Born too soon
Despite extraordinary advances, preterm birth is still the biggest cause of death of children under five. Imperial researchers are setting out to change that.
Every minute, somewhere in the world, 25 babies are born early. That’s 13 million babies a year born preterm, or one in ten. And while there have been extraordinary advancements in their care and treatment, and acceptance that preterm babies – even those delivered many weeks early – can survive, that number isn’t coming down.
“Being born preterm is the single biggest cause of the death of children under the age of five anywhere in the world,” says Phillip Bennett, Professor of Obstetrics and Gynaecology and Director of the Institute of Reproductive and Developmental Biology. Globally, he says, there are huge discrepancies in survival rates. In high-income nations, a baby born at about 32 weeks has around a 95 per cent chance of survival, but of those born in a low-income country at the same gestational age, only half will survive.
Babies that survive being born preterm can spend long periods in neonatal intensive care units, separated from their family. They’re at risk of various long-term health problems, including physical and learning disabilities, and are subject to behavioural, emotional and educational difficulties.
One of the challenges with preterm birth is that it can be caused by a wide range of different problems, and doctors aren’t currently able to predict who is at risk. But now, researchers at Imperial are working, as part of the Imperial NIHR Biomedical Research Centre, to understand what causes babies to be born prematurely – and what treatments might be effective to prevent this.
A vital part of their work lies in partnerships with two charities. Professor Bennett directs (with colleagues Tom Bourne and Lesley Regan) the Tommy’s National Miscarriage Research Centre at Imperial, and (with Lynne Sykes, who is funded by the Parasol Foundation, and David MacIntyre) the March of Dimes Prematurity Research Centre (PRC). Established in 2018, the March of Dimes PRC has already made significant discoveries. The centre has focused on the connection between preterm birth and the maternal microbiome: the community of microorganisms inside a pregnant woman’s body.
“In the past 30 or 40 years, it’s become increasingly recognised that infections are a significant cause of preterm birth,” says Bennett. “But it’s not a classical infection, it’s more a relationship between the bacteria that normally live in the genital tract, and a woman’s immune response to it. Our work has focused on those bacterial immune system interactions, and we’ve made two important findings.”
The March of Dimes team has developed a diagnostic test to simultaneously determine if a mother’s microbiome is healthy or not and if the mother is mounting an adverse immune response to it. The test could help identify women at risk of preterm birth sooner, allowing obstetricians to closely monitor them. They are also developing the use of live biotherapeutics (“A bug that is a drug,” says Bennett) to change the bacteria present from an unhealthy spectrum to a healthy one.
Another arm of the research focuses on when to deliver babies that are not growing at the rate they should be in the womb. “In about ten per cent of pregnancies there’s a small baby, and two to three per cent are genuinely growth restricted,” says Christoph Lees, Professor of Obstetrics. Fetal growth restriction (FGR) accounts for half of the cases of stillbirth in the UK, so working out when to deliver these babies is important. “Deliver them too early and you can cause potential harm and days or weeks on the neonatal unit,” says Lees. “But delivering too late can lead to stillbirth. It is a difficult balancing act.”
A benchmark study
Currently there are many different methods and tests to monitor FGR in women but no consensus on the optimal timing of delivering such babies in late preterm pregnancy. To try to clarify this, Lees leads the Trial of Randomised Umbilical and Fetal Flow in Europe 2 (TRUFFLE 2) study. It follows the successful TRUFFLE 1 study, which looked at the same issue in babies born extremely early, between 26 and 32 weeks. The results of that study inform how those pregnancies are treated globally. “It has become a benchmark for the management of early growth restriction,” says Lees. “We understand small babies much better now.”
While TRUFFLE 1 made a significant impact on our understanding of very early preterm birth, there are many more babies close to term – 32 to 36 weeks – that are growth restricted. “Fortunately, they’re far less likely to have severe illnesses and far more likely to survive, but they do end up on the neonatal unit for quite a long time, and the decision on when to deliver is very important to avoid stillbirth,” says Lees.
TRUFFLE 2 works with pregnant women whose babies are smaller or growing more slowly than expected between 32 and 37 weeks. Their babies are closely monitored with ultrasound scans, computerised heart rate tests and Doppler tests for blood flow to the placenta and brain. “The reason we monitor blood flow to the brain is because we know that when babies are not growing as well as they should be, they redirect more of their blood flow to their brain to try and protect it from damage,” explains Dr Bonnie Mylrea-Foley, Clinical Research Fellow and study coordinator for TRUFFLE 2. “We know that this is associated with worse outcomes, so once we see that change, we know that the baby may be compromised.”
What we’re trying to understand is: do babies do better if we deliver them earlier or do they do better if we continue to monitor them and try and get the pregnancy to go on as long as possible?
At that point, women will be randomly assigned to one of two groups. In one group the babies will be delivered immediately; in the other group they will be monitored closely and delivered if the baby’s heart rate or scans show signs of deteriorating health. All babies in the study have their newborn outcomes recorded and are followed up until they are two years old to assess their neurodevelopment.
“What we’re trying to understand is: do babies do better if we deliver them earlier or do they do better if we continue to monitor them and try and get the pregnancy to go on as long as possible?” says Mylrea-Foley. “What is the turning point, where the balance of the risk of remaining in the womb is greater than the risk of being born slightly early?”
The study has recruited women in dozens of hospitals across the UK and Europe. As Lead Research Midwife on TRUFFLE 2, Jenny Goodier liaises with patients taking part. “When women become eligible for the trial, they are often dealing with the new knowledge that their baby is small, which can be a worrying and stressful time,” says Goodier. “However, I think the main reason women do decide to take part is that they want to help other parents in their position in the future. They tell me that if their participation can help how we manage pregnancies like theirs for other families, that they would like to do anything to help.”
A common worry of patients is that they will be put into the ‘wrong’ group. “A lot of women do struggle with that,” says Mylrea-Foley. “However, we explain that both of the delivery options are things that are already happening as part of standard care and that might be recommended to them anyway, and we genuinely don’t know which one is better.” That’s something they hope will change once the study is completed.
A quest for innovation
Another aspect of Imperial’s work into premature birth is the Neonatal Data Analysis Unit, led by Neena Modi, Professor of Neonatal Medicine. One way her team works to improve preterm care is the creation of the globally unique National Neonatal Research Database (NNRD), a national resource holding real-world clinical data captured on all admissions to NHS neonatal units in England, Wales, Scotland and the Isle of Man.
“We use the NNRD to drive service change, evaluate health services and test treatments and new approaches to care,” says Modi. “For example, we showed that newborn outcomes improve with one-to-one nursing, and worsen if babies are transferred between neonatal units immediately after birth. We also showed that births of extremely preterm babies fell during the COVID-19 pandemic. This is an extremely important finding as no medical treatment in the history of medicine to date has successfully reduced preterm births.”
For all the impressive science behind the research into preterm birth, those involved are driven by the knowledge that their work has a huge impact on people’s lives. “It’s very important to remember that there are real people on the end of this and they need a lot of help and support,” says Bennett. “Many parents don’t know anything about preterm birth until it happens to them; then they might feel guilt or shame, and they certainly worry a lot about what’s going to happen in the future for them and their families. Being able to help people in most situations is a very fulfilling part of the role.”
Each scientific breakthrough is just one piece of the puzzle. “If we as a research group can do something that leads to better outcomes for women and babies, then I’m enormously proud of that,” says Lees. “It’s a constant quest for innovation and improvement, and one must never assume that you’ve come up with the final answer. But you can keep taking steps towards much better answers.”
For the latest news and updates on the TRUFFLE study, visit truffle-study.org
Imperial is the magazine for the Imperial community. It delivers expert comment, insight and context from – and on – Imperial's engineers, mathematicians, scientists, medics, coders and leaders, as well as stories about student life and alumni experiences.
This story was published originally in Imperial 55/Winter 2023–24.
Built with Shorthand