Metformin and Esomeprazole in Preterm Pre-eclampsia

BACKGROUND:

The pathophysiology of preeclampsia

To achieve normal vascular function during pregnancy, the placental vascular endothelium secretes vasoactive substances and growth factors, most notably vascular endothelial growth factor (VEGF), sFlt-1, placental growth factor (PlGF) and soluble endoglin (sEng). These substrates interact with maternal natural killer cells to promote remodeling of the uterine spiral arteries in order to create a uteroplacental interface. Circulating vasoconstrictors, such as Thromboxane A2, and vasodilators play an important role in regulating the vascular endothelium in response to the developing uteroplacental interface.

In patients with preeclampsia, however, trophoblast cells demonstrate insufficient invasion of the spiral arteries, leading to poor remodeling, narrow vessel diameter and high vascular resistance. The endothelial dysfunction occurs in two phases. In the first phase, defective placental trophoblastic invasion of the uterine spiral arteries occurs at 14-18 weeks of gestation. This dysfunctional invasion leads to poor uteroplacental blood flow and the release of antiangiogenic factors and vasoconstrictive substances in the second phase.

In Defense of Metformin, Esomeprazole

Lower sFlt1 levels were detected in placental villous explants from patients diagnosed with preterm preeclampsia and treated with metformin. Metformin downgraded endothelial cell secretion by 53% and placental cell secretion by 63%. Similarly, in a meta-analysis of patients on metformin for gestational diabetes (GDM), Kalafat and Sukur concluded that the use of metformin was associated with a reduced risk of preeclampsia (relative risk (RR): 0.56; 95% confidence interval (CI): 0.37-0.85; n = 1260 women)

A recent randomized controlled trial by Cluver et al included 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomized to extended release metformin and 90 to placebo. Investigators found that extended release metformin (3g daily) can prolong gestation in women with preterm pre-eclampsia

In vitro studies show proton pump inhibitors decrease soluble fems like tyrosine kinase -1 (sFlt-1) and soluble endoglin and improve markers of endothelial dysfunction. Esomeprazole reduces blood pressure in a preeclampsia transgenic mouse model that overexpresses sFlt-1.

Combination metformin and esomeprazole has shown promise in the treatment of preeclampsia as both agents reduce placental and endothelial secretion of sFlt-1 and soluble endoglin, and reduce endothelial dysfunction. Kaitu'u-Lino et al found that combining metformin and esomeprazole was additive at reducing sFlt-1 secretion and expression of sFlt-1 e15a mRNA isoform in primary cytotrophoblast, placental explants and endothelial cells.

Safety of Metformin, Esomeprazole

Metformin is a biguanide that inhibits hepatic gluconeogenesis and glucose absorption and stimulates glucose uptake in peripheral tissues.

In one large trial, 751 women with GDM were randomly assigned to receive insulin therapy or metformin. Both groups experienced similar rates of a composite outcome of perinatal morbidity, consisting of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, prematurity, and low Apgar scores. Additionally, five randomized clinical trials showed the safety of metformin as well as its efficiency in dealing with GDM compared with insulin. A meta-analysis by Gui et al. demonstrated that metformin was superior to insulin in reducing the incidence of preeclampsia.

Proton pump inhibitors (PPI) such as esomeprazole have long-term safety data in the treatment of gastric reflux in pregnancy. The Motherisk Program conducted a meta-analysis on use of PPIs in 593 pregnancies and showed no increase in risk of malformations. Furthermore, in a large cohort study from the Swedish Medical Birth Registry on 955 infants whose mothers used PPIs during pregnancy showed no difference in birth weights, rates of congenital malformations, perinatal death, or low Apgar scores.