LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia

Salvatore Andrea Mastrolia; Lena Novack; Jecko Thachil; Anat Rabinovich; Oleg Pikovsky; Vered Klaitman; Giuseppe Loverro; Offer Erez

doi:10.1160/TH16-02-0169

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(05): 868-878
DOI: 10.1160/TH16-02-0169

Coagulation and Fibrinolysis

Schattauer GmbH

LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia

A systematic review and meta-analysis

Authors

Salvatore Andrea Mastrolia

¹Department of Obstetrics and Gynecology, Azienda Ospedaliero-Universitaria Policlinico di Bari, School of Medicine, University of Bari “Aldo Moro”, Bari, Italy

²Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
Lena Novack

³Department of Public Health, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
Jecko Thachil

⁴Department of Hematology, Manchester Royal Infirmary, Manchester, UK
Anat Rabinovich

⁵Hematology Institute, Soroka University Medical Center, Beer-Sheva, Israel
Oleg Pikovsky

⁵Hematology Institute, Soroka University Medical Center, Beer-Sheva, Israel
Vered Klaitman

²Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
Giuseppe Loverro

¹Department of Obstetrics and Gynecology, Azienda Ospedaliero-Universitaria Policlinico di Bari, School of Medicine, University of Bari “Aldo Moro”, Bari, Italy
Offer Erez

²Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel

⁶Maternity Department D and Obstetrical Day care Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben Gurion University of the Negev, School of Medicine, Beer Sheva, Israel

Abstract

Summary

Placental mediated pregnancy complications such as preeclampsia and fetal growth restriction (FGR) are common, serious, and associated with increased morbidity and mortality. We conducted a systematic review and meta-analysis to determine the effect of treatment with low-molecular-weight heparins (LMWHs) for secondary prevention of these complications in non thrombophilic women. We searched the electronic databases PubMed, Scopus, and Cochrane Library for randomised controlled trials addressing this question. Five studies including 403 patients met the inclusion criteria, 68 developed preeclampsia and 118 FGR. The studies were very heterogeneous in terms of inclusion criteria, LMWH preparation, and dosage. Meta-analyses were performed using random-effect models. The overall use of LMWHs was associated with a risk reduction for preeclampsia (Relative risk (RR) 0.366; 95 % confidence interval (CI), 0.219–0.614) and FGR (RR 0.409; 95 % CI, 0.195–0.932) vs. no treatment. From the data available for analysis it appears that the use of Dalteparin is associated with a risk reduction for preeclampsia (p=0.002) and FGR (p<0.001); while Enoxaparin is associated with risk reduction for preeclampsia (p=0.013) but not for FGR (p=0.3). In spite of the small number of studies addressing the research question, and the high variability among them, our meta-analysis found a modest beneficial effect of LMWH for secondary prevention of preeclampsia and FGR. Further studies are needed to address these questions before a definite conclusion can be reached.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Dalteparin - Enoxaparin - placental mediated pregnancy complications - randomized controlled trial - secondary prevention

Full Text

References

References
1 Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol 2006; 108: 1005-1016.
2 Sibai B, Dekker G, Kupferminc M. Preeclampsia. Lancet 2005; 365: 785-799.
3 Ramsay JE, Stewart F, Greer IA. et al. Microvascular dysfunction: a link between preeclampsia and maternal coronary heart disease. Br J Obstet Gynecol 2003; 110: 1029-1031.
4 Wilson BJ, Watson MS, Prescott GJ. et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. Br Med J 2003; 326: 845.
5 Haukkamaa L, Salminen M, Laivuori H. et al. Risk for subsequent coronary artery disease after preeclampsia. Am J Cardiol 2004; 93: 805-808.
6 Mor O, Stavsky M, Yitshak-Sade M. et al. Early onset preeclampsia and cerebral palsy: a double hit model?. Am J Obstet Gynecol 2016; 214: 105. e1-9
7 Strand KM, Heimstad R, Iversen AC. et al. Mediators of the association between preeclampsia and cerebral palsy: population based cohort study. Br Med J 2013; 347: f4089.
8 Hack M, Flannery DJ, Schluchter M. et al. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J Med 2002; 346: 149-157.
9 Barker DJ. Fetal origins of coronary heart disease. Br Med J 1995; 311: 171-174.
10 Hernández-Díaz S, Toh S, Cnattingius S. Risk of preeclampsia in first and subsequent pregnancies: prospective cohort study. Br Med J 2009; 338: b2255.
11 Dukler D, Porath A, Bashiri A. et al. Remote prognosis of primiparous women with preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001; 96: 69-74.
12 Lykke JA, Paidas MJ, Langhoff-Roos J. Recurring complications in second pregnancy. Obstet Gynecol 2009; 113: 1217-1224.
13 McDonald SD, Best C, Lam K. The recurrence risk of severe de novo preeclampsia in singleton pregnancies: a population-based cohort. Br J Obstet Gynecol 2009; 116: 1578-1584.
14 Mostello D, Kallogjeri D, Tungsiripat R. et al. Recurrence of preeclampsia: effects of gestational age at delivery of the first pregnancy, body mass index, paternity, and interval between births. Am J Obstet Gynecol 2008; 199: 55. e1-7
15 Sibai BM, el-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986; 155: 1011-1016.
16 Trogstad L, Skrondal A, Stoltenberg C. et al. Recurrence risk of preeclampsia in twin and singleton pregnancies. Am J Med Genet A 2004; 126A: 41-45.
17 Brosens I, Pijnenborg R, Vercruysse L. et al. The „Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204: 193-201.
18 Romero R, Espinoza J, Kusanovic JP. et al. The preterm parturition syndrome. Br J Obstet Gynecol 2006; 113 (Suppl. 03) 17-42.
19 American College of Obstetricians and Gynecologists. Task Force on Hypertension in Pregnancy. Hypertension in Pregnancy. 2013. Washington DC: 3.
20 Roberge S, Demers S, Nicolaides KH. et al. Prevention of preeclampsia by low-molecular weight heparin in addition to aspirin: a meta-analysis. Ultrasound Obstet Gynecol 2015 Epub ahead of print.
21 Dodd JM, McLeod A, Windrim RC. et al. Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. Cochrane Database Syst Rev 2013; 07: CD006780.
22 Tyrrell DJ, Horne AP, Holme KR. et al. Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv Pharmacol 1999; 46: 151-208.
23 Ghesquière L, Clouqueur E, Garabedian C. et al. Can we prevent preeclampsia?. Presse Med 2016 Epub ahead of print.
24 Khong Y, Brosens I. Defective deep placentation. Best Pract Res Clin Obstet Gynaecol 2011; 25: 301-311.
25 Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998; 179: 1359-1375.
26 Björk I, Lindahl U. Mechanism of the anticoagulant action of heparin. Mol Cell Biochem 1982; 48: 161-182.
27 Petitou M, Duchaussoy P, Jaurand G. et al. Synthesis and pharmacological properties of a close analogue of an antithrombotic pentasaccharide (SR 90107A/ORG 31540). J Med Chem 1997; 40: 1600-1607.
28 Petitou M, Duchaussoy P, Lederman I. et al. Synthesis of heparin fragments: a methyl alpha-pentaoside with high affinity for antithrombin III. Carbohydr Res 1987; 167: 67-75.
29 Greer IA. Anticoagulants in pregnancy. J Thromb Thrombolysis 2006; 21: 57-65.
30 Koenig A, Norgard-Sumnicht K, Linhardt R. et al. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J Clin Invest 1998; 101: 877-889.
31 Skinner MP, Lucas CM, Burns GF. et al. GMP-140 binding to neutrophils is inhibited by sulfated glycans. J Biol Chem 1991; 266: 5371-5374.
32 Diamond MS, Alon R, Parkos CA. et al. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J Cell Biol 1995; 130: 1473-1482.
33 Götte M. Syndecans in inflammation. FASEB J 2003; 17: 575-591.
34 Redman CW, Sargent IL. Circulating microparticles in normal pregnancy and preeclampsia. Placenta 2008; 29 (Suppl A) S73-77.
35 van Rijn BB, Bruinse HW, Veerbeek JH. et al. Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia. Hypertension 2016; 67: 404-414.
36 Oggé G, Romero R, Chaiworapongsa T. et al. Leukocytes of pregnant women with small-for-gestational age neonates have a different phenotypic and metabolic activity from those of women with preeclampsia. J Matern Fetal Neonatal Med 2010; 23: 476-487.
37 Gervasi MT, Chaiworapongsa T, Pacora P. et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gyne-col 2001; 185: 792-797.
38 Rodger MA, Hague WM, Kingdom J. et al. Antepartum dalteparin vs no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 2014; 384: 1673-1683.
39 de Vries JI, van Pampus MG, Hague WM. et al. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset preeclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost 2012; 10: 64-72.
40 Martinelli I, Ruggenenti P, Cetin I. et al. Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood 2012; 119: 3269-3275.
41 Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Ob-stet Gynecol 2005; 105: 182-192.
42 Gils C, Nybo M. Thrombophilia prevalence among women with placenta-mediated pregnancy complications. Int J Gynaecol Obstet 2016 Epub ahead of print.
43 Simcox LE, Ormesher L, Tower C. et al. Thrombophilia and pregnancy complications. Int J Mol Sci 2015; 16: 28418-28428.
44 Silver RM, Zhao Y, Spong CY. et al. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 2010; 115: 14-20.
45 Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?. Hum Reprod 2000; 15: 1830-1833.
46 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62: e1-34.
47 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12.
48 DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials 2015; 45 Part A 139-145.
49 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 07: 177-188.
50 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in meta-ana-lyses. Br Med J 2003; 327: 557-560.
51 Mello G, Parretti E, Fatini C. et al. Low-molecular-weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women. Hypertension 2005; 45: 86-91.
52 Badawy AM, Khiary M, Sherif LS. et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28: 280-284.
53 Fawzy M, Shokeir T, El-Tatongy M. et al. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet 2008; 278: 33-38.
54 Rey E, Garneau P, David M. et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009; 07: 58-64.
55 Gris JC, Chauleur C, Faillie JL. et al. Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial. Thromb Haemost 2010; 104: 771-779.
56 Ebrashy A, Ibrahim M, Marzook A. et al. Usefulness of aspirin therapy in highrisk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial. Croat Med J 2005; 46: 826-831.
57 Roberge S, Demers S, Bujold E. Initiation of aspirin in early gestation for the prevention of preeclampsia. Br J Obstet Gynecol 2013; 120: 773-774.
58 Roberge S, Giguère Y, Villa P. et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and metaanalysis. Am J Perinatol 2012; 29: 551-556.
59 Bujold E, Roberge S, Lacasse Y. et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116: 402-414.
60 Bujold E, Morency AM, Roberge S. et al. Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis. J Obstet Gynaecol Can 2009; 31: 818-826.
61 Werner EF, Hauspurg AK, Rouse DJ. A Cost-Benefit Analysis of Low-Dose Aspirin Prophylaxis for the Prevention of Preeclampsia in the United States. Obstet Gynecol 2015; 126: 1242-1250.
62 LeFevre ML. Force USPST. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U. S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 161: 819-826.
63 Voelker R. USPSTF: Low-dose aspirin may help reduce risk of preeclampsia. J Am Med Assoc 2014; 311: 2055.
64 Chaiworapongsa T, Chaemsaithong P, Korzeniewski SJ. et al. Preeclampsia part 2: prediction, prevention and management. Nat Rev Nephrol 2014; 10: 531-540.
65 Committee Opinion No. 638: First-Trimester Risk Assessment for Early-Onset Preeclampsia. Obstet Gynecol. 2015; 126: e25-27.
66 Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- vs late-onset disease. Am J Obstet Gynecol 2013; 209: 544. e1-.e12
67 Stergiotou I, Crispi F, Valenzuela-Alcaraz B. et al. Patterns of maternal vascular remodeling and responsiveness in early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013; 209: 558. e1-.e14
68 Rodger MA, Paidas M, McLintock C. et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 2008; 112: 320-324.
69 Physicians ACoOaGWsHC. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol 2013; 122: 706-717.
70 Rambaldi MP, Mecacci F, Guaschino S. et al. Inherited and acquired thrombophilias. Reprod Sci 2014; 21: 167-182.
71 Rodger MA, Betancourt MT, Clark P. et al. The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med 2010; 07: e1000292.
72 Rodger MA, Walker MC, Smith GN. et al. Is thrombophilia associated with placentamediated pregnancy complications? A prospective cohort study. J Thromb Haemost 2014; 12: 469-478.
73 Rodger MA, Carrier M, Le Gal G. et al. Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood 2014; 123: 822-828.

Supplementary Material

Online Supplementary Material (PDF) (PDF) (opens in new window)