A Cambridge-led study has shown why many women experience nausea and vomiting during pregnancy and why some women, including the Duchess of Cambridge, become so sick that they need to be admitted to hospital.
GDF15 linked to maternal risk of nausea and vomiting during pregnancy Summary GDF15, a brainstem-acting hormone, has been implicated in nausea and vomiting of pregnancy (NVP), including its most severe form, hyperemesis gravidarum (HG), but a complete mechanistic understanding is lacking. Here we report that fetal production of GDF15 and maternal sensitivity to it contribute substantially to the risk of HG . We confirmed that higher levels of GDF15 in maternal blood are associated with vomiting during pregnancy and HG. Using mass spectrometry to detect a naturally labeled GDF15 variant, we demonstrate that the vast majority of GDF15 in maternal plasma is derived from the fetoplacental unit . By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. In contrast, women with beta-thalassemia, a condition in which GDF15 levels are chronically high, report very low levels of NVP. In mice , the acute food intake response to a bolus of GDF15 is bidirectionally influenced by previous levels of circulating GDF15 in a manner that suggests that this system is susceptible to desensitization . Our findings support a putative causal role of fetal-derived GDF15 in human pregnancy nausea and vomiting, with maternal sensitivity, at least in part determined by exposure to the hormone before pregnancy, being an important influence on its severity. They also suggest mechanism-based approaches for the treatment and prevention of HG. |
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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 the amount of hormone produced by the fetus and how much exposure the mother had to this hormone before becoming pregnant.
The discovery, published in Nature , points to a potential way to prevent pregnancy diseases by exposing mothers to GDF15 before pregnancy to build their resilience.
Up to seven out of ten pregnancies are affected by nausea and vomiting. In some women (it is believed to be between one and three in every 100 pregnancies) it can be serious, even threatening the life of the fetus and the mother and requiring intravenous fluid replacement to prevent dangerous levels of dehydration. The so-called hyperemesis gravidarum is the most common cause of hospitalization of women during the first three months of pregnancy.
Although some therapies exist to treat pregnancy illnesses and are at least partially effective, widespread ignorance about the disorder, compounded by fear of using medications during pregnancy , means that many women with this condition do not receive adequate treatment.
Until recently, the cause of pregnancy diseases was completely unknown. Recently, some evidence, from biochemical and genetic studies, has suggested that it could be related to the placenta’s production of the hormone GDF15, which acts on the mother’s brain making her feel nauseous and vomiting .
Now, an international study, involving scientists from the University of Cambridge and researchers from Scotland, the United States and Sri Lanka, has made a major breakthrough in understanding the role of GDF15 in diseases of pregnancy, including hyperemesis gravidarum.
The team studied data from women recruited to several studies, including Rosie Nursing 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 the blood of pregnant women, and studies in cells and mice.
The researchers showed that the degree of nausea and vomiting a woman experiences during pregnancy is directly related to both the amount of GDF15 produced by the fetal part of the placenta and delivered to the bloodstream, and how sensitive she is to the pro-effect. emetic of this hormone.
GDF15 is produced at low levels in all tissues outside of pregnancy. A mother’s sensitivity to the hormone during pregnancy depends on how much she was exposed to before pregnancy: women with normally low levels of GDF15 in their blood have a higher risk of developing severe nausea and vomiting during pregnancy.
The team found that a rare genetic variant that puts women at much higher risk of hyperemesis gravidarum was associated with lower levels of the hormone in 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 before pregnancy, experience little or no nausea or vomiting.
Professor Sir Stephen O’Rahilly, co-director of the Institute of Metabolic Sciences at the Wellcome-Medical Research Council at the University of Cambridge, who led the collaboration, said: "Most women who become pregnant will experience nausea and discomfort at some point and While this is not pleasant, for some women it can be much worse: they become so sick that they require treatment and even hospitalization.
"Now we know why: the baby growing in the womb produces a hormone at levels that 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 could prevent this from happening. It also gives us more confidence 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 to treat this disorder."
Mice exposed to high, acute levels of GDF15 showed signs of loss of appetite, suggesting they were experiencing nausea, but mice treated with a long-acting form of GDF15 did not show similar behavior when exposed to acute levels of the drug . hormone. Researchers believe that building a woman’s tolerance to the hormone before pregnancy could be the key to preventing disease.
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 this condition. "When I was pregnant, I became so sick that I could barely move without feeling sick. When I tried to find out why, I realized how little was known about my condition, even though morning sickness is very common. Hopefully "Now that we understand the cause of hyperemesis gravidarum, we are one step closer to developing effective treatments to prevent other mothers from going through what I and many other women have experienced."
The work involved collaboration between scientists from the University of Cambridge, the University of Southern California, the University of Edinburgh, the University of Glasgow and the University of Kelaniya, Colombo, Sri Lanka. The main UK funders of the study were the Medical Research Council and Wellcome, with support from the National Institute for Health and Care Research’s Cambridge Biomedical Research Centre.
