Fifty years, two million babies: A remarkable medical success story

The number of Australian children who die from HDN has fallen more than a hundred-fold since anti-D preventative ...
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The number of Australian children who die from HDN has fallen more than a hundred-fold since anti-D preventative treatment was introduced.

In 1999, Nicole Mannix-Power was young, fit and expecting her third baby. On February 16, in the midst of an enervating Sydney summer, one of her girlfriends at work noticed she didn't look very well.

"She said to me, 'Are you okay?'" she recalls. "And I said, 'No, I am so fricking tired I feel like dying.'" It was hot, she was 36 weeks pregnant, she had two young boys at home: of course she was exhausted. Still, this seemed extreme. "My friend said, 'Have you felt the baby move lately?' I was like, 'Oh, I'm busy, I'm sure it has.'"

"Go straight home," her friend told her. "Go straight to the doctor."

Nicole Mannix-Power with daughters Ruby and Chloe, who both survived their mother's RH- sensitisation.
JANIE BARRETT/Fairfax Media

Nicole Mannix-Power with daughters Ruby and Chloe, who both survived their mother's RH- sensitisation.

I meet Mannix-Power at Sydney Airport, where she organises freight for Cathay Pacific. She's slim and healthy-looking, with curly hair pulled firmly back, wearing a neat maroon skirt and sensible court shoes. Remembering that day almost two decades ago, her eyes fill with tears. She wipes them away. "When I got there, they put the thing on my belly, and there was no heartbeat. I thought, 'Oh my God.'"

Mannix-Power's baby – a girl – had died in utero, less than a month before she was due to be born. She had died of Rhesus D Haemolytic Disease of the Foetus and Newborn, or HDN, a disease in which a mother's body creates an antibody that destroys her unborn child's red blood cells. It can cause severe spleen and liver problems, brain damage, and death in babies.

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Sydney specialist Dr Danny Challis and his team provided fortnightly treatments allowing Nicole Mannix-Power to have two ...
LOUIE DOUVIS/Fairfax Media

Sydney specialist Dr Danny Challis and his team provided fortnightly treatments allowing Nicole Mannix-Power to have two healthy babies.

"Historically, HDN was one of the major causes of infant mortality and lifelong severe disability in our population," explains Professor Robert Flower, transfusion scientist at the Australian Red Cross Blood Service. "It was a terrible, terrible condition." And it still has the potential to affect one in every six newborns in Australia. That's about 40,000 babies every year.

Such a figure seems almost impossible to imagine. And these days we don't have to imagine it, thanks to a small group of people – less than 150 nationwide at present, and only 515 over five decades – who donate blood once a fortnight to save these babies' lives. They are known as the anti-D donors, and their blood contains what researchers once called the most miraculous product since penicillin – an antibody that protects babies from HDN.

This year marks the 50th year of Australia's extraordinary involvement in the story of anti-D, as the antibody is known. It was an Australian doctor who helped discover the use of this antibody. Australia was the first country in the world to start a donor program to obtain anti-D and the first country to administer it to pregnant women.

Today, Australian researchers lead the world in helping identify and protect babies at risk of HDN. Half a century after the world's first baby – an Australian baby, as it happens – was saved by anti-D, it seems possible that basic human kindness and cutting-edge science may finally trump one of biology's cruellest quirks: the tragedy by which a mother kills her own baby. 

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HDN derives, bizarrely, from a basic biological fact: blood group. About 17 per cent of Australia's population has Rh(D)- blood: O-, A-, B- or AB-. The rest are Rh+. Generally speaking, Rh- women are no different from anyone else – except during pregnancy. If an Rh- woman is carrying an Rh+ child, and that child passes blood cells to the mother in utero (as happens in almost every pregnancy), a potentially catastrophic reaction takes place in the mother's body. Her system responds as if her baby's blood cells are a foreign bacteria or virus, and she begins producing antibodies that destroy them.

This first Rh+ baby is often unaffected, because the antibodies don't develop in time to do significant harm. But the mother's body retains them for life, a condition known as "sensitisation". And once she's sensitised, in any subsequent pregnancy, if the new foetus is also Rh+, the mother's antibodies will multiply and eradicate that new baby's red blood cells too. The effect on babies varies dramatically between women and between pregnancies. But for most women, their response grows more powerful with each Rh+ pregnancy, which means the damage to their babies becomes more severe, too.

"In the women I saw, the first baby was okay," recalls Robyn Barlow, a vivacious woman who began work for the Blood Service in 1967, and recruited many of the anti-D donors who would go on to combat HDN. "Then the second baby was mildly or moderately affected, then the third one was dead. There were many, many mothers who just went on losing babies. I remember one lady who lost 10 babies. Ten dead babies! How did she survive that? I don't know: I do not know how she did it."

Incredibly, it was this same group of women, bereft of their own babies, who would form the core of the anti-D donor group that would go on to protect an estimated two million children in Australia…and counting. But for that, they required a medical breakthrough made in New York by a group of three researchers: one English, one American and a young Australian from Bendigo called John Gorman.

In his later, distinguished years, photographs of Dr John Gorman – all dramatic eyebrows and sweeping comb-over – make him look slightly forbidding, but his face retains a kind of broad openness, as if he's about to kick a footy or whistle to a blue heeler. He was, however, doing neither in the early 1960s: he was working in New York investigating HDN. The disease had first been described 20 years earlier, but there was (and still is) no cure.

Gorman and his colleagues came up with a radical suggestion: to try to avoid the sensitisation that causes HDN in the first place. Their idea was to inject the Rh- mother with the very same antibody – RhD immunoglobulin, or anti-D – that she would naturally produce if Rh+ blood entered her system. The theory was that the introduced antibody would "mop up" any of the baby's blood cells circulating in the mother's system, thus preventing her from mounting her own response. The introduced antibodies would be present in such low numbers, and for such a short amount of time, that they wouldn't harm the baby.

So the very thing known to kill babies was being proposed as their salvation. To the man on the street it seemed insane – and apparently the medical establishment felt the same. The American National Institutes of Health called the idea "a nonsense", and the major funding bodies refused to support it. Nonetheless, Gorman and co ran a trial (on Rh- volunteers at New York's Sing Sing prison, of all places) and found that it worked. On January 31, 1964, they performed the first anti-D injection on a pregnant woman in history: Gorman's sisterin-law, Australian Kath Gorman. She went on to have seven children.

The ability of anti-D to prevent HDN was formally announced at the International Blood Transfusion Congress in Sydney in 1966. It caused a sensation. Only months later, the first anti-D donors in Australia were recruited, and the country's anti-D donor program began the following year. Two years later, Australia became the first country in the world to be self-sufficient in its supply of anti-D.

In some ways, these donors are the most incredible part of the entire anti-D story. Because the very first people asked to participate were the same women who had had HDN-affected babies themselves. These women had watched their babies die or seen them grow up brain-damaged or deaf or with other permanent impairments. Some of these women had been sterilised after repeated stillbirths or neonatal deaths. And the treatment itself was too late for them: anti-D can't help once a woman is already sensitised. So these women were being asked to help others be luckier than they had been.

Almost without exception, they said yes. "They were very eager to help," explains an early Rh project director, Dr Baden Cooke. "It seemed that the more they had suffered themselves, the more they wanted to help other women."

Such women are still recruited today. Robyn Barlow can recall, not so long ago, sitting in a doctor's reception waiting to talk to one. "I could see this couple sitting there, and the woman was sobbing and the husband had his arm around her, and I said to my colleague, 'I hope that's not who we've come to see.' And then they were called in, and we were called in, and I just thought, 'This is terrible.'

"I felt like I was intruding on somebody's grief. She was absolutely stricken: her eyes didn't leave the floor the entire time I was talking. So I said, 'We've come to ask you to donate, but please don't think about it now. I'll ring you in a few days.' It was only six weeks since she'd lost the baby. Later I thought, 'I can't do this anymore.' "Anyway, I let a few days go by, then I took a deep breath and rang her. And she said yes, she'd do it. We made thousands of ampoules of anti-D with her blood." 

Anti-D donor women like this were soon joined by men, who make the antibody exactly as women do after booster shots of Rh+ blood, but without the obvious implications for pregnancy. In the early days, these men risked viral infections such as Hepatitis C (and later HIV) from the booster shots, but they joined up anyway.

One such man was chief engine officer with NSW State Rail workshops (now retired), James Harrison. At 14, he received a lifesaving blood transfusion and, at 18, in a spirit of repayment, he became a blood donor. Ironically, part of the transfusion he received was Rh+ blood, so his system was already making the anti-D antibodies, and he naturally produces a very strong, consistent antibody count. He is known in antiD circles as "the man with the golden arm".

In 50 years, Harrison has never missed an appointment. Every fortnight, his blood (like that of all anti-D donors) is extracted at the blood bank, then his plasma is separated from his red blood cells; then his red blood cells are reinjected to prevent anaemia. The whole process is "a major impost", points out the Red Cross's Robert Flower. "It's not just five minutes every 10 years; it's half a day once a fortnight. It's an extraordinary level of dedication."

Harrison, however, is unfazed. "I made my 1157th donation this Monday past," he explains genially. Until 2015, every batch of anti-D made in Australia contained his antibodies. His daughter Tracey, who is Rh-, received anti-D containing his antibodies in both her pregnancies. Harrison turned 80 last year, but has no plans to stop donating. "I've got plenty of time," he explains. "I've said I'll give it up when they have to use two hands to push the needle in and they won't use my leg."

Today anti-D remains the only preventative treatment for HDN. Every Rh- woman in Australia receives it at 28 and 34 weeks of pregnancy, and again post-natally. Indeed, for the past several decades it's been so routine that one woman I speak to had mistaken it for a vitamin shot. Thanks to it, the number of Australian children who die from HDN has fallen over a hundred-fold, to approximately 0.01 deaths per 1000 – about four babies a year in all of Australia. In 1980, Gorman and his two colleagues, plus two English research scientists who worked on anti-D at the same time, received the Lasker Award – the American equivalent of the Nobel Prize.

Today, Australia's Red Cross Blood Service continues to be a world leader in anti-D research. Associate professor Cate Hyland is a principal research fellow at the Blood Service. She and her team recently developed a test strategy that, for the first time, identifies the Rh status of certain groups of African women in the Australian population whose blood groups may not be identified by normal testing.

"Most work has traditionally been done on Caucasian populations, because they have the highest occurrence of Rh- blood groups," explains Hyland. "But we believe we should be able to provide accurate results for every Australian, whatever their background. Africans have an Rh- incidence of 5 to 8 per cent – but that's still significant. So we've designed a test strategy that allows us to define exactly what their blood group variants are, and we've actually discovered some novel blood group gene types. It's important for the management of the mother, because you can absolutely pinpoint whether she's at risk for making the antibody."

The Blood Service has shared this knowledge and expertise via the Africa Society for Blood Transfusion, and recently began negotiations with African scientists who hope to apply these principles, and newly discovered genetic variants, in their own testing development. In Australia, meanwhile, "our goal", says Dr David Irving, director of research and development at the Blood Service, "is to formulate this extremely complex technology into a routine test that can be administered to anyone who needs it".

The other great push in research is to create a synthetic anti-D antibody. "People have tried making an artificial anti-D antibody for 30 years," explains Flower. "And it has just never worked. The truth is, we still don't know exactly what it is about these antibodies that protects mothers. You can isolate the antibody, and it will mop up [the baby's Rh+] cells, but it won't protect the mother."

Flower and his colleagues have just begun to attempt analysis and replication of not only the anti-D antibody, but the complete mixture that comes from donors' plasma. If they're successful, they will change the face of HDN treatment and plasma donation worldwide. As one Blood Service employee puts it: "What we really need is James Harrison in a jar." Until then, 40,000 mothers and babies in Australia each year will have to rely on the octogenarian's real thing.

Paula Parry is a smiling, energetic woman with dark hair. She had no idea what anti-D was until she lost a baby at eight weeks in 2010. "My obstetrician explained how lucky we were that no blood from the baby had mixed with mine [during the eight weeks of the pregnancy]. He made it really clear. He said, 'If you bleed [in any pregnancy], you've got to get to a doctor and get anti-D.' " 

During her second pregnancy, Parry suffered persistent bleeding. "I was basically having anti-D every two weeks, to counteract any potential blood from the baby." At 26 weeks, she lost her baby – but not from HDN. "All those anti-D shots meant I was still not sensitised."

Six months later, when Parry fell pregnant for the third time, she was again administered with anti-D shots. This pregnancy progressed smoothly: her son Alex, now five, was born completely healthy, a triumph of anti-D prevention.

Parry, however, haemorrhaged after the birth and was rushed to theatre, where she received three blood transfusions – one of which, in an incredible mistake, was Rh+ blood. All this time and effort, scrupulously guarding against the possibility of any Rh+ blood entering her system, and suddenly she was pumped full of it? "I know," she says wryly. "It was not anyone's finest hour." In the following days, by repeated doses of anti-D and minute monitoring, the hospital cleared the Rh+ cells without Parry becoming sensitised. "Good mop-up," as she puts it.

When Alex was a toddler, Parry fell pregnant for the fourth time, and miscarried. Soon afterwards, she fell pregnant again. "At which point, my obstetrician sat me down and said, 'Paula, this is your last shot. If this baby is stillborn and you fall pregnant again, I will not look after you. It's too high-risk.' "

Nine months later, Parry gave birth to a healthy girl named Georgia, now two years old and herself Rh-. (It's one of the ironies of HDN that, in the midst of repeated Rh+ tragedy, if a woman conceives an Rh- baby, she will carry it without any Rh-related problems at all.) "So she'll have her own issues when it comes to pregnancy," Parry says. "But hopefully her experience will be like mine. HDN was a complete non-issue because of how well I was managed."

Even today, nobody really knows why Nicole Mannix-Power's story isn't more like Paula Parry's. Nobody knows, in other words, why anti-D sometimes fails. Perhaps Mannix-Power had had an unidentified foetal bleed and wasn't given anti-D, or she wasn't given enough, or not quickly enough. Whatever the reason, that day in 1999, there was nothing to be done. She was admitted to hospital and induced to bring on labour.

Some hours later, she gave birth to a daughter, Montana May. "They put a sign on your door – a little butterfly, which means 'deceased baby, grieving mother'. They gave her to me and said, 'You can hold her for as long as you want.' " She clasps her hands. "She was fully anaemic. You could just see by her skin – her lips, her eyelids. But she was 36 weeks. She was normal. She was perfect."

A year later, Mannix-Power fell pregnant again. This time, she was referred to the specialists at Sydney's Royal Hospital for Women. There she met Dr Danny Challis. A slightly rumpled man with dark hair and an extremely low-key manner, Challis is interested in things like early ultrasound machines and the possibility that Catherine of Aragon, Henry VIII's first wife, who suffered several late miscarriages and stillbirths, was Rh-.

Challis has more than 20 years' experience in dealing with babies of sensitised Rh- mothers. His expertise, and that of doctors like him, represents the only hope when anti-D fails. In such a scenario, there's no way to stop the mother producing the antibodies, and there's no way to prevent those antibodies attacking the baby's red blood cells. The only option is to try to replace those lost blood cells.

You can do this two ways. The first is to completely replace the baby's blood at birth. The second is to begin treatment even earlier – which is how Mannix-Power came to have fortnightly intra-uterine transfusions from her 20th week of this fourth pregnancy, in which Challis and his team, guided by ultrasound, used a long needle to trickle new blood into the umbilical vein in her daughter's liver.

Mannix-Power had enormous faith in Challis, but even so, "it was really hard. Every time you had the transfusion, you had to go home and rest up because the likelihood of a miscarriage was so high. It was horrendous. Every time I would think, 'Oh God, please. Just hang on.' "

Her second daughter hung on. Chloe was born by caesarean section at 30 weeks, weighing 2000 grams, and spent nine weeks in hospital. Last year, as a 16-year-old, she won the 100-metre beach sprint at the World Surf Lifesaving Club Championships in the Netherlands.

Over the past 50 years, anti-D therapy has virtually wiped out a condition that each year once killed hundreds of babies and led to life-long health issues in thousands more. It is an example of medicine's triumph, not simply over disease, but biology itself.

Yet, as women like Mannix-Power know, life is more complex than medicine. A year after her healthy daughter Chloe was born, Nicole's husband Luke, still devastated by the loss of their first daughter to HDN, committed suicide. "The loss of our daughter just killed him, killed him," she says. "But then we got this beautiful girl and I thought he'd be happy. But he was too far gone. I didn't know: I would never have picked it in a million years."

Such are the unclassifiable costs of HDN. "You never know what the loss of a child does," says Robyn Barlow. "You see the tragedy of the child's death. But there are also the dreams that parents have for their babies. And that loss, you don't see."

Ten years ago, Mannix-Power married her second husband. After much soul-searching, she decided to try for one more baby. "I remember Danny Challis seeing me and saying, 'No. Oh no. Really? We're doing this again?'" They did do it again: more transfusions, another birth at 30 weeks. And another healthy girl, Ruby, now nine.

Since then, much has changed in MannixPower's life. She's left enormous tragedy behind, raising four healthy children with her husband. But she hasn't forgotten. Once a fortnight, every fortnight, she leaves work early and goes to the blood bank, where she donates her plasma for the production of anti-D. Her antibody count is still so high she's never needed a booster shot.

Oddly, she hates needles, so she doesn't watch it happening. "But I do it because, if other people hadn't done it, I wouldn't have my girls," she says. "It's that simple."

 - Sydney Morning Herald

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