Int J Adv Pharm Biol Sci Vol.2, Issue 3, COMPARISON BETWEEN NIFEDIPINE AND METHYLDOPA ON BLOOD PRESSURE AND FETAL OUTCOME IN PRE-ECLAMPSIA

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1 Int J Adv Pharm Biol Sci Vol.2, Issue 3, INTERNATIONAL JOURNAL OF ADVANCE PHARMACEUTICAL AND BIOLOGICAL SCIENCES Vol. 2, Issue. 3, July-September 2012 ISSN Research Article Available online COMPARISON BETWEEN NIFEDIPINE AND METHYLDOPA ON BLOOD PRESSURE AND FETAL OUTCOME IN PRE-ECLAMPSIA Ganeshan.S 1*, Dr. Narmadha M.P 2, Dr. Paranjothy 1, Lakshmi Narayanan B 1, Alin Bose J 1, Dr. Viswanath B A 1 1 Aditya Bangalore Institute of Pharmacy Education and Research, Bangalore Swamy Vivekananda College of Pharmacy, Tiruchengode, Tamilnadu Received: 28 th May 2012, Revised and Accepted: 10 th July 2012 *Corresponding author: ganeshanpharma@gmail.com ABSTRACT Objective: To compare the effects of Nifedipine and Methyldopa on maternal blood pressure as well as fetal outcome in patients with Pre-eclampsia. Design: A randomized control study. Subjects: A total of 120 patients with PIH were allocated alternatively to either group. The patients in Group A received methyldopa (250 mg/day); Group B received methyldopa along with atenolol (25 mg/day) and Group C received nifedipine (10 mg/day). Measurements: Blood pressure, blood counts, kidney function tests, lipid profiles, urin alysis, Apgar score, baby birth weight, in relation to parity, recurrent fits, mode of delivery, length of hospital stay and Perinatal outcomes were noted. Results: The mean blood pressure on entry was 152/104 mm/hg in the group. During treatment the mean diastolic pressure was significantly reduced in nifedipine group (16%) p. There were no changes in lipid profiles were triglycerides ( ) and high density lipoprotein ( ) p were increased. Platelet count was decreased in all treatment groups with p value Serum creatinine was elevated ( ) and uric acid with mean ( ). The results showed no difference between the groups with respect to mode of delivery and baby birth weight. Conclusion: The results showed that nifedipine treatment lead to a better BP control and a safer fetal outcome with reduction of blood pressure, proteinuria, serum creatinine level and platelet count in normal range. Apgar score was better for nifedipine when compared to methyldopa or methyldopa along with atenolol. Keywords: Pre-eclampsia, Methyldopa, Nifedipine, Atenolol, Apgar score. INTRODUCTION High blood pressure complicates almost 10% of all pregnancies. 1 It is a major cause of maternal mortality world wide. 2 Preeclampsia may lead to eclampsia, intrauterine growth retardation, perinatal morbidity and mortality. 3,4 Pre-eclampsia is an important health problem everywhere, danger for both the mother

2 and the fetus, unpredictable in its onset or progress and incurable except by termination of pregnancy. 4 Pre-eclampsia may endanger the life of the mother by uncontrolled high blood pressure or by cerebral hemorrhage which is a prominent feature in a women dying of preeclampsia. 5 Not only the hypotensive agents be able to lower the blood pressure, but also they prevent the maternal complications and to improve fetal outcomes. 6 The antihypertensive drugs that may be used in pregnancy are methyldopa, betablockers, calcium channel blockers and vasodilators. Methyldopa has been available for many years and is widely used. Current literature supports the safety and efficacy of nifedipine and atenolol is used in essential hypertension in pregnancy. So the main aim of our study is to compare the antihypertensive effect of nifedipine with that of Methyldopa / methyldopa + atenolol. The drug methyldopa has extensive experience with its use in pregnancy and there is no evidence of adverse effects on the fetus. The disadvantage is the maternal side effect profile, which includes lethargy, drowsiness and depression. Nifedipine is a calcium channel blocker which reduces blood pressure mainly by vasodilatation. It has more gradual onset and longer period of action. The main objective of antihypertensive treatment in preeclampsia is to prevent intra cranial bleeding and left ventricular failure in pregnant women. 7 MATERIALS AND METHODS The study was a randomized control study; patients were primigravidae with mild Preeclampsia. Mild pre-eclampsia is the blood pressure of 140/90 mm/hg or above, but below 160/100 mm/hg in two readings and their urine showing 2+ or more of albumin by dipstick. Women were considered to enter this study, if blood pressure is more than 140/90 mm/hg and age group between years. Those women with history of significant medical complications (e.g., diabetes, chronic nephritis) were excluded. Patients were randomly allocated to the treatment group, Group A Patients receiving 250 mg of Methyldopa (n = 40), Group B patients receiving methyldopa along with Atenolol (n = 40), Group C Patients receiving 10 mg of Nifedipine (n = 40) and control (n = 40) were normal healthy pregnant women. Detailed questionnaire including demographic data, clinical and obstetrical history were filled. All the patients were asked about their complaints specifically and symptoms that is headache, abdominal pain, vomiting, visual disturbances, palpitations, dizziness and fatigue. In all patients blood pressure was measured by mercury sphygmomanometer and recorded. The maternal investigations included: platelet count, hemoglobin, lipid profiles (LDL, TC, TG, HDL and VLDL), serum creatinine, blood urea, proteinuria, uric acid and other tests such as HIV, HBs Ag. The data were noted at the time of admission and I and II review. Perinatal outcomes such as baby birth weight, Apgar score were also noted after the delivery. STATISTICAL ANALYSIS Data were recorded as mean, standard deviation and standard error of mean (SEM). Statistical analysis used is ANOVA (Tukey Kramer multiple comparisons test) and the P value <0.05 was considered significant. RESULTS Out of 120 primigravidae cases enrolled for the study, 40 patients received a fixed dose of (250 mg/day) methyldopa, 40 patients received methyldopa (250 mg/day) along with atenolol (25 mg/day) and 40 patients received nifedipine (10 m g / d a y ). D i f f e r e n t c l i n i c a l a n d b i o c h e m i c a l v a r i a b l e i n t h e 192

3 Variable Age in years BMI (kg/m 2 ) TG (< 150 mg/dl) On Admission On Final Review HDL(35-60mg/dl) On Admission On Final Review Serum Creatinine ( mg/dl) On Admission On Final Review Table 1 Mean SD of the treatment groups and control Methyldopa Methyldopa+ Atenolol Nifedipine Control 21.3± ± ± ±2.60 (0.3475) (0.600) (0.3899) (0.5831) 23.28± ± ± ±0.81 (0.2987) (0.7179) (0.2857) (0.1813) 182.6± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.18 P values Uric Acid (2-7mg/dl) On Admission On Final Review 7.70± ± ± ± ± ± ±0.73 >0.005 >0.005 Table 2 Maternal outcomes in the various treatment groups Variables Days of stay in the hospital Methyldopa Methyldopa + Atenolol Nifedipine <10days 10 to 20 days 28 (70%) 12 (30%) 30 (75%) 10 (25%) 32 (80%) 07 (20%) Vaginal delivery 38 (95%) 38 (95%) 40 (100%) Caesarean delivery 2 (5%) 2 (5%) None Recurrent fits 3 (7.5%) 2 (5%) None 193

4 There was no significant difference among the three treatment groups in the variables BMI, Hemoglobin, LDL, TC, VLDL, FBG, Blood Urea and Proteinuria were found to be within normal limits. However the difference between three test groups and control were significant. None of the patients in the three groups showed intra uterine growth retardation. Out of total 120 cases 75% stayed for less than 10days in the hospital. Both systolic and diastolic blood pressure was found to be elevated in pre-eclampsia women than that of control group women. Treatment of pre-eclampsia with different anti hypertensives definitely helped to reduce blood pressure (BP), but BP did not attain normal status. Proportion of decrease was found to be more in nifedipine group women. Lipid profile showed levels of LDL, TC and VLDL (103.9, , mg/dl). However triglycerides and HDL did not attain normal level. All the treated groups showed elevated levels of triglycerides (182.6, and mg/dl) P (0.0285), when compared to control women (133.5mg/dl) and were slightly reduced in the third trimester (177.37, and mg/dl) P (0.0312). Mean HDL was less than normal and did not show improvement during study period. No significant difference was observed in hemoglobin between test and controls (11.49 g/dl vs g/dl) P (0.2055). Platelet count showed decreased levels in all the groups, additionally levels of decrease in platelets was very high in test groups when compared to control group (1.068 Vs lakhs cells/mm 3 ) (P ). Fasting blood glucose did not show significant differences among groups. Pre-eclampsia raises serum creatinine level and this is evident in our results also. Nifedipine treatment helps to reduce comparatively better than other drugs, but serum creatinine has not at all reached normal in any of the groups. Blood urea levels are not affected in preeclampsia women, it showed normal status. Analysis of urine of pre-eclampsia women shows comparatively higher level of proteinuria with that of control women (301.5 Vs mg/24 Hrs). Treatment has not shown any change in proteinuria level. Uric acid is also increased in preeclampsia and shows only a slightest decrease in uric acid level and this decrease in three groups was not statistically different. All patients were under obstetrician s supervision for at least a week time before delivery and vaginal section was the common mode of delivery among pre-eclampsia patients (95%) and (5%) each in methyldopa and methyldopa + atenolol group women undergone caesarean section (Table 2). There were no significant differences in the mean baby birth weight of test and control women. Apgar score showed significant difference. Nifedipine treated group showed similar score as that of control whereas the remaining two groups showed a less score. None of the patients developed abruptio placenta. There were two neonatal deaths in methyldopa along with atenolol group. (Table 3) Apgar score is measured to assess the health of new born child immediately after child birth. It is done routinely 60 seconds after the birth of the infant and then is repeated five minutes after birth. The Apgar score is a number calculated by scoring the heart rate, respiratory effort, muscle Tone, Skin color and reflex irritability. Each of these objective signs can receive 0, 1 (or) 2 points. Scores 3 and below are generally regarded as critically low, 4 to 6 fairly low and 7 to 10 generally normal. DISCUSSION This study was carried out to compare the effects of methyldopa, methyldopa with atenolol and nifedipine in mild preeclampsia. Pre-eclampsia is particularly common in young pregnant women, in our 194

5 t e + a n if e d Int J Adv Pharm Biol Sci Vol.2, Issue 2, Table 3 Different neonatal outcomes Methyldopa Methyldopa+ Nifedipine Control P values Variable Atenolol Baby birth weight (kg) (0.0099) (0.2088) ( ) ( ) * Apgar scores 0 to3-critically low 4 to 6- fairly low 7 to 10- normal (0.1382) (0.2134) ( ) ( ) Apgar score (Appearance, Pulse, Grimace, Activity, Respiration) Figure 2 Systolic BP of different treated groups BLOOD PRESSURE mm Hg methyldopa methyldopa+atenolol nifedipine control systolic blood pressure on admission systolic blood pressure on review Figure 2 Diastolic BP of different treated groups BLOOD PRESSURE mm Hg Diastolic blood pressure on admission Diastolic blood pressure on review m t e h ldy m opa t e y h ldop a i p i n e c on l tro l ono l 195

6 study we observed that 71.1% were young women; this is in concordance with Choudhary 8 study (97.2%). In preeclampsia women, triglycerides are usually high, this has been reported by Rubina aziz et al 9 with a mean triglyceride of mg/dl and our Indian pre-eclampsia women presented with a mean triglyceride of mg/dl. Though in both populations, the level is high; in Indian women it is comparatively less. A study by Ceyhan et al 10 showed no difference in hemoglobin in mild and severe pre-eclampsia. In our study participants also, we found that the hemoglobin values were normal. According to Jaremo et al 11, they found that there was a significant decrease of platelet count in pre-eclampsia group. Platelet count was significantly low (80%) in our pre-eclampsia group and it was very low ( , , , lakhs cells/mm 3 ) in all the treatment groups when compared to normal pregnancy and not much improved during treatment. In normal pregnancy, there is a concomitant decrease in serum creatinine and urea concentrations. In case of preeclampsia there is a rise in serum creatinine with normal blood urea. According to Saloka et al 12, 80% of the pre-eclampsia group had increased serum creatinine with normal blood urea, while all pre-eclampsia women in our study had an increased level of serum creatinine and also normal blood urea. According to James J Walker 13 reported that there will be increased level of proteinuria and uric acid levels in pre-eclampsia patients. Same was observed in our study with an increase in proteinuria at the time of admission which touched the upper limit of normal range at the end of treatment but still remained high when compared to control group. There was also an elevated uric acid which slightly decreased in all groups though it was statistically insignificant. Antihypertensive treatment in preeclampsia could help to decrease uric acid slightly but levels remain high as compared to control group. Among the three antihypertensive drugs, nifedipine was better in reducing uric acid levels. According to Choudhary 8, majority of patients were discharged within 10 days. In our study many of the patients (75%) resumed to normal BP after delivery and were discharged within 10 days (7.4 ± 1.506) of their hospital admission. Rest of the 25% patients required further stay for BP control and they were discharged within 20 days (12.6 ± 1.430) of hospital admission. Elhassan et al 14, in their study found that there were no significant differences in maternal complications, with that of control. There were no maternal complications in our study group with only 3.3% caesarean section. The mean birth weight of babies showed no significant difference in all the three treatment groups. According to literature, birth weights of babies tend to increase in pre-eclampsia. Our study results also show a slight increase in baby weight than that of control group ( , , kg/m 2 ). However it did not affect either mother or baby, probably due to timely treatment. Babies born to normal healthy mothers showed highest Apgar score (8.95) in comparison with babies born to mothers treated for pre-eclampsia and their score was in the lower limit of normal score. Among the three groups treated, babies in nifedipine group showed a greater Apgar score than other two groups (8.025, and 7.3). Borghi 15 reported a better BP control in nifedipine group compared to methyldopa group with 20% and 16% reduction in diastolic blood pressure respectively. In our study participants also BP was well controlled in nifedipine group when compared to methyldopa group or methyldopa along with atenolol group. Nifedipine showed a significant decrease in a reduction of up to 16% diastolic 196

7 pressure and 14% decrease with methyldopa treatment (Figure 1 and 2). Our study shows blood pressure control in both groups treated with either methyldopa or nifedipine. Nifedipine acts by direct arterial vasodilation by inhibiting entry of calcium ions in smooth muscle which could be helpful to relieve vasospasm. Nifedipine decreases the amplitude and frequency of uterine contractions and inhibits both spontaneous and induced contractions. CONCLUSION Nifedipine shows a better blood pressure control than methyldopa or methyldopa along with atenolol by preventing the progress of mild pre-eclampsia to severe pre-eclampsia, without prolonging the pregnancy or increasing birth weight. The effectiveness of nifedipine as an antihypertensive agent, smooth muscle relaxant and tocolytic agent and its lack of major maternal or fetal side effects make it a safe and effective drug for pregnant women in whom its use is indicated. Although there were no direct fetal benefits, this study would be beneficial if conducted in larger population with follow up for long years. REFERENCES 1. National high blood pressure education program working group, report on high blood pressure in pregnancy. Amer.J.Obstet.Gynec.1990; 163: Kauntiz A.M, Hughes J.M, Grimes D.H, Smith J.C, Rochat R.W and Kaffrissen M.E. Causes of maternal Mortality in the United States of America.J.Obstet. Gynec 1985; 65: Martikainen A.M, Heinonen K.M and Saarikosi S.V. The effect of hypertension in pregnancy on fetal and neonatal condition. Intern. J. Obstet. Gynec. 1989; 30: Sibai B.M, Mercer B and Sarinoglu C. Severe pre-eclampsia in the second trimester: Recurrence risk and long-term prognosis. Amer.J.Obstet.Gynec. 1991; 165: Rubin PC, Clark DM, Summer DJ, Low R.A, Butter L, Reynolds B, Steedman D and Reld J.L. Placebocontrolled trial of atenolol in treatment of pregnancy-associated hypertension. Lancet. 1983; 1: Chamberlain G.V, Lewis P.J, De Sweit M and Bulpitt C.J. How obstetricians manage hypertension in pregnancy. Brit. Med. J. 1978; 1: Arias F. Practical guide to high risk Pregnancy and Delivery. 2 nd ed. Harcourt India private limited. 2001; p Choudhary P. Eclampsia: a hospital based retrospective study. Kathmandu university medical journal. 2003; 1(4): Rubina Aziz, Tabassum Mahboob.Pre-eclampsia and lipid profile. Pak J Med Sci. Oct Dec 2007; Vol 23: No (5): Ceyhan T, Beyan C, Bafler, Kaptan K, Güngör S. The effect of pre-eclampsia on complete blood count, platelet count and mean platelet volume. Ann Hematol 2006; 85: Jaremo P, Lindahl TL, Lennmarken C, Forsgren H. The use of platelet density and volume measurements to estimate the severity of preeclampsia. Eur J Clin Invest. 2000; 30: Salako BL, Odukogbe O, Adedapo KS, Aimakhu C. Serum albumin, creatinine, uriacacid and hypertensive disorders of pregnancy. East African medical journal. 2003; p

8 13. James J Walker. Pre-Eclampsia. The Lancet 2000; Oct 7; 356: Elhassan EM, Mirghani AB. Methyldopa versus no drug treatment in the management of mild preeclampsia. East African medical Journal. 2002; p Borghi C. Comparison between nifedipine and methyl dopa on bloodpressure control, uteroplacental hemodynamic and fetal outcome in pre-eclampsia. Communication. 2005; 198