The purpose of this study is to better understand diagnosis and treatment of preterm preeclampsia. Currently, there are limited laboratory tests that can be used to diagnosis preeclampsia. Additionally, there are few treatments for this condition. This clinical trial will explore treatment options, Metformin and Esomeprazole, as well as serum markers that could improve the diagnosis and treatment of preterm preeclampsia.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
4
Oral Metformin schedule: Day 1: 500 milligrams in morning Day 2: 500 milligrams two times a day Day 3: 1000 milligrams in morning, 500 milligrams in evening Day 4 onwards: 1000 milligrams two times a day based on individual tolerance Oral Esomeprazole schedule: 40 milligrams Oral Esomeprazole daily until delivery which can be tapered down to 20 milligrams daily based on individual tolerance.
40 milligrams Oral Esomeprazole daily until delivery which can be tapered down to 20 milligrams daily based on individual tolerance.
Christianacare Health System
Newark, Delaware, United States
Mean plasma difference in sFlt-1
sFlt-1 from serum samples
Time frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Mean plasma difference in vascular endothelial growth factor (VEGF)
VEGF from serum samples
Time frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Mean plasma difference in placental growth factor (PIGF)
PIGF from serum samples
Time frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Mean plasma difference in soluble endoglin (sEng)
sENG from serum samples
Time frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
sFlt-1:PIGF ratio
sFLT-1:PIGF from serum samples
Time frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
Prolongation of gestation
Difference in time of expectant management between experimental and control group.
Time frame: Over the first 14 days after randomization and during the remainder of pregnancy, an average of 3-4 months
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