Hyperemesis gravidarum (HG) is a condition of severe intractable vomiting during pregnancy, leading to weight loss and volume reduction (1), which can be life-threatening. HG can cause Wernicke’s encephalopathy (2) and postpartum posttraumatic stress in the mother (3). It can also cause a fourfold increase in risk of adverse foetal outcomes such as preterm delivery, low birth weight and foetal death (4), alongside a threefold increased risk of neurodevelopmental delay in children (5).
GDF15 has been found to play a role in the pathophysiology of HG, especially as the feto-placental unit is a major source of GDF15 (6). A recent study found the GDF15 level in maternal circulation was significantly higher in the first trimester in women with HG compared with those without (7). However, significant overlap in GDF15 levels between HG cases and controls showed the limits of its use as a standalone diagnostic tool to distinguish HG from other causes of vomiting in pregnancy. Mothers with HG were also found to have GDF15 variants associated with a lower plasma GDF15 level in the non-pregnant state (7). A survey conducted by the same researchers (7) observed that NV symptoms were found markedly less in patients with thalassemia, associated with high pre-pregnancy levels of GDF15 (8), than controls. Another experiment showed mice chronically exposed to long-acting GDF15 became desensitized, showing no reduced food intake, unlike controls who exhibited the expected decrease (7).
Since high GDF15 levels in pregnancy are linked to a higher risk of HG, while low pre-pregnancy levels may prevent it, this indicates potential for clinical intervention. Administering a bolus of GDF15 has shown to result in NV in humans, suggesting that inhibiting GDF15 during pregnancy could be effective (9). Alongside this, inhibiting GDF15 in non-human primates significantly reduces vomiting caused by drugs like cis-platinum that acutely elevate GDF15 levels (10). This suggests prescribing high doses of GDF15 to those trying to conceive could desensitize them to it, potentially reducing HG risk. Conversely, administering antibodies to block GDF15 or its receptors could be a strategy to alleviate nausea and vomiting during pregnancy.
Approximately 80% of women who experience HG are likely to have it again in future pregnancies. A study has shown that the GDF15 risk allele is associated with familial HG and risk of recurrence (11). This could help clinicians advise patients with the GDF15 risk allele about their risk of HG and recurrence.
Altogether, a drug that safely decreases GDF15 levels in pregnancy could be effective in treating women who carry the risk allele for HG. While GDF15 is not yet a viable diagnostic tool, future research comparing GDF15 genotypes and levels in HG cases and controls could pave the way for its development into one.
The placenta's evolution to produce substantial GDF15 levels from early pregnancy likely accounts for the frequent nausea and vomiting in pregnant women. Sherman and Flaxman's hypothesis posits that this evolutionary trait aims to shield both mother and fetus from food-borne illnesses and toxins, crucial during the fetus's high vulnerability to teratogens and the mother's increased susceptibility to infections due to immunosuppression in early pregnancy.