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What causes HG? The story of GDF15

Various theories have been suggested as the cause of nausea and vomiting of pregnancy and HG, but until recently, none of them had any strong evidence to support them. Recent work published in 2017 and 2018 shows very strong evidence that a protein called GDF15 is the cause of HG.

The trouble with hCG
Often women are told that a hormone called human Chorionic Gonadotropin (hCG) is the cause. There is some evidence that hCG is associated with HG, but there are cases where hCG is high, and there is no HG, and vice versa. Also, part of the reason why hCG seemed like a good fit was that it rises rapidly in the first trimester of pregnancy, and tails off towards the beginning of the second. This could explain normal NVP (nausea and vomiting of pregnancy), but not HG which lasts for much longer, often till birth. Also, there has been no good suggestion for why hCG would make you feel sick. Despite this, doctors and midwives will confidently tell women that hCG is the cause, or, even less convincingly, it's caused by 'hormones' as if this is a reasonable explanation.

In fact, very little research effort has been dedicated to finding the cause of NVP or HG. A review paper by Sandven and Abdelnoor in 2010 found only 37 studies which had attempted to find a cause for HG, and many of these were poor quality. (Sandven & Abdelnoor, 2010, Arch Gynecol Obstet (2010) 282:1–10 DOI 10.1007/s00404-010-1372-x).

GDF15 - The breakthrough
In late 2017 and early 2018 two papers were published which provide the best evidence yet that the cause of HG is a protein called GDF15. For more about these discoveries and the context see Spewing Mummy's guest blogpost The significance of GDF15 for Hyperemesis Gravidarum

In short, GDF15 is a gene which has long been known to affect appetite and cause feelings of nausea and vomiting. Mice given GDF15 will reduce their food intake. It is also known that GDF15 is produced by the placenta and rises very rapidly in early pregnancy. The discovery published in late 2017 was that, after more than a decade of searching, the receptors for GDF15 were finally discovered - in the vomiting centre of the brain Mullican et al 2017, Nature Medicine. It seems that the sole purpose of GDF15 in the human body is to make you feel sick.

In early 2018, Marlena Fejzo and colleagues published a paper, also in Nature (Fejzo et al 2018 Nature), which showed that two genes are associated with HG, one of which is GDF15. She then confirmed this link in another set of data of hundreds of women with HG. She then analysed the blood of women with HG and found that they do indeed have higher levels of GDF15 in their blood.

This is the most convincing explanation to date of what causes HG. The really positive aspect of this is that, now that we know the cause, there is the prospect of developing a drug to actually treat the cause of HG, rather than just treating the symptoms with antiemetics. There is also the prospect that we may be able to develop a test for the mutation which is associated with HG to try to predict whether our daughters have inherited it.

Marlena has followed up this study with another one which demonstrates that GDF15 runs in families, and is associated with recurrence of HG (Fejzo et al 2018, GebFra Scienceso adding more evidence to the case for GDF15.

Marlena Fejzo has suffered from HG herself, and is partly funded by the Hyperemesis Education and Research Foundation in the USA. Her motivation to study the genetics of HG is driven by her own experience and her desire to help other women with HG. She has very little funding for this work, and the HER foundation is largely funded by personal donations. To find out more about their research on genetics, see HER Foundation blog