Misoprostol In 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 Treatment
Prevention
• Identify high risk cases
Medical
Tamponade
• Good technique • Active management
Misoprostol
Laparotomy
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 Time to onset of uterine activity Time to maximum uterine tonus
Oral
Vaginal
Sublingual
7.8 min
19.4 min
10.7 min
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 Time to peak concentration
Oral
Sublingual
Rectal
Vaginal
(min)
400 mcg
28-34
600 mcg
18-20
26
60-80 41
Peak concentration (pg/ml) 400 mcg
227-288
600 mcg
328-381
575
125 184
AUC 4 hours (pg/hrs/mL) 400 mcg
273
600 mcg
190
503 311
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
Heat stable
Not available world 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 Treatment
Prevention
• Identify high risk cases
Medical
Tamponade
• Good technique • Active management
Misoprostol
Laparotomy
MISOPROSTOL IN PREVENTING POSTPARTUM HEMORRHAGE 22 studies, 30017 participants
Primary outcomes blood loss >500ml, 1000ml, need for additional uterotonics Oral 400 and 600 mcg Rectal 400 and 600 mcg Sublingual 400 and 600 mcg
Placebo
VS
Methylergometrine 200 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 Rectal 400
VS
Placebo
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 Rectal 400
VS
Placebo
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 Sublingual 400 and 600 mcg
VS
400 mcg, 0.5 mg 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 Rectal 400 and 600 mcg Sublingual 400 and 600 mcg
Methylergometrine 200 mcg,
RR 1.23 VS
400 mcg, 0.5 mg 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 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 Caliskan et al, Am J Obstet Gynecol, 2002
ORAL ROUTE IS COMPARABLE 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 Caliskan et al, Obstet Gynecol, 2003
HOW MANY SHOULD WE TREAT ? VS
OXYTOCIN
Preventing PPH > 500 mL VS
OXYTOCIN + ERGOMETRİNE
Preventing PPH > 500 mL
Nausea and vomiting Hypertention
NO TREATMENT
NNT= 8 OXYTOCIN
NNT= 61 NNH= 61 NNH= 96
Maughan et al, Am Fam Physician, 2006
HOW MANY SHOULD WE TREAT ? MISOPROSTOL 600mcg p.o.
Preventing PPH > 500 mL Preventing PPH > 1000 mL
MISOPROSTOL 400mcg rectal
VS
VS
Preventing PPH > 1000 mL
NO TREATMENT
NNT= 12-18 NNT= 30-100 NO TREATMENT
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 + MISOPROSTOL 400 mcg p.o.
VS
OXYTOCIN 10 U
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 + MISOPROSTOL 400 mcg rectal
VS
OXYTOCIN 10 U
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
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
•Calculated intraoperative blood loss is similar •Misoprostol can be used in C/S under regional anesthesia
400mcg po misoprostol
10 IU Syntocinon
Lapaire et al, Int J Gynecol Obstet, 2006
MISOPROSTOL AT CESAREAN DELIVERY 352 women
200mcg buc misoprostol
20IU iv Oxy
placebo
•Misoprostol decreased additional uterotonic need •Postpartum hemorrhage >1000ml is similar in the two groups
20IU iv Oxy Hamm et al, AJOG, 2005
POSTPARTUM HEMORRHAGE MANAGEMENT STRATEGY Treatment
Prevention
• Identify high risk cases
Medical
Tamponade
• Good technique • Active management
Misoprostol
Laparotomy
MISOPROSTOL IN TREATING POSTPARTUM HEMORRHAGE
Three randomized controlled trials 468 participants
800mcg rectal misoprostol
VS
Placebo
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 1000 mcg miso 1 po + 2 sl + 2 rectal
10U Oxy or 1 amp syntometrine 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
21
5.1 – 86.5
7.7
2.3 – 25.4
Pyrexia ≤ 1hr
2.8
1.4 – 5.3
2-6 hrs
6.3
3.7 – 10.8
Diarrhea 2-6 hrs 7 - 12 hrs
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
POSTPARTUM HEMORRHAGE MANAGEMENT STRATEGY Treatment
Prevention
• Identify high risk cases
Medical
Tamponade
• Good technique • Active management
Misoprostol
Laparotomy
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 Time to onset of uterine activity Time to maximum uterine tonus
Oral
Vaginal
Sublingual
7.8 min
19.4 min
10.7 min
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 Time to peak concentration
Oral
Sublingual
Rectal
Vaginal
(min)
400 mcg
28-34
600 mcg
18-20
26
60-80 41
Peak concentration (pg/ml) 400 mcg
227-288
600 mcg
328-381
575
125 184
AUC 4 hours (pg/hrs/mL) 400 mcg
273
600 mcg
190
503 311
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
Heat stable
Not available world 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 Treatment
Prevention
• Identify high risk cases
Medical
Tamponade
• Good technique • Active management
Misoprostol
Laparotomy
MISOPROSTOL IN PREVENTING POSTPARTUM HEMORRHAGE 22 studies, 30017 participants
Primary outcomes blood loss >500ml, 1000ml, need for additional uterotonics Oral 400 and 600 mcg Rectal 400 and 600 mcg Sublingual 400 and 600 mcg
Placebo
VS
Methylergometrine 200 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 Rectal 400
VS
Placebo
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 Rectal 400
VS
Placebo
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 Sublingual 400 and 600 mcg
VS
400 mcg, 0.5 mg 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 Rectal 400 and 600 mcg Sublingual 400 and 600 mcg
Methylergometrine 200 mcg,
RR 1.23 VS
400 mcg, 0.5 mg 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 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 Caliskan et al, Am J Obstet Gynecol, 2002
ORAL ROUTE IS COMPARABLE 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 Caliskan et al, Obstet Gynecol, 2003
HOW MANY SHOULD WE TREAT ? VS
OXYTOCIN
Preventing PPH > 500 mL VS
OXYTOCIN + ERGOMETRİNE
Preventing PPH > 500 mL
Nausea and vomiting Hypertention
NO TREATMENT
NNT= 8 OXYTOCIN
NNT= 61 NNH= 61 NNH= 96
Maughan et al, Am Fam Physician, 2006
HOW MANY SHOULD WE TREAT ? MISOPROSTOL 600mcg p.o.
Preventing PPH > 500 mL Preventing PPH > 1000 mL
MISOPROSTOL 400mcg rectal
VS
VS
Preventing PPH > 1000 mL
NO TREATMENT
NNT= 12-18 NNT= 30-100 NO TREATMENT
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 + MISOPROSTOL 400 mcg p.o.
VS
OXYTOCIN 10 U
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 + MISOPROSTOL 400 mcg rectal
VS
OXYTOCIN 10 U
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
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
•Calculated intraoperative blood loss is similar •Misoprostol can be used in C/S under regional anesthesia
400mcg po misoprostol
10 IU Syntocinon
Lapaire et al, Int J Gynecol Obstet, 2006
MISOPROSTOL AT CESAREAN DELIVERY 352 women
200mcg buc misoprostol
20IU iv Oxy
placebo
•Misoprostol decreased additional uterotonic need •Postpartum hemorrhage >1000ml is similar in the two groups
20IU iv Oxy Hamm et al, AJOG, 2005
POSTPARTUM HEMORRHAGE MANAGEMENT STRATEGY Treatment
Prevention
• Identify high risk cases
Medical
Tamponade
• Good technique • Active management
Misoprostol
Laparotomy
MISOPROSTOL IN TREATING POSTPARTUM HEMORRHAGE
Three randomized controlled trials 468 participants
800mcg rectal misoprostol
VS
Placebo
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 1000 mcg miso 1 po + 2 sl + 2 rectal
10U Oxy or 1 amp syntometrine 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
21
5.1 – 86.5
7.7
2.3 – 25.4
Pyrexia ≤ 1hr
2.8
1.4 – 5.3
2-6 hrs
6.3
3.7 – 10.8
Diarrhea 2-6 hrs 7 - 12 hrs
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
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