IVF News

A US woman who became infertile after cancer treatment has stunned doctors by becoming pregnant naturally, following a transplant of ovarian tissue into her abdomen. Ann Dauer, from Canton, Ohio has now given birth to a healthy baby girl, named Sienna. Mrs Dauer had one of her ovaries removed and frozen prior to having chemotherapy for Hodgkins lymphoma. In August 2004, after completing her treatment, Mrs Dauer had slices of ovarian tissue implanted under the skin of her abdomen.

Doctors at the Weill Cornell Medical Centre in New York had planned to remove eggs from the grafted tissue for use in IVF treatment, but Mrs Dauer conceived naturally just three months after the transplant. 'I did the ultrasound and almost fell off my chair', said team leader Kutluk Otkay. The pregnancy miscarried, but Mrs Dauer conceived naturally again the following month. 'Her treatment was almost guaranteed to make her menopausal', said Otkay, adding 'this really shouldn't have happened'.

Although two other women have given birth after frozen-thawed ovary transplants, one in Belgium and one in Israel, both had tissue transplanted in the ovary's normal position. In Mrs Dauer's case, the position of the graft should have made natural conception impossible. There are three possible explanations for the birth of Sienna Dauer: spontaneous recovery of natural fertility, recovery of the remaining ovary aided by hormones produced by the transplanted tissue and - most controversially - the 'reseeding' of the remaining ovary with ovarian stem cells.

Although some patients have regained their natural fertility following cancer treatment, the chances of Mrs Dauer doing so had been estimated as one in five million. But the chances of hormones from the transplanted tissue helping the remaining ovary recover are also thought to be low, since several other patients have undergone a similar procedure without conceiving naturally. The third explanation - that ovary stem cells travelled through the blood and 'kick-started' egg production in the remaining ovary - is controversial because the existence of such cells has not yet been proven.

Jonathan Tilly and his colleagues at Massachusetts General Hospital have found evidence of 'ovary stem cells' in mice - cells that are capable of producing fresh eggs throughout the animal's reproductive life. Earlier this year, they published a study suggesting that such cells originate in the bone marrow, rather than the ovaries themselves. 'It's just possible that the transplanted ovary supplied something that the damaged ovary didn't have, and that germ cells have moved through the blood to reseed it and allow it to start working again', said Otkay.

Although it is impossible to prove that the grafted ovary tissue somehow restarted egg production in Mrs Dauer's remaining ovary, Dr Otkay says that another of his patients has shown egg follicle development after having similar treatment. Professor Bill Ledger, of the University of Sheffield, told the Times newspaper that while spontaneous recovery was the most likely explanation, the stem cell theory was 'fascinating and credible'. 'It has a certain biological plausibility if the mouse work is accurate', he said.

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A Romanian woman is set to become the world's oldest mother at the age of 67. Adriana Iliescu, a retired university lecturer, is said to be almost seven months pregnant with twin girls following ten years of fertility treatment. She also underwent hormone treatment for nine years to delay her menopause.



In 2003, a 65-year old Indian woman became the oldest woman to give birth. She had used an egg donated from her 26-year old niece, which was fertilised with her husband's sperm. Now, Ms Iliescu is set to beat that record having become pregnant after artificial insemination using donated sperm. Liz Buttle became the UK's oldest mother in 1997 when she had a son at the age of 60.



Ms Iliescu said that she had put all her efforts into having a career and found no time to build relationships or start a family. 'After retiring I regretted it bitterly', she said, adding 'but I never gave up hope'. She continued: 'I believed a woman has a right to give birth and that is why I followed my dream, no matter how old I was'.



But some people are not so happy with the news. Alexandru Manzu, from the Romanian Save The Children charity, said 'Romanian orphanages are full with children - we cannot support cases like this that are only likely to worsen the problem'. He continued: 'What chance has a woman of this age raising her children to adulthood where they can support themselves? She will be 85 when they are 18 and old enough to leave home'.



Meanwhile, another report suggests that the practice of egg donation is on the rise in Romania, with increasing numbers of women choosing to donate eggs to infertile couples. According to the BBC report, women can earn ?150 for each donation, which is the same as the average monthly wage. This has meant that many women from other countries, including the UK, now go to Romania for treatment using donated eggs.
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Lyon, France: An international group of fertility specialists has developed an easy-to use mathematical formula that allows a personalised approach to ovarian stimulation therapy for women seeking fertility treatment. Clinical tests demonstrated that when clinicians used the formula (or algorithm) to calculate the best starting dose for each patient, both the number of oocytes retrieved and pregnancy rates rose.
 
Professor François Olivennes told the 23rd annual meeting of the European Society of Human Reproduction and Embryology today (Monday 2 July) that the algorithm was based on four factors that predicted ovarian response and that were measured routinely when women were evaluated for fertility treatment: normal (or basal) levels of follicle stimulating hormone (FSH), body mass index, age and the number of small growing (antral) follicles in the ovary detected during screening.
 
“This FSH dose algorithm is simple and easy to use and utilises readily available patient characteristics,” said Prof Olivennes, coordinator of the Centre de FIV Eylau La Muette, Paris, France. “It is the first to be tested in a prospective multi-national clinical study and it provided each patient with an individualised starting dose of FSH, which could be maintained throughout treatment and resulted in an excellent treatment outcome as testified by the number of oocytes retrieved and the high pregnancy rates.
 
“This approach should enable us to improve patient management, treatment outcomes and safety by reducing the chances of having to either cancel cycles because the ovaries have not been stimulated enough or of ovarian hyperstimulation syndrome (OHSS) developing because the ovaries have been over-stimulated.”
 
Moderate or severe OHSS can occur in 3-8% of IVF cycles [1]. Moderate OHSS can be accompanied by nausea and vomiting. Severe OHSS, which is an uncommon event, can be accompanied by ovarian enlargement and fluid imbalances, sometimes resulting in thrombosis and, very rarely, in death.
 
Prof Olivennes was presenting the research on behalf of a multi-national team, the CONSORT Study Group (CONsistency in r-FSH Starting dOses for individualised tReatmenT). The group treated 161 ART patients, younger than 35, in 18 centres around the world. The doctors used the algorithm to allocate the women to receive one of five different doses of a follicle stimulating hormone called “recombinant human follicle stimulating hormone, filled by mass” (r-hFSH FbM or GONAL-f FbM). [2]
 
The doses, measured in international units (IU), were 75, 112.5, 150, 187.5 and 225. The women were treated for an average of 11 days. Oocytes were retrieved from 84.4% of women, and 80.9% of the women subsequently underwent embryo transfer. Pregnancies per cycle were 31.3%, 31.1%, 35.3%, 50% and 20% per starting dose of 75IU, 112.5IU, 150IU, 187.5IU and 225IU respectively, with an average pregnancy rate of 34.2%. There were two cases of severe OHSS associated with pregnancy. One case of severe OHSS occurred in a patient allocated to the 75 IU dose group but who received a higher starting dose of FSH from the attending physician.
 
Prof Olivennes said: “The results of the CONSORT clinical study to validate a simple FSH starting dose calculator are very promising, with a high clinical pregnancy rate. It represents an important step forward in aiding clinicians using GONAL-f FbM to individualise the starting dose based upon four easily measured patient characteristics: basal level of FSH in early spontaneous cycle, age (less than 35 years old), body mass index and antral follicle count in early spontaneous cycle.  
 
“However, we still have more work to do before the algorithm can be used for all patients in the clinic.Firstly, the FSH dose calculator has only been validated for GONAL-f FbM – there are other types of FSH in use. Secondly, we have demonstrated its usefulness in women younger than 35 undergoing ART; further work is required to extend its use in other patient groups.  
 
“The results of this clinical study will provide us with an opportunity to fine-tune the model so as to allow us to further improve its usefulness before making it more generally available. One of the next steps that we are considering is to make the CONSORT FSH dose calculator available to fertility specialists through a dedicated web site, with an appropriate follow-up procedure.
 
“At present, reproductive medicine specialists determine starting doses so as to induce multiple follicle development based upon some of the characteristics used to develop our model, other tests of ovarian reserve, and their previous clinical experience. We hope that this research will represent a move towards an evidence-based approach to the use of FSH.”

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Women trying to have a baby using standard in-vitro fertilisation (IVF) techniques are spending money on unnecessary drugs that have harmful side-effects and which could be compromising their health, according to the authors of a new report published in the Lancet medical journal.

In standard IVF, two embryos are usually implanted, after stimulating the woman's ovaries with large doses of hormones, which can cause side-effects such as hot flushes, night sweats, insomnia, reduced libido and depression. This treatment can sometimes trigger ovarian hyper-stimulation syndrome, and also increases the risk of multiple births, which carry a higher risk of complications for mother and baby and can induce premature birth.

A report published in 1999 described an approach that uses reduced drug doses, has a shortened treatment period, and involves implanting just one embryo at a time (so-called 'single embryo transfer', or SET). This method is known as 'soft IVF' and uses hormone antagonists which bypass the side-effects that are triggered by conventional IVF drugs. In the latest study, Bert Fauser's team at the University Medical Centre in Utrecht compared 'soft' and 'standard' IVF treatment in 404 patients.

Their results show that replacing one embryo in the womb at a time, and freezing another for use in a second, has the same live birth rate (44 per cent) over one year as standard IVF. They also noted that this approach reduces the risk of ovarian hyper-stimulation, and that the chances of having twins is dramatically cut to 1 in 200 births from 1 in 8 births in standard IVF. They also claim that the soft version was cheaper overall by 2400 Euros per pregnancy.

The authors believe that soft IVF will revolutionise conventional IVF as it will benefit patients and clinics by encouraging repeat attempts at IVF, 'Our findings should encourage more widespread use of mild ovarian stimulation and single embryo transfer in clinical practice', the researchers said. They continued: 'However adoption of our mild IVF treatment strategy would need to be supported by counselling both patients and healthcare providers to redefine IVF success and explain the risks associated with multiple pregnancies'.

It is thought that getting SET accepted as routine practice will be challenging in the UK. Professor Bill Ledger, an IVF specialist at the University of Sheffield, acknowledged the ever increasing gap between demand and supply on NHS resources and reflects that it just is not feasible for the NHS to follow recommendations by the National Institute for Health and Clinical Excellence (NICE) set out in its 2004 report, which recommended providing all couples with three free cycles of IVF treatment. He continued by saying, 'Some patients want to complete the procedure as quickly as possible and see twins as the most desirable outcome. While 75 per cent of IVF treatment in the UK continues to be paid for by the patients themselves, many couples will opt for double embryo transfer because it is much less costly'.

Professor Ledger also explained that it would be difficult to get private IVF clinics to adopt new guidelines because the Human Fertilisation and Embryology Authority (HFEA) rates their position in the 'league table' according to their success per cycle, and as mild IVF may take more cycles, this could reflect badly upon them. A spokesperson from the HFEA said: 'We are about to launch a consultation about trying to minimise multiple births because they are the single biggest risk involved in IVF'. The authority is due to announce its new policy in the autumn.

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A sixty year-old woman has become the oldest women in the US to give birth to twins. The two healthy boys were delivered in the US Hackensack University Medical Centre on 22 May.

The twins were conceived via IVF in a South African clinic. The couple, Frieda Birabaun, a psychologist and her husband Ken, a New York attorney, are said to be delighted with the new arrivals. They have three other children - two boys aged six and 33 and a girl aged 29. Their youngest son was also conceived via IVF and the couple is reported to have been partly motivated to have a fourth child to provide a sibling for their youngest son.

Stories of women over 60 giving birth following IVF pregnancies has generated debate in recent years around how old is too old to become a parent. The oldest woman in the world to give birth - also to twins - was 67 at the time of delivery, in Spain last December.

Frieda Birabaun is reported to view the issue of later motherhood in terms of women's rights. She has said that she wants women to feel empowered by the possibility of bearing children later in life, and wants women to realise that they have choices.

The possibility of conceiving so late in life, via IVF, raises ethical questions about how much choice women should have over when they have children. The risks associated with pregnancy are known to increase with age and the number of viable fetuses per pregnancy. Concerns have also been raised about the impact of having older parents on the welfare of the child. In developed countries, however, people are living longer and healthier lives and to prevent access to assisted reproduction on the basis of age alone could be perceived as unjust age discrimination.

In US there is no upper age limit on access to assisted reproduction, although the Society for Assisted Reproductive Technology (SART), which represents 85 per cent of clinics in the US, recommends that IVF should be offered to women under 50, using donor eggs, and under 44, using their own eggs. In the UK, National Institute of Health and Clinical Excellence (NICE) guidelines specify that access to IVF on the National Health Service should be only be offered to women between the ages of 23 and 39.
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BioNews reporting from ESHRE conference, Berlin:

Using a mobile phone and taking the anti-impotence drug Viagra may both affect a man's fertility, according to a report in the Sunday Times. A study carried out by researchers at the University of Szeged in Hungary found a link between 'heavy use' of mobile phones and a 30 per cent drop in sperm counts. But the research, due to be presented at the annual European Society of Human Reproduction and Embryology (ESHRE) meeting in Berlin, did not take into account other factors. Meanwhile, another study due to be reported at the conference suggests that Viagra use can interfere with the fertilisation process in mice.

The Hungarian researchers studied 221 men for 13 months, and compared the sperm of men who used their phones heavily with those that did not. They found that those who carried their phone with them nearly all of the time had up to a 30 per cent reduction in their sperm count. The scientists stress that further work is needed to confirm the link, but conclude that 'the prolonged use of cell phones may have a negative effect on spermatogenesis and male fertility, that deteriorates both concentration and motility'. However, the study has been criticised because it did not take into account other factors, such as the stress levels or age of the participants. A spokesperson for the Mobile Operators Association told the Sunday Times that 'successive studies have found no adverse health effects'.

Researchers at Queens University Belfast are due to present a study carried out on mice, which suggests that Viagra use could affect the ability of sperm to fertilise an egg. The research, which builds on findings presented at the British Fertility Society meeting in March 2004, shows that female mice mated with males given Viagra produced fewer embryos than those mated with untreated mice. The scientists also found that Viagra use was linked to a reduced rate of embryo growth.

The team says the study shows that Viagra 'significantly reduces' fertilisation and embryo growth rates, and has implications for men using the drug who are contemplating having children. However, when the scientists first announced their findings in March, John Dean, secretary general of the European Society for Sexual Medicine cautioned that lab findings may not reflect what is happening in the human body. He told BBC News Online that, in the five years that Viagra has been around, 'no overall detrimental effect on fertility has been observed'.
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The probability of having a male baby is affected by fertility treatments, Australian scientists have found. Up to 4.6 percent more boys were born with some treatments and up to 2.8 percent more girls with others. The national population-based study is the first to assess the impact of fertility treatments on the ratio of boys to girls born.

Ms Jishan Dean, co-author of the study from the School of Women's and Children's Health, University of New South Wales said in a press release: 'The results from this study demonstrate that a particular assisted reproductive technology (ART) procedure or treatment course can alter the probability of having a male baby from the natural sex ratio at birth'.

The team looked at 13,368 Australian and New Zealand babies born to 13,165 women between 2002 and 2006 following fertility treatment using single embryo transfer. They found that IVF caused 53.0 percent of live births to be boys, 2.5 percent more than the long-term Australian average.

Implanting embryos four days after fertilisation (blastocyst stage) also increased the probability of having a male baby to 54.1 percent, but implanting after two or three days (cleavage stage) reduced this to 49.9 percent. Half of all births following ICSI(intracytoplasmic sperm injection) were girls.

The imbalance was even greater when these techniques were used in combination. IVF and blastocyst-stage embryo transfer increased the probability of having a male baby to 56.1 percent; ICSI and cleavage-stage transfer decreased the probability to 47.7 percent.

Ms Dean called for more research into the underlying causes of the gender imbalance. Professor Philip Steer, editor-in-chief of the British Journal of Obstetrics and Gynaecology (BJOG), which published the research, agreed. He said: 'It is important that we don't allow such imbalances to occur unintentionally, simply because we have neglected to study the factors that influence the secondary sex ratio (SSR) in the increasing proportion of the population who use ART'.

Dr Allan Pacey, from the University of Sheffield, said: 'Patients should certainly not consider using this as a method of trying to have a boy or girl, since the procedure used needs to be selected to try and maximise the chance of pregnancy'.

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Overweight women are at greater risk of miscarrying a genetically normal baby in the early stages of pregnancy than women who maintain a healthy weight, according to a new study by scientists at the Stanford University School of Medicine in California, US. The researchers, presenting at the annual American Society for Reproductive Medicine (ASRM) conference, suggested that this indicates that a mother's weight can affect the outcome of an otherwise healthy pregnancy.

The UK's National Health Service (NHS) estimates that around a quarter of all pregnancies in the UK end in miscarriage. The majority of these occur in the first 12 weeks of pregnancy, but can occur up to 24 weeks. The cause of miscarriage is not always known, but it is thought that between 50 and 70 per cent occur as a result of chromosomal abnormalities (genetic defects) in the fetus. The California researchers tested DNA from 204 fetuses miscarried in the first eight weeks of pregnancy. They compared the rate of chromosomal abnormalities in the fetuses from women with a normal body mass index (BMI) with the rate of abnormalities in fetuses from women with a BMI that classified them as overweight or obese. They found that 53 per cent of babies lost by overweight women had no chromosomal abnormalities compared to just 37 per cent of babies lost by women of a more healthy BMI.

Dr Inna Landres, who led the research team, said that these findings indicate that 'obesity predisposes women to miscarry normal babies.' The reason for this is not yet understood, but Dr Landres suggested that one explanation could be altered levels of hormones such as oestrogen and androgens seen in overweight women. She emphasised: 'It's important to identify elevated BMI as a risk factor for miscarriage and counsel those women who are affected on the importance of lifestyle modification.'

An individual's BMI is calculated by dividing their weight in kilograms by their height in metres squared. A BMI of 18 to 25 is considered normal, whilst over 25 is classed as overweight and over 30 as obese. All the women in the current study were attending an academic centre for fertility counselling and had their BMI calculated before conception.

Dr Mark Hamilton, chairman of the British Fertility Society (BFS), said: 'It is recognised that women who are overweight are at a greater risk of miscarriage. It has not been defined if that risk is related to genetic problems for the embryos or the obesity itself is linked to implantation mechanisms. This study will aid our understanding of the known association with being overweight and reproductive loss.'

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New work in stem cell research has challenged the long-standing belief that women are born with all the eggs they will ever need. The results were published in the journal Nature Stem Cell, although the study was received with caution.

The scientists at Shanghai Jiao Tong University claim to have detected germline stem cells in the ovaries of old and young mice that produce eggs, or ooctyes, and can be fertilised to produce healthy offspring. This goes against the dogma that female mammals are born with all their eggs, and that immature eggs ripen and are ovulated or die off until the supply runs out. Sperm are continuously produced in males from stem cells, but in females the number of eggs is fixed at birth.

Kang Zou and Ji Wu lead the research that isolated female germline stem cells (FGSCs) from the ovaries of adult mice and five-day old pups. They grew these cells into a colony in a culture dish and genetically modified them to produce a green fluorescent protein, a standard technique for labelling cells. They then replaced them into the ovaries of sterilised mice.

The mice produced new eggs which, when fertilised, gave rise to healthy, fertile babies, many of which contained the green fluorescent protein, indicating that they came from eggs from the FGSCs. The scientists say that 'these findings contribute to basic research into oogenesis and stem cell self-renewal, and open up new possibilities for use of FGSCs in biotechnology and medicine'.

If these findings can be replicated, they may hold major implications for fertility treatment for women made infertile by, for example, cancer treatments, or for women who wish to have children later in life. The work is controversial, however, since many experts doubt that the Chinese team have proved that the offspring actually came from the ovarian stem cells. Jonathan Tilly, of the Massachusetts General Hospital in Boston, made a similar claim about five years ago but others were unable to replicate his work. 

Professor Robin Lovell-Badge from the National Institute of Medical Research, London, says that 'extraordinary claims require extraordinary evidence', implying that the work was incomplete. He continues, however, that 'if true, and especially if applicable to humans, then this is very important. For example, it could provide a means to restore fertility to women who have few eggs or who have had to undergo cancer treatments, by isolating these cells, expanding their number in culture and keeping them frozen until needed for IVF'.

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