ESHRE release: How many embryos to transfer?‏

Swedish researchers develop new method to avoid twins while maintaining high live birth rates Stockholm, Sweden: Swedish researchers have, for the first time, developed a reliable way of deciding whether one or two embryos should be transferred during fertility treatment; the method simultaneously maintains a high chance of women giving birth to a live baby, while reducing the risk of twins. Dr Jan Holte told the annual meeting of the European Society for Human Reproduction and Embryology, that if this model were to be applied in all fertility clinics, it had the potential to reduce the twin rates to the level of just under two percent seen in the normal population. Already, another four clinics have started to use the model.
Sweden leads the world in attempts to reduce multiple pregnancies by transferring only one embryo to a woman’s womb during fertility treatment whenever possible. In 2007 (the most recent year for which data are available*), 69.9% of embryo transfers were single embryos, 30.1% were double embryo transfers, and only 5.3% of deliveries after fertility treatment were multiple deliveries – the lowest multiple delivery rate in the world. “However, until now, evidence-based strategies have been lacking for guidance on when to perform single embryo transfer in order to achieve the best possible balance between maintaining a high level of live birth rates, but reducing twin implantation rates,” said Dr Holte, who is medical director, a senior consultant and responsible for research at the Carl Von Linnéklinikken, Uppsala Science Park (Uppsala, Sweden).
Over a four-year period between 1999-2002 Dr Holte and his colleagues analysed a series of 3223 embryo transfers and recorded 80 different factors that played a role in the success of fertility treatment. They found that four variables were significant in predicting pregnancy outcome: the quality of the embryo, the age of the woman, ovarian responsiveness (the number of eggs retrieved in relation to the dose of ovarian stimulating hormones), and information about whether the woman had had previous IVF attempts with either fresh or frozen-thawed embryos, how many, and whether or not they resulted in a pregnancy.
Using these four variables, they constructed a mathematical model that predicted the chances of pregnancy after the transfer of one or two embryos and of the risk of twins. Over a subsequent four-year period between 2004-2007, they applied the model in the clinic for 3410 embryo transfers. They aimed to achieve a risk of twins of no more than 15% and any women that had a higher risk had only one embryo transferred in one cycle. Transfers of embryos that had been frozen, stored and then thawed before implantation followed the same model. During this period the proportion of single embryo transfers increased to 76.2% (compared to 11.1% in the previous period between 1999-2002), and the rate of twin deliveries was reduced from 26.1% to 1.9%. Live birth rates per fresh embryo transfer fell from 29.1% to 24.6%, but when transfers of frozen-thawed embryos were included the live birth rate was similar during the two periods: 31.1% in the earlier period and 30.7% in the later period.
Dr Holte also made adjustments to take account of the fact that women in the later period tended to be older and have a less favourable prognosis than those in the earlier period and, therefore, would have a lower predicted live birth rate. Once he had done this, the live birth rate (including frozen-thawed embryos) in the later period was higher at 36% versus 31.1% in the earlier period. Just as significant as the dramatic drop in twin births were the outcomes for babies born between 2004-2007. Average birth weights increased from 3086g to 3412g; the frequencies of babies born prematurely (before week 33) and babies with birth weights below 2500g were reduced by two-thirds; the frequency of babies born small for gestational age was reduced by 26%; and deaths either just before, during or just after birth were reduced by 58%.
Dr Holte said: “These improved outcomes were entirely due to the lower rate of twins. There was no significant differences in outcomes between the two periods when comparing only babies born as a result of a single pregnancy.” The researchers found that their model correctly predicted the pregnancy rates that occurred in all women, regardless of their chances of becoming pregnant. Dr Holte explained: “The predicted chance of pregnancy for an individual couple ranged between around 5% up to around 60% per attempt. When the treatments were grouped according to their predicted chances into ‘stratas’ or groups of 0-10%, 10-20%, 20-30%, 30-40%, 40-50% and >50%, the corresponding observed clinical pregnancy rates were shown to fit very accurately with the predicted results. “To our knowledge, this is the first time that a model has been developed that successfully predicts pregnancy and the risk of twin implantation during fertility treatment.
The results suggest that application of the model may reduce twin rates to the desired level, in our case to that of the normal Swedish population, while totally preserving pregnancy rates and markedly reducing risks for the offspring.” Multiple pregnancies, where a woman becomes pregnant with two or more embryos, carry a high risk to both mothers and babies; complications can include miscarriage, premature birth, low birth weight, cerebral palsy and death. For this reason, fertility doctors increasingly try to find ways of avoiding them without jeopardising women’s chances of becoming pregnant. The model has been validated by another, independent Swedish clinic, with similarly good results over a five-year period, and now three other clinics (two in Sweden and one in Italy) have started to use it. Dr Holte and his colleagues are continuing to refine and test the model further.

Could ovarian stimulation cause an increase in chromosome copy number abnormalities in the oocytes of older mothers?ESHRE study may answer those

Ovarian stimulation undertaken by women of advanced maternal age (over 35 years) receiving fertility treatment may be disrupting the normal pattern of meiosis – a critical process of chromosome duplication followed by two specialised cell divisions in the production of oocytes and sperm – and leading to abnormalities of chromosome copy numbers (aneuploidy) that result in IVF failure, pregnancy loss or, more rarely, the birth of affected children with conditions such as Down’s syndrome, which is caused by the inheritance of three copies of chromosome 21 (trisomy 21).
Researchers involved in ESHRE’s polar body screening study (launched in 2009) will tell the annual conference of the European Society of Human Reproduction and Embryology today (Monday) that results from the study are leading to a new understanding about how such abnormalities are developing, and they believe that the ovarian stimulation a woman receives might be playing a part. Understanding the mechanisms involved could help older women who are trying to have a healthy baby with their own oocytes.Professor Alan Handyside, Director of The London Bridge Fertility, Gynaecology and Genetics Centre, London, UK, and colleagues from eight countries undertook a proof of principle study of a novel method of screening polar bodies, small cells that are the by-product of oocyte development, using the new technology of microarray comparative genomic hybridisation (array CGH) in order to find whether this was a reliable method of analysing the chromosomal status of an oocyte. This is because many more chromosome copy number abnormalities arise in the oocyte than in sperm.
"In doing so, we obtained a lot of data at the individual chromosome and chromatid level," says Professor Joep Geraedts, co-ordinator of the ESHRE Task Force on preimplantation genetic screening (PGS). (A chromatid is one of the two identical copies of DNA making up a duplicated chromosome). "So we decided to analyse these data separately to see whether they could provide us with information that could be useful in determining better treatment strategies for the future."
"In this unique study, we were able to use the new technology of array CGH to examine the copy number of all 23 pairs of chromosomes, in all three products of female meiosis in over 100 oocytes with abnormal numbers of chromosomes," says Professor Handyside. "What happens in female meiosis is that the 23 pairs of chromosomes duplicate and each pair of duplicated chromosomes comes together and the four single chromosomes, or ‘chromatids’, become ‘glued’ together along the whole length of each chromosome. This actually occurs before the woman is born and is the stage at which DNA is swapped between the grandparents’ chromosomes.
"Sometimes, decades later, just before ovulation, the glue ‘dissolves’ first between the two duplicated chromosomes and finally after fertilisation between the two individual chromosomes. This enables pairs of chromosomes to segregate in the first meiotic division producing the first polar body. In the second meiotic division the second polar body is produced, resulting in a single set of chromosomes in the fertilised oocyte or ‘zygote’, which, when combined with the single set in the fertilising sperm, restores the 23 pairs," he says.
The researchers believe that ovarian stimulation may be disturbing this process in older women because the chromosomes are becoming unglued prematurely, particularly the smaller ones like chromosome 21. Ovarian stimulation uses hormonal medication to stimulate the ovaries to release a larger number of oocytes than normal, in order to provide enough good quality oocytes for fertilisation in vitro.
Following natural conception in older mothers, Down’s pregnancies are predominantly caused by errors in the first female meiotic division. "Our evidence demonstrates that, following IVF, there are multiple chromosome errors in both meiotic divisions, suggesting more extensive premature separation of single chromosomes resulting in more random segregation, which in turn results in multiple chromosome copy number changes in individual oocytes," says Professor Handyside.
"We need to look further into the incidence and pattern of meiotic errors following different stimulation regimes including mild stimulation and natural cycle IVF, where one oocyte per cycle is removed, fertilised and transferred back to the woman. The results of such research should enable us to identify better clinical strategies to reduce the incidence of chromosome errors in older women undergoing IVF."
"We also believe that our research will help identify women who want to have their own offspring but have practically no chance of doing so that we can advise them to use donor oocytes," says Professor Geraedts. "This in itself is already a big step forward that will aid couples hoping for a healthy pregnancy and birth to be able to achieve one."

Self-referral: A significant factor in imaging growth

A recent study in the Journal of the American College of Radiology suggests that self-referral in medical imaging may be a significant contributing factor in diagnostic imaging growth. Self-referred imaging is identified as physicians (or non-physicians) who are not radiologists directing their patients to their own on-site imaging services or the referral of patients to outside facilities in which the referring physicians have financial interest.
In the current political and economic climate, there is a desire to reduce health care costs; diagnostic imaging expenditure is one area of particular interest.
Researchers identified the relative risk of physicians' referring patients for imaging to facilities in which the physicians have financial interest (self-referrers) compared with physicians' referring patients for imaging to facilities in which they have no financial interest (radiologist referrers).
"This meta-analysis of the available medical literature estimates that non-radiologist self-referrers of medical imaging are approximately 2.48 times more likely to order imaging than clinicians with no financial interest in imaging, which translates to an increased imaging utilization rate of 59.7 percent," said Ramsey K. Kilani, MD, lead author of the study.
"The utilization fraction of imaging attributable to self-referral in our study was calculated as 59.7 percent. According to the 2008 GAO report, $14.1 billion was spent on diagnostic imaging in 2006; of this amount, 64 percent ($9.0 billion) was to physician offices. Of that $9.0 billion, 68 percent went to non-radiologists. Using the 59.7 percent utilization fraction attributable to self-referral, a theoretical associated cost was calculated at $3.6 billion," said Kilani.
"The cost of this excess imaging to Medicare Part B is likely to be in the billions of dollars annually, on the basis of the best available data. This level of spending on potentially unnecessary medical imaging is concerning in light of the growing emphasis on reducing health care expenditures," he said.

*Source: American College of Radiology

Foods with baked milk may help build tolerance in children with dairy allergies

Introducing increasing amounts of foods that contain baked milk into the diets of children who have milk allergies helped a majority of them outgrow their allergies, according to a study conducted at Mount Sinai School of Medicine's Jaffe Food Allergy Institute. The data are reported in the May 23 issue of the Journal of Allergy and Clinical Immunology. Researchers studied 88 children, ages 2 to 17 years old, who were diagnosed with milk allergy, evaluating their tolerance to foods containing baked milk, such as muffins, waffles and cookies. The high temperatures used in baking cause the proteins in milk to break down, reducing the allergenicity.
Over the course of five years, researchers used a series of food challenges to introduce the children to foods that had progressively less-heated forms of milk. At the end of the study period, 47 percent of the children in the experimental group could tolerate unheated milk products, such as skim milk, yogurt and ice cream, compared to only 22 percent in a control group, indicating that controlled, increased exposure to baked milk products accelerates the rate at which children outgrow their milk allergies.
"This study shows that many children with allergies do not need to completely avoid all milk products," said Anna Nowak-Wegrzyn, MD, co-author of the study, and an Associate Professor of Pediatrics, Allergy and Immunology at Mount Sinai School of Medicine. "It's also an encouraging sign that through careful medical supervision, children can grow out of their allergies much quicker."
In the study's first food challenge, children were given a plain muffin or waffle containing baked milk. Sixty five of the 88 children, approximately 75 percent, experienced no allergic reactions. Parents of those children were given specific guidelines on how to incorporate baked milk products such as muffins, cookies and cakes into their child's daily diet. The children who reacted to the muffin continued avoiding foods containing milk.
After a period of six to 12 months, the 65 children who passed the initial muffin food challenge returned to the clinic for the second food challenge and were given cheese pizza. Baked cheese is cooked at a lower temperature than baked goods and contains higher amount of milk protein. Seventy-eight percent of the children in this group experienced no allergic reactions and were told to incorporate baked cheese into their diets. Children who reacted to the baked cheese continued eating muffins and returned after a period of six to 12 months to be re-challenged with pizza. If they showed no allergic reactions, they moved on in the study.
After an average of three years, the study participants who showed no reaction to baked cheese returned for the final food challenge, and were given foods with unheated milk such as skim milk, yogurt and ice cream. Of the 65 children who passed the initial muffin challenge, 60 percent could tolerate unheated milk.
"While we need to continue our research to determine how to best apply these results to the clinical setting, these data are an exciting step towards our ultimate goal of finding curative therapies for food allergies," said Dr. Nowak.

**Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Delayed access to tertiary care associated with higher death rate from type of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF)―scarring and thickening of the lungs from unknown causes―is the predominant condition leading to lung transplantation nationwide. Columbia University Medical Center researchers confirmed that delayed access to a tertiary care center for IPF is associated with a higher risk of death. The findings were published online in the American Journal of Respiratory and Critical Care Medicine on June 30, 2011.
A group led by Columbia researcher David J. Lederer followed 129 IPF patients at an academic medical center. They looked at the length of time from the onset of shortness of breath to the first visit to the center. A longer delay was associated with increased risk of death, independent of age, gender, socioeconomic status, lung capacity, disease severity, type of health insurance, or education. The researchers also found no association between the length of delay and the likelihood of the patient's receiving a lung transplant.
IPF leads to respiratory failure and death, usually within three years. It is a relatively rare disease, which afflicts 100,000�,000 Americans, almost all over the age of 50. Characterized by shortness of breath upon exertion, it is often misdiagnosed, especially in people with other ailments.
A delay in making a correct diagnosis can lead to ineffective, or even harmful, treatments. For example, doctors sometimes still treat IPF with steroids, because the disease was originally thought to have an inflammatory component. Now scientists know that steroids are counterproductive. A delay in diagnosis can also delay evaluation for a lung transplant. Although research is underway on potential drug therapies, currently lung transplantation is the only effective treatment.
"The initial symptoms of IPF are subtle, and accurate diagnosis may not be feasible for community-based pulmonologists," explains Lederer, Herbert Irving Assistant Professor of Clinical Medicine and co-director of the New York-Presbyterian Hospital Interstitial Lung Disease Program and Lung Transplant Program.
For that reason, earlier access would be aided by improved methods of early detection. But until then, the recognition, or even suspicion, of IPF should prompt referral to a tertiary care center.

**Source: Columbia University Medical Center

Gastric bacterium Helicobacter pylori protects against asthma

Infection with the gastric bacterium Helicobacter pylori provides reliable protection against allergy-induced asthma, immunologists from the University of Zurich have demonstrated in an animal model together with allergy specialists from the University Medical Center of the Johannes Gutenberg University Mainz. Their results published in the prestigious Journal of Clinical Investigation confirm the hypothesis recently put forward that the dramatic increase in allergic diseases in industrial societies is linked to the rapid disappearance of specific micro-organisms that populate the human body. Allergy-induced asthma has been on the increase in the industrialized world for decades and has virtually taken on epidemic proportions. The rapid rise in allergic airway disease is attributed to air pollution, smoking, the hygiene hypothesis and the widespread use of antibiotics. The hygiene hypothesis states that modern hygiene measures have led to a lack of exposure to infectious agents, which is important for the normal maturation of the immune system. In an article published in the Journal of Clinical Investigation, scientists from the University of Zurich and the University Medical Center of the Johannes Gutenberg University Mainz now reveal that the increase in asthma could be put down to the specific disappearance of the gastric bacterium Helicobacter pylori (H. pylori) from Western societies.
H. pylori is resistant to gastric acid. According to estimates, around half of the world's population might be infected with the bacteria. The affliction often has no symptoms, but under certain conditions can cause gastritis, gastric and duodenal ulcers, and stomach cancer. Consequently, H. pylori is often killed off with antibiotics as a precaution, even if the patient does not have any complaints.

Early infection with H. pylori protects against asthma
For their study, the researchers infected mice with H. pylori bacteria. If the mice were infected at the age of a few days old, they developed immunological tolerance to the bacterium and even reacted insignificantly – if at all – to strong, asthma-inducing allergens. Mice that were not infected with H. pylori until they had reached adulthood, however, had a much weaker defense. "Early infection impairs the maturation of the dendritic cells and triggers the accumulation of regulatory T-cells that are crucial for the suppression of asthma," says Anne Müller, a professor of molecular cancer research at the University of Zurich, explaining the protective mechanism.
If regulatory T-cells were transferred from infected to uninfected mice, they too enjoyed effective protection against allergy-induced asthma. However, mice that had been infected early also lost their resistance to asthma-inducing allergens if H. pylori was killed off in them with the aid of antibiotics after the sensitization phase. According to lung and allergy specialist Christian Taube, a senior physician at III. Medical Clinic of the Johannes Gutenberg University Mainz, the new results confirm the hypothesis that the increase in allergic asthma in industrial nations is linked to the widespread use of antibiotics and the subsequent disappearance of micro-organisms that permanently populate the human body: "The study of these fundamental mechanisms is extremely important for us to understand asthma and be able to develop preventative and therapeutic strategies later on."

**Source: University of Zurich

Pre-pregnancy diet affects the health of future offspring

Poor maternal diet before conception can result in offspring with reduced birth weights and increased risk of developing type II diabetes and obesity. This work, which is being presented at the Society for Experimental Biology Annual Conference in Glasgow on Saturday the 2nd of July, used an animal model to illustrate the importance of maternal diet even before pregnancy begins.
During the study mice that were fed a low protein diet for ten weeks before conception (but had a normal diet during pregnancy) gave birth to offspring that had lower birth weights, showed catch-up growth after weaning and increased insulin sensitivity.
These effects combined can lead to problems later in life. MSc researcher, Ms Anete Dudele, from the University of Aarhus, explains: "Low birth weight and catch-up growth is associated with enhanced insulin-sensitivity in young adults, this then deteriorates into insulin resistance and type II diabetes with increased age. There is also evidence that male offspring are more likely to develop obesity."
Humans and mice respond in the same way to poor diet during pregnancy; their offspring show low birth weights and increased risk of obesity, type II diabetes and cardiovascular disease. "If humans respond in the same way as mice to pre-conception diet as well then women should not only consider what they eat during pregnancy but also before pregnancy if they want to reduce the risk of their future children acquiring lifestyle diseases," says Ms. Dudele.
Cardiovascular disease is often associated with obesity and type II diabetes and future research by the team will determine whether offspring born to mothers who had poor pre-conception diets are predisposed to these types of problems as well.

**Source: Society for Experimental Biology