Postpartum haemorrhage: prevention

Abstract

Introduction

Loss of more than 500 mL of blood is usually caused by failure of the uterus to contract fully after delivery of the placenta, and occurs in over 10% of deliveries, with a 1% mortality rate worldwide. Other causes of postpartum haemorrhage include retained placental tissue, lacerations to the genital tract, and coagulation disorders. Uterine atony is more likely in women who have had a general anaesthetic or oxytocin, an overdistended uterus, a prolonged or precipitous labour, or who are of high parity.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of drug and of non-drug interventions to prevent primary postpartum haemorrhage? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: active management of the third stage of labour, carboprost injection, controlled cord traction, ergot compounds (ergometrine/methylergotamine), immediate breastfeeding, misoprostol (oral, rectal, sublingual, or vaginal), oxytocin plus ergometrine combinations, oxytocin, prostaglandin E2 compounds, and uterine massage.

Key Points

Loss of more than 500 mL of blood is usually caused by failure of the uterus to contract fully after delivery of the placenta, and occurs in over 10% of deliveries with a 1% mortality rate worldwide.

• Other causes of postpartum haemorrhage include retained placental tissue, lacerations to the genital tract and coagulation disorders.

• Uterine atony is more likely in women who have had a general anaesthetic or oxytocin, an over-distended uterus, a prolonged or precipitous labour, or who are of high parity.

Active management of the third stage of labour, with controlled cord traction, early cord clamping plus drainage and prophylactic oxytocic agents, reduces the risk of postpartum haemorrhage and its complications.

• Active management increases nausea, vomiting, and headache, but generally improves maternal satisfaction.

• Controlled cord traction may reduce the risk of retained placenta and need for medical treatment, and can be used in any resource setting.

• Uterine massage is often used to prevent postpartum haemorrhage, and is supported by a single RCT. It can be used in any resource setting.

Oxytocin has been shown to effectively reduce the risk of postpartum haemorrhage compared with placebo.

• A combination of oxytocin plus ergometrine may be slightly more effective than oxytocin alone, although there are more adverse effects.

Ergot alkaloids seem as effective as oxytocin, but are also associated with adverse effects including nausea, placenta retention, and hypertension.

Prostaglandin treatments vary in their efficacy, but are all associated with adverse effects.

• Carboprost and prostaglandin E2 compounds may be as effective as oxytocin and ergot compounds, but have gastrointestinal adverse effects, such as diarrhoea.

• Misoprostol seems ineffective compared with placebo when administered orally, rectally, or vaginally, and is associated with adverse effects including shivering and fever.

• Sublingually administered misoprostol may be more effective than placebo in preventing postpartum heamorrhage (evidenced by a single RCT). Sublingual misoprostol has similar effects to injected agents, but is associated with more adverse effects. Confirmatory data would be helpful, as these results differ substantially from the many RCTs on other modes of administration of misoprostol, and it is unclear if there is something unique about sublingual administration.

• When available, oxytocin, ergometrine, or combinations are preferred to misoprostol, as misoprostol seems less effective, and is associated with more adverse effects. Sublingual administration is the preferred route for misoprostol.

About this condition

Definition

Postpartum haemorrhage is characterised by an estimated blood loss greater than 500 mL. The leading cause of postpartum haemorrhage is uterine atony — the failure of the uterus to contract fully after delivery of the placenta. Postpartum haemorrhage is divided into immediate (primary) and delayed (secondary). Primary postpartum haemorrhage occurs within the first 24 hours after delivery, whereas secondary postpartum haemorrhage occurs between 24 hours and 6 weeks after delivery. This review addresses the effects of strategies for prevention of postpartum haemorrhage after vaginal delivery in low- and high-risk women, specifically looking at strategies to prevent uterine atony. Future updates will examine strategies to prevent postpartum haemorrhage due to other causes, as well as treatment strategies.

Incidence/ Prevalence

The WHO reports that obstetric haemorrhage causes 127,000 deaths annually worldwide, and is the world’s leading cause of maternal mortality. Nearly all of these deaths are due to postpartum haemorrhages, which occur nearly 14 million times each year. In Africa, haemorrhage is estimated to be responsible for 30% of all maternal deaths. The imbalance between resource-rich and resource-poor areas probably stems from a combination of: increased prevalence of risk factors such as grand multiparity, lack of safe blood banking, no routine use of prophylaxis against haemorrhage, and lack of measures for drug and surgical management of atony.

Aetiology/ Risk factors

In addition to uterine atony, immediate postpartum haemorrhage is frequently caused by: retained placental tissue; trauma such as laceration of the perineum, vagina, or cervix; rupture of the uterus; or coagulopathy. Risk factors for uterine atony include: use of general anaesthetics; an over-distended uterus, particularly from multiple gestations, a large fetus, or polyhydramnios; prolonged labour; precipitous labour; use of oxytocin for labour induction or augmentation; high parity; chorioamnionitis; or history of atony in a previous pregnancy.

Prognosis

Most postpartum haemorrhage, particularly in Europe and the USA, is well tolerated by women. However, in low-resource settings, where women may already be significantly anaemic during pregnancy, blood loss of 500 mL is significant. Although pregnancy-related death is rare in the USA, postpartum haemorrhage accounts for 17% of deaths. Maternal death is 50-100 times more frequent in resource-poor countries, and postpartum haemorrhage is responsible for a similar proportion of deaths as in the USA. Other significant morbidities associated with postpartum haemorrhage include renal failure, respiratory failure, multiple organ failure, need for transfusion, need for surgery including dilatation and curettage, and, rarely, hysterectomy. Some women with large blood loss will later develop Sheehan's syndrome.

Aims of intervention

To prevent death; to reduce volume of blood loss, need for manual removal of placenta, need for transfusion, and need for medical or surgical treatment of postpartum haemorrhage.

Outcomes

Primary outcomes include maternal mortality, serious maternal morbidity including need for admission to an intensive care unit, renal failure, respiratory failure, multiple organ failure, need for additional medical (e.g. drugs like oxytocin, blood transfusions) or surgical (e.g. hysterectomy, hypogastric artery ligation, uterine curettage) treatment. Secondary outcomes include the mother's ability to care for the newborn, ability to breastfeed, patient satisfaction, volume of blood loss (estimated by drop in haemoglobin or haematocrit, or measured by direct collection). Adverse effects of postpartum haemorrhage include retained placental tissue, anaemia, Sheehan's syndrome, and uterine inversion.

Methods

Clinical Evidence search and appraisal September 2007. The following databases were used to identify studies for this review: Medline 1966 to September 2007, Embase 1980 to September 2007, and The Cochrane Database of Systematic Reviews 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language (including "open" studies) and containing at least 40 people of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. The only ergot compound that we searched for was ergometrine/methergine (ergonovine, methylergonovine, ergotrate, methylergometrine, ergotamine). In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency, which are continually added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.

Table.

GRADE evaluation of interventions for postpartum haemorrhage: prevention

Important outcomes	Morbidity, need for further interventions, mortality, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of non-drug interventions to prevent primary postpartum haemorrhage?
At least 5 RCTs (at least 6477 women)	Morbidity	Active management v expectant management alone or combined with oxytocin	4	0	0	0	0	High	Effect-size point added for RR less than 0.5
At least 5 RCTs (at least 6477 women)	Need for further interventions	Active management v expectant management alone or combined with oxytocin	4	0	0	0	0	High
At least 5 RCTs (at least 6477 women)	Adverse effects	Active management v expectant management alone or combined with oxytocin	4	0	0	0	0	High
2 (1948)	Morbidity	Controlled cord traction v minimal intervention	4	−1	0	−1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for differences in timing and mode of oxytocin administration
1 (477)	Morbidity	Controlled cord traction plus immediate cord drainage v expectant management	4	−1	−1	0	0	Low	Quality point deducted for incomplete reporting. Consistency point deducted for lack of consistent benefit
1 (477)	Need for further interventions	Controlled cord traction plus immediate cord drainage v expectant management	4	0	0	0	0	High
1 (200)	Morbidity	Uterine massage v routine active management	4	0	0	0	0	High
1 (200)	Need for further interventions	Uterine massage v routine active management	4	0	0	0	0	High
What are the effects of drug interventions to prevent primary postpartum haemorrhage?
At least 7 RCTs (at least 3323 women)	Morbidity	Oxytocin v placebo/no intervention	4	−1	−1	0	0	Low	Quality point deducted for inclusion of quasi-randomised trials. Consistency point deducted for lack of consistent benefit
5 RCTs (at 2327 women)	Need for further interventions	Oxytocin v placebo/no intervention	4	−2	0	0	0	Low	Quality points deducted for incomplete reporting of results and for inclusion of quasi-randomised trial
At least 7 RCTs (at least 5030 women)	Morbidity	Oxytocin v ergot compounds	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of quasi-randomised trial
At least 4 RCTs (at least 3770 women)	Need for further interventions	Oxytocin v ergot compounds	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of quasi-randomised trial
3 (445)	Morbidity	Carboprost injection v ergot compounds	4	0	0	0	0	High
2 (at least 529 women)	Morbidity	Carboprost injection v oxytocin plus ergometrine	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting
At least 3 RCTs (at least 3409 women)	Morbidity	Ergot compounds v placebo/no intervention	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 RCTs (at least 2409 women)	Need for further interventions	Ergot compounds v placebo/no intervention	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
At least 4 RCTs and 1 CCT (at least 2891 women)	Morbidity	Oxytocin plus ergometrine combinations v ergot compounds	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of controlled trial
At least 1 RCT and 1 CCT (at least 1927 women)	Need for further interventions	Oxytocin plus ergometrine combinations v ergot compounds	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of controlled trial
At least 5 RCTs and 1 CCT (at least 9332 women)	Morbidity	Oxytocin plus ergometrine combinations v oxytocin alone	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of controlled trial
At least 5 RCTs and 1 CCT (at least 9332 women)	Need for further interventions	Oxytocin plus ergometrine combinations v oxytocin	4	−1	0	0	0	Moderate	Quality point deducted for inclusion of controlled trial
1 (46)	Morbidity	Sulprostone injection v placebo	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (46)	Need for further interventions	Sulprostone injection v placebo	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (51)	Morbidity	Sulprostone injection v oxytocin	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting
1 (661)	Morbidity	Sublingual misoprostol v placebo/no intervention	4	0	0	0	0	Moderate	Quality point deducted for incomplete reporting
2 (150)	Morbidity	Sublingual misoprostol v oxytocin	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (100)	Need for further interventions	Sublingual misoprostol v oxytocin	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
3 (370)	Morbidity	Sublingual misoprostol v ergometrine	4	0	0	0	0	High
2 (320)	Need for further interventions	Sublingual misoprostol v ergometrine	4	0	0	0	0	High
1 (60)	Morbidity	Sublingual misoprostol v oxytocin plus ergometrine combinations	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
At least 7 RCTs (at least 5153 women)	Morbidity	Oral misoprostol v placebo/no intervention	4	0	−1	−1	0	Low	Consistency point deducted for conflicting results. Directness point deducted for using ergometrine control as ‘no intervention’
At least 7 RCTs (at least 1620 women)	Need for further interventions	Oral misoprostol v placebo/no intervention	4	0	0	−1	0	Moderate	Directness point deducted for using ergometrine control as ‘no intervention’
2 (2849)	Mortality	Oral misoprostol v placebo/no intervention	4	0	0	0	0	High
3 (at least 2423 women)	Morbidity	Oral misoprostol v ergot compounds	4	0	0	0	0	High
3 (at least 2223 women)	Need for further interventions	Oral misoprostol v ergot compounds	4	0	0	0	0	High
13 (at least 25145 women)	Morbidity	Oral misoprostol v oxytocin	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
11 (at least 24310 women)	Need for further interventions	Oral misoprostol v oxytocin	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
4 (20199)	Mortality	Oral misoprostol v oxytocin	4	0	0	0	0	High
4 (3805)	Morbidity	Oral misoprostol v oxytocin/ ergometrine combinations	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
4 (3805)	Need for further interventions	Oral misoprostol v oxytocin plus ergometrine combinations	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
1 (542)	Morbidity	Rectal misoprostol v placebo/no intervention	4	0	0	0	0	High
1 (546)	Need for further interventions	Rectal misoprostol v placebo/no intervention	4	0	0	0	0	High
3 (1780)	Morbidity	Rectal misoprostol v oxytocin	4	0	0	0	0	High
4 (2013)	Need for further interventions	Rectal misoprostol v oxytocin	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
2 (1262)	Morbidity	Rectal misoprostol v oxytocin plus ergometrine combinations	4	0	−1	0	0	Moderate	Consistency point deducted for conflicting results
1 (798)	Need for further interventions	Rectal misoprostol v oxytocin plus ergometrine combinations	4	0	0	0	+1	High	Effect-size point added for RR between 0.5 to 0.2
1 (120)	Morbidity	Rectal misoprostol v carboprost injection	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (120)	Need for further interventions	Rectal misoprostol v carboprost injection	4	−1	0	0	+2	High	Quality point deducted for sparse data. Effect-size points added for RR greater than 5
1 (100)	Morbidity	Vaginal misoprostol v placebo/no intervention	4	−2	0	−1	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no direct comparison between groups

Type of evidence: 4 = RCT; 2 = ObservationalConsistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Active management

Management of the third stage of labour through a combination of interventions, usually including: immediate cord clamping, cutting, and drainage; controlled cord traction; and use of an oxytocic agent (oxytocin, a fixed combination of oxytocin plus ergometrine, ergot compound, etc.).

Controlled cord traction

involves applying traction to the umbilical cord after the uterus has begun to contract. This can be done constantly or intermittently, usually every few minutes.

Ergot compounds

Naturally occurring alkaloids that cause uterine contraction. Available for clinical use as ergometrine, methylergonovine, and methergine.

Expectant management

Management of the third stage by passive means. No active interventions such as oxytocic administration or cord traction are used. In general, the placenta is allowed to be delivered by a combination of gravity and natural uterine contractions, sometimes in conjunction with nipple stimulation.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Immediate cord drainage

Allowing the blood in the placenta to drain from the cut end of the umbilical cord immediately after the cord is clamped and cut.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Manual placenta removal

Removal of the placenta by a hand placed through the vagina into the uterus. It is usually performed for retained placental tissue or with postpartum haemorrhage occurring before delivery of the placenta.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Oxytocic agent

Any agent that makes the uterus contract.

Oxytocin

Peptide hormone endogenously synthesised in the hypothalamus (supraoptic and paraventricular nuclei) and released from the posterior pituitary, and important for uterine contractility. Given either intramuscularly or intravenously for the induction or augmentation of labour, and the prevention or treatment of postpartum haemorrhage.

Retained placental tissue

Placenta that has not been delivered within a specified length of time, often 30 minutes, from time of the delivery of the baby.

Sheehan's syndrome

is caused by necrosis of the pituitary gland with associated hypopituitarism, resulting from severe postpartum haemorrhage. Although it can cause hypotension and shock immediately postpartum, in most cases the onset is slower – days, weeks, or even years later. Common features are lack of lactation postpartum, amenorrhoea, loss of pubic hair, weight loss, and lethargy. Although increasingly rare in the western world, it is one of the most common causes of hypopituitarism in resource-poor countries.

Uterine massage

involves manually rubbing the uterine fundus through the abdominal wall immediately after birth.

Very low-quality evidence

Any estimate of effect is very uncertain.

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