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bjbj����	>ΐΐx�%�������������)))8a$�t)�$���"�������������$�����9�ig$��g$g$9������1C1C1Cg$����1Cg$�1C1C��4	������a�"?M�)+:��:����0�K�����<��t	�	������@���X1C� "Y���9�9��>Z����g$g$g$g$��������������������������������������������������������������������������������	�:	EFFECT OF FOLIC ACID ADMINSTERATION ON PLASMA HOMOCYSTEINE LEVEL IN PREECLAMPSAIA AMONG EGYPTEAN POPULATION

Yasser Ibrahim Orief (1), Elsayed Nayel (1), Mohamed Mohamed El Sawy (2)
Siham Atef Morsy (1) , Ahmed Samy Alagawany (1)

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Alexandria.
Department of Clinical Pathology, Faculty of Medicine, University of Alexandria.

Correspondence:

Yasser Orief 

Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University, Egypt.

E mail:   HYPERLINK "mailto:yaserorief@yahoo.com" yaserorief@yahoo.com

URL:     www.yaserorief.net

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Abstract 

Objective:
 Hyperhomocysteinemia (HHCh) appears to cause endothelial dysfunction through direct toxic and oxidative stress mechanisms. It can damage the decidual blood vessels and result in faulty placentation with its consequences. HHCh was found to be seven times more common in women with history of severe preeclampsia. The aim of this study was to determine the effect of folic acid administration on the maternal serum homocysteine level in mild and severe pre-eclamptic cases between 28 and 32 weeks of gestation. 
Setting: 
The study was conducted on forty pre-eclamptic patients recruited from Elshatby Maternity University Hospital, Alexandsria, Egypt.
Study design: 
The cases were subdivided into two groups; 20 mild and 20 severe pre-eclamptic cases. Each group was subdivided into two subgroups 
Ten cases will take folic acid 5mg daily from 28 to 32 weeks. 
Ten control cases (no folic acid administration).
Results: The present study found that plasma homocysteine level was lowered after folic acid administration for both mild and sever cases. In the control group who did not receive folic acid, they had high homocysteine level after one month than on admission. 
Conclusion: According to the results folic acid can be administrated till the second trimester of pregnancy to decrease   the risk of preeclampsia.
Condensation
folic acid can be administrated till the second trimester of pregnancy to decrease   the risk of preeclampsia.
Key words:
Preeclampsia, Homocysteine, folic acid.

Introduction
Preeclampsia is a multi-system disorder characterized by hypertension and proteinuria in the last half of pregnancy. Although most affected pregnancies deliver at term or near term with good maternal and fetal outcomes, these pregnancies are at increased risk for maternal and/or fetal mortality or serious morbidity. The clinical findings can manifest as a maternal syndrome of hypertension (systolic BP > 140 mmHg or diastolic BP> 90 mm Hg), proteinuria > 0.3 g/day) with or without oedema and /or a fetal syndrome of growth restriction. (1) Severe preclampsia is defined by the presence of one or more of the following: severe gestational hypertension (systolic > 160 mmHg or diastolic >110 mmHg on at least two occasions and severe proteinuria (5 g or more in 24 hr urine specimen or 3+or greater on two random urine samples collected at least 4 hours apart) with or without oedema.(2) Preclampsia complicates 5-7 % of all pregnancies, and its life threatening  manifestations make it a major cause of maternal and prenatal morbidity and mortality world wide, hence there is a critical need for strategies to predict, prevent   and improve  management of this disorder.(3) 
Homocysteine is produced when the amino acid methionine is broken down in the body. Elevated homocysteine levels (hyperhomocysteinemia) may cause irritation of the blood vessels leading to an increased risk of atherosclerosis as well as venous thrombosis which could eventually result in a heart attack and or stroke.
Homocysteine (Hcy) is a thiol-containign amino acid produced by the intracellular demethylation of methionine. Hcy is exported into plasma where it circulates mostly in its oxidized forms bound to plasma proteins. Smaller amounts of reduced homocysteine and disulfide homocystine (Hcy-SS-Hcy) are present. Total homocysteine represents the sum of all Hcy species found in plasma and serum (free plus protein-bound). Hcy is either metabolized to cysteine or to methionine. In the vitamin B6 dependent trans-sulphuration pathway Hcy is irreversibly catabolised to cysteine. A major part of Hcy is re-methylated to methionine, mainly by folate and cobalamin-dependent enzyme methionine synthase. Hcy accumulates and is excreted into the blood when these reactions are impaired. (4-6)
Some people have elevated homocysteine levels caused by a deficiency of B vitamins and folate in their diets. High homocysteine levels are also seen in people with kidney disease, low levels of thyroid hormones, psoriasis, and with certain medications (such as antiepileptic drugs and methotrexate). Patients who have the genetic variant called methylene tetrahydro folate reductase, (MTHFR) that impairs their ability to process folate are also having elevated levels of homocysteine.(7) 

 There are variable classifications for what is considered an elevated homocysteine level.  Normal  and  abnormal  values are set by individual laboratories. Typically, a level less than 13 �mol/L is considered normal. A level between 13 and 60 �mol/L is considered moderately elevated, and a value greater than 60 to 100 �mol/L is severely elevated.(8)
There are certain implications of having elevated homocysteine that are specifically relevant for women. Elevated homocysteine levels have been observed more frequently among women with certain pregnancy complications, including preeclampsia, placental abruption, recurrent pregnancy loss, and cases of  intrauterine growth retardation .(9) However, medical research suggests that elevated homocysteine levels may be a consequence of these complications, rather than the cause. 
The role of folic acid and homocystiene in the pathogenesis of preeclampsia has been recently described. However, their relationship with preeclampsia or ecclampsia is not well established.(10, 11) Several studies were conducted to show an association between the level of homocystien and preeclamptic disorders,(12) Preeclampsia in nulliparous women with elevated homocystien is 7.7 to 12.9 times more common than in normal controls.(13,14) The association of hyperhomocysteinemia and preeclampsia has been suggested initially by Dekker et al.(15) These authors demonstrated that hyperhemocystenemia was 7 times more common in women with a history of severe preeclampsia. According to these authors, women with early-onset of preeclampsia showed an 18% incidence of hyperhomocysteinemia compared with a 2.5% incidence in the normal population.(15)  
Materials and methods
The study was conducted on forty pre eclamptic patients recruited from the preeclampsia clinic in El Shatby Maternity University Hospital.
Inclusion criteria:
Pregnant females between the 28th & 32nd weeks of gestation.
Mild preeclamptic cases (ie, blood pressure more than 140/90 on  two occasions 6 hours apart after 20 weeks of gestation with Proteinuria 2 + with or without oedema).(1)
Severe preeclapmtic cases (ie, blood pressure more than 160/110, Patients having significant proteinuria more than 500 mg/24 hours and oedema)(1)

Exclusion criteria: 	
Pregnant females with chronic hypertension which is diagnosed if there is persistent elevation of blood pressure to at least 140/90 mmHg before 20th weeks of gestation on two occasions more than 24 hours apart. 
Pregnant females with gestational hypertension alone which is diagnosed when blood pressure is more than 140/90 mmHg without proteinuria.

The recruited patients are subdivided into two groups; 
Group I: 20 patients with mild preeclampsia. 

Group II: 20 patients with severe preeclampsia.
Each group will be subdivided into two subgroups 
Ten cases will take folic acid in a dose of 5mg the Nile-company pharmaceuticals and chemical industries daily from 28 to 32 weeks. 
Ten control cases (no folic acid administration).

After approval of the medical ethics committee and signing a written informed consent all patients will be subjected to:
Full history taking and complete general examination.

Laboratory investigation (before and after administration of folic acid):
Plasma homocysteine by ELISA. 
 Complete urine analysis to exclude urinary tract infection and to detect and measure proteinuria, 
Complete blood picture
Coagulation profile
kidney function tests: serum uric acid, creatinine clearance , blood urea , serum creatinine
 liver function tests: serum bilirubin, liver enzymes (ALT & AST)
Ultrasound examination before and after folic acid administration
Ultrasound scanning of the fetus to detect the growth rate
Umbilical artery and middle cerebral artery Doppler 

Statistics was performed using Statistical Package for Social Science (SPSS) version 17. Testing normality using Kolmogorov-Smirnov test proved that some of data sets (variables) are abnormally distributed, so median and standard error of the mean were used for descriptive statistics and non-parametric tests were used for comparison. Comparison of distribution for the categorical variable was performed using cross tabulation with Chi square test or any of the corrected Chi square as indicated. Alpha error was set to 5%. 


Results 
Preeclampsia is a pregnancy specific disorder characterized by vasospasm and endothelial dysfunction, and complicates 7�10 % of all gestations with serious fetomaternal morbidity and mortality. (16)
Homocysteine is an intermediate amino acid in the methionine metabolism, which does not take place in the structure of proteins. It is eliminated from the body via conversion into 1- cystathione by a reaction catalyzed by vitamin B6, and two methionine catalyzed by vitamin B12 and folic acid. Homocysteine is found in low concentrations in all tissues under normal conditions where as accumulates in tissues and plasma if those catalytic vitamins are depleted. Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases and common obstetric problems. Preeclamptic patients also tend to have higher plasma homocysteine levels. (17-19)
Serum concentrations of homocysteine decrease during normotensive pregnancy parallel to the physiologic fall of albumin concentration and folic acid supplementation, but increases in preeclampsia like some other pregnancy complications (20-22). Hyperho-mocysteinemia might be a cause rather than just a marker of adverse pregnancy outcome. In a study conducted on early pregnancy losses, hyperhomocyste-inemia was shown to decrease total vessel surface and hence to disrupt placental perfusion (23). 
In the present study, regarding blood pressure, there was statistical significant differences between mild and severe groups, severe group had values statistically higher than mild group before and after folic acid administration. (table I)
Regarding control group, the mean of systolic blood pressure for mild control was 153.50(9.73 and 146.00(9.66 on admission and  after one month respectively. Also, the mean systolic blood pressure for severe control was 177.00(14.38 and 160.50(17.55 on admission and after one month respectively 
Regarding mild group There was no statistical significant differences between cases and control after one month, regarding sever group, there was statistical significant differences between cases and control after one month, cases group have values statistically higher than control group after one month of treatment.
The present study showed that the elevated homocysteine level is directly correlated with key features of pre-eclampsia (p<0.00 for systolic, diastolic blood pressure and proteinuria) (tables I,II) and its levels were higher in sever than mild preeclampsia. So, high maternal homocysteine levels seem to have causal role in the etiopathogenesis and severity of pre-eclampsia. In fact our study suggests the measurement of serum homocysteine in all pregnant women as a part of routine antenatal care especially those with high risk of developing preeclampsia.
Sayyah, et al., (24) found that, there was no significant difference between the pre-eclampsia group that received 5 mg/day folic acid and control group regarding the mean arterial pressure in his study to evaluate the effect of high dose and low dose folic acid on the levels of hemocysteine (Hcy) concentration during the first trimester of pregnancy and at delivery, and to examine the association of Hcy serum levels and preeclampsia. It was a single blinded randomized clinical trial, which was conducted in Tabriz, Iran, from 2005 to 2008. 246 nulliparous pregnant women in 2 similar groups, received folic acid daily from early pregnancy until delivery (5 mg/day in group one and 0.5 mg/ day in group 2). The incidence of hypertension and laboratory changes in the levels of serum Hcy, lactate dehydrogenase, and uric acid in addition to the levels of urine creatinine and protein were compared between the groups. There was no presence of any type of hypertension in each group. The systolic blood pressures (BP) (mm Hg) at the first trimester were 114.01(8.78 for group one, 114.16�(9.05 for group 2, and at delivery, 117.24�(6.91 for group one, and 117.23�(11.48 for group 2 (p=0.32). The diastolic BP at the first trimester were 74.90(7.45 for group one, 73.30�(8.90 for group 2, and at delivery 76.46�(5.58 for group one, and 76.69�(8.62 for group 2 (p=0.42). Although the level of Hcy (�mol/L) decreased significantly at the delivery time in group one (11.81�(3.85 decreased to 6.44�(1.88), and 2 (9.08�(3.24, decreased to 7.44�(2.99), this decrement was more significant in the first group (p<0.001). The results show that folic acid supplement throughout pregnancy, irrespective of the dosage, could eliminate hypertensive disorders, and decreases serum level of Hcy, although it is reduced more significantly in the first group.
In the current study as regard cases ,as shown in table III, the mean concentration of homocysteine for mild group were 23.18(3.23 and 14.89(3.18 for cases before and  after folic acid administration respectively, before folic acid administration cases have values statistically higher than after folic acid administration. As regard mild control the mean of homocysteine was 24.55(3.30 and 29.03(3.81 on admission and after one month respectively, they had values statistically higher on admission than after one month. On the other hand, control group after one month have values statistically higher than cases after one month. As regard sever group the mean of homocysteine for severe cases were 22.89(2.55 and 17.96(2.74 before and  after folic acid administration respectively. 
As regard sever control, the mean of homocysteine were 19.18(3.27 and 27.47(3.50 on admission and after one month respectively. The values after one month were statistically higher than on admission. On the other hand, control group after one month have values statistically higher than cases after one month. When compared between mild and severe groups, regarding cases group, after folic acid administration severe group had values statistically higher than mild group, while regarding control group, mild control on admission, had values statistically higher than severe control. 
The present study agreed with Leeda et al. (25) who treated 14 patients with a history of severe preeclampsia syndrome and hyperhomocysteinemia in the previous pregnancy, with folic acid and found that although half of them developed preeclampsia the outcome was better. Also the present study agreed with Van Pampus et al. (26) who demonstrated that hyperhomocysteinemia was seven times more common in women with history of severe preeclampsia. Dekker et al.,(27) in a review of several prospective and retrospective studies found that the presence of hyperhomocysteinemia increased the relative risk (RR) of preeclampsia by 1.32�3.2, while the RR reached 9.7 in primiparas and 6.9 in obese patients. 
In another study Powers et al.(28) they found a significant difference in the serum levels of homocysteine between preeclamptics and controls (9.0 vs. 7.0 mol/l). The objective of this study was to confirm that the endothelial dysfunction is present in preeclampsia and absent in transient hypertension of pregnancy, and to determine whether the cardiovascular risk factor is associated with the degree of endothelial dysfunction. they measured total plasma homocysteine in samples collected at the time of admittance to labor and delivery in 17 women with preeclampsia, 16 women with transient hypertension of pregnancy (only increased blood pressure), and 34 normal pregnant women. Each subject with preeclampsia was matched by prepregnancy body mass index, race, and gestational age at delivery to one subject with transient hypertension of pregnancy and two controls.  They found that total plasma homocysteine was also significantly increased in the preeclamptic patients  compared to subjects with transient hypertension of pregnancy or normal pregnant women (8.3 (2.5 microM versus <5.5 (2.2 and 5.4 (3.4 microM respectively, p<0.01). The increased concentrations of homocysteine observed in preeclampsia are not a general feature of all hypertensive complications of pregnancy. Furthermore, endothelial dysfunction is present in preeclampsia and is not evident in transient hypertension of pregnancy. However, the apparent endothelial dysfunction in preeclampsia is not explained by the increase in homocysteine concentrations observed. More recent studies have found a positive association between hyperhomocysteinemia in preeclamptic patients and endothelial dysfunction. (29-32) 
Charles et al(33) studied the baseline serum folate in women who booked for antenatal care prior to, and after 17 weeks gestation to assess the role of folate supplementation and antepartum hemorrhage, pre-eclampsia, and low birth weight. According to the results of this trial, the effect of folic acid taken throughout the pregnancy is unclear, and folic acid supplementation commenced after the first trimester of pregnancy confers any benefit, and supports the recommendation that periconceptual folate supplements should not be continued throughout the pregnancy. In this study, folic acid was only given at 400 �g per day. 
Murphy et al. ( HYPERLINK "" \l "R31" 34) present additional analyses of data from their longitudinal study on homocysteine in plasma from 93 healthy women, collected 2 10 weeks before conception; at gestational weeks 8, 20, and 32; and immediately before delivery. Data presented show an increase in homocysteine from week 32 of gestation. They also found that the homocysteine concentration at delivery in mothers not supplemented with folic acid was essentially similar to that measured before conception. They also correlated the maternal homocysteine concentrations from preconception throughout pregnancy and at birth with homocysteine concentrations cord blood. The concentrations of both maternal and fetal homocysteine were lowered by folic acid supplementation. Finally, maternal homocysteine at preconception, at 8 weeks, and at birth was inversely related to birth weight. 
The present study disagreed with Fern�ndez, et al.(35) who showed that, the increase of plasma homocysteine (Hc) in pregnant women, who later develop preeclampsia/eclampsia and its pathogenic role in toxemia of pregnancy, is still controversial. Ninety six pregnant women of low economic background were studied on the first prenatal consultation; 27 women in the first trimester of pregnancy and 59 in the second. After 8 hours of fasting, venous blood was extracted and each patient was provided with 1 mg folic acid tablets and instructed to ingest one tablet daily, and to come back to the laboratory after three months. Basal homocysteine concentrations were 4.0(2.1 micromol/L and 4.8(2.1 micromol/L in the first and second trimesters respectively, with no significant modifications after three months of folic acid. Although the degree of desertion from the study was high, it was possible to determine the evolution of 65 pregnancies, ten of them developed preeclampsia (15.4%). No significant differences were found in Hc concentrations, or the frequency of hyperhomocysteinemia in the different stages of pregnancy, between women with normal gestation and those who developed preeclampsia.
Steegers-Theunissen et al., (36) in their study to assess associations between vitamin-dependent homocysteine metabolism and vascular-related pregnancy complications by considering interval between delivery and postpartum investigation and maternal age. A case-control study performed at the University Medical Center Nijmegen in the Netherlands. Patients had experienced pregnancy-induced hypertension (n = 37), preeclampsia (n = 144), hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 104), recurrent early pregnancy loss (n = 544), abruptio placentae (n = 135), intrauterine growth restriction (n = 144), or intrauterine fetal death (n = 104). Controls comprised 176 women with uncomplicated obstetric histories. Oral methionine loading tests and fasting vitamin profiles were performed more than 6 weeks after delivery. They found that hyperhomocysteinemia was associated with an approximately 2  to 3-fold increased risk for pregnancy-induced hypertension, abruptio placentae, and intrauterine growth restriction. Cobalamin deficiency was associated with HELLP syndrome, abruptio placentae, intrauterine growth restriction, and intrauterine fetal death. Pyridoxal 5-phosphate deficiency increased the risk for pregnancy-induced hypertension 4-fold. These associations lost their significance after adjustment for time interval and maternal age. High red cell folate was associated with a decreased risk for abruptio placentae and intrauterine growth restriction. An increased creatinine concentration was associated with pregnancy-induced hypertension, preeclampsia, HELLP syndrome, and abruptio placentae. Hyperhomocysteinemia and vitamin deficiencies are largely determined by the interval between delivery and postpartum investigation and by maternal age. Time interval and maternal age should be considered in the risk estimation for vascular-related pregnancy complications.
In the present study, regarding complete blood count (table IV) as regard mild group, mild cases and mild control after one month have values statistically higher than on admission. Regarding white blood cells (WBC) there was no statistical significant differences between mild and severe cases on admission and after month. On the other hand for the control group (mild and severe), they had values statistically higher on admission than after one month. Regarding platelets there were no statistical significant differences between both groups on admission, while after one month the severe cases had values statistically higher than mild group Also, after one month the mild control group had values statistically higher than severe control group. (P=0.023). 
     The Aspartate transaminase (AST), (tableV) In the cases of the mild pre-eclampsia group, AST ranged from 29 to 42 and 25 to 39 with a mean of 35.30(4.57 and 31.0(4.42 on admission and after one month respectively, test revealed significant differences between on admission and after one month (P=0.023),  in the control group, AST ranged from 15 to 38 and 29 to 40 with a mean of 28.0(6.46 and 35.20(4.02 on admission and after one month respectively, test revealed significant differences between on admission and after one month (P=0.004), there were statistical significant differences between cases and control regarding AST. (P=0.020). In the cases of severe pre-eclampsia group, AST ranged from 25 to 40 and  19 to 39 with a mean of 32.70(5.40 and 31.0(5.40 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.273), and in control group, AST ranged from 25 to 35 and 25 to 46 with a mean of 30.90(3.21 and 33.70(7.35 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.142), there were insignificant differences between cases and control regarding AST. (P=0.202). Regarding Alanine transaminase (ALT) (u/l),in the cases of mild pre-eclampsia group, ALT ranged from 15 to 36 and 12 to 30 with a mean of 22.70(6.00 and 20.20(4.94 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.161), and in control group, AST ranged from 19 to 39 and 13 to 40 with a mean of 28.70(7.35 and 21.60(7.52 on admission and after one month respectively, test revealed significant differences between on admission and after one month (P=0.023), there were insignificant differences between cases and control regarding ALT. (P=0.314) In severe pre-eclampsia group, regarding cases, ALT ranged from 15 to 33 and  15 to 39 with a mean of 24.90(7.02 and 24.10(7.68 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.405), and in control group, ALT ranged from 15 to 20 and 11 to 32 with a mean of 18.10(1.79 and 20.0(7.42 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.221), there were insignificant differences between cases and control regarding ALT. (P=0.120)There were statistical significant differences between mild and the severe groups on admission regarding ALT. (P2=0.001).
Regarding Renal function tests (table VI), in the cases of mild pre-eclampsia, urea ranged from 5 to 18 and 12.1 to 18.1 with a mean of 14.10(4.93 and 15.52(1.67 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.200) .In the control group, urea ranged from 3 to 11 and 5.6 to 13 with a mean of 7.34(2.38 and 9.92(2.03 on admission and after one month respectively, test revealed significant differences between on admission and after one month (P=0.009), there were statistical significant differences between cases and control regarding urea. (P=0.000) In the cases of severe pre-eclampsia, urea ranged from 8.1 to 17 and 5.8 to 16 with a mean of 12.61(3.22 and 10.34(4.36 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.101), and in control group, urea ranged from 9 to 61 and 5 to 12 with a mean of 15.30(16.08 and 8.82(2.40 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.112), there were insignificant differences between cases and control regarding urea. (P=0.173). Creatinine (mg/l)in the cases of mild pre-eclampsia group ranged from 0.4 to 0.9 and 0.4 to 0.8 with a mean of 0.74(0.18 and 0.61(0.14 on admission and after one month respectively, test revealed significant differences between on admission and after one month (P=0.045), and in control group, creatinine ranged from 0.3 to 1.2 and 0.35 to 0.9 with a mean of 0.54(0.27 and 0.62(0.17 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.219), there were insignificant differences between cases and control regarding Creatinine. (P=0.417).In the cases of severe pre-eclampsia group,creatinine ranged from 0.1 to 2.1 and 0.21 to 1.1 with a mean of 0.74(0.77 and 0.49(0.24 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.177), and in control group, creatinine ranged from 0.4 to 0.81 and 0.67 to 0.88 with a mean of 0.69(0.12 and 0.73(0.07 on admission and after one month respectively, test revealed insignificant differences between on admission and after one month (P=0.191), there were significant differences between cases and control regarding creatinine (P=0.004). These findings can be explained by the fact that the severity of preeclampsia may be selective and variable in its presentation causing multisystem generalized vasospasm i.e. cardiovascular, respiratory hepatic, renal, central nervous system and coagulation systems are affected to variable degrees as reported by the study of Hutter and Crighton et al.(37) 
     Regarding the Doppler indices, systolic/diastolic ratio (S/D ratio) and resistance index (RI) for both the umbilical and middle cerebral arteries (table VII) , our results agree with those of Mari et al.(38). They showed gradual increase in end-diastolic flow with subsequent decline in Doppler indices from 28 weeks to 32  of gestation. These changes may be explained by a decrease in placental vascular resistance. In fact, throughout pregnancy, the overall increase in placental size associated with increase in the number of villi results in a continuing expansion of the umbilical-placental vascular tree and therefore a decreasing vascular resistance. These changes in umbilical artery, flow velocity waves and Doppler indices are also in agreement with that reported by Adruini and Rizzo (39) who demonstrated that for the umbilical artery resistance index at 30 weeks, the 5th percentile was 0.74, the 50th percentile was 1.08 and the 95th percentile was 1.44. Also they are in agreement with  Kwon et al,(40) who defined the abnormal umbilical artery Doppler velocimetry in the 3rd trimester as umbilical artery systolic diastolic ratio more than 3. In the present study, at 30 weeks gestation, the 95% Lower confident limit was 2.06, the mean value was 2.50 and the 95% Upper confident limit, was 3.01. (39,40)  
 In the present study, serum foliate was significantly correlated to umbilical artery resistance index (table VIII, IX). This is in agreement with Vollset et al. ,(41) who stated that, serum foliate is significantly correlated to umbilical artery resistance index and pulsatility index. These results supports the hypothesis that foliate may be important in adequate trophoblastic proliferation including the tertiary stem villi.

Correlations (table X)
	There were no correlation between homocystein level before and after folic acid administration regarding the studied parameters.  Among mild cases, there were positive correlation between homocystein level before treatment regarding SBP and platelet count, while there was negative correlation between homocystein level after treatment and Proteinuria. (P=0.028). Among severe cases, there was positive correlation between homocystein level before treatment and DBP and Proteinuria, while there was  negative correlation between homocystein level after treatment and serum creatinine. (P=0.038). There was no correlation between homocystein level before and after treatment among mild control regarding the studied parameters. Among severe control, there was positive correlation between homocystein level before treatment and urea (P=0.033).

Comments:
     The current study determined that homocysteine level was lowered by folic administration till 28 -32 weeks of gestation in pre-eclamptic patients. Thereby, we recommend the routine clinical practice to prescribe folic acid at a dose of 5 mg/day for pregnant women, in the second and third trimesters in addition to the first trimester to decrease the incidence of developing pre-eclampsia specially in high risk patients. Further studies and meta analysis are still needed to support these results.
Acknowledgements
We herby acknowledge the nursing stuff of the pre-eclamsia unit of Elshatby Maternity University Hospital for their great effort in assisting in completion of this work.


	 

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Arduini D and Rizzo. Normal values of pulsatility index from fetal 9:Dklm������������M	_	�	���ɷɬ����������mV?V-h�e�h/#LB*CJOJQJ^J_HaJph-h�e�hP1|B*CJOJQJ^J_HaJph*h�e�h)oU5�B*CJH*\�_HaJphh9B�5�B*H*\�_Hphh9B�5�B*\�_Hphh9B�5�B*H*\�phh9B�5�B*\�ph#h�'�h)oU5�B*CJ \�aJ ph#h�'�h�'�5�B*CJ \�aJ ph#h�'�h�^�5�B*CJ \�aJ ph#h�'�hP1|5�B*CJ \�aJ phlm���?	�	�	�	�	�	�	

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Kwon JY, Kwon HS, Kim YH and Park YW. Abnormal Doppler velocimetry is related to adverse peri-natal outcome for borderline amniotic fluid index during third trimester J Obstet Gynaecol Res. Dec 2006; 32(6): 545-9. 
Vollset SE, Refsum H, Irgens LM et al. Plasma total homocysteine pregnancy complications and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutrit. 2000;71: 962�968

















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