The corticosteroid treatment based on Graham Liggins’s work has had a huge effect in saving the lives of premature babies.
To mark the 75th anniversary of the death of Henry Wellcome and the founding of the Wellcome Trust, we are publishing a series of 14 features on people who have been significant in the Trust’s history. In our 12th piece, science writer Nic Fleming looks at Graham ‘Mont’ Liggins, pioneering obstetrical researcher.
The lamb was just a few hours old, huddled up against its mother, its breathing laboured. What surprised Graham ‘Mont’ Liggins was that it was breathing at all. As part of his research into the triggers of labour, he had infused the pregnant ewe with cortisol. This appeared to have triggered a birth that was 37 days before full term, at a time when its immature lungs should have been incapable of inflating.
Alongside the likes of Alexander Fleming’s discovery of the antibiotic properties of penicillin, this is seen as one of the great moments of serendipitous scientific revelation of the 20th century. Four decades on from that morning in Liggins’s makeshift research facilities in the grounds of a hospital in Auckland, New Zealand, the subsequent development of corticosteroid treatment for women showing signs of giving birth prematurely is estimated to have helped save hundreds of thousands of lives.
Liggins was born in Thames, on New Zealand’s North Island, in 1926. His friends knew him as Mont because of his childhood love of a cartoon character called Monty the Mouse. The fourth son of a doctor, he studied medicine in the late 1940s, and worked as a GP before travelling to Britain to train as an obstetrician. He met his wife Celia in Newcastle upon Tyne, and they returned to his homeland in 1959, where he took up a post as a Senior Lecturer in Obstetrics and Gynaecology at the National Women’s Hospital. While his main job was delivering babies, he managed to squeeze his research interests around it, mainly during evenings and weekends.
At this time, Liggins asked his friend William Liley, the surgeon and intrauterine transfusion pioneer, for advice on how to choose a suitable research topic. Liley replied he should look for a major problem that was potentially solvable. The major problem was the easy part. Respiratory distress syndrome was, and still is, a major killer of newborn babies, because untreated immature lungs resemble small blobs of liver and cannot inflate. “I naively thought that all I had to do was solve the ancient question of what controlled the onset of labour at term, and the reason for premature onset would become apparent,” Liggins wrote in a 2004 letter to Sir Iain Chalmers, founder of the Cochrane Collaboration, which promotes better understanding and use of evidence in healthcare.
He had read about researchers at the University of California at Davis, who had a herd of cattle with pituitary gland and adrenal problems and also a high incidence of very prolonged gestation, and wondered whether it might be worth revisiting the old idea that the baby rather than the mother controlled the start of labour. The hunch led him to the Ruakura research station in Hamilton, 80 miles from his base in Auckland, where he had previously helped in some of Liley’s work on prenatal red cell transfusion. In his new visit, Liggins used his surgical skills to destroy the pituitary glands of lambs while still in the uterus, and found that the procedure did indeed delay the onset of labour. A sabbatical year at the University of California at Davis allowed him to confirm this finding, which he published in the ‘Journal of Endocrinology’ in 1968.
Liggins then returned to Auckland, with a Wellcome Trust grant to study the mechanisms responsible for human parturition. He began breeding sheep, keeping them across the road from the hospital, and set up a laboratory in an abandoned shed in the grounds. He wanted to see whether boosting levels of different steroids would have an effect on the onset of labour. An old memory – a farming neighbour had once asked him why lambs often die if they are born prematurely after dogs have worried their mothers – made him wonder about the role of the stress-response hormone cortisol. So he began a series of experiments in which he removed the pituitaries of fetal lambs; he then infused them with cortisol, a hormone produced indirectly by the gland. Each time he repeated the experiment, the ewe gave birth two days later.
“There’s nothing so exciting or satisfying as making a discovery,” he said in an interview recorded for Radio New Zealand in 2001. “It needn’t be a big one, just a discovery. I try to instil into people who are taking up science that it’s a thrill and a great privilege to have the opportunity to achieve [a discovery].”
It was at this point that an element of good fortune played its part. He expected the offspring of pregnant ewes he infused many weeks before term to be born with lungs incapable of functioning properly. The role of cortisol in lung development was not part of his hypothesis, and he had no idea he was about to hit on a potential treatment for respiratory distress syndrome in humans. Describing the moment in a recording made for an oral history project in 2003, he said: “To my surprise this lamb was still breathing. It had no right to be. It was so premature that its lungs should have been just like liver, and quite uninflatable. This struck me as surprising, and when we came to do the autopsy the lungs were partly inflated and this was absolutely surprising. So, weighing this up, I postulated that the cortisol had accelerated the maturation of enzymes in the lung that caused accelerated maturation.”
While this finding was exciting, it posed a problem for Liggins as he had a full-time job, was already engaged in his research into pregnancy and birth, and had no time to embark on a new study of lung maturation. So, another fortunate element to the story was that a leading expert on respiratory distress syndrome – Mary Ellen Avery, shortly to become the head of paediatrics at Montreal’s McGill University – was visiting New Zealand at the time. Three years earlier she had published the results of her research showing that respiratory distress syndrome in premature babies was caused by a lack of surfactant (the slick, foamy coating that helps lungs expand and become aerated). When Liggins and Avery met at the opening of a new women’s hospital in Christchurch, he told her he had identified lung maturation in lambs at 115 days (average gestation is 147 days). Avery and colleagues in the USA and Canada rapidly confirmed his findings on cortisol and accelerated lung maturation.
Together with Ross Howie, a colleague at the National Women’s Hospital and one of New Zealand’s leading paediatricians, Liggins designed a clinical trial to test the effects of a single injection of steroids in mothers undergoing premature labour. At the time, randomised controlled trials were a rarity, but to Liggins and Howie it seemed the obvious route to take. There were no ethics committees at the time, which helps explain the short time period between the animal observations and start of the human trial. It was the senior medical staff committee of the National Women’s Hospital that approved the trial. Over 22 months from December 1969, 282 women at risk of premature delivery were randomly assigned to receive either the standard treatment or the standard treatment plus two doses of steroids. The results were dramatic. Early neonatal deaths were 14.1 per cent in the control group and 3.2 per cent in the steroid group. Almost a quarter of the control group, 24 per cent, had respiratory distress syndrome, compared with just 4.3 per cent of those given steroids.
Given these results, the quality of the study and the huge numbers of young lives at stake, it is instructive that it took clinicians across the world 20 years to adopt the widespread use of prenatal corticosteroids. The paper was rejected for publication by the ‘Lancet’ on the grounds that it lacked general interest, before being published in the journal ‘Pediatrics’ in 1972. It concerned only the first wave of the study. Howie presented the results of the completed trial, on the outcomes for 1068 women and their babies, to a meeting of the UK Royal College of Obstetricians and Gynaecologists (RCOG) Preterm Labour Study Group in 1977. This again showed a huge reduction in neonatal mortality in babies exposed to steroids in utero. Howie later said of the group’s reaction: “They didn’t really want to hear.” The proceedings from this symposium included 14 papers on the delaying of labour, providing an indication of where the medical establishment’s focus of attention lay.
Some smaller replicated trials showed less positive outcomes and clinicians were concerned about the possibility of long-term side-effects. Howie also believed it was essential to check for unwanted side-effects and got funding from the World Health Organization for four- and six-year follow-up studies of the original cohort.
When Irish obstetrician Dr Patricia Crowley first heard about the work in a 1974 lecture, it had a particular impact on her because the first baby she had delivered as an undergraduate died from respiratory distress syndrome despite being born weighing seven pounds at 36 weeks. She attended the 1977 RCOG meeting at which Howie presented the findings, and went on to publish the first review of randomised controlled trials of antenatal steroids in 1981, at which time there were four. The US National Institutes of Health carried out its own study, published in 1984. It found an overall reduced incidence of respiratory distress syndrome, but no reduction in mortality, with differing effects in different subgroups. The authors advised that antenatal steroids should be used selectively and with caution. Some have criticised elements of the study’s methodology.
Crowley and others have said that by this point there was enough evidence for the treatment to have been widely adopted. “With hindsight, we could ask whether the Collaborative Group trial should ever have taken place, because at the time when recruitment was taking place for that trial there was already substantial evidence in the literature that antenatal steroids were effective and safe,” she told a Witness Seminar conducted by the Wellcome Trust Centre for the History of Medicine at University College London in 2004. “If we look at the 1000 or so babies who received antenatal steroids in the randomised trials prior to 1980, and the 1000 babies who received placebo in these trials, 130 of the babies who received placebo died, compared with 70 of the babies who received antenatal steroids. Were those who were recruiting participants for the NIH Collaborative Group trials unaware of these results?”
In 1990 Crowley published a meta-analysis of 12 trials, again showing significant reductions in respiratory distress syndrome and mortality. At this stage, the use of antenatal steroids for preterm babies was patchy across the world, with clinicians in Australia and New Zealand most likely to adopt the treatment. In other countries it was often used in less than 10 per cent of cases and nowhere was it more than 20 per cent. This was finally turned around with the inclusion of prenatal steroids for preterm births as one of 21 clinical guidelines published by RCOG in 1992, and a similar recommendation was published in the NIH’s Consensus Statement on Antenatal Steroids in 1994.
Graham Liggins
Why did it take 22 years for Liggins and Howie’s original landmark findings to be translated into widespread clinical practice? Jane Harding, Professor of Neonatology at the University of Auckland, went on to carry out a 30-year follow-up of the original trial after first encountering Liggins when he was one of her tutors at medical school. Liggins and Howie told her there were two main reasons it took so long for the treatment to be adopted. “Firstly this was an obstetric solution to a paediatric problem,” she said. “In other words there were turf wars. The paediatrics were saying ‘we know how to look after lung disease, don’t you bother about it’. There was a degree of failure to cross that professional divide. Liggins and Howie also believed there was a view that ‘nothing good can come out of the colonies’. It has always been difficult for the North Americans to take up new treatments that have been discovered elsewhere. It has been the tradition that they have to try it themselves before they are really convinced.”
Harding added a reason of her own. “There is also enormous inherent conservatism in the medical profession, which is probably mostly appropriate. Steroids are drugs regarded with particular suspicion because they have always been known to have many, often profound, effects.” Others point out that pharmaceutical companies had much more to gain from promoting expensive new drugs to prolong pregnancy than the use of steroids costing a few pence.
The Wellcome Trust funded Liggins’s research from 1968 to 1976, with three grants totalling a little over £41 000. In a letter to Dr Peter Williams, the then Director of the Trust, dated February 1977, Liggins wrote: “It is difficult to convey the extent of my gratitude to you for the support you gave me as a ‘dark horse’ which has had such a profound effect on my career.” Williams, in his reply, said: “It is very satisfactory to know that such a ‘dark horse’ came in as a front runner.”
Liggins carried out research and made discoveries in many other areas, including early work on fertility as well as studying the placenta and the mechanisms involved in fetal breathing. In the late 1970s he worked with others in the Antarctic to try to work out how seals could hold their breath for so long, and how pregnant female seals provided their fetuses with sufficient oxygen. He found that the seals had higher levels of cortisol, and that those that dived the deepest had the highest levels – suggesting that the hormone helps them withstand the pressure at depth. He gained numerous awards and honours, becoming a Fellow of the Royal Society in 1980 and being knighted in 1991. In 2001 the University of Auckland named its new biomedical and clinical research centre the Liggins Institute. He died in the summer of 2010 at the age of 84.
The story of Liggins’s discovery of the benefits of prenatal corticosteroids for premature babies and the work’s eventual adoption into clinical practice raises a series of issues and offers numerous lessons. “A clever person with an inventive mind can make a real difference to clinical medicine even working in a small laboratory anywhere in the world,” said Sir Peter Gluckman (current Chief Science Advisor to the Prime Minister of New Zealand), who was taught by Liggins as a medical student in 1971 and later became a collaborator and friend. “You don’t have to be part of a big research empire to be able to make a real difference. It was very inspiring to me to see someone who had taken his own idea from the original experimental observation right through to clinical trial and validation in such a remarkably short period of time.”
The solid design of the landmark 1972 study also demonstrated the importance of randomised controlled trials. Work by Crowley and others showed the key role of systematic reviews and randomised controlled trials that laid the foundations for the clinical guidelines that eventually, belatedly ensured the translation of Liggins’s most important discovery into clinical practice. The Cochrane Collaboration’s logo, adopted on its founding in 1993, shows a series of horizontal lines and a vertical axis, representing the results of the first seven trials of prenatal corticosteroids.
“We wanted to show that, within ten years of the Liggins and Howie trial, there had been crystal-clear evidence that this was a very important way of reducing neonatal deaths,” founder Sir Iain Chalmers said at the 2004 Witness Seminar. “In the brochures we used and the talks we gave to introduce the objectives of the [UK Cochrane] Centre to others, we made the point that tens of thousands of babies had suffered and died unnecessarily because information had not been assembled in a systematic review and meta-analysis to show the strength of the evidence.”
Liggins’s work is often cited as an example of the importance and potential of animal research. It is, as Gluckman says, a reminder that the value of a scientific discovery cannot be judged by the renown of the researcher making it, nor by the reputation of his or her institution. It highlights the facts that editors of prestigious journals sometimes get it wrong and that the interests of patients and pharmaceutical companies do not always overlap. The story also provides a warning against clinicians jealously guarding what they see as their turf from the insights and contributions of ‘outsiders’. Howie has stated that part of the reason their original trial came about was the unusually good collaborative relationship between obstetricians and paediatricians at the National Women’s Hospital at the time, and a research environment that encouraged the questioning of authority and convention.
Harding says that the way that Liggins’s key discovery came about unexpectedly, out of his more fundamental focus on the initiation of labour, provides a lesson for science funders who base their decisions on pre-set potential applications at the expense of basic science. “It’s an interesting warning against the narrow and predetermined endpoints for some research programmes, and highlights the importance of serendipity in progress.”
The word serendipity is often used to describe Liggins’s eureka moment, on seeing the lamb that was breathing despite having been born so premature that its lungs should, according to conventional wisdom, have been unable to inflate. There is no doubt that many important scientific discoveries have been serendipitous. Yet the word’s definition – the making of fortunate discoveries by accident – does not seem to do the man justice. When someone with an original and open mind does thorough, well-designed science, they are at least partly responsible for any good fortune that helps them on their way.
“Many scientists have unexpected results,” said Gluckman. “You could have 50 scientists do that experiment with the steroids and not think about the fact that the lamb had survived. The mark of the great scientist, and Mont was truly a great scientist, is to recognise the significance of the unexpected or outlying results.”
Nic Fleming
Nic Fleming writes about science, medicine and technology for a range of publications. Staff positions have included stints at the ‘Daily Express’ and ‘Daily Telegraph’. Freelance assignments over the last three years have included taking three commercially available genetic tests for common diseases to demonstrate wide variability in results for a ‘Sunday Times’ investigation, a story about the serious methodological flaws in the Interphone study on mobile phones and brain tumours for the ‘Economist’, and pieces exposing the factual inaccuracies in government statements and media reporting on the previously legal high mephedrone for ‘New Scientist’ and the ‘Guardian’.
Find out more about activities marking the Wellcome Trust’s 75th anniversary, including links to other features as they are published.
Image credits:
Baby: Wellcome Library, London
Liggins: Bruce Jarvis/Liggins Institute, University of Auckland
Filed under: 75th anniversary, 75th stories, Biomedical Sciences, Features Tagged: Animal health, Antenatal medicine, Graham Liggins, Lungs, Medicine, Neonatal medicine, Nic Fleming, Premature babies, Prenatal medicine
