Efficacy of metformin therapy to reduce pregnancy-induced hypertensive disorders in women with silent impaired insulin-sensitivity.

ROMERO J; SPINEDI E

Barcelona

Congreso; European Society of Human Reproduction and Embryology 2018 Meeting; 2018

European Society of Human Reproduction and Embryology

Study question:Could metformin therapy, throughout pregnancy, be effective to reduce the risk of late pregnancy-induced hypertensive disorders (PIHD) in women with defective insulin-signaling system function?Summary answer:Metformin therapy, throughout pregnancy, reduced the development of third trimester gestation-induced hypertensive disorders in women with silent defective insulin-signaling system function from 23.6% to 13.8%.What is known already:Pregnant women with impaired insulin sensitivity are at a high risk for developing pregnancy-induced hypertensive disorders (PIHD). Previous data support that 2 h-insulinemias greater than 215.25 pM after 75 g-glucose overload could be a predictor for detecting women at high risk of developing PIHD. Indeed, compared with pregnant women at low risk (2 h-insulinemias lower than 215.25 pM), those at high risk displayed a 4-fold higher occurrence of gestational hypertension and pre-eclampsia. Additionally, it is accepted that metformin (MTF) therapy is able to prevent poor pregnancy outcome in women diagnosed for gestational diabetes mellitus (GDM).Study design, size, duration:We performed a 2-year-prospective study in 226 multiparous women that became spontaneously pregnant either under oral MTF therapy (2g/day; n=29) or not (n=198). During gestational week 25-26, women were subjected to an oral glucose tolerance test (OGTT) measuring insulinemias on both sample-times. Thereafter, women were classified at low (being the 2 h-insulinemias lower than 215.25 pM) or at high (being the 2 h-insulinemias greater than 215.25 pM) risk for developing PIHD (LR-PIHD and HR-PIHD, respectively. Participants/materials, setting, methods:Overnight fasting pregnant women (age 29-37 years) were bled before (sample time-zero) and 2 h after 75 g-oral glucose load (OGTT). Glucose (enzymatic-colorimetric assay) and insulin (chemiluminescence) plasma concentrations were determined in samples times zero and 2 h from the OGTT. Finally, HOMA-IR score (glucose in mM x insulin in mIU/mL x 0.044) and Glucose (in mg/dL) to Insulin (in mIU/mL) ratio (G:Ir) were calculated for both time-samples. Anthropometric data were recorded throughout pregnancy. Main results and the role of chance:Biochemical data indicate that 125 and 101 women were at LR-PIHD and HR-PIHD, respectively, MTF-treated women pertained to the HR-PIHD group. Comparing data from HR-PIHD MTF-treated (n=29) versus MTF-untreated women (n=72), although time-zero glycemias were similar, time-2 h glycemias were significantly (P<0.05) lower in MTF-treated than in MTF-untreated women. Plasma insulin and HOMA-IR values were statistically similar in both groups, regardless of the sample-time examined. Finally, G:Ir values were significantly (P<0.05) higher in MTF-treated than in MTF-untreated women although in sample-time zero only. While 17/72 MTF-untreated women developed any PIHD, conversely, PIHD was noticed in 4/29 MTF-treated women. Starting woman body mass index, weight-gain throughout pregnancy, gestational length, multiparity and, the appearance of polihydramnios and newborn respiratory distress were similar among groups; none stillbirth was noticed. Although mean values of weight at birth were similar among groups, macrosomic babies were born to MTF-untreated mothers only (3/72). Finally, while PIHD (hypertension/pre-eclampsia) were developed by 17/72 (23.6%) MTF-untreated women, a better pregnancy outcome was noticed in MTF-treated women because only 4/29 (13.8%) developed PIHD. Data indicate that pregnancy outcome in women at HR-PIHD, due to their impaired insulin sensitivity (2h-insulinemias >215.25 pM), could be highly beneficed if treated with MTF throughout pregnancy. Limitations, reasons for caution:Data emerging from this prospective study need to be corroborated by studying the beneficial effect of MTF therapy throughout gestation, on poor pregnancy outcome in a larger sample-population of pregnant women at high risk of developing PIHD, defined as having 2 h-insulin values greater than 215.25 pM during an OGTT. Wider implications of the findings:We have established that by applying the simple criterion ¨2-h insulinemia > 215.25 pM during an OGTT¨, pregnant women with silent impaired insulin sensitivity are at high risk of developing PIHD, however, such increased risk could be reduced when these women are treated with MTF throughout pregnancy. Trial registration number:Not applicable. Keywords: OGTT Insulinemia Gestational Hypertensive Disorders Metformin