Evidence GDF15 Plays a Role in Familial and Recurrent Hyperemesis Gravidarum.

Introduction Hyperemesis gravidarum (HG), a pregnancy complication characterized by severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies. It is associated with both maternal and fetal morbidity. HG is highly heritable and recurs in approximately 80% of women. In a recent genome-wide association study, it was shown that placentation, appetite, and the cachexia gene GDF15 are linked to HG. The purpose of this study was to explore whether GDF15 alleles linked to overexpression of GDF15 protein segregate with the condition in families, and whether the GDF15 risk allele is associated with recurrence of HG. Methods We analyzed GDF15 overexpression alleles for segregation with disease using exome-sequencing data from 5 HG families. We compared the allele frequency of the GDF15 risk allele, rs16982345, in patients who had recurrence of HG with its frequency in those who did not have recurrence. Results Single nucleotide polymorphisms (SNPs) linked to higher levels of GDF15 segregated with disease in HG families. The GDF15 risk allele, rs16982345, was associated with an 8-fold higher risk of recurrence of HG. Conclusion The findings of this study support the hypothesis that GDF15 is involved in the pathogenesis of both familial and recurrent cases of HG. The findings may be applicable when counseling women with a familial history of HG or recurrent HG. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under development. Based on our findings, patients carrying GDF15 variants associated with GDF15 overexpression should be included in future studies of GDF15-GFRAL-based therapeutics. If safe, this approach could reduce maternal and fetal morbidity.

Analysis of pre- and post-pregnancy issues in women with hyperemesis gravidarum.

The purpose of this study is to determine the frequency of reporting of both pre-pregnancy and post-pregnancy psychosocial and physical issues in women with hyperemesis gravidarum (HG). Conditions in 449 women with HG were compared to 459 unaffected women (controls). Binary responses were analyzed using either Chi-squared or Fishers Exact test. Continuous responses were analyzed using a t-test. Among 60 pre-pregnancy conditions surveyed, 10 common (>5%) maternal pre-pregnancy conditions were significantly more frequently reported by women with HG. Twenty rare (<5% controls) pre-pregnancy conditions with significantly increased reporting in the HG group were identified. Thirty (50%) pre-pregnancy conditions were similarly reported between cases and controls. Among 80 post-pregnancy factors surveyed, women with HG also showed significantly higher reporting for 7 common and 50 rare post-pregnancy outcomes. Women with HG are significantly more likely to self-report physical and psychosocial issues both before and after pregnancy.