Choice of Anticonvulsant for Prevention and Management of Eclamptic Seizures

J.P. Souza
Medical Officer, Maternal and Perinatal Health Unit Department of Reproductive Health and Research World Health Organization Geneva, Switzerland

Background
PE/E accounts for significant maternal and perinatal morbidity and mortality particularly in the developing countries Stopping the progression of PE to E is key to improving outcome Making the right choice of anticonvulsant is important for optimal care Substandard care in management persists despite overwhelming evidence on effective interventions

Anticonvulsants for PE/E: magnesium sulfate

First introduced for eclampsia in the 1920s Not a traditional anticonvulsant Mechanism of action is poorly understood Dosage regimens have evolved over the years Side effects:
Common: flushing

Anticonvulsants for PE/E: diazepam

A benzodiazepine First suggested for eclampsia in the 1960s

A traditional anticonvulsant also used for a wide range of conditions Common side effects: drowsiness, confusion and amnesia

Anticonvulsants for PE/E: phenytoin

Suggested for eclampsia in the 1980s Widely used for acute and long-term control of seizures Acts as anticonvulsant without causing sedation Prevents onset of but not useful for aborting seizures Side effects: hypotension, cardiac arrhythmias, nystagmus and ataxia.

Anticonvulsants for PE/E: lytic cocktail

Usually a combination of chlorpromazine (antipsychotic) promethazine (H1 histamine antagonist) and pethidine (opioid analgesic) Individual component has sedative effects on the CNS No longer in widespread use Side effects:
cardiac arrhythmias (chlorpromazine) hallucinations, incoordination (promethazine), seizures (chlorpromazine, promethazine and pethidine)

WHO Guideline Development Process

Assessment of need for guideline
Prioritization survey Requests from Member States Controversies around practices IBP-KG discussion Scoping for relevant PICOT questions & critical outcomes Cochrane systematic reviews Other studies (RCTs, observational) New systematic reviews? Updating of existing reviews?

Stakeholders consultation to prioritize critical issues Secretariat to identify number and type of systematic reviews and other studies

Establish clear timeline with individual/groups to retrieve evidence

Evidence synthesis

Reviews of effectiveness (GRADE appr.) Quality of evid+ Strength of recommendatn

Online technical consultation on recomm. Virtual global consultation Agreement on recommendations Implementation plan & update

Public (electronic) consultations

Final recommendation expert panel meeting

Critical outcomes for WHO recommendations on PE/E

Outcomes
Eclampsia

Proxy
PE (if it is an intervention for preventing PE); Severe hypertension; Severe PE/HELLP -Organ failure

Recurrence of convulsions Severe maternal morbidity

Maternal death
Perinatal death

-Stillbirth, neonatal death, any baby death

Admission to neonatal intensive care unit

Apgar scores at 5 < 7

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Adverse events of intervention

Toxicity (as defined); Calcium gluconate administration for MgSO4

Evidence summaries: prevention of eclampsia

A Cochrane review of 15 RCTs investigated the relative effects of anticonvulsants for prevention of eclampsia (Duley et al, 2010)
Magnesium sulfate versus placebo or no anticonvulsants
Magnesium sulfate versus phenytoin

Magnesium sulfate versus diazepam

Magnesium sulfate versus nimodipine Magnesium sulfate versus isosorbide Magnesium chloride with methyldopa.

Magnesium sulfate and other anticonvulsants for prevention of eclampsia

Evidence Source
Eclampsia Any serious maternal morbidity Respiratory arrest Maternal death Any reported side effects Toxicity (resp. depr. + absent tendon reflexes Calcium gluconate given 5 Apgar score < 7 Admission to NICU Stillbirth or neonatal death

Magnesium sulfate versus placebo or no anticonvulsants

6 RCTs, 11,444 women

Evidence Quality

6 RCTs, n=11,444; RR 0.41, (0.29- 0.58) HIGH

2 RCTs, n=10,332; RR 1.08, (0.89-1.32) HIGH

1 RCT, n= 10,110; RR 2.50, (0.4912.88) HIGH

2 RCTs, n=10,795; RR 0.54, (0.26-1.10) HIGH

1 RCT, n= 9992; RR 5.26, (4.59-6.03) HIGH

3 RCT, n=10,899; RR 5.96 (0.72-49.40) MODERATE

2 RCTs, n=10,795; RR 1.35, (0.63-2.88) HIGH

1 RCT, n=8260; RR 1.02, (0.85-1.22). HIGH

1 RCT, n=8260; RR 1.01, (0.96-1.06) HIGH

3 RCTs, n=9961; RR 1.04, (0.93-1.15) HIGH

Magnesium sulfate versus phenytoin

4 RCTs, 2343 women

Evidence Quality

3 RCTs, n=2291; RR 0.08, (0.01-0.60)

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1 RCT, n=2141; RR 0.58, (0.26-1.30)

1 RCT, n=2141; RR 1.00, (0.63-1.59)

1 RCT, n=2165; SB: RR 0.62, (0.27-1.41)/ ND: RR 0.26, (0.03-2.31) MODERATE

MODERATE

MODERATE

MODERATE

Magnesium sulfate versus diazepam

2 RCTs, 66 women
Evidence Quality

2 RCTs, n=66; RR 3.00, (0.1369.31) VERY LOW

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Magnesium sulfate versus nimodipine

1 RCT, 1650 women

Evidence Quality

1 RCT, n=1650; RR 0.33, (0.14-0.77) LOW

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Evidence summaries: treatment of eclampsia

Three Cochrane reviews separately investigated the effects of magnesium sulfate compared to: Diazepam (Duley et al, 2000) Phenytoin (Duley et al, 2010a)

Lytic cocktail (Duley et al, 2010b)

Magnesium sulfate and other anticonvulsants for treatment of eclampsia - maternal outcomes
Evidence Source
Recurrence of convulsions

Maternal death

Any serious morbidity

ICU
admission

Renal failure

Pulm. oedema

Resp. depr.

Mech.
ventilation

CVA

Cardiac arrest

Coma >24 hours

Magnesium sulfate versus diazepam

Cochrane review 7 RCTs, 1396 women Evidence Quality 7 RCTs, n=1390; RR 0.43, (0.33-0.55) 6 RCTs, n=1336; RR 0.59, (0.38-0.92) 2 RCTs, n=956; RR 0.88, (0.64-1.19) 3 RCTs, n=1034; RR 0.80 (0.59, 1.07)
MODERATE

5 RCTs, n=1164; RR 0.85 (0.53-1.36)

3 RCTs, n=1013; RR 0.86 (0.35 to 2.07)

MODERATE

3 RCTs, n=1025; RR 0.86 (0.57 to 1.30)

MODERATE

3 RCTs, n=1025; RR 0.73, (0.45 to 1.18)

MODERATE

4 RCTs, n=1225; RR 0.62, (0.32-1.18)

4 RCTs, n=1085; RR 0.80 (0.41 -1.54)

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HIGH

MODERATE

MODERATE

MODERATE

Magnesium sulfate versus phenytoin

Cochrane review 6 RCTs, 972 women Evidence Quality 6 RCTs, n=972; RR 0.34 (0.24-0.49) 3 RCTs, n=847; RR 0.50 (0.24-1.05) 1 RCT, n=775; RR 0.94 (0.73-1.20) 1 RCT, n=775; RR 0.67 (0.500.89) HIGH 3 RCTs, n=902; RR 1.52 (0.98-2.36) 3 RCTs, n=902; RR 0.92 (0.45-1.89) 1 RCT, n= 775; RR 0.71 (0.46-1.09) 2 RCTs, n=825; RR 0.68 (0.500.91) 1 RCT, n=775; RR 0.54, (0.20-1.46). 1 RCT, n=775; RR 1.16, (0.39-3.43) --

HIGH

MODERATE

MODERATE

MODERATE

MODERATE

MODERATE

MODERATE

Magnesium sulfate versus lytic cocktail

Cochrane review 3 RCTs, 397 women Evidence Quality 3 RCTs, n=397; RR 0.06 (0.03-0.12) 3 RCTs, n=397; RR 0.14 (0.03-0.59) --2 RCTs, n=307; RR 0.64 (0.22-1.85) -2 RCTs, n=198; RR 0.12 (0.02-0.91) 1 RCT, n=90; RR 0.20 (0.014.05) 1 trial, n=108; RR 0.22 (0.01-4.54). 2 RCTs, n=307; RR 0.26 (0.03-2.34) 1 RCT, n=108; RR 0.04 (0.00-0.74)

MODERATE

MODERATE

LOW

MODERATE

Magnesium sulfate and other anticonvulsants for treatment of eclampsia - fetal outcomes
Evidence Source Stillbirth Neonatal death Perinatal death Admission to Special care Nursery 5 Apgar score < 7

Magnesium sulfate versus diazepam Cochrane review 7 RCTs, 1396 women Evidence Quality Magnesium sulfate versus phenytoin Cochrane review 6 RCTs, 972 women Evidence Quality
2 RCTs, n=665; RR 0.83 (0.61-1.13) 2 RCTs, n=665; RR 0.95 (0.59-1.53) 2 RCTs, n=665; RR 0.85 (0.67-1.09) 1 RCT, n=518; RR 0.73 (0.58-0.91) 1 RCT, n=518; RR 0.86 (0.52-1.43) 5 RCTs, n=799; RR 0.97 (0.70-1.34) 4 RCTs, n=759; RR 1.18 (0.75-1.84) 4 RCTs, n=788 ; RR 1.04 (0.81-1.34) 3 RCTs, n=634; RR 0.92 (0.79-1.06) 3 RCTs, n=643; RR 0.70 (0.54-0.90)

MODERATE

HIGH

HIGH

MODERATE

MODERATE

MODERATE

HIGH

MODERATE

Magnesium sulfate versus lytic cocktail Cochrane review 3 RCTs, 397 women Evidence Quality
2 RCTs, n=177; RR 0.33 (0.01-7.16) 2 RCTs, n=177; RR 0.37 (0.14-1.00). Any baby death: 2 RCTs, n=177; RR 0.35 (0.05-2.38) ---

VERY LOW

VERY LOW

VERY LOW

Alternative magnesium sulfate regimens for treatment of pre-eclampsia and eclampsia

Evidence derived from a Cochrane review of 6 RCTs involving 866 women (Duley et al, 2010c) 2 RCTs (451 women) compared regimens for eclampsia 4 RCTs (415 women) compared regimens for PE

Alternative magnesium sulfate regimens for treatment of PE and E

Evidence Source Eclampsia Maternal death Recurrenc e of convulsio ns Any serious morbidity Renal failure Resp arrest Toxicity (Resp depr. Calcium gluconate given Any side effects Stillbirth or neonatal death Admissio n to SCBU 5 Apgar score < 5

Loading dose alone versus loading dose plus maintenance regimen for women with eclampsia
1 RCT, 401 women N/A 1 RCT, n=401; RR 0.89 (0.37-2.14) 1 RCT, n=401; RR 1.13 (0.42-3.05) ------Stillbirth: 1 RCT n=401; RR 1.13 (0.661.92)
VERY LOW

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Quality

VERY LOW

VERY LOW

Lower dose regimens versus standard dose regimens over 24 hours for women with eclampsia
N/A 1 RCT, 50 women -1 RCT, n=50R R 3.00, (0.1370.30). -Oliguria: 1 RCT, n=50, RR 0.20 (0.031.59)
VERY LOW

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Absent tendon reflexes: 1 RCT, n=50; RR 0.25 0.06-1.06

VERY LOW

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Quality

VERY LOW

Intravenous versus standard intramuscular maintenance regimen for 24 hours for women with pre-eclampsia
1 RCT, 17 women 1 RCT, n=17; RR Not estimable
VERY LOW

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1 RCT, n=17; RR 3.33 (0.1571.90)

VERY LOW

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1 RCT, n=17; RR 3.33 (0.1571.90)

VERY LOW

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1 RCT, n=17; RR 1.25 (0.0917.02)

VERY LOW

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Quality

Short versus standard (24 hours) duration of postpartum maintenance regimen for women with pre-eclampsia
3 RCTs, 398 women 3 RCTs, n=394; RR Not estimable LOW -----1 RCT, n=196; RR Not estimable LOW ------

Quality

Evidence Interpretation
Evidence supports the use of magnesium sulfate in severe PE to prevent progression to eclampsia Clear evidence that magnesium sulfate treatment in eclampsia reduces the incidence of further fits Clear evidence that magnesium sulfate is more effective than diazepam, phenytoin and lytic cocktail in preventing further eclamptic fit No clear evidence on which MgSO4 dosage regimen is better than the other Most trials providing the evidence used clinical monitoring in women undergoing treatment and none used serum monitoring

http://www.who.int/publications/guidelines/en/

WHO Recommendations
Magnesium sulfate is recommended for the prevention of eclampsia in women with severe pre-eclampsia in preference to other anticonvulsants. (High Quality Evidence, Strong Recommendation) Magnesium sulfate is recommended for the treatment of women with eclampsia in preference to other anticonvulsants. (Moderate Quality Evidence, Strong Recommendation) The full intravenous or intramuscular magnesium sulfate regimens are recommended for the prevention and treatment of eclampsia. (Moderate Quality Evidence, Strong Recommendation) For settings where it is not possible to administer the full magnesium sulfate regimen, the use of magnesium sulfate loading dose followed by immediate transfer to a higher level health-care facility is recommended for women with severe pre-eclampsia and eclampsia. (Very low Quality Evidence, Weak Recommendation)

Implications for clinical practice

Magnesium sulfate is the drug of choice for preventing and treating convulsions in severe PE & E (WHO 2003. Managing Complications in Pregnancy and Childbirth) Magnesium sulfate schedules for severe PE and eclampsia (WHO MCPC): Loading dose
4 g of 20% magnesium sulfate solution IV over 5 min Plus10 g of 50% magnesium sulfate solution IM (5 g in each buttock)

Maintenance dose
5 g of 50% magnesium sulfate solution IM into alternate buttock every four hours If 50% solution is not available, give 1 g of 20% magnesium sulfate solution IV every hour by continuous infusion For recurrent convulsions: 2 g of 50% magnesium sulfate IV over 5 min

http://www.who.int/publications/guidelines/en/