|Year : 2023 | Volume
| Issue : 2 | Page : 153-159
A randomized controlled trial of loading dose alone versus pritchard regimen of magnesium sulphate, for seizure prophylaxis in severe preeclampsia
Anthony Adinoyi Obanimoh, Aliyu Yabagi Isah, Habiba Ibrahim Abdullahi, Nathaniel Daniel Adewole, Bissalah Ahmed Ekele
Department of Obstetrics and Gynaecology, University of Abuja Teaching Hospital, Abuja, Nigeria
|Date of Submission||02-Jun-2021|
|Date of Decision||30-Oct-2021|
|Date of Acceptance||12-Dec-2022|
|Date of Web Publication||4-Apr-2023|
Habiba Ibrahim Abdullahi
Department of Obstetrics and Gynaecology, University of Abuja Teaching Hospital, Abuja
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Preeclampsia poses a significant risk of maternal and neonatal morbidity and mortality. Magnesium sulfate superiority for seizure prophylaxis in severe preeclampsia has been proven globally. However, the search for the lowest effective dose is an area of continuing research. Aim: The aim of this study was to compare the effectiveness of loading dose with the Pritchard regimen of magnesium sulfate for seizure prophylaxis in severe preeclampsia. Materials and Methods: A total of 138 eligible women after 28-week gestation with severe preeclampsia were randomized to either receiving a single loading dose of MgSO4 (study arm: n = 69) or Pritchard regimen of MgSO4 (control: n = 69). The effectiveness was assessed by the development of seizure. The results obtained were analyzed using SPSS version 21. Categorical variables were analyzed using the Chi-square test and normally distributed continuous variables were analyzed with t-test and Fisher's exact test. P < 0.05 was considered statistical significance. Results: There were no significant differences between those who received only the loading dose when compared with those who had Pritchard regimen other than a single recorded convulsion among the control group (P = 0.316). Similarly, except for the duration of hospital stay which was significantly longer in the Pritchard group (P = 0.019), both the arms of the study shared similar maternal and fetal outcomes. Conclusion: This study suggests the effectiveness of just the loading dose of magnesium sulfate when compared with the standardized Pritchard regimen in the prevention of seizure among women with severe preeclampsia. The study also demonstrated safety and similarity in fetal-maternal outcome. The loading dose only had an added advantage of shorter duration of hospital stay.
| Abstract in French|| |
Contexte: La prééclampsie pose un risque important de morbidité et de mortalité maternelle et néonatale. La supériorité du sulfate de magnésium pour 15 prophylaxies épileptiques dans la prééclampsie sévère a été prouvée à l'échelle mondiale. Cependant, la recherche de la dose efficace la plus faible est un domaine de recherche continue. Objectif: L'objectif de cette étude était de comparer l'efficacité de la dose de charge avec le schéma de Pritchard de sulfate de magnésium pour la prophylaxie de 17 épilepsies dans la prééclampsie sévère. Matériels et méthodes: Un total de 138 femmes éligibles après 28 semaines de gestation atteintes de 18 prééclampsie ont été randomisés pour recevoir soit une dose de charge unique de MgSO4 (groupe d'étude : n = 69) soit un régime de Pritchard de MgSO4 (contrôle : n = 69). L'efficacité a été évaluée par le développement de saisie. Les résultats obtenus ont été analysés à l'aide de SPSS version 21. Les 19 variables catégorielles ont été analysées à l'aide du test du chi carré et les variables continues normalement distribuées ont été analysées à l'aide du test t et du test exact de Fisher. 20 P < 0,05 était considéré comme une signification statistique. Résultats: Il n'y avait pas de différences significatives entre ceux qui n'avaient reçu que la dose de charge 21 par rapport à ceux qui avaient reçu le régime de Pritchard autre qu'une seule convulsion enregistrée parmi le groupe témoin (P = 0,316). 22 De même, à l'exception de la durée du séjour à l'hôpital qui était significativement plus longue dans le groupe Pritchard (P = 0,019), les deux bras de l'étude 23 partageaient des résultats maternels et fœtaux similaires. Conclusion: Cette étude suggère l'efficacité de la seule dose de charge de sulfate de magnésium par rapport au régime de Pritchard standardisé dans la prévention des convulsions chez les femmes atteintes de prééclampsie sévère. L'étude a également démontré 24 l'innocuité et la similarité des résultats fœto-maternels. La dose de charge n'avait qu'un avantage supplémentaire de durée d'hospitalisation plus courte. 25.
Mots-clés: Éclampsie, dose de charge, sulfate de magnésium, régime de Pritchard, prophylaxie des crises, prééclampsie sévère
Keywords: Eclampsia, loading dose, magnesium sulfate, Pritchard regimen, seizure prophylaxis, severe preeclampsia
|How to cite this article:|
Obanimoh AA, Isah AY, Abdullahi HI, Adewole ND, Ekele BA. A randomized controlled trial of loading dose alone versus pritchard regimen of magnesium sulphate, for seizure prophylaxis in severe preeclampsia. Ann Afr Med 2023;22:153-9
|How to cite this URL:|
Obanimoh AA, Isah AY, Abdullahi HI, Adewole ND, Ekele BA. A randomized controlled trial of loading dose alone versus pritchard regimen of magnesium sulphate, for seizure prophylaxis in severe preeclampsia. Ann Afr Med [serial online] 2023 [cited 2023 Jun 2];22:153-9. Available from: https://www.annalsafrmed.org/text.asp?2023/22/2/153/373559
| Introduction|| |
Hypertensive disorders in pregnancy are among the common medical complications of pregnancy, affecting 5%–10% of pregnancies. They are among the three leading causes of maternal mortality worldwide. The spectrum of these disorders ranges from chronic hypertension, gestational hypertension, preeclampsia, and superimposed preeclampsia in the setting of chronic hypertension. Each condition increases the risk of maternal and neonatal morbidity and mortality; the greatest risk is associated with preeclampsia either de novo or in the setting of chronic hypertension., Apart from the peripartum complications of preeclampsia such as convulsion, women who have had preeclampsia have an increased risk of cardiovascular disease and almost a four-fold increased risk of hypertension and approximately two-fold increased risk of fatal and nonfatal ischemic heart disease, stroke, and venous thromboembolism in later life. The child is also more likely to suffer from metabolic syndrome, cardiovascular disease, and hypertension at an earlier age.
Preeclampsia is associated with increased maternal and perinatal morbidity and mortality, and the World Health Organization noted that they contributed 14% of maternal death globally in 2014. Where maternal mortality is high, most of these deaths are attributed to eclampsia rather than preeclampsia. For every preeclampsia-related death that occurs in the United States, there are probably 50–100 other women who experienced “near miss” significant maternal morbidity that stops short of death but still results in significant health risk and health cost.
The management of severe preeclampsia includes evaluation, rational use of antihypertensive and anticonvulsants as seizure prophylaxis, continuous monitoring, and planning for delivery at an optimal time for mother and/or baby to achieve “cure.” The superiority of magnesium superiority for seizure prophylaxis has been proven generally against other diverse therapies, showing a reduction of up to 58% in the incidence of seizures in the patients with preeclampsia. The doses of the two regimens widely used internationally (Zuspan and Pritchard) for seizure prophylaxis for severe preeclampsia and treatment of eclampsia are similar.
The two largest MgSO4 trials showed comparable clinical efficacy, nevertheless highlighted the lack of understanding of the minimum effective dose for eclampsia prevention and treatment., More so, the pharmacological profile of Pritchard regimen indicated that the minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted level of 2–3.5 mmol/L raising suspicion that continuing the treatment might not have been the only effective strategy for optimal prevention.
Likewise, titrating MgSO4 injections to achieve a preset therapeutic range may risk toxic levels without necessarily improving clinical protection against seizures. Regardless of the slight differences in the pharmacokinetic profiles of the two currently recommended regimens, there was no justification to further increase the total dose of MgSO4 for prophylaxis and treatment of eclampsia, hence dose reduction becomes imperative.
In addition to the adverse health consequences, the economic burden of preeclampsia on the health system is significant because of the cost of medical services needed to treat the women and their infants, who are often born preterm. Stevens et al. in 2012 documented the medical cost associated with preeclampsia up to 1 year postdelivery to have an aggregated increment of $2.18 billion to the US health-care system and $1.03 billion and $1.15 billion for maternal health-care costs and infants' health-care cost, respectively. Likewise, the current cost of Pritchard regimen in our facility is between $4–$6 and $9–$11 per person for the loading and maintenance doses, respectively, making it difficult for most of the patients to continue and complete the prescribed regimen.
Majority of the reported maternal side effects due to administration of MgSO4 were usually dependent on the route of administration, the duration of therapy, and dose used. The common dose regimens used were based mainly on the average body weight of Western women whose body weights are often far higher than their counterparts in low- and middle-income countries, and this has been suspected to likely predispose the latter to more side effects of the drug.
Attempts have been made by previous researchers to address some of these challenges. Sokoto (ultra-short) regimen by Ekele et al. and low-dose Dhaka regimen of magnesium sulfate protocols are quick examples and alternatives to standard-dose therapy in eclamptic. Whether these noble short courses can be reduced while maintaining the efficacy profile of MgSO4 is a major drive for this study. These attempts are furthermore empowered by randomized controlled trials which showed that seizures can be effectively controlled in cases of eclampsia by giving only the loading dose in different continents., Only a few randomized studies have elucidated the efficacy of lower doses of MgSO4 as seizure prophylaxis in severe preeclampsia.,,, It appears, therefore, that the search for the lowest effective dose to prevent convulsion remains an area of continuing research.
The purchase price of magnesium sulfate constitutes a substantial proportion of the overall cost of treatment. Hence, there is growing interest in the use of shorter regimens. The administration of MgSO4 and monitoring of associated side effects may also be challenging in a busy unit, low health workers to patients' ratio, poverty, and lack of facilities, especially if the monitoring is prolonged.
This study therefore aimed at determining the efficacy of only a single loading dose MgSO4 for seizure prophylaxis in patients with severe preeclampsia, to address some of these concerns.
Objectives and hypothesis
This study aimed to compare the effectiveness of just the loading dose of magnesium sulfate with Pritchard regimen of magnesium sulfate for seizure prophylaxis in severe preeclampsia.
- To determine the efficacy of loading dose of MgSO4 in the prevention of convulsion in patients with severe preeclampsia
- To determine maternal and perinatal outcomes between these two groups.
There is no difference in the efficacy between loading dose MgSO4 and Pritchard regimen for seizure prophylaxis in severe preeclampsia.
There is a difference in the efficacy between loading dose MgSO4 and Pritchard regimen for seizure prophylaxis in severe preeclampsia.
| Materials and Methods|| |
This was a randomized study to compare the efficacy of loading dose only of MgSO4 and Pritchard regimen for seizure prophylaxis in severe preeclampsia conducted at the Department of Obstetrics and Gynaecology of the University of Abuja Teaching Hospital (UATH), Abuja, Nigeria.
UATH is one of the Federal Tertiary Health Institutions in the Federal Capital Territory (FCT). It serves as a referral center to several private and general hospitals in the FCT and also in the North Central States of Kogi, Niger, Nasarawa, and Kaduna State.
The center is a 350-bed capacity hospital and the maternity ward has a total of 38 beds, while the labor ward has 12 beds. About 2500 deliveries are conducted annually.
Women with a diagnosis of severe preeclampsia (blood pressure [BP] ≥160/110 with proteinuria ≥2+) at 28 weeks' gestation or more during pregnancy, in labor, or after delivery with a single live fetus and who had given consent to be part of the study were recruited. Women who were receiving any prior anticonvulsant or had contraindications to MgSO4 (like myasthenia gravis) were excluded. Furthermore, those with gestational hypertension, mild preeclampsia, eclampsia, chronic hypertension without superimposed severe preeclampsia, gestational age <28 weeks, intrauterine fetal death, and multiple gestations were excluded.
The sample size was determined using the formula for calculating the sample size for dichotomous clinical equivalence trial.
The total sample size for this study was 138, i.e., 69 participants per arm.
This study was not blinded because the placebo to be administered required multiple injections and the primary outcome measure was seizure which could be measured objectively.
Randomization was performed using a computer-generated list. Concealment was done utilizing sequentially numbered, opaque, sealed envelopes indicating their medication. The study group (Group A) received a loading dose only of MgSO4, and the control group (Group B) received Pritchard regimen of MgSO4.
A total of 138 who met the inclusion criteria women were recruited serially. The purpose of the study was explained and written informed consent was obtained from all the participants on admission either through the antenatal clinic or obstetric emergency unit.
All the participants had a structured questionnaire-based interview by researchers and assistants at first contact to collect information on demographical characteristic, clinical, and obstetric history and perform clinical examinations. The files of the participants were tagged for identification. The researchers alongside the assistants were trained to ensure uniformity.
Women with severe preeclampsia were treated with antihypertensive (as applicable) and antenatal corticosteroids (as indicated) as per departmental protocol. Clinical monitoring of blood pressure and magnesium toxicity was done using the departmental protocol, and 10% calcium gluconate was kept ready to treat any toxicity which could occur. Laboratory investigations such as complete blood count including platelets, liver enzymes, serum creatinine and urea, catheter specimen urinalysis, and bedside clotting time were done at presentation and when indicated. Fetal monitoring was done using any or a combination of the following; fetal kick count, fetal heart rate monitoring by auscultation, cardiotocography, ultrasound scan and modified biophysical profile, as appropriate.
These women were counseled individually. The delivery plan was either by induction of labor, augmentation of labor, or cesarean section as appropriate.
There were two groups of participants. The study Group (A) received a single loading dose only 14 g of MgSO4 (as an intravenous 4 g of 50% MgSO4 after diluting in 12 ml of sterile water over 10 min followed immediately by 5 g of undiluted 50% MgSO4 intramuscularly on each buttock). The control Group (B) received Pritchard regimen of 14 g MgSO4 as a loading dose as described above and 4 h maintenance doses of 5 g of undiluted 50% MgSO4 intramuscularly on alternate buttocks for 24 h, unless signs of magnesium toxicity such as loss of patellar reflex, a respiratory rate <16 cpm, or urine output <100 ml appeared.
In case of convulsion before the commencement of the maintenance dose, additional 2 g 50% MgSO4 diluted in 6 ml sterile water was to be given slowly intravenously over 5 min, and if the participant was in the study group, she was to be given the maintenance dose of the standard Pritchard regimen of MgSO4 but analyzed under the original arm they were assigned (intention to treat [ITT]).
The brand of magnesium sulfate used for this study was Magphate® injection BP. It is composed of 500mg of magnesium sulfate heptahydrate per mL (50% w/v) containing approximately 2 mmol of magnesium ios (mg2+) per mL. It was manufactured by Lincoln Pharm Ltd. for Zolon Healthcare Limited in 2018 with a shelf life of 24 months and NAFDAC registration number of A4-2027.
The cost of the MgSO4 was borne by the researchers.
All the women were carefully followed up until discharge from the obstetric unit.
The main outcome measure was the development of eclamptic seizure. The secondary outcome measures include blood pressure; development of side effects such as flushing, nausea, and vomiting; and other side effects, admission into the intensive care unit, and clinical signs of magnesium toxicity. The labor events such as mode of delivery, blood loss at the delivery duration of hospital stay, and mortality were all noted. Regarding perinatal parameters, APGAR scores in the 1st and 5th min, birth weight, admission into special care baby unit (SCBU), and mortality were also studied.
Data were prospectively collected from eligible participants using a closed- and open-ended pretested structured questionnaire that was completed by the researchers and research assistants on admission in the maternity and labor wards. The questionnaire for each participant had her enrollment number, hospital number, and phone number for ease of identification and follow-up. It was divided into the following subsections: demographic variables, clinical and laboratory parameters, magnesium sulfate administration and clinical toxicity, maternal outcome, and fetal outcome measures.
An ITT analysis was to be performed if there was an occurrence of seizure in the study group. Data were analyzed using the IBM SPSS Statistics for Windows, Version 21.0. (Armonk, NY: IBM Corp). Categorical data were analyzed using the Chi-square test and normally distributed continuous variables were analyzed with t-test or Fisher's exact test. P < 0.05 was considered to be statistically significant.
The ethical clearance for this study was obtained from the Health Research Ethics Committee for Research of the UATH.
Participation in the study was completely voluntary. The cost of the research was borne completely by the researchers.
All information gathered as well as the outcome of the study were treated with utmost confidentiality. Clients' anonymity was maintained as they were identified by code numbers.
Responsibility to do and maximize good was ensured (beneficence). Ethical duty to do no harm or wrong to the participants was also ensured (nonmaleficence).
All women were treated fairly irrespective of their decision either or not to participate in the study (Justice). No woman was denied any form of service upon decline to give consent nor was any woman promised facilitation of service to coerce her into giving consent.
The dignity of all participants was ensured and ethical responsibility to tell the truth was maintained during the study.
There was individual counseling of each woman before recruiting them for the study, after which written consent was obtained from those that agreed to participate.
The research was conducted between January 2019 and August 2019.
| Results|| |
A total of 138 patients were randomized to receive either only loading dose of magnesium sulfate (n = 69) or Pritchard regimen of magnesium sulfate (n = 69), followed up, and eventually analyzed. None of the participants opted out after enrollment. While the loading-only dose was used for the study arm, the Pritchard regimen was administered to the control.
The mean age of the participants was 30.59 ± 5.75 (study) versus 30.0 ± 5.46 (control), with no statistically significant difference between them (P = 0.916). In a similar vein, there was a similarity in the parity of the women between the two arms of the study, as shown in [Table 1].
Pregnancy remote from term was more in the study group 68.8% while pregnancy at term was more in the control group 55.7%. However, both the groups were similar in terms of gestational age at presentation (P = 0.215).
The mean weight of the participants was 78.00 ± 14.28 (study) versus 78.25 ± 14.88 (control).
[Table 2] represents the result concerning the baseline clinical and laboratory variables. No statistically significant difference was found between the groups in any of the variables.
Convulsion was occurred in one participant, and this was in the control group. There was, however, no statistically significant difference between the two groups (P = 0.316), as shown in [Table 3].
No participant had clinical magnesium toxicity in both the groups.
[Table 3] shows the drug side effect in the two groups. Ten (7.2%) of the participants had nausea/vomiting: 6 in the study group and 4 in the control group, the difference of which was not statistically significant (P = 0.511).
[Table 4] shows the maternal outcome. About 44.9%, 43.5%, and 11.6% of participants had their deliveries at term, near term, and remote from term, respectively. There was no statistically significant difference between the two groups. Six (4.3%) participants had induction of labor: 2 in the study group and 4 in the control group. This did not show a statistically significant difference (P = 0.404). Twenty-one percent had a vaginal delivery and 79% had a cesarean section. About half (51%) of those who had vaginal delivery were in the study group, whereas in the control group, 55% had a cesarean section. Again, there was no statistically significant difference in the mode of delivery between the groups (P = 0.834). The mean blood loss at delivery was 480.44 ± 161.61 ml (study) and 501.74 ± 153.74 ml (control) with no statistically significant difference (P = 0.916). When the duration of hospital stay was compared, there was a shorter hospital stay in the study group 5.52 ± 1.52 than recorded in the control 6.48 ± 2.98, and this difference was statistically significant (P = 0.019).
[Table 5] addresses the neonatal outcome. The mean APGAR scores at 1 min were 7.25 ± 0.98 versus 7.17 ± 1.31 and 5 min were 8.87 ± 0.83 versus 8.81 ± 0.91 in the study and control groups, respectively (P = 0.701 and 0.707, respectively). The mean birth weight was 2.49 ± 0.82 (study) versus 2.61 ± 0.76 (control). There was no statistically significant difference when these were compared (P = 0.374). About 36% of the neonates were admitted into the SCBU though more from the study arm 53.1% versus 46.9%. However, this was not statistically significant (P = 0.594). The overall perinatal mortality was 21 (15.2%), 11 (52.4%) in the study group and 10 (47.6%) in the control group, and this difference was not statistically significant (P = 0.813).
| Discussion|| |
The effectiveness of loading dose MgSO4 in the management of eclampsia has been documented with similar results in the management of preeclampsia. In this study following the administration of loading dose (the study group) and Pritchard regimen (the control group), one patient in the control group (1.4%) had a seizure after an hour of administration of the loading dose while none was recorded among the study group. This could be a chance occurrence as it demonstrated no significant difference following analysis. A possibility of background brain injury could not be ruled out as brain computed tomography scan was not done for the patient.
In a similar study done by Shoaib et al. using a 14-g single dose, 2% of the patients had a seizure with the Prichard regimen and none in the study group. However, this is different from the findings of Rimal et al. who showed a 3.3% seizure rate in the control arm and 6.7% in the study arm despite the fact that they had a smaller sample size (n = 60). Furthermore, Ranganna et al. while using a lower dose in the study group (12 g loading dose only) and modified Pritchard regimen (12 g loading dose and 4 g 4 h for 24 h as maintenance) as control found a similar seizure rate of 2% in both the groups. Ranganna et al.'s study was, however, different from our study perhaps because of the lower doses of magnesium sulfate used in both the arms. In one randomized study conducted by Dasgupta et al. in a tertiary center, a higher seizure rate of 4% among the study group receiving only loading dose of 14 g (n = 50) than the standard Pritchard group (n = 150) of 2.6%. However, a meta-analysis and systematic review of six randomized controlled trials of loading dose versus Pritchard regimen showed no difference in the rate of occurrence of seizures in both the arms.
The inconsistency in the percentage of those that had seizures in both the arms from the above studies made it difficult for a generalized statement to be made as to the likely cause. Perhaps, a routine computerized tomography for all preeclamptic patients may lay the foundation as to the confounding factors that may explain such variance.
Magnesium sulfate does not completely prevent seizure activity in preeclamptic patients and is associated with an appreciable failure rate of approximately 1%. Furthermore, Pritchard regimen while potentially safer requires repeated painful intramuscular administration of injections. In the present study, its efficacy as a single loading dose was compared versus the standard Pritchard regimen and the single dose was found equally effective in preventing seizures.
This study showed no clinical toxicity in both the groups and laboratory evidence of such not sought for either. Ekele and Badung had demonstrated that the mean serum magnesium level in eclamptic while on Pritchard regimen was 1.92–2.82 mmol/l and that there was no clinical evidence of magnesium toxicity negating the routine use of magnesium sulfate assay while on treatment even when the laboratory facility is available. This current study finding was contrary to the randomized study done by Dasgupta et al. when comparing loading dose only versus Pritchard. Their study showed a significance in clinical toxicity among the Pritchard group. Similarly, studies have shown clinical evidence of magnesium toxicity while using the Pritchard regimen as seizure prophylaxis.
The maternal side effects of nausea and vomiting were shown to be more in this study among the control. This might have not been unrelated to the duration of exposure to the MgSO4. Various studies had also shown similar higher rates of maternal side effect while using the Pritchard regimen.,,, Perhaps, the non observation of such side effects in this study may strengthen the adoption of only the loading dose, moreso that it demonstrated similar efficacy with Pritchard regimen. In addition, the duration of hospital stay had been proven in the previous studies to be shorter in the loading dose-only arm,,, as was observed in this study.
| Conclusion|| |
This study shows that loading dose only of MgSO4 was as effective as the Pritchard regimen for seizure prophylaxis in severe preeclamptics, with comparable safety and similar maternal and neonatal outcomes in addition to a shorter hospital stay.
The adoption of a loading dose only of MgSO4 as seizure prophylaxis in severe preeclampsia may overcome the challenges of administration and monitoring and also reduce the financial burden associated with the standard Pritchard regimen while maintaining similar efficacy. A properly conducted multi-centered, randomized controlled trial is recommended.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]