Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia

OBJECTIVE: We have recently demonstrated that an elevated plasma homocysteine in early pregnancy is associated with the development of severe preeclampsia. The aim of this study was to determine whether an elevated plasma homocysteine in early pregnancy is also associated with the development of nonsevere preeclampsia.STUDY DESIGN: Blood was obtained from patients attending for a first antenatal visit. Subjects were asymptomatic women who subsequently developed nonsevere preeclampsia. Controls were matched for parity, gestational age, and date of sample collection. Plasma homocysteine was measured using fluorescence polarization immunoassay.RESULTS: There were 71 cases of nonsevere preeclampsia sampled at a mean gestational age (±SD) of 15.9±3.6 weeks and 142 controls at 15.6±3.4 weeks. The preeclampsia cases had a mean (±SD) homocysteine level of 8.4±2.4 μmol/L, whereas controls had a mean homocysteine of 7.07±1.5 μmol/L (P≤.0001).CONCLUSION: Women who develop nonsevere preeclampsia have higher plasma homocysteine levels in early pregnancy compared with women who remain normotensive throughout pregnancy. An elevated plasma homocysteine value in early pregnancy may be associated with a 4-fold increased risk for development of nonsevere preeclampsia.     

Plasma homocysteine levels elevated and inversely related to insulin sensitivity in preeclampsia

OBJECTIVE: To study the plasma levels of homocysteine in preeclampsia and relate them to insulin sensitivity. METHODS: In association with a 3-hour intravenous glucose-tolerance test (glucose 0.3 g/kg at 0 and 0.03 IU insulin 20 minutes later), we measured plasma levels of homocysteine, vitamin B12, and folic acid in 22 women with preeclampsia and 16 controls between 29 and 39 weeks' gestation. In 14 women with preeclampsia and 11 controls, plasma samples also were collected 3 months after delivery. RESULTS: Levels of homocysteine in women with preeclampsia (6.7 +/- 0.4 micromol/L, mean +/- standard error) were higher (P < .001) than those in controls (3.8 +/- 0.2 micromol/L) and related significantly to the level of proteinuria (r = .49, P = .02). Vitamin B12 concentrations were lower in women with preeclampsia (166.0 +/- 10.4 compared with 212.4 +/- 16.4 pmol/L, P = .02), whereas levels of folic acid showed no difference between the groups. After delivery, levels of homocysteine increased to 9.1 +/- 0.6 and 8.2 +/- 0.6 micromol/L in women with preeclampsia and controls, vitamin B12 increased to 298.8 +/- 28.6 compared with 334.9 +/- 24.0 pmol/l, and folic acid decreased to 10.6 +/- 2.0 compared with 7.9 +/- 0.8 nmol/L, with no difference emerging between the groups. In women with preeclampsia but not in controls, plasma homocysteine was negatively related to insulin sensitivity (r = -.51, P = .02). The mean 2.9-fold increase in glucose or 52.5-fold increase in insulin during the insulin-sensitivity test failed to affect homocysteine levels. CONCLUSION: Women with preeclampsia have high plasma homocysteine levels that are inversely related to insulin sensitivity.     

Plasma thiol status in preeclampsia

OBJECTIVE: To measure plasma thiol levels in women with normal pregnancies, women with preeclampsia, and nonpregnant controls to define plasma thiol's effect on glutathione homeostasis and pathophysiology of preeclampsia. METHODS: Total plasma cysteine, gamma-glutamylcysteine, homocysteine, cysteinylglycine, and glutathione levels were measured in ten nonpregnant women, ten women with normotensive pregnancies, and 20 women with preeclampsia at delivery. RESULTS: Median total plasma levels of all thiols in normotensive pregnant women were significantly lower than in nonpregnant women. Median total plasma cysteine and homocysteine levels in women with preeclampsia were significantly higher compared with pregnant controls (254 versus 190 micromol/L, P < .001; and 13.3 versus 8.4 micromol/L, P < .02, respectively), whereas glutathione levels were significantly lower in women with preeclampsia compared with those in pregnant controls (5.1 versus 6.3 micromol/L, P < .05). CONCLUSION: In women with preeclampsia, homocysteine and cysteine levels, which are lowered in normotensive pregnancy, were comparable to levels in nonpregnant women, whereas glutathione levels were lower. Those results suggest that in women with preeclampsia, glutathione use is higher or its synthesis is disturbed. Therefore, glutathione might affect pathophysiology of preeclampsia.     

Serum homocysteine at 16 weeks and subsequent preeclampsia

OBJECTIVE: To determine whether elevated homocysteine levels precede the development of preeclampsia. METHODS: Study subjects were selected from a population-based cohort of 1049 nulliparous women from whom serum was collected for Down syndrome screening at 16 weeks' gestation. For 34 women who developed preeclampsia, 68 control women were chosen who remained normotensive. Homocysteine was analyzed by high-performance liquid chromatography and fluorescence detection. The sample size allowed detection of a 1.25-micromol/L difference at a significance level of 0.05 and the power of 0.81. RESULTS: At 16 weeks' gestation, concentrations (mean, 95% confidence interval) of homocysteine in women who developed preeclampsia, 6.99 (6.42, 7.55) micromol/L, were similar to those who remained normotensive, 6.91 (6.45, 7.34) micromol/L. CONCLUSION: Significant changes in homocysteine metabolism did not predate the appearance of clinical preeclampsia.     

Increased fetal DNA in the maternal circulation in early pregnancy is associated with an increased risk of preeclampsia

OBJECTIVE: The aim of our study was to determine if fetal DNA is present in the maternal circulation in early pregnancy before the clinical manifestation of preeclampsia, and if this could be predictive of the development of preeclampsia. STUDY DESIGN: Blood were obtained from patients attending for a first antenatal visit. Cases were asymptomatic women who subsequently developed preeclampsia matched to control women for parity and gestational age. Real-time polymerase chain reaction (PCR) using TaqMan primers and probes directed against SRY gene sequences quantified fetal DNA in the maternal circulation. RESULTS: There were 88 cases of women with preeclampsia and 176 control women, both sampled at a mean gestation (+/-SD) of 15.7 +/- 3.6 weeks. The presence of fetal DNA in the maternal circulation in early pregnancy is associated with an 8-fold increased risk of developing preeclampsia. CONCLUSION: Increased fetal DNA is present in the maternal circulation in early pregnancy in women who subsequently develop pre-eclampsia and there appears to be a graded response between the quantity of fetal DNA and the risk of developing pre-eclampsia.     

Abnormal folate metabolism as a risk factor for first-trimester spontaneous abortion

OBJECTIVE: To assess the potential role of folic acid in early pregnancy loss by measuring homocysteine (hcy) levels in healthy, pregnant women who present with a current first-trimester miscarriage. STUDY DESIGN: This was a cross-sectional analysis comprising 13 patients aged 18-31 years old who had a scheduled dilatation and curettage for a first-trimester miscarriage. The controls were 15 patients of similar maternal age presenting for a first-trimester prenatal care visit. Following completion of a 21-item, structured questionnaire, patients were excluded from the study if they had any known risk factors for a first-trimester miscarriage. The remaining patients provided blood samples for measurement of homocysteine and red blood cell folate. Cases and controls were compared using a standard 2-sample t test. In order to detect a clinically relevant 2.3 micromol/L difference in homocysteine levels, 11 cases and 8 controls were needed. RESULTS: The mean hcy level in cases (5.8 umolmol/L) vs. controls (5.7 micromol/L) was not significantly different (p = 0.83), and all individual values fell within the normal range expected in pregnant women. Red blood cell folate levels (cases=586 ng/mL, controls=611 ng/mL) were also not significantly different (p = 0.72), and no cases of folate deficiency were detected. Maternal age (cases=26, controls=25) and gestational age (cases = 8.8 weeks, controls = 8.4 weeks) were similar between the 2 groups. CONCLUSION: In this community-based pilot study, abnormal folate metabolism was not an apparent risk factor for spontaneous first-trimester pregnancy loss.     

Renal handling of homocysteine during normal pregnancy and preeclampsia

OBJECTIVE: Maternal plasma homocysteine decreases in normal pregnancy and is significantly increased in preeclampsia. The goal of this study was to investigate the role of the maternal kidney in the changes of plasma homocysteine during normal pregnancy and preeclampsia. METHODS: Plasma and 24-hour urine samples were collected in the same women before, during (first, second, and third trimesters), and after normal pregnancy; and in a separate cross-sectional study of normal pregnant, preeclamptic and nonpregnant women and homocysteine concentrations were measured. RESULTS: Longitudinally, maternal plasma homocysteine decreased significantly by the first trimester compared with prepregnancy and postpartum levels (5.6 +/- 1.8 versus 6.8 +/- 0.5 and 7.4 +/- 0.4 microM, respectively, P<.05 by analysis of variance) and paralleled a significant increase in the renal clearance of homocysteine (2.9 +/- 0.4 versus 1.8 +/- 0.2 and 1.6 +/- 0.2 L/24 hours, respectively, P<.001). In addition, plasma homocysteine was significantly elevated in preeclampsia compared with normal pregnancy (4.4 +/- 0.6 versus 3.2 +/- 0.2 microM, P<.04); however, renal clearance was not different (1.2 +/- 0.1 versus 1.0 +/- 0.1 L/24 hours, P=.55). CONCLUSION: Increases in renal clearance contribute to the decrease in plasma homocysteine during normal pregnancy. However, changes in renal handling do not appear to contribute to the increase in plasma homocysteine in preeclampsia.     

Serum homocysteine levels in pregnant women with preeclampsia

Preeclampsia is one of the most common and severe pregnancy complications, which ethiology remains unclear. It is certain that endothelial dysfunction plays a key role in the development of preeclampsia. Homocysteine is an important independent cardiovascular risk factor, which might induce the endothelial dysfunction observed in preeclampsia. 26 pregnant women--14 with preeclampsia (group 1) and 12 healthy term pregnant controls (group 2) were enrolled in the study between December 2003 and August 2004. Six of the women in this group had a superimposed preeclampsia. The mean homocysteine level in the first group was 11,04 mol/l, while in the control group it was 6,24 micromol/l (p < 0.05). The women with a severe preeclampsia had a significantly higher serum homocysteine levels than those with mild form (F = 0.025). Seven of the patients (50%) gave birth before 34th weeks of gestation. The study finds a link between the serum homocysteine as an endothelial dysfunction marker and the development of preeclampsia and a relation between the severity of preeclampsia and the degree of the elevation of the serum homocysteine levels.     

Plasma homocysteine in early and late pregnancies complicated with preeclampsia and isolated intrauterine growth restriction

BACKGROUND: Elevated circulating homocysteine is an independent risk factor for cardiovascular disease. Increased homocysteine plasma levels have been reported to occur in approximately 20-30% of women with preeclampsia and it has been suggested that they may predict the subsequent development of preeclampsia. METHODS: In a cohort of 1874 pregnant women followed longitudinally, who participated in the Down screening program, 27 developed preeclampsia and 36 intrauterine growth restriction (IUGR). A control group of 63 uneventful pregnancies was selected. Plasma homocysteine was assayed in the early second trimester and at delivery in all groups. Data were compared with Wilcoxon's matched-pair test. RESULTS: No statistically significant difference of plasma homocysteine between controls and preeclamptic or IUGR pregnancies in the early second trimester were found. There was a significant difference, only at delivery, between the preeclamptic subjects and the controls. CONCLUSIONS: We failed to demonstrate a plasma homocysteine predictive value in pregnancies subsequently complicated by preeclampsia and IUGR. As previously stated, we found that an elevated homocysteine plasma level is associated with overt preeclampsia.     

Hyperhomocysteinaemia: a risk factor for preeclampsia?

Preeclampsia represents one of the most frequent complications of pregnancy, however, little is known about its aetiology. Damage of the endothelial layer lining the blood vessel wall is thought to play an important role in the pathophysiology of preeclampsia, accordingly, mild hyperhomocysteinaemia has been reported to be more prevalent among preeclamptic women. Therefore, we investigated the role of hyperhomocysteinaemia in preeclampsia by measuring plasma levels of homocysteine and studying the prevalence of the 677(C-->T) polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which may lead to reduced MTHFR enzyme activity and subsequently to higher plasma homocysteine levels.Plasma samples of 10 healthy non-pregnant women, 10 normotensive pregnant women, and 20 women with preeclampsia were analysed for total homocysteine levels by high performance liquid chromatography. Furthermore, 167 Dutch non-pregnant women previously hospitalised for preeclampsia and 403 population-based controls were analysed for the 677(C-->T) polymorphism by polymerase chain reaction followed by restriction fragment length polymorphism analysis (PCR/RFLP).In normotensive pregnancy homocysteine levels were lower compared with levels in healthy non-pregnant controls (8.4 versus 13.7micromol/l, P<0.001). Women with preeclampsia showed higher concentrations than women during normotensive pregnancy (13.3 versus 8.4micromol/l, P<0.02). However, levels of homocysteine in preeclampsia were comparable to those found in healthy non-pregnant women. PCR/RFLP showed no significant difference in the incidence of the 677(C-->T) polymorphism in the MTHFR gene between preeclamptic women with or without HELLP syndrome and controls (13 and 9% homozygous for the less common T-allele, respectively; OR 1.5, 95% CI 0.8-2.6, P=0.17).In contrast with previous reports, we cannot confirm that mild hyperhomocysteinaemia is a risk factor for preeclampsia. Pregnancy induced hyperhomocysteinaemia found in preeclampsia might better be explained by fluctuations in plasma volume than by the presence of the 677(C-->T) polymorphism in the MTHFR gene.     

Plasma homocyst(e)ine concentrations in eclamptic and preeclamptic African women postpartum.

OBJECTIVE: To examine the relationship between plasma homocyst(e)ine and risk of eclampsia and preeclampsia among sub-Saharan African women who delivered at Harare Maternity Hospital in Zimbabwe. METHODS: We ran a hospital-based, case-control study at Harare Maternity Hospital, University of Zimbabwe, Harare, Zimbabwe comprising 33 pregnant women with eclampsia and 138 with preeclampsia. Controls were 185 normotensive pregnant women. Plasma was collected postpartum and homocyst(e)ine levels were measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Women with eclampsia or preeclampsia had significantly higher mean homocyst(e)ine levels than normotensive controls (12.54 or 12.77 micromol/L versus 9.93 micromol/L, respectively, P<.001). The odds ratio (OR) for eclampsia was 6.03 among women in the highest quartile of the control homocyst(e)ine distribution (median 13.9 micromol/L) compared with women in the lowest quartile (median 6.2 micromol/L). The corresponding OR for preeclampsia was 4.57. Nulliparas with elevated homocyst(e)ine had a 12.90 times higher risk of preeclampsia compared with multiparas without elevated homocyst(e)ine. CONCLUSION: Postpartum plasma homocyst(e)ine concentrations are higher among Zimbabwean women with eclampsia and preeclampsia compared with normotensive women.     

Uterine artery Doppler and mid-trimester maternal plasma homocysteine in subsequent pre-eclampsia.

OBJECTIVE: To investigate whether mid-trimester maternal plasma homocysteine concentration is elevated in women who develop pre-eclampsia and in those women identified at high risk by abnormal uterine artery Doppler examination. METHODS: This was a multicenter study involving healthy women undergoing screening for pre-eclampsia by uterine artery Doppler velocimetry at 22-24 weeks' gestation. Abnormal uterine artery blood flow was defined as a mean pulsatility index (PI) above the 95th centile (1.6). Controls (mean PI < 1.6) were matched for gestational age and date of blood sample collection. Maternal plasma homocysteine concentration was measured retrospectively using a chemiluminescent immunoassay. RESULTS: In total, 683 women were recruited. Maternal plasma homocysteine concentration did not vary with gestation. Maternal plasma homocysteine concentration in women who subsequently developed pre-eclampsia (n = 80, 12%) was not significantly different from women with uncomplicated pregnancies (n = 536, 78%) (median 5.1, range 2.7-14.1 micromol/l vs. median 5.5, range 1.9-27.9 micromol/l, p = 0.44). There were no significant differences in the maternal plasma homocysteine concentration in women with abnormal uterine artery Doppler findings (n = 275) compared with controls (n = 408), (median 5.6, range 2.6-17.7 micromol/l vs. median 5.4, range 1.9-27.9 micromol/l, p = 0.13). CONCLUSION: Mid-trimester maternal plasma homocysteine concentration is not elevated in women who developed pre-eclampsia even in those at high risk defined by abnormal uterine artery Doppler velocimetry.     

Low-dose folic acid supplementation reduces plasma levels of the cardiovascular risk factor homocysteine in postmenopausal women

OBJECTIVE: The aim of our randomized, controlled trial was to verify the effect of folic acid supplementation on homocysteine levels in postmenopausal women. STUDY DESIGN: Thirty-six women were divided randomly into 2 groups as follows: a placebo group (n = 18) and a group receiving 500 microg folic acid per day for 4 weeks (n = 18). To assess concentrations of plasma homocysteine, venous blood samples were taken on enrollment and after 4 weeks of treatment. RESULTS: Mean plasma homocysteine levels were 10.9 +/- 2.7 micromol/L in the placebo group and 7.8 +/- 2.35 micromol/L (P <.01) in the group receiving 500 microg folic acid per day for 4 weeks. The thirds (referred to as tertiles) of women with the highest baseline homocysteine plasma levels showed the greatest reduction in homocysteine, with a mean decrease of 4.35 micromol/L (32%; P <.01), in comparison with a decrease of 3.35 micromol/L (29%; P <.01) in the middle tertile and 1.3 micromol/L (22.4%; P =.09) in the lower tertile. CONCLUSIONS: The results show that low doses of folic acid are associated with a significant reduction in plasma concentrations of homocysteine. The highest initial levels of homocysteine showed the most important reduction after therapy.     

Hyperhomocyst(e)inemia and elevated soluble vascular cell adhesion molecule-1 concentrations are associated with an increased risk of preeclampsia

Hyperhomocyst(e)inemia (HHcy) is a risk factor of endothelial dysfunction and preeclampsia. Soluble vascular cell adhesion molecule-1 (sVCAM-1), a specific marker of endothelial dysfunction, is elevated in preeclampsia. Few have assessed the joint contribution of these biomarkers in predicting preeclampsia. We assessed the extent to which HHcy and elevated sVCAM-1 are independently and jointly associated with preeclampsia. We conducted a case-control analysis of 100 preeclampsia cases and 100 controls to test our study hypothesis. Maternal plasma was collected before labor onset. Total plasma homocysteine (tHcy) was measured using high-performance liquid chromatography with electrochemical detection procedures. Plasma sVCAM-1 was determined using ELISA. Using the distribution of each analyte among controls, elevated tHcy was defined as plasma tHcy >6.6 micromol/l and elevated sVCAM-1 was defined as plasma concentrations >845 ng/ml (i.e., values above the median). Odds ratios (OR) and 95% confidence intervals (CIs) were calculated. Compared with women without elevated tHcy and without elevated sVCAM-1 (the referent group), those with elevated sVCAM-1 alone had a 4.1-fold increased risk of preeclampsia (95% CI 1.2-13.8). The OR for women with elevated tHcy alone was 2.2 (95% CI 0.6-7.9). The OR for women with elevated tHcy and sVCAM-1 was 13.2 (95% CI 4.1-42.2). Elevated tHcy and sVCAM-1 together were strongly associated with an increased risk of preeclampsia. Larger, prospective studies are needed to confirm these findings and to determine the extent to which elevated tHcy and sVCAM-1 together in early pregnancy are predictive of preeclampsia risk.     

Plasma homocysteine in late pregnancies complicated with preeclampsia and in newborns

The aim of this study was to determine the relationship between maternal serum homocysteine levels in preeclampsia and the severity of the disease, neonatal serum homocysteine levels, maternal complications, and fetal outcome. Fifty pregnant women were included in this prospective study, of which 25 were severe (group I) and 25 were non-severe preeclamptic (group II). Maternal and neonatal serum homocysteine levels were measured by the fluorescence polarization immunoassay (FPIA) method. Maternal homocysteine levels in both groups were compared. The association of maternal and neonatal serum homocysteine levels with maternal complications and fetal outcome was investigated. When the maternal serum homocysteine cut-off value was accepted as 15 micromol/L, significant differences in relation to maternal (eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome) and fetal (in utero mort fetalis, low birthweight) complications were observed between the group with maternal serum homocysteine level > 15 micromol/L and the group with maternal serum homocysteine level < or = 15 micromol/L ( p < 0.05). Hyperhomocysteinemia during pregnancy is a risk factor for both development of preeclampsia and its complications. Given that the diagnosis and treatment of hyperhomocysteinemia is possible, clinical trials to determine whether treatment to reduce homocysteine would be valuable in the prevention of both maternal and fetal complications in preeclampsia should be designed.     

Maternal and fetal plasma homocysteine concentrations at birth: the influence of folate, vitamin B12, and the 5,10-methylenetetrahydrofolate reductase 677C-->T variant

OBJECTIVE: The purpose of this study was to determine the nutritional and genetic factors that influence fetal plasma homocysteine concentrations. STUDY DESIGN: Maternal and umbilical cord venous blood was taken from 201 women who were delivered after uncomplicated pregnancies of 37 to 41 gestational weeks. Red blood cell folate, plasma folate, plasma vitamin B12, and plasma homocysteine concentrations were measured in all samples. Cord and maternal bloods were also genotyped for the 677C-->T variant. RESULTS: The fetal circulation had lower homocysteine concentrations (7.87 +/- 2.87 micromol/L; mean +/- SD) than the maternal circulation (8.34 +/- 2.94 micromol/L; P =.003), but there was a strong linear association between the levels in these 2 compartments (r = 0.72; P <.0001). Overall, the maternal homocysteine level had the strongest influence on the fetal homocysteine concentration (P <.0001), with the fetal and maternal vitamin B12 having important additional effects (P =.016 and P =.0045, respectively). Fetal plasma folate and 5,10-methylenetetrahydrofolate reductase 677C-->T genotype had no significant effects (P =.23 and P =.54, respectively), probably because of folic acid supplement use. CONCLUSION: The maternal homocysteine level is the primary predictor of blood homocysteine in the developing fetus. If lowering maternal blood homocysteine proves critical to preventing pregnancy complications, it will be important to maintain optimal vitamin B12 status in addition to optimal tissue folate status.     

Age, menopausal status and homocysteine levels in women around menopause

OBJECTIVE: To obtain data on the relation between age, menopause and homocysteine levels in women around menopause, we collected data for a sample of about 500 women attending a menopause clinic in Milan, Italy. STUDY DESIGN: Eligible for the study were all women aged 45-75 years, never HRT users consecutively observed for the first time at the Menopause Center of the 1st Obstetric Gynecological Clinic of the University of Milan. Fasting blood samples for total homocysteine plasma levels were collected during the visit. Of the 490 study subjects, 107 were pre-menopausal and 383 post-menopausal. RESULTS: In the total series, the mean homocysteine level was 8.3 micromol/L (S.D. 3.7, range 3.2-48.8). The values increased from 7.8 micromol/L in women aged <47 years to 9.0 micromol/L in those aged >59. Among pre-menopausal women the mean homocysteine level was 7.7 micromol/L compared to 8.3 micromol/L in post-menopausal women: this difference disappeared on the adjusted values. In post-menopausal women only, no clear relationship emerged between years since menopause and homocysteine levels. CONCLUSION: In our population, age, and not menopausal status, was the main determinant of homocysteine levels in women around menopause.     

A randomized placebo-controlled study of the effect of transdermal vs. oral estradiol with or without gestodene on homocysteine levels

OBJECTIVE:To assess the effect of transdermal vs. oral administration of E2 on plasma homocysteine levels and to evaluate the impact of adding a progestogen to these regimens. DESIGN: Prospective, double-blind, double-dummy, placebo-controlled study. SETTING: Outpatient clinics in two university hospitals and two teaching hospitals in The Netherlands. PATIENT(S): One hundred fifty-two healthy hysterectomized postmenopausal women. INTERVENTION(S): Thirteen 28-day treatment cycles with placebo (n = 49); transdermal 17beta-E2, 50 microg (n = 33), oral E2, 1 mg (n = 37), or oral E2, 1 mg, plus gestodene, 25 microg (n = 33), followed by four cycles of placebo in each group. MAIN OUTCOME MEASURE(S): Fasting plasma total homocysteine concentrations at baseline and cycle 4, 13, and 17. RESULT(S): Mean (+/-SD) homocysteine concentrations in the oral E2 group decreased from baseline to cycle 4 (9.0 +/- 2.5 micromol/L vs. 8.2 +/- 2.0 micromol/L; mean change, -7.6%). Homocystine values in the oral E2 plus gestodene group did not change substantially from baseline to cycle 4 (8.9 +/- 1.6 micromol/L vs. 8.6 +/- 2.0 micromol/L; mean change, -4.4%). No significant changes were observed in the transdermal E2 group. After four washout cycles, the homocysteine concentration had returned to baseline values in all groups. CONCLUSION(S): Oral E2 therapy reduced the homocysteine concentration more than did therapy with transdermal E2 or oral E2 plus gestodene. This finding may indicate a role of liver metabolism and suggests that gestodene has a negative effect on these changes.     

Homocysteine and folate levels as risk factors for recurrent early pregnancy loss

OBJECTIVE: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations. METHODS: In a case-control study, we measured homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5'-phosphate, and cobalamin concentrations in 123 women who had at least two consecutive spontaneous early pregnancy losses each and compared concentrations with those of 104 healthy controls. RESULTS: Women with recurrent early pregnancy losses had significantly lower serum folate concentrations than controls, whereas the other measurements were similar to those of controls. Elevated homocysteine, fasting greater than 18.3 micromol/L and afterload greater than 61.5 micromol/L, was a risk factor for recurrent early pregnancy loss, with odds ratios (ORs) and 95% confidence intervals (95% CIs) of 3.6 (1.2, 12.7) and 2.7 (0.9, 8.8) in the group with recurrent miscarriages: 6.4 (1.9, 24.3) and 4.3 (1. 2, 17.3) in primary aborters, and 4.2 (1.3, 15.4) and 3.4 (1.0, 12. 8) in those with three or more miscarriages. The ORs (95% CIs) in the same study populations for serum folate concentrations less than 8.4 nmol/L were 2.1 (0.9, 4.8), 2.7 (1.0, 7.8), and 3.2 (1.3, 8.1), respectively. A significant dose-response relationship between serum folate concentrations and risk of recurrent early pregnancy loss suggested a protective effect by high serum folate concentrations. CONCLUSION: Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.     

Complement activation in relation to development of preeclampsia

Six hundred eighty-five primigravidas followed as a series had complement activation evaluated by the formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes in venous blood. Samples for complement determinations were obtained four times during pregnancy, in pregnancy weeks 12-16, 20-24, 28-32, and 34-36. Seven of the women developed preeclampsia and one of them the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). Eleven others with uncomplicated pregnancies were selected as a control group. Plasma samples were taken from these 18 women at delivery and 1 and 7 days after delivery. At delivery, plasma C5a levels were significantly greater in the preeclamptics than in controls, and four of the seven preeclamptics had elevated plasma C3a values compared with controls. One week after delivery, these plasma anaphylatoxins had returned to normal. Elevations of the anaphylatoxins could not be detected before the women developed clinical signs of preeclampsia. No alterations in terminal C5b-9 complement complexes could be observed in the women with preeclampsia. However, the women who developed HELLP syndrome had elevated plasma concentrations of C3a, C5a, and terminal C5b-9 complement complex at delivery. These values returned to the normal range 1 week after delivery. We conclude that complement activation in the systemic circulation does not occur early in pregnancy and that plasma concentrations of C3a, C5a, or terminal C5b-9 complement complex cannot be used as predictors of preeclampsia.