Correlation of Hyperhomocysteinemia with the Severity of Pregnancy-induced Hypertension—A Case–Control Study

INTRODUCTION

Hypertension is the most common medical problem encountered during pregnancy.

Preeclampsia, a pregnancy-specific syndrome, is a major cause of maternal and perinatal morbidity and mortality with a worldwide incidence of 5 to 8% of all pregnancies.¹

Gestational hypertension is a new hypertension developing after 20 weeks without significant proteinuria (>300mg protein in a 24-hour urine collection or >30mg/mol in a spot urinary protein:creatinine sample).

Preeclampsia is a new hypertension developing after 20 weeks with significant proteinuria.

Severe preeclampsia is preeclampsia with severe hypertension (≥ 160/110 mm Hg) and/or with symptoms (severe headache; vision problems, such as blurring or flashing before the eyes; severe pain just below the ribs; vomiting; and sudden swelling of the face, hands, or feet), and/or biochemical and/or hematological impairment.

Eclampsia is a convulsive condition associated with preeclampsia.

HELLP syndrome is hemolysis, elevated liver enzymes, and low platelet count.

How pregnancy incites or aggravates hypertension remains unresolved despite decades of research. There are many theories about the etiology and pathogenesis of preeclampsia including endothelial dysfunction, inflammation, and angiogenesis.

Toxic factors released by the placenta cause endothelial cell dysfunction by directly affecting endothelial cells or by stimulating maternal oxidative stress and inflammatory cytokines.

Oxidative stress is the imbalance of antioxidants (e.g., high density lipoprotein (HDL) and transferrin) and prooxidants. Important prooxidants are homocysteine and low density lipoprotein (LDL). Oxidative stress leads to the formation of oxygen-free radicals and lipid peroxides, which are highly reactive and are directly toxic to the endothelial cells.

With this endothelial damage, there is decreased production of vasodilators (prostacyclin) and inactivation of circulating vasodilators (nitric oxide), ultimately leading to vasospasm.

The homocysteine-mediated vascular changes are similar to those associated with preeclampsia, therefore, a hypothesis has been proposed that hyperhomocysteinemia may be associated with this condition.²

Homocysteine is a sulfur-containing essential amino acid primarily derived from demethylation of dietary methionine required for the growth of cells and tissues in the human body.³

Homocysteine concentrations are tightly regulated by two main enzymatic pathways. Homocysteine can be remethylated to methionine by a pathway requiring folic acid as a methyl donor. In addition to adequate folic acid, the pathway requires vitamin B12 as an important cofactor. Alternatively, homocysteine can be removed by transsulfuration, a pathway dependent on the cofactor vitamin B6.⁴

High concentrations of plasma total homocysteine are associated with serious pregnancy complications, including PIH, preeclampsia,⁵ and placental abruption.⁶

Higher maternal total homocysteine concentration is associated with a small increased risk for small for gestational age offsprings.⁷

It is one of the leading causes of maternal mortality, but the etiopathology of preeclampsia is still an enigma. One metabolic effect of folate deficiency is an elevated plasma homocysteine concentration. It is not yet known whether an elevated total homocysteine concentration is harmful by itself through its vascular effect or is merely a reflection of the folate status. Hence, this study was done to see the association of homocysteine and folic acid with hypertensive disorders of pregnancy.

MATERIALS AND METHODS

This prospective study was conducted in the Department of Obstetrics and Gynaecology, at a tertiary care hospital and medical college, Amritsar, Punjab. The study group included 60 pregnant subjects, including 30 subjects with hypertensive disorders of pregnancy presenting in outdoor or emergency as cases and 30 normotensive subjects enrolled for normal antenatal care as controls.

RESULTS

In our study, among the 30 hypertensive subjects (cases), 21 (70%) had a normal serum homocysteine (%3C; 15 μmol/L), while 9 subjects (30%) had hyperhomocysteinemia (%3E; 15 μmol/L).

On comparing this with 30 normotensive subjects (controls), 29 subjects (96.60%) had serum homocysteine within the normal range, while only 1 subject had hyperhomocysteinemia. This comparison was found to be statistically significant (Table 1).

We found that the mean value of serum homocysteine was 14.65 + 9.247 μmol/L among the 30 cases (hypertensive subjects), whereas the mean serum homocysteine was 8.63 + 3.71 μmol/L in controls (normotensive subjects). This difference was statistically significant (Table 2).

Among the 30 hypertensive subjects (cases), 18 subjects who had a positive history of intake of folic acid supplementation in the antenatal period of the present pregnancy had a mean serum homocysteine of 10.31 + 6.31 μmol/L, whereas 12 subjects in the same group who did not receive any folic acid supplementation had a higher mean serum homocysteine of 12.16 + 12.77 μmol/L. This comparison was found to be statistically significant. On comparing them with controls, all the subjects had folic acid supplementation in the antenatal period and their mean serum homocysteine was found to be 8.63 + 3.71 μmol/L, which was less than the mean serum homocysteine in the cases (Table 3).

All the normotensive subjects (n = 30) had a mean serum homocysteine of 8.41 + 3.57 μmol/L. Out of the 30 hypertensive subjects, 7 subjects had gestational hypertension, with a mean serum homocysteine of 8.18 + 3.79 μmol/L, whereas 5 subjects who had mild preeclampsia had a mean serum homocysteine of 8.85 + 5.57 μmol/L. On analysis, these data were not found to be statistically significant (Table 4).

Among the 30 hypertensive subjects, 7 had gestational hypertension with a mean serum homocysteine of 8.18 + 3.79 μmol/L, 5 subjects had mild preeclampsia with a mean serum homocysteine of 8.85 + 5.57 μmol/L, 11 had severe preeclampsia with a mean serum homocysteine of 9.93 + 5.10 μmol/L, 3 subjects who developed HELLP syndrome had a mean serum homocysteine of 19.63 + 26.29 μmol/L, and 4 subjects who developed eclampsia had a mean serum homocysteine of 16.06 + 4.68 μmol/L. This correlation was found to be statistically significant (Table 5).

DISCUSSION

In our study, we found that the mean value of serum homocysteine was 14.65 + 9.247 μmol/L among the hypertensive subjects, whereas the mean serum homocysteine was 8.63 + 3.71 μmol/L in the normotensive subjects. The results were similar to another study conducted by Makedos et al., who found in their study that the mean level of serum homocysteine was 11.11 μmol/L in preeclamptic women, while it was lower in normotensive subjects, i.e., 6.40 μmol/L.⁸ Powers et al. in the year 2001 conducted a study and also found a similar and significant difference in the serum level of homocysteine in preeclamptic subjects and normotensive subjects.⁹ Zeeman et al. in the year 2003 studied that the serum homocysteine concentration in patients with preeclampsia was higher in comparison to those with uncomplicated pregnancies.¹⁰

In our study, among the hypertensive subjects, those who had a positive history of intake of folic acid supplementation in the antenatal period of the present pregnancy had a mean serum homocysteine of 10.31 + 6.31 μmol/L, whereas those who did not receive any folic acid supplementation had a mean serum homocysteine of 12.16 + 12.77 μmol/L. In the control group, however, all the subjects had folic acid supplementation in the antenatal period, showing a lesser mean homocysteine concentration (8.63 + 3.71 μmol/L).

Our results were similar to another study conducted by Qureshi et al. in the year 2010, where they found a significant difference in the serum homocysteine value in the pre-supplementation and the post-supplementation group of women. Those in the pre-supplementation group had a mean serum homocysteine of 19.10 ± 4.87 μmol/L, while it was 10.01 + 1.25 μmol/L in the post-supplementation group. In a healthy pregnant woman, the mean serum homocysteine was 14.60 + 0.25 μmol/L in the pre-supplementation group, while it was 9.12 + 0.54 μmol/L in the post-supplementation group.¹¹ Patrick et al. conducted a study in 2004 and found an inverse relationship between serum homocysteine and serum folate concentration in preeclampsia.⁴

Leeda et al. observed a significant reduction in the mean fasting homocysteine levels from 16.6 to 6.1 μmol/L following daily supplementation of folate for 10 weeks in women with a history of preclampsia.¹²

In our study, we found that the normotensive subjects had a mean serum homocysteine of 8.41 + 3.57 μmol/L. Out of all the hypertensive subjects, those having gestational hypertension had a mean serum homocysteine of 8.18 + 3.79 μmol/L, whereas those with mild preeclampsia had a mean serum homocysteine of 8.85 + 5.57 μmol/L. Our study was similar to another study conducted by Haranzadeh et al. in 2008, in which they concluded that there is no significant difference in the mean serum homocysteine level between normotensive pregnant women (8.8 + μmol/L vs 10.4 + 2.3 μmol/L) and women with mild preeclampsia.¹³

In our study, out of all hypertensive subjects, those who had mild preeclampsia had a mean serum homocysteine of 8.85 + 5.57 μmol/L, subjects with severe preeclampsia had a mean serum homocysteine of 9.93 + 5.10 μmol/L, those who developed HELLP syndrome had a mean serum homocysteine of 19.63 + 26.29 μmol/L, and lastly subjects with eclampsia had a mean serum homocysteine of 16.06 + 4.68 μmol/L. Thus, it was seen that in more severe cases of the disease, the mean value of serum homocysteine was also higher as compared to mild preeclampsia and gestational hypertension. Ingec et al., in the year 2005, also demonstrated a positive relationship between increased serum homocysteine and the severity of preeclampsia.¹⁴ Singh et al. in 2008 supported the fact, through their study, that the severity of preeclampsia was directly related to homocysteine concentration.¹⁵ Guven et al. conducted a study in the year 2009 and found that the mean serum homocysteine levels in subjects with mild PIH were 8.2 μmol/L, while in subjects with severe PIH, the mean value was 8.9 μmol/L.¹⁶

CONCLUSION

Since hypertensive disorders of pregnancy are one of the leading causes of maternal and neonatal morbidity and mortality, it is important to identify and reduce the modifiable risk factors associated with them; one of them being hyperhomocysteinemia, which has been shown to have implications in adverse maternal and neonatal outcomes. Folic acid is an important determinant of serum homocysteine. Hence, regular folic acid supplementation should be prescribed and measurement of serum homocysteine for the risk assessment of developing PIH can be undertaken.

REFERENCES

1. Baumann MU, Bersinger NA, Surbek DV. Serum markers for predicting preeclampsia. Mol Aspects Med 2007;28:227–244.

2. Rajkovic A, Catalano PM, Malinow MR. Elevated homocyst(e)ine levels with preeclampsia. Obstet Gynaecol 1997;90:168–171.

3. Refsum H, Ueland PM, Nygard O, et al. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62.

4. Patrick TE, Powers RW, Daftary AR, et al. Homocysteine and folic acid are inversely related in black women with Preeclampsia. Hypertension 2004;43:1279–1282.

5. Dekker GA, de Vries JI, Doelitzsch PM, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–1048.

6. Goddijn-Wessel TAW, Wouters MGAJ, van de Molen EF, et al. Hyper-homocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynaecol Reprod Biol 1996;66:23–29.

7. Hogeveen M, Blom HJ, den Heijer M, et al. Maternal homocysteine and small for gestational age offspring: systematic review and meta-analysis. Am J Clin Nutr 2012;95:130–136.

8. Makedos G, Papaniculaou A, Hitoglou A, et al. Homocysteine, folic acid and B12 serum levels in pregnancy complicated with pre eclampsia. Arch Gynecol Obstet 2007;275:121–124.

9. Powers RW, Evans RW, Ness RB, et al. Homocysteine and cellular fibronectin are increased in preeclampsia, not transient hypertension of pregnancy. Hypertens Pregnancy 2001;(20):69–77.

10. Zeeman GG, Alexander JM, Mcintire DD, et al. Homocysteine plasma concentration levels for the prediction of preeclampsia in women with chronic hypertension. Am J Obstet Gynecol 2003;189:574–576.

11. Qureshi SB, Ahmad M, Qureshi PM, et al. Hyperhomocysteinemia, vascular related pregnancy complications and the response to vitamin supplementation in pregnant women of Pakistan. J Pak Med Assoc 2010;60(9):741–745.

12. Leeda M, Riyazi N, de Vriesa JI, et al. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998;179:135–139.

13. Hasanzadeh M, Ayatollahi H, Farzadnia M, et al. Elevated plasma total homocysteine in preeclampsia. Saudi Med J 2008;29(6):875–878.

14. Ingec M, Borekci B, Kadanali S. Elevated plasma homocysteine concentrations in severe preeclampsia and eclampsia. Tohoku J Exp Med 2005;206(3):225–231

15. Singh U, Gupta HP, Singh RK, et al. A study of changes in homocysteine levels during normal pregnancy and pre-eclampsia. J Indian Med Assoc 2008;106(8):503–505.

16. Guven MA, Coskun A, Ertaz IE, et al. Association of maternal serum CRP, IL-6, TNF-ALPHA, homocysteine, folic acid and vitamin B12 levels with the severity of preeclampsia and fetal birth weight. Hypertens Pregnancy 2009;28:190–200.