Transcript Current Obstetric ‘Facts’

Reducing deaths from postpartum haemorrhage
Justus Hofmeyr
East. Cape Dept of Health, University of the Witwatersrand/ Fort Hare
Mdantsane, Eastern Cape
(near East London, South Africa)
Labour ward, Cecilia Makiwane Hospital
Effective Care Research Unit
Reported maternal deaths in SA 1999-2001:
n=2445 (MMR about 200/100 000);
35
30
25
20
15
SA %
10
5
0
Non-pregnancy Hypertension
sepsis (HIV)
Haemorrhage
Eclampsia
Comparison of more developed and
less developed provinces
Eastern Cape
Maternal
Proportion of
mortality ratio deaths due to
/100 000
obstetric
haemorrhage
>200
16%
Western Cape 50
6%
Effective Care Research Unit
Research overview: Prevention of PPH
• 1980’s: Uterotonic effects of traditional
herbal remedies
• 1989: First randomised trials of misoprostol
in 3rd stage of labour
• Systematic reviews
• 2003: First placebo-controlled trials of
misoprostol in addition to routine care for
treatment of PPH (SA and Gambia):
Cochrane reviews of randomised trials of PPH
prevention: Blood loss >1000ml (%)
oral mis
vs inj
subling m
vs plac*
5 trials,
2305 women
oral mis
vs plac
erg/oxy
v erg*
oral+inj*
vs inj
vs oral m
>500ml
.
.
oxytoc v
ergot(*)
rectal+inj
vs inj
rectal mis
vs inj
oxytoc v
nothing
*=significant,
(*)=borderline
erg/oxy
v oxy(*)
0
2
4
6
rectal mis
vs plac
8
0
5
10
15
20
Misoprostol for PPH treatment:
published reports
Authors
N
Misoprostol
PPH stopped
O’Brien 1998
14
1000 rectal
14 (100%)
A-Aleem 2000
18
1000 rectal
16 (88%)
Adekanmi 2001
1
800 uterine
1 (100%)
Ozan 2000
Sojai 2001
Oboro 2003
Total
2
5
1
41
400 oral 2hrly
200 rectal
800 uterine
2 (100%)
5 (100%)
1 (100%)
39 (95%)
Misoprostol for treatment of PPH: Systematic review
(2003): One Trial: misoprostol rectally vs injectable
oxytocics. Main outcome: failure to stop bleeding
(assessed clinically, unblinded)
Pharmacokinetic Studies: Time to
peak concentration (minutes)
90
80
70
60
Ziemann 400
Danielsson 400
Tang 400
A-Aleem 600
Khan 600
50
40
30
20
10
0
Oral
Sublingual
Rectal
Vaginal
Pharmacokinetic Studies: Peak
concentration (pg/ml)
600
500
Ziemann 400
Danielsson 400
Tang 400
Andolina 400
A-Aleem 600
Khan 600
400
300
200
100
0
Oral
Sublingual
Rectal
Vaginal
Misoprostol vs placebo (in addition to
routine management): measured blood
loss of 500 ml or more after enrolment
Høj L., Cardoso P., Nielsen B.B.,
Hvidman L., Nielsen J., Aaby P.
Effect of sublingual misoprostol on severe
postpartum haemorhhage in a primary
health centre in Guinea-Bissau: randomized
double blind controlled trial.
BMJ 2005;331;723-7.
One death in the misoprostol group
Results: Blood loss after delivery
(Hoj 2005)
Inadequate reporting of safety issues
from clinical trials in academic journals
Susan C Morgan,
• ‘..it would appear reasonable to include adverse
event to misoprostol as a possible cause for the
death. It is known that misoprostol can cause
hypotension which could be particularly
hazardous in the context of blood loss and
undiagnosed cardiovascular or cerebrovascular
disease.’
Re: Inadequate reporting of safety issues
from clinical trials in academic journals
Lars Høj
• ‘.. the event was appropriately reported for
inclusion in meta-analyses to come.’
Questions for authors regarding the
effect of sublingual misoprostol on
postpartum haemorrhage
Nancy L. Sloan, Beverly Winikoff,
Jennifer Blum
• ‘Finally, as with our study, the one maternal
death occurred in the misoprostol group.
Perhaps it is time to conduct a specific trial
that measures the impact of administering
misoprostol in the third stage of labour on
maternal death as a primary endpoint.’
Review of misoprostol in the third stage of
labour and maternal mortality
Justus Hofmeyr, Metin Gülmezoglu
Methods:
• We searched The Cochrane Controlled Trials
Register and the electronic data base
Pubmed/Medline on the word 'misoprostol' in
December 2005
• Randomised comparisons of misoprostol used for
the prevention or treatment of postpartum
haemorrhage, with placebo or alternative methods
(usually injectable uterotonics).
Results:
• We identified 32 prevention and three treatment
trials of postpartum haemorrhage where misoprostol
was used as one of the interventions
• In 24 trials no mention of maternal deaths was
made.
• 3 prevention and 1 treatment trial reported maternal
deaths
Review: all misoprostol in 3rd stage trials
with maternal deaths
Deaths in non-misoprostol groups
Trial
Dosage
Circumstances of deaths
WHO 2000
Prevention PPH (2 cases)
600 oral
Deaths in misoprostol groups
Trial
Dosage
Circumstances of deaths
WHO 2000
Walraven
2005 Gambia
600 oral
PPH (2 cases)
Prevention 1. PPH (2200ml)
600 oral
2. DIC due to malaria (blood loss 300ml)
Hoj 2005
Prevention Blood loss 1417ml, apparently controlled.
Guinea-Bissau 600 subl. Died after 90 minutes ? Cause
Hofmeyr 2004 Treatment 1. Continued bleeding. Hysterectomy.
South Africa 200 oral
Multiple transfusions. Died after 2 days
400 subl. 2. Bleeding form torn cervix, cardiac arrest
400 rectal 7.5 hours after birth
3. Previous caesarean section. Bled 500ml
before and 425ml after enrolment.
Hypotension and cardiorespiratory arrest 1
hour after enrolment.
Limitations of this review
• Numbers are small, with wide confidence limits
• Consistent, at the 95% confidence level, with
anything between a modest reduction and a large
increase in maternal mortality with misoprostol
• This was a post -hoc analysis in response to an
observed clustering of maternal deaths, and the
statistical calculations need to be interpreted with
circumspection.
Discussion
• Blood loss is a proxy outcome – we assume
that reduced blood loss will translate to
reduced deaths
• Is it feasible for reduced blood loss to be
associated with more deaths?
Example of falsely reassuring proxy
outcomes
• Common cause of death from myocardial
infarction is ventricular tachyarrhythmia
• Class 1 antiarrhythmics effective in reducing
ventricular arrhythmias after myocardial infarction
• Assumed would reduce deaths and became routine
for post-myocardial infarction care
Mortality following ventricular arrhythmia suppression by
encainide, flecainide, and moricizine after myocardial
infarction. The original design concept of the Cardiac
Arrhythmia Suppression Trial (CAST). Epstein AE, et al.
JAMA 1993; 270:2451-5
• OBJECTIVE--To test the hypothesis that in
survivors of myocardial infarction, the suppression
of ventricular premature depolarizations improves
survival free of cardiac arrest and arrhythmic death.
• INTERVENTION--Administration of encainide,
flecainide, moricizine, or placebo to suppress
ventricular premature depolarizations.
(2) Mortality following ventricular arrhythmia suppression by
encainide, flecainide, and moricizine after myocardial
infarction. The original design concept of the Cardiac
Arrhythmia Suppression Trial (CAST). Epstein AE, et al.
JAMA 1993; 270:2451-5
• RESULTS--At 1 year from the time of randomization to
blinded therapy, mortality of placebo-treated patients 5%
vs 10% of active drug-treated patients (P = .0006).
• CONCLUSIONS--The suppression of asymptomatic or
mildly symptomatic ventricular arrhythmias after
myocardial infarction does not improve survival and can
increase mortality. Treatment strategies designed solely to
suppress these arrhythmias should no longer be followed.
• [Estimated deaths from use of anyi-arrythmics: 10,000]
Hypothesis
• Apart from its uterotonic effects, misoprostol has
known pharmacologic effects on multiple systems,
such as thermoregulation
• It is plausible that a drug with ubiquitous
pharmacologic effects might have unexpected
adverse effects on homoeostatic mechanisms,
when used in the third stage of labour
• Blood loss is a proxy outcome – we assume that
reduced blood loss will translate to reduced deaths
Conclusion:
• These results should not be construed as evidence of
an adverse effect of misoprostol on maternal
mortality
• We propose, for further investigation, the
hypothesis that misoprostol may have an as yet
unexplained adverse effect on maternal
homoeostatic functions in the third stage of labour.
Way forward: Suggestions
1. Ongoing systematic review of maternal
mortality in misoprostol trials
2. Continued research on the benefits and
risks of 3rd stage misoprostol
3. Monitoring of implementation programs
4. Further research to determine lowest
effective dose and best route
UTERINE MASSAGE TO REDUCE
POSTPARTUM HAEMORRHAGE: A
RANDOMIZED TRIAL
Ferreira S, Singata M, Mangesi L, Abdel-Aleem H*,
Hofmeyr GJ. Effective Care Research Unit, Eastern Cape
Dept of Health, University of the Witwatersrand/Fort Hare,
*Department of Obstetrics and Gynecology, Assiut
University Hospital, Assiut, Egypt
Introduction:
• Active management of the third stage of labour, including
injectable uterotonics, is effective in reducing postpartum
haemorrhage (PPH)
• Worldwide, most deaths from PPH occur in women
delivering at home, without access to uterotonic drugs
• There is a need to investigate simple measures, which can
be applied universally at community level to reduce the
burden of postpartum haemorrhage.
• The International Federation of Gynaecologists and
Obstetricians (2003) recommend routine massage of the
uterus after delivery of the placenta.
• Massage is thought to stimulate uterine contraction,
possibly through stimulation of local prostaglandin release
and thus to reduce haemorrhage.
Introduction (2)
• There is very little empirical research to evaluate the
effectiveness of uterine massage in the third stage of
labour
• If sustained routine massage is shown to be
effective, promotion of this simple method through
educational campaigns would have the potential to
reduce maternal mortality from postpartum
haemorrhage on a very wide scale.
• If not effective, attention can be directed towards
other methods of reducing postpartum haemorrhage.
Objective:
• To determine the effectiveness of sustained uterine
massage to reduce postpartum haemorrhage
• Collaborative program: Departments of Obstetrics
and Gynaecology, East London Hospital Complex
and Assiut University, Egypt
Preliminary Study
H Abdel-Aleem, G J Hofmeyr, M Shokry, E El-Sonoosy
• Conducted in the Dept. of O&G, Assiut University Hospital
• Pregnant women admitted in labor were invited to participate.
• If the labor progressed to spontaneous vaginal delivery, women
were randomly allocated, to one of two groups:
– (1) Combined routine active management (oxytocin 10 IU I.V
or I.M., immediate cord clamping and controlled cord
traction) plus intermittent uterine massage every 10 minutes
for 60 minutes (manual stimulation of the whole surface of
the uterus using steady repetitive movements, as firmly as can
be achieved without causing distress to the mother, till the
uterus became contracted).
– (1) Routine active management.
• A plastic drape was placed under the woman’s buttocks to collect
all blood loss after delivery of the baby for 30 and 60 minutes.
Uterine massage vs Control:
Mean Blood Loss (ml)
Uterine massage vs Control:
PPH and Use of additional uterotonics
Discussion
• Limitations:
– small sample size
– staff could not be blinded to the group allocation.
• The chance of bias with respect to blood loss
assessment was minimized by using objective, direct
measurement. However, the use of other
interventions could have been influenced by
knowledge of the group allocation.
• Larger studies are needed to ascertain with more
precision the effect of uterine massage on more
substantive outcomes, and also the effectiveness in
the absence of availability of injectable uterotonics.
Large study Protocol
• Pregnant women expected to deliver normally are invited to
participate
• If the labour progresses to spontaneous vaginal delivery,
consented women are enrolled by drawing the next in a
randomly allocated numbered series of opaque sealed
envelopes, to one of three groups:
• 1. Routine management. Oxytocin 10u IMI
• 2. Sustained uterine massage: Uterine massage commenced
shortly after delivery and sustained for 30 minutes.
Oxytocin delayed until after the 30-minute period of
massage, unless blood loss of 500ml is measured before that
time.
• 3. Combined routine management plus sustained uterine
massage.
Protocol (2)
• In all 3 groups controlled cord traction is carried
out according to hospital policy.
• A low profile plastic “fracture” bedpan is placed
under the woman’s buttocks to collect all blood loss
after delivery of the baby for 30 minutes.
• There is no other interference in the routine care of
the woman.
• The primary outcomes are: 1. Blood loss >300ml
within 30 minutes; 2. Placenta delivered >30
minutes after birth.
Analysis:
• Data will be entered into an excel data spreadsheet
and analysed using epi info 2002
• Outcome data will be compared using relative risks
with 95% confidence intervals and for comparisons
of medians the Mann-Whitney 2 sample test.
• To show a reduction of blood loss >300ml in 30
minutes from 13.5% to 9% with sustained uterine
massage will require 800 women per group (2400
women).
Conclusions
• Uterine massage has been recommended without
evidence of effectiveness or guidelines as to how
and for how long it should be performed
• Sustained uterine massage is a promising
intervention for widespread use in both hospital and
non-hospital settings
• Funding needed to complete a large, multicentre
trial