Cambridge-led study confirms why women feel nausea in pregnancy – and why some suffer hyperemesis gravidarum
A study led by the University of Cambridge has uncovered why many women experience nausea and vomiting during pregnancy and why some - like the then Duchess of Cambridge - become so sick they have to be admitted to hospital.
A hormone produced by the fetus – the protein GDF15 - is to blame, according to the research, published in Nature.
How sick this makes the mother feels depends on a combination of how much is produced by the fetus and how much exposure the mother had to the hormone before becoming pregnant.
The finding could signal the way to preventing the problem by exposing mothers to GDF15 ahead of pregnancy to build up their resilience.
Prof Sir Stephen O’Rahilly, co-director of the Institute of Metabolic Science and director of the MRC Metabolic Diseases Unit at Cambridge, who led the international collaboration, said: “Most women who become pregnant will experience nausea and sickness at some point, and while this is not pleasant, for some women it can be much worse – they’ll become so sick they require treatment and even hospitalisation. 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."
Up to seven in 10 pregnant women are affected by nausea and vomiting. In between one and three in 100 pregnancies, this can be severe and even threaten the life of the fetus and the mother, requiring intravenous fluid replacement to prevent dangerous levels of dehydration.
This condition - hyperemesis gravidarum - is the commonest cause of admission to hospital of women in the first three months of pregnancy.
There are some at least effective therapies to treat pregnancy sickness but there is widespread ignorance of the disorder, compounded by fears of using medication in pregnancy. This mean many women suffering with the condition are inadequately treated.
Recent evidence from biochemical and genetic studies suggested the condition might relate to the production by the placenta of the hormone GDF15 acting on the mother’s brain to cause nausea and vomiting.
The researchers in Cambridge, together with others in Scotland, the USA and Sri Lanka, studied data on women from a number of studies, including from Cambridge’s Rosie maternity hospital and Peterborough City Hospital. Using a combination of approaches including human genetics, new ways of measuring hormones in pregnant women’s blood, and studies in cells and mice, they showed the degree of nausea and vomiting experienced in pregnancy related directly to the amount of GDF15 made by the fetal part of placenta and sent into the mother’s bloodstream, and her sensitivity to the nauseating effect of the hormone.
GDF15 is made at low levels in all tissues. The team found a rare genetic variant - associated with lower levels of the hormone in the blood and tissues outside of pregnancy - puts women at a much greater risk of hyperemesis gravidarum.
And 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.
Prof O'Rahilly said: "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.”
The team exposed mice to acute, high levels of GDF15, and they showed signs of loss of appetite, suggesting that they were experiencing nausea.
Mice treated with a long-acting form of GDF15 did not show similar behaviour.
Co-author Dr Marlena Fejzo, from the Department of Population and Public Health Sciences at the University of Southern California, whose team previously identified the genetic association between GDF15 and hyperemesis gravidarum, said: “When I was pregnant, I became so ill that I could barely move without being sick. When I tried to find out why, I realised 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.”
If you have experienced hyperemesis gravidarum and would like to find out how you can help the research team, fill out the online survey at https://www.redcap-ide-cam.org.uk/surveys/?s=DPMR7C399WTFLM3L
There's a kind of dismissive behaviour around you of, ‘Oh, for God's sake, you've just got morning sickness’
Charlotte Howden began to feel nausea around week six or seven of her pregnancy.
“It’s just what we've been told to expect in early pregnancy,” she recalled.
But a week later, it got much worse - and she was sick up to 30 times a day and was 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.”
And she could not keep any fluids - even water - down. Even swallowing saliva made her sick - and a common symptom of hyperemesis gravidarum (HG) is excessive saliva production. 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,” she said.
When she returned, she was offered a urine test for levels of ketones, a chemical produced by the liver as high levels can indicate a serious problem.
This, it seemed, was the only way she would be diagnosed with dehydration and referred for treatment. But as she had not been taking any fluids, taking the test was incredibly difficult.
“For some reason, it’s only women with HG who are asked to give a sample, when in other conditions it is obvious from the way someone looks,” she says.
Charlotte’s GP prescribed her the first line medication for HG but it 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!”
Then a second ketone test showed something was obviously wrong and she was told to get to the hospital immediately.
She was admitted to the early pregnancy ward - 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.’”
Once rehydrated, she was discharged, but become very sick again and was re-admitted. “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.
“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.’”
The consultant gave her medication that finally made her “feel incredible” for 12 hours. But when 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 said.
But rehydrated and re-energised, she battled back - getting through to the consultant, who was astonished 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 was until Charlotte reached about week 16 of her pregnancy that she was finally on the right treatment. Terrified to stop taking it, she continued with it until around week 37.
After giving birth to a healthy son, Henry, in 2016, she was determined no woman should go through what she did and in 2020, presented the world’s first documentary on HG, Sick - The Battle Against HG.
She became involved with the charity Pregnancy Sickness Support, which has 600 volunteers offering support and running telephone helplines.
Now its chief executive, she raises awareness among healthcare professional and pushes for HG to be taught on all midwifery courses.
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.
“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?”
The research 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.
