title: Mapping the theories of preeclampsia: the role of homocysteine.
abstract: OBJECTIVE
  We conducted a systematic review to examine the hypothesized mechanism through which homocysteine could lead to preeclampsia.
  
  
  METHODS
  We searched MEDLINE, EMBASE, BIOSIS, SciSearch, and bibliographies of primary and review articles, and we contacted experts.
  
  
  METHODS
  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 B(6), vitamin B(12), genetic polymorphisms, oxidative stress, and endothelial dysfunction in the pathway linking hyperhomocysteinemia to preeclampsia.
  
  
  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; I(2) = 38.8%). Among studies with temporality, the size of association was smaller than that among those without (weighted mean difference 0.68 mumol/L versus 3.36 mumol/L; P < .006). There was no dose-response relationship between homocysteine concentration and severity of preeclampsia. The mechanisms underlying hyperhomocysteinemia (folate and vitamin B(12) deficiency and genetic polymorphisms) were not found to be plausible, but markers of oxidative stress and endothelial dysfunction were higher in hyperhomocysteinemia.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Reproductive and Child Health, Department of Obstetrics and Gynaecology, Birmingham Women's Hospital, University of Birmingham, Birmingham B15 2TG, United Kingdom. L.Mignini@bham.ac.uk
authors.forename: Luciano E
authors.initials: LE
authors.lastname: Mignini
authors.forename: Pallavi M
authors.initials: PM
authors.lastname: Latthe
authors.forename: Jose
authors.initials: J
authors.lastname: Villar
authors.forename: Mark D
authors.initials: MD
authors.lastname: Kilby
authors.forename: Guillermo
authors.initials: G
authors.lastname: Carroli
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Khan
mesh_terms: D000328:Adult; D000367:Age Factors; D015415:Biomarkers / Q000097:blood; D005260:Female; D005492:Folic Acid / Q000097:blood; D005865:Gestational Age; D006710:Homocysteine / Q000097:blood* / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D015994:Incidence; D008423:Maternal Age; D010298:Parity; D011225:Pre-Eclampsia / Q000097:blood* / Q000517:prevention & control*; D011237:Predictive Value of Tests; D011247:Pregnancy; D011322:Primary Prevention; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015996:Survival Rate; D014805:Vitamin B 12 / Q000097:blood
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; D014805:Vitamin B 12