Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial

Groom, Katie; McCowan, Lesley; Lee, Arier; Mens, Thijs E. van; Hannan, Natalie J.; Chamley, Larry; Stone, Peter; McLintock, Claire; Mackay, Laura K.; Lee, A.; Said, Joanne; Kane, Stefan C.; Walker, Susan; Tong, Stephen; Mens, T. van; Ganzevoort, Wessel; Middeldorp, Saskia

doi:10.1016/j.ajog.2017.01.014

Cited by 73 publications

(91 citation statements)

References 48 publications

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“…These conditions are associated with preterm birth (PTB) and remain the leading cause of perinatal morbidity and mortality worldwide. Pathological mechanisms leading to preeclampsia and FGR display considerable overlap [134]. Infections, stress, substance abuse (e.g., smoking), maternal under-nutrition, chromosomal abnormalities, genetic and epigenetic modifications and syndromes with an unknown genetic (inherited) basis are primary mediators of FGR [135].…”

Section: Role Of Er Stress In Pregnancy Complications and Pretermmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology

Güzel

Arlıer

Guzeloglu‐Kayisli

et al. 2017

IJMS

207

131

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The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the specific cellular site of synthesis, folding, modification and trafficking of secretory and cell-surface proteins. The ER is also the major intracellular calcium storage compartment that maintains cellular calcium homeostasis. During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis. Impaired ER homeostasis results in aberrant cellular responses, contributing to the pathogenesis of various diseases. Both female and male reproductive tissues undergo highly dynamic cellular, molecular and genetic changes such as oogenesis and spermatogenesis starting in prenatal life, mainly controlled by sex-steroids but also cytokines and growth factors throughout reproductive life. These reproductive changes require ER to provide extensive protein synthesis, folding, maturation and then their trafficking to appropriate cellular location as well as destroying unfolded/misfolded proteins via activating ER-associated degradation mediated proteasomes. Many studies have now shown roles for ER stress/UPR signaling cascades in the endometrial menstrual cycle, ovarian folliculogenesis and oocyte maturation, spermatogenesis, fertilization, pre-implantation embryo development and pregnancy and parturition. Conversely, the contribution of impaired ER homeostasis by severe/prolong ER stress-mediated UPR signaling pathways to several reproductive tissue pathologies including endometriosis, cancers, recurrent pregnancy loss and pregnancy complications associated with pre-term birth have been reported. This review focuses on ER stress and UPR signaling mechanisms, and their potential roles in female and male reproductive physiopathology involving in menstrual cycle changes, gametogenesis, preimplantation embryo development, implantation and placentation, labor, endometriosis, pregnancy complications and preterm birth as well as reproductive system tumorigenesis.

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Section: Role Of Er Stress In Pregnancy Complications and Pretermmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology

Güzel

Arlıer

Guzeloglu‐Kayisli

et al. 2017

IJMS

207

131

View full text Add to dashboard Cite

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“…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]. The conclusions of systematic reviews and meta-analyses summarizing this literature are conflicting.…”

Section: Lmwh For Preeclampsia Prevention: Evidence From Clinical Trialsmentioning

confidence: 85%

“…The criteria utilized to identify women as 'high risk' of developing preeclampsia have thus far differed greatly between trials. The majority of trials utilized inclusion criteria of prior preeclampsia, placental-mediated complication or pregnancy loss to identify women who are considered at high risk of preeclampsia in the current pregnancy; this was the approach in the recent HEPEPE and EPPI trials [31,32]. The primary outcome of these clinical trials has typically consisted of a composite clinical outcome, including preeclampsia, small for gestational age, placental abruption, and maternal or perinatal death.…”

Section: Patient Selectionmentioning

confidence: 99%

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

McLaughlin

Scholten

Parker

et al. 2018

Brit J Clinical Pharma

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Low molecular weight heparin has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women; however, the results from these trials have been conflicting. This review discusses the potential mechanisms of action of low molecular weight heparin for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials, and the importance of trial standardization. Preeclampsia preventionPreeclampsia is a hypertensive disorder of pregnancy, clinically diagnosed by new-onset hypertension after 20 weeks' gestation with evidence of organ injury [1]. The potential maternal and perinatal complications of preeclampsia are significant, including maternal seizures, fetal growth restriction (FGR) and stillbirth. Approximately 5% of women develop preeclampsia, with the majority of women experiencing mild preeclampsia that occurs near term and is safely managed by delivery [2]. Only 1% of pregnant women develop early-onset preeclampsia, where both the maternal and fetal implications are substantially greater, typically resulting in FGR and the need for iatrogenic preterm delivery before 34 weeks' gestation [2]. Early-onset preeclampsia is hypothesized to be a direct consequence of the interactions between a dysfunctional placenta and maternal cardiovascular system, while late-onset preeclampsia is hypothesized to be largely triggered by maternal constitutional factors [3][4][5]. Typically, women with early-onset preeclampsia present with an acute, severe syndrome that threatens the life of both the mother and her fetus. In contrast, late-onset preeclampsia is a less severe illness with a favourable clinical outcome in countries with well-developed maternity systems. However, in countries with limited medical resources, preeclampsia remains among the most frequent causes of maternal death [6].The early-and late-onset subsets of preeclampsia exhibit different types and severity of placental pathologies and express divergent maternal haemodynamics. Early-onset preeclampsia is strongly associated with placental disease characterized by maternal vascular malperfusion, where the abnormal placental villi secrete excessive amounts of antiangiogenic proteins and reduced levels of pro-angiogenic proteins into the maternal circulation [7][8][9]. Women with early-onset disease, typically associated with FGR, develop hypertension earlier in pregnancy that is characterized by increased systemic vascular resistance, reduced cardiac output and stroke volume along with relative bradycardia [5]. In contrast, late-onset preeclampsia is less commonly associated with severe placental disease, and consequently exhibits less British Journal of Clinical Pharmacology Br J Clin Pharmacol (2018) 84 673-678 673

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“…However, LMWH does not appear to significantly reduce the rates of pre‐eclampsia or SGA births when used alone, suggesting that is has synergetic effects with aspirin. Despite these promising findings, several recent large multicenter trials, such as the EPPI , HEPEPE and TIPPS trials, did not find similar beneficial effects of LMWH therapy for pre‐eclampsia prevention. Furthermore, the use of heparin and its derivatives for the prevention of pre‐eclampsia carries more potential risk than the use of low‐dose aspirin, such as bleeding and heparin‐induced thrombocytopenia, although such risks were demonstrated to be minimal in recent randomized clinical trials .…”

Section: Current Pharmacological Interventionsmentioning

confidence: 96%

“…Despite these promising findings, several recent large multicenter trials, such as the EPPI , HEPEPE and TIPPS trials, did not find similar beneficial effects of LMWH therapy for pre‐eclampsia prevention. Furthermore, the use of heparin and its derivatives for the prevention of pre‐eclampsia carries more potential risk than the use of low‐dose aspirin, such as bleeding and heparin‐induced thrombocytopenia, although such risks were demonstrated to be minimal in recent randomized clinical trials . One of the primary limitations of these large trials is the inclusion of all patients with the pre‐eclamptic syndrome without consideration of the underlying etiology, thereby diluting the potential efficacy of LMWH therapy, which may benefit only a subset of patients.…”

Section: Current Pharmacological Interventionsmentioning

confidence: 96%

Molecular actions of heparin and their implications in preventing pre‐eclampsia

Wat

Audette

Kingdom

2018

Journal of Thrombosis and Haemostasis

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Pre-eclampsia, a hypertensive disorder of pregnancy, continues to be a significant cause of global maternal morbidity. Low-dose aspirin remains the only standard-of-care prophylactic therapy for preventing pre-eclampsia, but is limited in efficacy. Heparin and its derivatives may further enhance the efficacy of aspirin therapy to prevent pre-eclampsia, but the mechanisms mediating this augmentative effect are not known. Although heparin is an anticoagulant agent, it also possesses many anticoagulant-independent properties that may be relevant in the prevention of pre-eclampsia, including effects on placental, vascular and inflammatory function. This review summarizes the non-anticoagulant properties of heparin, and extrapolates how these actions may influence the trajectory of pre-eclampsia pathogenesis as a means of pathway-specific therapy.

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Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial

Abstract: The use of enoxaparin in addition to standard high-risk care does not reduce the risk of recurrence of preeclampsia and small-for-gestational-age infants in a subsequent pregnancy.

Cited by 73 publications

References 48 publications

Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology

Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology

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

Molecular actions of heparin and their implications in preventing pre‐eclampsia

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