19 June 2010

Children of a Fertile Revolution

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Melbourne IVF

Melbourne IVF's founder the late Ian Johnston, and current Melbourne IVF Director and leading fertility specialist Dr John McBain, were part of the Melbourne Egg Project the collaborative team responsible for the pioneering work that conceived and delivered Candice Reed on 23rd June 1980, Australia's first and the world's third IVF conceived child.

The leftover pituitary gonadotrophin for my use in in-vitro fertilisation patients was stored in an old shoebox in a laboratory at Royal Women's Hospital in Melbourne. The box sat to one side of the urinary control samples we used in our 24-hour assays of key hormones indicating the progress of an infertile woman's ovulatory cycle as well as our efforts to encourage successful ovulation.

On the other side of the world, Hugh Robinson's team at my old University Hospital in Glasgow was using ultrasound to see and measure the process. They could observe the daily growth of the ovarian follicle that was secreting the hormones that we measured so laboriously after the kidney had excreted them and the woman had collected every drop of urine she passed for days on end.

Ultrasound monitoring of the ovaries would come to us 18 months later when Hugh completed the Scots migration to Melbourne that I had begun in 1976.

We were good at treating ovulation disorders and had been since 1963, when my colleague at the Women's, Jim Brown, succeeded in extracting egg-stimulating gonadotrophin hormones from donor pituitary glands for our use. The glands were being collected as a source of growth hormones for children with pituitary dwarfism. We were essentially tapping the same source for gonadotrophin.

If you were infertile in Melbourne in 1977 you should have chosen ovulation failure as your diagnosis. That was so, as James Evans and his co-workers in the urine laboratory at the Women's could completely restore you to normal fertility. That is, if you didn't mind a 20 per cent risk of twins, 8 per cent of triplets and 2 per cent of quadruplets. And these were world-best figures.

You were even luckier if your ovarian dysfunction was due to an excess of the then relatively recently measured pituitary hormone, prolactin. Roger Pepperell, the new professor at the Women's, was treating patients with a drug that blocked the hormone and was getting results as good as those with gonadotrophins but without the multiple pregnancies.

Otherwise, things were a bit grim for infertile couples back then. Those with tubal blockage or severe male factor problems were virtually untreatable, at least to any sort of acceptable pregnancy rate. That was despite the microsurgical skills of Ian Johnston and Andrew Speirs at the Women's. Ian had started the frozen donor sperm bank a year earlier, populated by the efforts of the uncounselled, poorly advised and anonymous University of Melbourne medical students from across Swanston Street.

In the earlier 1970s Carl Wood at the Queen Victoria Hospital and Ian at the Women's had each become excited about the possibilities successful IVF and subsequent embryo transfer might bring to women where tubal blockage prevented the egg and sperm meeting inside the reproductive tract.

What was required seemed simple enough: a way to predict when the egg was mature, indicating the best day for an ovulatory trigger injection, followed 36 hours later -- just before rupture of the egg-bearing follicle -- by a laparoscopic capture of the egg under full general anaesthesia.

Also required was a safe and nourishing environment for the harvested eggs and sperm. That required incubation with a known and controllable temperature and gas mixture. The culture fluid was derived from culture systems known to support cell culture, but the special needs of the early human embryo were then unknown.

Those Melbourne trailblazers had the great good sense to pool their resources collaboratively in what was known as the Melbourne Egg Project. Ovarian stimulation was handled by Jim Brown and then me at the Women's, and laboratory culture by Alex Lopata from Monash University. Egg collection was the job of the surgical teams comprising Carl Wood, John Leeton and Mac Talbot at the Queen Vic; and, at the Women's, Ian Johnston, Anand Maharaj and Andrew Speirs.

In 1977, the team performed 65 egg collections in natural, minimally stimulated and hyper stimulated cycles at the Women's and 18 at the Queen Vic. The number was lower there as Queen Vic was a general hospital and, therefore, less generous with surgical theatre time for what was considered to be experimental work of marginal importance. Unfortunately, no pregnancies resulted from that year's work.

Meanwhile, a cash crisis was brewing. The Melbourne Egg Project had two streams of funding beyond Alex's senior lecturer salary from Monash: a grant from the Ford Foundation and the surgical fees charged to patients for the egg collection procedures, which went back into the kitty. Carl told us the grant would not be renewed and consequently the project's continuation was in jeopardy.

Ian's response was that the Women's would go it alone if necessary. It was a spirited response but one that, in retrospect, saw the gradual splitting of the project into two geographical camps. That process accelerated with Alan Trounson -- now head of the California Institute for Regenerative Medicine in San Francisco -- joining the Queen Vic team in early 1978 and Alex coming under the umbrella of the University of Melbourne department at the Women's.

Then we got the news in 1978 that the efforts of Bob Edwards and Patrick Steptoe had resulted in the birth at Manchester's Oldham General Hospital of Louise Brown, the world's first IVF baby, and a second unnamed birth also at Oldham.

The announcement of Louise Brown's birth had a two-fold effect in Melbourne. The disappointment of not being first, aside, the English team's insistence that their success was due to using the drug-free natural cycle meant Jim Brown and I were sidelined. Their assumption was that the hormonal treatments we were using were poisoning the eggs or doing something to stop the IVF process from being successful.

This scientific cringe was completed when Patrick Steptoe came to Melbourne to talk about his team's success. Michael Forrest, fertility specialist at the Mercy Maternity Hospital and Moonee Valley committee member, snared good tickets to the Cox Plate for Patrick and Sheena, his wife.

Steptoe told an expectant gathering in the Women's boardroom that IVF could never work with ovarian stimulation, the approach we had been using. It became clear during discussions that neither he nor Edwards had any idea why they had been successful in these cases when so many of us had failed. To his credit, Bryan Hudson --director of the Howard Florey Institute and the acknowledged conductor of the "Melbourne endocrine orchestra" - put on his hat and coat and left half-way through Steptoe's presentation.

In time, a pregnancy did happen in Melbourne, following the English recipe to the letter. But it was one out of 50 or so attempts. Candice Reed's mother, Linda, was IVF patient No 42.

But, following another year of disappointments we reinstituted our earlier stimulation protocols, this time with gonadotrophins of urinary origin. We did that because pituitary derived hormones were banned in the wake of the emergence of cases of the neurological disorder Creutzfeldt-Jakob disease. Today, the stimulation hormones are genetically engineered in the lab.

In March 1980 I was sufficiently rehabilitated to be sent, some months before Candice's birth, with Linda Reed to appear on The Mike Walsh Show with Ita Buttrose as host. As we waited in the green room, a nervous young man in a floral shirt paced up and down before he went on to sing, for the first time on television, I Still Call Australia Home. Peter Allen, of course, went on to international fame. And so did Candice Reed. Happy birthday, Candice.

Unsung heroines of IVF

Linda Reed and other women undergoing so-called natural cycle IVF in the late 1970s faced an arduous, rigorous and mostly unsuccessful process.

They collected urine samples for daily monitoring until their oestrogen levels indicated it was time for an ovarian ultrasound.

That required a bursting-full bladder to measure the diameter of the egg-bearing follicle and ensure it was on an ovary that could be accessed laparoscopically. They then faced a two-to-three day hospital stay, with three-hourly urine collections to detect the first rise in luteinising hormone, the signal for laparoscopy, which had a 70 per cent chance of finding and removing an egg.

Egg and sperm were then combined in the lab, with a 60 per cent to 70 per cent chance of successful fertilisation. Two days later the embryo was transferred to the mother, who was most likely to have a negative pregnancy test. If so, it was back to step one.

Today, IVF isn't a walk in the park, but all the procedures are done on an out-patient basis with the exception of two hours of day surgery to collect eggs.

Clearly, women such as Candice Reed's mother were true pioneers.

John McBain is head of Reproductive Services at Royal Women's Hospital and a director of Melbourne IVF. He was a member of the team responsible for the conception of Candice Reed.

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