Pre-Eclampsia and Inherited Thrombophilia: A Reappraisal

ABSTRACT

Pre-eclampsia (P-EC) is a major cause of maternal and fetal morbidity and mortality. Inherited thrombophilia has been suggested to increase the risk of P-EC or may accelerate the pathophysiological process. In the past 20 years, numerous studies and meta-analyses have yielded contradictory results regarding the association between inherited thrombophilia and P-EC/hemolysis, elevated liver enzymes, low platelets syndrome. Although studies published until 2002 reported on an increased prevalence of inherited thrombophilia in pre-eclamptic women, most subsequent studies did not. Inconsistency of data may be due to numerous confounders such as ethnicity, different definitions of P-EC, severity of illness, and methods of testing. Mild P-EC is unlikely to be associated with thrombophilic gene defects, whereas severe and early-onset P-EC is significantly related to inherited and acquired thrombophilia. Thrombophilic patients with severe P-EC appear to have an increased risk of overall maternal morbidity and recurrences of P-EC compared with pre-eclamptic women without thrombophilia. It remains a matter of debate if women with a previous history of (severe) P-EC should be screened for inherited thrombophilias and if the administration of low molecular weight heparin should be recommended in women with positive results to prevent adverse outcomes in subsequent pregnancies. Large prospective studies are urgently needed to determine the benefits and risks of prophylactic strategies.

KEYWORDS

Pre-eclampsia - inherited thrombophilia - conflicting data - confounders - management

REFERENCES

• 1 Kupferminc M J. Thrombophilia and pregnancy.  Reprod Biol Endocrinol. 2003;  1 111
• 2 Sibai B M, Dekker G, Kupferminc M. Pre-eclampsia.  Lancet. 2005;  365 (9461) 785-799
• 3 Dekker G A, de Vries J I, Doelitzsch P M et al. Underlying disorders associated with severe early-onset preeclampsia.  Am J Obstet Gynecol. 1995;  173 (4) 1042-1048
• 4 Kupferminc M J, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med. 1999;  340 (1) 9-13
• 5 Kupferminc M J, Fait G, Many A, Gordon D, Eldor A, Lessing J B. Severe preeclampsia and high frequency of genetic thrombophilic mutations.  Obstet Gynecol. 2000;  96 (1) 45-49
• 6 Franchini M. Haemostasis and pregnancy.  Thromb Haemost. 2006;  95 (3) 401-413
• 7 Rodger M A, Paidas M, McLintock C et al. Inherited thrombophilia and pregnancy complications revisited.  Obstet Gynecol. 2008;  112 (2 Pt 1) 320-324
• 8 Kujovich J L. Thrombophilia and pregnancy complications.  Am J Obstet Gynecol. 2004;  191 (2) 412-424
• 9 Stella C L, How H Y, Sibai B M. Thrombophilia and adverse maternal-perinatal outcome: controversies in screening and management.  Am J Perinatol. 2006;  23 (8) 499-506
• 10 Robertson L, Wu O, Langhorne P Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study et al. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132 (2) 171-196
• 11 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.  Eur J Obstet Gynecol Reprod Biol. 2002;  101 (1) 6-14
• 12 Morrison E R, Miedzybrodzka Z H, Campbell D M et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review.  Thromb Haemost. 2002;  87 (5) 779-785
• 13 Kosmas I P, Tatsioni A, Ioannidis J PA. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis.  J Hypertens. 2003;  21 (7) 1221-1228
• 14 Lin J, August P h. Genetic thrombophilias and preeclampsia: a meta-analysis.  Obstet Gynecol. 2005;  105 (1) 182-192
• 15 Dizon-Townson D, Miller C, Sibai B M National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus.  Obstet Gynecol. 2005;  106 (3) 517-524
• 16 Larciprete G, Gioia S, Angelucci P A et al. Single inherited thrombophilias and adverse pregnancy outcomes.  J Obstet Gynaecol Res. 2007;  33 (4) 423-430
• 17 Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia.  J Med Genet. 1997;  34 (6) 525-526
• 18 Brattström L, Wilcken D E, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis.  Circulation. 1998;  98 (23) 2520-2526
• 19 Mello G, Parretti E, Marozio L et al. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study.  Hypertension. 2005;  46 (6) 1270-1274
• 20 Kahn S R, Platt R, McNamara H et al. Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study.  Am J Obstet Gynecol. 2009;  200 (2) 151, e1-e9 discussion e1-e5
• 21 Kist W J, Janssen N G, Kalk J J, Hague W M, Dekker G A, de Vries J I. Thrombophilias and adverse pregnancy outcome—a confounded problem!.  Thromb Haemost. 2008;  99 (1) 77-85
• 22 Facchinetti F, Marozio L, Frusca T et al. Maternal thrombophilia and the risk of recurrence of preeclampsia.  Am J Obstet Gynecol. 2009;  200 (1) 46, e1-e5
• 23 Sibai B M, 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 (5) 1011-1016
• 24 van Rijn B B, Hoeks L B, Bots M L, Franx A, Bruinse H W. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia.  Am J Obstet Gynecol. 2006;  195 (3) 723-728
• 25 Muetze S, Leeners B, Ortlepp J R et al. Maternal factor V Leiden mutation is associated with HELLP syndrome in Caucasian women.  Acta Obstet Gynecol Scand. 2008;  87 (6) 635-642
• 26 Rigó Jr J, Nagy B, Fintor L et al. Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase.  Hypertens Pregnancy. 2000;  19 (2) 163-172
• 27 von Tempelhoff G F, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodies in patients with preeclampsia or HELLP-syndrome. Hemolysis, elevated liver-enzymes, low platelets.  Thromb Res. 2000;  100 (4) 363-365
• 28 Nagy B, Hupuczi P, Papp Z. High frequency of methylenetetrahydrofolate reductase 677TT genotype in Hungarian HELLP syndrome patients determined by quantitative real-time PCR.  J Hum Hypertens. 2007;  21 (2) 154-158
• 29 Demir S C, Evruke C, Ozgunen T, Kadayifci O, Altintas U, Kokangul S. The relationship between pregnancy induced hypertension and congenital thrombophilia.  Saudi Med J. 2006;  27 (8) 1161-1166
• 30 Muetze S, Eggermann T, Leeners B et al. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with HELLP syndrome.  J Thromb Thrombolysis. 2009;  27 (2) 141-145
• 31 Wiwanitkit V. Correlation between plasminogen activator inhibitor-1 4G/5G polymorphism and pre-eclampsia: an appraisal.  Arch Gynecol Obstet. 2006;  273 (6) 322-324
• 32 Kupferminc M J, Fait G, Many A et al. Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias.  Hypertens Pregnancy. 2001;  20 (1) 35-44
• 33 Gris J C, Mercier E, Quéré I et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.  Blood. 2004;  103 (10) 3695-3699
• 34 Silver R M, Warren J E. Preconception counseling for women with thrombophilia.  Clin Obstet Gynecol. 2006;  49 (4) 906-919
• 35 James A H, Brancazio L R, Ortel T L. Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy.  Clin Adv Hematol Oncol. 2005;  3 (3) 187-197
• 36 Bates S M, Greer I A, Pabinger I, Sofaer S, Hirsh J. American College of Chest Physicians . Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (6, Suppl) 844S-886S
• 37 Duhl A J, Paidas M J, Ural S H Pregnancy and Thrombosis Working Group et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes.  Am J Obstet Gynecol. 2007;  197 (5) 457, e1-e21
• 38 AWMF-Leitlinie 003/001. Prophylaxe der venösen Thromboembolie (VTE). Berlin, Germany: German Society of Angiology; April 1, 2009
• 39 Royal College of Obstetricians and Gynaecologists .Thrombosis and Embolism during Pregnancy and the Puerperium: Reducing the Risk. Green-top Guideline No. 37. London, United Kingdom: Royal College of Obstetricians and Gynaecologists; January 2010