A remarkable tale of New Zealand science

Premature babies around the world were dying because doctors were reluctant to use a New Zealand-pioneered medical treatment. So scientists set about tracing a thousand 30-year-olds from the original medical trial to prove the treatment was safe.

Kristie Van Der Molen was at the office when she started seeing stars in her eyes. She mentally added ‘seeing stars’ to her list of other troubling symptoms: a puffy appearance, stomach pain and a severe headache. She thought, "Oh shit. I have pre-eclampsia.” She was right, in fact, her condition was so dangerous that soon her vital organs would be failing. But she kept working. “By the fifth or sixth person telling me I looked awful, I decided I would go to A and E, which is something I never do,” she says. “I didn't think anything was wrong with the baby. But I knew something wasn't right with me.”

It was July 12, 2016 and Van Der Molen was 27 weeks’ pregnant with her first child. Her baby’s lungs were undeveloped and he showed no signs of wanting to leave the womb. He didn’t have much choice, though. Van Der Molen’s liver was struggling, her platelets were dropping and her blood pressure was through the roof. The first thing the obstetrician told her when she got to hospital was, "We’re going to need to deliver your baby."

“I went into total shock, as you would,” says Van Der Molen. “They administered the first steroid injection straight away ... I remember them saying it would hurt but I was so swollen I didn't feel anything.” She got sicker as the night progressed. “My body was basically shutting down. My skin was so tight my mum actually thought it would split on my feet.”

Doctors fought to keep her stable long enough to administer a second steroid injection, 12 hours after the first one. The injections would speed development of her baby’s lungs and help prepare him for exit. Baby Remy was born by caesarean section at 9.50am on July 13, three hours after the second injection.

Van Der Molen wouldn’t meet him for another 24 hours. She wouldn’t be allowed to hold his hand until he was three weeks old. Altogether Remy spent 118 days in intensive care and had two emergency surgeries. But he lived. “He was so small and I went through so many emotions ... being able to have your heart so filled with joy because you have your baby, yet so broken,” says Van Der Molen. “The only consolation I can take is that he won’t remember it.”

Today Remy is a laughing 7-month-old who loves baths and cuddles. “He loves being given frights,” says his mum. “We are so blessed to have him.” Yet in another time, or another country, Remy mightn’t have made it.

Kristie Van Der Molen at 26 weeks pregnant. Her son Remy was born the following week after she developed life-threatening complications. Photo: Supplied

A fighting chance

If Remy was born 50 years ago, his chances would have been slim. In the early and mid-1960s the survival rate of babies born weighing less than a kilogram (usually before 28 weeks' gestation, or three months or more before their due dates) was less than 10 percent at National Women’s Hospital, New Zealand’s flagship maternity hospital. Babies weighing between a kilo and a kilo-and-a-half at birth (usually those born two-to-three months early) had a 50/50 chance. “Babies born as late as 34, 35, even 36 weeks gestation often died,” says Jane Harding, a researcher of perinatal health and a distinguished professor at the Liggins Institute in Auckland.

Today we expect modern medicine to save most early arrivals. Since about 1990 babies born two or three months early have had a better-than-90 per cent chance, says Harding. More recent advances mean even tiny under-28-weekers, like Remy, live more than nine times out of 10. Hospitals have better nutrition, ventilators and medicines than ever before.

Yet hospitals could have saved even more babies had they embraced a New Zealand-pioneered treatment. A life-saving idea — the steroids given to Van Der Molen — was ignored for decades by obstetricians in many countries. It took years of graft and the contents of an old, locked hospital cupboard to get the injections in widespread use, and debate is still happening today.

"Terrible to watch"

Many ailments used to overcome premature babies born before the 1970s, but the main killer was lung disease. A pre-term baby’s lungs are stiff, like a balloon when you first start blowing it up. Our lungs need surfactant — a detergent-like substance — to prevent them collapsing like new balloons every time we breathe out.

Preterm babies don’t make surfactant; they don’t need to, because they get oxygen from their mothers. But if they have to leave the womb early — as an estimated 15 million babies do around the world annually — stiffness in their lungs can cause respiratory distress syndrome.

A baby with respiratory distress syndrome looks as though its chest is caving inwards with every breath, as it desperately tries to suck oxygen. “It’s a terrible thing to watch, little babies just labouring to breathe,” says Harding.

As early as the late 1960s Mont Liggins, the brilliant medical researcher who gave his name to the Liggins Institute, came up with a new way to save these babies. Liggins kept a flock of research sheep on the grassy slopes of Cornwall Park, not far from National Women’s Hospital, which he used for trialling medical treatments. He discovered that giving ewes steroids boosted survival rates among pre-term lambs, which would usually die of lung disease. It turned out giving steroids to the mother sped up the foetus’s lung development, including hastening production of surfactant.

Next Liggins and his collaborator Ross Howie tried the steroids in pregnant women who were at risk of delivering early. The first results were remarkable. Mortality among the preterm babies fell from 15 percent to 3 percent. When mothers were given steroids within 24 hours of giving birth, none of their babies died of respiratory distress or brain haemorrhages. By the early 1970s Liggins and Howie had recruited almost 1200 women to a randomised controlled trial of antenatal corticosteroids — still the largest and best test of the injections anywhere. Half the women were given real steroids, the rest a placebo.

“It was dramatic,” says Harding, who’s been made an Officer of the NZ Order of Merit, won a Gluckman medal and been named North and South magazine’s New Zealander of the Year for her life-saving work with newborns. “Life-changing. It was the first widely-used treatment for a baby given before birth.”

But for decades babies and mothers didn’t get the treatment, even in wealthy countries. In many places, they still don’t.

Mont Liggins's flock of research sheep on the slopes of Cornwall Park. Photo: Liggins Institute

Finding Mont's babies

New Zealand babies were started getting antenatal steroids early, says Harding, because Liggins and Howie worked at National Women’s Hospital, which was seen as a leader of clinical practice here.

Doctors elsewhere seemed to baulk: The drugs were powerful, and the patients (babies) were delicate. A large part of the problem seemed to be that busy specialists didn’t have time to review the latest evidence showing the treatment worked, says Harding.

Over the next two decades, more than a dozen studies involving more than two thousand babies confirmed Liggins' and Howie’s findings.

The stakes could scarcely have been higher. Every year, more than one in 10 babies globally is born before 37 weeks’ gestation, according to the World Health Organisation, and a million babies die from complications of prematurity. That makes pre-term birth the leading cause of death among children under five.

In 1992 the Cochrane Collaboration, a global network of scientists that summarises medical evidence for doctors, highlighted how thousands of babies had died needlessly because doctors didn’t have the most up-to-date evidence. The collaboration adopted as its logo a graph showing the lives that could have been be saved if antenatal steroids were used.

In 1994 the United States’ National Institutes of Health published a consensus statement saying there was good evidence for using antenatal steroids and reminded doctors that this was a rare treatment that actually saved money as well as lives. The message, says Harding, was “get on with it.”

But now worrying results were coming out of animal studies. Tests of corticosteroids on animals suggested giving pregnant females repeated doses might increase their offspring’s risk of developing metabolic problems. That might raise the offspring’s risk of developing diabetes and heart disease.

“Some of us were getting quite frustrated, saying, look there is really, really good evidence that this stuff saves lives,” says Harding. “Why are we worrying about whether they are going to have diabetes 50 years later? How many studies do you need?”

Harding decided to do something. So she opened Ross Howie’s old cupboard.

Sharp sleuthing

Harding realised she might have a way to reassure people about the steroids. As a young woman she’d trained under Liggins and Howie, then worked and studied overseas before returning to Auckland and a job at National Women’s Hospital. She happened to have been allocated Howie’s old office.

Potential evidence of the injections’ safety was sitting in front of her, albeit concealed behind a locked door. In the cupboard in her office were two boxes of old, handwritten records: the original paperwork from the 1970s trial. By now it was the early 2000s. The babies would be 30 years old. If they were going to have health problems, signs should be emerging by now.

Liggins and Howie agreed to let Harding and her colleagues use their data. But tracking the babies-turned-adults wasn’t easy. The paper records listed the mothers’ names and the birthdays and sex of their babies, but not the babies’ names. Fortunately for the scientists, women having kids in the 1970s almost never had different names from their children.

“First we went to the national register of births to try and find a baby whose birth matched the records,” says Harding. “If the mother’s name was very unusual we might only find one match, but if the mother’s name was common we’d find several.”

The researchers took all the possible matches and looked the names up in the electoral roll, searching for possible addresses. “We wrote to people saying, we think you might have been involved in this study, and very often people would write back and say, ‘Yes that was me’,” says Harding. “It was also quite common for people to write back and say, 'That wasn’t me but you might need to talk to Mrs so-and-so round the corner’. New Zealand is a small place and people were very generous in their attempts to help.”

The adults from the trial were scattered all over the world, in Australia, England, Bermuda, Canada, Peru, Italy and Israel. Sometimes the researchers managed to trace them through a parent or sibling. They were helped by the fact that many of the 30-year-olds believed being in the trial had saved them. “Because at the time a large number of preterm babies died, most mothers were incredibly grateful to be part of the study … and they passed that on to their children,” says Harding.

Of the 1142 babies born in the original trial, 988 had survived longer than a month. Harding and her team managed to find and test 534 of the survivors. Some of the people living overseas agreed to be tested, when they returned on holiday. The results? Mont’s babies were pretty healthy.

Professor Jane Harding used notes from a 1972 trial to track down 534 babies - now 30 years old - to research the effects of steroid injections on premature babies. Photo: Liggins Institute

Living proof

The researchers wanted to test for every possible problem that had cropped up in animal studies as being associated with antenatal steroid use. Nurses took people’s weights and heights, measured their heads, checked their fat levels and hormones and tested their blood glucose and blood pressure. “We looked at their size, growth, cholesterol levels, diabetes risk, bone density, lung function,” says Harding. “In a sub-group we also looked at their brains — cognitive function, quality of life, mental health,” she says.

The 30-year-olds were not quite as strong as they would have been had they arrived on their due dates. For example, some had blood pressure and other issues associated with being born early. The fact that so many early babies now survived was going to create costs for the health system, the researchers noted.

But these problems were no more common among the group whose mums received the steroids than they were among the placebo babies. In other words, the risk came from being born prematurely, not from the steroid injections. Whatever was affecting lab animals whose mothers were given antenatal steroids, it wasn’t showing up in humans.

The findings were persuasive because the babies had been selected at random back in the late 1960s and early 70s, so there shouldn’t be a bias caused by hospitals choosing the sickest mums or babies for treatment. Harding and her colleagues published their findings in top medical journals in 2005 and 2006.

The sleuthing didn’t magically erase worries about the steroids. But Harding says it certainly helped. Today, antenatal steroids top the World Health Organisation’s list of recommended treatments to save early babies’ lives.

Lingering questions

Debate still swirls about the proper use of antenatal steroids — even in New Zealand, the treatment’s birthplace. Because the benefit of using them is strongest for the first week, the recommendation in New Zealand and Australia is for doctors to administer a course of two injections again if a woman hasn’t delivered in that time. The treatment can keep being repeated if an early birth keeps looking likely.

Doctors are not necessarily doing this, even here. Harding and others are doing a study to see how closely hospitals are sticking to the guidance. “We don’t think it is being followed,” she says. “There’s always a gap between the recommendation and actual practice. Our study is to find out what is that gap, and why is it people aren’t following the recommendation, and what can we do about it?”.

Again, researchers are doing follow-up studies in patients to reassure people. Last October Caroline Crowther of the Liggins Institute published a study with Harding and others of 7-year olds whose mothers received repeat courses of steroids. It found no added problems with the children, whose hearts, hormone levels, growth, behaviour and cognitive development seemed fine. “There have been trials still going on about whether repeat doses have a benefit and there is still considerable controversy, [which is] why we reported the seven-year follow-up,” says Harding. “It’s the same issue. How long do you wait? Is seven years enough?”

There’s other work to be done, too, tailoring the treatment for different women, she says. “We are still finding the best way to treat certain groups, for example if the mother has diabetes what does it mean? There are lots of questions still to be answered.”

Moving barriers

In poorer countries, there’s a much more basic controversy over using steroids. One study suggested efforts to increase the use of corticosteroids might actually hurt babies’ chances of surviving in places without decent nutrition and neonatal care. The study was of efforts to increase the treatment — not the treatment itself. Still, the WHO recommends injections only be given if doctors have good estimates of due dates and can supply good care for early labour and birth.

Even among women who should be treated, access is patchy, and young and poorly-educated mothers seem least likely to get the injections. A review of 300,000 births in low and middle-income countries found about half the women recommended to get corticosteroids didn’t receive them, with treatment rates ranging from 16 percent in Afghanistan to 91 percent in Jordan. Those were probably over-estimates, since many early arrivals were missed.

Harding doesn’t claim steroids can save all the world’s premature babies. “If you don’t have incubators and appropriate nutrition and access to clean water, preterm babies are not going to survive, whether or not they get steroids,” she says. “But given an equivalent level of care, antenatal steroids will substantially improve both babies’ lives and their death rates.”

Two years ago, she and others wrote an opinion piece in the Lancet medical journal, lamenting the slow uptake of the drugs. By then, 21 studies involving more than 4000 babies had tested Liggins and Howie’s treatment. Maybe, Harding and the others suggested, it was time to move on from testing and focus on why so many mothers weren’t getting access to treatments that worked. “We should be doing better,” they said. “Let’s not wait another 40 years.”

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