Why is pre-eclampsia still causing the deaths of mothers and their babies?

Having had one normal pregnancy, Emma Bailey assumed that her second experience of childbirth would progress relatively smoothly. But, at 34 weeks, she began to suffer sudden bursts of stabbing pain just underneath her ribcage.

“It was really excruciating pain,” she remembers. “I was admitted to hospital, but they sent me home, saying it was probably just anxiety. I then had to be readmitted the very next day because I was in agony.”

The pain she was experiencing is a known indication of one of the most serious forms of pre-eclampsia, a pregnancy complication that causes dangerously high blood pressure levels. In rare cases, it can initiate a liver and blood-clotting disorder called HELLP syndrome, which can be fatal to mother and baby.

Yet rather than initiating the only known form of treatment – delivering the baby as soon as possible – consultants at Broomfield hospital in Chelmsford, Essex, seemed to be unaware of the danger she was in.

“I was in hospital for four days, undergoing tests and seeing various consultants, all while being given strong pain relief for the rib pain, which no one could explain to me,” says Bailey. “By the time they acted, I was on the floor because my liver had ruptured and I was bleeding out. They rushed me in to do an emergency caesarean, but it wasn’t in time to save my daughter.”

Named Mia, she died two days later, while Bailey had to be placed in an induced coma, before enduring many weeks in intensive care while her liver healed.

“I survived but I very nearly didn’t,” she says. “It’s horrible to talk about, but I feel I need to raise awareness to stop this happening to other women.”

For while pre-eclampsia affects up to 6% of all pregnancies and causes approximately 500,000 foetal deaths and 70,000 maternal deaths worldwide each year, mostly in low- and middle-income nations, our understanding of why pre-eclampsia occurs, and how to treat it, is still rudimentary.

While routine blood pressure monitoring during pregnancy has helped reduce maternal deaths from pre-eclampsia in the UK, they still occur. According to the latest MBRRACE (Mothers and Babies: Reducing Risk Through Audit and Confidential Enquiries) report for 2019-21, produced by Oxford University’s national perinatal epidemiology unit, the number of women dying in childbirth, or in the six weeks after pregnancy, has risen by 15% in the UK in the past decade. Nine women died from pre-eclampsia during the three years covered by the report, all of which are likely to have been preventable deaths.

Newborn baby
Often with pre-eclampsia, the only option is to deliver the baby early. Photograph: Getty Images

“The two major causes of death in pre-eclampsia are stroke and prolonged fitting,” says Ian Wilkinson, clinical pharmacologist and professor of therapeutics at Cambridge University. “What happens in pre-eclampsia is that blood pressure goes up but the capillaries become leaky, which leads to a bleed in the brain and a stroke. Or the brain becomes very irritated [inflamed] and women start to fit. But when you go through the cases where women have died, it’s often that they either haven’t realised that symptoms like a severe headache are a sign of an emergency, or the people looking after them haven’t monitored them as well as they should do.”

But deaths from pre-eclampsia are the tip of the iceberg when it comes to its overall impact. Women who experience the condition during pregnancy have a 20-fold greater risk of developing permanent high blood pressure compared with those who have no pregnancy complications at all. As a result, they have a two to threefold greater risk of a stroke or heart attack later in life.

Pre-eclampsia also appears to affect the biology of the developing baby such that those children are more likely to be born with congenital heart disease and kidney disorders and are at a greater risk of experiencing problems with blood pressure and related cardiovascular conditions throughout their lives.

But scientists are hoping that new studies will yield insights that can improve our ability to identify women most at risk and target treatments towards them.

Lack of awareness

The recommendation from the National Institute for Health and Care Excellence is that women perceived to be at high risk of pre-eclampsia should receive a daily 75-150mg dose of aspirin from 12 weeks of pregnancy until birth.

While this is not a cure, numerous studies have suggested aspirin can help by suppressing the production of various hormones thought to be involved in the development of the condition. However, it appears that many women who could benefit from aspirin treatment are not getting it.

A bottle of calcium tablets
High doses of calcium have been shown to reduce the risk of pre-eclampsia.

“If it’s your first pregnancy and you’re over the age of 40, you’re meant to be on aspirin,” says Andrew Shennan, professor of obstetrics at King’s College London, who is based at St Thomas’ hospital. “That’s a lot of women, but worryingly there are many who will not get it, and it’s not even discussed with them. We looked back recently at our hospital, and only one in five of the women who should have received aspirin were getting it. So that’s a bit of a shocker and we probably need to do something about it.”

When it comes to assessing pre-eclampsia risk, the picture is complex, and Shennan suggests that there is still a lack of awareness among healthcare professionals regarding who is most likely to be vulnerable. Women with existing autoimmune conditions or diabetes, a body mass index greater than 35, a history of previous pregnancy complications or a family history of pre-eclampsia, and those expecting multiple babies are all more susceptible. Population studies in the UK have also shown that the condition disproportionally affects black women and those from Asian backgrounds.

Because pre-eclampsia is thought to be linked to poor blood vessel formation in the placenta, a new blood test, known as placental growth factor testing, is now available on the NHS. This is thought to be a reliable way of assessing which pregnant women have the condition, but many experts believe there is a need to intervene sooner.

At Addenbrooke’s hospital in Cambridge, Wilkinson and obstetric medicine registrar Bernadette Jenner are recruiting first-time mums-to-be for a new Wellcome-funded clinical trial called Poppy (preconception to post-partum study of cardiometabolic health in primigravid pregnancy). The aim is to follow the women before, during and after their pregnancy, and conduct repeated tests to assess their blood vessel and heart health.

The hope is that this will uncover new clues that can be used to more accurately pinpoint women with underlying vulnerabilities relating to placental health and long-term cardiovascular risk, making them more likely to develop pre-eclampsia. “I hope it will lead to a better way of predicting the women who develop pre-eclampsia,” says Jenner. “Then we can better target interventions towards them.”

The need for effective treatments

But while identifying at-risk women at an earlier stage will represent a step forward, outcomes will only truly improve if there are more therapies available to treat pre-eclampsia. Apart from low-dose aspirin, the only option available to doctors is to monitor the condition and, if necessary, deliver the baby prematurely, something that is associated with a large number of adverse health outcomes.

Babies born even a few weeks early are more likely to experience long-term social and emotional difficulties, while being born before 34 weeks can lead to complications such as cerebral palsy, visual and hearing problems, and reduced intelligence. “The fact that a baby needs to be born early to cure the problem is a big issue,” says Shennan. “Being born early has a major impact on the body.”

In the wake of the thalidomide scandal in the 1950s and 1960s, which resulted in more than 10,000 babies worldwide being born with severe defects, drug developers have largely shied away from developing novel treatments aimed at pregnant women. As a result, Wilkinson says that most clinical trials have focused on supplementation either with various vitamins and minerals or pills such as aspirin that have a very well-known safety profile.

Shireen Meher, a consultant in maternal foetal medicine at Birmingham Women’s and Children’s NHS foundation trust, is interested in whether high-dose calcium supplementation can help prevent pre-eclampsia or lessen its severity. She points to one review of eight clinical trials, involving a total of more than 10,000 women on low-calcium diets, which showed that a high dose of mineral supplementation reduced pre-eclampsia risk by about 36%. However, the quality of this data was considered relatively low because of significant variations in the underlying risk of pre-eclampsia in the women who participated in the trials, meaning that more evidence is needed.

“It’s thought that low calcium might raise blood pressure by triggering the release of some hormones in the blood such as the parathyroid hormone and renin,” says Meher. “The thinking is that giving calcium supplements might reduce this hormone release and prevent the constriction of blood vessels, which leads to hypertension.”

While existing data suggests that calcium supplementation is only beneficial for women who do not get adequate dietary calcium, Meher believes that more women in the UK could be deficient in the mineral than previously thought.

She is in the process of recruiting 7,756 pregnant women believed to have an elevated risk of pre-eclampsia as part of a Birmingham University trial called CaPE (calcium supplementation for prevention of pre-eclampsia in high-risk women). The aim is to see whether taking 2g calcium daily throughout pregnancy could lower their risk. “We’ve done a baseline survey with some of the women we’ve recruited so far and many of them don’t have adequate calcium in their diet,” she says, “If it works, calcium is a very attractive intervention – it’s cheap, easily available and as far as we know, there are no safety concerns.”

However, Shennan believes that there is also a need for more robust treatments to address some of the elements of the disease process, suggesting that the messenger RNA technology used in Covid-19 vaccines and emerging cancer therapies may have a role to play.

“Using this, you can perhaps suppress certain chemicals that are thought to be fundamental to the disease process,” he says. “These are blood markers which are measures of how the placenta is working, and there’s some suggestion that by suppressing them, you might be able to ameliorate the problem or at least extend the period before people get sick. It’s still in early phases but big organisations like the Gates Foundation are interested in this, a kind of infusion that would actually treat pre-eclampsia.”

For Bailey, the main hope is that more can be done to raise awareness within the healthcare system of how dangerous pre-eclampsia can be, particularly if the signs are not spotted and monitored early enough.

Along with her husband Grant, she sued Broomfield hospital after her experience and they settled out of court. She gave birth to a healthy daughter, Grace, in 2021.

“After Mia’s death, I had to wait for my liver to fully repair. And then, a year and a bit later, I fell pregnant again,” she says. “It was a nerve-racking nine months but we had a really good specialist this time at St Thomas’ hospital, who went through all the ways they were going to try and stop it happening, such as giving me aspirin throughout the pregnancy, and I had no complications, thankfully.

“So now we just want to raise awareness of the symptoms, to prevent other families losing their children.”