Hyperemesis gravidarum – are you sure it’s not all in your head?

Hyperemesis gravidarum is a pregnancy complication consisting of characteristic nausea and vomiting, loss of more than 5% of body mass and dehydration. It affects 0,3 – 10,8% of pregnant women and it can put the mother’s health and life in serious danger. Constant vomiting can lead to nutrient and electrolyte deficiencies, which have their own complications, as well as organ damage due to constant strain. Additionally, lower quality of life and suffering may endanger patients’ mental health and lead to a desire to abort a wanted pregnancy or suicidal thoughts.

It’s all in your head

Up until recently, very little was known about hyperemesis gravidarum. Given that morning sickness is a characteristic symptom of pregnancy and there are usually no ill effects on the foetus, this form of “morning sickness” wasn’t taken seriously for a long time. To this day, women are sharing unacceptable experiences with healthcare workers convincing them that the symptoms will pass on their own or that they are subconsciously trying to sabotage the pregnancy. One of the women suffering from HG in her own pregnancy was dr. Marlena Fejzo, today a leading scientist in hyperemesis gravidarum research, as well as research on other diseases affecting women.

Scientist on a mission

In the beginning, dr. Fejzo gave out online surveys from which she concluded there is a genetic component to HG. The next step in understanding what causes HG was a genetic analysis of patients, which the NIH (National Institute of Health) repeatedly refused to fund. A couple of years later, Fejzo collaborated with 23andMe, an American company providing DNA analysis to consumers and shedding light on their background, physical traits and predispositions towards diseases. When using 23andMe, female consumers answered additional questions regarding their experiences during pregnancy, which is where Fejzo first heard of the GDF15 gene…

The offending hormone

The GDF15 gene carries the genetic code for the GDF15 protein, a hormone produced by the placenta during pregnancy whose physiological function remains unclear. This hormone binds to the GFRAL receptor which is located in parts of the mother’s brain crucial for vomiting as well as appetite and body mass regulation. Fejzo and her collaborators noticed that pregnant women who didn’t experience HG had much lower levels of GDF15 in their blood circulation in comparison with women who did experience HG. Furthermore, some gene variants, such as GDF1 C211G, affect gene expression both during pregnancy and outside of it. Women who have low levels of this hormone prior to pregnancy are at an increased risk of HG when the hormone’s levels rise rapidly during pregnancy.

It is interesting to note that women with beta thalassemia, an inherited blood disorder, are at a lower risk of HG. This disease has been tied to a chronical increase in GDF15 levels which points to the possibility of GFRAL desensitization. Due to the same mechanism of action, smokers are also at a lower risk of HG!

Some other facts support the hypothesis that a sudden increase in GDF15 really is the cause of hyperemesis gravidarum. Most study participants who were administered a GDF15 bolus injection experienced nausea and vomiting. Furthermore, blocking this hormone when taking cisplatin, which itself increases its levels, has been effective in combating nausea.

The potential for therapy?

Medication that has shown therapeutic potential includes drugs that would increase GDF15 levels, working as its analogue and desensitizing GFRAL receptors, as well as drugs with an antagonistic effect on the receptors. Monoclonal antibodies, small molecules and peptide antagonists are among the molecules being considered for drug development. However, one existing drug has shown potential in hyperemesis gravidarum prevention. This drug, a first line antidiabetic, is metformin, which increases GDF15 levels and desensitizes its receptor. Further research is required to determine the appropriate administration dose and timing as well as its safety profile when it comes to HG prophylaxis.

What do we have so far?

Naturally, the most important treatment is still adequate replenishment of fluids, electrolytes and nutrients. Some antiemetics, such as ondansetron, metoclopramide and dimenhydrinate have proven effective in HG treatment. When it comes to refractory symptoms, medications such as corticosteroids (methylprednisolone, prednisolone, hydrocortisone), antipsychotics (chlorpromazine, droperidol, olanzapine), antiepileptics (gabapentin) and antidepressants (mirtazapine) can be administered. Some of these drugs have been tied to fetal malformations and are only used in extreme situations during pregnancy which only further highlights the need to develop safer alternatives for patients experiencing hyperemesis gravidarum.

Translated by: Anđela Jakiša