Choice of Anticonvulsant for Prevention
and Management of Eclamptic Seizures
Femi Oladapo
Maternal and Fetal Health Research Unit,
Department of Obstetrics & Gynaecology,
Olabisi Onabanjo University,
Sagamu, Nigeria
On behalf of the Guideline Development Group for the
WHO Recommendations on Preeclampsia and Eclampsia
Outline
• Background
• Anticonvulsants for PE/E
• WHO guideline development process
• Evidence summary on clinical effectiveness
• Interpretation of evidence
• Implications for clinical practice
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
• Uncertain pathophysiology and associated multisystemic
complications raise safety concerns regarding drug treatment
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
Less common: nausea, vomiting, muscle weakness, thirst, headache,
drowsiness and confusion
Rare: respiratory depression, respiratory and cardiac arrest

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
•
Core medicine in the World Health Organization's 'Essential Drugs
List‘
•
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)
•
First introduced and used to be standard treatment in India
•
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
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
• 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?
Evidence synthesis
• Reviews of effectiveness (GRADE appr.)
• Quality of evid+ Strength of recommendatn
Public (electronic) consultations
• Online technical consultation on recomm.
• Virtual global consultation
Final recommendation expert panel
meeting
• Agreement on recommendations
• Implementation plan & update
Critical outcomes for WHO recommendations on PE/E
Outcomes
Proxy
Eclampsia
PE (if it is an intervention for
preventing PE); Severe hypertension;
Severe PE/HELLP
Recurrence of convulsions
--
Severe maternal morbidity
Organ failure
Maternal death
--
Perinatal death
Stillbirth, neonatal death, any baby
death
Admission to neonatal intensive care
unit
--
Apgar scores at 5’ < 7
--
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
1 RCT,
n= 9992;
RR 5.26,
(4.59-6.03)
3 RCT,
n=10,899;
RR 5.96
(0.72-49.40)
2 RCTs,
n=10,795;
RR 1.35,
(0.63-2.88)
1 RCT,
n=8260;
RR 1.02,
(0.85-1.22).
1 RCT,
n=8260;
RR 1.01,
(0.96-1.06)
3 RCTs,
n=9961;
RR 1.04,
(0.93-1.15)
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)
2 RCTs,
n=10,795;
RR 0.54,
(0.26-1.10)
HIGH
HIGH
HIGH
MODERATE
HIGH
HIGH
HIGH
HIGH
--
--
--
--
--
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
Magnesium sulfate versus phenytoin
4 RCTs,
2343
women
Evidence
Quality
3 RCTs,
n=2291;
RR 0.08,
(0.01-0.60)
--
MODERATE
Magnesium sulfate versus diazepam
2 RCTs,
66
women
Evidence
Quality
2 RCTs,
n=66; RR
3.00, (0.1369.31)
--
--
--
--
--
--
--
--
--
--
--
VERY LOW
Magnesium sulfate versus nimodipine
1 RCT,
1650
women
Evidence
Quality
1 RCT,
n=1650;
RR 0.33,
(0.14-0.77)
LOW
--
MODERATE
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
Renal failure
admission
Pulm.
oedema
Resp. depr.
Mech.
3 RCTs,
n=1013;
RR 0.86
(0.35 to
2.07)
3 RCTs,
n=1025;
RR 0.86
(0.57 to
1.30)
3 RCTs,
n=1025;
RR 0.73,
(0.45 to
1.18)
MODERATE
MODERATE
MODERATE
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)
MODERATE
MODERATE
CVA
Cardiac
arrest
Coma >24
hours
4 RCTs,
n=1225;
RR 0.62,
(0.32-1.18)
4 RCTs,
n=1085;
RR 0.80
(0.41 -1.54)
--
ventilation
Magnesium sulfate versus diazepam
Cochrane
review
7 RCTs,
1396
women
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)
Evidence
Quality
HIGH
MODERATE
MODERATE
MODERATE
5 RCTs,
n=1164;
RR 0.85
(0.53-1.36)
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
MODERATE
MODERATE
HIGH
3 RCTs,
n=902;
RR 1.52
(0.98-2.36)
1 RCT,
n=775;
RR 0.54,
(0.20-1.46).
1 RCT,
n=775;
RR 1.16,
(0.39-3.43)
MODERATE
MODERATE
1 trial,
n=108;
RR 0.22
(0.01-4.54).
2 RCTs,
n=307;
RR 0.26
(0.03-2.34)
--
Magnesium sulfate versus lytic cocktail
Cochrane
review
3 RCTs,
397
women
3 RCTs,
n=397;
RR 0.06
(0.03-0.12)
3 RCTs,
n=397;
RR 0.14
(0.03-0.59)
Evidence
Quality
MODERATE
MODERATE
--
--
2 RCTs,
n=307;
RR 0.64
(0.22-1.85)
--
2 RCTs,
n=198;
RR 0.12
(0.02-0.91)
LOW
1 RCT,
n=90;
RR 0.20
(0.014.05)
1 RCT,
n=108;
RR 0.04
(0.00-0.74)
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
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
Magnesium sulfate versus diazepam
Cochrane review
7 RCTs, 1396
women
5 RCTs, n=799; RR 0.97
(0.70-1.34)
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)
MODERATE
MODERATE
MODERATE
HIGH
MODERATE
Magnesium sulfate versus lytic cocktail
Cochrane review
3 RCTs,
397 women
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)
Evidence Quality
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
Stillbirth:
1 RCT
n=401;
RR 1.13
(0.661.92)
--
--
--
--
--
--
--
--
Loading dose alone versus loading dose plus maintenance regimen for women with eclampsia
1 RCT,
401
women
N/A
Quality
1 RCT,
n=401; RR
0.89
(0.37-2.14)
1 RCT,
n=401;
RR 1.13
(0.42-3.05)
VERY LOW
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).
--
VERY LOW
Quality
Oliguria:
1 RCT,
n=50,
RR 0.20
(0.031.59)
--
VERY
LOW
Absent
tendon
reflexes:
1 RCT,
n=50;
RR 0.25
0.06-1.06
--
--
--
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
Quality
VERY LOW
--
--
--
1 RCT,
n=17;
RR 3.33
(0.1571.90)
--
VERY
LOW
1 RCT,
n=17;
RR 3.33
(0.1571.90)
--
--
VERY
LOW
1 RCT,
n=17;
RR 1.25
(0.0917.02)
VERY
LOW
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
Quality
LOW
--
--
--
--
--
1 RCT,
n=196;
RR Not
estimable
LOW
--
--
--
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
Implications for clinical practice
•
Development of WHO Recommendations on PE & E is currently underway
•
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
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