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THE USE OF MISOPROSTOL IN

POSTPARTUM HEMORRHAGE

Asist. Prof. ERAY ÇALIŞKAN


Kocaeli University, School of
Medicine
Kocaeli - TURKEY
POSTPARTUM HEMORRHAGE
MANAGEMENT STRATEGY

Prevention Treatment

• Identify Medical Tamponade Laparotomy


high risk
cases
• Good
technique
• Active
management Misoprostol
RATIONALE FOR
MISOPROSTOL
 Intrauterine pressure and cumulative uterine
activity of 200 to 400 mcg misoprostol is similar
to syntometrine (5U oxytocin + 0.5mg
ergometrine)

 The mean onset of action of oral misoprostol


(6.1± 2.1 min) was significantly slower than that
of intramuscular syntometrine (3.2 ±1.5 min

Chong et al., BJOG, 2001


ROUTE OF MISOPROSTOL

400 mcg
Oral Vaginal Sublingual
misoprostol
Time to onset of
uterine activity 7.8 min 19.4 min 10.7 min

Time to maximum
uterine tonus 25-39 min 46-62 min 47-51 min

Danielsson et al., Obstet Gynecol, 1999; Aronsson et al., Hum Reprod, 2004
PHARMACOKINETICS OF
MISOPROSTOL
Dose Oral Sublingual Rectal Vaginal
Time to peak concentration (min)
400 mcg 28-34 26 60-80
600 mcg 18-20 41
Peak concentration (pg/ml)
400 mcg 227-288 575 125
600 mcg 328-381 184
AUC 4 hours (pg/hrs/mL)
400 mcg 273 503
600 mcg 190 311
AUC 6 hours (pg/hrs/mL)
400 mcg 300-403 744 434
PHARMACOKINETICS OF
MISOPROSTOL

Schaff et al, Contaception, 2005


PHARMACOKINETICS OF
MISOPROSTOL

Tang et al, Hum Reprod, 2002


PHARMACOKINETICS OF
MISOPROSTOL

Khan and El-Refaey, Obstet Gynecol, 2003


PHARMACOKINETICS OF
MISOPROSTOL IN HUMAN
MILK

5% peak plasma level


Max conc. in milk is 60th min

Abdel-Aleem et al, Eur J Obstet Gynecol, 2002


PHARMACOKINETICS OF
MISOPROSTOL IN HUMAN
MILKhalf-life is ½ of Methylergometrin
Elimination
Breast feeding after 3 hours is safe

Vogel et al, Am J Obstet Gynecol, 2004


PROS AND CONS OF
MISOPROSTOL IN PPH

 Effective as uterotonic  Not available world

 Heat stable wide

 Cheap 1tb = 0.8$ (US)


 Off-label use – litigation

 Easy to transport
 Treatment algorithm is
not clear
 Easy to administer
 Side effects
POSTPARTUM HEMORRHAGE
MANAGEMENT STRATEGY

Prevention Treatment

• Identify Medical Tamponade Laparotomy


high risk
cases
• Good
technique
• Active
management Misoprostol
MISOPROSTOL IN
PREVENTING POSTPARTUM
HEMORRHAGE
 22 studies, 30017 participants
 Primary outcomes blood loss >500ml, 1000ml,
need for additional uterotonics

Oral 400 and 600 mcg Placebo


Rectal 400 and 600 mcg Methylergometrine 200 mcg,
VS
Sublingual 400 and 600 mcg 400 mcg, 0.5 mg
Oxytocin 2.5 IU, 5 U, 10 U

Langenbach, a meta analysis, Int J Gynecol Obstet, 2006


MISOPROSTOL ->1000ml
blood loss
RR 0.85 (95% CI: 0.63-1.14)
Oral 400 and 600 mcg
VS Placebo
Rectal 400

Langenbach, a meta analysis, Int J Gynecol Obstet, 2006


MISOPROSTOL – additional
oxytocics
RR 0.69 (95% CI: 0.53-0.90)
Oral 400 and 600 mcg
VS Placebo
Rectal 400

Langenbach, a meta analysis, Int J Gynecol Obstet, 2006


MISOPROSTOL ->1000ml
blood loss
Oral 400 and 600 mcg Methylergometrine 200 mcg,
RR 1.36, 1% excess risk of severe
Rectal 400 and 600 mcg
PPH VS 400 mcg, 0.5 mg
Sublingual 400 and 600 mcg
Oxytocin 2.5 IU, 5 U, 10 U

Langenbach, a meta analysis, Int J Gynecol Obstet, 2006


MISOPROSTOL – additional
oxytocics
Oral 400 and 600 mcg Methylergometrine 200 mcg,
RR 1.23
Rectal 400 and 600 mcg
VS 400 mcg, 0.5 mg
Sublingual 400 and 600 mcg
Oxytocin 2.5 IU, 5 U, 10 U

Langenbach, a meta analysis, Int J Gynecol Obstet, 2006


BUT….FOR SEVERE PPH

 A sub analysis of oral and sublingual


misoprostol vs oxytocics revealed no
statistical difference RR: 1.13 (0.81-1.56)
 Rectal misoprostol reach peak concentrations
in a longer time
 It is possible that many studies intervened
with additional oxytocics before rectal
misoprostol took effect

Langenbach, a meta analysis, Int J Gynecol Obstet, 2006


RECTAL ROUTE IS NOT IDEAL

1606 women

400mcg 10 U Miso + Meth +


misoprostol oxytocin Oxy Oxy

PPH > 500 ml Miso > Oxy > Miso + Oxy > Meth + Oxy

PPH > 1000 ml Miso > Oxy > Miso + Oxy > Meth + Oxy

Caliskan et al, Am J Obstet Gynecol, 2002


ORAL ROUTE IS
COMPARABLE
1579 women

400mcg 10 U Miso + Meth +


misoprostol oxytocin Oxy Oxy

PPH > 500 ml Miso ~ Oxy > Miso + Oxy = Meth + Oxy

PPH > 1000 ml Miso ~ Oxy > Miso + Oxy = Meth + Oxy

Caliskan et al, Obstet Gynecol, 2003


HOW MANY SHOULD WE
TREAT ?
OXYTOCIN VS NO TREATMENT

 Preventing PPH > 500 mL NNT= 8

OXYTOCIN + ERGOMETRİNE VS OXYTOCIN

 Preventing PPH > 500 mL NNT= 61


 Nausea and vomiting NNH= 61
 Hypertention NNH= 96
Maughan et al, Am Fam Physician, 2006
HOW MANY SHOULD WE
TREAT ?
MISOPROSTOL 600mcg p.o. VS NO TREATMENT

 Preventing PPH > 500 mL NNT= 12-18


 Preventing PPH > 1000 mL NNT= 30-100

MISOPROSTOL 400mcg rectal VS NO TREATMENT

 Preventing PPH > 1000 mL NNT= 42 ??

Surbek et al, Obstet Gynecol, 1999; Derman et al, Lancet, 2006;


Bamigboye et al Am J Obstet Gynecol, 1998
HOW MANY SHOULD WE
TREAT ?
OXYTOCIN 10 U + VS OXYTOCIN 10 U
MISOPROSTOL 400 mcg p.o.

 Preventing PPH > 500 mL NNT= 24

 Preventing PPH > 1000 mL NNT= 40

 Shivering NNH= 14
 Fever > 38°C NNH= 38
 Vomiting and diarrhea was comparable

Caliskan et al, Obstet Gynecol, 2003


HOW MANY SHOULD WE
TREAT ?
OXYTOCIN 10 U + VS OXYTOCIN 10 U
MISOPROSTOL 400 mcg rectal

 Preventing PPH > 500 mL NNT= 66

 Preventing PPH > 1000 mL NNT= 142

 Shivering NNH= 12
 Fever > 38°C NNH= 31
 Vomiting and diarrhea was comparable

Caliskan et al, Am J Obstet Gynecol, 2002


MISOPROSTOL AT CESAREAN
DELIVERY

56 women •Estimated and calculated


intraoperative and
portoperative blood loss is
similar
5IU iv Oxy
•Misoprostol is a cost
800mcg po 20 IU Oxy effective alternative to
misoprostol oxytoxin infusion

Lapaire et al, Int J Gynecol Obstet, 2006


MISOPROSTOL AT CESAREAN
DELIVERY

60 women •Calculated intraoperative


blood loss is similar

•Misoprostol can be used


in C/S under regional
anesthesia
400mcg po 10 IU
misoprostol Syntocinon

Lapaire et al, Int J Gynecol Obstet, 2006


MISOPROSTOL AT CESAREAN
DELIVERY

352 women •Misoprostol decreased


additional uterotonic need

•Postpartum hemorrhage
200mcg buc >1000ml is similar in the
misoprostol placebo
two groups

20IU iv Oxy 20IU iv Oxy

Hamm et al, AJOG, 2005


POSTPARTUM HEMORRHAGE
MANAGEMENT STRATEGY

Prevention Treatment

• Identify Medical Tamponade Laparotomy


high risk
cases
• Good
technique
• Active
management Misoprostol
MISOPROSTOL IN TREATING
POSTPARTUM HEMORRHAGE
 Three randomized controlled trials
 468 participants

800mcg rectal misoprostol Placebo


VS

10U Oxy or 1 amp syntometrine 10U Oxy or 1 amp syntometrine


600 mcg miso 1 po +2 sl 3 tb placebos

10U Oxy or 1 amp syntometrine 10U Oxy or 1 amp syntometrine


1000 mcg miso 1 po + 2 sl + 2 rectal Placebo 1 po + 2 sl + 2 rectal

Hofmeyr et al, a systemic review, BJOG, 2005


MISOPROSTOL IN TREATING
POSTPARTUM HEMORRHAGE

 On going blood loss of 500 ml or more is less


with misoprostol RR 0.57 (0.34-0.96)
 Subjective cessation of hemorrhage is more
with misoprostol RR 0.18 (0.04-0.76)
 Pyrexia is higher RR 6.4 (1.7-24)
 Shivering is higher RR 2.3 (1.7-3.2)

Hofmeyr et al, a systemic review, BJOG, 2005


MISOPROSTOL IN TREATING
POSTPARTUM HEMORRHAGE
 A recent large RCT with 238 participants
 1000 mcg misoprostol 1po 2 sl 2 rectal vs
placebo
 Reduced blood loss > 500ml 1 hr after
treatment 0.56 (0.21-1.46)
 Underpowered study, more maternal deaths
in the misoprostol group ?

Hofmeyr et al, BMC Pregnancy and childbirth, 2004


MISOPROSTOL IN TREATING
POSTPARTUM HEMORRHAGE
 Descriptive studies used doses of 800 to
1000 mcg misoprostol
 Misoprostol was used as the last line of
medical treatment in cases unresponsive to
oxytocin and ergometrine
 Rectal, oral, intrauterine routes were used
 Their results are better than controlled trials
 They have the inherent potential of bias
COST EFFECTIVENESS OF
MISOPROSTOL
 1tb 200 mcg misoprostol = 1 amp
ergometrine = 1 US $
 In a hypothetical cohort of 10.000 women
misoprostol 1000mcg in cases with
postpartum hemorrhage >500 ml can save:
 115.335 US $ in costs of referral
 13.991 – 1.563.593 US $ in costs of therapy

Bradley et al, Int J Gynecol Obstet, 2007


SIDE EFFECTS OF
MISOPROSTOL
MISOPROSTOL 600mcg po VS PLACEBO

Side effect RR 95 % CI
Shivering 4.03 2.8 – 5.7
Pyrexia > 37.8 °C 6.23 3.8 – 9.9
Nausea 5 0.59 – 42.5
Vomiting 2 0.37 – 10.8
Diarrhea 1 0.06 – 15.9

Hofmeyr et al, SAMJ, 2001


SIDE EFFECTS OF
MISOPROSTOL
MISOPROSTOL 600mcg po VS 10 IU OXYTOCIN

Side effect time RR 95 % CI


Shivering ≤ 1hr 6.4 3.9 – 10.4
2-6 hrs 4.7 1.9 – 11.2
Diarrhea 2-6 hrs 21 5.1 – 86.5
7 - 12 hrs 7.7 2.3 – 25.4
Pyrexia ≤ 1hr 2.8 1.4 – 5.3
2-6 hrs 6.3 3.7 – 10.8
Lumbiganon et al, BJOG, 2001
CONCLUSION
 Current data supports misoprostol use for the
prevention of postpartum hemorrhage
 The earlier administration may result in better
prevention
 More studies are needed for its role in the
treatment of postpartum hemorrhage
 Identical placebos should be produced for
any potential bias
CONCLUSION
 Further pharmacological data are needed to
deliver misoprostol rapidly
 Sublingual route is the most promising but
p.o. route can also be used with or without
rectal combination
 Doses of ≤ 600 mcg have less side effects
 Political action is needed for its wider use
THANK YOU