Reproduction Abstracts

GDF15 was identified in 1999 by Breit as a member of the TGF beta superfamily produced by a wide range of cells in response to cellular stressors. Breit showed that it reduced food intake through actions in the hindbrain and subsequently several groups identified its receptor; a heterodimer of GFRAL and Ret. In 2000 Breit reported that GDF15 levels were elevated in thvalente plasma of pregnant women and that placental expression of GDF15 was high. In 2017/18, Fejzo et al. reported that genetic variants close to GDF15 were strongly associated with Hyperemesis Gravidarum and that women with HG had higher circulating levels of GDF15 and the O’Rahilly lab, working independently, found that women who vomited in pregnancy had higher levels of GDF15 than those who did not. In 2019, our collaborators at Pfizer reported that GDF15 administration was aversive in mice.

The O’Rahilly and Fejzo labs collaborated to discover the following

1. Using, for the first time, an assay that reliably measured GDF15, we established that levels of GDF15 in maternal plasma were significantly higher both in women with HG vs controls (at ~9 weeks gestation) and in a separate study in women reporting vomiting in pregnancy vs those who did not (at ~15 weeks gestation). There was, however, substantial overlap in GDF15 levels between affected and unaffected women so, alone, GDF15 levels could not fully explain HG.

2. Using a natural labelling experiment, we established that >95% of the GDF15 present in maternal circulation was encoded by the fetus.

3. Studying rare and common variants in the maternal GDF15 gene we showed that alleles that are associated with HG are associated with lower levels of circulating GDF15 in the non-pregnant state.

4. We found that women with thalassemia, who have very high levels of GDF15 rarely develop significant nausea or vomiting in pregnancy.

5. We showed that pre-exposure of mice to elevated levels of GDF15 reduces the effect of a subsequent bolus of GDF15, establishing that GDF15 is a hormone exposure to which induces desensitisation.

In conclusion, pregnancy sickness including HG appears to be due to combination of higher levels of GDF15 produced by the placenta from the fetal genome and greater sensitivity of the mother to the effects of GDF15, something which is strongly influenced by pre-pregnancy exposure to the hormone. These findings have obvious implications for therapy and prevention, both of which are being explored.

Keywords: GDF15, Hyperemesis gravidarum, pregnancy sickness