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The use of misoprostol for management of postpartum hemorrhage
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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 high risk cases
• Good technique
• Active management
Medical Tamponade Laparotomy
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 misoprostol Oral Vaginal Sublingual
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
Abdel-Aleem et al, Eur J Obstet Gynecol, 2002
5% peak plasma level
Max conc. in milk is 60th min
PHARMACOKINETICS OF MISOPROSTOL IN HUMAN
MILK
Vogel et al, Am J Obstet Gynecol, 2004
Elimination half-life is ½ of Methylergometrin
Breast feeding after 3 hours is safe
PROS AND CONS OF MISOPROSTOL IN PPH
Effective as uterotonic
Heat stable
Cheap 1tb = 0.8$ (US)
Easy to transport
Easy to administer
Not available world
wide
Off-label use – litigation
Treatment algorithm is
not clear
Side effects
POSTPARTUM HEMORRHAGE MANAGEMENT STRATEGY
Prevention Treatment
• Identify high risk cases
• Good technique
• Active management
Medical Tamponade Laparotomy
Misoprostol
MISOPROSTOL IN PREVENTING POSTPARTUM HEMORRHAGE 22 studies, 30017 participants Primary outcomes blood loss >500ml, 1000ml,
need for additional uterotonics
Langenbach, a meta analysis, Int J Gynecol Obstet, 2006
Oral 400 and 600 mcg
Rectal 400 and 600 mcg
Sublingual 400 and 600 mcg
Placebo
Methylergometrine 200 mcg, 400 mcg, 0.5 mg
Oxytocin 2.5 IU, 5 U, 10 U
VS
MISOPROSTOL ->1000ml blood loss
RR 0.85 (95% CI: 0.63-1.14)
Langenbach, a meta analysis, Int J Gynecol Obstet, 2006
Oral 400 and 600 mcg
Rectal 400PlaceboVS
MISOPROSTOL – additional oxytocics
RR 0.69 (95% CI: 0.53-0.90)
Langenbach, a meta analysis, Int J Gynecol Obstet, 2006
Oral 400 and 600 mcg
Rectal 400PlaceboVS
MISOPROSTOL ->1000ml blood loss
RR 1.36, 1% excess risk of severe PPH
Langenbach, a meta analysis, Int J Gynecol Obstet, 2006
VS
Oral 400 and 600 mcg
Rectal 400 and 600 mcg
Sublingual 400 and 600 mcg
Methylergometrine 200 mcg,
400 mcg, 0.5 mg
Oxytocin 2.5 IU, 5 U, 10 U
MISOPROSTOL – additional oxytocics
RR 1.23
Langenbach, a meta analysis, Int J Gynecol Obstet, 2006
VS
Oral 400 and 600 mcg
Rectal 400 and 600 mcg
Sublingual 400 and 600 mcg
Methylergometrine 200 mcg,
400 mcg, 0.5 mg
Oxytocin 2.5 IU, 5 U, 10 U
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
Caliskan et al, Am J Obstet Gynecol, 2002
1606 women
400mcg misoprostol
10 U oxytocin
Miso + Oxy
Meth + Oxy
PPH > 500 ml Miso > Oxy > Miso + Oxy > Meth + Oxy
PPH > 1000 ml Miso > Oxy > Miso + Oxy > Meth + Oxy
ORAL ROUTE IS COMPARABLE
Caliskan et al, Obstet Gynecol, 2003
1579 women
400mcg misoprostol
10 U oxytocin
Miso + Oxy
Meth + Oxy
PPH > 500 ml Miso ~ Oxy > Miso + Oxy = Meth + Oxy
PPH > 1000 ml Miso ~ Oxy > Miso + Oxy = Meth + Oxy
HOW MANY SHOULD WE TREAT ?
Preventing PPH > 500 mL NNT= 8
OXYTOCIN NO TREATMENTVS
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 ?
Preventing PPH > 500 mL NNT= 12-18 Preventing PPH > 1000 mL NNT= 30-100
MISOPROSTOL 600mcg p.o. NO TREATMENTVS
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
MISOPROSTOL 400mcg rectal
HOW MANY SHOULD WE TREAT ?
Preventing PPH > 500 mL NNT= 24
OXYTOCIN 10 U + MISOPROSTOL 400 mcg p.o.
OXYTOCIN 10 UVS
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 ?
Preventing PPH > 500 mL NNT= 66
OXYTOCIN 10 U + MISOPROSTOL 400 mcg rectal
OXYTOCIN 10 UVS
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
5IU iv Oxy
800mcg po misoprostol
20 IU Oxy
•Estimated and calculated intraoperative and portoperative blood loss is similar
•Misoprostol is a cost effective alternative to oxytoxin infusion
Lapaire et al, Int J Gynecol Obstet, 2006
MISOPROSTOL AT CESAREAN DELIVERY
60 women
400mcg po misoprostol
10 IU
Syntocinon
•Calculated intraoperative blood loss is similar
•Misoprostol can be used in C/S under regional anesthesia
Lapaire et al, Int J Gynecol Obstet, 2006
MISOPROSTOL AT CESAREAN DELIVERY
352 women
20IU iv Oxy
200mcg buc misoprostol placebo
•Misoprostol decreased additional uterotonic need
•Postpartum hemorrhage >1000ml is similar in the two groups
Hamm et al, AJOG, 2005
20IU iv Oxy
POSTPARTUM HEMORRHAGE MANAGEMENT STRATEGY
Prevention Treatment
• Identify high risk cases
• Good technique
• Active management
Medical Tamponade Laparotomy
Misoprostol
MISOPROSTOL IN TREATING POSTPARTUM HEMORRHAGE Three randomized controlled trials 468 participants
Hofmeyr et al, a systemic review, BJOG, 2005
800mcg rectal misoprostol PlaceboVS
10U Oxy or 1 amp syntometrine
600 mcg miso 1 po +2 sl
10U Oxy or 1 amp syntometrine1000 mcg miso 1 po + 2 sl + 2 rectal
10U Oxy or 1 amp syntometrine
3 tb placebos
10U Oxy or 1 amp syntometrinePlacebo 1 po + 2 sl + 2 rectal
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
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
MISOPROSTOL IN TREATING POSTPARTUM HEMORRHAGE
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
COST EFFECTIVENESS OF MISOPROSTOL
Bradley et al, Int J Gynecol Obstet, 2007
SIDE EFFECTS OF MISOPROSTOL
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
MISOPROSTOL 600mcg po VS PLACEBO
SIDE EFFECTS OF MISOPROSTOL
Lumbiganon et al, BJOG, 2001
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
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