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Homocysteine and folate in pregnancy.

The importance of folate during pregnancy was addressed 40 years ago by Bryan Hibbard (1) in his study of folate status in 1484 low-income obstetric patients from Liverpool. He assessed folate status as urinary excretion of formiminoglutamic acid. Abnormal formiminoglutamic acid excretion was related not only to placental abruption and spontaneous abortion but also to adverse outcomes in previous pregnancies, including prematurity, congenital defects, and perinatal mortality. Shortly thereafter, Hibbard and Smithells (2) suggested that folate deficiency in pregnancy may be related to central nervous system malformations, and Smithells started a series of observational and intervention studies demonstrating that adequate folate status reduced the risk of neural tube defects (NTDs), observations that eventually in the early 1990s were confirmed in large, randomized intervention trials (3, 4).

It is now established that periconceptional folate supplementation reduces the occurrence and recurrence of NTDs (3,4). The results obtained in many observational studies suggest that low folate intake or low circulating folate increases the risk of preterm delivery and low birth weight (5). However, a recent Dutch study on several B vitamins measured before and during pregnancy in healthy, well-nourished women demonstrated no association between the vitamin concentrations and birth weight or risk of early pregnancy loss (6). The results from randomized intervention trials with folic acid have been equivocal (5). Thus, the link between maternal folate status and birth weight is uncertain.

The conclusions of the observational studies on vitamins and adverse pregnancy outcomes have been questioned because of methodologic weaknesses. These include inaccurate assessment of vitamin intake, measurement errors attributable to variable plasma-volume expansion during pregnancy, and confounders such as drug use and stress, intake of other micronutrients, and energy intake and socioeconomic status (7). In particular, smoking is a potential confounder because it is related to poor vitamin status, high total homocysteine (tHcy) (8), and low birth weight (9). Analyses should therefore also be carried out among nonsmokers.

The concentration of tHcy in plasma is a responsive marker of impaired folate status. In 1991, Steegers-Theunissen et al. (10) suggested that maternal hyperhomocysteinemia was a risk factor for NTDs. Subsequent studies demonstrated increased tHcy in mothers of children with NTDs even in the absence of low circulating folate, suggesting a direct adverse effect of homocysteine on the developing fetus (4). Several studies also demonstrated that high tHcy is a risk factor of placenta-mediated diseases, such as preeclampsia, spontaneous abortion, placental abruption, and recurrent pregnancy loss (11-13).

Several malformations and obstetric complications associated with tHcy have been investigated in relation to the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism, which affects intracellular folate distribution and is associated with increased tHcy under conditions of impaired folate status (14). Because genotype, in contrast to vitamin or homocysteine status, is not changed during pregnancy or by pregnancy-related complications, associations with variant genotypes may give clues as to the mechanisms involved. NTDs show a consistent relationship with the MTHFR TT genotype (of both the mother and the baby), suggesting that the TT genotype may predispose to increased tHcy in women with NTD pregnancies and may also partly explain the protective effect of folate supplementation (4,15).

However, the MTHFR 677C>T polymorphism shows a weak or inconsistent association with other pregnancy complications, including placenta-mediated disease, intrauterine growth retardation, and low birth weight (11, 16,17), and the mechanisms involved are unclear. Homocysteine could be directly involved by causing vasculopathy leading to inadequate maternal-fetal circulation. This is in accordance with the observed relationship between high tHcy and defective chorionic villous vascularization in mothers with recurrent early pregnancy loss (18). Alternatively, increased tHcy maybe only a marker of underlying conditions that are directly related to pregnancy complications, such a subclinical vascular disease, reduced glomerular filtration rate (19) (which is inversely associated with tHcy (20), and inadequate plasma-volume expansion (21,22).

Most studies on maternal tHcy and pregnancy complications have measured tHcy near the time of delivery (23,24) or up to years after the index pregnancy (5,13), whereas only a few studies have measured tHcy before or during pregnancy (25-27). This is a possible shortcoming because the time interval between exposure and event may attenuate the association, because the disease itself may affect the tHcy concentration, and because of marked changes in plasma tHcy during pregnancy (16).

Low plasma tHcy during an uncomplicated pregnancy was first demonstrated by Kang et al. (28) almost 20 years ago, and this has subsequently been confirmed by numerous investigators (16). Plasma tHcy concentrations are 30-60% lower in pregnant women than in nonpregnant women, and the lowest tHcy values are observed in the second trimester. In a recent longitudinal study of tHcy during pregnancy, Murphy et al. (29) demonstrated that the reduction cannot be accounted for by folic acid supplementation, plasma-volume expansion, or a decrease in serum albumin. They suggest that low tHcy represents a physiologic adaptation to pregnancy, mediated by endocrine changes. In line with this, it has been speculated whether homocysteine plays a role in regulating hemostasis during pregnancy (16) and myometrial contractility at labor (30).

In this issue of Clinical Chemistry, Murphy et al. (31) present additional analyses of data from their longitudinal study on tHcy in plasma from 93 healthy women, collected 2-10 weeks before conception; at gestational weeks 8, 20, and 32; and immediately before delivery. The novel data presented here show an increase in tHcy from week 32 of gestation, and the tHcy concentration at delivery in mothers not supplemented with folic acid was essentially similar to that measured before conception. Furthermore, maternal tHcy concentrations correlated from preconception throughout pregnancy and at birth, which in turn correlated with tHcy concentrations in cord blood. The concentrations of both maternal and fetal tHcy were lowered by folic acid supplementation. Finally, maternal tHcy at preconception, at 8 weeks, and at birth was inversely related to birth weight. This association was upheld after adjustment for maternal smoking.

As emphasized by the authors (31), the correlation between preconceptional tHcy and tHcy during pregnancy points to the possibility that preconceptional tHcy may predict tHcy-associated pregnancy complications. Large prospective studies are needed to investigate this possibility. It also seems rational that preconceptional tHcy may identify mothers at increased risk of complications and who may benefit from folic acid supplementation, but this idea gains limited support from the equivocal results from the intervention trials with folic acid cited above (5). Finally, the observed lower birth weights in babies of mothers with the highest tHcy agrees with some (13,32-34), but not all (24, 26, 35, 36), published studies and adds to an apparently confusing body of literature on the relationship between maternal tHcy and birth weight or intrauterine growth retardation.

The discrepant results may be related to study design, including the population investigated. The study of Murphy et al. (31) and two other studies reporting an inverse association (34), including a large population-based study of ~6000 mothers (13), investigated birth weight and tHcy in healthy unselected mothers. These studies had a cross-sectional design. Infante-Rivard et al. (24) compared tHcy in 483 mothers (cases) giving birth to babies with birth weights below the 10th percentile with that in 409 mothers with healthy babies (controls). The authors unexpectedly observed lower tHcy among mothers of lowbirth-weight babies. A notable characteristic of this study is that it was carried out in a folate-fortified population, and the overall maternal tHcy was low. Furthermore, tHcy concentrations were measured after birth. Conceivably, nutritional or hemostatic factors that predict severe growth restriction may be different from those that are associated with moderate variability in birth weight.

In conclusion, impaired folate status, the associated high tHcy, and the MTHFR TT genotype are associated with NTDs. The prevention of ~50% of recurrent and first NTDs by folic acid supplementation probably represents one of the most important advances in preventive medicine of the 1990s. Low folate status and hyperhomocysteinemia have been linked to other malformations and pregnancy complications and adverse outcomes, but the direction of causality and the importance are uncertain. Large intervention trials as well as prospective studies measuring tHcy and folate status before and during pregnancy are needed to establish the role of these and related factors as predictors or etiologic factors of adverse pregnancy outcomes and complications.

References

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(2.) Hibbard ED, Smithells RW. Folic acid metabolism and human embryopathy. Lancet 1965;i:1254.

(3.) Botto LID, Moore CA, Khoury MJ, Erickson JD. Neural-tube defects. N Engl J Med 1999;341:1509-19.

(4.) van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ. Folate, homocysteine and neural tube defects: an overview. Exp Biol Med (Maywood) 2001;226: 243-70.

(5.) Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 2000;71:1295S-303S.

(6.) de Weerd S, Steegers-Theunissen RP, de Boo TM, Thomas CM, Steegers EA. Maternal periconceptional biochemical and hematological parameters, vitamin profiles and pregnancy outcome. Eur J Clin Nutr 2003;57:1128-34.

(7.) Kramer MS. The epidemiology of adverse pregnancy outcomes: an overview. J Nutr 2003;133:1592S-6S.

(8.) Vollset SE, Refsum H, Nygard 0, Ueland PM. Life style factors associated with hyperhomocysteinemia. In: Carmel R, Jacobsen DW, eds. Homocysteine in health and disease. Cambridge: Cambridge University Press, 2001:341-455.

(9.) Wilcox AJ. Birth weight and perinatal mortality: the effect of maternal smoking. Am J Epidemiol 1993;137:1098-104.

(10.) Steegers-Theunissen RP, Boers GH, Trijbels FJ, Eskes TK. Neural-tube defects and derangement of homocysteine metabolism. N Engl J Med 1991;324:199-200.

(11.) Ray 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.

(12.) Hague WM. Homocysteine and pregnancy. Best Pract Res Clin Obstet Gynaecol 2003;17:459-69.

(13.) Vollset 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;71:962-8.

(14.) Nelen WLDM, Blom HJ. Pregancy complications. In: Ueland PM, Rozen R, eds. MTHFR polymorphisms and disease. Georgetown, TX: Landes Bioscience/Eurekah.com, 2004.

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(16.) Holmes VA. Changes in haemostasis during normal pregnancy: does homocysteine play a role in maintaining homeostasis? Proc Nutr Soc 2003;62:479-93.

(17.) Nurk E, Tell GS, Refsum H, Ueland PM, Vollset SE. Complications and adverse outcomes of pregnancy and maternal methylenetetrahydrofolate reductase polymorphisms. The Hordaland homocysteine study. Am J Med 2004;in press.

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(19.) Baylis C. Glomerular filtration rate in normal and abnormal pregnancies. Semin Nephrol 1999;19:133-9.

(20.) Wollesen F, Brattstrom L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999;55:1028-35.

(21.) Arias F. Expansion of intravascular volume and fetal outcome in patients with chronic hypertension and pregnancy. Am J Obstet Gynecol 1975;123: 610-6.

(22.) Duvekot JJ, Peeters LL. Renal hemodynamics and volume homeostasis in pregnancy. Obstet Gynecol Surv 1994;49:830-9.

(23.) Rajkovic A, Mahomed K, Malinow MR, Sorenson TK, Woelk GB, Williams MA. Plasma homocyst(e)ine concentrations in eclamptic and preeclamptic African women postpartum. Obstet Gynecol 1999;94:355-60.

(24.) Infante-Rivard C, Rivard GE, Gauthier R, Theoret Y. Unexpected relationship between plasma homocysteine and intrauterine growth restriction. Clin Chem 2003;49:1476-82.

(25.) Sorensen TK, Malinow MR, Williams MA, King IB, Luthy DA. Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest 1999;48:98-103.

(26.) Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, et al. Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am J Clin Nutr 2002;76:1385-91.

(27.) Cotter AM, Molloy AM, Scott JM, Daly SF. Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia. Am J Obstet Gynecol 2003;189:391-4; discussion 4-6.

(28.) Kang SS, Wong PW, Zhou JM, Cook HY. Total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism 1986;35:889-91.

(29.) Murphy MM, Scott JM, McPartlin JM, Fernandez-Ballart JD. The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study. Am J Clin Nutr 2002;76:614-9.

(30.) Ayar A, Celik H, Ozcelik 0, Kelestimur H. Homocysteine-induced enhancement of spontaneous contractions of myometrium isolated from pregnant women. Acta Obstet Gynecol Scand 2003;82:789-93.

(31.) Murphy MM, Scott JM, Arija V, Molloy AM, Fernandez-Ballart JD. Fetal homocysteine and birth weight are affected by maternal homocysteine before conception and throughout pregnancy. Clin Chem 2004;50:140612.

(32.) Burke G, Robinson K, Refsum H, Stuart B, Drumm J, Graham I. Intrauterine growth retardation, perinatal death, and maternal homocysteine levels. N Engl J Med 1992;326:69-70.

(33.) de Vries JI, Dekker GA, Huijgens PC, Jakobs C, Blomberg BM, van Geijn HP. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997;104:1248-54.

(34.) Malinow MR, Rajkovic A, Duell PB, Hess DL, Upson BM. The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism. Am J Obstet Gynecol 1998;178:228-33.

(35.) Hogg BB, Tamura T, Johnston KE, Dubard MB, Goldenberg RL. Secondtrimester plasma homocysteine levels and pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction. Am J Obstet Gynecol 2000;183:805-9.

(36.) D'Anna R, Baviera G, Corrado F, lentile R, Granese D, Stella NC. Plasma homocysteine in early and late pregnancies complicated with preeclampsia and isolated intrauterine growth restriction. Acta Obstet Gynecol Scand 2004;83:155-8.

Per Magne Ueland *

Stein Emil Vollset

LOCUS for Homocysteine and Related Vitamins

University of Bergen

Bergen, Norway

* Address correspondence to this author at: LOCUS for Homocysteine and Related Vitamins, Department of Pharmacology, University of Bergen, N-5021 Bergen, Norway. Fax 47-55-973115; e-mail per.ueland@ikb.uib.no.

DOI: 10.1373/clinchem.2004.035709
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Title Annotation:Editorial
Author:Ueland, Per Magne; Vollset, Stein Emil
Publication:Clinical Chemistry
Date:Aug 1, 2004
Words:2386
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