Is Magnesium Sulphate more Effective than Placebo in Prevention of Seizure in Mild Preeclampsia? A Randomized Placebo-Controlled Clinical Trial

Gestational hypertension and mild preeclampsia represent the most common medical complications of pregnancy [1]. Preeclampsia is characterized by the new onset of hypertension and proteinuria. Severe pre-eclampsia can involve several organs such as liver, kidneys, clotting system and brain [2-6]. Eclampsia refers to the occurrence of newonset generalized tonic-clonic seizures in women with preeclampsia [7]. Pre-eclampsia and eclampsia are the second leading direct cause of maternal morbidity [8]. Eclampsia occurs in 2-3 percent of women with severe feature of preeclampsia that does not receive anti-seizure prophylaxis [4]. Many obstetricians administer intrapartum and postpartum seizure prophylaxis to all women with preeclampsia, based on randomized trials that demonstrated that magnesium sulfate reduced the risk of convulsion in preeclampsia [9,10]. The mechanisms that MgSO4 is effective in prevention of convulsion in eclempsia are probably vasodilation and lowering of systemic blood pressure, protecting the blood-brain barrier (BBB) from cerebral edema [11-13]. Magnesium also may act by stimulating production of prostacyclin by endothelial cells causing vasodilation [7]. Several reports have suggested that gestation may influence vascular reactivity to MgSO4 and that sensitivity varies with vascular bed [14,15]. In a meta-analysis of randomized trials of women with preeclampsia (any severity), magnesium sulfate was more effective for prevention of seizure than placebo or no treatment, and also was better than Phenytoin or an antihypertensive drug alone [16].


Introduction
Gestational hypertension and mild preeclampsia represent the most common medical complications of pregnancy [1]. Preeclampsia is characterized by the new onset of hypertension and proteinuria. Severe pre-eclampsia can involve several organs such as liver, kidneys, clotting system and brain [2][3][4][5][6]. Eclampsia refers to the occurrence of newonset generalized tonic-clonic seizures in women with preeclampsia [7]. Pre-eclampsia and eclampsia are the second leading direct cause of maternal morbidity [8]. Eclampsia occurs in 2-3 percent of women with severe feature of preeclampsia that does not receive anti-seizure prophylaxis [4]. Many obstetricians administer intrapartum and postpartum seizure prophylaxis to all women with preeclampsia, based on randomized trials that demonstrated that magnesium sulfate reduced the risk of convulsion in preeclampsia [9,10]. The mechanisms that MgSO 4 is effective in prevention of convulsion in eclempsia are probably vasodilation and lowering of systemic blood pressure, protecting the blood-brain barrier (BBB) from cerebral edema [11][12][13]. Magnesium also may act by stimulating production of prostacyclin by endothelial cells causing vasodilation [7]. Several reports have suggested that gestation may influence vascular reactivity to MgSO 4 and that sensitivity varies with vascular bed [14,15]. In a meta-analysis of randomized trials of women with preeclampsia (any severity), magnesium sulfate was more effective for prevention of seizure than placebo or no treatment, and also was better than Phenytoin or an antihypertensive drug alone [16].
However, Because of seizure is an infrequent outcome in women with mild preeclampsia who do not receive seizure prophylaxis, American College of Obstetricians and Gynecologists [5] recommendations is that MgSO 4 not be administered universally in preeclamptic women with blood pressure of less than 160/110 mm Hg and with no maternal symptoms for the prevention of convulsion [5]. Our objective was to

Materials and Method
After approval from ethics committee, present double blind randomized clinical trial study was conducted on pregnant women who admitted in Arash Hospital, Tehran, Iran during 2013-2016. Term primi-parous singleton mild preeclamtic women in ≥ 37 week gestational age were entered. Patients with the symptoms and signs of sever pre eclampsia such as organ damage and systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg, heart disease, hypersensitivity to MgSO 4 and smoker patients, multi fetal patients, drug user's patients were excluded. According to inclusion criteria, patients were randomly entered into two groups. Group A received loading dose, 4 g, of 20% MgSO 4 in 100 ml of serum Ringer intravenously over 20-30 min followed by 2 g/h IV infusion. group B received 4 g of placebo included distilled water in the same shape in 100 ml of ringer intravenously over 20-30 min followed by 2 g/h IV infusion. Therapy was continued for 24 h post-partum or after last convulsion whichever was later. They were monitored every 4 h for presentation of patellar reflex, normal urine output and respiratory rate, systolic and diastolic blood pressure, laboratory data. Occurrence of convulsions, Apgar score at one and five minutes of fetus and the type of delivery were recorded as outcomes.
All data analyses were conducted using SPSS version 16.0 for windows (SPSS Inc., Chicago, IL, USA). Descriptive statistics for continuous variables were presented as mean ± SD and for categorical variables as numbers (percentage). The baseline characteristics of the two groups were compared using independent t-test for continuous variables and the Chi-square test for categorical variables. Moreover, the convulsions between groups were compared using Chi-square test. The level of statistical significance was set at 0.05. All analyses were performed on an intent-to-treat basis. The conduct and analysis of the trial adhered to the 2010 CONSORT guidelines.

Results
Baseline and demographic characteristics are shown in Table 1. The mean age of group A was 22.32 ± 6.51 and the mean age of group B was 22.54 ± 5.58. The mean gestational age of group A was 38.21 ± 1.10 and the mean gestational age of group B was 38.32 ± 1.41. There were no statistically significant differences between two groups in maternal age and gestational age.

Discussion
In the present study, 3 (1.2%) seizures were happened in group B that received placebo. We found that the rate of caesarean section in group A was higher significantly than group B. One and five min Apgar scores were not different significantly between two groups. Although seizure is an infrequent outcome in women without severe features of preeclampsia, several studies demonstrated that magnesium sulfate treatment reduced the risk of convulsion in all women with preeclampsia [9].
Indeed one study has reported that a significant number of eclamptic women had either normal blood pressure or mild-tomoderate hypertension immediately before seizure and the findings are apparently in support of initiating MgSO 4 prophylaxis to all women with mild pre-eclampsia [17]. But Baha et al. represent that there are not acceptable benefit-to-risk ratio of administration of MgSO 4 for prophylaxis in mild preeclampsia and routine use is not recommended [18]. Also Livingston and et al suggest that MgSO 4 did not prevent disease progression to severe preeclampsia and seizure in women with mild preeclampsia [19].
Roy et al. [8] considered to tocolytic effects of MgSO 4 , reported that caesarean section rate increased significantly in administration of MgSO 4 . In our study the rate of caesarean section in MgSO 4 group was higher significantly than placebo group. Similar to our study in Livinsgton study neonates born from women assigned MgSO 4 had similar mean Apgar scores at 1 and 5 min as those born to women assigned placebo [19].

Conclusion
There are not statistically significant different between MgSO 4 and placebo for prevention of seizure in mild preeclampsia, but in practice may be included many variables for making decision. We recommend further studies with larger sample size and more accurate methods.
14. Euser AG, Cipolla MJ (2005) Resistance artery vasodilation to magnesium sulfate during pregnancy and the postpartum state. Am J Physiol Heart Circ Physiol 57: H1521. Values given as mean ± SD or number (percentage) unless otherwise indicated