Hostname: page-component-78c5997874-mlc7c Total loading time: 0 Render date: 2024-11-19T13:22:03.959Z Has data issue: false hasContentIssue false

FOLATE METABOLISM AND PREECLAMPSIA

Published online by Cambridge University Press:  29 June 2012

YANFANG GUO
Affiliation:
OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada. Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada. School of Public Health, Central South University, Changsha, Hunan, PRC. Huaihua Medical College, Huaihua, Hunan, PRC.
GRAEME N. SMITH
Affiliation:
Queen's Perinatal Research Unit, Department of Obstetrics and Gynecology, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada.
SHI WU WEN
Affiliation:
OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada. Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada. School of Public Health, Central South University, Changsha, Hunan, PRC. Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada.
MARK C WALKER*
Affiliation:
OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Faculty of Medicine, Ottawa, Ontario, Canada. Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada.
*
Mark C Walker, OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa, Faculty of Medicine, 501 Smyth, Ottawa, Ontario K1H 8L6Canada. E-mail: mwalker@ohri.ca

Extract

Preeclampsia (PE) is a multisystem disorder of human pregnancy, affecting about 6% of all pregnancies worldwide, and is one of the leading causes of maternal and infant morbidity and mortality. Despite decades of research into the pathogenesis of this complex disease, the underlying mechanisms remain unclear. As a result, the options for prevention and management of PE are limited. In recent years, there has been a growing body of evidence suggesting that folate deficiency is associated with PE, and folic acid supplementation may reduce the risk of developing PE in certain populations. Folate contributes to cell division and growth, and folate metabolism is involved in a large number of physiological and pathophysiological processes in human development. Sufficient supply of folate is therefore particularly important during pregnancy. Nevertheless, the exact mechanisms of folic acid deficiency increasing the risk of developing PE are still unclear. This article reviews what is understood about the aetiology of PE and the relationship between folate metabolism and PE so as to enhance further discussions on the subject.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1Berg, CJ, Atrash, HK, Koonim, LM, Tucker, M. Pregnancy-related mortality in the United States, 1987–1990. Obstet Gynecol 1996; 88: 161–67.CrossRefGoogle ScholarPubMed
2Zhang, J, Zeisler, J, Hatch, MC, Berkowitz, G. Epidemiology of pregnancy-induced hypertension. Epidemiol Rev 1997; 19: 218–32.CrossRefGoogle ScholarPubMed
3Landau, R, Xie, HG, Dishy, V, Wood, AJ, Stein, CM, Smiley, RM. No association of the Asp298 variant of the endothelial nitric oxide synthase gene with preeclampsia. Am J Hypertens 2004; 17: 391–94.CrossRefGoogle ScholarPubMed
4Noris, M, Perico, N, Remuzzi, G. Mechanisms of disease: preeclampsia. Nat Clin Pract Nephrol 2005; 1: 98114.CrossRefGoogle Scholar
5Liu, A, Wen, SW, Bottomly, J, Walker, MC, Smith, G. Utilization of health care services of pregnant women complicated by preeclampsia in Ontario. Hypertens Pregnancy 2009; 28: 7684.CrossRefGoogle ScholarPubMed
6World Health Organization. The hypertensive disorders of pregnancy. Report of a WHO Study Group. World Health Organization Technical Report Series 758. Geneva: WHO, 1987: 63–69.Google Scholar
7Duley, L. Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol 1992; 99: 547–53.CrossRefGoogle ScholarPubMed
8Sibai, BM. Hypertension in pregnancy. Obstet Gynecol Cli North Am 1992; 19: 615–32.CrossRefGoogle ScholarPubMed
9Zhang, J, Meikle, S, Trumble, A. Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States. Hypertens Pregnancy 2003; 22: 203–12.CrossRefGoogle ScholarPubMed
10Irgens, HU, Reisaeter, L, Irgens, LM, Lie, RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001; 323: 1213–137.CrossRefGoogle ScholarPubMed
11Pridjian, G, Puschett, JB. Preeclampsia. Part 2: Experimental and genetic considerations. Obstet Gynecol Surv 2002; 57: 619–40.CrossRefGoogle ScholarPubMed
12Wilson, ML, Goodwin, TM, Pan, VL, Ingles, SA. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv 2003; 58: 3966.CrossRefGoogle ScholarPubMed
13Roberts, JM, Balk, JL, Bodnar, LM, Belizán, JM, Bergel, E, Martinez, A. Nutrient involvement in preeclampsia. J Nutr 2003; 133: 1684S1692S.CrossRefGoogle ScholarPubMed
14Chesley, LC. Hypertension in pregnancy: definitions, familial factor, and remote prognosis. Kidney Int 1980; 18: 234–40.CrossRefGoogle ScholarPubMed
15Higgins, JR, de Swiet, M. Blood-pressure measurement and classification in pregnancy. Lancet 2001; 357: 131–35.CrossRefGoogle ScholarPubMed
16National High Blood Pressure Education Program Working Group on High Pressure in Pregnancy (2000) Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 183: SS22.Google Scholar
17ACOG. Committee on Practice Bulletins-Obstetrics. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2001; 98: 159–67.Google Scholar
18Haram, K, Svendsen, E, Abildgaard, U. The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth 2009; 9: 8.CrossRefGoogle ScholarPubMed
19Barton, JR, Sibai, BM. Gastrointestinal complications of pre-eclampsia. Semin Perinatol 2009; 33: 179–88.CrossRefGoogle ScholarPubMed
20Barton, JR, Sibai, BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol 2008; 112: 359–72.CrossRefGoogle ScholarPubMed
21Podjarny, E, Losonczy, G, Baylis, C. Animal models of preeclampsia. Semin Nephrol 2004; 24: 596606.CrossRefGoogle ScholarPubMed
22Roberts, JM, Sheer, P. Antioxidant therapy to prevent preeclampsia. Semin Nephrol 2004; 24: 557–64.CrossRefGoogle ScholarPubMed
23Austgulen, R. Recent knowledge on mechanisms underlying development of preeclampsia. Tidsskr Nor Laegeforen 2004; 124: 2124.Google Scholar
24Roberts, JM, Hubel, CA. Is oxidative stress the link the in the two-stage model of pre-eclampsia? Lancet 1999; 354: 788–89.CrossRefGoogle ScholarPubMed
25Roberts, JM, Hubel, CA. The two stage model of preeclampsia: variations on the theme. Placenta. 2009; 23: S32S37.CrossRefGoogle Scholar
26Serrano, NC. Immunology and genetic of preeclampsia. Clinical and Development. Immunology 2006; 13: 197201.Google Scholar
27Qiao, F, Wu, Y. Causes of pregnancy-induced hypertension status and progress of the study. Huazhong Med J 2005; 29: 339400.Google Scholar
28Wu, Y, Qiao, F. Molecular genetic etiology of pregnancy-induced hypertension. Chin J Birth Health Heredity 2005; 13: 89.Google Scholar
29Goldman-Wohl, DS, Ariel, I, Greenfield, C, Hochner-Celnikier, D, Cross, J, Fisher, S et al. Lack of human Leukocyte antigen-G expression in extravillous trophoblasts is associated with preeclampsia. Mol Hum Reprod 2000; 6: 8895.CrossRefGoogle ScholarPubMed
30Bermingham, J, Jenkins, D, McCarthy, T, O'Brien, M. Genetic analysis of insulin-like growth factor Ⅱ and HLA-G in preeclampsia. Biochem Soc Trans 2000; 28: 215–19.CrossRefGoogle ScholarPubMed
31O'Brien, M, McCarthy, T, Jenkins, D, Paul, P, Dausset, J, Carosella, ED et al. Altered HLA-G transcription in preeclampsia is associated with the specific inheritance possible role of the HLA-G gene in susceptibility to the disease. Cell Mol Life Sci 2001; 58: 1943–49.CrossRefGoogle ScholarPubMed
32Austgulen, R. Recent knowledge on mechanisms underlying development of preeclampsia. Tidsskr Nor Laegeforen 2004; 124: 212–41.Google Scholar
33Pan, Z, Wang, Z, Chen, S. The cause of pregnancy-induced hypertension. Chinese Pract Gynecol Obstet 2007; 23: 465–67.Google Scholar
34Dekker, GA, Robillard, PY. Preeclampsia: a couple's disease with maternal and fetal manifestations. Curr Pharm Des 2005; 11: 699710.CrossRefGoogle ScholarPubMed
35Broughton-Pipkin, F, Roberts, JM. Hypertension in pregnancy. J Hum Hypertens 2000; 14: 705–24.CrossRefGoogle ScholarPubMed
36Hladunewich, M, Karumanchi, A, Lafayette, R. Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2007; 2: 543–49.CrossRefGoogle ScholarPubMed
37Chelbi, ST, Vaiman, D. Genetic and epigenetic factors contribute to the onset of preeclampsia. Mol Cell Endocrinol 2008; 282: 120–29.CrossRefGoogle Scholar
38Levine, RJ, Maynard, SE, Qian, C, Lim, KH, England, LJ, Yu, KF et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672–83.CrossRefGoogle ScholarPubMed
39Ito, M, Itakura, A, Ohno, Y, Nomura, M, Senga, T, Nagasaka, T, Mizutani, S: Possible activation of the renin-angiotensin system in the feto-placental unit in preeclampsia. J Clin Endocrinol Metab 2002; 87: 1871–78.CrossRefGoogle ScholarPubMed
40Venkatesha, S, Toporsian, M, Lam, C, Hanai, J, Mammoto, T, Kim, YM et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12: 642–49.CrossRefGoogle Scholar
41Maynard, SE, Min, JY, Merchan, J, Lim, KH, Li, J, Mondal, S, Libermann, TA et al. , Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111: 649–58.CrossRefGoogle ScholarPubMed
42Walsh, S. Eicosanoids in preeclampsia. Prostaglandins Leukot Essent Fatty Acids 2004; 70: 223–32.CrossRefGoogle ScholarPubMed
43Duckitt, K, Harrington, D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330: 565.CrossRefGoogle ScholarPubMed
44Ødegard, RA, Vatten, LJ, Nilsen, ST, Salvesen, KA, Austgulen, R. Risk factors and clinical manifestations of pre-eclampsia. BJOG 2000; 107: 1410–16.CrossRefGoogle ScholarPubMed
45Skjaerven, R, Wilcox, AL, Lie, RT. The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002; 346: 3338.CrossRefGoogle ScholarPubMed
46Zhang, J. Partner change, birth interval and risk of pre-eclampsia: a paradoxical triangle. Paediatr Perinat Epidemiol 2007; 21 Suppl 1: 3135.CrossRefGoogle ScholarPubMed
47Saftlas, A, Wang, W, Risch, H, Woolson, R, Hsu, C, Bracken, M. Prepregnancy body mass index and gestational weight gain as risk factors for preeclampsia and transient hypertension. Ann Epidemiol 2000; 10: 475.CrossRefGoogle ScholarPubMed
48Hrazdilova, O, Unzeitig, V, Znojil, V. Relationship of age and the body mass index to selected hypertensive complications in pregnancy. Int J Gynaecol Obstet 2001; 75: 165–69.CrossRefGoogle ScholarPubMed
49Skaznik-Wikiel, M, Czajkowski, K, Kugaudo, M, Teliga-Czajkowska, J. Assessment of pregnancy and aged 35 and older. Ginekol Pol 2003, 74: 607–11.Google ScholarPubMed
50Demir, SC, Kadyyfcy, O, Ozgunen, T, Evruke, C, Vardar, MA, Karaca, A et al. Pregnancy outcomes in young Turkish women. J Pediatr Adolesc Gynecol 2000; 13: 177–81.CrossRefGoogle ScholarPubMed
51Brown, MA, Buddle, ML. Inadequacy of dipstick proteinuria in hypertensive pregnancy. Aust N Z J Obstet Gynaecol 1995; 35: 366–69.CrossRefGoogle ScholarPubMed
52Jonsdottir, LS, Arnsgrimsson, R, Geirsson, RT, Sigvaldson, H, Sigfusson, N. Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 1995; 74: 772–76.CrossRefGoogle ScholarPubMed
53Broughton Pipkin, F. Risk factors for preeclampsia. N Engl J Med 2001; 12: 925–26.CrossRefGoogle Scholar
54Cundy, T, Slee, F, Gamble, G, Neale, L. Hypertensive disorders of pregnancy in women with Type 1 and Type 2 diabetes. Diabet Med 2002; 19: 482–89.CrossRefGoogle ScholarPubMed
55O'Brien, M, Dausset, J, Carosella, ED, Moreau, P. Analysis of the role of HLA-G in preeclampsia. Human Immunol 2000; 61: 1126–131.CrossRefGoogle ScholarPubMed
56Lie, RT, Rasmussen, S, Brunborg, H, Gjessing, HK, Lie-Nielson, E, Irgens, LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998; 316: 1343–347.CrossRefGoogle ScholarPubMed
57Esplin, MS, Fausett, MB, Fraser, A, Kerber, R, Mineau, G, Carrillo, J et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001; 344: 867–72.CrossRefGoogle ScholarPubMed
58Lockwood, CJ. Heritable coagulopathies in pregnancy. Obstet Gynecol Surv 1999; 54: 754–65.CrossRefGoogle ScholarPubMed
59Broughton-Pipkin, F, Roberts, JM. Hypertension in pregnancy. J Hum Hypertens 2000; 14: 705–24.CrossRefGoogle ScholarPubMed
60Shen, Y, Jiang, X. Pre-pregnancy high risk factors in pregnancy-induced hypertension. Foreign Med Sci 2005; 16: 7678.Google Scholar
61Barton, JR, Sibai, BM. Prediction and Prevention of Recurrent preeclampsia. Obstet Gynecol 2008; 112: 359–72.CrossRefGoogle ScholarPubMed
62Fiore, G, Capasso, A. Effects of vitamin E and C on placental oxidative stress: an in vitro evidence for the potential therapeutic or prophylactic treatment of preeclampsia. Med Chem 2008; 4: 526–30.CrossRefGoogle ScholarPubMed
63Kontic-Vucinic, O, Terzic, M, Radunovic, N. The role of antioxidant vitamins in hypertensive disorders of pregnancy. J Perinat Med 2008; 36: 282–90.CrossRefGoogle ScholarPubMed
64James, AH, Brancazio, LR, Price, T. Aspirin and reproductive outcomes. Obstet Gynecol Surv 2008; 63: 4957.CrossRefGoogle ScholarPubMed
65Trumbo, PR, Ellwood, KC. Supplemental calcium and risk reduction of hypertension, pregnancy-induced hypertension,and preeclampsia: an evidence-based review by the US Food and Drug Administration. Nutr Rev 2007; 65: 7887.CrossRefGoogle ScholarPubMed
66Briceño-Pérez, C, Briceño-Sanabria, L, Vigil-De Gracia, P. Prediction and prevention of preeclampsia. Hypertens Pregnancy 2009; 28: 138–55.CrossRefGoogle ScholarPubMed
67Duley, L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33: 130–37.CrossRefGoogle ScholarPubMed
68Roelands, J, Jamison, MG, Lyerly, AD, James, AH. Consequences of smoking during pregnancy on maternal health. J Womens Health 2009; 18: 867–72.CrossRefGoogle ScholarPubMed
69Engel, SM, Janevic, TM, Stein, CR, Savitz, DA. Maternal smoking, preeclampsia, and infant health outcomes in New York City, 1995–2003. Am J Epidemiol 2009; 169: 3340.CrossRefGoogle ScholarPubMed
70Wen, SW, Chen, XK, Rodger, M, White, RR, Yang, Q, Smith, GN et al. Folic acid supplementation in early second trimester and the risk of preeclampsia. Am J Obstet Gynecol 2008; 198: 45.e17.CrossRefGoogle ScholarPubMed
71Subar, AF, Block, G, James, LD. Folate intake and food sources in the US population. Am J Clin Nutr 1989; 50: 508–16.CrossRefGoogle ScholarPubMed
72Ulrich, CM, Reed, CM, and Nijhout, HF. Modeling folate, one-carbon metabolism, and DNA methylation. Nut Rev 2008; 66 (Suppl.1): S27S30.CrossRefGoogle ScholarPubMed
73Vollset, SE, Refsum, H, Irgens, LM, Emblem, BM, Tverdal, A, Gjessing, HK et al. , Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes. The Hordaland Homocysteine Study. Am J Clin Nutr 2000; 71: 962–68.CrossRefGoogle ScholarPubMed
74Dekker, GA, De Vries, JIP, Doelitzsch, PM, Huijgens, PC, Von Blomberg, BU, Jakobs, C et al. , Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995; 173: 1042–48.CrossRefGoogle ScholarPubMed
75Kupfermic, MJ, Eldor, A, Steinman, N, Many, A, Bar-Am, A, Jaffa, A et al. , Increased frequency of genetic thrombophilias in women with complications of pregnancy. N Engl J Med 1999; 340: 913.CrossRefGoogle Scholar
76Hogg, BB, Tamura, T, Johnston, KE, Dubard, MB, Goldenberg, RL. Second-trimester plasma homocysteine levels and pregnancyinduced hypertension, preeclampsia, and intrauterine growth restriction. Am J Obstet Gynecol 2000; 183: 805809.CrossRefGoogle ScholarPubMed
77Powers, R, Evans, R, Majors, A, Ojimba, J, Ness, R, Grombleholme, W et al. , Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol 1998; 179: 1605–11.CrossRefGoogle ScholarPubMed
78Laivuori, H, Risto, KAAJA, Turpeinen, U, Viinikka, L, Ylikorkala, O. Plasma homocysteine levels elevated and inversely related toinsulin sensitivity in eeclampsia. Obstet Gynecol 1999; 93: 489–93.Google Scholar
79De la Calle, M. Hiperhomocisteinemia asociada a preeclampsia. Actualidad Obste´trico Ginecoo´gica 2000; 5: 243–45.Google Scholar
80Refsum, H, Ueland, PM, Nygard, O, Vollset, SE. Homocysteine and cardiovascular disease. Ann Rev Med 1998; 49: 3162.CrossRefGoogle ScholarPubMed
81Leeda, M, Riyazi, N, De Vries, J, Jakobs, C, Van Geijn, H, Dekker, G. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998; 179: 135–39.CrossRefGoogle ScholarPubMed
82De Vries, JIP, Dekker, GA, Huijgens, PC, Jakobs, C, Blomberg, BME, van Geijn, HP. Hyperhomocysteinemia and protein S deficiency in complicated pregnancies. Brit J Obstet Gynecol 1997; 104: 1248–254.CrossRefGoogle Scholar
83Kang, SS, Wong, PW, Malinow, MR. Homocysteinemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 1992; 12: 279–98.CrossRefGoogle Scholar
84Cararach, V, Bellart, J, Comino, R, Gratacos, E, Iglesias, M, Perales, A et al. , Documentos de Consenso SEGO. Grupo estados hipertensivos del embarazo. SEGO 1998; 45–78.Google Scholar
85De la Calle, M. Hiperhomocisteinemia y preeclampsia. Doctoral Thesis Madrid 2000.Google Scholar
86Sibai, BM. Thrombophilias and adverse outcomes of pregnancy. What should a clinician do? New Engl J Med 1999; 340: 5051.CrossRefGoogle Scholar
87Rajkovic, A, Catalano, PM, Malinow, MR. Elevated homocysteine levels with preeclampsia. Obstet Gynecol 1997; 90: 168–71.CrossRefGoogle ScholarPubMed
88Yang, YS, Song, HD, Li, RY, Zhou, LB, Zhu, ZD, Hu, RM et al. The gene expression profiling of human visceral adipose tissue and its secretory function. Biochem Biophys Res Commun 2003; 300: 839–46.CrossRefGoogle Scholar
89Van der Put, NMJ, Steegers-Theunissen, RPM, Frosst, P et al. , Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: 10701071.CrossRefGoogle ScholarPubMed
90Van der Put, NMJ, Van den Heuvel, LP, Steegers-Theunissen, RPM, Trijbels, FJM, Eskes, TKAB, Mariman, ECM et al. Decreased methylenetetrahydrofolate reductase activity due to the 677C! T mutation in families with spina bifida offspring. J Mol Med 1996; 74: 691–94.CrossRefGoogle Scholar
91Whitehead, AS, Gallagher, P, Mills, JL, Whitehead, AS, Gallagher, P, Mills, JL et al. , A genetic defect in 5,10-methylenetetrahydrofolate reductase in neural tube defects. Q J Med 1995; 88: 763–66.Google ScholarPubMed
92Ou, CY, Stevenson, RF, Brown, VK, Schwartz, CE, Allen, WP, Khoury, M et al. C677T homozygosity associated with thermolabile 5,10-methylenetetrahydrofolate reductase as a risk factor for neural tube defects. Am J Hum Genet 1995; 57 (suppl): A223.Google Scholar
93Shields, DC, Kirke, PN, Mills, JL, Ramsbottom, D, Molloy, AM, Burke, H et al. The thermolabilevariant of methylenetetrahydrofolate reductase and neural tube defects: an evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet 1999; 64: 1045–55.CrossRefGoogle ScholarPubMed
94Frosst, P, Blom, HJ, Milos, R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 1995; 10: 111–13.CrossRefGoogle ScholarPubMed
95Nelen, WL, Steegers, EA, Eskes, TK, Blom, HJ. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997; 350: 861.CrossRefGoogle ScholarPubMed
96Van der Put, NMY, Gabreels, F, Stevens, EMB. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 1998; 62: 1044–51.CrossRefGoogle ScholarPubMed
97Van der Molen, EF, Arends, GE, Nelen, WL, Van der Put, NJ, Heil, SG, Eskes, TK et al. , A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 2000; 182: 1258–63.CrossRefGoogle ScholarPubMed
98Grandone, E, Margaglione, M, Colaizzo, D, Cappucci, G, Paladini, D, Martinelli, P et al. , C > T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77: 1052–54.Google Scholar
99Sohda, S, Arinami, T, Hamada, H, Yamada, N, Hamaguchi, H, Kubo, T. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J Med Genet 1997; 34: 525–26.CrossRefGoogle ScholarPubMed
100Kim, YJ, Williamson, RA, Murray, JC, Andrews, J, Pietscher, JJ, Peraud, PJ et al. , Genetic susceptibility to preeclampsia: roles of cytosine tothymine substitution at nucleotide 677 of the gene for methylene tetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation. Am J Obstet Gynecol 2001; 184: 1211–217.CrossRefGoogle Scholar
101Powers, RW, Minich, LA, Lykins, DL, Ness, RB, Crombleholme, WR, Roberts, JM. Methylenetetrahydrofolate reductase polymorphism, folate, and susceptibility to preeclampsia. J Soc Gynecol Invest 1999; 6: 7479.CrossRefGoogle ScholarPubMed
102Laivuori, H, Kaaja, R, Ylikorkala, O, Hiltunen, T, Kontula, K. 677 C/T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia. Obstet Gynecol 2000; 96: 277–80.Google Scholar
103Prasmusinto, D, Skrablin, S, Hofstaetter, C, Fimmers, R, van der Ven, K. The methylenetetrahydrofolate reductase 677 C/T polymorphism and preeclampsia in two populations. Obstet Gynecol 2002; 99: 1085–92.Google Scholar
104Van der Put, NMY, Gabreels, F, Stevens, EMB. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 1998; 62: 1044–51.CrossRefGoogle ScholarPubMed
105Kaiser, T, Brennecke, SP, Moses, EK. C677T methylenetetrahydrofolate reductase polymorphism is not a risk factor for pre-eclampsia/eclampsia among Australian women. Hum Hered 2001; 51: 2022.CrossRefGoogle Scholar
106Lachmeijer, AM, Arngrimsson, R, Bastians, WJ, Pals, G, Ten, LP, de Vries, JI. Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia. Am J Obstet Gynecol 2001; 184: 394402.CrossRefGoogle ScholarPubMed
107Also-Rallo, E, Lopez-Quesada, E, Urreiztia, R, Vilaseca, MA, Lailla, JM, Balcells, S, Grinberg, D et al. Polymorphisms of genes involved in homocysteine metabolism in preeclampsia and in uncomplicated pregnancies. Eur J Obstet Gynecol Reprod Biol 2005; 120: 4552.CrossRefGoogle ScholarPubMed
108Raijmakers, MT, Zusterzeel, PL, Steegers, EA, Peters, WH. Hyperhomocysteinaemia: a risk factor for preeclampsia? Eur J Obstet Gynecol Reprod Biol 2001; 95: 226–28.CrossRefGoogle ScholarPubMed
109Sebastio, G, Sperandeo, MP, Panico, M, Gtsnvhid, T, Kraus, JP, Andria, G. The molecular basis of homocystinuria due to cystathionine betasynthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet 1995; 56: 1324–333.Google ScholarPubMed
110Tsai, MY, Bignell, M, Yang, F, Welge, BG, Graham, Kj. Hanson NQ. Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels. Atherosclerosis 2000; 149: 131137.CrossRefGoogle Scholar
111Doolin, MT, Barbaux, S, McDonnell, M, Hoess, K, Whitehead, AS, Mitchell, LE. Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet 2002; 71: 1222–226.CrossRefGoogle ScholarPubMed
112Wilson, A, Platt, R, Wu, Q, Lecklerc, D, Christensen, B, Yang, H et al. , A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Gen Metab 1999; 67: 317–23.CrossRefGoogle ScholarPubMed
113Merchant, AT, Msamanga, G, Villamor, E, Saathoff, E, O'brien, M, Hertzmark, E et al. Multivitamin supplementation of HIV-positive women during pregnancy reduces hypertension. J Nutr 2005; 135: 1776–781.CrossRefGoogle ScholarPubMed
114Bodnar, LM, Tang, G, Ness, RB, Harger, G, Roberts, JM. Periconceptional multivitamin use reduces the risk of preeclampsia. Am J Epidemiol 2006; 164: 470–77.CrossRefGoogle ScholarPubMed
115Hernandez-Diaz, S, Werler, MM, Louik, C, Mitchell, AA. Risk of gestational hypertension in relation to folic acid supplementation during pregnancy. Am J Epidemiol 2002; 156: 806–12.CrossRefGoogle ScholarPubMed
116Poston, L, Briley, AL, Seed, PT, Kelly, FJ, Shennan, AH; Vitamins in Pre-eclampsia (VIP) Trial Consortium. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145–154.CrossRefGoogle ScholarPubMed
117Rumbold, AR, Crowther, CA, Haslam, RR, Dekker, GA, Robinson, JS; ACTS Study Group. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006; 354: 1796–806.CrossRefGoogle Scholar
118Wilson, RD, Johnson, JA, Wyatt, P, Allen, V, Gagnon, A, Langlois, S et al. Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada and The Motherrisk Program. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 2007; 29: 1003–26.CrossRefGoogle Scholar
119Health Canada. Nutrition for a healthy pregnancy: Guideline for the Childbearing Years. 1999. Ottawa: Minister of Public Works and Government Services Canada.Google Scholar
120Czeizel, AE, Tomcsik, M. Acute toxicity of folic acid in pregnant women. Teratology 1999; 60: 34.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
121Czeizel, AE, Métneki, J, Dudás, I. Higher rate of multiple births after periconceptional vitamin supplemenation. N Engl J Med 1994; 23: 1687–688.CrossRefGoogle Scholar
122Bønaa, KH, Njølstad, I, Ueland, PM, Schirmer, H, Tverdal, A, Steigen, T et al. , NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 157888.CrossRefGoogle Scholar
123Lonn, E, Yusuf, S, Arnold, MJ, Sheridan, P, Pogue, J, Micks, M et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567–77.Google Scholar
124Cole, BF, Baron, JA, Sandler, RS, Haile, RW, Ahnen, DJ, Bresalier, RS et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297: 2351–359.CrossRefGoogle ScholarPubMed
125Charles, D, Ness, AR, Campbell, D, Davey Smith, G, Hall, MH. Taking folate in pregnancy and risk of maternal breast cancer. BMJ 2004; 329: 1375–376.CrossRefGoogle ScholarPubMed
126Oakley, GP, Mandel, JS. Folic acid fortification remains an urgent health priority. BMJ 2004; 329: 1375–376.CrossRefGoogle ScholarPubMed
127Larsson, SC, Giovannucci, E, Wolk, A. Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 2007; 99: 6476.CrossRefGoogle ScholarPubMed
128Braekke, K, Ueland, PM, Harsem, NK, Karlsen, A, Blomhoff, R, and Staff, AC. Homocysteine, Cysteine, and Related Metabolites in Maternal and Fetal Plasma in Preeclampsia. Ped Res 2007; 62: 319–24.CrossRefGoogle ScholarPubMed
129Antoniades, C, Shirodaria, C, Warrick, N, Cai, S, de Bono, J, Lee, J. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006; 114: 1193–201.CrossRefGoogle ScholarPubMed
130Brown, KS, Huang, Y, Lu, ZY, Jian, W, Blair, IA, Whitehead, AS. Mild folate deficiency induces a proatherosclerotic phenotype in endothelial cells. Atherosclerosis 2006; 189: 133–41.CrossRefGoogle ScholarPubMed
131MacKenzie, KE, Wiltshire, EJ, Gent, R, Hirte, C, Piotto, L, Couper, JJ. Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics 2006; 118: 242–53.CrossRefGoogle ScholarPubMed
132Title, LM, Giddens, K, Ur, E. Folic acid improves endothelial dysfunction in type 2 diabetes-an effect independent of homocysteine-lowering. Vasc Med 2006; 11: 101109.CrossRefGoogle ScholarPubMed
133Graham, IM, Daly, LE, Refsum, HM, Robinson, K, Brattsrom, LE, Ueland, PM et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997; 277: 1775–781.CrossRefGoogle ScholarPubMed
134Ray, JG, Laskin, CA. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review. Placenta 1999; 20: 519–29.CrossRefGoogle ScholarPubMed
135Ashworth, JR, Warren, AY, Johnson, IR, Baker, PN. Plasma from pre-eclamptic women and functional change in myometrial resistance arteri. Br J Obstet Gynecol 1998; 105: 459–61.CrossRefGoogle Scholar
136Roberts, JM, Taylor, RM, Goldfein, A. Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens 1991; 4: 700708.CrossRefGoogle ScholarPubMed
137Bernasconi, AR, Liste, A, Del Pino, N, Rosa Diez, GJ, Heguilén, RM. Folic acid 5 or 15 mg/d similarly reduces plasma homocysteine in patients with moderate-advanced chronic renal failure. Nephrology 2006; 11: 137–41.CrossRefGoogle ScholarPubMed
138Chuang, CZ, Boyles, A, Legardeur, B, Su, J, Japa, S, Lopez-S, A. Effects of riboflavin and folic acid supplementation on plasma homocysteine levels in healthy subjects. Am J Med Sci 2006; 331: 6571.CrossRefGoogle ScholarPubMed
139Olthof, MR, Bots, ML, Katan, MB, Verhoef, P. Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers. PLoS Clin Trials 2006; 1: e10.CrossRefGoogle ScholarPubMed