A baby girl born deaf can hear unaided for the first time, after receiving ground-breaking gene therapy when she was eleven months old at Addenbrooke’s Hospital in Cambridge.

A Cambridge-led study supported by the NIHR Cambridge BRC has shown why many women experience nausea and vomiting during pregnancy – and why some women, including the Duchess of Cambridge, become so sick they need to be admitted to hospital.

The culprit is a hormone produced by the fetus – a protein known as GDF15. But how sick the mother feels depends on a combination of how much of the hormone is produced by the fetus and how much exposure the mother had to this hormone before becoming pregnant.

The discovery, published today (13 December 2023) in Nature, points to a potential way to prevent pregnancy sickness by exposing mothers to GDF15 ahead of pregnancy to build up their resilience.

As many as seven in ten pregnancies are affected by nausea and vomiting. In some women – thought to be between one and three in 100 pregnancies – it can be severe, even threatening the life of the fetus and the mother and requiring intravenous fluid replacement to prevent dangerous levels of dehydration. So-called hyperemesis gravidarum is the commonest cause of admission to hospital of women in the first three months of pregnancy.

Although some therapies exist to treat pregnancy sickness and are at least partially effective, widespread ignorance of the disorder compounded by fear of using medication in pregnancy mean that many women with this condition are inadequately treated.

Until recently, the cause of pregnancy sickness was entirely unknown. Recently, some evidence, from biochemical and genetic studies has suggested that it might relate to the production by the placenta of the hormone GDF15, which acts on the mother’s brain to cause her to feel nauseous and vomit.

Now, an international study, involving scientists at the University of Cambridge and researchers in Scotland, the USA and Sri Lanka, has made a major advance in understanding the role of GDF15 in pregnancy sickness, including hyperemesis gravidarum.

The team studied data from women recruited to a number of studies, including at the Rosie Maternity Hospital, part of Cambridge University Hospitals NHS Foundation Trust and Peterborough City Hospital, North West Anglia NHS Foundation Trust. They used a combination of approaches including human genetics, new ways of measuring hormones in pregnant women’s blood.

The researchers showed that the degree of nausea and vomiting that a woman experiences in pregnancy is directly related to both the amount of GDF15 made by the fetal part of placenta and sent into her bloodstream, and how sensitive she is to the nauseating effect of this hormone.

GDF15 is made at low levels in all tissues outside of pregnancy. How sensitive the mother is to the hormone during pregnancy is influenced by how much of it she was exposed to prior to pregnancy – women with normally low levels of GDF15 in blood have a higher risk of developing severe nausea and vomiting in pregnancy.

The team found that a rare genetic variant that puts women at a much greater risk of hyperemesis gravidarum was associated with lower levels of the hormone in the blood and tissues outside of pregnancy. Similarly, women with the inherited blood disorder beta thalassemia, which causes them to have naturally very high levels of GDF15 prior to pregnancy, experience little or no nausea or vomiting.

“We now know why: the baby growing in the womb is producing a hormone at levels the mother is not used to. The more sensitive she is to this hormone, the sicker she will become. Knowing this gives us a clue as to how we might prevent this from happening. It also makes us more confident that preventing GDF15 from accessing its highly specific receptor in the mother’s brain will ultimately form the basis for an effective and safe way of treating this disorder.”

Previous studies of mice exposed to acute, high levels of GDF15 showed signs of loss of appetite, suggesting that they were experiencing nausea, but mice treated with a long-acting form of GDF15 did not show similar behaviour when exposed to acute levels of the hormone. The researchers believe that building up woman’s tolerance to the hormone prior to pregnancy could hold the key to preventing sickness.

Co-author Dr Marlena Fejzo from the Department of Population and Public Health Sciences at the University of Southern California whose team had previously identified the genetic association between GDF15 and hyperemesis gravidarum, has first-hand experience with the condition. “When I was pregnant, I became so ill that I could barely move without being sick. When I tried to find out why, I realized how little was known about my condition, despite pregnancy nausea being very common.

“Hopefully, now that we understand the cause of hyperemesis gravidarum, we’re a step closer to developing effective treatments to stop other mothers going through what I and many other women have experienced.”

The work involved collaboration between scientists at the University of Cambridge, University of Southern California, University of Edinburgh, University of Glasgow and Kelaniya University, Colombo, Sri Lanka. The principal UK funders of the study were the Medical Research Council and Wellcome, with support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Professor Sir Stephen O’Rahilly added: “The support of the NIHR Cambridge Biomedical Research Centre has been critical for the success of this study. The BRC has provided crucial support to our Peptidomics lab to help with our analysis and access to resources like the BRC supported Clinical Biochemistry Assay lab has been essential to deliver this significant breakthrough in understanding hyperemesis gravidarum.

“The BRC provides us with an opportunity to collaborate with expertise from University of Cambridge, Cambridge University Hospitals and other research themes like Professor Gordon Smith, whose samples from his POPS study was vital in our discovery. Without the necessary infrastructure and resources the BRC provides, this study would not have been made possible.”

Professor Miles Parkes, NIHR Cambridge BRC director said: “Its great to see this great breakthrough coming out of the O’Rahilly group. It represents a major step towards better treatment of hyperemesis gravidarum – the most severe and dangerous form of nausea and vomiting in pregnancy that often leads to mums spending long periods in hospital. This work has been supported at each step by the research infrastructure of the NIHR Cambridge Biomedical Research Centre. It emphasises the importance of this NHS-funded infrastructure in delivering major biomedical discoveries of potentially transformational significance with regards to improved health of patients in Cambridge and around the world”

“I was told: ‘Oh, for God’s sake, you’ve just got morning sickness. Pull yourself together.’”

Charlotte Howden considered herself to be in good health prior to getting pregnant in her early thirties. Her pregnancy was proceeding as normal until around week six or seven, when she began feel nauseous. Even then, she didn’t see any reason to be concerned.

“It’s just what we’ve been told to expect in early pregnancy,” she says.

Around a week after the onset of nausea, Charlotte’s condition got worse. Much worse. She found herself being sick as often as 30 times a day, unable to keep food down.

“Every time I tried to eat something, which is obviously what I wanted to do, not only because I felt hungry, but because I was pregnant, that would then instantly make me sick.”

Worse still, she could not keep any fluids down – not even water. Her condition – which she now knows to be hyperemesis gravidarum (HG) – became so bad that even to swallow saliva would make her sick. And a cruel irony is that a common symptom of HG is excessive saliva production.

When Charlotte finally accepted that there was something wrong, that this was not normal pregnancy sickness, she turned to her GP.

“They just said ‘There’s nothing we can do for you. Have you tried ginger? Try and limit your daily activities to best get through this. Try eating a little and often.’”

Returning to the GP, she was offered a urine test for levels of ketones, a chemical produced by the liver (high levels can indicate a serious problem) – the only way, it seemed, that she would be diagnosed with dehydration and referred for treatment. And given that she had not been taking any fluids, this made taking the test incredibly difficult.

“For some reason, it’s only women with HG who are asked to give a sample, when other conditions it is obvious from the way someone looks,” she says.

Charlotte was not referred, but instead her GP prescribed her the first line medication for HG. This did little to help.

“It just makes you comatose, so you sleep the whole day. But I had a full time job, I had responsibilities, financial and otherwise. Sleeping 20 hours a day is not an effective way to live!”

A second ketone test showed that something was obviously wrong. She was told to get to the hospital immediately.

Charlotte was admitted to the early pregnancy ward, which she describes as a traumatic experience.

“You’re with women who are losing their pregnancies, and you’re very much still pregnant. There’s a kind of dismissive behaviour around you of, ‘Oh, for God’s sake, you’ve just got morning sickness. That woman over there has just had a miscarriage. Pull yourself together.’”

After being rehydrated, she was discharged, only to become very sick again and be re-admitted. This cycle repeated, taking its toll.

“Mentally you end up thinking to yourself there is no point in going back to hospital. The definition of insanity is doing the same thing over and over again. You feel completely broken.”

Eventually, she had had enough.

“When I went in again for my third time, I begged [the consultant] to help me because I was very close to making the decision to terminate. She said ‘Look, just give me 24 hours.’”

This time, the consultant gave her medication that finally made her “feel incredible” for 12 hours. Discharged, she would need to get a repeat prescription from her GP – something they were unwilling to do.

“There was a complete disconnect between my GP and the consultant,” she says. Fortunately, Charlotte, rehydrated and re-energised, was ready to fight. She managed to get through to the consultant, who was astounded to hear she was being refused the medication.

“She got on the phone to the GP and I won’t repeat the language she used, but she was very stern, quite rightly, because what’s the point of treating someone in hospital and then just sending them home to come back in a couple of days’ time?”

It took Charlotte until around week 16 of her pregnancy before she was finally on the right treatment to overcome her sickness. She continued taking the medication until around week 37 as she was “petrified to stop taking it”.

In 2016, Charlotte gave birth to a healthy son, Henry. She is determined that no woman should have to go through what she did. In 2020, she presented the world’s first documentary on HG, Sick – The Battle Against HG.

Charlotte became involved with the charity Pregnancy Sickness Support, joining an army of around 600 volunteers who offer peer support and man telephone helplines. She is now its Chief Executive and uses her position to raise awareness of the condition among women and healthcare professionals, including pushing for HG to be taught on all midwifery courses.

Charlotte is hopeful that this new study will lead to a way of treating – and even preventing – HG. She is grateful to Professor O’Rahilly and Dr Fejzo for their work – and in particularly, for taking the condition seriously.

“When you are suffering from a condition and no one can tell you why, you start to think, oh, is it me? Is it something I’ve done?” she says. “I’m so grateful for the dedication of the researchers, because this isn’t a condition that really ever made the headlines until the now Princess of Wales suffered with it. It wasn’t an area of research that people were really interested in. It was just morning sickness – why should we care?”

Reference

Fejzo, M et al. Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy. Nature; 13 Dec 2023; DOI: 10.1038/s41586-023-06921-9