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Obstetrics & Gynecology 1999;93:489-493
© 1999 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Plasma Homocysteine Levels Elevated and Inversely Related to Insulin Sensitivity in Preeclampsia

HANNELE LAIVUORI, MD, RISTO KAAJA, MD, PhD, URSULA TURPEINEN, PhD, LASSE VIINIKKA, MD, PhD and OLAVI YLIKORKALA, MD, PhD

From the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland.

Address reprint requests to: Hannele Laivuori, MD, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, PO Box 140 FIN-00029 HYKS, Finland, E-mail: hannele.laivuori{at}pp.fimnet.fi


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
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 µmol/L, mean ± standard error) were higher (P < .001) than those in controls (3.8 ± 0.2 µmol/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 µmol/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.

Even moderately elevated levels of homocysteine are, in men and nonpregnant women, an independent risk factor for atherosclerosis and other occlusive vascular disorders.1,2 Although the mechanism of the damaging effect of hyperhomocysteinemia on vascular health is not understood fully, it may include endothelial cell injury and thrombus formation.3 Preeclampsia can be defined as a pregnancy-specific occlusive vascular disorder characterized by endothelial cell dysfunction and increased platelet aggregation.4 Only one study exists on homocysteine and preeclampsia, and it suggests that in this disease levels of homocysteine are elevated.5 Nonpregnant women with a history of severe preeclampsia6 or placental abruption/infarction7,8 show elevated levels of homocysteine at baseline or 6 hours after intake of methionine, which serves as a substrate for homocysteine synthesis. In addition, women with preeclampsia also have elevated levels of insulin,9 and indeed, preeclampsia is associated with insulin resistance (unpublished data). Further, it is known that several characteristics of insulin resistance syndrome prevail for up to 17 years after a preeclamptic pregnancy,10,11 which perhaps explains these women’s increased risk for vascular disorders.12,13

We designed this study to determine plasma levels of homocysteine in women with preeclampsia during and after pregnancy and to evaluate whether their homocysteine levels are associated with insulin sensitivity.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
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With the permission of the ethics committee, we studied 22 nulliparous women with acute preeclampsia (blood pressure [BP] >140/90 mmHg at least two times 6 hours apart, proteinuria >=0.3 g/day) and 16 normotensive, nulliparous control women between 29 and 39 weeks’ gestation (Table 1Go). All preeclamptic findings disappeared within 2 weeks after delivery, which confirmed that these patients had suffered pure preeclampsia. All women with preeclampsia and controls gave informed consent. The enrollment period was January 1, 1996, to April 30, 1997. The patients and controls were recruited from the maternity clinics, the prenatal clinic, and the antenatal ward of Helsinki University Central Hospital, Helsinki, Finland. Patients with severe preeclampsia were excluded from the study. All patients and controls were normoglycemic as assessed by 2-hour oral glucose tolerance test and did not use any medication.


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  		Table 1. Characteristics (Mean ± Standard Error) of 38 Nulliparous Study Subjects
 
After a 12-hour fast, whole-body insulin sensitivity was measured by the minimal model technique (unpublished data). Briefly, a dose of glucose (0.3 g/kg, intravenous [IV] administration) was followed by a dose of human regular insulin (Velosulin Human; Novo Nordisk A/S Pharmaceuticals, Bagsværd, Denmark) (0.03 IU/kg IV) 20 minutes later, and frequent blood samples were collected for up to 3 hours; true insulin sensitivity was calculated from simultaneous changes in glucose and insulin.14 Before injection of glucose and 3 hours thereafter, blood was drawn into tubes containing ethylenediaminetetraacetic acid (EDTA), and plasma was separated by centrifugation (4C, 3180 revolutions per minute, 10 minutes) and frozen at -20C. Plasma samples were assayed for total homocysteine (homocysteine-cysteine, mixed disulfides, and protein-bound homocysteine) by high-performance liquid chromatographic method and fluorescence detection15,16 with minor modifications. To 100 µL of plasma we added 10 µL of internal standard (0.9 mM N-acetyl cysteine) and 50 µL of reducing agent (2 M NaBH4) and incubated the mixture at room temperature for 5 minutes. Proteins were precipitated by addition of 100 µL of perchloric acid (0.6 M, containing 1 mM EDTA). To derivatize the thiols in 50 µL of clear supernatant, we added 50 µL of thiol-specific reagent, ammonium-7-fluoro-2,1,3-benzoxadiazole-4-sulfonate (SBD-F), 1 g/L in borate buffer, and heated this for 1 hour at 60C. We used a Lichrospher 100 RP-18 (Merck KGaA, Darmstadt, Germany), 250 x 4.6 mm, column with a mobile phase of 9% acetonitrile in 0.1 M phosphate buffer, pH 2.15 at a flow rate of 1 mL/minute. Plasma samples were available 3 months after delivery for 14 women with preeclampsia and 11 controls. Eight women from the patient group and five women from the control group were lost to follow-up because after delivery mothers often were tired and preoccupied with their newborns and thus unwilling to participate in further examinations. None of our patients were on oral contraceptives postpartum.

Because vitamin B12 and folic acid are essential in methionine-homocysteine metabolism,3 we also simultaneously measured vitamin B12 and folic acid from baseline plasma samples by a competitive protein-binding method (SimulTRAC radioassay kit; ICN Pharmaceuticals Inc., Orangeburg, NY). Mean interassay coefficient of variation was less than 13% for homocysteine at 8.5 µmol/L, 6% for vitamin B12 at 270 pmol/L, and less than 10% for folic acid at 13 nmol/L, respectively.

Statistical analysis was performed with the Statview II program (Abacus Concepts, Berkeley, CA). Values for continuous variables are given as the mean ± standard error of the mean. Data were compared with Student two-tailed unpaired and paired t test. Relationships between plasma homocysteine and different parameters were investigated by linear regression.


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
Except for preeclamptic findings and increased insulin resistance in the preeclamptic group, the study groups were comparable (Table 1Go).

Women with preeclampsia had higher homocysteine and lower vitamin B12 than the controls, but their folicacid levels tended to be lower (Figure 1Go, Table 2Go). Three months after delivery, levels of homocysteine (Figure 1Go) and vitamin B12 had increased and those of folic acid decreased; neither level showed a difference between the groups (Table 2Go).



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  		Figure 1. Fasting homocysteine levels in 22 women with preeclampsia (solid circles) and 16 controls (open circles) during pregnancy and 3 months after delivery (14 women with prior preeclampsia and 11 women with prior normal pregnancy).

 

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  		Table 2. Levels (Mean ± Standard Error) of Basal Plasma Homocysteine, Vitamin B12, and Folic Acid During Preeclamptic and Normotensive Pregnancy and 3 Months After Delivery
 
In women with preeclampsia, homocysteine correlated positively with the level of proteinuria (0.3–10.5 g/day) (r = .49, P = .02), but not with systolic BP (r =.09, P = .69), diastolic BP (r = .03, P = .91), or uric acid levels (r = .18, P = .42). Homocysteine levels were not related to body mass index before pregnancy (preeclamptic group: r = .16, P = .48; control group: r = .26, P = .33), weight gain during pregnancy up to time of the study (preeclamptic group: r =2.05, P = .84; control group: r = 2.26, P = .33), or weeks of gestation in either group (preeclamptic group: r = .03, P = .89; control group: r = 2.02, P = .93). In addition, homocysteine was in negative correlation to birth weight, but this significance was present only when the whole study population was considered (r = 2.58, P < .001).

In women with preeclampsia, homocysteine was in significant negative correlation with insulin sensitivity (r = 2.51, P = .02) (Figure 2Go), and in significant positive correlation with the area under the curve of the first 10-minute insulin levels (r =.62, P = .002) during the insulin-sensitivity test (Figure 2Go). Control women showed no such correlations. The increase in glucose (2.9-fold) and in insulin (52.5-fold) during the insulin-sensitivity test (unpublished data) had no effect on levels of homocysteine (Figure 3Go).



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  		Figure 2. Plasma homocysteine showed a significant negative correlation to insulin sensitivity (left panel) and positive correlation to area under the first 10-minute insulin curve (right panel) (Kaaja R, Laivuori H, Laakso M, Tirranen MJ, Ylikorkala O, unpublished data) in 22 women with preeclampsia. Dotted lines indicate 95% confidence intervals.

 


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  		Figure 3. Fasting and 3-hour plasma homocysteine levels during the minimal model in 22 women with preeclampsia (solid circles) and 16 control women (open circles).

 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
Endothelial damage occupies a key position in the pathogenesis of preeclampsia, but the biochemical reason for this damage remains unknown.4 Hyperhomo-cysteinemia may cause endothelial damage and vascular disease,3 the development of which is acccelerated by decreased insulin sensitivity. Women with preeclampsia also are characterized by decreased insulin sensitivity (Kaaja R, Laivuori H, Laakso M, Tirranen MJ, Ylikorkala O, unpublished data).9 Therefore, we compared the plasma levels of homocysteine between pre-eclamptic and normotensive women. Our study model allowed us access to a well-characterized study population of women who had fasted carefully for 12 hours. This aspect is of significance because dietary factors may affect plasma homocysteine levels.17

Our data show that plasma homocysteine levels in patients with preeclampsia were on average 1.8 times as high as than those in control women, a finding in excellent agreement with the only previous study showing a similar elevation in plasma homocysteine in preeclampsia.5 A new finding is our demonstration of the relationship between homocysteine level and severity of preeclampsia, as expressed by the magnitude of proteinuria. In addition, levels of vitamin B12, which play a role in the reformation of methionine from homocysteine,3 were reduced in preeclampsia. This finding is in contrast with that of the Rajkovic et al study.5 However, no correlation appeared between plasma homocysteine and vitamin B12.

Our data do not allow us to deduce the cause of elevations in plasma homocysteine in preeclampsia. Both preeclamptic and control groups had a similar standard of living and a similar Finnish diet. Therefore, it is unlikely that any dietary factor could provide an explanation for the marked rise in plasma homocysteine in preeclampsia. We offer several possible explanations. First, renal insufficiency leads to an elevation in homocysteine,18,19 making it likely that preeclamptic changes in renal function, as manifested by such events as marked proteinuria, could account, at least in part, for our preeclamptic women’s elevations in plasma homocysteine. This is supported by our finding of positive correlation between plasma homocysteine and the magnitude of proteinuria. Second, fetal demands for homocysteine may have been lower in women with preeclampsia. It has been shown recently in healthy parturients that maternally derived homocysteine is transported by the placenta into the umbilical vein, where it is extracted by the fetus.20 This could explain the inverse correlation between neonatal weight and maternal plasma homocysteine seen in our study and that of Malinow et al.20 Reformation of methionine from homocysteine for fetal demands may have been smaller in women with preeclampsia and smaller fetuses, thus leaving more homocysteine to be preserved in maternal plasma. Third, a relative reduction in vitamin B12 in preeclampsia, as seen in our patients, may contribute to this effect because vitamin B12 is essential for the reformation of methionine from homocysteine.17 Finally, we must acknowledge the possibility that the frequency of the common mutation in the methylenetetrahydrofolate reductase gene21 could have been greater in our women with preeclampsia than in our control women, thereby causing increased plasma homocysteine concentrations. But because the frequency of this mutation is on the order of 5–10% in an unselected population,22 it appears unlikely that many of our patients with preeclampsia would have had this mutation. The normalization of homocysteine levels in the preeclamptic group after delivery also argues against this explanation. Unfortunately, our study population is far too small to assess the frequency of this mutation.

It has been known that plasma homocysteine decreases during pregnancy, but the reason for this change is unknown at present.23,24 We can confirm this by showing that in our subjects plasma homocysteine rose within 3 months after delivery and that plasma homocysteine levels were similar in preeclamptic and control women. This does not exclude the possibility that these women could have had a genetic or other tendency toward elevated levels of homocysteine—a fact that can be determined only with the aid of a methionine-loading test.6

We noted an inverse correlation in preeclampsia between plasma homocysteine and insulin sensitivity. At the moment, we do not know whether there is any cause-consequence relation between the two or whether they are primary or secondary changes in preeclampsia. It was, however, of interest to discover that drastic changes in blood glucose or insulin during the insulin-sensitivity test failed to affect plasma homocysteine in 3 hours. The half-life of homocysteine in plasma in non-pregnant healthy subjects is on the order of 3.5 hours,25 but it is four times as high in patients with chronic renal failure.26 We do not know the half-life of homocysteine during normal or preeclamptic pregnancy, but probably it is of the same order as in nonpregnant healthy subjects.25 Our data on stable homocysteine levels 3 hours after huge peaks in glucose and insulin may therefore be seen as one piece of evidence that enzymes taking part in homocysteine metabolism3 may not be sensitive to huge fluctuations in glucose and insulin levels during normal or preeclamptic pregnancy.


   Footnotes
 
This study was supported by grants from the Academy of Finland and the Clinical Research Institute and the Research funds of the Helsinki University Central Hospital.

PII S0029-7844(98)00527-4

Received June 29, 1998. Received in revised form September 28, 1998. Accepted October 8, 1998.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Stampfer MJ, Malinov MR, Willet WC, Newcomer LM, Upson B, Ullman D, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268: 877–81.[Abstract]

2. Graham IM, Daly LE, Refsum HM, Robinson K, Brattsröm LA, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project. JAMA 1997;277: 1775–81.[Abstract]

3. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042–50.[Free Full Text]

4. Roberts JM, Redman CW. Preeclampsia: More than pregnancy-induced hypertension. Lancet 1993;341:1447–51.[Medline]

5. Rajkovic A, Catalano PM, Malinow RM. Elevated homocyst(e)ine levels with preeclampsia. Obstet Gynecol 1997;90:168–71.[Abstract]

6. Dekker GA, de Vries JIP, Doelitzsch PM, Huijgens PC, von Blomberg BME, Jakobs C, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995; 173:1042–8.[Medline]

7. Goddijn-Wessel TAW, Wouters MGAJ, vd Molen EF, Spuijbroek MDEH, Steegers-Theunissen RPM, Blom HJ, et al. Hyperhomocysteinemia: A risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996;66:23–9.[Medline]

8. Owen EP, Human L, Carolissen AA, Harley EH, Odendaal HJ. Hyperhomocysteinemia—A risk factor for abruptio placentae. J Inherit Metab Dis 1997;20:359–62.[Medline]

9. Sowers JR, Saleh AA, Sokol RJ. Hyperinsulinemia and insulin resistance are associated with preeclampsia in African-Americans. Am J Hypertens 1995;8:1–4.[Medline]

10. Laivuori H, Tikkanen MJ, Ylikorkala O. Hyperinsulinemia 17 years after preeclamptic first pregnancy. J Clin Endocrinol Metab 1996; 81:2908–11.[Abstract]

11. Laivuori H, Kaaja R, Rutanen E-M, Viinikka L, Ylikorkala O. Evidence of high circulating testosterone in women with prior preeclampsia. J Clin Endocrinol Metab 1998;83:344–7.[Abstract/Free Full Text]

12. Jónsdóttir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfússon N. Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 1995;74:772–6.[Medline]

13. Hannaford P, Ferry S, Hirsch S. Cardiovascular sequelae of toxemia of pregnancy. Heart 1997;77:154–8.[Abstract/Free Full Text]

14. Bergman RN. Toward physiological understanding of glucose intolerance. Minimal model approach. Diabetes 1989;38:1512–27.[Abstract]

15. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, et al. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: Sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem 1994;40:873–81.[Abstract/Free Full Text]

16. Daskalakis I, Lucock MD, Anderson A, Wild J, Schorah CJ, Levene MI. Determination of plasma total homocysteine and cysteine using HPLC with fluorescence detection and an ammonium 7-fluoro-2,1,3-benzoxadiazole-4-sulphonate (SBD-F) derivatization protocol optimized for antioxidant concentration, derivatization reagent concentration, temperature and matrix pH. Biomed Chromatogr 1996;10:205–12.[Medline]

17. Ueland P, Refsum H, Stabler S, Malinow R, Andersson A, Allen R. Total homocysteine in plasma or serum: Methods and clinical applications. Clin Chem 1993;39:1764–79.[Abstract]

18. Wilcken DE, Gupta VJ. Sulphur containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide. Eur J Clin Invest 1979;9: 301–7.[Medline]

19. Chauveau P, Chadefaux B, Coude M, Aupetit J, Hannedouche T, Kamoun P, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int Suppl 1993;41: S72–7.[Medline]

20. 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.[Medline]

21. Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T. Methylenetetrahydrofolate reductase polymorphism and preeclampsia. J Med Genet 1997;34:525–6.[Abstract]

22. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111–3.[Medline]

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24. Andersson A, Hultberg B, Brattström L, Isaksson A. Decreased serum homocysteine in pregnancy. Eur J Clin Chem Clin Biochem 1992;30:377–9.[Medline]

25. Guttormsen AB, Mansoor AM, Fiskerstrand T, Ueland PM, Refsum H. Kinetics of plasma homocysteine in healthy subjects after peroral homocysteine loading. Clin Chem 1993;39:1390–7.[Abstract]

26. Guttormsen AB, Ueland PM, Svarstad E, Refsum H. Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure. Kidney Int 1997;52:495–502.[Medline]




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