1. Medical interventions for management of PPH
Maryam Kashanian MD
Professor Of Iran University Of Medical Sciences,
Akbarabadi Teaching Hospital.

2. Post-partum hemorrhage
PPH is a life-threatening obstetric complication
and the leading cause of maternal death.
The usual manner for its management includes:
first, noninvasive and nonsurgical methods,
and, then invasive and surgical methods.

3. As a general preventive approach,
the use of oxytocin for active management of the third stage of labour is strongly recommended,
because it reduces PPH by more than 60% .

4. Uterine atony is the most common cause of PPH.

5. ACOG: What is the appropriate medical management approach for excessive postpartum bleeding?
Uterotonic agents should be the first-line treatment for PPH due to uterine atony.
Management may vary greatly among patients, depending on etiology and available treatment options, and often a multidisciplinary approach is required.
When uterotonics fail following vaginal delivery, exploratory laparotomy is the next step.

6. Oxytocin (Pitocin)
IV: 10–40 units in 1 liter normal saline or lactated Ringer’s solution Continuous or
IM: 10 units
Avoid undiluted rapid IV infusion, which causes hypotension.
Maximum dose: Not more than 3 l of IV fluids containing oxytocin(WHO)
Do not give as an IV bolus(WHO)

7. Methylergonovine (Methergine)
IM: 0.2 mg , Every 2–4 h
Avoid if patient is hypertensive.
Some practitioners prefer direct injection of methylergonovine maleate into the uterine corpus. (ACOG)
IM or IV (slowly): 0.2 mg (WHO),
Repeat 0.2 mg IM after 15 minutes If required, give 0.2 mg IM or IV (slowly every 4 hours(WHO)
Maximum dose: 5 doses (Total 1.0 mg)(WHO)
Precautions/ contraindications: Pre-eclampsia, hypertension, heart disease

8. Oxytocin vs ergometrine
blood loss >1000 ml : No difference .
Blood transfusion : more in oxytocin.
use of additional uterotonics : No signifcant difference .
adverse side-effects: signifcantly lower in oxytocin : vomiting, and elevated BP.

9. Oxytocin-ergometrine fixed dose combination vs. oxytocin
fixed-dose combination of oxytocin (5 IU) and ergometrine (0.5 mg):
blood loss >1000 ml: no difference.
blood transfusion: no difference.
additional uterotonics: lower in the oxytocin-ergometrine combination .
side-effects: notably higher incidence of elevated diastolic BP in the oxytocin-ergometrine fixed dose combination.

10. Oxytocin-ergometrine fixed dose combination vs ergometrine
None of the critical outcomes was addressed in the studies.

11. Carbetocin (carbaoxytocin), vs oxytocin
blood loss ≥1000 ml: No data.
blood transfusion or surgical treatments: No data
use of additional uterotonics: similar
use of uterine massage: less in the carbetocin group .
side-effects: too limited to allow any judgments.

12. Carbetocin vs. Oxytocin-ergometrine fixed dose combination
blood loss ≥1000 ml: Fewer women in the carbetocin group.
Use of additional uterotonics : similar.
side-effects : lower in the carbetocin group (nausea, hypertension up to 60 minutes postpartum.

13. Carbetocin for preventing PPH.
Cochrane Database Syst Rev. 2012 Apr 18;(4):CD
therapeutic uterotonics: less in carbetocin compared to oxytocin.
incidence of PPH: no difference compared to oxytocin.
blood loss: less in Carbetocin compared to syntometrine.
adverse effects: fewer in Carbetocin compared to syntometrine.
Further research is needed to analyse the cost-effectiveness of carbetocin as a uterotonic agent.

14. 15-methyl PGF2α (Carboprost) (Hemabate)
IM: 0.25 mg , Every 15–90 min,
IM: 0.25 mg, every 15 minutes (WHO)
Maximum dose : 8 doses (Total 2 mg).
Avoid in asthmatic patients;
relative contraindication if hepatic, renal, and cardiac disease.
Diarrhea, fever, tachycardia can occur.
Some practitioners prefer direct injection of PG F2α into the uterine corpus. (ACOG).
PG F2a should not be given IV. It may be fatal. (WHO)

15. If bleeding occurs at the time of caesarean section, intramyometrial injection of carboprost should be used
if laparotomy is undertaken following failure of pharmacological management, intramyometrial carboprost injection should be the first-line measure once the uterus is exposed.
It is also possible to inject intramyometrial carboprost through the abdominal wall in the absence of laparotomy.

16. Dinoprostone (Prostin E2)
Suppository: vaginal or rectal
20 mg, Every 2 h.
Avoid if patient is hypotensive.
Fever is common.
Stored frozen, it must be thawed to room temperature.

17. Intramuscular prostaglandins vs. injectable uterotonics)
blood transfusion: No difference
Use of additional uterotonics: NO difference
Vomiting : more in PGs

18. Sulprostone(Sulprostone is an analogue of prostaglandin E2 (PGE2) vs
Sulprostone(Sulprostone is an analogue of prostaglandin E2 (PGE2) vs. injectable uterotonics
non significant reduction in the risk of severe PPH in both low-risk and high-risk women receiving sulprostone.
The Van Selm study was terminated early because of concerns regarding myocardial infarctions in women treated with sulprostone and mifepristone.

19. Misoprostol (Cytotec, PGE1)
800–1000 µg rectally.

20. Carboprost (15-methyl PGF2α) vs. misoprostol
blood loss : No evidence was found relating to the priority outcomes.
blood transfusion : less in the carboprost .
shivering : less in the carboprost.

21. Misoprostol vs. injectable uterotonics
risk of blood loss of ≥1000 ml: more in oral misoprostol (400–800 μg).
the incidence of severe morbidity, including maternal death: no significant difference .
These trials did not report the outcome of invasive or surgical treatments.

22. All agents can cause nausea and vomiting.

23. carboprost, would seem preferable for the treatment of PPH in UK settings.
Where parenteral PGs are not available or where there are contraindications (usually asthma) to PG F2, misoprostol (PG E1) may be an appropriate alternative.
There is no evidence that on the use of misoprostol with breastfeeding,
therefore a washout period of usually 24 hours should be considered.

24. misoprostol vs. conventional uterotonics,
• no difference in the rate of severe morbidity
but misoprostol is associated with more adverse events than placebo, in a dose dependent manner .
NICE do not recommend one uterotonic medication over another .

25. Recommendations for management of PPH(WHO)
oxytocin should be preferred over ergometrine alone, a fixed-dose combination of ergometrine and oxytocin, carbetocin, and PGs.
▪ If oxytocin is not available, or if the bleeding does not respond to oxytocin, ergometrine or oxytocin-ergometrine fixed-dose combination should be offered as second-line treatment.
▪ If the above second-line treatments are not available, or if the bleeding does not respond to the second-line treatment, a PG should be offered as the third line of treatment.

26. the cost of carbetocin is high compared with the other options.
▪ Misoprostol may be considered as a third line of treatment for the management of PPH, because of its ease of administration and low cost compared with injectable PGs(PG F2α).
the cost of carbetocin is high compared with the other options.
Moreover, it found no evidence that carbetocin has a significant advantage over oxytocin.

27. WHO
There is no added benefit of offering misoprostol as adjunct treatment for PPH in women who have received oxytocin during the third stage of labour.
Where oxytocin is available, and is used in the management of the third stage of labour, oxytocin alone should be used in preference to adjunct misoprostol for the management of PPH.
In women who have not received oxytocin as a prophylactic during the third stage of labour, oxytocin alone should be offered as the drug of choice for the treatment of PPH.

28. The recommendations below may also be used in cases of PPH due to uterine atony following caesarean section.
These recommendations are based primarily on data following vaginal birth, and that specific data on PPH due to uterine atony following caesarean section were scarce and not evaluated separately from data on vaginal births.

29. αF2 پروستاگلاندین
تزریق عضلانی 0.25 میلی گرم تكرار هر دقيقه تا حداکثر 8 دوز(2 ميلي گرم)
منع مصرف: آسم و بیماری فعال قلبی، ريوي، بيماري كبدي
عوارض داریی: تهوع، استفراغ، اسهال، تب گذرا، تاکیکاردی، حساسیت به دارو،گر گرفتگی، سردرد، لرز و افزایش فشار خون و برونکواسپاسم
هرگز وريدي استفاده نشود.
نكته: در زمان سزارين ميتوان در ديواره رحم تزريق كرد و اگر سزارين نشده ولي به علت خونريزي لاپاراتومي شده ميتوان تزريق ديواره رحم داشت واگر لاپاراتومي نشده بود باز هم از ديواره شكم ميتوان تزريق رحمي انجام داد.

30. ● Bimanual uterine compression to stimulate contractions
● Bimanual uterine compression to stimulate contractions. ● Ensure bladder is empty (Foley catheter). ● Syntocinon 5 units by slow IV injection (may have repeat dose). ● Ergometrine 0.5 mg by slow IV or IM injection (contraindicated in women with hypertension). ● Syntocinon infusion (40 units in 500 ml Hartmann’s solution at 125 ml/hour) unless fluid restriction is necessary. ● Carboprost 0.25 mg by IM injection repeated at intervals of not less than 15 minutes to a maximum of 8 doses (contraindicated in women with asthma). ● Direct intramyometrial injection of carboprost 0.5 mg (contraindicated in women with asthma), with responsibility of the administering clinician as it is not recommended for intramyometrial use. ● Misoprostol 1000 µg rectally.

31. Despite decades of empirical use in clinical practice,there are no trials comparing ergometrine and oxytocin as first-line agents for the treatment (rather than prevention) of PPH.
It seems appropriate to use both agents, although oxytocin is to be preferred initially especially in women with prior hypertension or pre-eclampsia.
The British National Formulary continues to recommend a dose of ‘5–10 units by slow IV injection’ : the risk of profound hypotension,
when given as an IV bolus, the drug should be given slowly in a dose of not more than 5 units’.

32. How should secondary PPH be treated?
Secondary PPH is often associated with endometritis.
When antibiotics are clinically indicated, a combination of ampicillin (clindamycin if penicillin allergic) and metronidazole is appropriate.
In cases of endomyometritis (tender uterus) or overt sepsis, then the addition of gentamicin is recommended.
Surgical measures should be undertaken if there is excessive or continuing bleeding, irrespective of ultrasound findings.

33. Is there a use for recombinant factor VIIa therapy
Is there a use for recombinant factor VIIa therapy? RCOG Green-top Guideline
Recombinant activated factor VII (rFVIIa) was developed for the treatment of haemophilia.
Over the past decade, it has also been used to control bleeding in other circumstances.
the case reports suggested that rFVIIa reduced bleeding.
In the face of life-threatening PPH, and in consultation with a haematologist, rFVIIa may be used as an adjuvant to standard pharmacological and surgical treatments.
A suggested dose is 90 µg/kg, which may be repeated in the absence of clinical response within 15–30 minutes.
Although there is no clear evidence of thrombosis with the use of rFVIIa in obstetric practice, there have been case reports of thrombosis with the use in cardiac surgery.

34. RCOG Green-top Guideline
Women with PPH are particularly susceptible to defibrination (severe hypofibrinogenaemia) and this is particularly relevant to the most severe cases that will be considered for rFVIIa;
rFVIIa will not work if there is no fibrinogen and effectiveness may also be suboptimal with severe thrombocytopenia (less than 20 x 109/l).
Therefore, fibrinogen should be above 1g/l and platelets greater than 20 x 109/l before rFVIIa is given.
If there is a suboptimal clinical response to rFVIIa, these should be checked and acted on (with cryoprecipitate, fibrinogen concentrate or platelet transfusion as appropriate) before a second dose is given.

35. Human recombinant factor VIIa is a new treatment modality shown to be effective in controlling severe, life-threatening hemorrhage by acting on the extrinsic clotting pathway.
IV dosages vary by case and generally range from 50 to 100 mcg/kg every 2 hours until hemostasis is achieved.
Cessation of bleeding ranges from 10 minutes to 40 minutes after administration .
Concern has been raised because of apparent risk of subsequent thromboembolic events following factor VIIa use .
Compared with other agents, factor VIIa is extremely expensive.
Additional clinical experience in all specialties will help determine factor VIIa’s role in the treatment of patients with PPH

36. WHO
not enough evidence to make any recommendation regarding the use of recombinant factor VIIa for the treatment of PPH.
Recombinant factor VIIa for the treatment of PPH should be limited to women with specific haematological indications.

37. Recombinant Factor VIIa in Post-partum Hemorrhage: A New Weapon in Obstetrician's Armamentarium N Am J Med Sci Apr; 4(4): 157–162.
One of the most spectacular advancements in the control of PPH has been the use of recombinant activated factor (rFVIIa), both
as initial and a life- and uterus-saving therapy.
rFVIIa also reduces costs of therapy and use of blood components in massive PPH.
In cases of intractable bleeding with no other obvious indications for hysterectomy, administration of rFVIIa should be considered before surgery.

38. Clin Obstet Gynecol. 2010 Mar;53(1):219-27
Clin Obstet Gynecol. 2010 Mar;53(1): The use of recombinant activated FVII in postpartum hemorrhage.
Recently, a number of case reports or case series have reported the successful "off-label" use of recombinant activated factor VII (rFVIIa) in PPH unresponsive to conventional treatments.
In this review, a critical analysis of the published literature on the use of rFVIIa in severe PPH was performed.

39. Clin Obstet Gynecol. 2010 Mar;53(1):219-27
Clin Obstet Gynecol. 2010 Mar;53(1): The use of recombinant activated FVII in postpartum hemorrhage.
Overall, a total of 272 PPH women were collected among the largest case series and/or international registries.
No randomized controlled trials have been conducted in this area.
Currently, the literature data suggest that, at a median dose of 81.5 microg/kg, rFVIIa is effective in stopping or reducing bleeding in 85% of the cases.

40. the use of rFVIIa may be of benefit in life-threatening PPH.
Br J Anaesth. 2005 May;94(5): Recombinant factor VIIa for life-threatening post-partum haemorrhage.
We present 12 cases of severe PPH treated with recombinant factor VIIa (rFVIIa). 
the use of rFVIIa may be of benefit in life-threatening PPH.

41. راهنمای کشوری
RFVIIα
) 90µg/kgمعادل حدود 3 ويال1 ميليگرمي براي يك زن با وزن حدود 70 كيلوگرم)
پس از اطمينان از جمع بودن رحم، عدم وجود پارگي، باقي نبودن جفت و پرده هاو ادامه خونريزي و در صورت برقراري همه شرايط :
پلاكت بيشتر از 50 هزار در ميلي ليتر،
فيبرينوژن بيشتر از يك گرم در ليتر،
مختل نبودن زمان پروترومبين(PT )،
اسيديته خون(ph )بيشتر يا مساوي 2/7،
درجه حرارت بدن بيشتر يا مساوي 35 درجه سانتي گراد
RFVIIα ممکن است برای کمک به درمان كنترل خونريزي بکار رود بشرطی که PPH تهدید کننده حیات بوده و به درمان ها پاسخ نداده باشد.

42. Is there a use for antifibrinolytic drugs?
evidence is conflicting,
there is a consensus view that fibrinolytic inhibitors (such as tranexamic acid) seldom, if ever, have a place in the management of obstetric haemorrhage.

43. WHO Tranexamic acid may be offered as a treatment for PPH if:
(i) administration of oxytocin, followed by second-line treatment options and PGs, has failed to stop the bleeding; or
(ii) it is thought that the bleeding may be partly due to trauma.

44. راهنمای کشوری
ترانگزاميك اسيد ممكن است در مواردي كه تجويز اكسي توسين و پروستاگلاندين در توقف خونريزي ناموفق باشد و خونريزي تا حدي در اثر تروما باشد. در كنترل خونريزي پس از زايمان مورد استفاده قرار گيرد. تزريق آهسته هر يك سي سي در يك دقيقه و در صورت ادامه خونريزي تكرار آن نيم ساعت بعد

45. Lancet. 2017 Apr 26. pii: S (17)
 Early tranexamic acid, 1 gram IV infusion, in addition to usual care reduces death due to bleeding in women with PPH.

46. Lancet. 2017 Apr 26. pii: S (17)
Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis.
In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries.
We randomly assigned women to receive either 1 g IV tranexamic acid or matching placebo in addition to usual care.
If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given.

47. Lancet. 2017 Apr 26. pii: S (17)
Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65-1·00; p=0·045),
especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52-0·91; p=0·008). 

48. All other causes of death did not differ significantly by group.
Hysterectomy was not reduced with tranexamic acid .
The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid.
Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid VS placebo group.

49. Lancet. 2017 Apr 26. pii: S (17)
Tranexamic acid reduces death due to bleeding in women with PPH with no adverse effects.
When used as a treatment for PPH, tranexamic acid should be given as soon as possible after bleeding onset.

50. vasopressin
sub-endometrial vasopressin injection at the placenta site may be beneficial .
In one review, local injection of 4 units of vasopressin in 20 mL of saline into the placental implantation site significantly reduced blood loss without increasing the morbidity.

51. What measures can be taken to ensure optimal management of PPH?
Training for all birth attendants in the management of PPH is recommended by RCOG .
A formal follow-up meeting which analyses the case and addresses what could be done better in the future should be triggered for every significant PPH.

52. Documentation
Accurate documentation of a delivery with PPH is essential.
Inadequate documentation in obstetrics can lead to potential medico-legal consequences.
It may be helpful to use a structured pro forma to aid accurate record keeping.
PPH should be notified through a clinical incident reporting or risk management system in place.
It is important to record: ● the staff in attendance and the time they arrived ● the sequence of events ● the time of administration of different pharmacological agents given, their timing and sequence ● the time of surgical intervention, where relevant ● the condition of the mother throughout the different steps ● the timing of the fluid and blood products given.

53. Trials. 2015 Apr 17;16:169. Fibrinogen concentrate versus placebo for treatment of postpartum haemorrhage: study protocol for a randomised controlled trial.
The trial aims to provide evidence on the efficacy and safety of fibrinogen concentrate during acute bleeding in an obstetric setting.

54. Br J Anaesth. 2015 Apr;114(4): Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial.
no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe PPH in patients with normofibrinogenaemia.