Preconception metformin and hyperemesis gravidarum in Denmark: clinical implications of growth differentiation factor 15's etiological role

Background Hyperemesis gravidarum, a condition characterized by severe nausea and vomiting in pregnancy, is now understood to be partly attributable to high placentally derived growth differentiation factor 15 concentrations, which increase rapidly from early pregnancy. Intriguingly, accumulating evidence has suggested that low preconception growth differentiation factor 15 concentrations predispose to hyperemesis gravidarum, suggesting that growth differentiation factor 15 preconditioning may offer a modifiable factor, which could be harnessed as the first preventive strategy for hyperemesis gravidarum. Metformin, a drug that is safe and widely used in pregnancy, increases the growth differentiation factor 15 level. Objective This study aimed to determine whether and at what duration and timing of preconception metformin use might lower the prevalence or recurrence of hyperemesis gravidarum. Study Design This was a population-based registry study of all pregnancies with a gestational age of ≥10 weeks between 1998 and 2018 in Denmark. Metformin use was estimated by the redemption of metformin prescription before pregnancy. The main outcome was the prevalence of hyperemesis gravidarum based on the International Classification of Diseases codes. Results In 1,447,968 pregnancies, 1.9% had a hyperemesis gravidarum diagnosis, with a recurrence rate of 26.0%. Preconception metformin use did not decrease hyperemesis gravidarum prevalence (1.9%) or recurrence (27%). However, preconception metformin use continued for ≥6 months was associated with a lower prevalence of hyperemesis gravidarum of 1.1% (adjusted odds ratio, 0.49 [95% confidence interval, 0.31–0.75]) than preconception metformin use for <2 months. If metformin was continued up to conception (last redemption within the first month after conception), the prevalence of hyperemesis gravidarum was 1.2% (adjusted odds ratio, 0.61 [95% confidence interval, 0.38–0.95]), compared with the discontinuation of metformin longer before conception. The effect remained after correcting for metformin indication and other potential confounders. Conclusion Our findings suggest that metformin in preconception, with 6-month usage and continued usage up to 1 month after conception, may present the first preventive strategy for patients at high risk of hyperemesis gravidarum. Owing to the observational nature of our study, randomized trials need to further investigate the utility of this strategy.