Research discovers cause of severe morning sickness that hospitalised Princess of Wales
The cause of severe morning sickness that led to the Princess of Wales being hospitalised while pregnant has been discovered by scientists. The Cambridge University-led study has revealed why many women experience nausea and vomiting during pregnancy – and why some, including Kate, become so sick they need to be admitted to hospital. The culprit is a hormone produced by the foetus – a protein known as GDF15, according to the findings published in the journal Nature.
But how sick the mum feels depends on a combination of how much of the hormone is produced by the foetus and how much exposure the mother had to the hormone before becoming pregnant. Researchers say their discovery points to a potential way to prevent pregnancy sickness by exposing mums to GDF15 ahead of pregnancy to build up their resilience. As many as seven in 10 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 unborn baby and the mother and requiring intravenous fluid replacement to prevent dangerous levels of dehydration. The condition – called hyperemesis gravidarum – is the most common cause of admission to hospital for women in the first three months of pregnancy. Although some therapies exist to treat pregnancy sickness and are at least partially effective, scientists say that widespread ignorance of the disorder compounded by fear of using medication in pregnancy mean that many women with the condition are inadequately treated.
The cause of pregnancy sickness was entirely unknown until recently when some evidence, from biochemical and genetic studies, 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 from the University of Cambridge as well as 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 research team studied data from women recruited to a number of studies, including at the Rosie Maternity Hospital, part of Cambridge University Hospitals NHS[1] Foundation Trust and Peterborough City Hospital, North West Anglia NHS Foundation Trust.
The researchers used 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 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 foetal 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.
Professor Sir Stephen O’Rahilly, who led the research, 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.
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.” 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 a woman’s tolerance to the hormone prior to pregnancy could hold the key to preventing sickness. Co-author Dr Marlena Fejzo of 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. She 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.” De Feizo added: “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.”
Results ‘bring hope’ to sufferers
Charlotte Howden considered herself to be in good health prior to getting pregnant in her early 30s. Her pregnancy was proceeding as normal until around week six or seven, when she began to feel nauseous.
Even then, she didn’t see any reason to be concerned. Charlotte, now 40, said: “It’s just what we’ve been told to expect in early pregnancy.” But around a week after the onset of nausea, her condition got much worse.
She found herself being sick up to 30 times a day and unable to keep food down. She said: “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. Ironically, a common symptom of HG is excessive saliva production. When Charlotte finally accepted that there was something wrong, she turned to her GP.
She said: “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 – 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.
She said: “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.” Charlotte was not referred, but instead her GP prescribed her the first-line medication for HG. This did little to help.
She said: “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.
She said: “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 sick again and be re-admitted. The cycle repeated, taking its toll.
She said: “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’d had enough. Charlotte said: “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. Discharged, she would need to get a repeat prescription from her GP – something they were unwilling to do. She recalled: “There was a complete disconnect between my GP and the consultant.”
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. Charlotte said: “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, who is now eight years old.
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, who lives in Hampshire, became involved with the charity Pregnancy Sickness Support, joining around 600 volunteers who offer peer support and operate 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 particular for taking the condition seriously.
She added: “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?’ 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?”