The Death of St. Fione,

High Doses of Hormones Faulted in Fertility Care
Heather Ainsworth for THE NEW YORK TIMES
Published: July 16, 2012

After in vitro fertilization, Debra Demidon experienced a serious complication.


Doctors diagnosed severe ovarian hyperstimulation syndrome (OHSS), a complication seen in some women who undergo fertility treatment. It landed Ms. Demidon in the hospital for five days; doctors ultimately drained 6.5 liters of fluid from her body. She missed three weeks of work, and by the time it was over, she and her husband had spent all of their savings.

“It was my first time doing IVF, and I’ll never do it again,” said Ms. Demidon, 28, a quality assurance specialist in Cayuga, N.Y. “It was awful. When you have that much fluid in you, it puts pressure on everything.”

OHSS is a little-known complication of fertility treatments that rely on high doses of hormones, which are standard in the United States and the United Kingdom; the syndrome is not the only health problem to be linked to in vitro fertilization. Fertility clinics in Europe and Japan have turned to a safer, low-dose form of IVF, but clinics here have largely resisted on the grounds that the success rates for low-dose IVF are not as high.

Pregnancy rates are lower, and more cycles of IVF are necessary” with low-dose IVF, said Dr. Glenn L. Schattman, a fertility doctor at NewYork-Presbyterian/Weill Cornell Medical Center and president of the Society for Assisted Reproductive Technology.

But some critics are urging the industry to reconsider.

“Mild stimulation is clearly much healthier for women,” said Francine Coeytaux, founder of the Pacific Institute for Women’s Health, a nonprofit organization based in Los Angeles. “The reason hyper-stimulation happened is because these fertility clinics compete against each other by posting their success rates.”

In high-dose IVF, a woman is first given injections of a drug, often Lupron, to suppress her ovaries, causing temporary menopausal symptoms. Then the ovaries are stimulated with hormones, such as follicle-stimulating hormone and luteinizing hormone, in order to produce more eggs. The duration of stimulation is longer, and the hormone dose significantly higher, than in the low-dose programs common overseas.

Women normally generate one egg per cycle, but high-dose stimulation can help women produce 20 to 30 eggs, or even more. By contrast, women receiving mild, low-dose IVF produce 8 to 10 eggs. The ovaries are not suppressed at the outset, and there is no manipulation of the patient’s cycle.

According to the National Institutes of Health, high-dose stimulation leads to OHSS in 10 percent of IVF patients. The ovaries become swollen and, as in Ms. Demidon’s case, can leak fluid into the chest and abdomen. Symptoms can range from mild to serious; in rare cases, OHSS can be life-threatening.

A recent inquiry into maternal deaths in the United Kingdom found that OHSS following high-dose IVF is now one of the leading causes of maternal mortality in England and Wales. But it may not be the only complication. One recent study suggested that high-dose IVF contributes to lower birth weights, compared with the babies of women who receive minimal doses of hormones. And experts have debated for decades whether IVF contributes to an increased risk of breast and ovarian cancer; studies have reached conflicting conclusions.

Lupron, used to suppress the ovaries, has raised concerns as well. The drug is approved to treat prostate cancer; its use in IVF is off-label (meaning it is not FDA-approved for this purpose). Thousands of women have reported adverse reactions, including memory loss, liver disorders, bone loss and severe muscle, joint and bone pain, said Marcy Darnovsky, associate executive director of the Center for Genetics and Society, a public interest group in Berkeley, Calif.

“Lots of drugs are used off-label, but is this use appropriate?” said Ms. Darnovsky. “Considering the number of women who’ve taken these drugs over the past 25 years, you’d think much more rigorous studies and analysis would have been done on them.”

Because of these concerns, some reproductive specialists are switching to a milder form of IVF. The low-dose technique relies on fewer drugs to stimulate the ovaries, and can result in fewer complications and a quicker recovery time.

Dr. Pasquale Patrizio, a professor of obstetrics and gynecology at Yale University and director of the Yale Fertility Center, said he has been using low-dose IVF with good results. “It’s a shift of minds in the last few years, as we’ve been realizing that there’s no need to stimulate ovaries so aggressively as we’ve done before,” he said.

But other experts say that because the low-dose method produces fewer eggs, women have lower pregnancy rates per cycle. It could take more cycles, and perhaps more money, for a woman to conceive.

“By doing more cycles, there are greater risks by exposing women to more medication, more egg retrievals, and more anesthesia,” said Dr. Schattman of NewYork-Presbyterian/Weill Cornell Medical Center. “It’s not patient-friendly, and you’ll find lots of doctors who don’t agree with it.”

The exorbitant cost of standard IVF — $15,000 to $30,000 per cycle, often not covered by insurance — can prevent women from doing more than one or two cycles. Many women, and their doctors, believe that high-dose IVF increases the odds of conceiving without multiple cycles.

Dr. William E. Gibbons, director of the division of reproductive medicine at Baylor College of Medicine and an early pioneer of IVF in the United States, said he does not believe that the data support a switch to mild IVF.

“More eggs equals more embryos and a better chance of pregnancy — and standard IVF produces more eggs,” he said.

But low-dose IVF can be much less expensive, costing only about a third of standard IVF, according to Dr. Patrizio. The drugs are cheaper (about $500 per cycle), less medicine is necessary and less monitoring is needed, he said.

Because it also reduces the risk of OHSS, fewer patients require hospitalization, Dr. Patrizio added, reducing costs even more.

Dr. Geeta Nargund, president of the International Society for Mild Approaches in Assisted Reproduction, has been at the forefront of using low-dose IVF in England.

“It’s a win-win situation,” she said. “We can offer successful IVF to women while protecting their health and safety, and making it better for their children, at a lower cost. Mild-stimulation IVF is also significantly better for the quality of the embryos and the birthrate of children.” The physical and emotional discomfort for women is significantly lessened, she said; in fact, most women don’t feel anything.

“If we can have IVF stimulation at a lower cost and without OHSS,” Dr. Patrizio said, “then it would be a great step forward for the United States.”


IVF clinics accused of putting money before safety

Jeremy Laurance

Monday 14 May 2012

IVF clinics in the UK are practising aggressive fertility treatments that are putting women and children at unjustified risk, experts say.

The commercially driven industry uses unnecessary procedures, high doses of powerful drugs and risky interventions to help desperate couples spending thousands of pounds to conceive.

But a milder, safer approach to IVF could provide equivalent success rates over a longer period at a lower cost and could enable the NHS to double the number of patients treated for the same budget. The UK is lagging behind other countries in adopting the approach, the experts say.

Professor Geeta Nargund, head of reproductive medicine at St George’s Hospital, south London, told a conference in Copenhagen that there was increasing evidence that the standard method of IVF used in the UK, involving stimulating the ovaries with high doses of drugs to produce large numbers of eggs for harvesting, was detrimental to the health of women and caused chromosomal abnormalities in the resulting embryos.

“High-dose stimulation can have distressing side effects on the woman, the most serious of which is called ovarian hyper-stimulation syndrome (OHSS). This condition in its severe form is potentially fatal and women have died,” Professor Nargund told the conference. She added: “A recent confidential inquiry into maternal deaths in the UK showed that OHSS was now one of the biggest causes of maternal mortality in England and Wales.”

There were almost 30,000 cases of OHSS – which can cause chest pains shortness of breath and, in rare cases, kidney failure and death – between 1991 and 2007 in the UK, according to figures obtained from the Human Fertilisation and Embryology Authority (HFEA) in response to a request under the Freedom of Information Act.

“There is no doubt that women subjected to this kind of stimulation are at serious health risk and yet the HFEA appears to hide behind a confidentiality clause when it comes to releasing clinical complications,” Professor Nargund said, speaking at the congress of the International Society for Mild Approaches in Assisted Reproduction, of which she is president.

IVF has grown increasingly popular over the last two decades with 45,000 women treated in the UK in 2010. The use of less toxic drugs to stimulate the ovaries, known as “mild” IVF, produces fewer eggs and a lower pregnancy rate per cycle. But it means recovery is quicker and patients can repeat the treatment within a month. Standard IVF takes months to recover from.

Clinics in Scandinavia, Belgium, Holland, France, Canada, Japan and South Korea have adopted mild IVF, but, in the US and UK, high-dose IVF is preferred.

“The aim should be to do no harm to the mother and the child. If we continue with expensive, aggressive, old-fashioned IVF it will exclude too many from treatment. We could double the number of patients treated at no extra cost and the complications would be less,” Professor Nargund said.

Bill Ledger, former head of the IVF unit at the Royal Hallamshire Hospital, Sheffield, and a former member of the HFEA who is now a professor of obstetrics and gynaecology at the University of New South Wales, Australia, said: “It is time for a change. In the past we were so desperate to help couples have children we used high doses of drugs and put back three embryos. Now we have the luxury of good pregnancy rates it is time to emphasise safety as well as efficacy.”

Professor Ian Cooke, former president of the British Fertility Society and chief executive of the Low Cost IVF Foundation, said: “We are over-stimulating women, driving the cost up and the complications up. The first aim should be to reduce complications.”

Susan Seenan, deputy chief executive of the Infertility Network UK, which represents infertile couples, said: “The first thing women will want to know is what are their chances of a baby with mild IVF? If patients have to undergo multiple cycles it might mean more disappointment and upset.”

A spokesperson for the HFEA said: “There is currently no data which we hold that is an accurate marker of poor clinical practice or is a predictor for the likelihood of a patient experiencing OHSS. The HFEA continues to monitor this research even though it has limited regulatory powers in this area.”

Case study

Lee Cowden, a music teacher, was on holiday with her husband, Iain, a few days after receiving drug treatment to stimulate her ovaries at a London clinic, in preparation for IVF, when she felt suddenly unwell.

I sat up in bed and told my husband I had terrible chest pains and couldn’t breathe. He called an ambulance. At first, they thought it was indigestion. Then they realised I had had a heart attack.”

Lee was 25 and newly married. She had known since her teens that she would need help to have a baby because she had polycystic ovary syndrome and had sought treatment at an IVF clinic soon after she was married in 2004.

Doctors concluded her heart attack was a reaction to the high dose of fertility drugs. The clinic treating her had doubled the dose after the initial one failed to work. She was told she could never have fertility treatment again because of the danger. But a year later, she started a mild course of IVF at another clinic.

“They used small doses of drugs with careful monitoring. I got pregnant at the first attempt with Molly, who is now five.

“I am amazed how women writing on fertility forums want 20 or 30 eggs so they can freeze embryos. They don’t realise the risks and the sky-high cost of the drugs. I calculated I could have four cycles of mild IVF for one of standard IVF.”



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