigated whether a particular exposure (in this case, emotional distress) is associated with an outcome (in this case, pregnancy after fertility treatment). The difficulty with this sort of review is that the studies included are likely to have differed in some ways. For example, the populations studied and the methods and technology used may have differed between studies. In particular, emotional distress is a very subjective experience.

To account for this, studies should ideally use validated methods for assessing emotional distress.  The reviewers in this study did assess whether this was the case in the studies they included, and found that most of the studies did use validated methods. In addition, in order to assess whether emotional distress could affect the outcome of fertility treatment, it would be important to measure emotional distress before the start of the treatment. To ensure that this was the case, the review only included studies that did do this.

 

What did the research involve?

The researchers searched medical databases from 1985 to 2010 and hand-searched relevant publications and reports of fertility conferences to identify potential studies. They were interested in studies that investigated whether a woman’s level of emotional distress (anxiety or depression) before fertility treatment affected her chances of becoming pregnant. For inclusion in the review, studies had to assess the outcome of one cycle of assisted reproductive technology (in vitro fertilisation, intracytoplasmic sperm injection or gamete intra-fallopian transfer).

To be included, the studies had to have data available on pre-treatment anxiety or depression for women who became pregnant and women who did not. For their search, the researchers did not specify that the studies had to use particular methods for assessing anxiety or depression, but they did assess whether a reliable validated tool had been used. The researchers said that for those studies that used multiple measures for assessing emotional distress, they prioritised the assessments of “state anxiety”, which reflects a person’s current emotional state and is sensitive to “anticipatory” emotions (tension or worry, for example). The review used data on depression for studies that did not measure anxiety.

The researchers also looked at whether the pregnant and non-pregnant groups in each study differed in other factors that could affect the women’s chances of pregnancy, such as age, previous use of assisted reproductive technology, previous births and duration of infertility. They gave each study an overall quality rating based on a standard rating system.

The researchers say that they looked at outcomes after only a single cycle of treatment to prevent variations in the number of treatment cycles and duration of treatment from affecting the results. Researchers classified studies according to how they defined a successful pregnancy: a positive pregnancy test, ?-human chorionic gonadotrophin urine or blood test within 21 days of embryo transfer, positive ultrasound scan or live birth.

Independent researchers assessed the studies’ eligibility, quality and extracted data. The main outcome measure was the mean (average) difference in pre-treatment anxiety and depression score between the group of women who became pregnant and the group who did not.

 

What were the basic results?

Fourteen cohort studies met the researchers’ eligibility criteria. The studies included 3,583 women undergoing a cycle of fertility treatment in 10 countries. The average age of women was 29.7-36.8 years, and the average duration of infertility was 2.6-7.8 years.

Three studies included only women who had never used an assisted reproductive technology before, and the other 11 studies included a mix of women who had or hadn’t previously used this method of reproduction. The studies collected data between 1992 and 2006. The most commonly used measure of emotional distress was the validated Spielberger state-trait anxiety inventory. In almost half the studies, distress was assessed in the month before the treatment cycle began. In 11 studies, 80% of the participants completed follow-up. Three studies included groups of pregnant and non-pregnant women who were similar in all four key factors that could affect the chance of pregnancy (age, previous use of assisted reproductive technology, previous births and duration of infertility). Six studies included groups that were similar in at least two of these factors. Overall, six studies were considered to be of high quality, three of average quality and five of low quality.

The researchers found that pre-treatment emotional distress was not associated with pregnancy outcome after a single cycle of assisted reproductive technology. The pooled results of all 14 studies demonstrated that women who became pregnant did not have significantly different average pre-treatment anxiety and depression scores from women who did not become pregnant. Statistical tests showed that the included studies did not show significant variation in their results.

Analyses of whether results differed in different subgroups of women showed that previous use of assisted reproductive technology had no effect. Neither did the characteristics of the non-pregnant group (whether it excluded women who did not respond to ovarian stimulation or whose embryos were not fertilised), nor did timing of the emotional assessment. Studies of different quality ratings also did not appear to vary in their results. However, the researchers reported that they found some evidence of publication bias (in other words, studies reporting certain results may not have been published). An analysis that predicted the effect these unpublished studies might have had on the results still showed no difference in pre-treatment anxiety or depression scores between pregnant and non-pregnant groups.

 

How did the researchers interpret the results?

The researchers concluded that the findings of their systematic review and meta-analysis “should
reassure women and doctors that emotional distress caused by fertility problems or other life events
will not compromise the chance of becoming pregnant [through fertility treatment]”.

 

Conclusion

This well-conducted systematic review and meta-analysis has several strengths:

• The study population was relatively large, including 14 studies and 3,583 women.
• The researchers ensured that the included studies had measured emotional distress before fertility treatment began, which means the levels of distress observed are more likely to have preceded pregnancy.
• Most studies had used validated assessment questionnaires and inventories to reliably assess anxiety and depression.
• The researchers chose to assess pregnancy outcomes after only one treatment cycle to prevent their results being affected by differences in the number of fertility treatment cycles given and cycle duration.
• Their statistical assessment of variability between the studies demonstrated that the results of the studies did not differ significantly, and therefore were more suitable for pooling.

However, there are a couple of points to note:

• As the researchers say, there was some evidence of publication bias, and other studies relevant to this question may not have been available. Had they been included, the results may have been different.
• The studies that were included did not all report how women were selected to participate, and therefore it is not clear whether the population in these studies was representative of women receiving fertility treatment as a whole.
• Not all of the studies had pregnant and non-pregnant groups which were balanced for potential confounding factors that could have affected results (age, previous use of assisted reproductive technology, previous births, and duration of infertility). These findings would be made more robust if this were the case.
• Only one out of the 14 studies assessed the outcome of live birth. The rest looked at positive pregnancy test results and positive scans. Therefore, the outcome of the pregnancies in the studies, and whether they resulted in the birth of a healthy baby, is unknown.

Overall, this review provides a reliable summary of the existing studies on this question. Based on this, pre-treatment emotional distress does not appear to reduce a woman’s chances of successful pregnancy through fertility treatment. It is worth noting that these results cannot tell us whether emotional distress has any effect on chances of natural conceptions.

Links To The Headlines

Fertility treatment success is not prevented by stress. BBC News, February 25 2011

Stress ‘does not stop IVF working’. The Daily Telegraph, February 25 2011

Stress ‘won’t ruin chances of becoming pregnant during IVF’. Daily Mail, February 25 2011

Links To Science

Boivin J, Griffiths E, Venetis CA. Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies. BMJ 2011; 342: d223