misoprostol in postpartum hemorrhage

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


Schaff et al, Contaception, 2005


Tang et al, Hum Reprod, 2002


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




• Good technique



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)



Rectal 400PlaceboVS

MISOPROSTOL – additional oxytocics

RR 0.69 (95% CI: 0.53-0.90)



Rectal 400PlaceboVS

MISOPROSTOL ->1000ml blood loss

RR 1.36, 1% excess risk of severe PPH


VS




Methylergometrine 200 mcg,

400 mcg, 0.5 mg


MISOPROSTOL – additional oxytocics

RR 1.23


VS




Methylergometrine 200 mcg,

400 mcg, 0.5 mg


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


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


Nausea and vomiting NNH= 61 Hypertention NNH= 96

Maughan et al, Am Fam Physician, 2006


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



OXYTOCIN 10 U + MISOPROSTOL 400 mcg p.o.

OXYTOCIN 10 UVS


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

Caliskan et al, Obstet Gynecol, 2003



OXYTOCIN 10 U + MISOPROSTOL 400 mcg rectal

OXYTOCIN 10 UVS


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


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


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




• Good technique



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

misoprostol in postpartum hemorrhage

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