Hypertension in Pregnancy, Early Online:1–10, 2010Copyright © Informa Healthcare USA, Inc.ISSN: 1064-1955 print / 1525-6065 onlineDOI: 10.3109/10641955.2010.507840

LHIP1064-19551525-6065Hypertension in Pregnancy, Vol. 1, No. 1, Jul 2010: pp. 0–0Hypertension in PregnancyVitamin C and E Supplementation Does Not Reduce the Risk of Superimposed PE in PregnancyHypertension in PregnancyKalpdev, Saha, and Dhawan

Arun Kalpdev,1 Subhash Chander Saha,1 and Veena Dhawan2

1Department of Obstetrics & Gynecology, Post Graduate Institute of Medical Research and Education (PGIMER), Chandigarh, India2Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research (PGIMER), Chandigarh, India

Background. Oxidative stress could play a role in the development of preeclampsia.There is some evidence to suggest that vitamin C and E supplements can reduce therisk of the disorder. We hypothesized its beneficial role in a group of pregnant womenwith essential hypertension. Methods. In this randomized controlled trial, we enrolled50 pregnant women with essential hypertension. We assigned the women 1000 mgvitamin C and 400 IU natural vitamin E (RRR a tocopherol; n = 25), daily from the sec-ond trimester of pregnancy until delivery or no supplementation (n = 25). Our primaryendpoint was development of superimposed preeclampsia, and main secondary end-points were aggravation of hypertension, need for admission, need to increase antihy-pertensive drugs, and small size for gestational age (<fifth customized birthweightcentile). Results. We analyzed 50 women who completed the study. The incidence ofsuperimposed preeclampsia was similar in vitamin and control groups (8% [n = 2] vs12% [n = 3], p = 1.000). Vitamin C and E supplementation also did not prevent aggrava-tion of hypertension in group of women who took it (12% [n = 3] vs 32% [n = 8], p = 0.172).Small size for gestational age babies did not differ between groups (4% [n = 2] vs 6%[n = 3], p = 1.000). Conclusion. Vitamin C and E supplementation does not preventdevelopment of superimposed preeclampsia in women with essential hypertension.Our results did not show any significant benefit of vitamin supplementation. Therewas some trend in lessening of hypertensive complications of pregnancy. Our resultsfailed to find any correlation between development of superimposed preeclampsia andoxidative stress.

Keywords Antihypertensives, Case–control study.

INTRODUCTIONPregnancies complicated by chronic hypertension are at increased risk ofdevelopment of superimposed preeclampsia. The reported rate of superim-posed preeclampsia in mild hypertension ranges from 10 to 22% and withsevere chronic hypertension approaches 50% (1). Essential hypertension isassociated with several vascular changes akin to oxidative damage. It is possi-ble that these changes make these hypertensive women more prone to develop

Address correspondence to Dr. Arun Kalpdev, Department of Obstetrics & Gynecology, Postgraduate Institute of Medical Education & Research, Sector 12, Chandigarh, 160012 India. E-mail: kalpdevdoc_arun@rediffmail.com

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superimposed preeclampsia. It has been documented that preeclampsia isaccompanied by oxidative stress that contributes to vascular dysfunction anddevelopment of preeclampsia (2,3). Oxidative stress arises from increased pro-duction of reactive oxygen species (ROS) or deficiency in antioxidant nutri-ents. It has been suggested that deficiency in antioxidants would be associatedwith the development of preeclampsia (2,4). The placenta, maternal leuko-cytes, and the maternal endothelium are likely contributors for free radicalgeneration in preeclampsia. The free radical generation can result in theplatelet aggregation and vasospasm, the two important characteristics ofpreeclampsia, by inactivating endothelium-derived relaxing factor (5) andinhibiting prostacyclin synthesis (6,7).

Antioxidant vitamins stabilize highly reactive free radicals and act as thefirst line of defense against free radical attack and lipid peroxidation (8).Vitamin E and vitamin C are powerful antioxidants (8–10). Vitamin E(a-tocopherol) is the major lipid-soluble antioxidant that protects cells againstlipid peroxidation and the inflammatory response (11) and has an importantfunction in regulating blood pressure. Vitamin C has been reported to have adirect effect on the inhibition of the constrictor response of resistance arteriesto a variety of stimuli. Synergism between the actions of vitamin E and vita-min C is also reported (12). Vitamin C and E maintain the vasodilator statusof blood vessels by inhibiting the formation of free radicals by oxidation ofnitric oxide (NO), the most important endothelium-dependent vasodilator,which is highly susceptible to oxidative damage.

Till date, various controlled trials have used antioxidants, that is, vitaminC and E (13), lycopene (14), selenium (15), and garlic (16) supplementation forprevention of preeclampsia but results are conflicting. Recently, two largemulticentric, randomized controlled trials results have failed to show any ben-efit of high-dose antioxidant supplementation in the prevention of preeclamp-sia (17,18). Aforementioned studies included heterogenous groups, inclusive ofvarious risk factors for development of preeclampsia, of women for predictingthe role of vitamin supplementation. There are no studies as yet where vita-min C and vitamin E supplementation have been used solely in pregnantwomen with essential hypertension.

As the etiology of essential hypertension, as well as its initiation, mainte-nance, pathogenesis, pathophysiology, and cardiovascular complications, isattributed to oxidative stress with an imbalance between ROS and the antiox-idant defense mechanisms (19–23), and additionally, hypertensive patientshave more oxidative stress with more ROS produced and a greater-than-normal response to oxidative stress, it was hypothesized that in this specificgroup vitamin C and vitamin E prophylaxis will reduce the incidence of super-imposed preeclampsia, a dreaded complication, in chronic hypertensivewomen.

METHODOLOGYParticipantsThis study was undertaken in the Department of Obstetrics and Gynecologyin the Postgraduate Institute of Medical Education and Research (PGIMER),

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Chandigarh, India. Fifty consecutive pregnant women with essential hyper-tension who attended Hypertensive Disorders of Pregnancy (HDP) Clinic ofPGIMER were enrolled for the randomized controlled trial. The study wasapproved by PGIMER Institutional Review Committee.

Our study started in June 2005 till June 2007. Last woman from druggroup delivered on January 30, 2007.

EligibilityWomen booked in HDP clinic with essential hypertension, with singletonpregnancy at gestational age 16–22 weeks, and giving consent for participa-tion in the study were included in the study. Women with multifetal gestation,known fetal abnormalities, illicit drug or alcohol abuse during current preg-nancy, intent to deliver elsewhere, women with renal hypertension, womenwith proteinuria at booking, and women taking preparations containing vita-min C and E were excluded from the study.

A diagnosis of chronic hypertension complicating pregnancy was madewhenever hypertension (blood pressure ≥140/90 mm Hg) preceded pregnancyor was diagnosed prior to 20 weeks’ gestation in the absence of gestational tro-phoblastic disease (24). Essential hypertension was defined as chronic hyper-tension with no obvious renal or other causes found.

InterventionWomen were randomized using computer-generated numbers to either vita-min group (receiving vitamin C and vitamin E) or control group (not receivingvitamin C and E). Women enrolled for vitamin supplementation received 500mg vitamin C twice daily (Limcee™ tablets; Nicholas Pharmaceuticals Ltd.,Vadodhra, India) and 400 I.U. natural vitamin E once daily (Bio-E™ soft gela-tin capsules; Dr. Reddy’s Pharmaceuticals Ltd., Hyderabad, India). All womenreceived iron, folic acid, and calcium as prophylaxis as per clinic protocol. Carewas taken to avoid preparations containing vitamin C and E.

Conduct of StudyAll women were followed up in HDP clinic of PGIMER as per clinic protocol.Detailed history was taken for each case. At booking each woman underwentfollowing tests as per clinic protocol: blood grouping, complete haemogram,serum electrolytes, renal function tests, urine routine examination, urineculture sensitivity, 24 h urine protein, glucose tolerance test, ultrasound of kid-neys, fundus examination, anticardiolipin antibody, and lupus anticoagulant.

Antenatal checkup was carried out every 2–3 weeks or more frequently ifrequired. Vitamin C and E supplementation was started from the time ofrecruitment. Antenatal admission was done as per patients’ requirements.During the antenatal follow-up, in each visit, women were screened for spoturine albumin, newly developed complaints were asked for, trend of bloodpressure since last visit was noticed, and proper intake of vitamin C and Ewas ensured. Frequent telephonic contacts were made to enquire about drugsintake and related side effects.

Antihypertensive treatment was given as per patients requirements. Anti-hypertensive medication was given to keep systolic blood pressure ≤140 and

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4 Kalpdev, Saha, and Dhawan

diastolic blood pressure ≤90 mmHg. Women were admitted if systolic BP was≥140 and/or diastolic BP was ≥100 mmHg on two subsequent records, 4–6 hapart. Increment in antihypertensive drugs was made when blood pressurerecord reached the level of systolic BP >140 and/or diastolic BP >100 mmHg ontwo subsequent records 6 h apart. As per clinic protocol, elective induction oflabor was advised beyond 37 weeks’ period of gestation even in uncomplicatedpregnant women, particularly if they were on antihypertensive medication.

Outcome MeasuresIn this study primary outcome measure was development of superimposedpreeclampsia. Secondary outcome measures were aggravation of hyperten-sion, need for admission, need to increase antihypertensive drugs, incidence ofHELLP, isolated low platelet count, liver enzymes ≥5 times in absence ofobstetric cholestasis, and eclampsia. Fetal/neonatal outcomes were incidenceof growth retardation/prematurity, gestation at delivery, birthweights, livebirth/still birth rates, APGAR scores at birth.

Preeclampsia superimposed on chronic hypertension was defined as new-onset proteinuria ≥300 mg/24 h in hypertensive women with no proteinuriabefore 20 weeks’ gestation or a sudden increase in proteinuria or bloodpressure or platelet count <100,000/mm3 in women with hypertension andproteinuria before 20 weeks’ gestation. No woman was recruited who had pro-teinuria at beginning. Aggravation of hypertension was defined as increase inblood pressure records requiring increment of or initiation of antihypertensivemedications for blood pressure control. Small for Gestational Age (SGA) wasdefined according to PGIMER neonatal growth curves which follow Lubchenco’sfetal growth retardation charts (25). Babies with birthweight < 1SD for thatgestational age were defined as SGA babies.

Biomarkers Assessment MethodsFerric reducing antioxidant power (FRAP) and malondialdehyde (MDA) levelsin venous blood samples were measured in all women at recruitment and atdelivery. From each woman 5 ml of venous blood sample was obtained todetermine FRAP and MDA levels. Antioxidant status of blood was measuredby performing FRAP assay and MDA assay to measure oxidative stress inblood. Blood samples were taken and send to the laboratory of ExperimentalMedicine and Biotechnology, PGIMER. Estimation of these biochemical mark-ers was done in Department of Experimental Medicine and Biotechnology. Allthe standards and chemical (extra pure grade) were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA) and Merck (Berlin, Germany). Forhigh-performance liquid chromatography (HPLC) procedures, all solvents andreagents used were of HPLC grade.

Total Antioxidant status was determined using a FRAP assay as describedby Benzie and Strain et al. (26). FRAP values were calculated from ferroussulfate standard curve. Results were expressed as μmol/L (μM) of plasma.Lipid peroxidation was determined by measuring levels of MDA as thiobarbitu-ric acid (TBA) adduct using colorimetric method of Satoh et al. (27). Sampleswere quantified using peak area at 532 nm OD. 1,1,3,3-tetraethoxy-propane(Sigma-Aldrich Chemical Co.) was used as a standard. The final values were

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Hypertension in Pregnancy 5

expressed as nM MDA/mg protein (nM/mg). The protein levels were quanti-fied using Bradford protein estimation at 595 nm OD.

Outcome measures were recorded in a prospective manner. A proforma wasdesigned for keeping patients record. After recruitment, patient was followedat the time of admission in labor ward and labor details were recorded.

STASTICAL ANALYSISData were analyzed by the software SPSS for Windows, release 11.5 (SPSS,Chicago, IL, USA), chi-square test, analysis of variance (ANOVA test), paired“t” test, and unpaired “t” test, where appropriate. Most of the variables at thetime of randomization had a non-normal distribution and therefore were ana-lyzed by the nonparametric Mann–Whitney test.

RESULTSAt study entry, maternal baseline characteristics in the two groups were similar(Table 1). Women were enrolled between 13 and 19 weeks’ period of gestation(POG). In drug group, women took vitamin C and E supplementation for mean132.72 days (SD 15.81, range 101–155 days).

Outcome MeasuresTable 2 shows the primary and secondary maternal outcomes. There were nosignificant differences between the vitamin group and the control group in therisk of preeclampsia. Aggravation of hypertension was an important outcomemeasure. None of the women recruited in the study developed eclampsia,

Table 1: Baseline characteristics.

Control group (n = 22) Vitamin group (n = 22)

Parity*Nulliparous 11 8Multiparous 14 14

BMI (kg/m2) 22.53 ± 5.05 24.17 ± 5.64Systolic BP (mmHg) 132.96 ± 8.51 131.36 ± 6.65Diastolic BP(mmHg) 85.44 ± 6.44 86.13 ± 4.79Biomarkers

FRAP (μM/L) 633.957 ± 211.96 613.55 ± 202.56MDA (nM) 0.130 ± 0.047 0.083 ± 0.062

*Values in numbers, rest all values mean ± standard deviation.

Table 2: Maternal outcome (n, % age)

Control group (n = 22)

Vitamin group (n = 22) p-Value

Superimposed preeclampsia 3 (12%) 2 (8%) 1.000Aggravation of hypertension 8 (32%) 3 (12%) 0.142Need for admission 8 (32%) 3 (12%) 0.142

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6 Kalpdev, Saha, and Dhawan

HELLP syndrome, isolated low platelet count, increased liver enzymes, pulmo-nary edema, hypertensive encephalopathy, retinopathy, or acute renal failure.Though the difference was not statistically significant, there was a trendtowards lesser hypertension-related complications in women who had receivedvitamin C and E supplementation. Increased proportion of women in controlgroup (80% vs 68%, p = 0.558) required initiation or increment of antihyper-tensive medications during pregnancy.

FETAL/NEONATAL OUTCOMEThere was no significant difference between fetal outcomes among bothgroups (Table 3). Mean gestational age at delivery was 36.17 weeks (SD 2.13)in control group and 37.17 weeks (SD 1.47) in drug group, respectively(p = 0.062), showing a trend towards prolongation of pregnancy in women ofdrug group.

Women in control group had more preterm birth compared to vitamingroup. Small size for gestational age babies did not differ between groups.There was no significant difference between the two groups of infants in themeasures of APGAR scores.

BIOMARKERS COMPARISON AT DELIVERYFRAP values showed greater increase in the vitamin group (272.04 μM) com-pared to control group (136.33 μM). Increment in FRAP values were statisti-cally significant in both the groups but vitamin group showed more increasecompared to the control group (p = 0.000 > p = 0.003) (Table 4). FRAP valuesshowed consistent change in relation to change in blood pressure when com-pared among the groups. Vitamin supplementation group had higher incre-ment in FRAP values compared to control group. In women who had noincrease in blood pressure during pregnancy, vitamin group had moreincrease in FRAP values compared to control group (33.99 vs 16.5%). Simi-larly, in subgroup including women with aggravation of hypertension, val-ues of FRAP were raised more in vitamin group (89.59 vs 31.84%), and insubgroup of women with superimposed preeclampsia FRAP values showedmore increment in vitamin group (77.25%) compared to control group(14.73%).

Table 3: Fetal/Neonatal outcome.

Control group (n = 22)

Vitamin group (n = 22) p-Value

Gestational age at delivery (weeks)* 36.17 ± 2.13 37.17 ± 1.47 0.062Preterm birth

<37 week 10 (40%) 3 (12%) 0.053<34 week 4 (13%) 1 (4%) 0.349

Birthwt. (kg)* 2.45 ± 0.53 2.71 ± 0.60 0.223Small for gestational age (SGA) 2 (8%) 3 (6%) 1.000

*Values in mean ± SD, rest of the values n (% age).

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Hypertension in Pregnancy 7

MDA levels did not show any significant increment at the time of deliveryeither in vitamin (p = 0.680) or in control group (p = 0.649) (Table 4). Inwomen with no change in blood pressure, in women with aggravation ofhypertension, and in women with superimposed preeclampsia, MDA levels didnot differ between vitamin and control groups in spite of vitamin C and Esupplementation.

DISCUSSIONOxidative stress has been a very promising candidate as an intervention sitein the pathogenesis of preeclampsia, and preliminary studies of the efficacy ofvitamins C and E in reducing the risk for the disease were encouraging (28).However, two recent large randomized controlled trials failed to show adecrease in the occurrence of preeclampsia in women receiving vitamin E andC supplementation (17,18).

In recently conducted VIP trial (17), 15% women in drug group compared to13% women in placebo group developed preeclampsia. Subgroup analysisshowed that in women with chronic hypertension 20% women in vitamin C andE group compared to 19% women in placebo group [RR 1·05, CI (0.82–1.35)]developed superimposed preeclampsia. Similar to these finding we also failedto find any significant difference in incidence of superimposed preeclampsia inwomen who had received vitamin C and E prophylaxis.

In the present study, more number of women in the control group comparedto that in vitamin group required addition of antihypertensive drugs for con-trolling blood pressure although the result did not show statistically signifi-cant difference. Contrary to this study result, Rumbold et al. (18) found anincreased risk of being prescribed antihypertensive drugs and of being admit-ted antenatally for hypertension in the vitamin group (5.2% women in vitamingroup cf. 3.4% women in placebo group) (17). In VIP trial (17) 3% women invitamin supplementation group compared to 1% women in placebo groupneeded intravenous antihypertensive therapy. Antenatal inpatient hospitalstay was also similar in both the groups.

Table 4: Biomarkers comparison (values in mean ± standard deviation).

Control group (n = 22)

Vitamin group (n = 22) p-Value

FRAP (μM)Recruitment 633.95 ± 241.96 616.55 ± 232.56 0.942Delivery 770.28 ± 216.13 888.59 ± 241.82 0.345No change in blood pressure 738.86 ± 258.48 826.12 ± 212.57 0.289Aggravation of hypertension 835.83 ± 162.36 1168.95 ± 191.32 0.022Superimposed preeclampsia 727.36 ± 128.37 1092.85 ± 272.73 0.125

MDA (nM/mg)Recruitment 0.13 ± 0.04 0.08 ± 0.06 0.005Delivery 0.12 ± 0.06 0.07 ± 0.05 0.007No change in blood pressure 0.11 ± 0.03 0.08 ± 0.05 0.023Aggravation of hypertension 0.14 ± 0.09 0.06 ± 0.01 0.203Superimposed preeclampsia 0.08 ± 0.07 0.05 ± 0.01 0.606

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8 Kalpdev, Saha, and Dhawan

In the present study preterm delivery rate in control group was more com-pared to that in drug group (40% vs 12%, p = 0.053). Compared to that in VIPtrial (17), mean gestational age at delivery was 37.4 weeks in vitamin groupand 37.6 weeks in placebo group.

In control group, significantly more women (p = 0.053) delivered at lessthan 37 weeks’ period of gestation. Very preterm delivery rate (<34 weeks’period of gestation), however, was similar in drug and control groups. A ten-dency towards prolongation of pregnancy in vitamin supplementation groupwas noted in our study. Our findings were opposite to the results shown by therecent trials (17,18). In VIP trial (17), 29% women in vitamin group comparedto 24% women in the placebo group [RR 1.07, CI 0.93–1.19] delivered at lessthan 37 weeks’ period of gestation. Proportion of women delivering at lessthan 34 weeks’ period of gestation was 12 and 10% in vitamin and placebogroups, respectively [RR 1.20, CI 0.95–1.59]. In the study by Rumbold et al.(18), preterm delivery rate was similar in placebo as well as in drug group (RR1.02, CI 0.73–1.43). Women delivering at less than 37 weeks’ period of gesta-tion were 6.9% in vitamin group compared to 6.7% in the placebo group.Again, 2.1 and 2.0% women delivered at less than 34 weeks’ period of gesta-tion in vitamin and in placebo group, respectively [RR 1.06, CI 0.57–1.97].Contrary to the findings in these trials, vitamin supplementation was noted toprolong the pregnancy duration in the study by Gulmezoglu et al. (29). In thisstudy, in women with severe preeclampsia, diagnosed between 21 and32 weeks of gestation, the proportion of women delivered within 14 days was52% (14/24) in the antioxidant group compared with 76% (19/29) in the pla-cebo group (RR 0.68, CI 0.45–1.04). This study showed a tendency towardsprolongation of pregnancy in the antioxidant group.

Oxidative Stress Markers – Antioxidant Levels MeasurementsMean value of MDA level was lower, though not statistically significant, invitamin group at recruitment and at delivery. This significant difference inMDA levels at recruitment and delivery could be a chance phenomenon.Contrary to our expectations, we found no significant change in the MDAlevels in women who developed superimposed preeclampsia and women withaggravation of hypertension in drug group as well as in control group. Ourfindings did not suggest any increase in “Oxidative Stress” in preeclampticwomen as compared to normotensive women or women with aggravation ofhypertension. Our findings are similar to various studies that had not foundany evidence of oxidative stress in preeclampsia (30–32).

There is a lack of consensus on whether there is an association between lipidperoxidation and preeclampsia. Llurba et al. (30) suggested that there is a lackof a generalized state of oxidative stress in women with preeclampsia. Thestudies by Diedrich et al. (31) and Bowen et al. (32) suggested that oxidativestress increases with the severity of HELLP syndrome and eclampsia. Thesestudies concluded that in less severe forms of the disease, the antioxidants andthe placenta were able to scavenge pro-oxidants. Regan et al. (33) pointed outthat the interpretation of conventional methods of lipid peroxidation may belimited by factors such as nonspecificity of the route of peroxide formation,imprecise analytical methodology, and ex vivo lipid peroxidation.

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Hypertension in Pregnancy 9

In the present study, FRAP levels were significantly higher at delivery incontrol as well as in drug groups (p = 0.003 vs p = 0.000). Nonsignificantlyhigher increment in FRAP levels were noticed with vitamin C and E supple-mentation. FRAP value did not show any consistent change with developmentof superimposed preeclampsia and aggravation of hypertension irrespective ofvitamin C and E supplementation. Although our selection of FRAP assay wasdependent on very peculiar characteristics of the assay, the FRAP reactionconditions are far from physiological and it must be noted that in vitro testingof plasma may not reflect in vivo hierarchies or activities (34,35). Biomarkersseen in this study do not support the hypothesis that preeclampsia is a resultof oxidative stress.

This study failed to show benefit of vitamin C and E supplementation inreducing the incidence of superimposed preeclampsia. There was a trendtowards lesser hypertensive complications, for example, aggravation of hyper-tension, need for hospitalization, and preterm birth, for those who took vitaminC and E supplementation. Further study with larger number of women isneeded to clarify the role of antioxidants in women with essential hypertension.

CONCLUSIONTill date no study has been published to find the role of antioxidants/vitaminC and E supplementation, exclusively, in women with chronic essential hyper-tension for prevention of superimposed preeclampsia and conclude for mater-nal and perinatal outcome. Our results did not show any significant benefit ofvitamin supplementation, though there was some trend in lessening of hyper-tensive complications of pregnancy. Our results failed to find any correlationbetween development of superimposed preeclampsia and oxidative stress.However, our study was small and much larger study is required to reach anyconclusion.

Declaration of InterestThe authors report no conflicts of interest. The authors alone are responsiblefor the content and writing of the paper.

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