Postpartum Hemorrhage – Medications to Treat Uterine Atony 

ACOG defines PPH as cumulative blood loss ≥ 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (including intrapartum) regardless of route of delivery. Unfortunately, postpartum hemorrhage (PPH) is still a leading cause of maternal mortality worldwide.  Following this summary, you can find excellent professional resources at the California Maternal Quality Care Collaborative (CMQCC) and ACOG Safe Motherhood Initiative sites. 

CLINICAL ACTIONS:

In the setting of PPH, consider the 4 ‘T’s

• Tone (atony)
• Trauma (laceration)
• Tissue (retained products)
• Thrombin (coagulopathy)

Uterine atony is the single most common cause of PPH (70-80%)

• Empty bladder, perform bimanual pelvic exam, remove clots and initiate uterine massage
• There is lack of evidence to determine which specific uterotonics are superior (good and consistent scientific evidence – ACOG level A)
  • Choice at provider’s discretion
• If uterine atony is identified,  the following drugs have been shown to be effective:

DRUG	DOSE	CONTRA INDICATIONS
Oxytocin (Pitocin)	10-40 units per 500-1000ml solution continuous infusion OR 10 units IM	Hypersensitivity to this medication
Methyl-ergonovine (Methergine)	0.2 mg IM every 2 to 4 hours	Avoid: Hypertension, Preeclampsia, Cardiovascular Disease
Prostaglandin F2 Alpha (Hemabate)	250 micrograms IM (may repeat in q15 – 90 minutes, maximum 8 doses) OR Intramyometrial: 250 micrograms	Avoid: Asthma Caution: Hypertension, Active Hepatic, Pulmonary, Cardiac Disease
Misoprostol (Cytotec)	600 – 1000 micrograms PR, PO or SL	Hypersensitivity to this medication

NOTE: Contraindications include hypersensitivity to the specific medication

More on Tranexamic Acid (TXA)

ACOG Update (2017)

• In the WOMAN trial (see Related OBG Topics below) women with PPH received
  • 1 g in 10 mL (100 mg/mL) of tranexamic acid intravenously at a rate of 1 mL per min (i.e., over 10 min)
  • 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 could be given
• Tranexamic acid, administered within 3 hours of birth, has been shown to significantly reduce maternal death due to PPH by approximately 30%
• Based on improved outcomes and lack of adverse events including thromboembolism, ACOG has updated the practice bulletin to include the following

Although the generalizability of the WOMAN trial and the degree of effect in the United States is uncertain, given the mortality reduction findings, tranexamic acid should be considered in the setting of obstetric hemorrhage when initial medical therapy fails. (Level B evidence)

World Health Organization Update (2017)

Based on evidence review, WHO also supports the use of tranexamic acid with postpartum hemorrhage

Early use of intravenous tranexamic acid (within 3 hours of birth) in addition to standard care is recommended for women with clinically diagnosed postpartum haemorrhage following vaginal birth or caesarean section (Strong recommendation, moderate quality of evidence)

Administration of TXA should be considered as part of the standard PPH treatment package and be administered as soon as possible after onset of bleeding and within 3 hours of birth

The reference point for the start of the 3-hour window for starting TXA administration is time of birth

If time of birth is unknown, the best estimate of time of birth should be used as the reference point

TXA should be used in all cases of PPH, regardless of whether the bleeding is due to genital tract trauma or other causes

CONSIDERATIONS IN COVID POSITIVE PATIENTS

Tranexamic Acid (TXA)

• COVID-19 appears to be a hypercoagulable state
• TXA can be considered for the treatment of PPH in keeping with guidance for non-COVID-19 patients
• However, ACOG states

because of the possible additive effect of the increased risk of thrombosis from COVID-19 infection and the hypercoagulative state of pregnancy, it may be prudent to consider this increased likelihood of clotting before administering TXA for postpartum hemorrhage

Hemabate

• While Hemabate is not used in asthma due to risk for bronchospasm, patients with COVID-19 have respiratory symptoms consistent with viral pneumonia
• While there is no data specific to COVID-19 and this medication, “Hemabate is not generally withheld” in patients with viral pneumonia

SYNOPSIS:

The key to managing PPH is identifying the severity of the situation early and quantifying estimated blood loss (EBL).  A second large bore (16 gauge or larger) should be placed and Ringers Lactate used to replace blood loss at 2:1 while, simultaneously as the team is notified, medications are administered to the patient and massive transfusion protocol is initiated.  Initiate fundal massage and place a Foley catheter.

KEY POINTS:

• ABCs
  • Airway: Assess and stabilize
  • Breathing: Supplemental oxygen, 5-7 L/min by tight face mask
  • Circulation: do NOT wait for change in vitals
    • Compromised blood volume: pallor, delayed capillary refill and decreased urinary output
    • Late signs: decreased BP and tachycardia
• Consider intrauterine balloon tamponade or compression sutures for refractory atony
• Surgical Interventions may be a life-saving measure and should not be delayed while waiting to correct coagulopathy
• Quantitative measurement of blood loss is more acurate than visual estimation (see ‘Learn More – Primary Sources’ below) and require 2 key elements
  • Direct measurement of blood loss
  • Protocols for collecting and reporting a cumulative record of blood loss following delivery

Note: The FDA, the World Health Organization, and other professional bodies have released an alert following drug-error deaths related to TXA | TXA use during cesarean delivery has been associated with fatal accidental intrathecal administration because the ampoules of local anesthetic and tranexamic acid are similar in appearance | TXA should not be stored on or near an anesthetic trolley

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Learn More – Primary Sources:

ACOG Safe Motherhood Initiative – Obstetric Hemorrhage

FIGO recommendations on the management of postpartum hemorrhage 2022

AWHONN video: Quantification of Blood Loss

ACOG Committee Opinion 794: Quantitative Blood Loss in Obstetric Hemorrhage

ACOG Practice Bulletin 183: Postpartum Hemorrhage

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

California Maternal Quality Care Collaborative (CMQCC): OB Hemorrhage ToolkitV3.0

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

ACOG COVID-19 FAQs for Obstetrical Care

Tranexamic acid at cesarean delivery: drug‐error deaths

Uterine-sparing surgical procedures to control postpartum hemorrhage

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A New Intrauterine Device to Treat Postpartum Hemorrhage

BACKGROUND AND PURPOSE:

• A new device has been developed that can apply low-level intrauterine vacuum (70–90 mm Hg) to facilitate uterine contractions and constrict blood vessels
• D’Alton et al. (Obstetrics & Gynecology, 2020) evaluated the effectiveness and safety of this device to treat PPH

METHODS:

• Multicenter, prospective, single-arm treatment study
• Participants
  • Delivery ≥34 weeks
  • Normal uterine anatomy
  • Atony-related blood loss
    • Vaginal delivery: 500 to 1,500 mL
    • Cesarean: 1,000–1,500 mL
  • Unresponsive to uterotonics and uterine massage
• Intervention
  • Intrauterine vacuum device
• Primary effectiveness outcome
  • Proportion of participants treated with intrauterine vacuum device that did not require escalating interventions
• Primary endpoints
  • Device-related adverse events
    • Incidence | Severity | Seriousness
• Secondary endpoints
  • Time to bleeding control
  • Rate of transfusion
  • Device usability scored by each practitioner

RESULTS:

• 106 participants
• Successful treatment: 94% (95% CI, 88 to 98%)
  • Median time to control: 3 minutes (IQR 2.0 to 5.0 min)
• Adverse events related to the device
  • 8 events
  • All were outlined as risks in the study
  • All were resolved without serious clinical sequelae
  • Adverse events included
    • Endometritis | Disruption of vaginal laceration repair | Presumed endometritis | Bacterial vaginosis | Vaginal candidiasis
• Transfusions
  • 1 to 3 units: 33%
  • ≥4 units: 5%
• Ease of use
  • Reported ease of use: 98%
  • Reported would recommend it: 97%

CONCLUSION:

• Among successfully treated patients, control of abnormal bleeding was quickly established
• The authors state that while an RCT should be considered in the future, the device

…offers a therapeutic modality that may be considered early in the treatment of abnormal postpartum uterine bleeding or postpartum hemorrhage

Learn More – Primary Sources:

Intrauterine Vacuum-Induced Hemorrhage-Control Device for Rapid Treatment of Postpartum Hemorrhage

Postpartum Hemorrhage Prophylaxis: The World Health Organization Recommendations

SUMMARY:

Uterotonics for PPH prophylaxis are administered immediately prior to or after placental delivery. The World Health Organization (WHO), based on an extensive review, has provided guidance on the efficacy and safety of uterotonics for the prevention of PPH. In addition, the WHO recommendations provide evidence-based guidelines on the drugs of choice. These recommendations apply to both vaginal and cesarean delivery.

KEY POINTS:

Efficacy and Safety

• Only one of the following uterotonics should be used for PPH prophylaxis
  • Oxytocin | Carbetocin | Misoprostol | Ergometrine/methylergometrine | Oxytocin and ergometrine fixed-dose combination
• Oxytocin 10 IU IM/IV
  • Recommended for all births
  • Requires refrigerated transport and storage (2–8 °C)
    • Consider another uterotonic if refrigeration cannot be guaranteed
  • Carbetocin 100 µg IM/IV
    • Recommended for all births
    • Heat-stable carbetocin does not require refrigeration
    • Note: Recommendation is ‘context specific’ and applies in settings where cost is comparable to other effective uterotonics
  • Misoprostol 400 µg or 600 µg PO
    • Recommended for all births
    • Different routes of administration are available aside from oral (buccal, sublingual, rectal)
      • Choice of PO based on women’s preference
    • Counsel patients about possible adverse side effects such as shivering, fever and diarrhea
  • Ergometrine/methylergometrine 200 µg IM/IV
    • Recommended for PPH prevention
    • Requires refrigeration
    • Note: Recommendation is ‘context specific’ in settings where hypertensive disorders can be safely excluded prior to administration
  • Oxytocin and ergometrine fixed dose combination 5 IU/500 µg IM
    • Recommended for PPH prevention
    • Requires refrigeration
    • Note: Recommendation is ‘context specific’ in settings where hypertensive disorders can be safely excluded prior to administration
  • Carboprost or sulprostone (injectable prostaglandins)
    • Not recommended

Choice of Uterotonic

• Oxytocin 10 IU IM/IV is the primary recommended uterotonic agent for all births, when there is choice of uterotonics
• If oxytocin is not available or quality “cannot be guaranteed”
  • Other acceptable uterotonics listed above are recommended
• If injectable uterotonics cannot be used due to lack of skilled personnel
  • WHO recommends that community and lay health workers can administer oral misoprostol (400 µg or 600 µg)

Learn More – Primary Sources:

WHO recommendations Uterotonics for the prevention of postpartum haemorrhage

Uterotonic agents for preventing postpartum haemorrhage: a network meta‐analysis

Heat Stable Carbetocin: A Heat-Stable Alternative to Oxytocin?

BACKGROUND AND PURPOSE:

• Oxytocin is the first line drug for prevention of PPH but due to the necessity for cold-storage, it is not always a viable option in many parts of the world
• Heat-stable carbetocin is an oxytocin analogue
  • Maintains stability with ≥95% peptide purity over 36 months, even at 30°C and 75% relative humidity
    • 6 months at 40°C
    • 3 months at 50°C
  • Optimum pH  5.45 (5.25–5.65)
  • Not sensitive to freezing or light
• Widmer et al. (NEJM 2018) compared the efficacy of heat-stable carbetocin to oxytocin for PPH prevention

METHODS:

• Randomized, double-blind, controlled non-inferiority trial
  • 23 hospital sites in 10 countries (2015-2018)
  • Vaginal deliveries
• Patients were randomized to the following study arms
  • Heat-stable carbetocin 100 µg IM
  • Oxytocin 10 IU IM
• Postpartum blood loss calculated as follows
  • Blood collected in plastic drape
  • Blood collected for 1 hour or for 2 hours if bleeding continued
  • Drape (including the blood) was weighed (grams) converted to volume (mm) after weight of drape subtracted
• Primary outcomes
  • Composite outcome of (1) proportion of women with blood loss of at least 500 ml; (2) Use of additional uterotonic agents at 1 hr and up to 2 hrs
  • Proportion of women with blood loss of at least 1000 ml
• Secondary outcomes
  • Other measurements related to blood loss (e.g., additional medications/interventions)
  • Adverse effects

RESULTS:

• 29,645 women underwent randomization
• Primary outcome #1: The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents
  • 14.5% in the carbetocin group vs 14.4% in the oxytocin group
  • Consistent with non-inferiority of carbetocin
• Primary outcome #2: The frequency of blood loss of at least 1000 ml
  • 1.51% in the carbetocin group vs 1.45% in the oxytocin group
  • Close to showing non-inferiority of carbetocin but may have been underpowered (upper 95% confidence limit exceeded the noninferiority margin)
    • Researchers planned on 2% 1000 ml blood loss but in the study, 1000 ml blood loss was approximately 1.5%
  • The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between groups

CONCLUSION:

• Heat-stable carbetocin performed similarly to oxytocin in preventing blood loss of at least 500 ml or use of other uterotonic agents
• Noninferiority was not shown for the outcome of blood loss of at least 1000 ml (study was not sufficiently powered for this outcome)
• The authors state “These data inform care of women in parts of the world where a lack of heat stability is a barrier to the effective prevention of postpartum hemorrhage.”

Learn More – Primary Sources:

Heat-stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth

Development and stability of a heat‐stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle‐income countries

How Effective is Intrauterine Balloon Tamponade for Severe Postpartum Hemorrhage

BACKGROUND AND PURPOSE:

• 90% of maternal deaths from postpartum hemorrhage (PPH) are considered preventable
• Recent publications report balloon tamponade success rates to be approximately 80%
  • Previous studies did not include control groups
• Revert et al. (Obstetrics & Gynecology, 2017) compared the rates of invasive procedures for postpartum hemorrhage between a perinatal network that uses intrauterine balloon tamponade vs another that does not

METHODS:

• Population-based retrospective cohort study (2011 – 2012)
• Patients: All women who gave birth in two French perinatal networks
• Both units used standardized French national PPH guidelines
• Intervention cohort incorporated the use of intrauterine balloon tamponade for
  • PPH due to uterine atony unresponsive to prostaglandin E2 analog after vaginal delivery or
  • Delayed PPH after cesarean delivery
• If PPH remained uncontrolled following noninvasive treatments, invasive procedures were initiated, including
  • Uterine artery embolization, surgical arterial ligation, compressive uterine sutures or hysterectomy
• Outcomes were quantified based on discharge data from the national French medical information system
• General and obstetric characteristics were included in two separate models according to mode of delivery to estimate the independent association of the network with invasive procedures

RESULTS:

• In the balloon tamponade cohort, there was
  • A significantly lower proportion of women undergoing at least one invasive procedure (3.0/1,000 vs 5.1/1,000; P<.01)
  • A significantly lower proportion of women undergoing arterial embolization (0.2/1,000 vs 3.7/1,000; P<.01)
• After controlling for potential confounding factors
  • The risk of an invasive procedure among women who delivered vaginally remained significantly lower with the use of balloon tamponade for vaginal birth (adjusted odds ratio [OR] 0.14; 95% CI 0.08–0.27) but not cesarean (adjusted OR 1.19; 95% CI 0.87-1.61)

CONCLUSION:

• The authors recognize study limitations including (1) the lack of coding for compression suture and (2) the two cohorts were not identical in application of anti-PPH invasive procedures
• The results of this large population cohort study confirm previous literature
• Intrauterine balloon tamponade for PPH following vaginal delivery is associated with lower use of invasive procedures

Learn More – Primary Sources:

Intrauterine Balloon Tamponade for Severe Postpartum Hemorrhage