Postpartum misoprostol for preventing maternal mortality and morbidity

  • Review
  • Intervention

Authors

  • G Justus Hofmeyr,

    Corresponding author
    1. University of the Witwatersrand, University of Fort Hare, Eastern Cape Department of Health, Department of Obstetrics and Gynaecology, East London Hospital Complex, East London, Eastern Cape, South Africa
    • G Justus Hofmeyr, Department of Obstetrics and Gynaecology, East London Hospital Complex, University of the Witwatersrand, University of Fort Hare, Eastern Cape Department of Health, Frere and Cecilia Makiwane Hospitals, Private Bag X 9047, East London, Eastern Cape, 5200, South Africa. justhof@gmail.com.

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  • A Metin Gülmezoglu,

    1. World Health Organization, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, Geneva, Switzerland
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  • Natalia Novikova,

    1. Walter Sisulu University, Department of Obstetrics and Gynaecology, East London Hospital Complex, East London, South Africa
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  • Theresa A Lawrie

    1. Royal United Hospital, The Cochrane Gynaecological Cancer Group, Bath, UK
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Abstract

Background

The primary objective of postpartum haemorrhage (PPH) prevention and treatment is to reduce maternal deaths. Misoprostol has the major public health advantage over injectable medication that it can more easily be distributed at community level. Because misoprostol might have adverse effects unrelated to blood loss which might impact on mortality or severe morbidity, it is important to continue surveillance of all relevant evidence from randomised trials. This is particularly important as misoprostol is being introduced on a large scale for PPH prevention in low-income countries, and is commonly used for PPH treatment in well-resourced settings as well.

Objectives

To review maternal deaths and severe morbidity in all randomised trials of misoprostol for prevention or treatment of PPH.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 January 2013).

Selection criteria

We included randomised trials including pregnant women who received misoprostol in the postpartum period, versus placebo/no treatment or other uterotonics for prevention or treatment of PPH, and reporting on maternal death, severe morbidity or pyrexia.

We planned to include cluster- and quasi-randomised trials in the analysis, as a very large number of women will be needed to obtain robust estimates of maternal mortality but we did not identify any for this version of the review. In future updates of this review we will include trials reported only as abstracts if sufficient information is available from the abstract or from the authors.

Data collection and analysis

Two review authors independently assessed trials for inclusion and extracted data.

Main results

We included 78 studies (59,216 women) and excluded 34 studies.There was no statistically significant difference in maternal mortality for misoprostol compared with control groups overall (31 studies; 11/19,715 versus 4/20,076 deaths; risk ratio (RR) 2.08, 95% confidence interval (CI) 0.82 to 5.28); or for the trials of misoprostol versus placebo: 10 studies, 6/4626 versus 1/4707 ; RR 2.70; 95% CI 0.72 to 10.11; or for misoprostol versus other uterotonics: 21 studies, 5/15,089 versus 3/15,369 (19/100,000); RR 1.54; 95% CI 0.40 to 5.92. All 11 deaths in the misoprostol arms occurred in studies of misoprostol ≥ 600 µg.

There was a statistically significant difference in the composite outcome ‘maternal death or severe morbidity’ for the comparison of misoprostol versus placebo (12 studies; average RR 1.70, 95% CI 1.02 to 2.81; Tau² = 0.00, I² = 0%) but not for the comparison of misoprostol versus other uterotonics (17 studies; average RR 1.50, 95% CI 0.50 to 4.52; Tau² = 1.81, I² = 69%). When we excluded hyperpyrexia from the composite outcome in exploratory analyses, there was no significant difference in either of these comparisons.

Pyrexia > 38°C was increased with misoprostol compared with controls (56 studies, 2776/25,647 (10.8%) versus 614/26,800 (2.3%); average RR 3.97, 95% CI 3.13 to 5.04; Tau² = 0.47, I² = 80%). The effect was greater for trials using misoprostol 600 µg or more (27 studies; 2197/17,864 (12.3%) versus 422/18,161 (2.3%); average RR 4.64; 95% CI 3.33 to 6.46; Tau² = 0.51, I² = 86%) than for those using misoprostol 400 µg or less (31 studies; 525/6751 (7.8%) versus 185/7668 (2.4%); average RR 3.07; 95% CI 2.25 to 4.18; Tau² = 0.29, I² = 58%).

Authors' conclusions

Misoprostol does not appear to increase or reduce severe morbidity (excluding hyperpyrexia) when used to prevent or treat PPH. Misoprostol did not increase or decrease maternal mortality. However, misoprostol is associated with an increased risk of pyrexia, particularly in dosages of 600 µg or more. Given that misoprostol is used prophylactically in very large numbers of healthy women, the greatest emphasis should be placed on limiting adverse effects. In this context, the findings of this review support the use of the lowest effective dose. As for any new medication being used on a large scale, continued vigilance for adverse effects is essential and there is a need for large randomised trials to further elucidate both the relative effectiveness and the risks of various dosages of misoprostol.

Résumé scientifique

Misoprostol post-partum pour la prévention de la morbidité et de la mortalité maternelles

Contexte

Le principal objectif de la prévention et du traitement de l'hémorragie post-partum (HPP) est de réduire la mortalité maternelle. Le misoprostol offre un avantage majeur pour la santé publique par rapport au médicament injectable en ce qu'il est plus facile à distribuer au sein de la population locale. Comme le misoprostol risque de provoquer des effets indésirables sans rapport avec la perte de sang qui sont susceptibles d'avoir un impact sur la mortalité ou la morbidité sévère, il est donc important de continuer la surveillance de toutes les données pertinentes obtenues dans les essais randomisés. Cela est particulièrement important car le misoprostol est en cours d'introduction à une grande échelle pour la prévention de l'HPP dans les pays à faible revenu, et est couramment utilisé pour le traitement de l'HPP dans les pays riches également.

Objectifs

Examiner la mortalité et la morbidité sévère maternelles dans tous les essais randomisés du misoprostol pour la prévention ou le traitement de l'HPP.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais du groupe Cochrane sur la grossesse et la naissance (vendredi 11 janvier 2013).

Critères de sélection

Nous avons inclus les essais randomisés ayant recruté des femmes enceintes qui ont reçu le misoprostol dans la période post-partum, versus un placebo/l'absence de traitement ou d'autres utérotoniques pour la prévention ou le traitement de l'HPP, et rendant compte de la mortalité, de la morbidité sévère ou de la pyrexie maternelles.

Nous avions prévu d'inclure les essais en grappes et quasi-randomisés dans l'analyse, puisqu'un très grand nombre de femmes seront nécessaires pour obtenir des estimations fiables de la mortalité maternelle mais nous n'en avons identifié aucun pour cette version de la revue. Dans les futures mises à jour de cette revue, nous inclurons les essais rapportés uniquement sous forme de résumés si les informations disponibles dans le résumé ou auprès des auteurs sont suffisantes.

Recueil et analyse des données

Deux auteurs de la revue ont, de façon indépendante, évalué les essais à inclure et extrait les données.

Résultats principaux

Nous avons inclus 78 études (soit 59 216 femmes) et exclu 34 études.Il n'y avait globalement aucune différence statistiquement significative au niveau de la mortalité maternelle pour le misoprostol par rapport aux groupes témoins (31 études ; décès : 11/19 715 femmes contre 4/20 076 ; risque relatif (RR) 2,08, intervalle de confiance (IC) à 95 % 0,82 à 5,28) ; ou dans les essais du misoprostol versus placebo : 10 études, décès : 6/4 626 femmes contre 1/4 707 ; RR 2,70 ; IC à 95 % 0,72 à 10,11 ; ou pour le misoprostol versus d'autres utérotoniques : 21 études, décès : 5/15 089 femmes contre 3/15 369 (19/100 000) ; RR 1,54 ; IC à 95 % 0,40 à 5,92. Les 11 décès survenus dans les bras de traitement par misoprostol se sont tous produits dans les études menées avec le misoprostol ≥ 600 µg.

Il y avait une différence statistiquement significative dans le résultat composite ‘mortalité maternelle ou morbidité sévère’ pour la comparaison misoprostol versus placebo (12 études ; RR moyen 1,70, IC à 95 % 1,02 à 2,81 ; Tau² = 0,00, I² = 0 %) mais pas pour la comparaison misoprostol versus d'autres utérotoniques (17 études ; RR moyen 1,50, IC à 95 % 0,50 à 4,52 ; Tau² = 1,81, I² = 69 %). Dès que nous avons exclu l'hyperpyrexie du résultat composite dans les analyses exploratoires, il n'y avait aucune différence significative dans l'une ou l'autre de ces comparaisons.

La pyrexie > 38 °C a été plus importante avec le misoprostol par rapport aux témoins (56 études, 2 776/25 647 (10,8 %) contre 614/26 800 (2,3 %) ; RR moyen 3,97, IC à 95 % 3,13 à 5,04 ; Tau² = 0,47, I² = 80 %). L'effet a été plus important dans les essais utilisant le misoprostol 600 µg ou plus (27 études ; 2 197/17 864 (12,3 %) contre 422/18 161 (2,3 %) ; RR moyen 4,64 ; IC à 95 % 3,33 à 6,46 ; Tau² = 0,51, I² = 86 %) que dans les essais utilisant le misoprostol 400 µg ou moins (31 études ; 525/6 751 (7,8 %) contre 185/7 668 (2,4 %) ; RR moyen 3,07 ; IC à 95 % 2,25 à 4,18 ; Tau² = 0,29, I² = 58 %).

Conclusions des auteurs

Le misoprostol ne semble pas augmenter ou réduire la morbidité sévère (sauf l'hyperpyrexie) lorsqu'il est administré pour prévenir ou traiter l'HPP. Le misoprostol n'a pas augmenté ou diminué la mortalité maternelle. Toutefois, le misoprostol est associé à un risque accru de pyrexie, en particulier avec les doses de 600 µg ou plus. Comme le misoprostol est utilisé de façon prophylactique chez de très nombreuses femmes en bonne santé, il convient d'insister tout particulièrement sur les moyens permettant de limiter les effets indésirables. Dans ce contexte, les conclusions de cette revue soutiennent l'utilisation de la dose minimale efficace. Comme pour tout nouveau médicament utilisé à une grande échelle, une vigilance continue pour les effets indésirables est essentielle tout comme il est nécessaire d'effectuer des essais randomisés à grande échelle afin d'élucider plus précisément l'efficacité relative et les risques des différentes doses de misoprostol.

Plain language summary

Postpartum misoprostol for preventing maternal mortality and morbidity

Bleeding from the uterus or womb after childbirth is normal, but excessive bleeding (haemorrhage) is an important cause of death and can be reduced by medication that causes the uterus to contract. Misoprostol is one such medication and is a tablet marketed to treat certain stomach ulcers but which also contracts the uterus and reduces bleeding. It may also have harmful side effects, in particular raised body temperature (pyrexia) and shivering. Misoprostol can more easily be distributed at community level than less stable, injectable medication such as oxytocin to prevent or treat severe bleeding in woman after giving birth (postpartum haemorrhage). This review investigated whether giving misoprostol to women after birth to prevent or treat excessive bleeding reduces maternal deaths and severe complications other than blood loss (which is covered in separate reviews). We included 78 randomised controlled studies involving 59,216 women. The variety of study designs, populations studied, routes of administration and co-interventions, as well as the exceptionally high incidence of hyperpyrexia in Ecuador were limiting factors. Maternal deaths, and the combined outcome, death or severe illness resulting in major surgery, admission to intensive care or vital organ failure (excluding very high fever) were not reduced by misoprostol. The known side effects of misoprostol (fever and very high fever) were worse with dosages of 600 µg or more than with lower dosages. Therefore, the review supports the use of the lowest effective misoprostol dose to prevent or treat maternal bleeding after the birth of the baby, and calls for more research to find out the optimal dosage, with continued surveillance for serious side effects.

Résumé simplifié

Misoprostol post-partum pour la prévention de la morbidité et de la mortalité maternelles

Le saignement de l'utérus après l'accouchement est normal, mais un saignement excessif (hémorragie) est une cause de décès importante et peut être réduit par un traitement médicamenteux qui permettra à l'utérus de se contracter. Le misoprostol est l'un de ces médicaments et se présente sous forme de comprimé prescrit pour traiter certains ulcères gastriques mais qui contracte l'utérus et réduit le saignement également. Il peut aussi avoir des effets secondaires délétères, en particulier une élévation de la température corporelle (pyrexie) et des frissons. Le misoprostol est plus facile à distribuer au sein de la population locale qu'un médicament injectable moins stable, tel que l'ocytocine, pour prévenir ou traiter les saignements sévères chez la femme après l'accouchement (hémorragie post-partum). Cette revue a évalué si l'administration de misoprostol aux femmes après l'accouchement pour prévenir ou traiter les saignements excessifs permet de réduire la mortalité maternelle et les complications sévères autres que la perte de sang (qui est traitée dans des revues distinctes). Nous avons inclus 78 essais contrôlés randomisés impliquant au total 59 216 femmes. La diversité des schémas d'étude, des populations étudiées, des voies d'administration et des co-interventions, ainsi que l'incidence exceptionnellement élevée d'hyperpyrexie en Équateur ont été des facteurs limitants. La mortalité maternelle, et le critère de jugement combiné, le décès ou une maladie grave entraînant une chirurgie majeure, l'admission en unité de soins intensifs ou une insuffisance d'un organe vital (sauf une fièvre extrêmement élevée) n'ont pas été réduits par le misoprostol. Les effets secondaires connus du misoprostol (fièvre et fièvre extrêmement élevée) ont été plus graves avec des doses de 600 µg ou plus qu'avec des doses plus faibles. Par conséquent, la revue soutient l'utilisation de la dose minimale efficace de misoprostol pour prévenir ou traiter les saignements maternels après la naissance du bébé, et préconise d'effectuer des recherches supplémentaires afin de déterminer la dose optimale, ainsi qu'une surveillance continue des effets secondaires graves.

Notes de traduction

Traduit par: French Cochrane Centre 4th September, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Laički sažetak

Misoprostol nakon poroda za prevenciju oboljenja i smrti majke

Krvarenje iz maternice nakon poroda je normalno, ali prekomjerno krvarenje je važan uzrok smrti i može se umanjiti lijekovima koji uzrokuju stezanje (kontrakciju) maternice. Misoprostol je jedan od takvih lijekova i dostupan je kao tableta koja se koristi za liječenje nekih ulkusa želuca, ali također steže maternicu i smanjuje krvarenje. Može imati i štetne nuspojave, posebice povišenu tjelesnu temperaturu (pireksija) i drhtanje. Misoprostol se može jednostavnije distribuirati na razini zajednice od manje stabilnih pripravaka za injekcije kao što je oksitocin u terapiji teškog krvarenja u žena nakon poroda (postpartalna hemoragija). Ovaj Cochrane sustavni pregled ispitao je pomaže li davanje misoprostola nakon poroda za prevenciju ili smanjenje krvarenja u redukciji smrti majke i teških komplikacija osim gubitka krvi (pokriveni u drugim pregledima). Uključeno je 78 randomiziranih kontroliranih studija s ukupno 59.261 žena. Ograničavajući faktori bili su različiti načini na koji su studije provedene, kao i različiti načini primjene i dodatne intervencije, kao i iznimno visoka pojavnost hiperpireksije u Ekvadoru. Smrti majke i kombinirani ishod, smrt ili ozbiljna bolest koja dovodi do operacije, prijema u jedinice intenzivne njege ili zatajenje vitalnih organa (isključujući visoku tjelesnu temperaturu) nisu umanjeni misoprostolom. Poznate nuspojave misoprostola (groznica i jako visoka tjelesna temperatura) bile su izraženije s dozama višima od 600 µg nego kod nižih doza. Stoga ovaj sustavni pregled podupire upotrebu najniže učinkovite doze misoprostola u prevenciji i terapiji krvarenja majke nakon poroda i ukazuje da je potrebno više istraživanja kako bi se utvrdilo optimalno doziranje, a isto tako da je potrebno nastaviti nadzor pacijentica kako bi se utvrdilo postoji li mogućnost razvoja ozbiljnih nuspojava.

Bilješke prijevoda

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Background

Description of the condition

The primary objective of postpartum haemorrhage (PPH; bleeding after childbirth) prevention and treatment is to reduce maternal deaths. Because mortality is generally too infrequent to be measured in randomised trials, blood loss is used as a surrogate outcome.

The postpartum period, also known as the puerperium, begins with the birth of the baby and placenta and ends six weeks after birth. Maternal mortality includes the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to, or aggravated by the pregnancy or its management, but not from accidental or incidental causes (AbouZahar 2003). Maternal morbidity, which is investigated in this review, includes major surgery (laparotomy, uterine artery ligation, internal iliac artery ligation, B-Lynch suture, hysterectomy, extensive vaginal repair), admission to the intensive care unit, vital organ failure (transient or permanent), and severe pyrexia (body temperature above 40ºC).

This review will focus only on maternal mortality and severe morbidity associated with the use of misoprostol for prevention and treatment of PPH. Other outcomes such as PPH and side-effects have been reviewed previously (Hofmeyr 2009), and are covered in The Cochrane Library by the reviews of prostaglandins for preventing PPH (Tuncalp 2012), and treatments for PPH (Mousa 2007). For this reason, PPH will not be reported on in this review.

The majority of trials on misoprostol were performed in low-income countries where PPH is more common in comparison to high-income countries. Maternal mortality is also much higher in low-income countries. Although the impact of this review will be more significant for low-income countries with a high incidence of PPH and maternal mortality, it is also important for high-income countries where misoprostol is commonly used for treatment of PPH.

Description of the intervention

Misoprostol is one of several uterotonic agents used for the prevention and treatment of PPH. It is an inexpensive and stable prostaglandin E1 analogue, and has been shown to stimulate uterine contractility in pregnancy (Norman 1991). Administered orally or vaginally, it is effective for induction of abortion and of labour, though it poses certain risks (Hofmeyr 1998).

Misoprostol has the major public health advantage over less stable, injectable medication such as oxytocin that it can more easily be distributed at community level (Rajbhandari 2010). A recent Monte Carlo simulation depicting mortality and anaemia-related morbidity attributable to PPH estimated that community-based distribution of misoprostol for prevention of PPH would lower mortality by 81% and for treatment of PPH by 70% (Sutherland 2010). A systematic review of misoprostol distribution for use at home births found evidence of a reduction in PPH, but concluded that more robust evidence was needed (Hundley 2013).

Misoprostol gained popularity as a treatment for PPH in both low- and high-income countries on the basis of several uncontrolled observational studies showing dramatic effects.

While common sense suggests that reduced blood loss should translate to reduced mortality, this intuitive link is not necessarily straightforward. It would be possible for a treatment to reduce blood loss while having other adverse effects which increase mortality. A good example of such a counter-intuitive effect is class I antiarrhythmics, which reduce post-myocardial infarction arrhythmias, but double mortality (Echt 1991). Misoprostol has ubiquitous effects on many organ systems. It is, therefore, important to monitor the effects on overall mortality as for any new intervention promoted on the basis of surrogate outcomes.

This review includes studies of misoprostol by any route or in any dose used to prevent or treat PPH compared with either placebo or another uterotonic. Other uterotonics may include oxytocin, ergometrine, sulprostone or combinations.

How the intervention might work

Misoprostol has well-established uterotonic effects. Given after birth, it decreases PPH in certain circumstances, though less effectively than oxytocin (Tuncalp 2012). However, being a prostaglandin analogue, misoprostol has ubiquitous effects on many organ systems. Pyrexia and shivering are common, dose-related side- effects (Lumbiganon 1999). A systematic review found an overall five-fold increase in pyrexia with misoprostol, which was dose-related and greatest with the sublingual route and least with the rectal route (Elati 2012). Hyperpyrexia (body temperature of 40°C or more) is a serious adverse event which may be life-threatening (Chong 1997). Adverse cardiovascular events reported following the use of sulprostone (which was subsequently withdrawn from the market) for treatment of PPH may have been related to pulmonary artery vasoconstriction, an adverse effect also described with misoprostol (Qian 1994). A statistically significant decrease in heart rate with misoprostol has been reported, which might impair the cardiovascular compensation for blood loss postpartum (Brecht 1987). Thus, while misoprostol might reduce PPH, it is possible that adverse effects might compromise homoeostasis in the postpartum period. To date, there is no direct evidence from randomised trials that postpartum misoprostol reduces maternal mortality.

Why it is important to do this review

Misoprostol is being advocated for wide use in prevention and treatment of PPH (Smith 2013), and is recommended for such in certain settings by the World Health Orgnization (Smith 2013; Tang 2013), the Clinical Practice Obstetrics Committee; Society of Obstetricians and Gynaecologists of Canada (Leduc 2009) and the American College of Obstetricians and Gynecologists (ACOG 2006). The Royal College of Obstetricians and Gynaecologists Green-Top Guideline no 52 of 2009 (revised 2011), recommends misoprostol 1000 µg rectally for treatment of PPH when other interventions fail (RCOG 2009) (http://www.rcog.org.uk/files/rcog-corp/GT52PostpartumHaemorrhage0411.pdf). Guidance for the use of misoprostol for the prevention (FIGO 2012a) and treatment (FIGO 2012b) of PPH has been issued by the International Federation Of Gynecology And Obstetrics. Given the fact that misoprostol has been introduced into practice through opportunistic use by clinicians, a number of investigator-initiated randomised trials and recommendations from global organisations, rather than by a manufacturing company with responsibility for post-marketing surveillance, it is most important to prospectively monitor maternal deaths and severe morbidity in all randomised trials of postpartum misoprostol to determine the net impact of the beneficial effects, known adverse effects, as well as any unknown adverse effects. The Cochrane review on treatments for primary PPH recommends: "A system of "adverse event registration" should be used to identify serious maternal morbidity and mortality associated with the use of misoprostol in clinical practice." (Mousa 2007) This is important both for low-resource settings where misoprostol is being introduced on a large scale for routine use after childbirth, and for well-resourced settings where misoprostol is commonly used to treat PPH when other uterotonics fail. Currently, no Cochrane review can monitor all adverse outcomes in trials of misoprostol, because trials of prevention (Tuncalp 2012) and treatment (Mousa 2007) are considered in separate reviews.

Objectives

To review maternal deaths and severe morbidity in all randomised trials of misoprostol for prevention or treatment of postpartum haemorrhage.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials. We also planned to include cluster- and quasi-randomised trials in the analysis, as a very large number of women will be needed to obtain robust estimates of maternal mortality but we did not identify any for this version of the review. We will include trials reported only as abstracts if sufficient information is available from the abstract or from the authors.

Types of participants

Pregnant women ≥ 24 weeks' gestation who received misoprostol during the third stage of labour or in the postpartum period, versus placebo/no treatment or other uterotonics for prevention or treatment of postpartum haemorrhage (PPH). We included studies conducted in women who delivered by caesarean section.

Types of interventions

A: Different doses and different routes (sublingual, oral, vaginal, rectal) of misoprostol used for prevention or treatment of PPH compared versus B: other uterotonics, other doses or routes, or placebo/no treatment. We included comparisons of misoprostol versus placebo/no treatment or other routes or dosages in women who received routine uterotonics (e.g. we included misoprostol plus routine uterotonics versus placebo plus routine uterotonics as misoprostol versus placebo).

We considered it important to include in a single analysis comparisons of misoprostol versus both placebo/no treatment and versus other uterotonics for the following reasons:

  1. The main objective of the review was to monitor unexpected adverse effects related to misoprostol use in the third stage of labour, which, if existent, would be expected to occur irrespective of the comparator.

  2. Because severe adverse effects and death are likely to be rare, all relevant randomised trials needed to be considered in a single analysis in order to have the power to detect such effects as early as possible.

Types of outcome measures

Primary outcomes
  1. Maternal death

Secondary outcomes
  1. Death or severe morbidity defined as any of the outcomes below.

  • 1.1 Major surgery (laparotomy, uterine artery ligation, internal iliac artery ligation, B-Lynch suture, hysterectomy, extensive vaginal repair)

  • 1.2 Admission to the intensive care unit

  • 1.3 Vital organ failure (temporary or permanent)

  • 1.4 Hyperpyrexia (body temperature ≥ 40ºC)

  1. 2. For dose comparisons, we also considered the outcome 'pyrexia ≥ 38°C'.

Because of the large number of women in the misoprostol groups with hyperpyrexia, we conducted a non-pre-specified analysis of maternal death or severe morbidity, excluding hyperpyrexia, to determine whether there were differences in morbidity from causes other than hyperpyrexia.

In a future update of the review, we will consider including another non-pre-specified analysis including blood transfusion as a component of severe morbidity.

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (11 January 2013). 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of Embase;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group. Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

We did not apply any language restrictions.

Data collection and analysis

Selection of studies

Review author Tess Lawrie (TL) assessed for inclusion all the potential studies we identified as a result of the search strategy. We checked the selection against the selection made for a previous published version of the review (Hofmeyr 2009). For a subset of newer studies not assessed for the previous review, Justus Hofmeyr (GJH) repeated the assessment. We resolved any disagreement through discussion or, if required, we consulted Metin Gulmezoglu (AMG).

To the included studies, we allocated study identifiers which indicated the country (or countries) and date: misoprostol dosage in µg; route of misoprostol administration (PO = orally; SL = sublingually or buccally; PR = rectally); whether compared with a uterotonic ('U') or placebo ('P'), and whether used at caesarean section ('CS'); for example: 'Egypt 2009:800PR vs U'.

Data extraction and management

We designed a form to extract data. For eligible studies, TL extracted the data using the agreed form and compared these with the data extraction performed for the previous version of this review of (Hofmeyr 2009). For a subset of newer studies not assessed for the previous review, GJH performed a second data extraction. We resolved disagreements through discussion or, if required, we consulted AMG. We entered data into Review Manager software (RevMan 2011) and checked for accuracy. When information regarding any of the above was unclear or there were missing data, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

TL assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011). See Appendix 1 for the 'Risk of bias' tool.

Measures of treatment effect

All review outcomes required dichotomous data only. We have presented most of the results of these data as summary risk ratios (RR) with 95% confidence intervals (CI). For the outcome maternal mortality, we used both RRs and Peto odds ratios (ORs) to exclude discrepancies between the two summary statistics (results not shown).

Unit of analysis issues

The unit of analysis for all outcomes was the individual participant. We did not identify any cluster-randomised trials for this version of the review. For trials with more than two treatment groups, we extracted only the relevant pair-wise comparisons that included misoprostol. If misoprostol was compared at different doses with other uterotonics or placebo, we extracted the data for each misoprostol dose comparison separately and entered them separately into the meta-analyses. If misoprostol was compared with two or more other types of standard uterotonics, we combined all relevant control intervention groups into a single control group, such that, for dichotomous outcomes, both the sample sizes and the number of people with events were summed across groups.

Dealing with missing data

For included studies, we noted levels of attrition. For all outcomes, we carried out analyses, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We regarded heterogeneity as substantial if the I² was greater than 30% and either the T² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases

If there were 10 or more studies in the meta-analysis, we investigated reporting biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry visually. If asymmetry was suggested by a visual assessment, we performed exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2011). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random-effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. Where we used random-effects analyses, the results are presented as the average treatment effect with 95% CIs, and the estimates of T² and I².

Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, we investigated it using subgroup analyses and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, used random-effects analysis to produce it.

We carried out the following subgroup analyses.

  1. By type of comparator: misoprostol versus placebo/no treatment; misoprostol versus other uterotonics; comparator mixed or unclear.

  2. By indication for misoprostol use: misoprostol to treat PPH; misoprostol to prevent PPH; indication mixed or unclear.

  3. By dose of misoprostol: 600 µg or more; 400 µg or less; more than 400 µg to less than 600 µg; dose mixed or unclear.

  4. By dose and route of misoprostol administration: orally; sublingually; rectally; vaginally; route mixed or unclear. We subdivided each route by dosages as in (3) above.

We used the following outcomes in subgroup analysis: 'maternal mortality' and 'maternal mortality or severe morbidity'. In addition, we performed an exploratory subgroup analysis for the outcome 'pyrexia ≥ 38°C'. For random-effects and fixed-effect meta-analyses, we assessed differences between subgroups by inspection of the subgroups’ confidence intervals, non-overlapping confidence intervals indicated a statistically significant difference in treatment effect between the subgroups, and by formal tests of subgroup differences.

In future versions of this review, we plan to perform subgroup analyses by co-treatment with routine uterotonics in both groups as follows: routine uterotonics used; routine uterotonics not used; use of routine uterotonics mixed or unclear.

Sensitivity analysis

We performed sensitivity analysis to determine the effects of trial quality on results, by excluding trials of lower quality for the following outcomes: 'maternal mortality' and 'maternal mortality or severe morbidity'. No effects of trial quality on the results were found (data not shown).

Results

Description of studies

Results of the search

We located 117 studies. We excluded 34, and four are awaiting classification due to awaiting translation (1), full text publication (2) or further information (1), see Studies awaiting classification.

Included studies

We included 78 studies (59,216 women); 71 postpartum haemorrhage (PPH) prevention studies and seven PPH treatment studies; 68 studies were conducted in women who underwent vaginal birth and 10 were conducted in women who underwent caesarean section. Misoprostol was compared to placebo (23), no additional treatment (2), other uterotonic agents (51) or uterotonic and placebo (2), at doses ranging from 50 µg to 1000 µg, via oral (35), sublingual (22), buccal (2), rectal (19), vaginal (1) and intrauterine routes (1).

Most of these studies reported side effects including fever, however several did not specifically report maternal morbidity and mortality data. For the initial WHO Bulletin version of the review, we obtained additional data from the authors of ten studies (Gambia 2004:600PO/SL vs P; Gambia 2005:600PO vs U; Guinea-B 2005:600SL vs P; India 2004a:400SL vs U; India 2005:600PO vs U; India 2005:600PO vs U; Nigeria 2003:600PO vs U; Turkey 2002:400PR vs P/U; WHO 1999:400/600PO vs U; Zim 2001:400PO vs U;). For the current review, we requested these additional data from contact authors of 24 studies and obtained them from the following (13): India 2012a:400SL vs U; India 2012b:400SL vs U; Spain 2009:400SL200PRvsN; Nigeria 2007:400PO vs U; Nigeria 2011:400SL vs P; Nigeria 2011:600PO vs U; Pakistan 2008:600SL vs P; Egypt 2009:800PR vs U; India 2009:400SL vs U; EEV 2010:800SL vs U; Egypt 2012b:CS400SL vs P; India 2010:CS800PR vs U; and India 2012:CS400SL vs P. No additional maternal deaths were identified through communication with the authors of these included trials. Several studies only contributed data relating to the incidence of fever, and three studies contributed no data (Bangla 2007:400PO vs U; China 2003:400PO vs N; Iran 2009:CS400SL vs U).

For more details see Characteristics of included studies.

Excluded studies

We excluded 34 studies. For details see Characteristics of excluded studies.

Risk of bias in included studies

See Figure 1.

Figure 1.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

The risk of allocation bias was considered low in 51 studies, unclear in 26 and high in one.

Blinding

The risk of performance bias and detection bias was considered low in 42 studies, unclear in 13 and high in 23.

Incomplete outcome data

The risk of attrition bias was considered low in 62 studies and unclear in 16.

Selective reporting

The risk of reporting bias was considered low in 65 studies, unclear in 12 and high in one.

Other potential sources of bias

The risk of other potential sources of bias was considered low in 62 studies and unclear in 16. Publication bias was assessed in funnel plots (Figure 2; Figure 3; Figure 4; Figure 5). Only for the outcome 'Pyrexia ≥ 38°C' was there some visual asymmetry (Figure 5).

Figure 2.

Funnel plot of comparison: 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, outcome: 1.1 Maternal deaths.

Figure 3.

Funnel plot of comparison: 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, outcome: 1.2 Maternal deaths or severe morbidity.

Figure 4.

Funnel plot of comparison: 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, outcome: 1.4 Maternal deaths or severe morbidity excluding hyperpyrexia.

Figure 5.

Funnel plot of comparison: 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, outcome: 1.5 Pyrexia ≥ 38°C.

Effects of interventions

Primary outcome: Maternal mortality

There was no statistically significant difference in maternal mortality with misoprostol compared to all control groups (31 studies; 11/19,715 (56/100,000) versus 4/20,076 deaths (20/100,000); risk ratio (RR) 2.08, 95% confidence interval (CI) 0.82 to 5.28; Analysis 1.1), or for any of the comparison subgroups; however, point estimates favoured the comparison groups:

  • Misoprostol versus placebo: 10 studies, 6/4626 (130/100,000) versus 1/4707 (21/100,000); RR 2.70; 95% CI 0.72 to 10.11; Analysis 1.1. Most of these deaths occurred in trials of treatment (three studies; 5/851 versus 0/870; RR 6.16; 95% CI 0.75 to 50.85; Analysis 2.1).

  • Misoprostol versus other uterotonics: 21 studies, 5/15,089 (3/100,000) versus 3/15,369 (19/100,000); RR 1.54; 95% CI 0.40 to 5.92; Analysis 1.1.

All maternal deaths occurred in studies evaluating misoprostol doses ≥ 600 µg versus controls (Analysis 3.1). There was no statistically significant difference between these groups overall: 18 studies: 11/16,202 (68/100,000) versus 4/16,226 (25/100,000); RR 2.08; 95% CI 0.82 to 5.28; Analysis 3.1. Maternal deaths occurred in studies using the oral, sublingual and mixed routes of administration. No deaths occurred in studies using misoprostol 400 µg or less (12 studies; 0/3483 versus 0/3820). This may be because, in general, 400 µg was used in prevention rather than treatment studies, with a lower associated risk of mortality.

Secondary outcomes:

Maternal death or severe morbidity

'Maternal death or severe morbidity' was significantly higher with misoprostol compared with placebo: 12 studies; 43/5003 (0.86%) versus 24/5082 (0.47%); average RR 1.70, 95% CI 1.02 to 2.81; Tau² = 0, I² = 0%; Analysis 1.2. One study (SATAEV 2010:600SL vs P), contributed most of the morbidity events (41/67 events). When we excluded this study in a sensitivity analysis, there was no longer a statistically significant difference between the misoprostol and placebo groups (11 studies; average RR 1.15, 95% CI 0.51 to 2.57; I² = 0%; Analysis 1.3).

There was no statistically significant difference between misoprostol and other uterotonics: 17 studies; average RR 1.50, 95% CI 0.50, 4.52; Tau² = 1.81, I² = 69%, Analysis 1.2; however, there was significant heterogeneity in this subgroup. This was due to the very large effect in one study (EEV 2010:800SL vs U), contributed to by an unusually high rate of hyperpyrexia in one site (58/66 cases occurred in Ecuador). We performed sensitivity analysis by excluding this study. Following this exclusion, the point estimate of the average RR reduced to 1.16, results remained not statistically significantly different, and the heterogeneity disappeared (16 studies; RR 1.09, 95% CI 0.67 to 1.76; I² = 0%; Analysis 1.3).

When we excluded both (EEV 2010:800SL vs U and SATAEV 2010:600SL vs P), the overall relative effect of misoprostol versus control was not significantly different between the groups (27 studies; average RR 1.16, 95% CI 0.78 to 1.72; I² = 0%, Analysis 1.3).

Considering all the studies of misoprostol versus placebo or other uterotonics, most cases of 'maternal death or severe morbidity' occurred in studies using 600 µg misoprostol or more (19 trials; average RR 1.67; 95% CI 0.80 to 3.45; Analysis 3.2). When we excluded the two outlier studies as above in a sensitivity analysis (EEV 2010:800SL vs U and SATAEV 2010:600SL vs P), the results for 'maternal death or severe morbidity' remained statistically non-significant, Analysis 3.3).

Maternal death or severe morbidity, excluding hyperpyrexia

To determine whether differences in the outcome 'maternal death or severe morbidity' were mainly due to cases of hyperpyrexia, we conducted a non-prespecified analysis of the outcome excluding hyperpyrexia. There was no difference between misoprostol and the comparison groups overall (29 studies; RR 0.97; 95% CI 0.67 to 1.41; I² = 0%, Analysis 1.4), or when subgrouped by misoprostol dosage (Analysis 3.4). This suggests that the increased morbidity with misoprostol was mainly due to hyperpyrexia, with most events occurring in two large multicentre studies of misoprostol for the treatment of PPH (EEV 2010:800SL vs U; SATAEV 2010:600SL vs P). In these latter studies, hyperpyrexia occurred mainly in Ecuador.

Pyrexia ≥ 38°C

There was considerable heterogeneity in the effect on pyrexia, which was increased with misoprostol (56 studies, 2776/25,647 (10.8%) versus 614/26,800 (2.3%); average RR 3.97, 95% CI 3.13 to 5.04, Tau² = 0.47, I² = 80% random-effects model; Analysis 1.5). This increase occurred both in trials of misoprostol versus placebo (20 studies; 1059/6212 (17%) versus 265/6228 (4.3%); average RR 3.25; 95% CI 2.30 to 4.59; Tau² = 0.40, I² = 79%) and versus other uterotonics (39 studies; 1717/19,435 (8.8%) versus 349/20,572 (1.7%); average RR 4.70; 95% CI 3.36 to 6.57; Tau² = 0.59, I² = 81%; Analysis 1.5). The effect was greater for trials using misoprostol 600 µg or more (27 studies; 2197/17,864 (12.3%) versus 422/18,161 (2.3%); average RR 4.64; 95% CI 3.33 to 6.46; Tau² = 0.51, I² = 86%; Analysis 3.5) than for those using misoprostol 400 µg or less (31 studies; 525/6751 (7.8%) versus 185/7668 (2.4%); average RR 3.07; 95% CI 2.25 to 4.18; Tau² = 0.29, I² = 58%; Analysis 3.5).

Discussion

Summary of main results

The number of maternal deaths is too small for meaningful statistical analysis. The range of plausible effects lies between a small (18%) reduction and a large (5.28 times) increase with misoprostol. The outcome 'death or severe morbidity' was increased with misoprostol, due to a large increase in hyperpyrexia in dosages of 600 µg or more. When hyperpyrexia was excluded from the definition, there was no difference between groups. As most of these hyperpyrexia events occurred in Ecuador, this may indicate a genetic predisposition. Pyrexia was, as expected, increased with misoprostol and this effect was dose-related.

Overall completeness and applicability of evidence

This review only includes studies of women who received misoprostol after giving birth for prevention or treatment of PPH. It does not include studies of women receiving misoprostol for abortion or induction of labour, for which different dosages of misoprostol are used. Therefore, these results are not applicable to these other uses of misoprostol, which require a separate review.

Although not statistically significantly different to the control group data, all maternal deaths and most maternal morbidity with misoprostol occurred with dosages of ≥ 600 µg. We consider the current evidence to be incomplete, particularly with regard to the optimal dosage of misoprostol in relation to maternal mortality and morbidity, which requires further investigation in large randomised trials.

Quality of the evidence

The methodological quality of studies was variable, but most of the studies that contributed data on maternal death were at a low risk of bias. We consider the quality of evidence with regard to maternal mortality or morbidity to be moderate due to the small numbers of events and further evidence is likely to change our confidence in the estimates of effect.

A feature of the review is the considerable heterogeneity of results which may be related to the variety of study designs, populations studied and co-interventions. Sensitivity analysis performed by removing studies at higher risk of bias did not remove the heterogeneity. However, two studies were responsible for much of the heterogeneity related to maternal morbidity, especially the exceptionally high incidence of hyperpyrexia in Ecuador. When we excluded these studies in sensitivity analysis, heterogeneity related to the composite outcome 'death or severe morbidity' was eliminated. Hyperpyrexia data from these studies seem incompatible with those of other studies, however, they may indicate that genetic differences contribute to the pyrexial events with misoprostol use. Therefore, for the composite outcome, we consider the results of the non-prespecified analysis (that excludes hyperpyrexia per se, and not the two trials) to be of a better quality and more widely applicable.

Potential biases in the review process

We pooled the relative effects of comparator groups (placebo and uterotonics) in our meta-analyses in order to improve the power of our meta-analyses, and on the basis that severe adverse effects of misoprostol, if existent, would be expected to occur in the misoprostol groups irrespective of the comparator. We have also presented the results for all outcomes by individual comparator groups, as well as the pooled results, and therefore do not consider this to be a substantial source of bias in the review. In addition, we have used random-effects methods for most meta-analyses, except for maternal mortality which is a relatively rare outcome, or where there was no evidence of heterogeneity in the data.

It is possible that our composite outcome may be improved by including other outcomes, e,g, blood transfusions, which may be better indicators of severe morbidity. We plan to reconsider this composite outcome in future versions of this review. However, severe morbidity including hyperpyrexia may have been underestimated as some studies did not perform a quantitative assessment of pyrexia but included other severe morbidity, and so we included these in this meta-analysis (e.g. Nigeria 2011:600PO vs U). On the other hand, hyperpyrexia may be less important as an indicator of severe morbidity as it does not appear to have long-term effects on the woman or lead to near-misses or prolonged hospitalisation.

Many authors find it redundant to report that there were no maternal deaths in their studies, especially those small studies conducted in low-risk women. If no maternal death was mentioned in the paper, we asked the authors to confirm that no death had occurred. If we were unable to contact them, we excluded the study from the outcome analysis. By excluding studies where the reporting of maternal deaths was omitted, we may have over-estimated the risk of maternal death slightly; however, the studies excluded on this basis were numerically small and unlikely to have had a large effect.

Agreements and disagreements with other studies or reviews

The findings are consistent with our previous review (Hofmeyr 2009). We are not aware of other reviews that have focused on maternal deaths in randomised postpartum misoprostol trials.

Authors' conclusions

Implications for practice

We have not found evidence that misoprostol significantly increases or decreases the risk of maternal death or serious morbidity (excluding hyperpyrexia) when used in the prevention and treatment of PPH. This review focusses on safety and has not addressed the effectiveness of misoprostol in terms of blood loss, which is covered in separate Cochrane reviews (Mousa 2007; Tuncalp 2012). Tuncalp 2012 found that misoprostol was less effective than injectable uterotonics with respect to blood loss, and more effective than placebo in settings in which injectable uterotonics were not used.

The increased risk of hyperpyrexia with doses of 600 µg or above is reason for concern. Hyperpyrexia is occasionally life-threatening, and at least (as is shivering and pyrexia) an unpleasant experience for women at a time that interactions with her newborn baby are of great importance. In one study of misoprostol 800 µg sublingually for the treatment of postpartum haemorrhage included in this review (EEV 2010:800SL vs U), 229 (47%) of women experienced shivering and 55 found it intolerable, while 66 women (14%) experienced hyperpyrexia > 40°C, of whom 22 found the pyrexia intolerable. These hyperpyrexia results are incompatible with the other included studies and are unlikely to be representative of most women using misoprostol. However, they do indicate that certain women may have a genetic predisposition to a hyperpyrexia response. Pyrexia > 38°C, however, was reported across all trials using misoprostol 600 µg or more.

Our previous review found no difference in effectiveness in terms of blood loss between misoprostol 600 µg or more and 400 µg, using both direct and adjusted indirect comparisons (Hofmeyr 2009). The current review has found no evidence of benefit in terms of 'maternal mortality or severe morbidity' with misoprostol in any dosage versus placebo, and increased adverse effects (pyrexia) in dosages of 600 µg or more. Given the fact that misoprostol is used prophylactically in very large numbers of healthy women, in settings without access to more effective uterotonics, the greatest emphasis should be placed on limiting adverse effects. In this context, the findings of this review support use of the lowest effective dose.

Implications for research

As for any new medication being used on a very large scale, continued vigilance for adverse effects is essential. In the context of ongoing programs to introduce misoprostol for routine management of the third stage of labour, there is a need for very large (cluster) randomised trials to further elucidate both the relative effectiveness and the risks of adverse effects of various dosages of misoprostol. There is also a need for more studies of the effects of various dosages of postpartum misoprostol on physiologic parameters such as pulmonary artery vasoconstriction (Qian 1994) and heart rate (Brecht 1987).

Acknowledgements

Pregnancy and Childbirth Group editorial base for technical support; Verena Linder, Sandra Ferreira and Gilda Piaggio for contributions to previous, non-Cochrane versions of this review.

As part of the pre-publication editorial process, this review has been commented on by four peers (an editor and three referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

The World Health Organization (and G Justus Hofmeyr, Natalia Novikova and Theresa A Lawrie) retain copyright and all other rights in their respective contributions to the manuscript of this Review as submitted for publication.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

Comparison 1. Misoprostol versus control (placebo or uterotonic) subgrouped by comparator
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maternal deaths3139791Risk Ratio (M-H, Fixed, 95% CI)2.08 [0.82, 5.28]
1.1 Misoprostol vs placebo or nothing109333Risk Ratio (M-H, Fixed, 95% CI)2.70 [0.72, 10.11]
1.2 Misoprostol vs other uterotonics2130458Risk Ratio (M-H, Fixed, 95% CI)1.54 [0.40, 5.92]
2 Maternal deaths or severe morbidity2939127Risk Ratio (M-H, Random, 95% CI)1.46 [0.81, 2.64]
2.1 Misoprostol vs placebo or nothing1210085Risk Ratio (M-H, Random, 95% CI)1.70 [1.02, 2.81]
2.2 Misoprostol vs other uterotonics1729042Risk Ratio (M-H, Random, 95% CI)1.50 [0.50, 4.52]
3 Maternal deaths or severe morbidity (sensitivity analysis)2939127Risk Ratio (M-H, Fixed, 95% CI)2.51 [1.86, 3.39]
3.1 Misoprostol vs placebo or nothing1210085Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.09, 2.81]
3.2 Misoprostol vs other uterotonics1729042Risk Ratio (M-H, Fixed, 95% CI)3.12 [2.10, 4.63]
4 Maternal deaths or severe morbidity excluding hyperpyrexia2939127Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.67, 1.41]
4.1 Misoprostol vs placebo or nothing1210085Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.66, 2.01]
4.2 Misoprostol vs other uterotonics1729042Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.50, 1.40]
5 Pyrexia ≥ 38°C5652447Risk Ratio (M-H, Random, 95% CI)3.97 [3.13, 5.04]
5.1 Misoprostol vs other uterotonics3940007Risk Ratio (M-H, Random, 95% CI)4.70 [3.36, 6.57]
5.2 Misoprostol vs placebo or nothing2012440Risk Ratio (M-H, Random, 95% CI)3.25 [2.30, 4.59]
Analysis 1.1.

Comparison 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, Outcome 1 Maternal deaths.

Analysis 1.2.

Comparison 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, Outcome 2 Maternal deaths or severe morbidity.

Analysis 1.3.

Comparison 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, Outcome 3 Maternal deaths or severe morbidity (sensitivity analysis).

Analysis 1.4.

Comparison 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, Outcome 4 Maternal deaths or severe morbidity excluding hyperpyrexia.

Analysis 1.5.

Comparison 1 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator, Outcome 5 Pyrexia ≥ 38°C.

Comparison 2. Misoprostol versus control (placebo or uterotonic) subgrouped by comparator and indication
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maternal deaths3139791Risk Ratio (M-H, Fixed, 95% CI)2.08 [0.82, 5.28]
1.1 Prevention: misoprostol vs placebo or nothing77612Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.14, 7.07]
1.2 Prevention: misoprostol vs other uterotonics1928671Risk Ratio (M-H, Fixed, 95% CI)1.77 [0.37, 8.34]
1.3 Treatment: misoprostol vs placebo31721Risk Ratio (M-H, Fixed, 95% CI)6.16 [0.75, 50.85]
1.4 Treatment: misoprostol vs other uterotonics21787Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.74]
2 Maternal deaths or severe morbidity29 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Prevention: misoprostol vs placebo or nothing88204Risk Ratio (M-H, Random, 95% CI)0.98 [0.39, 2.43]
2.2 Prevention: misoprostol vs other uterotonics1427191Risk Ratio (M-H, Random, 95% CI)0.92 [0.52, 1.64]
2.3 Treatment: misoprostol vs placebo41881Risk Ratio (M-H, Random, 95% CI)2.14 [0.76, 6.01]
2.4 Treatment: misoprostol vs other uterotonics31851Risk Ratio (M-H, Random, 95% CI)6.45 [0.21, 201.46]
3 Maternal deaths or severe morbidity excluding hyperpyrexia2939127Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.67, 1.41]
3.1 Prevention: misoprostol vs placebo or nothing88204Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.36, 2.27]
3.2 Prevention: misoprostol vs other uterotonics1427191Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.39, 1.26]
3.3 Treatment: misoprostol vs placebo41881Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.66, 2.69]
3.4 Treatment: misoprostol vs other uterotonics31851Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.52, 5.29]
4 Pyrexia ≥ 38°C5552921Risk Ratio (M-H, Random, 95% CI)3.99 [3.16, 5.04]
4.1 Prevention: misoprostol ≥ 600 µg vs placebo or nothing86308Risk Ratio (M-H, Random, 95% CI)5.15 [2.89, 9.19]
4.2 Prevention: misoprostol 400 µg vs placebo84208Risk Ratio (M-H, Random, 95% CI)2.24 [1.55, 3.23]
4.3 Prevention: misoprostol < 400 µg vs placebo1250Risk Ratio (M-H, Random, 95% CI)4.5 [0.99, 20.41]
4.4 Prevention: misoprostol ≥ 600 µg vs other uterotonics1426056Risk Ratio (M-H, Random, 95% CI)5.45 [3.64, 8.15]
4.5 Prevention: misoprostol 400 µg vs other uterotonics2412138Risk Ratio (M-H, Random, 95% CI)3.98 [2.62, 6.04]
4.6 Prevention: misoprostol < 400 vs other uterotonics1300Risk Ratio (M-H, Random, 95% CI)10.55 [0.62, 178.27]
4.7 Treatment: misoprostol vs placebo41874Risk Ratio (M-H, Random, 95% CI)2.88 [2.40, 3.47]
4.8 Treatment: misoprostol ≥ 600 µg vs other uterotonics21787Risk Ratio (M-H, Random, 95% CI)3.43 [0.61, 19.29]
Analysis 2.1.

Comparison 2 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator and indication, Outcome 1 Maternal deaths.

Analysis 2.2.

Comparison 2 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator and indication, Outcome 2 Maternal deaths or severe morbidity.

Analysis 2.3.

Comparison 2 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator and indication, Outcome 3 Maternal deaths or severe morbidity excluding hyperpyrexia.

Analysis 2.4.

Comparison 2 Misoprostol versus control (placebo or uterotonic) subgrouped by comparator and indication, Outcome 4 Pyrexia ≥ 38°C.

Comparison 3. Misoprostol vs control subgrouped by misoprostol dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maternal deaths3039731Risk Ratio (M-H, Fixed, 95% CI)2.08 [0.82, 5.28]
1.1 Misoprostol = or > 600 µg dose1832428Risk Ratio (M-H, Fixed, 95% CI)2.08 [0.82, 5.28]
1.2 Misoprostol = or < 400 µg dose127303Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Maternal deaths or severe morbidity2838534Risk Ratio (M-H, Random, 95% CI)1.43 [0.78, 2.64]
2.1 Misoprostol = or > 600 µg dose1933041Risk Ratio (M-H, Random, 95% CI)1.67 [0.80, 3.45]
2.2 Misoprostol = or < 400 µg dose95493Risk Ratio (M-H, Random, 95% CI)0.78 [0.28, 2.17]
3 Maternal deaths or severe morbidity (sensitivity analysis)2838534Risk Ratio (M-H, Fixed, 95% CI)2.45 [1.81, 3.32]
3.1 Misoprostol = or > 600 µg dose1933041Risk Ratio (M-H, Fixed, 95% CI)2.81 [2.04, 3.89]
3.2 Misoprostol = or < 400 µg dose95493Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.14, 1.46]
4 Maternal deaths or severe morbidity excluding hyperpyrexia2939127Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.67, 1.41]
4.1 Misoprostol = or > 600 µg dose2033634Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.67, 1.51]
4.2 Misoprostol = or < 400 µg dose95493Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.29, 2.12]
5 Pyrexia ≥ 38°C5550444Risk Ratio (M-H, Random, 95% CI)3.96 [3.11, 5.05]
5.1 Misoprostol = or > 600 µg dose2736025Risk Ratio (M-H, Random, 95% CI)4.64 [3.33, 6.46]
5.2 Misoprostol = or < 400 µg dose3114419Risk Ratio (M-H, Random, 95% CI)3.07 [2.25, 4.18]
Analysis 3.1.

Comparison 3 Misoprostol vs control subgrouped by misoprostol dose, Outcome 1 Maternal deaths.

Analysis 3.2.

Comparison 3 Misoprostol vs control subgrouped by misoprostol dose, Outcome 2 Maternal deaths or severe morbidity.

Analysis 3.3.

Comparison 3 Misoprostol vs control subgrouped by misoprostol dose, Outcome 3 Maternal deaths or severe morbidity (sensitivity analysis).

Analysis 3.4.

Comparison 3 Misoprostol vs control subgrouped by misoprostol dose, Outcome 4 Maternal deaths or severe morbidity excluding hyperpyrexia.

Analysis 3.5.

Comparison 3 Misoprostol vs control subgrouped by misoprostol dose, Outcome 5 Pyrexia ≥ 38°C.

Comparison 4. Misoprostol vs control subgrouped by route of administration
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maternal deaths3038391Risk Ratio (M-H, Fixed, 95% CI)2.08 [0.82, 5.28]
1.1 Oral1227572Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.33, 4.60]
1.2 Sublingual128361Risk Ratio (M-H, Fixed, 95% CI)2.51 [0.49, 12.86]
1.3 Rectal52220Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.4 mixed route1238Risk Ratio (M-H, Fixed, 95% CI)7.24 [0.38, 138.60]
2 Maternal deaths or severe morbidity2737567Risk Ratio (M-H, Random, 95% CI)1.55 [0.85, 2.83]
2.1 Oral927935Risk Ratio (M-H, Random, 95% CI)1.07 [0.60, 1.92]
2.2 Sublingual138420Risk Ratio (M-H, Random, 95% CI)2.20 [0.79, 6.16]
2.3 Rectal4974Risk Ratio (M-H, Random, 95% CI)0.37 [0.07, 1.99]
2.4 Mixed route1238Risk Ratio (M-H, Random, 95% CI)11.37 [0.64, 203.41]
3 Maternal deaths or severe morbidity excluding hyperpyrexia2737567Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.69, 1.48]
3.1 Oral927935Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.43, 1.51]
3.2 Sublingual138420Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.66, 1.99]
3.3 Rectal4974Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.07, 1.65]
3.4 Mixed route1238Risk Ratio (M-H, Fixed, 95% CI)11.37 [0.64, 203.41]
Analysis 4.1.

Comparison 4 Misoprostol vs control subgrouped by route of administration, Outcome 1 Maternal deaths.

Analysis 4.2.

Comparison 4 Misoprostol vs control subgrouped by route of administration, Outcome 2 Maternal deaths or severe morbidity.

Analysis 4.3.

Comparison 4 Misoprostol vs control subgrouped by route of administration, Outcome 3 Maternal deaths or severe morbidity excluding hyperpyrexia.

Appendices

Appendix 1. Risk of bias tool

(1) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); or

  • unclear risk of bias.   

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re-included missing data in the analyses which we undertook.

We assessed methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We assessed the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We assessed whether each study was free of other problems that could have put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we consider it likely to impact on the findings.  We explored the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis'. 

Contributions of authors

GJH conceived the review and developed the fist draft of the protocol. NN, AMG and GJH contributed to the development of the protocol. TL and GJH contributed to selection of studies and data extraction. GJH prepared the first draft of the review. All authors contributed to the final version of the review.

Declarations of interest

GJH and AMG have participated in trials eligible for consideration of inclusion in the review. They did not participate in decisions regarding such trials. GJH has received research funding from Gynuity, a non-profit organisation, for conducting a trial of misoprostol for preventing postpartum haemorrhage.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research, UK.

    Cochrane Review Incentive Scheme Award 12/183/03

Differences between protocol and review

An exploratory, non-prespecified, analysis of maternal death or severe morbidity excluding hyperpyrexia was conducted to determine whether the increase in maternal death nor severe morbidity with misoprostol was due entirely to increased hyperpyrexia.

For future versions of this review, we may reformulate the composite outcome 'maternal death or severe morbidity', possibly to include 'blood transfusions'. Furthermore, it may be of value to adapt the protocol to include studies of misoprostol use for retained placenta.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Australia 1999:400PO vs U

MethodsMulticentre parallel RCT conducted in Australia, Papua New Guinea and China.
ParticipantsWomen in labour, who were expected to deliver vaginally. Excluded if medical disease, CS or hypertension.
Interventions

PPH prevention study

Arm 1 (455 women): misoprostol 400 μg PO vs oxytocin (10 IU).
Arm 2 (475 women): oxytocin (5 IU) + ergometrine 0.5 mg IM

OutcomesBlood loss, PPH, Hb change, length of third stage, additional uterotonics, transfusion rates.
Notes

930 women were randomised; 865 received treatment. The main reason for not receiving treatment was CS or the development of hypertension.

Authors concluded that misoprostol was inferior to standard treatment to prevent PPH.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by table, in balanced blocks.
Allocation concealment (selection bias)Low riskSequentiallly numbered sealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Bangla 2007:400PO vs U

MethodsParallel, open-label, RCT conducted in a tertiary hospital in Dhaka, Bangladesh between Jan 2003 to Dec 2003.
ParticipantsWomen in labour with a singleton, vertex presentation. Induced, augmented and spontaneous labour was included. Excluded if there was a known risk of PPH or if there had been a previous CS birth.
Interventions

PPH prevention study

Arm 1 (210 women): misoprostol 400 µg PO.

Arm 2: (190 women): oxytocin 10 IU IM.

OutcomesPPH, duration of 3rd stage, estimated blood loss, additional oxytocics, blood transfusion and retained placenta.
Notes

2 women in the misoprostol group and 1 woman in the oxytocin group required manual removal of the placenta. No other morbidity/mortality data were reported.

In the report, the numbers of women with fever were combined with the number of women with diarrhoea (4 in misoprostol group vs 2 in oxy group). Shivering was significantly more frequent in the misoprostol group (13 vs 2 women; P < 0.01).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data noted except for the number of women evaluated for the duration of the 3rd stage of labour, which is not stated on Table-V.
Selective reporting (reporting bias)Low riskMost expected outcomes reported.
Other biasUnclear riskIt is stated that demographic and labour characteristics were 'well-balanced and comparable' however these data are not presented.

Belgium 1999:600PO vs U

MethodsDouble-blind parallel RCT; Dec 1997 to April 1998.
Participants200 pregnant women expecting a vaginal birth from 32+ weeks. Excluded if CS, hypertensive disorders, gestational age < 32 weeks, intrauterine death, uterine malformations, allergy to prostaglandins or alkaloids, inflammatory bowel disease, obliterative vascular and coronary disease and sepsis.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 600 μg PO.

Arm 2 (100 women): methylergometrine 200 μg IV.

OutcomesNeed for further oxytocic drugs, blood pressure, side effects, mean Hb and haematocrit three days after birth.
Notes213 enrolled; 13 excluded after randomisation due to the need for CS or failure to collect blood samples. Authors concluded that misoprostol was associated with more side effects.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer; blocks allocation from computer-generated list of study numbers.
Allocation concealment (selection bias)Low riskIdentical study boxes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk< 20% attrition.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

BETV 2010:800SL vs U

MethodsDouble-blind, parallel, non-inferiority RCT. Enrolment between Aug 2005 to Jan 2008 at 5 hospitals in Burkino Faso, Egypt, Turkey and Vietnam (2 secondary and 3 tertiary-care).
Participants809 women with PPH following active management of 3rd stage of labour with oxytocin. PPH defined by EBL of 700 mL in calibrated drape or clinical judgment. Excluded if PPH not due to uterine atony, if oxytocin not received in 3rd stage or if mode of delivery was CS.
Interventions

PPH treatment study

Arm 1 (407 women): misoprostol 800 SL + placebo (saline infusion over 15 min).

Arm 2 (402 women): 40 IU oxytocin infusion over 15 min + placebo (4 x SL tablets).

OutcomesCessation of active bleeding within 20 min; additional blood loss ≥ 300 mL; time to active bleeding controlled; additional blood loss (mL); additional blood loss ≥ 500 mL; total blood loss; additional interventions.
Notes

A well-conducted study. Investigators concluded that '800 µg sublingual misoprostol is a viable alternative to 40 IU IV oxytocin for treatment of primary PPH after oxytocin prophylaxis during the third stage of labour. Misoprostol stopped bleeding as rapidly as did oxytocin and with a similar quantity of additional blood loss. Although rare for both groups, women given misoprostol were more likely to bleed an additional 1000 mL or more than were those given oxytocin.'

Active bleeding was controlled within 20 min in 363 (89%) of women in the misoprostol group and 360 (90%) of women in the oxytocin group (RR 0.99, 95% CI 0.95 to 1.04), however, women given misoprostol were more likely to undergo intrauterine exploration under anaesthesia than were those given oxytocin (RR 1·66 95% CI 1·00 to 2·76).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated in blocks of 10. Code revealed after data collection.
Allocation concealment (selection bias)Low riskSealed and numbered opaque boxes opened in sequence.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskCode revealed after data collection.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals or missing data.
Selective reporting (reporting bias)Low riskReported according to CONSORT. All expected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Canada 2002:400PR vs U

MethodsRCT conducted in 3 teaching hospitals in Toronto.
ParticipantsWomen in labour > 32 weeks with no known risk for PPH, vertex presentation, no previous CS.
Interventions

PPH prevention study

Arm 1 (110 women): misoprostol 400 μg PR after delivery.

Arm 2 (113 women): oxytocin 5 IU IV or IM, or 10 IU IM.

OutcomesBlood loss, Hb, haematocrit difference, duration of third stage, manual removal of placenta, side effects, blood transfusion.
NotesAuthors concluded that rectal misoprostol is equivalent to IV oxytocin for prevention of PPH.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentral centre statistician performed block randomisation for participating centres.
Allocation concealment (selection bias)Low riskNumbered, opaque, sealed packs.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Canada 2007:400PO vs U

MethodsParallel RCT conducted in Nova Scotia; recruitment October 2000 to February 2004.
Participants622 women in labour with singleton, vertex pregnancy. Excluded if placenta previa, abruptio placentae, coagulation abnormalities, unstable asthma, and CS.
Interventions

PPH prevention study

Arm 1 (311 women): misoprostol 400 μg PO.

Arm 2 (311 women): oxytocin 5 IU IV.

OutcomesHaematocrit drop > 10%, Hb, use of additional oxytocin, blood loss > 1000 mL, blood transfusion, manual removal of placenta, side effects.
NotesAuthors concluded that 'the routine use of 400 μg oral misoprostol was no less effective than 5 U of IV oxytocin in reducing blood loss after delivery, as assessed by change in postpartum hematocrit. The adverse effects of misoprostol were mild'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskAll expected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

China 2001:600PO vs U

MethodsParallel RCT.
Participants2058 women with singleton pregnancy and a vaginal birth.
Interventions

PPH prevention study

Arm 1 (1026 women): misoprostol 600 µg PO.

Arm 2 (1032 women): oxytocin 5 IU + ergometrine 0.5 mg IM.

OutcomesBlood loss, need for additional oxytocin, side effects.
NotesAuthors concluded that 'Misoprostol may be used as an alternative to intra-muscular oxytocin. However there is a need for additional oxytocics'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot clear.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

China 2003:400PO vs N

MethodsNon-blinded RCT conducted in China between October 2002 to April 2003.
ParticipantsWomen with uncomplicated pregnancy and birth. excluded if pregnancy complications, CS, coagulation disorders or allergy to misoprostol.
Interventions

PPH prevention study

Arm 1 (80 women): misoprostol 400 µg (200 µg immediately after delivery and 200 µg 60 min later).

Arm 2 (76 women): no additional treatment.

OutcomesPPH (defined as EBL ≥ 400 mL in the 2 hours following delivery), mean blood loss, adverse effects.
NotesMethods unclear in general, therefore potentially high risk of bias. We were unable to contact the authors for clarification.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk'randomly assigned'.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded; no placebo.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded; no placebo.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing data for the study’s primary outcome but side-effect data were not clearly described.
Selective reporting (reporting bias)High riskSide effects were not reported in detail. Morbidity and mortality were not reported.
Other biasUnclear riskMethods unclear in general, therefore potentially high risk of bias.

China 2004a:600SL vs U

MethodsParallel RCT.
ParticipantsHealthy women with singleton pregnancies at term. Excluded if: increased risk of PPH; labour augmentation.
Interventions

PPH prevention study

Arm 1 (30 women):M 600 μg SL.

Arm 2 (30 women):syntocinon 5 IU + ergometrine 0.5 mg IV.

OutcomesBlood loss, PPH, additional oxytocin, side effects.
NotesAuthors concluded that 'the use of sublingual misoprostol or IV syntometrine in spontaneous vaginal delivery resulted in a comparable amount of blood loss'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by random numbers table.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

China 2004b:400PO vs P

MethodsDouble-blind RCT.
Participants326 women.
Interventions

PPH prevention study

Arm 1: 400 μg PO.

Arm 2: oral placebo.

All women received syntometrine 1 ampoule IM.

OutcomesHb change, blood loss > 500 or 1000 mL, additional oxytocin, side effects.
NotesAuthors concluded that 'misoprostol in addition to standard intramuscular syntometrine does not confer extra benefits over intramuscular syntometrine alone'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOnly conference abstract available. Number of women in each arm and withdrawals/missing data not stated.
Selective reporting (reporting bias)Unclear riskNot assessable. Only conference abstract available.
Other biasLow risk'Demographic characteristics were similar in both groups.'

China 2007:400PO vs U

MethodsParallel double-blind RCT conducted between April 200 and January 2001 in a tertiary hospital in Hong Kong.
ParticipantsWomen with a singleton pregnancy beyond 34 weeks of gestation, low risk for PPH and expecting a vaginal birth. Excluded if fibroids, polyhydramnios, fetal macrosomia or any significant history of antepartum haemorrhage.
Interventions

PPH prevention study

Arm 1 (178 women): misoprostol 400 µg PO.

Arm 2 (177 women): syntometrine 1 ampoule IM.

OutcomesChange in Hb, blood transfusion, blood loss, manual removal of placenta, need for additional oxytocin, side effects.
NotesAuthors concluded that 'orally administered misoprostol at a dose of 400 µg is an acceptable alternative in preventing postpartum blood loss, as measured by the peri-partum change in hemoglobin level and was not associated with an increased incidence of side effects.'
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
High riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk5 post randomisation exclusions due to missing Hb levels. All had blood loss < 500 mL.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Colombia 2002:50SL vs U

Methods3-arm RCT.
ParticipantsWomen delivering vaginally.
Interventions

PPH prevention study

Arm 1 (25 women): misoprostol 50 μg SL.

Arm 2 (25 women): oxytocin 16 mLU/min IV.

Arm 3 (25 women): methylergometrine 0.2 mg IM.

OutcomesBlood loss, side effects.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasUnclear riskMore augmentations in oxytocin group.

EEV 2010:800SL vs U

MethodsDouble-blind, non-inferiority, parallel RCT conducted in Ecuador, Egypt and Vietnam.
ParticipantsWomen with PPH due to uterine atony who had not received a uterotonic drug during labour. Women were excluded if the mode of birth was CS, if they had received a uterotonic drug during labour, had delivered outside the study site, were allergic to prostaglandin, or had PPH due to other causes.
Interventions

PPH treatment study

Arm 1 (448): misoprostol 800 µg SL + saline (placebo) IV infusion.

Arm 2 (490): oxytocin 40 IU IV infusion + 4 SL (placebo) tablets.

OutcomesCessation of active bleeding within 20 min, additional blood loss, and side effects.
NotesA well-designed and conducted study. Significantly more women in the misoprostol group needed blood transfusions compared with the oxytocin group: 41/488 (8%) vs 26/490 (5%), respectively. Most cases (58 of 66) of high fever (≥ 40°) were documented at the site in Ecuador.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random allocation sequence in blocks of 10.
Allocation concealment (selection bias)Low riskConsecutively numbered, sealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskActive treatment was administered with a matching placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Randomisation code was broken on completion of data collection. Code was held centrally.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected and prespecified outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Egypt 2009:800PR vs U

MethodsDouble-blind, parallel RCT conducted in a university hospital in Egypt.
Participants

514 women with spontaneous normal birth of a live, singleton neonate and absence of any contraindications for misoprostol or oxytocin use.

Women were excluded if they delivered by CS; or had a history of antepartum haemorrhage or bleeding tendency; or hypertensive disorder of pregnancy.

Interventions

PPH prevention study

Arm 1 (257 women): misoprostol 800 µg PR + 5 mL saline (placebo) IV injection.

Arm 2: (257 women) oxytocin 5 IU IV injection + rectal (placebo) suppository.

OutcomesBlood loss ≥ 500 mL; additional uterotonics; blood transfusion required; drop in haematocrit ≥ 10%.
Notes

A well-conducted study. Investigators found no statistically significant difference between the groups in the need for blood transfusions,additional uterotonics or haematocrit change. They concluded that routine use of 800 μg of rectal misoprostol is effective in reducing blood loss after delivery.

We obtained additional unpublished data relating to morbidity from the investigators. There were no women in either group who needed major surgery or ICU admission, nor did any have hyperpyrexia, massive bleeding over 1000 mL or major organ failure.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation.
Allocation concealment (selection bias)Low riskSealed, opaque, consecutively numbered envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind: active drug plus similar placebo alternative administered to both intervention groups.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Randomisation code broken on completion of the study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals or loss to follow-up.
Selective reporting (reporting bias)Low riskAll expected outcomes reported (including some unpublished data).
Other biasLow riskBaseline characteristics were similar.

Egypt 2012a:CS400PR vs P

MethodsOpen-label RCT conducted in Egypt.
ParticipantsPregnant women were included if they were 39+ weeks of pregnancy, uncomplicated singleton pregnancy, up to fifth parity, and scheduled elective repeat CS. Excluded 'if it was speculated that the indication for c/section....might interfere with results'.
Interventions

PPH prevention study

Arm 1 (200 women): misoprostol 400 µg PR.

Arm 2 (200 women): placebo 2 tabs PR.

All participants received 10 IU oxytocin after cord clamping.

OutcomesBlood loss, neonatal outcomes including Apgar scores.
NotesLittle usable data. Morbidity and mortality data were not reported and could not be obtained from authors.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated tables.
Allocation concealment (selection bias)Low riskSealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Egypt 2012b:CS400SL vs P

MethodsParallel RCT conducted in Egypt.
Participants18-35 year old women with uncomplicated singleton pregnancies of at least 36 weeks’ gestation scheduled for elective CS via a Pfannenstiel incision under general anaesthesia. Excluded if allergy to prostaglandins, bronchial asthma, anaemia, bleeding disorders, cardiac, inflammatory bowel disease, with multiple pregnancies, pre-eclampsia, placenta previa, abruptio placenta, previous PPH, antepartum haemorrhage, with the presence of conditions requiring prophylactic oxytocin infusion after delivery such as grand multiparity (parity ≥ 4), presence of uterine fibroids, evidence of intrauterine growth restriction or other fetal abnormality.
Interventions

PPH prevention study

Arm 1 (191 women): misoprostol 400 µg SL.

Arm 2 (191 women): placebo 2 tabs SL.

All women received a 10 IU oxytocin infusion after cord clamping.

OutcomesBlood loss, uterine tone, need for additional oxytocics and Apgar scores.
NotesAuthors concluded that 'preoperative administration of sublingual misoprostol 400 µg is safe and effective in attenuating the maternal bleeding and uterine atony from isoflurane anaesthesia for cesarean delivery'. Morbidity and mortality data were not reported but obtained from authors.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 women in the placebo arm and 12 in misoprostol arm had missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

France 2001:600PO vsP vsU

Methods3-arm RCT conducted in Amiens, France, from November 1999 to June 2000.
Participants602 women in labour. Excluded if < 32 weeks, previous haemorrhage during birth, fetal death in utero, multiple pregnancy, pre-eclampsia, CS.
Interventions

PPH prevention study

Arm 1 (186 women): misoprostol 600 μg PO.

Arm 2 (196 women): oxytocin 2.5 IU IV.

Arm 3 (220 women): no uterotonic.

OutcomesBlood loss, PPH, Hb change, side effects.
NotesAuthors reported 46% less PPH in the oxytocin group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by drawn envelopes containing treatment codes.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo drop outs or withdrawals reported.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasUnclear riskNot clear.

Gambia 2004:600PO/SL vs P

MethodsParallel RCT.
Participants160 women with PPH following delivery due to uterine atony. Exclude if CS, blood loss < 500 mL in the first hour after delivery, birth < 28 weeks of gestation.
Interventions

PPH treatment study

Arm 1 (79 women): misoprostol 600 µg (200 PO and 400 SL).

Arm 2 (81 women): placebo.

OutcomesBlood loss, side effects, additional uterotonics, postpartum Hb.
NotesAuthors stated that 'No severe side effects were noted in the use of misoprostol'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Low riskSequentially numbered opaque packs.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskTablets were similar but had different shapes so personnel might have been aware of group allocation.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot adequately blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Gambia 2005:600PO vs U

MethodsDouble-blind RCT in home birth setting of 26 villages in rural Gambia.
Participants1229 women undergoing home births with a traditional birth attendant.
Interventions

PPH prevention study

Arm 1 (630 women): misoprostol 600 μg PO plus placebo.

Arm 2 (599 women): placebo plus ergometrine (2 mg).

OutcomesBlood loss, postpartum Hb, Hb change, side effects, maternal deaths.
Notes

2 maternal deaths in the misoprostol arm.

Authors concluded that 'Six hundred micrograms of oral misoprostol is a promising drug to prevent life-threatening PPH in this setting'.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Low riskSequentially numbered opaque sealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Ghana 2000:400PO vs U

MethodsDouble-blind parallel RCT conducted in a university hospital in Accra, Ghana between June 1998 and May 1999.
Participants401 women expecting normal vaginal birth. Excluded if risk factors for PPH were present, including grand multipara and multiple gestation.
Interventions

PPH prevention study

Arm 1 (203 women): misoprostol 400 μg in powdered form PO (in 50 mL of water) and 1 mL IM injection of normal saline (placebo).

Arm 2 (198 women): lactose placebo PO (in 50 mL of water) and 1 mL IM 10 IU oxytocin.

OutcomesPostpartum Hb, Hb change, estimated blood loss, manual removal of placenta, blood transfusion, side effects.
NotesAuthors concluded that misoprostol is as effective as oxytocin in minimising blood loss.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Low riskSequential numbered opaque envelope.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk9 women did not have Hb results.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasUnclear riskBaseline characteristics were similar.

Ghana 2006: 800PR vs U

MethodsRCT conducted at district hospitals in Ghana.
Participants450 women in advanced labour. Excluded if there was a medical contraindication to prostaglandins.
Interventions

PPH prevention study

Arm 1 (224 women): misoprostol 800 µg PR.

Arm 2 (226 women): oxytocin 10 IU IM.

OutcomesPostpartum Hb, Hb change, PPH, estimated blood loss, blood transfusion, side effects, maternal mortality.
NotesAuthors concluded that misoprostol is effective.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by computer.
Allocation concealment (selection bias)Low riskSequentially numbered opaque sealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition. 10 women did not have Hb results.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Guinea-B 2005:600SL vs P

MethodsLocal health centres in Guinea-Bissau between March 2003 and August 2004.
Participants661 women giving birth at a participating health centre.
Interventions

PPH prevention study

Arm 1 (330 women): misoprostol 600 µg SL.

Arm 2 (331 women): identical placebo.

OutcomesPPH, blood loss > 1000 mL, Hb drop, side effects.
Notes

1 maternal death from PPH in the misoprostol arm.

Authors conclude that 'Sublingual misoprostol reduces the frequency of severe PPH'.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by random numbers list.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2004a:400SL vs U

MethodsParallel RCT conducted in New Delhi, India
ParticipantsLow risk pregnant women at term with spontaneous onset of labour.
Interventions

PPH prevention study

Arm 1 (60 women): misoprostol 400 μg SL.

Arm 2 (60 women): methylergometrine 0.2 mg IV.

OutcomesPPH, blood loss, side effects
NotesAuthors concluded that SL misoprostol appears to be as effective as IV methylergometrine in the prevention of PPH.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk'randomized'.
Allocation concealment (selection bias)Unclear riskSealed, consecutively numbered envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2005:600PO vs U

MethodsParallel RCT conducted in New Delhi, India, 2002 to 2003.
ParticipantsPrimigravidas with singleton pregnancy undergoing vaginal birth.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 600 μg PO.
Arm 2 (100 women): methylergometrine 0.2 mg IV.

OutcomesPostpartum Hb, Hb change, PPH, blood loss, haematocrit, blood transfusion, side effects, additional oxytocic and manual removal of placenta.
NotesAuthors concluded that misoprostol was as effective as methylergometrine in the management of third stage of labour.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk'random allocation' by random number sequence.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDenominators not stated in tables. Withdrawals not stated.
Selective reporting (reporting bias)Unclear riskExpected outcomes reported but denominators not clearly stated in tables.
Other biasUnclear riskBrief report.

India 2006a:CS400SL vs U

MethodsParallel RCT conducted in New Delhi, India between August 2004 to August 2005.
ParticipantsPregnancy women delivering by CS under regional anaesthesia. Women with high risk factors for PPH excluded.
Interventions

PPH prevention study

Arm 1 (50 women): misoprostol 400 μg SL.

Arm 2 (50 women): 20 IU oxytocin in 1 L lactated Ringer’s solution at 125 mL/hour.

OutcomesPostpartum Hb, Hb change, blood loss, haematocrit, side effects, additional oxytocic.
NotesAuthors concluded that 'Sublingual misoprostol appears to be as effective as IV infusion of oxytocin in reducing blood loss at cesarean section'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals after randomisation.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2006b:400PO vs U

Methods3-arm RCT conducted in Vellore, India.
Participants2023 women in labour.
Interventions

PPH prevention study

Arm 1 (730 women): misoprostol 400 μg PO.

Arm 2 (617 women): oxytocin 10 IU IM.

Arm 3 (676 women): ergometrine 0.2 mg IV.

OutcomesMean blood loss, rates of blood loss between 500 and 1000 mL, hematocrit fall greater than 10%, need for additional oxytocics, side effects.
NotesAuthors concluded that 'Oral misoprostol is as effective as conventional oxytocic agents in preventing postpartum haemorrhage and can be recommended for use in low-resource settings'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasUnclear riskGroup sizes unbalanced but baseline characteristics were similar.

India 2006c:600PO vs P

MethodsParallel RCT conducted in rural India between September 2002 and December 2005.
ParticipantsWomen in third stage of labour having home or health centre births. Excluded if previous CS or high risk for PPH or pregnancy complications.
Interventions

PPH prevention study

Arm 1 (812 women): M 600 μg PO.

Arm 2 (808 women): identical placebos.

OutcomesPPH, mean blood loss, side effects, transfer, surgery, ICU.
NotesAuthors concluded that 'Oral misoprostol was associated with significant decreases in the rate of acute PPH'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low risk'non-distinguishable envelopes.'
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinded.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasUnclear riskBaseline characteristics were similar.

India 2006d:400PR vs U

MethodsConducted in a rural health centre in India.
ParticipantsWomen in labour at term. Excluded if oxytocin induction or augmentation of labour, CS, pregnancy duration less than 37 weeks, multiple pregnancy, Hb concentration less than 8 g/dL, and known allergy to prostaglandins.
Interventions

PPH prevention study

Arm 1 (60 women): misoprostol 400 µg PR.

Arm 2 (60 women): carboprost 125 µg IM.

OutcomesPPH, mean blood loss, side effects, need for additional oxytocics.
NotesAuthors concluded that 'Two tablets (400 µg) of misoprostol intrarectally appear to be as effective as 125 Ag of 15-methyl prostaglandin F2a intramuscularly'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInterventions administered “randomly”.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2006e:400SL vs U

MethodsDouble-blind RCT conducted in India in 2005/6.
ParticipantsWomen in labour at low risk of PPH.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 400 µg SL.

Arm 2 (100 women): ergometrine 0.2 mg IM.

OutcomesPostpartum Hb, Hb change, PPH, blood loss, haematocrit, blood transfusion, side effects, additional oxytocic and manual removal of placenta.
NotesAuthors concluded that 'SL misoprostol is easy to administer by trained birth attendants with minimal side effects...'
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2006f:600PR vs U

MethodsPilot RCT conducted in Chandigarh, India.
Participants200 women in spontaneous labour.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 600 µg PR.

Arm 2 (100 women): oxytocin 10 IU IM.

OutcomesHb change, PPH, blood loss, side effects, additional oxytocic and manual removal of placenta.
NotesAuthors concluded that 'Our pilot study supports the hypothesis that 600 µg misoprostol administered rectally is an effective and safe alternative to oxytocin'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo evidence of missing data.
Selective reporting (reporting bias)Unclear riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were stated as similar.

India 2008:100/200SL vsU

MethodsRandomised non-blinded 3-arm RCT conducted in a rural tertiary hospital in India.
ParticipantsWomen with spontaneous onset of labour at term. Excluded if grand multiparity (parity > 5), multiple gestation, pregnancy-induced hypertension, antepartum haemorrhage, labour induction or augmentation, CS (past/present), Hb concentration of < 8 gm/dL or other obstetric problems and known hypersensitivity to prostaglandins.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 100 µg SL.

Arm 2 (100 women): misoprostol 200 µg SL.

Arm 3 (100 women): ergometrine 0.2 mg IV.

OutcomesBlood, loss, duration of 3rd stage, additional uterotonics, side effects.
Notes

Investigators concluded that 'a low dose of sublingual misoprostol appears to be as effective as a low dose of IV methylergometrine in the prevention of post-partum haemorrhage in low-risk cases’.

Crude assessments of blood loss were used in this study. 

We combined data from the 2 misoprostol arms (100 µg and 200 µg) where we considered it to be clinically meaningful. Morbidity and mortality data were requested by email on the 11/1/13.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskDivided into 3 groups using random number tables.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing data not clear as denominators were absent from tables.
Selective reporting (reporting bias)Low riskAll expected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

India 2009:400/600SL vsU

MethodsDouble-blind, parallel, 4-arm RCT conducted in a university hospital in India.
Participants300 women in labour with a healthy singleton pregnancy at term. Excluded if known hypersensitivity/contraindication to prostaglandins, intrauterine fetal demise, antepartum haemorrhage, multiple pregnancy, malpresentation, cardiac disease, Rhesus-negative mother, hypertensive disorders, and severe anaemia (Hb 7 g/dL).
Interventions

PPH prevention study

Arm 1 (75 women): misoprostol 400 µg SL plus IM placebo and SL placebo (x1).

Arm 2 (75 women): 600 µg SL plus IM placebo.

Arm 3 (75 women): oxytocin 5 IU IV plus SL placebo (x3).

Arm 4 (75 women): ergometrine 0.2 mg IV plus SL placebo (x3).

OutcomesBlood loss, 3rd stage duration, need for additional oxytocics, adverse effects.
Notes

For the purposes of this review, dichotomous data for arms 1 and 2 were combined for mortality and morbidity outcomes where clinically meaningful, (i.e. misoprostol groups vs other uterotonics). Morbidity and mortality data were requested on 10/1/13 by email.

Investigators concluded that 'Administration of 600 µg of sublingual misoprostol was more effective than 400 µg of misoprostol, IV oxytocin, and IV ergometrine for the AMTSL'.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers.
Allocation concealment (selection bias)Low riskSequential identical packets containing matched medication.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. Each packet contained 3 identical tablets, a 2-mL syringe with a needle, and a 1-mL ampoule.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing data for primary outcomes. Morbidity and mortality data requested.
Selective reporting (reporting bias)Unclear riskNot all pre-specified outcomes were clearly reported. Additional data requested.
Other biasLow riskBaseline characteristics were similar in the 4 groups.

India 2009:400SL vs U

MethodsRCT with 3 parallel study arms, conducted in a tertiary hospital in India.
ParticipantsPregnant women at ≥ 32 weeks of gestation with either spontaneous or induced labour were eligible to participate in the study. Excluded if grandmultipara (≥ 5), multiple gestation, < 32 weeks of gestation, HELLP syndrome, hydramnios, known blood coagulation disorders, history of asthma or drug allergy, heart disease, severe renal disease, epilepsy, hypertension and Hb concentration < 8 g%.
Interventions

PPH prevention study

Arm 1 (66 women): misoprostol 400 µg SL.

Arm 2 (67 women): ergometrine 0.2 mg IM.

Arm 3 (67 women): PGF2α 0.125 mg IM.

OutcomesBlood loss more than 500 mL, need for additional oxytoxic drug, change in Hb level, and side effects.
Notes

Data were extracted for the misoprostol vs ergometrine groups only.

Vomiting occurred significantly more frequently in the misoprostol group than the ergometrine group (8/66 vs 1/67; P = 0.006), as did shivering.

Investigators concluded that 'sublingual misoprostol appears to be as effective as intramuscular methylergometrine and intramuscular 15-methyl PGF2α in the prevention of PPH'. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskAll expected outcomes reported. Additional morbidity data requested.
Other biasLow riskBaseline characteristics were similar.

India 2010:CS800PR vs U

MethodsParallel double-blind RCT conducted in a hospital in Kolkata, India, from December 2007 to May 2009.
ParticipantsWomen with term pregnancy undergoing CS. Excluded if there were risk factors for PPH; cardiovascular, respiratory or hepatic disease; 2 or more previous CS, fetal distress, or known hypersensitivity to prostaglandin.
Interventions

Prevention study

Arm 1 (100 women): misoprostol 800 µg (4 tabs) PR plus 8 ampoules of placebo IVI.

Arm 2 (100 women): oxytocin 40 IU IVI plus 4 x placebo tablets PR.

OutcomesBlood loss and side effects.
Notes5 women in the control group and 1 woman in the misoprostol group were excluded from analyses because of traumatic intra-operative bleeding (5) and placenta accreta (1). We added these data back in.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers in 1:1 ratio.
Allocation concealment (selection bias)Low riskSealed opaque packets.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing data. 5 women in the control group and 1 woman in the misoprostol group were excluded from analyses because of traumatic intra-operative bleeding (5) and placenta accreta (1). We added these data back in.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2012:CS400SL vs P

MethodsParallel RCT conducted in a military hospital in Uttar Pradesh, India from June 2003 and July 2005.
ParticipantsWomen undergoing emergency or elective CS.
Interventions

PPH prevention study

Arm 1 (90 women): misoprostol 400 µg SL.

Arm 2 (84 women): placebo.

All women received an IV infusion of oxytocin 20 U in 1000 mL saline solution was started at 10 mL/min for 30 min, which was followed by 2.0 mL/min for 6 hours.

OutcomesBlood loss > 500 mL and 1000 mL, need for additional oxytoxic drug, change in Hb, and side effects.
Notes

Authors concluded that 'Sublingual misoprostol reduces intraoperative blood loss and the need for additional uterotonic agents at cesarean birth'.

Authors emailed to confirm no deaths (1/3/13).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque packets.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

India 2012a:400SL vs U

MethodsDouble-blind, parallel, RCT conducted from Sept 2009 to August 2010 at a teaching hospital in India.
Participants

Women with spontaneous vaginal birth of a singleton neonate, vertex presentation, and absence of any contraindications for misoprostol or oxytocin use.

Excluded if they had known risk factors for PPH, including obesity, grand multiparity (> 4), polyhydramnios, fetal macrosomia, prepartum haemorrhage, prolonged labour, labour augmented by oxytocin infusion, instrumental delivery, or history of PPH in previous pregnancy, anaemia (Hb level b8 g/dL), severe pre-eclampsia, bronchial asthma, coagulopathy, previous CS, cardiovascular, respiratory, liver or haematological disease, and known hypersensitivity to prostaglandin.

Interventions

PPH prevention study

Arm 1 (265 women): misoprostol 400 µg SL plus placebo injection (distilled water).

Arm 2 (265 women): oxytocin 10 IU IM plus placebo tablets SL.

OutcomesBlood loss, PPH, Hb change, need for additional uterotonics, adverse effects and complications, need for blood transfusion.
Notes

A well-conducted study.

Investigators concluded that '400 µg of sublingual misoprostol was a safe and effective alternative to 10 units of intramuscular oxytocin in the routine management of third stage labour for prevention of PPH among low-risk women. Larger studies involving a high-risk population are essential to establish the efficacy and potential benefits of the sublingual route of misoprostol administration'.  

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random number sequence.
Allocation concealment (selection bias)Low riskPre-prepared, sealed opaque packets containing the unlabelled treatments.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. Active drug plus identical placebos given.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Active drug plus identical placebos given.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo post-randomisation exclusions. Three women were lost to follow-up.
Selective reporting (reporting bias)Low riskAll expected outcomes reported. (Confirmation requested 8/1/13 that there was no severe morbidity.)
Other biasLow riskBaseline characteristics were similar.

India 2012b:400SL vs U

MethodsDouble-blind placebo-controlled, parallel RCT conducted in a teaching hospital in India.
ParticipantsWomen with a singleton pregnancy at > 28 weeks of gestation, cephalic presentation, anticipating a normal spontaneous vaginal birth. Excluded instrumental birth, women with medical disorders, and stillbirths.
Interventions

PPH prevention study

Arm 1 (321 women): misoprostol 400 µg SL powdered form plus 2 mL placebo injection.

Arm 2 (331 women): 10 IU oxytocin IM plus powdered SL placebo.

OutcomesMean blood loss, PPH and side effects.
Notes

Investigators concluded that 'Sublingual powdered misoprostol is more effective than IM oxytocin in reducing the blood loss. All side effects, including fever, were short-lived and required no medical intervention'.

Additional morbidity data were requested on the 11/1/13 by email.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation.
Allocation concealment (selection bias)Low riskThe study medications and placebos were packaged in appropriately coded envelopes by administrative staff from the pharmacy.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, placebo-controlled. Placebo (starch) powder was handled and coded in the same manner as the misoprostol powder and injections looked identical.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAn independent clinical pharmacist prepared and maintained the concealed randomisation list.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Indonesia 2002:600PO vs U

MethodsRCT.
ParticipantsPregnant women at term undergoing vaginal birth.
Interventions

PPH prevention study

Arm 1 (98 women): misoprostol 600 μg PO.

Arm 2 (98 women): oxytocin 10 IU IM.

OutcomesMean blood loss, PPH and side effects.
NotesConference abstract only.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo denominators given with results.
Selective reporting (reporting bias)Unclear riskConference abstract only.
Other biasUnclear riskConference abstract only.

Iran 2009:CS400SL vs U

MethodsOpen-label, parallel RCT conducted in an Iranian Hospital between Aug and Dec 2007.
ParticipantsWomen with singleton term pregnancies undergoing CS were included. Women with an additional risk for post-caesarean haemorrhage, including: multiple gestation, prolonged labour of more than 12 hours, 2 or more previous CS, a history of uterine rupture and anaemia were excluded.
Interventions

Prevention study

Arm 1 (50 women): misoprostol 400 µg SL.

Arm 2 (50 women): oxytocin 20 IU IV.

OutcomesBlood loss, additional uterotonic, side effects, blood transfusion.
NotesMorbidity and mortality data were requested but not obtained.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk'Simple randomisation'.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDenominators not given.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasLow riskBaseline differences were similar.

Jamaica 2009:400PR vs U

MethodsParallel, open-label RCT conducted in a Jamaican university hospital.
ParticipantsWomen in labour. Excluded if previous PPH, hypertensive disorders, previous CS, IUD, fever > 38◦C, APH or anaemia.
Interventions

PPH prevention study

Arm 1 (70 women): misoprostol 400 µg PR.

Arm 2 (70 women): syntometrine IMI (10 IU oxytocin +0.5 mg ergometrine).

OutcomesPPH, measured blood loss up to 1 hour postpartum, need for additional uterotonics, adverse effects.
Notes

Oxytocin was used in the first and second stages of labour in almost half of the women in both groups.

2 participants experienced severe lower abdominal pain 1 hour after misoprostol insertion that responded to meperidine hydrochloride.

The investigators concluded that the clinical effect of misoprostol 400 µg PR is similar to standard therapy with syntometrine and is well-tolerated.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated block randomisation.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data. Although the total number of participants in each arm is omitted in the data tables, it is stated in the text that 'All one hundred and forty participants completed the study', 70 in each group.
Selective reporting (reporting bias)Low riskAll pre-specified outcomes reported. Additional data requested 7/1/13.
Other biasLow riskBaseline characteristics were similar.

Korea 2007:CS400PR vs P

MethodsParallel RCT conducted in a university hospital in Korea.
ParticipantsWomen undergoing CS for delivery.
Interventions

PPH prevention study

Arm 1 (96 women): misoprostol 400 µg PR.

Arm 2 (118 women): lactose placebo 20 IU.

OutcomesPPH, blood loss, haematocrit change, additional oxytocin, fever.
NotesNo mortality data. We were unable to contact authors for more details.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDescribed as 'randomised'.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskTotal number enrolled not given in abstract.
Selective reporting (reporting bias)Unclear riskOnly the abstract was available.
Other biasUnclear riskOnly the abstract was available. The sizes of the treatment groups were unbalanced.

Mexico 2009:CS800IU vs P

MethodsParallel RCT with women recruited from the “Hospital de Ginecología y Obstetricia de Monterrey” in Mexico.
ParticipantsWomen with term single or multiple pregnancy requiring CS. 'We excluded if placenta previa, blood dyscrasia or myomatosis, and women with 'obstetrical haemorrhage caused by uterine lacerations'.
Interventions

PPH prevention study

Arm 1 (100 women): 800 µg intra-uterine after removal of the placenta.

Arm 2 (100 women): similar placebo tablets (sorbitol) intra-uterine (IU).

All women in both groups also received 20 IU oxytocin IVI over 15 min.

OutcomesHb and haematocrit change, pain, fever, shivers, nausea, vomiting, blood pressure change.
Notes

Little usable data. Morbidity and mortality data not reported and we were unable to contact the authors.

The authors concluded that 'administering misoprostol combined with oxytocin by intrauterine route reduces post-caesarean blood loss and produces few side effects'.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk'The tablets were placed in 200 separate envelopes and assigned a number that was chosen randomly.'
Allocation concealment (selection bias)Low risk'The content of the envelopes were not revealed until the end of the study.'
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Mozam 2001:400PR vs U

MethodsDouble-blind parallel RCT conducted in Maputo.
Participants700 women with uncomplicated vaginal birth (30 to 42 weeks' gestation). Induction/augmentation excluded.
Interventions

PPH prevention study

Arm 1 (324 women): misoprostol 400 µg dissolved in 5 mL saline PR as a microenema + 1 mL saline placebo.
Arm 2 (339 women): IM vs oxytocin 10 IU IM + 5 mL saline microenema (placebo).

OutcomesPPH, blood loss, haematocrit change, additional oxytocin, fever.
Notes37 women excluded after randomisation due to CS or incomplete data collection.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk'randomly allocated.'
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble placebos prepared daily by pharmacist independent of the trial and provided to the researchers upon request.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition < 20%. 37 women 'excluded after randomisation due to CS or incomplete data collection'.
Selective reporting (reporting bias)Unclear riskExpected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Nepal 2011:1000PR vs U

MethodsParallel, non-blinded RCT conducted in a University Hospital in Nepal from Sep 2009 to Feb 2010.
ParticipantsWomen with singleton, low-risk vaginal deliveries. Excluded if chorioamnionitis, preterm labour, polyhydramnios, previous CS, contraindications to prostaglandins.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 1000 µg PR.

Arm 2 (100 women); oxytocin 10 IU IM.

OutcomesPPH, change in Hb, side effects.
Notes

investigators concluded that 'Misoprostol is an efficacious and safe alternative to conventional uterotonic agents like oxytocin in active management of third stage of labour especially in developing countries at community level and at the peripheral centres’. 

Additional mortality and morbidity data requested and obtained from authors.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk’Randomly allocated as per the lottery technique...’
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes reported. Mortality and morbidity data obtained via email.
Other biasLow riskBaseline characteristics were similar.

Nigeria 2003:600PO vs U

MethodsRCT conducted in Kwale, Nigeria.
ParticipantsPregnant women expecting to deliver vaginally. Excluded if CS or risk factors for PPH.
Interventions

PPH prevention study

Arm 1 (247 women): misoprostol 600 μg in powder form dissolved in 50 mL water PO.

Arm 2 (249 women): oxytocin 10 IU IM.

OutcomesPPH, change in Hb, side effects.
NotesAuthors concluded that 'oral misoprostol can replace intramuscular oxytocin in reducing PPH in low-risk women, in developing countries'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table.
Allocation concealment (selection bias)Low riskOpaque sealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot clear.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes reported.
Other biasLow riskBaseline characteristics were similar.

Nigeria 2007:400PO vs U

MethodsSingle-blind RCT conducted in a rural hospital setting in Nigeria.
ParticipantsWomen with a singleton, low-risk pregnancy who had a spontaneous vertex delivery. Women were excluded if there were contra-indications to misoprostol or ergometrine including hypertensive disorders of pregnancy, pre-existing cardia disease, asthma, renal or hepatic disorders; fibroids; previous history of PPH; multiple pregnancy; or polyhydramnios.
Interventions

PPH prevention study

Arm 1 (432 women): misoprostol 400 µg PO.

Arm 2 (432 women): methylergometrine 500 µg IM.

If PPH was diagnosed in either group, an additional dose of 500 µg methylergometrine and/or 20 IU of syntocinon in 500 mL of normal saline was given.

OutcomesTotal blood loss, duration of the third stage of labour, peripartal change in haematocrit, side effects.
Notes

The mean duration of the 3rd stage of labour was statistically significantly longer in the misoprostol group (19.6 min vs 9.4 min; P < 0.0001).

Vomiting was statistically significantly less common in the misoprostol group vs the ergometrine group (1/432 vs 12/432), as was headache (1/432 vs 54/432).

There were no maternal deaths or severe morbidity (unpublished data obtained via email).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk ‘An independent statistician generated sets of four random letters, which were in boxes’.
Allocation concealment (selection bias)High risk‘...each box contained four separate random allocations which was equivalent to an opaque sealed envelope stratified in a block of four’. Allocation was performed by picking a piece of paper from the next treatment envelope that contained 4 allocations. This could be subject to bias as once the box was opened, the next 4 treatments could potentially be revealed.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskParticipants were blinded (low risk); personnel were not (high risk).
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Unclear riskMaternal deaths and morbidity not reported/described.
Other biasLow riskBaseline characteristics were similar between the 2 groups.

Nigeria 2010:400PO vs U

MethodsA parallel RCT conducted in a university hospital setting in Nigeria.
ParticipantsWomen in labour with low-risk pregnancies. Women were excluded if they had the following: CS, haematocrit < 30%, pre-eclampsia/eclampsia, grandmultiparae (5 deliveries or more), multiple pregnancies, coagulation disorders, induced labour and other medical disorders in pregnancy.
Interventions

PPH prevention study

Arm 1 (100 women): misoprostol 400 µg PO.

Arm 2 (100 women): oxytocin 10 IU IM.

OutcomesPPH, blood loss, Hb change, side effects, need for additional oxytocics.
NotesMortality and morbidity data were requested but not obtained.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table; block randomisation.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal missing data.
Selective reporting (reporting bias)Low riskMost expected outcomes reported. Maternal death and morbidity were not specifically stated, probably because there were no cases.
Other biasLow riskBaseline characteristics were similar.

Nigeria 2011:400SL vs P

MethodsMulticentre, double-blind, placebo-controlled, parallel RCT conducted in Nigeria between Jan 2007 and Sept 2008.
ParticipantsMultiparous women in labour. Excluded if severe allergic condition or severe asthma, age below 18 years, temperature above 38 °C, or abortion of the pregnancy.
Interventions

PPH prevention study

Arm 1 (672 women): misoprostol 400 µg SL (in addition to standard uterotonic treatment).

Arm 2 (673 women): placebo (in addition to standard uterotonic treatment).

OutcomesPPH, blood loss, side effects, severe maternal morbidity (defined as Hb < 6 g/dL, blood transfusion needed, manual removal of placenta, hysterectomy).
Notes

All centres had a policy of active management of the third stage of labour involving the intramuscular or IV administration of either 10 IU oxytocin or 0.25 mg/0.5 mg ergometrine immediately after birth of the child.

Published data on additional uterotonics are confusing as they are presented separately for oxytocin and ergometrine and it is not clear whether these data are mutually exclusive. Manual removal of placenta was necessary in 3.5% vs 4.1% of women in the misoprostol and placebo groups respectively (NS).

Authors concluded that ‘misoprostol given in addition to routine uterotonics as a component of active management of the third stage of labour showed small but insignificant improvements over placebo for most outcomes considered’.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random number sequence in blocks of 6-8.
Allocation concealment (selection bias)Low riskSealed, sequentially numbered opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data < 20%.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Nigeria 2011:600PO vs U

MethodsParallel, multicentre, RCT conducted from Sept 2007 to March 2009. Methods of randomisation/allocation are not clear in the published report.
ParticipantsPregnant women in labour at term. Excluded if allergic to either drug, CS, APH, multiple pregnancy, malpresentation, grandmultipara, and co-existing medical disorders.
Interventions

PPH prevention study

Arm 1 (907 women): misoprostol 600 µg PO.

Arm 2 (912 women): oxytocin 10 IU IM.

OutcomesPPH, blood loss, Hb change, need for additional oxytocics and need for blood transfusion or surgical procedures.
Notes

The investigators attributed the relatively poor performance of oxytocin in this study to the high ambient temperatures experienced in the study region and the difficulty in effective storage of oxytocin, which is degraded by heating.

Additional data and information was obtained from investigators.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk100 treatment options (50 of each group) were placed in each container. Folded prescription sheets were picked out of a small opening in the container after shaking.
Allocation concealment (selection bias)Unclear riskAlthough the prescription sheets were folded it seems possible that allocations could be swapped.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk1865 enrolled, 46 questionnaires 'invalidated' and the data were further reduced to 900 women in each group ‘through a process of computer randomisation', i.e. 19 women were randomly selected and excluded to make groups of equal size. The investigators no longer have details of these women.
Selective reporting (reporting bias)Unclear riskSide effects and morbidity data were provided to us on request on the 20/1/13.
Other biasUnclear riskBaseline data were not reported separately for each group.  

Nigeria 2011:CS400SL vs U

MethodsParallel RCT conducted in a teaching hospital in Nigeria.
ParticipantsWomen undergoing emergency or elective CS. Excluded if multiple gestation, placenta previa, antepartum haemorrhage or unexplained vaginal bleeding, general anaesthesia, pre-existing medical illnesses and contraindications to prostaglandins (e.g. asthma, glaucoma), eclampsia or severe preeclampsia and prolonged obstructed labour.
Interventions

PPH prevention study

Arm 1 (50 women): misoprostol 400 µg SL.

Arm 2 (50 women): oxytocin 20 IU IVI.

OutcomesIntra-operative blood loss, haematocrit and side effects.
NotesLittle usable data. Morbidity and mortality data were requested but not obtained.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasUnclear riskBaseline characteristics were similar.

Pakistan 2008:600SL vs P

MethodsDouble-blind, parallel RCT conducted in 4 university hospitals in Pakistan (1 tertiary and 3 secondary); enrolment took place from Dec 2005 to April 2007.
ParticipantsWomen with PPH (blood loss > 500 mL) due to uterine atony were included. Women with CS and gestational age less than 28 weeks at time of birth were excluded.
Interventions

PPH treatment study

Arm 1 (29 women): misoprostol 600 µg SL.

Arm 2 (32 women): matched placebo.

All women also received standard treatment with IV oxytocin (bolus 5–30 units and infusion 10–80 units in 500–1000 mL saline) with or without ergometrine or prostaglandin F2α.

OutcomesAdditional blood loss  ≥ 500 mL; change in Hb, side effects, need for additional interventions, hysterectomy and mean blood loss.
Notes

Investigators did not achieve the expected accrual (900 women) due to the low rate of PPH experienced in this study (1.2%).

All women received oxytocin 10 IU IV (or oxytocin 5 IU plus 0.4mg ergometrine IM or IV) on delivery of the anterior shoulder. Oxy/ergometrine prophylaxis was the standard prophylaxis at 2/4 sites and approximately half of the women in each group received it.

‘Oxytocin infusion was given for all PPH cases; two-thirds were given IV oxytocin in bolus; and one-third of cases received 0.2–0.4 mg ergometrine IV. 6 cases (4 in the misoprostol group and 2 in the placebo group) were given an additional dose of 200–400 µg misoprostol either rectally or sublingually. Prostaglandin alpha F-2 was administered to 1 woman in misoprostol group and 3 in the placebo group.’

‘There were no differences in the dose, route or choice of standard uterotonics given for PPH treatment between the two study groups.’

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised in blocks of 10, stratified by site, using a computer-generated random sequence provided by Gynuity Health.
Allocation concealment (selection bias)Low riskSequential sealed envelopes.                                                   
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Code was kept centrally and concealed until all data were entered.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition; protocol deviations reported included 1 woman who only received a 400 µg dose and 2 did not have blood loss measured.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Pakistan 2011:600PO vs P

MethodsDouble-blind, parallel, RCT conducted in rural Pakistan between June 2006 and June 2008.
ParticipantsWomen delivering primarily at home in 46 villages in rural Pakistan, served by 17 primary healthcare facilities. Excluded if presenting with pregnancy complications such as hypertension, non-cephalic presentation, polyhydramnios, previous CS, suspected multiple pregnancy, suspected still birth, antepartum haemorrhage, and Hb < 8 g/dL.
Interventions

PPH prevention study

Arm 1 (534 women): misoprostol 600 µg PO.

Arm 2 (585 women): placebo (3x matched tablets).

OutcomesPPH rate, drop in Hb > 2 g/dL, blood loss ≥ 750 mL and ≥ 1000 mL, mean blood loss, postpartum Hb < 9 and < 11 g/dL.
Notes

Investigators concluded that misoprostol is a safe and effective alternative intervention for use at home deliveries where other uterotonics are not used/available.

Data collection on adverse effects did not occur at the time of delivery but at the LHV’s follow-up visit to the woman’s home 1–2 days postpartum, therefore these outcomes were subject to recall bias. In addition, body temperature was not systematically measured after administration of study medication and was simply recalled later as ‘fever’, therefore it is likely that these results are underestimated/inaccurate.

Statistically significantly less women in the misoprostol group experienced a drop in Hb of > 3 g/dL compared with the placebo group (5.1% vs 9.6%; RR 0.53 to 95% CI 0.34 to 0.83).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random code in blocks of 6 was maintained by Gynuity Health Projects.
Allocation concealment (selection bias)Low riskStudy medication was packed in sequentially numbered colour-coded boxes.
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Given 3 misoprostol tablets or identical placebo.

Both women and TBAs were blinded to study assignment.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskRandomisation code not revealed until data collection and cleaning were completed.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition. 3 women lost to follow-up. Blood loss data were not available in 44/1116 women.
Selective reporting (reporting bias)Low riskCONSORT guidelines used. All expected outcomes were reported.
Other biasUnclear riskData collection on adverse effects did not occur at the time of delivery but at the LHV’s follow-up visit to the woman’s home 1–2 days postpartum, therefore subject to recall bias. With the exception of median pre-delivery Hb levels, baseline and delivery characteristics of women were similar.

SA 1998a:400PR vs U

MethodsParallel RCT conducted at Natalspruit, Johnannesburg in 1995/6.
ParticipantsLow risk women in labour.
Interventions

PPH prevention study

Arm 1 (241 women): misoprostol 400 μg PR.

Arm 2 (250 women): ergometrine-oxytocin 1 ampoule IM.

OutcomesDuration of third stage of labour, blood loss and Hb.
NotesAuthors concluded that 'Misoprostol rectally for management of the third stage of labour merits further investigation'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk> 20% missing data for Hb and blood pressure measurements but low for other outcomes.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasUnclear riskSome post-randomisation exclusions of hypertensive women. Baseline blood pressure was significantly higher in the misoprostol group.

SA 1998b:400PO vs P

MethodsParallel RCT conducted in a teaching hospital in Johannesburg, South Africa.
ParticipantsLow-risk women expected to deliver vaginally.
Interventions

PPH prevention study

Arm 1 (250 women): misoprostol 400 µg PO.

Arm 2 (250 women): placebo.

OutcomesPPH, blood loss ≥ 1000 mL, side effects.
NotesAuthors concluded that 'misoprostol shows promise'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated in blocks of 8.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawals after randomisation and no missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

SA 1998c:400PR vs P

MethodsParallel RCT conducted in Johannesburg, South Africa.
Participants550 women after normal vaginal birth.
Interventions

PPH prevention study

Arm 1 (271 women): misoprostol 400 μg PR.

Arm 2 (275 women): placebo PR.

OutcomesPPH, blood loss ≥ 1000 mL, need for oxytocics, side effects.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSequential container with similar looking tablets.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 lost records.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

SA 1998d:600/400PO vs P

MethodsParallel RCT conducted in a teaching hospital in Johannesburg, South Africa.
ParticipantsWomen in labour.
Interventions

PPH prevention study

Arm 1 (500 women): misoprostol 600 µg PO or 400 µg PO.

Arm 2 (500 women): placebo.

OutcomesBlood loss and side effects.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskConference abstract only.
Selective reporting (reporting bias)Unclear riskConference abstract only.
Other biasUnclear riskConference abstract only.

SA 2001a:600PO vs P

MethodsRCT conducted in Johannesburg, South Africa.
ParticipantsWomen in labour.
Interventions

PPH prevention study

Arm 1 (300 women):misoprostol 600 µg PO.

Arm 2 (300 women): placebo.

OutcomesShivering and pyrexia.
NotesAuthors concluded that the study had 'quantified certain side-effects of postpartum misoprostol'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskConference abstract only. No denominators given.
Selective reporting (reporting bias)Unclear riskConference abstract only.
Other biasLow risk'Groups were well matched.'

SA 2001b:800PR vs U

MethodsParallel RCT conducted in two centres in South Africa.
ParticipantsWomen with PPH following vaginal birth or CS.
Interventions

PPH treatment study

Arm 1 (32 women): misoprostol 800 μg PR plus normal saline placebo and infusion.

Arm 2 (32 women): 4 placebo tablets PR plus oxytocin 5 IU IM plus ergometrine 0.5 mg IM plus oxytocin infusion.

OutcomesBleeding cessation within 20 min of drug, uterine tone, side effects, morbidity.
NotesAuthors concluded that 'This study shows that misoprostol appears to be better than Syntometrine with a Syntocinon infusion at treating postpartum haemorrhage when caused by uterine atony'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque sequentially numbered envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskSingle-blind.
Blinding of outcome assessment (detection bias)
All outcomes
High riskAssessors not blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasUnclear riskMore CSs in the misoprostol group.

SA 2004:1000PO/SL/PR vs P

MethodsParallel RCT conducted in South Africa.
ParticipantsWomen with 'more than usual postpartum bleeding' due to uterine atony.
Interventions

PPH treatment study

Arm 1 (117 women): misoprostol 200 µg PO + 400 µg SL + 400 µg PR.

Arm 2 (121 women): placebo.

Routine treatment for PPH was also given.

OutcomesBlood loss ≥ 500 mL after enrolment, mean blood loss, Hb < 6 g/dL or blood transfusion, side effects, additional uterotonics, hysterectomy, death.
NotesAuthors concluded that 'Larger studies are needed to assess substantive outcomes and risks before misoprostol enters routine use'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSequentially numbered packs.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Code broken after data entry.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

SANU 2011:400SL vs P

MethodsHospital-based, decentralised, multicenter, randomised, placebo-controlled, double-blind trial conducted in 4 hospitals in SA, Uganda and Nigeria between March 2006 and August 2007. Data checking and entry of the completed data collection forms and initial analyses were undertaken at each local centre.
ParticipantsWomen without significant obstetric complications, who were expected to deliver vaginally. Excluded if CS or assisted vaginal birth.
Interventions

PPH prevention study

Arm 1 (547 women): misoprostol 400 µg SL.

Arm 2 (556 women): placebo.

Interventions were given in addition to standard active management of the third stage of labour.

OutcomesPPH, side effects, severe morbidity and mortality.
NotesInvestigators concluded that 'the present study did not confirm a beneficial effect of administering 400 µg of misoprostol, in addition to routine uterotonic therapy, during the third stage of labour, but was consistent with other trials showing a cumulative modest benefit. Where routine uterotonics are available for prophylactic use, any potential benefit of misoprostol might not outweigh the likelihood of adverse effects'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated numbers in blocks of 6-8.
Allocation concealment (selection bias)Low riskStudy drug packs were identical and prepared by Gynuity Health Projects, New York.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind. Randomisation code broken after data entry at the co-ordinating centre.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 women lost to follow-up and excluded from analyses.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar except for a 2.8 year difference in mean age.

SATAEV 2010:600SL vs P

MethodsParallel, double-blind, placebo-controlled RCT conducted in hospitals in South Africa, Argentina, Thailand, Egypt and Vietnam between July 2005 to August 2008
ParticipantsWomen with clinically diagnosed PPH due to atony. Women were not eligible for the trial if: birth was by CS, misoprostol could not be given sublingually, any severe allergic or bleeding disorders (e.g., haemophilia) were recorded, temperature was higher than 38·5°C, the delivery was defined as a miscarriage according to local gestational age limits, or the placenta was not delivered.
Interventions

PPH treatment study

Arm 1 (705 women): misoprostol 600 µg SL.

Arm 2 (717 women): matched placebo.

Both groups received standard uterotonics (usually 10 IU oxytocin IM or IV) to treat PPH. Participants were then randomly allocated to treatment by the health provider, and received the study drug as soon as possible after standard uterotonics.

OutcomesAdditional blood loss within 1 hour, need for blood transfusion, Hb < 8 g/dL, blood loss > 500 mL after randomisation, need for additional uterotonic, maternal death, severe morbidity (hysterectomy or admission to ICU), side effects.
Notes

Investigators reported side effects at 60 and 90 min post-randomisation. Significantly more women experienced hyperpyrexia in the misoprostol group compared with the placebo group, and this side effect was more than double the 60-minute frequency (3%)  at 90 min post-randomisation (7%) in the misoprostol group.

Investigators concluded that 'Findings from this study do not support clinical use of 600 μg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage’.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated block randomisation (blocks of 6-8).
Allocation concealment (selection bias)Low riskAllocation/treatment boxes were sealed and numbered sequentially.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition for all outcomes. Five women were lost to follow-up (2 vs 3).
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Spain 2009:400SL200PRvsN

MethodsOpen-label, parallel, multicentre RCT conducted in Spain and Cuba from April 2007 to October 2008.
Participants

Women age ≥18 years, with uncomplicated pregnancy and vaginal birth.

Exclusion criteria were instrumental delivery or CS, gestational age < 32 weeks, clotting disorders, prelabour Hb levels < 8 g/dl, liver or kidney dysfunction, gravidity ≥ 5, hypersensitivity or any contraindication for the use of prostaglandins.

Interventions

PPH prevention study

Arm 1 (705 women): misoprostol 400 µg SL plus 200 µg PR.

Arm 2 (705 women): no additional treatment.

Active management of the 3rd stage was performed for all women.

OutcomesPPH, blood loss, need for additional uterotonics.
Notes

Uterotonic agents were used (oxytocin, ergonovine amongst others) but it is not clear whether they were used routinely in all deliveries as part of standard management, or if they were only used to treat PPH. Clarification requested by email on 9/1/13 but not received.

Investigators concluded that 'The use of sublingual/rectal misoprostol plus active management appears to be useful for the prevention of PPH'.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low risk10 women were excluded due to protocol deviations (3 in the misoprostol group and 7 in the control group).
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar except for mean age which was 10 months older in the misoprostol group.

Switzer 1999:600PO vs P

MethodsParallel double-blind RCT.
Participants65 women with normal vaginal birth. Excluded if CS or high risk of PPH.
Interventions

PPH prevention study

Arm 1 (31 women): misoprostol 600 μg PO

Arm 2 (34 women): placebo

OutcomesEstimated blood loss, PPH, duration of third stage.
NotesAuthors concluded that 'misoprostol reduces blood loss compared with placebo'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Switzer 2006:CS800PO vsU

MethodsDouble-blind pilot RCT conducted in Switzerland.
ParticipantsWomen undergoing emergency CS with low risk for PPH. Exclusion criteria were emergency CS within 30 min of admission, fetal distress, fetal malformations, preeclampsia, or HELLP (haemolysis, elevated liver enzymes, and low platelet count), hypersensitivity to prostaglandins, coagulopathy, severe systemic disorders, myomectomy and fever > 38.5°C.
Interventions

PPH prevention study

Arm 1 (15 women): oxytocin 5 IU IV + M 800 mg.

Arm 2 (16 women): oxytocin 5 IU IV + oxytocin 20 IU in 1000 mL normal saline over 8 hours.

OutcomesPPH, blood loss, need for additional uterotonics.
NotesAuthors concluded 'misoprostol offers a safe and effective alternative to classic uterotonics in the prevention of PPH, and this warrants further evaluation in larger studies'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low risk'Numbered containers'.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskAll expected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Tibet 2009:600PO vs U

MethodsDouble-blind, parallel RCT. ITT analyses. Conducted in three Tibetan hospitals.
Participants

Pregnant women 18 years of age or older with a viable intrauterine singleton pregnancy > 28 weeks gestation were considered eligible.

Exclusion criteria included previous or planned CS, no fetal heart rate, preeclampsia, severe anaemia (Hb < 7), history of bleeding disorders, mental disability, body temperature > 38°C, serious medical illness, or active haemorrhage at the time of screening.

Interventions

PPH prevention study

Arm 1 (487 women): misoprostol 600 µg PO.

Arm 2 (480 women): ZB11.

ZB11 is a Tibetan traditional uterotonic medicine that is usually administered at the time of full dilatation.

OutcomesRate of PPH (EBL ≥ 500 mL); EBL 500 to 999 mL; EBL ≥ 1000 mL; additional uterotonics administered.
NotesA well-conducted study.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation list with a random block size for each hospital.
Allocation concealment (selection bias)Low riskSealed opaque study medication envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskEach study envelope contained two smaller envelopes: one envelope contained either ZB11 or ZB11 placebo, and the other envelope contained either misoprostol or misoprostol placebo. Women were given the ZB11 (or placebo) at full dilatation and misoprostol (or placebo) after birth of the baby.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition: 3 vs 4 withdrawals in the misoprostol and ZB11 group, respectively.
Selective reporting (reporting bias)Unclear riskAll pre-specified outcomes reported. Did not report severe morbidity events such as major surgery, hyperpyrexia or ICU admissions. Additional data requested 3/1/2013.
Other biasLow riskBaseline characteristics were similar.

Tunis 2009:CS200SL vs P

MethodsParallel RCT conducted in a hospital in Tunisia, between March and June 2007.
ParticipantsWomen with a singleton pregnancy, 32+ weeks, warranting birth by CS under regional anaesthesia. Excluded if placenta praevia, retroplacental clot, multiple pregnancy, premature labour (prior to 32 weeks' gestation), intra-uterine death (IUD), cs warranting general anaesthesia, anaemia (Hb < 8 g/dl), blood coagulation defect (congenital or receiving anticoagulant therapy), HELLP syndrome, antepartum haemorrhage, ruptured uterus, more than 2 previous CS deliveries, prolonged labour (greater than 12 hours), maternal pyrexia (temperature > 38°C).
Interventions

PPH prevention study

Arm 1 (125 women): misoprostol 200 µg SL.

Arm 2 (125 women): placebo tablet SL.

All women received 10 IU oxytocin bolus and 10 IU oxytocin in the drip over 30 min.

OutcomesHaematocrit change, Hb change, estimated blood loss, additional oxytocics and side effects.
NotesLittle usable data. Morbidity and mortality data requested but not obtained.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskOpaque, sealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Turkey 2002:400PR vs P/U

Methods4-arm RCT.
ParticipantsWomen undergoing vaginal birth. Exclusion criteria were gestational age of < 32 weeks, CS, and known hypersensitivity to prostaglandins.
Interventions

PPH prevention study

4 groups, all received corresponding placebos.

Arm 1 (401 women): oxytocin 10 IU IV + misoprostol 400 μg PR, followed by 2 doses, 4 and 8 hours after delivery, of misoprostol 100 μg.
Arm 2 (396 women): misoprostol 400 μg PR.

Arm 3 (407 women): oxytocin 10 IU IV.

Arm 4 (402 women): oxytocin 10 IU IV plus methylergometrine 1 mL IM.

OutcomesPPH, estimated blood loss, additional oxytocics and side effects.
NotesAuthors concluded that 'Rectal misoprostol is significantly less effective than oxytocin plus methylergometrine for the prevention of PPH'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPartial blinding.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded. The randomisation code was not broken until study completion.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Turkey 2003:400PO vs P/U

Methods4-arm RCT conducted in Ankara, Turkey, between January and October 2000.
ParticipantsWomen in labour. Exclusion criteria were gestational age of < 32 weeks, CS, and known hypersensitivity to prostaglandins.
Interventions

PPH prevention study.

Arm 1 (404 women): oxytocin 10 IU IV + misoprostol 400 μg PO, followed by 2 doses, 4 and 8 hours after delivery, of misoprostol 100 μg.
Arm 2 (388 women): misoprostol 400 μg PO.

Arm 3 (384 women): oxytocin 10 IU IV.

Arm 4 (398 women): oxytocin 10 IU IV plus methylergometrine 1 mL IM.

OutcomesPPH, estimated blood loss, additional oxytocics and side effects.
NotesAuthors concluded that 'oral misoprostol alone is as effective as oxytocin alone for the prevention of PPH'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskConsecutively numbered sealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPartial blinding.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Turkey 2005:400V/R vs P

Methods3-arm RCT conducted in Isparta, Turkey.
ParticipantsWomen in the third stage of labour. Women with profuse haemorrhage and delayed placental separation (> 30 min) were excluded.
Interventions

PPH prevention study.

Arm 1 (50 women): misoprostol 400 µg PV.

Arm 2 (50 women): misoprostol 400 µg PR.

Arm 3 (50 women): placebo.

OutcomesEstimated blood loss, haematocrit, Hb.
NotesAuthors concluded that 'neither vaginally nor rectally administered misoprostol (400 µg) seems to decrease postpartum bleeding after delivery of the placenta'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk126/150 analysed. 5, 2, and 6 women in each group were excluded due to 'blood loss greater than usual' and 'delayed separation of placenta'.
Selective reporting (reporting bias)Unclear riskSide effects were not reported.
Other biasLow riskBaseline characteristics were similar.

UK 2000:500PO vs U

MethodsParallel RCT conducted in a UK teaching hospital.
ParticipantsWomen with imminent vaginal birth. Excluded if CS birth, severe asthma, or water birth.
Interventions

PPH prevention study

Arm 1 (501 women): misoprostol 500 μg PO

Arm 2 (499 women): ergometrine for women (2%) at high risk of haemorrhage; women with hypertension (18%) received oxytocin; all others (80%) received ergometrineoxytocin.

OutcomesPPH, estimated blood loss, Hb, haematocrit change, additional oxytocics and side effects.
NotesAuthors concluded 'Oral misoprostol for the prevention of PPH was comparable to standard oxytocics'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by computer-generated random sequence.
Allocation concealment (selection bias)Low riskSealed, opaque, consecutively numbered envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition except for Hb and haematocrit due to participants refusal to have blood taken.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

UK 2001:CS400PO vs U

MethodsParallel RCT conducted in a UK teaching hospital.
ParticipantsWomen undergoing CS.
Interventions

PPH prevention study

Arm 1 (30 women): misoprostol 400 µg PO.

Arm 2 (30 women): oxytocin 10 IU IVI.

OutcomesIntra-operative blood loss, haematocrit and post-op Hb.
NotesNo deaths were reported and we assumed that no deaths occurred (see Potential biases in the review process).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline data were similar.

UK 2001:CS500PO vs U

MethodsPilot RCT conducted in a London teaching hospital.
ParticipantsWomen undergoing elective or emergency CS. Excluded if 2 or more previous CS or a previous ruptured uterus.
Interventions

PPH prevention study

Arm 1 (20 women):misoprostol 500 μg PO + normal saline 2 mL IV bolus.

Arm 2 (20 women): oxytocin 10 IU IV bolus + 2 placebo tablets.

OutcomesPPH, estimated blood loss, Hb drop, additional oxytocics and side effects.
NotesAuthors concluded that 'oral misoprostol could be used as an alternative oxytocic agent for the third stage at Caesarean section'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskSealed opaque envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing data.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline data were similar.

USA 2001:400PR vs U

MethodsParallel RCT conducted in a teaching hospital in California, USA.
ParticipantsWomen with vaginal birth.
Interventions

PPH prevention study

Arm 1 (201 women): misoprostol 400 μg PR + placebo (2 mL saline).

Arm 2 (199 women): oxytocin 20 IU IV infusion in 1 L of Ringer’s lactate solution + placebo PR (lactose tablets).

OutcomesPPH, blood loss, haematocrit drop, additional oxytocics, side effects.
Notes

400 randomised but 75 excluded due to CS (except for 2 women).

Authors concluded that 'Rectal misoprostol (400 µg) was no more effective than IV oxytocin in preventing PPH'.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number sequence.
Allocation concealment (selection bias)Unclear risk'Random allocation sequence concealed until the patient was enrolled.'
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskPost-randomisation withdrawals were due to CS delivery.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

USA 2004:200B vs P

MethodsParallel RCT.
ParticipantsWomen delivering vaginally between 22 and 42 weeks' gestation.
Interventions

PPH prevention study

Arm 1 (377 women): misoprostol 200 µg.

Arm 2 (379 women): placebo.

All women received oxytocin 20 IU IV infusion in 1 L of normal saline at 10 mL/min for 30 min.

OutcomesPPH, blood loss, haematocrit drop, additional oxytocics, side effects.
NotesAuthors concluded that 'buccal misoprostol is no more effective than placebo in reducing PPH'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table.
Allocation concealment (selection bias)Low riskSmall opaque vial.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

USA 2005:CS200B vs P

MethodsParallel RCT conducted in Orlando, USA.
ParticipantsWomen undergoing elective or emergency CS.
Interventions

PPH prevention study

Arm 1 (173 women): M 200 μg.

Arm 2 (179 women): placebo.

All women received oxytocin 20 IU IV in 1000 mL normal saline.

OutcomesPPH, blood loss, haematocrit drop, additional oxytocics, side effects.
NotesAuthors concluded that 'Buccal misoprostol reduces the need for additional uterotonic agents during cesarean delivery'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Low riskAllocation concealment by pharmacy-assigned numbers to opaque vials containing either misoprostol tablets or oxytocin ampoules.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

WHO 1999:400/600PO vs U

MethodsPilot multicentre RCT conducted in South Africa and Thailand.
ParticipantsWomen expecting to deliver vaginally.
Interventions

PPH prevention study

Arm 1 (199 women): misoprostol 600 μg PO.

Arm 2 (198 women): misoprostol 400 μg PO.

Arm 3 (200 women) oxytocin 10 IU IV.

OutcomesSide effects.
NotesAuthors concluded that 'Based on the findings of this pilot trial, the Trial Steering Committee decided that the main trial should aim to achieve maximum effectiveness with misoprostol and thus compare 600 pg misoprostol with 10 IU of oxytocin'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation sequence generated centrally.
Allocation concealment (selection bias)Low riskCentral allocation.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

WHO 2001:600PO vs U

MethodsA large multicentre RCT conducted in Argentina, Chile, Egypt , Ireland, Nigeria, South Africa, Switzerland, Thailand and Vietnam.
ParticipantsWomen expecting to deliver vaginally.
Interventions

PPH prevention study

Arm 1 (9264 women): misoprostol 600 μg PO.

Arm 2 (9266 women): oxytocin 10 IU IV or IM.

OutcomesPPH > 1000 mL, additional oxytocics, side effects.
NotesAuthors concluded that 'oxytocin is preferable to 600 μg oral misoprostol...where active management is the norm'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation sequence generated centrally.
Allocation concealment (selection bias)Low riskCentral allocation.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Zim 2001:400PO vs U

  1. a

    APH: antepartum haemorrhage
    CI: confidence interval
    CS: caesarean section
    EBL: endoscopic band ligation
    Hb: haemoglobin
    HELLP syndrome: haemolysis, elevated liver enzymes, and low platelet count
    ICU: intensive care unit
    IM: intramuscular
    IMI: intramuscular injection
    ITT: intention-to-treat
    IU: international units
    IUD: intrauterine device
    IV: intravenous
    IVIL intravenous infusion
    min: minutes
    NS: not significant
    PGF2α: prostaglandin F2α
    PO: per os
    PPH: postpartum haemorrhage
    PR: per rectum
    RCT: randomised controlled trial
    RR: risk ratio
    SL: sublingually
    vs: versus

MethodsRCT conducted in a teaching hospital in Harare, Zimbabwe.
ParticipantsWomen in the third stage of labour. Excluded if history of PPH, conditions causing disseminated intravascular coagulation, antepartum haemorrhage, coagulation disorders, operative delivery, multiple pregnancy, history of asthma and known allergies to prostaglandins or oxytocin.
Interventions

PPH prevention study

Arm 1 (243 women): 400 µg misoprostol PO + 1 mL saline (placebo).
Arm 2 (256 women): oxytocin 10 IU IM + 2 placebo tablets.

OutcomesPPH > 500 mL and > 1000 mL, additional oxytocics, side effects, manual removal of placenta, duration of third stage.
NotesAuthors concluded that '400 µg misoprostol orally was as effective as intramuscular oxytocin in the prevention of excessive blood loss in the third stage of labour'.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Low riskNumbered envelope.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPartial blinding (tablets similar but not identical).
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition < 20%.
Selective reporting (reporting bias)Low riskExpected outcomes were reported.
Other biasLow riskBaseline characteristics were similar.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CS: caesarean section
    IM: intramuscular
    PHC: Primary Health Centre
    PO: per os
    PPH: postpartum haemorrhage
    PR: per rectum
    RCT: randomised controlled trial
    TBA: traditional birth attendants
    vs: versus

Al-Harazi 2009Study methods were unclear. Study of misoprostol 600 SL vs misoprostol 600 PR to prevent PPH. Authors state 'A convenient sample was recruited for the study...' and 'we divided the sample into two groups'.
Chandhiok 2006A cluster-RCT where women in the intervention (misoprostol) group were managed differently to the women in the comparison group; i.e. the staff of the intervention PHCs received additional training in the active management of the 3rd stage, whereas staff in the comparison centres did not (3rd stage was not actively managed).
Chandra 2004Study methods were unclear.
Daly 1999Only the conference abstract of this study is available, with scant and inconsistent data.
Diab 1999Study methods were unclear.
Dickinson 2009RCT of misoprostol vs oxytocin vs placebo in women undergoing termination of pregnancy in the 2nd trimester (14/24 weeks).
Elati 2011Primarily an intrauterine pressure study. Oxytocin group not randomised. Randomisation was between different doses of misoprostol.
Jiang 2001Possibly an RCT but the study methods and outcomes are not clear.
Jin 2000Study methods were unclear.
Jirakulsawas 2000RCT conducted in Thailand available as a conference abstract only. There are insufficient data available in the abstract for inclusion.
Khan 2003Study methods were unclear.
Khanun 2011No indication in report that allocation was random. All women received oxytocin. One group received rectal and one oral misoprostol, 600 µg.
Kumar 2011RCT conducted in India available as a conference abstract only. The comparison intervention is not stated and there are insufficient data available in the abstract for inclusion.
Kushtagi 2006Not a study of misoprostol.
Leader 2002RCT of misoprostol following second trimester pregnancy loss.
Li 2002Study methods were unclear.
Li 2003Study methods were unclear.
Lokugamage 2000Study of misoprostol vs oxytocin during CS with insufficient data (conference abstract)
Mansouri 2011RCT of a comparison of the different routes of administration of misoprostol (PO vs PR).
Parsons 2006There were insufficient data in this report of an RCT in Ghana and the number of women randomised to each group was not stated.
Prata 2005Pilot cluster trial to assess whether TBAs can diagnose and treat PPH.
Rajbhandari 2010Post-intervention survey.
Ray 2001Study methods were very unclear. Reported as an RCT comparing misoprostol 400 PO with methylergometrine IM (no dose given).
Rogers 2007Not an RCT.
Sanghvi 2010Not an RCT.
Shrivasatava 2012Conference abstract with insufficient data to extract (percentages only), and the number of women randomised to each group is not stated. However, investigators state that ‘None of the women suffered from serious side effects’. No contact details for authors obtained.
Soltan 2009Not a study of misoprostol for PPH.
Tripti 2009Study methods were unclear. A comparative study not described as an RCT. Attempts to contact the investigators for clarification was unsuccessful.
van Beekhuizen 2009RCT of misoprostol for treatment of retained placenta (Tanzania).
Van Stralen 2013An RCT of misoprostol versus placebo for women with retained placenta and the absence of PPH.
Vogel 2004A phase 1 RCT (10 women in each study arm) of misoprostol 200 µg vs methylergometrine 250 µg and their respective concentrations in breast milk.
Xu 2003Study methods were unclear. Study of misoprostol to prevent PPH after CS.
Yan 2000Study methods were unclear. Study of misoprostol to reduce bleeding at CS.
Zhao 1998Study methods were unclear. Study of misoprostol to reduce bleeding at CS.

Characteristics of studies awaiting assessment [ordered by study ID]

Adanikin 2012

MethodsRCT
ParticipantsWomen post-caesarean section
InterventionsAll received oxytocin 5 u. In addition, misoprostol 600 µg PR vs oxytocin
OutcomesBlood loss, bowel motility
NotesInsufficient information in published abstract. Awaiting full publication

Beigi 2009 (Farsi)

MethodsRCT
ParticipantsNulliparous women
InterventionsPostpartum misoprostol 400 µg sublingually versus 20 u oxytocin IV
OutcomesPPH, duration of 3rd stage, Hb, side effects
NotesAwaiting translation and classification

Fawzy 2012

MethodsNot clear whether a randomised trial. The participants were "..divided into 3 groups according to the drug used for management of the third stage of labour"
ParticipantsWomen postpartum with no complications
InterventionsGroup 1: Ergometrine 10 mg IV. Group 2: Misoprostol 200 µg PR. Group 3: Misoprostol 200 µg sublingually
OutcomesEstimated blood loss; time of placental separation
NotesAwaiting classification pending further information on method of allocation

Is 2012

  1. a

    Hb: haemoglobin
    IM: intramuscular
    IV: intravenous
    PPH: postpartum haemorrhage
    PR: per rectum
    RCT: randomised controlled trial
    vs: versus

MethodsNot clear from abstract whether allocation was by randomisation
Participants200 low-risk postpartum women
Interventionsmisoprostol 400 µg PR versus IM ergometrine
OutcomesBlood loss, duration of 3rd stage of labour, Hb, side effects
NotesAwaiting classification pending full report

Characteristics of ongoing studies [ordered by study ID]

Diop 2011

Trial name or titleComparing misoprostol and oxytocin in UnijectTM for PPH prevention in Mali
MethodsA large, community-based, cluster-randomised, open-label trial to compare routine prophylactic use of 600 µg oral misoprostol and 10 IU oxytocin delivered by UnijectTM intramuscularly during the third stage of labour.
Participants1070 women delivering at home with a trained study provider who are able to provide informed consent. Women with known contraindications to prostaglandins are excluded.
Interventions

PPH prevention study (1070 women)

Arm 1: misoprostol 600 µg PO.

Arm 2: Uniject (10 IU oxytocin).

OutcomesHb change, side effects, additional uterotonics, manual removal of placenta, referrals to higher level of care.
Starting dateJuly 2012.
Contact informationL.Frye@gynuity.org
Notes 

Kalahroudi 2010

Trial name or titleComparison of the effect of rectal Misoprostol and Syntometrin in prevention of postpartum haemorrhage (IRCT ID:IRCT201008212854N5).
MethodsDouble-blind, parallel RCT conducted in Iran.
Participants

200 women.

Inclusion criteria: pregnant women with single pregnancy and candidate for vaginal birth. Exclusion criteria: presence of pre-eclampsia, hypotension, heart disease, asthma, hypertonic uterus, uterine rupture, or vaginal and cervical laceration, being high risk for postpartum bleeding such as: multiparity, uterine myoma, history of postpartum bleeding, or need for uterine curettage.

Interventions

PPH prevention study

Arm 1: misoprostol 600 µg PR.

Arm 2: Syntometrine 5 IU IM.

OutcomesUterine tone, Hb change.
Starting date21/4/10.
Contact informationDr Samimi: dr.samimi.2007@yahoo.com; abedzadeh@kaums.ac.ir
NotesEmailed 10/1/13 for info. No reply.

Moradi 2010

  1. a

    CS: caesarean section
    Hb: haemoglobin
    IM: intramuscular
    IU: international units
    µg: microgram
    PO: per os
    PPH: postpartum haemorrhage
    PR: per rectum
    RCT: randomised controlled trial

Trial name or titleComparison of misoprostol and oxytocin in reduction of postpartum haemorrhage (IRCT ID:IRCT138812223548N1).
MethodsNon-blinded, parallel RCT conducted in Iran.
Participants

300 women.

Inclusion criteria: pregnant women with singleton pregnancy, cephalic, spontaneous and induced delivery, term pregnancy. Exclusion criteria: instrumental delivery, TL during 24h after delivery, past history of abruption placenta, history of asthma, coagulopathy, history of postpartum haemorrhage, history of CS.

Interventions

PPH prevention study

Arm 1: misoprostol 400 µg PO.

Arm 2: oxytocin 10 IU IM.

OutcomesPPH, Hb change.
Starting date22/12/2009
Contact informationDr Moradi: smoradi@qums.ac.ir; simindokht56@yahoo.com
NotesEmailed 10/1/13 for info. No reply.

Ancillary