Low-Molecular-Weight Heparin Lowers the Recurrence Rate of Preeclampsia and Restores the Physiological Vascular Changes in Angiotensin-Converting Enzyme DD Women

Abstract

Abstract-Data from literature report that angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism affects the recurrence of preeclampsia and that low-molecular-weight heparin (LMWH) prevents adverse outcomes in thrombophilic women. We investigated the effect of LMWH on the pregnancy outcome, on maternal blood pressure values, and on uteroplacental flow in ACE DD nonthrombophilic women with history of preeclampsia. Eighty nonthrombophilic ACE DD women were randomized in 2 groups: 41 treated with dalteparin 5000 IU/day and 39 untreated (control group). Women underwent 24-hour automated blood pressure monitoring in the preconceptional period and every 2 weeks from weeks 8 to 36 and transabdominal color flow/pulsed Doppler examination at weeks 16, 20, and 24. LMWH reduced the risk of clinical negative outcomes (74.1% reduction of preeclampsia and 77.5% reduction of fetal growth restriction) and the severity (88.3% reduction of early onset of preeclampsia and 86.4% reduction of early onset of fetal growth restriction). In treated women, the relative risk for preeclampsia was 0.26 (Pϭ0.02), and the relative risk for fetal growth restriction was 0.14 (PϽ0.001). Systolic (Pϭ0.002) and diastolic (Pϭ0.002) blood pressures, as well as awake (Pϭ0.04) and asleep (Pϭ0.01) period values, and the resistance indexes of both uterine arteries (Pϭ0.002) were lower in the treated group. LMWH reduces the recurrence of preeclampsia, of negative outcomes, and the resistance of uteroplacental flow, and also prevents maternal blood pressure increase in ACE DD homozygote women with a previous history of preeclampsia.

Improved Outcomes in ART Pregnancies Complicated by Thrombophilia, Treated with Low Molecular Weight Heparin in Comparison to Spontaneously Conceived Low-Risk, Untreated Pregnancies: A Case Control Study

“…The relative risk of IUGR, prematurity, preeclampsia, fetal death, and abruption in ART pregnancies can be as high as 3 [1]. In the present study, the magnitude of reduction of the incidence of prematurity, preeclampsia, fetal demise, and IUGR speaks in support of the concept that the cause of the infertility may potentially be the same as the cause of placental insufficiency with all adverse consequences noted in untreated ART pregnancies [19][20][21]. LMWH improves implantation rates in patients with thrombophilia; furthermore, LMWH improves pregnancy outcomes and reduces recurrent pregnancy loss in patients with thrombophilic disorders [22,23].…”

Prophylactic Low Molecular Weight Heparin Improving Perinatal Outcome in Non-thrombophilic Placental-Mediated Complications

“…Similarly, Rey et al [8] in his study did not find any difference in gestational age between cases and controls. However, Mello et al [15] observed gestational age of delivery to be 37 weeks. Kupferminc et al [16] also noticed a higher gestational age of delivery in the study group.…”

“…LMWH promotes the differentiation and invasion of the trophoblast in vivo [17,18], prevents monocyte adhesion to activated endothelium [19], and inhibits tumor necrosis factor-a-induced leukocyte rolling [20]. These drugs decrease vascular resistance in vitro [21] and in vivo [15][16][17][18][19][20][21][22]. Therefore, LMWH may act by improving placental development as well as by inhibiting reactive pathways involved in Pre-eclampsia (PET) and Small for Gestation Age (SGA).…”

Low molecular weight heparin for the prevention of severe preeclampsia: where next?

“…Multiple clinical trials have reported that LMWH reduced the incidence of preeclampsia, as well as newborn weight < 5th percentile, FGR, major placental abruption or fetal loss after 20 weeks' gestation [20][21][22][23][24][25][26][27]; however, other trials of similar design have demonstrated no treatment effect with LMWH [28][29][30]. Most recently, the large, well-designed HEPEPE and EPPI trials reported that enoxaparin with ASA does not significantly reduce placental-mediated complications, including preeclampsia, when compared to aspirin alone [31,32].…”

“…Importantly, the mechanisms of action of LMWH for earlyonset preeclampsia prevention could be independent of its anticoagulant actions, as heparin does not exert obvious anticoagulant activity within the placentas of women at risk of preeclampsia [40]. In vivo experiments in both pregnant women and other clinical populations have demonstrated that LMWH exerts beneficial actions directly on the maternal vasculature, resulting in lower blood pressure, improved endothelial function and modification of circulating levels of angiogenic proteins in a positive manner [25,[41][42][43]. Ex vivo and in vitro experiments have confirmed beneficial effects of LMWH on vascular reactivity and endothelial function [44][45][46].…”