Vitamin C And Vitamin E Supplementation In Pregnant Women At Risk For Pre Eclampsia : A Randomized Controlled Trial.

A stract
Evidence suggests that antioxidant supplementation reduces risk of preeclampsia. Our aim was to investigate the potential benefit of antioxidants in women with risk factors of preeclampsia. A total of 285women identified at risk of preeclampsia were administered vitamin C !!! mg" vitamin E 2!!mg # placebo from 2 weeks of pregnanc$ till deliver$ in intention to treat. %he patients were randoml$ assigned to drug groups. %he &ncidence of preeclampsia" intrauterine growth retardation" and caesarean between placebo and vitamin group were compared and were found to be same. 'ut preterm birth reduced in statisticall$ significant number in vitamin group (O) * !.28" C& * !.2 + !.,," p * !.! -.

Introduction
.re+eclampsia is a multis$stem disorder characteri/ed b$ h$pertension and .roteinuria occurring in second half of the pregnanc$. %his condition is best described as a pregnanc$ specific s$ndrome of reduced organ perfusion secondar$ to vasospasm and endothelial activation. %he exact incidence of pre+eclampsia is unknown" but about 50 pregnant women develop pregnanc$ induced h$pertension. Out of this 150 will have one ma2or complication.2" Eclampsia is responsible for nearl$ 20 of all maternal mortalities in world2 and .80 mortalit$ in 34. As per 5ational 6amil$ 7ealth 8urve$ 2!!5+2!!9 &nternational institute of population 8ciences :umbai (2!!;-" !.10 women will have convulsions. 'ecause of the seriousness of the condition studies to find means of preventing and treating pre+eclampsia are ver$ important. 7$pertension along with hemorrhage and sepsis forms the deadl$ triad responsible for ma2orit$ of maternal deaths. %here is increasing evidence that pre+eclampsia is associated with both increased oxidative stress and reduced antioxidants defenses. Circulating levels of oxidative stress markers have been found to be elevated and that of antioxidants depressed in women with pre+

eclampsia compared to women without the disorder. 1" these observations on the effects of oxidative stress in pre+eclampsia have given rise to increase interest in the potential benefits of antioxidant therap$ given for the prevention of h$pertensive disorders of pregnanc$. Antioxidants are a diverse famil$ of components that function to prevent overproduction of and damage caused b$ noxious free radicals. Examples of antioxidants include <itamin E and C. various studies including one b$ Chappell et a l= showed that dail$ supplements of <itamin C !!!mg and =!!mg significantl$ reduced a pregnant woman>s risk of developing pre+eclampsia. 7owever" a recentl$ published review article obtained from Cochrane ?ibrar$ b$ 5icolas . .ol$/os et al. 5 stated that there was no difference in development of pre+eclampsia between vitamin and placebo groups. 8imilar findings were reported b$ other studies.9" ; &n view of conflicting findings" there is need for more studies including ours. &n most of the previous studies the dose of <itamin E given was =!!mg. 7owever" some reports including one b$ @usuf et al 8 in the literature reported adverse effects of <itamin E =!!mg and therefore it was decided to reduce its dose to 2!!mg for the present stud$.

! "ecti#es
%he aims of the stud$ wereA .rimar$ aim . %o investigate whether supplementation b$ <itamin C !!!mg and <itamin E 2!!mg decreases the incidence of h$pertensive disorders of pregnanc$ 8econdar$ aim . %o substantiate the observation that prime .ara are at more risk of preeclampsia as compared to multi+gravida. 2. %o find out the difference in incidence of pre+eclampsia" small for gestational age(below !th percentile- and .reterm or low birth weight babies(less than 2.5 kg- and Caesarean section rate between the vitamin and placebo group . 1. %o make recommendations accordingl$.

$%pot&esis

.re+eclampsia is associated with both increased oxidative stress and reduced antioxidants defenses. Circulating levels of oxidative stress markers have been found to be elevated and that of antioxidants depressed in women with pre+eclampsia compared to women without the disorder. %hese observations on the effects of oxidative stress in pre+eclampsia have given rise to increase interest in the potential benefits of antioxidant therap$ given for the prevention of h$pertensive disorders of pregnanc$. Antioxidants are a diverse famil$ of components that function to prevent overproduction of and damage caused b$ noxious free radicals. %his stud$ is designed to test the h$pothesis that treatment of pregnant women with antioxidants would alter endothelial cell in2ur$ linked to preeclampsia reducing the incidence of h$pertensive disorder during pregnanc$.

'et&ods
%he stud$ was conducted in the Bepartment of Obstetrics and C$necolog$ of Covernment :edical College 7ospital" Chandigarh. %he present stud$ was prospective randomi/ed control interventional trial conducted during the period extending from Dune 2!!9 to August 2!!;. A total of 285 primigravida attending antenatal clinic were enrolled#registered. %he group &A was administered orall$ vitamin+C !!!mg and vitamin+E 2!!mg and was labeled as intervention group (<itamin Croup-. %here were =5 sub2ects in this group. %he group &' consisting of =! primigravida sub2ects was randoml$ selected and was given oral placebo. 7ence it was labeled as placebo group. Bouble blinding was ensured b$ random allocation of stud$ sub2ects and coding of drugs .Another group comprising of !! multi+gravida women (group+&&- was also registered and was labeled as low risk group" intended to be meant for substantiating the findings that multi+gravida are at low risk for development of preeclampsia. 7ence a total of 185 sub2ects ( =5 of group &A" =! of group &' and !! of group &&- were enrolled for the stud$. All the above women were given iron and folic acid from 2 weeks of pregnanc$ onwards to complete !! doses. All the above women were followed up throughout pregnanc$ for an$ evidence of gestational h$pertension or pre+ eclampsia" and an$ evidence of intra uterine growth retardation (&3C)-" incidence of preterm births and Caesarean section rates. Assessors were trained for giving interventions and evaluating outcome parameters efficientl$ before conducting the stud$. 6or further anal$sis onl$ women satisf$ing following inclusion criteria were selectedA agreeing to participate in the stud$" were primigravida with singleton pregnanc$" and willing to deliver at our &nstitute. %he exclusion criteria were women with '. E 1!#85 mm7g at enrollment or alread$ on antih$pertensive treatment" with proteinuria" intent to deliver elsewhere" suffering from medical disorders like diabetes" h$poth$roidism etc" known fetal malformations" or alread$ using <itamin C (more than 5! mg- or vitamin E (more than E ;5 &3#da$-" or

58A&B (5on steroidal anti+inflammator$ drug-. 8tatistical anal$sis was done b$ using 5ormal test of proportions" Chi sFuare+test" Odds ratios along with ,50 confidence interval. 8.88+ 2 software was used for conducting statistical anal$sis.

Results
At the outset with the aim of substantiating whether primi are at higher risk for various complications like preeclampsia" preterm labor" &3C)" ?8C8 etc." their incidence in primi was compared with multi+gravida mother without an$ intervention in either group. %here were = cases of eclampsia out of total of !! multi gravida in contrast to cases in primigravida (group &'-. 8ince among multi+gravida (group+&&- pre+eclampsia" as compared to primi+gravida (group+&'- was significantl$ less even without intervention" this group && + was excluded from further anal$sis. Out of =! primigravida registered as group &'" 8 were lost to follow up and 9 delivered outside. %hus final anal$sis was for !, sub2ects. Out of total =5 primi+gravida registered and intended for intervention (&A group-" 9 lost to follow up and 22 delivered outside. 7ence final anal$sis for !; sub2ects was done. %he patients of placebo and vitamin group were well matched economicall$ and educationall$" compared to placebo group" vitamin group has less pre+eclampsia disorder but it was not statisticall$ significant (O) * !.==" p * !. 2-. 7owever a chance association finding of reduced rate of preterm birth (birth weight G 2.5 kg- was observed in supplemented group (O) * !.28" C& * !.2 to !.,," p * !.! - which is statisticall$ significant. Crowth retarded babies did not show an$ statisticall$ significant reduction in supplemented group as compared to placebo group (O) * !.,1" C& * !.18+2.1 " p * !.82" H2 * !.!1-.<itamin supplementation could not significantl$ reduce the caesarean rate (.*!.=2-" odds ratio corresponding to the mode of deliver$ was found to be !.;9. 5o adverse events or side effect was observed in an$ of the intervention group (%able -.

(Ta le)*+ C!'PARISI!, !F C!'P-ICATI!,S !F PRE)EC-A'PSIA I, TW! .R!/PS

0iscussion
%he overall incidence of pre+eclampsia was ;.!=0 which is in agreement with ;.90 incidence observed b$ 7auth et al., Observing no significant difference in the incidence of pre+eclampsia between vitamin and placebo group b$ present stud$ is in agreement with other authors.5"" 9 %he latter group used same doses of <itamin C but <itamin E dose was more (i.e. =!!mg- compared with 2!!mg used in our stud$. Compared with # !; (,. 0incidence in placebo group" the incidence of pre+eclampsia was lessI 5# !, (=.80- in vitamin group but its incidence in multi+gravida (group+&&- was also lowI onl$ =# !! (=0even without intervention" substantiating the finding of multiJgravida being at lower risk of pre+eclampsia. A 8outh Australia based stud$1 also concluded that no relation of eclampsia with vitamin C or E levels exists. %he$" however used a reduced dose of vitamin C ( 58 mgand vitamin E (9.;9 mg-. %he stud$ b$ Doseph A et al ; also concluded that no relationship exists even after using vitamin C ( !!!mg- and vitamin E (=!!mg-. Our anal$sis does not support to the h$pothesis that vitamin C ( !!! mg- and vitamin E (2!!mg- supplements given proph$lacticall$ from 2 weeks onwards leads to reduction in the rate of pre eclampsia in women at risk for this condition. One earl$ trial reported that vitamin C and vitamin E significantl$ did not reduce the risk of pre eclampsia. = 7owever" the most recent trials 1"5"9"; nor our trial could substantiate this finding. )isk of growth restricted babies did not show an$ statistical significance reduction in vitamin supplemented group. 6indings of a non randomi/ed stud$ , indicate that high dose vitamin E could lead to a reduction in the birth weight of babies" but no such association was found in our randomi/ed control trial. Even caesarean section rate did not show an$ statistical difference. %he rate of low birth babies born less than 1; weeks was lower in statisticall$ significant numbers in supplement group in our stud$" which is not supported b$ an$ previous stud$" instead in a trial b$ ? .oston the rate of low birth weight babies increased in supplemented group. 9 A Cochrane meta anal$sis1 of antioxidant supplements for pre+eclampsia suggests a modest benefit" but includes studies in which micronutrients other than antioxidants were used. &n another stud$ vitamin C supplements or placebo were given to women at risk of preterm labour to investigate the h$pothesis that gestation would be prolonged. %he stud$ was terminated earl$ because of an increase in spontaneous preterm labour in the treatment group. 'ut Cochrane reviews role of vitamin E and C 1 supplementation in pregnanc$ emphasi/e the need to establish the safet$ of their use in high doses in pregnant women. %he efficac$ of dietar$ supplementation of <itamin C ( !!! mg- and vitamin E (2!! mg- in high risk pregnant women for proph$laxis of pre+eclampsia reFuires larger multicentric trials to

support our results. &nterpretation of the results + taking into account our stud$ h$potheses antioxidant did not lead to reduction in the rate of pre eclampsia in women" but can reduce the rate of preterm deliveries.

Conclusion
%he supplementation of vitamin E and vitamin C to pregnant women at risk of preeclampsia did not alter the rate of development of preeclampsia" intrauterine growth retardation or the rate of caesarean sections in this stud$. <itamin E and vitamin C supplementation did decrease the risk of preterm deliveries in the vitamin group as compared to placebo group. 7owever" larger multicentric studies are needed to support these results.

Ackno1ledgements
%he stud$ was conducted in the Bepartment of Obstetrics and C$necolog$ of Covernment :edical College 7ospital" Chandigarh.%his stud$ was approved b$ &nstitutional Ethics Committee of Covernment :edical College Chandigarh. )egistration + under department of science and technolog$" Chandigarh Administration 5o + 8K%#).# + 2,# %echnolog$" Chandigarh" &ndia %he authors are thankful to :rs. 4amlesh a medical social worker" working at the Bepartment of C$necolog$ and Obstetrics Covernment :edical College and 7ospital Chandigarh. #!5#2 18+2 =1 BA%EB #!5. 6unding+%his stud$ received financial grant from Bepartment of 8cience and

Re2erences
. Cunningham 6C" Cant 56" ?eveno 4D et al. 7$pertensive disorders in pregnanc$. &n Lilliams Obstetrics" 22 Ed" 5ew @ork" :c Craw+7ill" 2!!5" pp ;92+8!8. 2. .ark 4. .reventive :edicine in Obstetrics" .ediatrics and Ceriatrics. .arks %extbook of .reventive and 8ocial :edicine. , edition 2!!; 'anarasi Bas 'hanot Dabalpur. p ==9. 1. )umbold A)" Crowther CA et al. <itamins C and E and the risks of pre+eclampsia and perinatal complications. 5 Engl D :ed 2!!9I 15=A ;,9+8!9. =. Chappell ?C" 8eed .%" 'rile$ A et al. Effect of antioxidants on the occurrence of preeclampsia in women at increased riskA a randomi/ed trial. ?ancet ,,,I15=(, 8-A8 !+ 8 9.

5. 5icolaos .. .ol$/os" Bavide :auri" :aria %sappi et al. Combined vitamin C and E supplementation during pregnanc$ for preeclampsia preventionA A s$stematic review. Obstetrical and C$necological 8urve$ 2!!;I92(1-A2!2+2!9. 9. .oston ?" 'rile$ A?" 8eed .%" 4ell$ 6D et al. <itamin C and E in pregnant women at risk for preeclampsia (<&. trial-A randomi/ed placebo M controlled trial. %he ?ancet 2!!9I19;A =5+5=. !(9-A 1 + 1 8. ;. Doseph A8" 8alvio 6" Doao ?." :aril/a <C et al. Antioxidant therap$ to prevent preeclampsia. Obstetrics and C$necolog$ 2!!;I 8. @usuf 8" Bagenais C" .ogue D et al. <itamin E supplementation and cardiovascular events in high risk patients. %he 7eart Outcomes .revention Evaluation 8tud$ &nvestigators. 5 Eng D :ed 2!!1I1=2 (1-A 5=+ 9!. ,. 7auth DC" Ewell :C" ?ewine )D et al. .regnanc$ outcomes in health$ nulliparous who developed h$pertension. Obstet C$necol 2!!!I 55A2=+28. !. 'oskovic )" Cargaun ?" Oren B" B2ulus D" 4oren C. .regnanc$ outcome following high doses of vitamin E supplementation. )eprod %oxicol 2!!5I 2!A 85+88 . 8te$n .8" Odendaal 7D" 8choeman D" 8tander C" 6anie 5" Crove B. A randomised double+blind placebo+controlled trial of Ascorbic acid supplementation for the prevention of pre+term labour. D Obstet C$necol 2!!1I 21A 5!+ 55.