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REVIEWS |
From the *Division of Reproductive and Child Health, Birmingham Women's Hospital, University of Birmingham, Birmingham, United Kingdom; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland; and Centro Rosarino de Estudios Perinatales (CREP), WHO Collaborative Center in Maternal and Child Health, Rosario 2000, Argentina.
Address reprint requests to: Luciano E. Mignini, Department of Obstetrics and Gynaecology, Birmingham Women's Health Care NHS Trust, B15 2TG, Birmingham, UK; e-mail: L.Mignini{at}bham.ac.uk.
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ABSTRACT |
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DATA SOURCES: We searched MEDLINE, EMBASE, BIOSIS, SciSearch, and bibliographies of primary and review articles, and we contacted experts.
METHODS OF STUDY SELECTION: Of the 25 relevant primary articles, 8 studies measured total serum homocysteine concentrations before the clinical onset of preeclampsia (1,876 women), whereas 17 measured it afterward (1,773 women). Meta-analytic techniques were used to examine consistency, strength, temporality, dose-response, and plausibility of the disease mechanisms implicating folate, vitamin B6, vitamin B12, genetic polymorphisms, oxidative stress, and endothelial dysfunction in the pathway linking hyperhomocysteinemia to preeclampsia.
TABULATION, INTEGRATION, AND RESULTS: Overall, there were higher serum homocysteine concentrations among pregnant women with preeclampsia than among those with uncomplicated pregnancies, but the results were heterogeneous (P = .12; I2 = 38.8%). Among studies with temporality, the size of association was smaller than that among those without (weighted mean difference 0.68 µmol/L versus 3.36 µmol/L; P < .006). There was no dose-response relationship between homocysteine concentration and severity of preeclampsia. The mechanisms underlying hyperhomocysteinemia (folate and vitamin B12 deficiency and genetic polymorphisms) were not found to be plausible, but markers of oxidative stress and endothelial dysfunction were higher in hyperhomocysteinemia.
CONCLUSION: Homocysteine concentrations are slightly increased in normotensive pregnancies that later develop preeclampsia and are considerably increased once preeclampsia is established. However, because of a lack of consistency in data, dose-response relationship, and biologic plausibility, the observed association cannot be considered causal from the current literature.
Some studies examining the relationship between serum homocysteine concentrations and preeclampsia have demonstrated,6,13,15–17 while others have refuted, an association.10,18,19 This may be due to differences in study designs, laboratory techniques, and disease definitions, among other reasons, which may be explored through systematic review. A relevant review20 summarized findings from only 2 studies.6,21 Because of the scarcity of evidence, lack of evaluation of temporal relationship, study quality, and biologic plausibility, it could not examine causality. More fundamentally, the hypothesized mechanisms of disease linking homocysteine to preeclampsia have not been established.
Because more studies have recently been published, we systematically reviewed the evidence to examine whether the link between serum homocysteine concentrations and preeclampsia meets causal criteria.22,23 This is part of the World Health Organization (WHO) Global Programme to Conquer Preeclampsia,24 in which hypothesized disease mechanisms are evaluated to select the most promising theories for concentrating preventive research efforts.
Our review protocol was designed to examine the hypothesized mechanism linking hyperhomocysteinemia to preeclampsia by using recommended methods for assessing causal association (using Hill's Criteria)22,23,25,26 and by conducting systematic reviews.
Figure 1 shows the biologic pathways by which homocysteine might cause preeclampsia. Homocysteine may be irreversibly transsulfurated to cysteine by the enzyme cystathionine ß-synthase, which requires vitamin B6 as a cofactor. Alternatively, it can be remethylated into methionine, and the required methyl group is then obtained from betaine or from 5-methyltetrahydrofolate, utilizing several enzymes where folate is required as a cosubstrate and vitamin B12 is required as a cofactor for the enzyme methionine synthase.29 If homocysteine is not metabolized to cysteine or methionine, it enters the bloodstream where most of it circulates in a protein-bound form.30,31 In such a scenario, mutations in regulatory genes, alterations of enzymes, and deficiencies of vitamins B6, B12, or folic acid may result in higher concentrations of homocysteine.32 The mechanism by which hyperhomocysteinemia participates in the pathogenesis of preeclampsia is complex and is still incompletely understood.10 It may be mediated through oxidative stress mechanisms33,34 or through direct damage to the vascular endothelium.
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The hypotheses developed above (Fig. 1) were tested in a systematic review that examined the consistency and strength of the association between homocysteine and preeclampsia. Using meta-analytic techniques, we assessed temporality of association, dose-response relationship, and biologic plausibility. We examined hypotheses implicating folate, vitamin B12, vitamin B6, genetic polymorphisms, oxidative stress, and endothelial dysfunction in the biologic pathway linking hyperhomocysteinemia to preeclampsia.
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STUDY SELECTION |
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Studies were selected in 2 stages. Initially, 2 of the authors (L.E.M. and P.M.L.) independently scrutinized the electronic searches and obtained the manuscripts of all citations that appeared to meet our predefined selection criteria. Inclusion or exclusion decisions were made only after examination of the manuscripts. Where multiple analyses from a single study were published separately, we used the latest publication for results and supplemented this with information on study characteristics and quality from earlier publications if necessary. Two authors (L.E.M. and P.M.L.) independently assessed all English language manuscripts, while articles in other languages were assessed by people familiar with the language under the supervision of L.E.M. Disagreements about inclusion or exclusion were resolved by consensus or arbitration through a third reviewer (K.S.K.).
Extracted data included demographic information (age, parity, gestational age when test was performed, serum folate, betaine, vitamin B6 and B12 concentrations, genetic polymorphisms, record of vitamin or folate supplementation), measurement of homocysteine (fasting or not, adequate handling of the sample, biochemical test used, adequate description of the methods used, blinding of laboratory analyst, coefficient of variation between the studies), and definition of preeclampsia.
Definitions of preeclampsia have always been problematical in study comparisons and are the basis of considerable confusion in the literature. The ideal definition, and that used in recent consensus documents,35 is the combination of de novo hypertension (blood pressure 
140 mm Hg systolic and/or 90 mm Hg diastolic, respectively, in a previously normotensive woman after 20 weeks of gestation) and proteinuria (urinary excretion of > 0.3 gm/24 h or > 2+ by urinary dipstick). However, since various other definitions were used in the studies selected for the analysis, a broad range of definitions was allowed, with a view to performing a stratified analysis.
Mean homocysteine concentrations and their standard deviations (SD) were expressed as micromoles per liter, and when no SD was reported, attempts were made to contact the investigators, and if unsuccessful, the value was estimated by standard techniques.36 Data on mean folate and vitamin B12 concentrations and their SDs were expressed as nanomoles per liter and picomoles per liter, respectively, and failure to report SDs were handled as described above. Finally, we extracted data to evaluate the association of oxidative stress and endothelial dysfunction with hyperhomocysteinemia. We evaluated the data extraction form for repeatability on the first 8 manuscripts, and all data were extracted in duplicate. Overall, the observer agreement regarding the various components of the data extraction form was 90–100%.
Estimates of homocysteine concentrations can vary according to validity of measurement procedures of total homocysteine.37 Therefore, all the steps in the procedure, from the time the sample was taken from the patient to the end of the measurement process itself, were carefully recorded. Other determinants sought were prandial status (eg, time elapsed since previous meal). However, because there is debate in the literature about whether the prandial state influences the circulating levels,38,39 we noted whether the fasting state was reported.
An important methodological concern relates to the continuing release of homocysteine by red blood cells after venipuncture, which may cause an artificial increase in serum concentration of 10% per hour.40,41 To avoid such spurious elevations, blood should be collected into chilled tubes containing ethylenediaminetetraacetic acid (EDTA) and placed on ice immediately after collection, and the serum be separated from the red cells within 1 hour.42 Using such procedures the serum homocysteine will remain stable for at least 24 hours at room temperature and for several years when stored frozen.41
The methods used among the studies to determine total homocysteine concentrations were variable and include high pressure liquid chromatography with electrochemical detection, high pressure liquid chromatography with fluorescence detection further subdivided by type of reducing/derivatizing agent, gas chromatography/mass spectrometry, enzyme immunoassay, and fluorescence polarization immunoassay.
The coefficient of interassay variation (CVa) has also been a matter of concern, because various degrees of imprecision and lack of correlation among serum plasma homocysteine methods have been demonstrated. Although there are some differences between these, we considered these methods interchangeable for performing a stratified analysis. Finally, blinding the laboratory personnel to the patient's disease status to minimize bias that might lead to measurement errors was also taken into consideration.46
Quality was defined as the degree to which primary investigators sought to minimize biases and errors in their protocol design, as well as its conduct and analysis.47 This is important per se in systematic reviews, but fundamentally quality is important in assessing causality because observed associations in biased research are not trustworthy. The quality items used were based on existing epidemiological principles26,27,48,49 and checklists.49 They included 1) cohort design, 2) adequate recruitment of subjects, 3) adequate definition of preeclampsia (see above), 4) adequate ascertainment of blood homocysteine concentration (see below), 5) blinding of clinicians to serum homocysteine concentrations, 6) a priori sample size estimation or power analysis, 7) control for confounding variables in analysis, and 8) correct temporality of the association, ie, serum sampling for homocysteine measurements before the clinical onset of preeclampsia.
Homocysteine determination was considered adequate (an arbitrary dichotomy to allow meta-regression) when at least 3 of the following 5 items were addressed in the study: recording whether blood was obtained in a fasting or nonfasting state, adherence to appropriate sample preparation and storage guidelines, use of sensitive and specific assays and completeness of their description,50 blinding of laboratory personnel, and whether CVa between the samples were reported. Two authors (L.E.M. and P.M.L.) independently assessed the studies for quality, and in cases of disagreement, used, when necessary, a third reviewer (K.S.K.) to arbitrate or to achieve consensus in the manner described above.
The study characteristics, quality, and results were stratified according to temporality of the association between homocysteine measurements and onset of preeclampsia. A mean difference and the 95% confidence intervals (CI) were computed in each study, and heterogeneity between studies was assessed qualitatively by using a forest plot (a graphical display of individual effects and CIs observed in studies included)47 and statistically by using 
2 and I2, a test that measures the degree of inconsistency across studies in a meta-analysis on a scale ranging from 0% to 100%.51,52 This permitted testing for consistency of association.26 Pooling of several individual results in meta-analysis (fixed- or random-effects models, as appropriate)53 produced weighted mean difference, an effect measure that assesses the strength of the overall association of total homocysteine concentration with preeclampsia. We were particularly interested in exploring whether the association was consistent and strong among studies with temporality.
In case of heterogeneity, we planned to look for possible explanatory factors using meta-regression analysis.54 We assessed for the effect of various factors by univariable analysis followed by multivariable analysis, an approach that has limited power when the number of studies is small.55 This would permit a statistical examination of whether the individual mean differences varied according to temporality of association, disease severity, dietary folate supplementation, gestational age at sample collection, quality of the studies, and type or quality of the laboratory methods. Here, the weighted mean difference was the dependent variable, and the analysis was weighted according to the inverse of its variance. The independent variables were dichotomous (yes/no), with unreported being classified as "no." Following a thorough exploration for heterogeneity, if no cause could be pinpointed, we considered use of meta-analysis very carefully.56 If there were unexplained heterogeneity (I2 > 50%)52 in subgroups, we used a random-effects model, which produces wider CIs than a fixed-effects model, and we interpreted these pooled estimates cautiously. A meta-regression for dose-response relationship was used to determine whether the mean difference was larger among studies with severe preeclampsia as the outcome compared with those studying all forms of the disorder.
Whether or not there was a biologically plausible association among hyperhomocysteinemia, preeclampsia, and the purported disease mechanisms (folate, vitamin B6, B12, genetics polymorphisms, oxidative stress, and endothelial dysfunction) was studied by reviewing the literature while restricting the analyses to studies with temporality. Meta-analysis was applied when appropriate.26 When rates were available, the odds ratio (OR) was used as a measure, and when continuous data with different units were available, the standardized mean difference, the difference between 2 means divided by an estimate of the within-group standard deviation, was used. Because there is controversy about normal ranges for homocysteine during pregnancy, we pooled mean values from healthy pregnant women included in the control groups to produce ranges for various trimesters of pregnancy generating CIs by bootstrap.57 Finally, funnel plot analysis between sample size and mean differences between preeclamptic and nonpreeclamptic women were used to explore for publication and related biases, using Egger test for asymmetry.54
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The mean concentration of homocysteine in first65 and second trimesters18,19,58–60,74,78 during normal pregnancy was 6.0 µmol/L (95% CI 5.0–7.0) compared with 7.2 µmol/L (95% CI 5.7–8.7) among pregnant women who developed preeclampsia. The mean concentrations in the third trimester6,19,21,60–64,67,68,71–73,77 were 7.1 µmol/L (95% CI 5.4–8.8) and 10.9 µmol/L (95% CI 9.4–12.3) in normal pregnant women and preeclamptic patients, respectively. In 2 studies19,60 total serum homocysteine concentrations were assessed serially. The point estimates of all studies except one62 showed an association between homocysteine concentration and preeclampsia (Fig. 4). Pooling of results, overall, showed that the weighted mean difference was 2.50 µmol/L (95% CI 1.82–3.17, P < .001). However, there was severe statistical heterogeneity of effects overall (I2 = 97.6%) but mostly due to studies without temporality (I2 = 98.3%). Among studies with temporality of association, the P value of the test for heterogeneity was P = .12, but there was moderate inconsistency (I2 = 38.8%). The association remained statistically significant among studies with temporality, although with a much lower effect size than that in studies without temporality, an interaction that was statistically significant (P = .006). The reasons for heterogeneity among results of studies included when explored by meta-regression analysis52,55 showed that dietary folate supplementation, gestational age at sample collection, quality of the studies, and type or quality of the laboratory methods did not affect the observed association (data not shown). Among studies with temporality of association, the mean difference in homocysteine was higher among studies with severe preeclampsia (weighted mean difference 1.42 µmol/L, 95% CI 0.53–2.30) compared with those with mild preeclampsia (weighted mean difference 0.60 µmol/L, 95% 0.30–0.89), but this biologic gradient did not reach statistical significance (P = .14).
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Figure 5 summarizes studies in which the purported etiological factors (folate, B12, and genetic polymorphisms) were evaluated. Folate and vitamin B12 concentrations were lower among pregnant women with preeclampsia than those with normotensive pregnancies, but the differences were not statistically significant (folate weighted mean difference –0.17 nmol/L, 95% CI 1.18–0.85, P = .75; vitamin B12 weighted mean difference –18.87 pmol/L, 95% CI –45.54–7.81, P = .64). As for genetic polymorphisms, only the homozygous TT genotype for the C667T allele of methylenetetrahydrofolate reductase showed a nonsignificant increase in preeclampsia (OR 1.65, 95% CI 0.89–3.06, P = .60).
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Figure 6 summarizes the results of studies assessing disease mechanisms (oxidative stress and endothelial dysfunction) through which hyperhomocysteinemia may lead to preeclampsia. Malondialdehyde, a metabolite of lipid peroxides detectable in serum, a marker of oxidative stress, was measured in 2 studies6,75; glutathione, one of the body's primary defenses against oxidative stress was measured in another study71; and the ratio of reduced-to-oxidized glutathione in whole blood was reported in a third study.70 Overall, there was a significant association between these markers of oxidative stress and preeclampsia (standardized mean difference 1.85, 95% CI 0.31–3.39, P = .02).
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In two studies6,67 higher concentrations of cellular fibronectin (a marker of endothelial dysfunction) were present in women with preeclampsia associated with hyperhomocysteinemia compared with pregnant women without preeclampsia. Moreover, in another study,76 nitric oxide levels were determined as a measure of endothelial function. Overall, there was a significant association of endothelial function and preeclampsia (standardized mean difference 1.41, 95% CI 0.39–2.44, P = .007).
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The strength of our inference depends on the rigor of the review methods employed. We used quantitative estimates of heterogeneity based on I252 and meta-regression to explore heterogeneity. Assessment of the consistency of effects across studies is an essential part of meta-analysis, because inconsistency (heterogeneity) of the studies’ results has an impact on recommendations.55 The heterogeneity observed in our analyses could also be due to interlaboratory differences not captured by our assessment, to differences in markers used to estimate oxidative stress and endothelial dysfunction, or to different definitions of preeclampsia. Moreover, because of limitations of study-level data, the influence by several factors, such us cigarette smoking and coffee consumption, could not be assessed. Despite these limitations, our review complied with recommended methods for systematic reviews27,28 and the available advice on reviews of biologic plausibility.23 Therefore, we are confident that our inference concerning the lack of a causal association between homocysteine and preeclampsia in the current literature is valid.
Efforts in preeclampsia prevention have been disappointing to date. Our review raises questions about the way in which the role of homocysteine in the etiology and/or pathophysiology of preeclampsia has been evaluated and disseminated. Current conclusions seem to have emanated from single or selected investigations without taking advantage of the power of systematic review. The many examples of discordance between basic science and clinical trials highlight the fact that investment in trials might be wasteful without first understanding basic mechanisms. It is clear that, in the process of developing clinical trials, existing research regarding basic science and theory of etiopathogenesis should be rigorously assessed.
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Footnotes |
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Received June 26, 2004. Received in revised form September 14, 2004. Accepted September 29, 2004.
doi:10.1097/01.AOG.0000151117.52952.b6
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