Assessment of magnesium sulphate usage in pre-eclamptic and eclamptic women in Omdurman Maternity Hospital, 2017: A cross-sectional study [version 1; peer review: 1 approved, 1 not approved]

Background: Eclampsia, the end phenomena of the preeclampsia spectrum, appears as new onset grand mal seizures in women with preeclampsia. Recently, the World Health Organization has recommended magnesium sulphate (MgSo4) as the main drug of choice to treat/prevent eclampsia. However, in Sudan no real assessment data about MgSo4 efficacy, benefits and risks in preeclamptic and eclamptic women has been reported. Methods: A cross-sectional hospital-based study was conducted between January and April 2017 at Omdurman Maternity Hospital using a checklist. Data was collected from the medical records of 130 preeclamptic/eclamptic pregnant women, including: age, blood pressure, protein urea appearance, admission diagnosis, reason for using MgSo4, policy of MgSo4 administration, outcomes after using MgSo4, side effects of using MgSo4, and MgSo4 toxicity recording. After data collection, IBM SPSS (version 21) was used to analyze the data. Results: Out of 130 recruited women, 78% were diagnosed with preeclampsia and 22% were diagnosed with eclampsia. Magnesium sulphate was indicated as a prophylactic in 88 patients and as treatment in 42 patients. Interestingly, only 9 patients had uncontrolledrecurrent seizures after using magnesium sulphate and only one patient developed drug related toxicity. Conclusion: After MgSO4 administration, the majority of patients (121; 93.1%) had controlled seizures and only one patient developed MgSO4 toxicity (respiratory paralysis). Therefore,  MgSo4represents an effective and safe drug of choice used to treat/prevent eclampsia in Sudan. Open Peer Review


Introduction
Preeclampsia/eclampsia is a pregnancy-specific disease with multisystem physiological disorder, which may lead to increased risk of maternal and perinatal mortality and morbidity 1 . Regarding etiology, no clear cause has been defined, but some reports indicate that oxidative stress and placental defects during early pregnancy may represent the main causes 2 . Preeclampsia is defined as pregnancy-related systemic disorder, which is associated with incidence new onset of hypertension as well as proteinuria 3 . Eclampsia is described as the beginning of grand mal seizure symptoms in preeclamptic women 4 . Epidemiologically, around 50,000-60,000 pregnant women die due to preeclampsia/ eclampsia each year, which represents around one-quarter of maternal deaths in Latin America, and approximately one-tenth of maternal deaths in Africa and Asia 5,6 .
Magnesium sulphate (MgSO 4 ) is one of the main interventions used to decrease the morbidity and mortality from preeclampsia/eclampsia. In 2011, MgSO 4 was been strongly suggested by the World Health Organization (WHO) to be the drug of choice for both treatment and prevention of eclampsia 7 . Currently, the WHO and other international organizations recommend two MgSO 4 prophylactic protocols for eclampsia. The first one is the Pritchard regimen, in which MgSO 4 is administered intramuscularly, while it is injected intravenously in the second protocol named as Zuspan regimen 8 . MgSO 4 might be toxic in some conditions, and the toxicity depends on the serum magnesium levels, for example: loss of the knee jerk may develop at 3.5-5 mmol/l; respiratory paralysis may occur at 5-6.5 mmol/l, cardiac conduction is altered at higher than 7.5 mmol/l 9 . Meanwhile, it can lead to death if the serum magnesium exceeds 12.5 mmol due to cardiac arrest 9 .
In Sudan, preeclampsia/eclampsia is considered as one of the main factors leading to an increase in morbidity and mortality among pregnant women 2 . There is not enough assessment data reported about MgSO 4 efficacy, benefits and risks in preeclamptic and eclamptic women in this setting. Thus, the present study was carried out to assess MgSO 4 usage in preeclamptic and eclamptic women in Khartoum, Sudan.

Study site and participants
A cross-sectional pilot hospital-based study was conducted between January and April 2017 at Omdurman Maternity Hospital (Khartoum, Sudan) using a checklist, which was completed by the researcher. Data was collected from patient medical records.
Eligibility criterion was as follows: women who were pregnant and had preeclampsia/eclampsia. The total number of preeclamptic/eclamptic patients admitted during the time period was 130 patients. Therefore, the data records of 130 preeclamptic/ eclamptic pregnant women were included in this study.

Data collection
The checklist (Extended data 10 ) collected the following data variables from records: age; blood pressure; protein urea appearance; admission diagnosis (eclampsia/pre-eclampsia); reason of using MgSo4 (prophylactic in pre-eclampsia or treatment in eclampsia); MgSo4 administration policy (loading dose and maintenance dose); outcomes after MgSo4 therapy; monitoring of MgSo4 side effects (BP, pulse rate, respiratory rate, pulse oximeter, urine output, deep tendon patellar reflexes); Mgso4 toxicity recording.

Source of bias
Misdiagnosis of admitted patients might be a source of bias. This was addressed as follows.
As per hospital policy, any patient who was admitted with blood BP≥ 140/90 and protein urea the following criteria were measured and only patients who have one or more of the following criteria were diagnosed and admitted as pre-eclamptic patients: refractory oliguria (<500 cc over 24 h), renal function compromise (minimal criterion would be a rise in serum creatinine of 1 mg/dl above baseline), persistent right upper quadrant or epigastric pain or both, persistent headache, scotomata or blurred vision, shortness of breath with reduced oxygen saturation or pulmonary edema, thrombocytopenia (platelets <100,000/cu.mm), hemolysis (based on peripheral smear analysis or increased bilirubin), impaired liver function of unclear etiology, and estimated fetal weight below 5th percentile for gestational age are important parameters to be noted.
Patients who were admitted with blood BP≥ 140/90, protein urea and grand mal seizures were diagnosed as eclamptic patients.

Data analysis
After data collection, IBM SPSS Statistics software (version 21) was used to descriptively analyze the data.

Ethical clearance
Ethical clearance (FPEC-06-2018) was obtained from the Ethical Committee of the University of Khartoum, Faculty of Pharmacy. Official agreement from the general manager and the medical directors of the hospital preceded the conduction of this study. After records were as being eligible for the study, the patients were contacted for their consent to use the records in this study. Since the majority of the patients were illiterate, oral informed consent was preferred to written informed consent. Figure 1A, 62 participants were 25-34 years (~48%). About 34% of participants were 15-24 years and only 18% were 35-45 years old. Regarding admitting diagnosis, the majority (78%) were diagnosed with preeclampsia, while 22% were diagnosed with eclampsia ( Figure 1B).

As shown in
Every patient recruited to the study was followed up while they received MgSo4 therapy. During follow-up some of the preeclamptic women developed eclampsia; therefore, the ratio of preeclampsia:eclampsia became 88:42 instead of 101:29.
MgSO 4 was used as a prophylactic agent in 88 preeclamptic women and as treatment for 42 eclamptic women, as shown in Figure 1C. Moreover, magnesium sulphate was administered as a loading dose in 51 (39.2%) patients, while most treated  Figure 1D and E).
To avoid practitioner-related errors, patients' vital signs and parameters must be monitored frequently during MgSO 4 administration 11 . In this study, only vital signs (Pulse Rate, Blood Pressure, Respiratory Rate, and Pulse Oximeter) were checked ten minutes after starting loading dose (LD). At the end of LD, 4 hourly checks were performed during maintenance dose (Figure 2A). Other important parameters, such as urine output and deep tendon patellar reflexes, were checked in 42% and 25% of patients, respectively.

Discussion
Being pregnant at age 35 or more is one of the highest risks of developing preeclampsia/eclampsia 12 , however, in the present study the 25-34 year age group was the largest age group of women with preeclampsia/eclampsia. MgSO 4 is considered as the golden choice for treatment and prevention of eclampsia, as endorsed by the WHO 7 . Therefore, it is no wonder that MgSO4 has been used to control every admitted eclamptic/preeclamptic case included in the present study.
Regarding the administration protocol, MgSO4 must be given by either Pritchard or Zuspan regimen. In Pritchard regimen, a loading dose of 4 g is injected intravenously, then a maintenance dose will be started immediately by intramuscular injections of 10 g followed by 5 g 6 times/day. In Zuspan regimen, 4 g dose is given a loading dose, then maintenance dose by using 1 to 2 g/h controlled infusion pump 13 . In present study, poor practice is observed as 61% of admitted patients didn't receive loading doses and two patients didn't receive maintenance dose.
Some reports indicate that the rate of eclamptic seizures was recorded as being lower than 35% of all recruited cases after using MgSO 4 , while in present study the rate of uncontrolledrecurrent seizures was only 7% after using MgSO 4 14 . In this study, no patient died as a result of using MgSO 4 whereas some literature indicates that "if MgSO 4 was universally prescribed for all pre-eclamptic pregnant women, the death from magnesium toxicity may be more than that from seizures" 14 . On the other hand, the prevalence of MgSO 4 toxicity is very mild and only one toxicity case had been reported worldwide to date 15 .

Conclusion
Although practitioners in the present study did not properly adhere to MgSo4 protocol, the successful output of its usage as a treatment for eclampsia and prophylaxis for pre-eclampsia was shown by the majority of patients (93.1%) only having controlled seizures, with only one patient developing toxicity.
Practitioners' adherence to MgSo4 protocol should be assured in the future to increase the percentage of the well-controlled patients.

Grant information
The author(s) declared that no grants were involved in supporting this work.

Maternal and Child Healthcare, Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil
Although the use of magnesium sulfate in preeclampsia and eclampsia is indeed a very important issue, the study is very small, it was conducted in a single center, the objectives are not clearly defined, the sample size has not been calculated, the data collection was performed for only 4 months and the study fails to add any new finding to the current state of the art. If we consider for example the outcome "seizure recurrence", which occurred at 7% of patients, considering a confidence level of 95% and an absolute precision of 2%, a sample size of 625 patients would be required.
The effectiveness of magnesium sulfate for seizure prevention and control in patients with preeclampsia and eclampsia has already been demonstrated in solid randomized controlled trials and systematic reviews available from the Cochrane Library, so an observational study would have to provide important additional information to be considered valid. With unclear objectives and inconsistent methods, without adequate presentation of the analysis variables, this is an important concern.
I also question a fact that seems very strange to me, only 39% of the patients had the loading dose of magnesium sulfate administered. How is this possible? A maintenance dose can only be done without an loading dose. If this was a prospective study it is a very serious and ethically unjustified mistake because this problem being identified the authors would have to warn the clinical staff and provide the patient with the best available treatment.
The study also does not follow STROBE recommendations. Therefore, I do not recommend its indexing. The study is a genuine and ethical presentation of the practices in the Omdurman Maternity Hospital in Sudan and has proved the efficacy of the magnesium sulfate in the treatment of preeclampsia and eclampsia. Magnesium sulfate is a valuable therapy in the management and prevention of eclampsia 1 . But many parts of the world obstetricians continue to have reservations of using magnesium sulfate due to the fear of apparent toxicity. As the evidence is coming up and the experience of the use of the drug is increasing, magnesium sulfate is proving to be an effective therapy for seizure prevention and control with the added advantage of fetal neuroprotection and pain alleviation. The fear among the physicians is a result of inadequate knowledge, and infrastructure and lack of organization and this are beautifully depicted in a recent study in Brazil 2 .

Is the work clearly and accurately presented and does it cite the current literature? No
The current publication in Sudan has scientifically designed and conducted the study and has come up with valuable information on the magnesium level and the significant advantages of using magnesium sulfate. This study is important as the blood levels of magnesium have been studied and correlated. In practice actually, it is not essential to determine the blood levels of magnesium. Clinical signs if studied well and closely monitored are enough to ensure the correct delivery of the drug at the right dose. Also, it is important to keep the calcium gluconate 3 injection handy as an antidote to excessive levels of magnesium sulfate. Magnesium sulfate especially is of benefit during labor management to prevent eclampsia 4 . I would also suggest the center to take up the universal and optimum delivery of magnesium sulfate as a quality improvement parameter and this would go a long way in reducing the perinatal adverse outcomes in the association of gestosis (preeclampsia). surgery I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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