Cambridge-led study discovers cause of pregnancy sickness – and potential treatment

A collaborative study led by Professor Sir Stephen O’Rahilly, joined by Centre for Trophoblast Research (CTR) researchers Prof Gordon Smith and Prof Steve Charnock Jones, 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.

Published today in Nature, the discovery 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, but 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, this 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 researchers 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, 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 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 are 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.

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.

- Stephen O’Rahilly

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.

Adapted from a press release by the Wellcome-MRC Institute of Metabolic Science: Cambridge-led study discovers cause of pregnancy sickness – and potential treatment - Wellcome-MRC Institute of Metabolic Science

Reference

Fejzo, M et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature; 13 Dec 2023; DOI: 10.1038/s41586-023-06921-9

Futher reading: 

This research was covered by the University of Cambridge, New York Times, and Nature News And Views

Professor Sir Stephen O’Rahilly has provided a blog detailing the story behind the paper, with highlights on the contributions from CTR researchers:

"We collaborated with my old friend Ashley Moffett in studying human trophoblast organoids and with the wonderful peptidomic expert in the Institute of Metabolic Science - Richard Kay, were able to demonstrate the very high secretion of GDF15 protein by human trophoblast organoids in vitro (Turco et al, Nature 2018 PMID 30487605)"

"The gene is ubiquitously expressed so even though it is high in the placenta it is possible that maternal circulating GDF5 came from a mixture of the fetal and the maternal genes. To solve this we turned again to Richard Kay and to our colleagues in the Department of Obstetrics and Gynaecology, Gordon Smith and Steve Charnock Jones, who have for many years been running a large prospective study of pregnant women and their offspring from whom stored plasma at timepoints throughout pregnancy was available, as well as RNA sequence data from term placenta. Using the RNAseq data we could identify the genotypes of foetus at the site of the common missense variant (H6D) and, in DNA from the mother, identify fetus/mother pairs where only one of the two contributed a particular allele. Richard could then use his mass spec tools to quantitate the amount of H or D containing GDF15 in maternal plasma. The results were stunning. At all-time points >95% (in most cases >99%). of the GDF15 in the mother’s blood had originated from the fetal, not the maternal, genome"