Prophylactic interventions after delivery of placenta for reducing bleeding during the postnatal period

  • Review
  • Intervention

Authors


Abstract

Background

There are several Cochrane systematic reviews looking at postpartum haemorrhage (PPH) prophylaxis in the third stage of labour and another Cochrane review investigating the timing of prophylactic uterotonics in the third stage of labour (i.e. before or after delivery of the placenta). There are, however, no Cochrane reviews looking at the use of interventions given purely after delivery of the placenta. Ergometrine or methylergometrine are used for the prevention of PPH in the postpartum period (the period after delivery of the infant) after delivery of the placenta in some countries. There are, furthermore, no Cochrane reviews that have so far considered herbal therapies or homeopathic remedies for the prevention of PPH after delivery of the placenta.

Objectives

To assess the effectiveness of available prophylactic interventions for PPH including prophylactic use of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, administered after delivery of the placenta, compared with no uterotonic agents as well as with different routes of administration for prevention of PPH after delivery of the placenta.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013), The Food and Drug Administration (FDA) (USA),  Medicines and Healthcare Products Regulatory Agency (MHRA) (UK), European Medicines Agency (EMA) (EU), Pharmaceuticals and Medical Devices Agency (PMDA) (Japan),  Therapeutic Goods Administration (TGA) (Australia), ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform (ICTRP), University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; Japan), Japan Pharmaceutical Information Center Clinical Trials Information (Japic-CTI; Japan), Japan Medical Association Clinical Trial Registration (JMACCT CTR; Japan) (all on 30 April 2013) and reference lists of retrieved studies

Selection criteria

All randomised or quasi-randomised controlled trials comparing prophylactic ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies (using any route and timing of administration) during the postpartum period after delivery of the placenta with no uterotonic agents or trials comparing different routes or timing of administration of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, during the postpartum period after delivery of the placenta.

Data collection and analysis

Two review authors independently assessed trial eligibility and the methodological quality of trials, extracted data using the agreed form. Data were checked for accuracy.

Main results

Five randomised studies involving 1466 women met the inclusion criteria. All studies were classified as having an unclear risk of bias. Two studies (involving 1097 women) compared oral methylergometrine with a placebo, and one (involving 171 women) compared oral methylergometrine with Kyuki-chouketsu-in, a Japanese traditional herbal medicine. The remaining two studies (involving 198 women) did not report the outcomes of interest for this review. None of the included studies reported primary outcomes prespecified in the review protocol (blood loss of 1000 mL or more over the period of observation, maternal death or severe morbidity). Overall, there was no clear evidence of differences between groups in the following PPH outcomes: blood loss of 500 mL or more (risk ratio (RR) 1.45; 95% confidence interval (CI) 0.39 to 5.47, two studies), amount of lochia during the first 72 hours of the puerperium (mean difference (MD) -25.00 g; 95% CI -69.79 to 19.79, one study), or amount of lochia by four weeks postpartum (MD -7.00 g; 95% CI -23.99 to 9.99).

The Japanese study with a relatively small sample size comparing oral methylergometrine with a Japanese traditional herbal medicine found that oral methylergometrine significantly increased the blood haemoglobin concentration at day one postpartum (MD 0.50 g/dL; 95% CI 0.11 to 0.89) compared to herbal medicine. Adverse events were not well-reported in the included studies. We did not find any studies comparing homeopathic remedies with either a placebo or no treatment.

Authors' conclusions

There was insufficient evidence to support the use of prophylactic oral methylergometrine given after delivery of the placenta for the prevention of PPH. Additionally, the effectiveness of prophylactic use of herbal medicine or homeopathic remedies for PPH is still unclear as we could not find any clear evidence. Trials to assess the effectiveness of herbal medicines and homeopathic remedies in preventing PPH are warranted.

Résumé scientifique

Interventions prophylactiques après la délivrance du placenta pour réduire les saignements durant la période postnatale

Contexte

Plusieurs revues systématiques Cochrane examinent la prophylaxie de l'hémorragie du post-partum (HPP) dans la troisième phase du travail et une autre revue Cochrane portant sur le moment choisi pour administrer des utérotoniques prophylactiques dans la troisième phase du travail (avant ou après la délivrance du placenta). Cependant, aucune revue Cochrane n’examine d’interventions administrées purement après la délivrance du placenta. Dans certains pays, l’ergométrine ou le méthylergométrine sont utilisés pour la prévention de l'HPP durant la période post-partum (la période après l'accouchement du nourrisson) après l'expulsion du placenta. De plus, aucune revue Cochrane n’a considéré les traitements à base de plantes ou les remèdes homéopathiques pour la prévention de l'HPP après la délivrance du placenta.

Objectifs

Évaluer l'efficacité des interventions prophylactiques disponibles pour le traitement de l'HPP y compris l'administration prophylactique d'ergotamine, d'ergométrine, de méthylergométrine, des traitements à base de plantes et des remèdes homéopathiques, après la délivrance du placenta, par rapport à l'absence d’agents utérotoniques ainsi que par différentes voies d'administration pour la prévention de l'HPP après la délivrance du placenta.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais cliniques du groupe Cochrane sur la grossesse et la naissance (30 avril 2013), Food and Drug Administration (FDA) (États-Unis), et Healthcare Products Regulatory Medicines Agency (MHRA) (Royaume-Uni), European Medicines Agency (EMA) (eu), Pharmaceuticals and Medical Devices Agency (PMDA) (Japon), Therapeutic Goods Administration (TGA) (Australie), ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform (ICTRP), University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; Japan), Japan Pharmaceutical Information Center Clinical Trials Information (Japic-CTI; Japan), Japan Medical Association Clinical Trial Registration (JMACCT CTR; Japan) (tous au 30 avril 2013) et les références bibliographiques des études trouvées

Critères de sélection

Tous les essais contrôlés randomisés ou quasi-randomisés comparant l'administration prophylactique d'ergotamine, d'ergométrine, de méthylergométrine, de traitements à base de plantes et des remèdes homéopathiques (à l'aide de n'importe quelle voie et à n’importe quel moment d'administration) pendant la période post-partum après la délivrance du placenta à l'absence d’agents utérotoniques ou les essais comparant les différentes voies ou les différents moments d'administration d'ergotamine, d'ergométrine, de méthylergométrine, des traitements à base de plantes et des remèdes homéopathiques, pendant la période post-partum après la délivrance du placenta.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment évalué l'éligibilité et la qualité méthodologique des essais, extrait les données à l'aide du formulaire agréé. Nous avons vérifié l’exactitude des données.

Résultats principaux

Cinq études randomisées portant sur 466 femmes remplissaient les critères d'inclusion. Toutes les études ont été classées comme ayant un risque de biais incertain. Deux études (impliquant 1 097 femmes) comparaient le méthylergométrine par voie orale à un placebo, et un essai (impliquant 171 femmes) comparait le méthylergométrine par voie orale par rapport au Kyuki-chouketsu-in, une plante médicinale traditionnelle japonaise. Les deux autres études (totalisant 198 femmes) ne rapportaient pas les critères de jugement principaux pour cette revue. Aucune des études incluses n'avait rendu compte de critères de jugement principaux prédéfinis dans le protocole de la revue (une perte de sang supérieure à 1 000 ml par rapport à la période d'observation, le décès maternel ou la morbidité grave). Dans l’ensemble, il n'y avait aucune différence claire entre les groupes pour les critères de jugement HPP suivants: la perte de sang supérieure à 500 ml (risque relatif (RR) 1,45; intervalle de confiance (IC) à 95% de 0,39 à 5,47, deux études), la quantité de lochia pendant les 72 heures suivant le post-partum (différence moyenne (DM) -25,00 g; IC à 95% de 69,79 à 19,79, une étude), ou la quantité de lochia pendant quatre semaines postpartum (DM -7,00 g; IC à 95% de 23,99 à 9,99).

L'étude japonaise de taille relativement petite comparant le méthylergométrine par voie orale avec des plantes médicinales japonaises traditionnelles, a constaté que le méthylergométrine par voie orale a augmenté significativement la concentration en hémoglobine sanguine un jour après la naissance (DM 0,50 g/dl; IC à 95% 0,11 à 0,89) par rapport aux plantes médicinales. Les effets indésirables n'ont pas été correctement rapportés dans les études incluses. Nous n'avons trouvé aucune étude comparant des remèdes homéopathiques à un placebo ou à l'absence de traitement.

Conclusions des auteurs

Il n'y avait pas suffisamment de preuves pour recommander l'utilisation de méthylergométrine prophylactique oral administré après la délivrance du placenta pour la prévention de l'HPP. De plus, l'efficacité de l'utilisation prophylactique de plantes médicinales ou de remèdes homéopathiques pour le traitement de l'HPP n’est toujours pas claire, étant donné que nous n'avons pas trouvé de preuves précises. Des essais pour évaluer l'efficacité des plantes médicinales et des remèdes homéopathique dans la prévention de l'HPP sont nécessaires.

Plain language summary

Prophylactic interventions after delivery of placenta for reducing bleeding during the postnatal period

Haemorrhage following childbirth (postpartum haemorrhage) is a major cause of maternal death and health problems in resource-poor settings in both low- and high-income countries. Postpartum haemorrhage is defined as blood loss from the genital tract of more than 500 mL, generally occurring within the first 24 hours after delivering the placenta and occasionally between 24 hours and six to 12 weeks. Possible causes are the uterus (womb) failing to contract after delivery (uterine atony), a retained placenta, inverted or ruptured uterus, and cervical, vaginal, or perineal lacerations. To address these issues, the joint policy statements between the International Confederation of Midwives, the International Federation of Gynecology and Obstetrics, and the World Health Organization recommend 'active management of third stage of labour', which includes the administration of a uterotonic drug (intravenous oxytocin), just before or just after delivery in order to help the uterine muscles to contract. The use of oral uterotonic drugs such as methylergometrine for the prevention of postpartum haemorrhage after delivery of the placenta is not recommended in the joint policy statements. Yet orally delivered uterotonic drugs, such as ergot alkaloids (including methylergometrine), herbal therapies, or homeopathic remedies are easy-to-administer agents that may be considered as possible alternatives after delivery of the placenta in developing countries, as in Japan. We set out to determine whether such agents are effective in preventing haemorrhage after childbirth. We found a total of five randomised clinical trials (involving 1466 women). In three of the trials (involving 1268 women), oral methylergometrine was compared with placebo (two trials) or the Japanese traditional herbal medicine Kyuki-chouketsu-in (one trial). The other two trials (involving 198 women) did not report information on relevant outcomes of interest for this review. Overall, there was no clear evidence that prophylactic oral methylergometrine was effective in reducing haemorrhage after childbirth. The trials were not of good quality and adverse events were not well-reported. We did not find any completed trials looking at the effectiveness of homeopathic remedies in reducing haemorrhage after childbirth. The effectiveness of such remedies warrants further investigation.

Résumé simplifié

Interventions prophylactiques après la délivrance du placenta pour réduire les saignements durant la période postnatale

Une hémorragie après l'accouchement (hémorragie du post-partum) est une cause majeure de mortalité maternelle et de problèmes de santé dans les environnements aux ressources limitées aussi bien dans les pays à faible revenu qu’à revenu élevé. L'hémorragie du post-partum est définie comme une perte de sang supérieure à 500 ml provenant de l'appareil génital, généralement survenant dans les premières 24 heures après la délivrance du placenta et parfois entre 24 heures et 6 à 12 semaines. Les causes possibles sont : l'utérus ne parvient pas à se contracter après l'accouchement (atonie utérine), une rétention du placenta, une inversion ou une rupture de l'utérus et des lacérations cervicales, vaginales ou périnéales. Pour répondre à ces questions, les déclarations de principes communs entre la Confédération Internationale des Sages-Femmes, la Fédération Internationale de Gynécologie et d’Obstétrique et l'Organisation mondiale de la Santé recommandent « une prise en charge active de la troisième phase du travail », qui inclut l'administration d'un médicament utérotonique (l'ocytocine par voie intraveineuse), juste avant ou juste après l'accouchement afin d'aider les muscles de l'utérus à se contracter. L'utilisation d'utérotoniques oraux tels que le méthylergométrine pour la prévention de l'hémorragie du post-partum après la délivrance du placenta n’est pas recommandée dans les déclarations de principes communs. Toutefois, les médicaments utérotoniques, tels que l'ergot de seigle (y compris le méthylergométrine), les traitements à base de plantes, ou homéopathiques, sont faciles à administrer oralement et pourraient être considérés comme une alternative possible après la délivrance du placenta dans les pays en voie de développement, tels qu’au Japon. Nous avons cherché à déterminer si ces agents sont efficaces pour prévenir les hémorragies après l'accouchement. Nous avons trouvé un total de cinq essais cliniques randomisés (portant sur 466 femmes). Dans trois des essais (impliquant 1268 femmes), le méthylergométrine oral était comparé à un placebo (deux essais) ou à une plante médicinale japonaise traditionnelle, le Kyuki-chouketsu-in (un essai). Les deux autres essais (portant sur 198 femmes) n'ont pas rapporté d’informations sur les critères de jugement pertinents pour cette revue. Dans l’ensemble, il n'y avait pas de preuve claire que le méthylergométrine prophylactique oral était efficace pour réduire les hémorragies après l'accouchement. Les essais n'étaient pas de bonne qualité et les effets indésirables n'ont pas été correctement rapportés. Nous n'avons trouvé aucun essai terminé étudiant l'efficacité des remèdes homéopathiques dans la réduction des hémorragies après l'accouchement. L'efficacité de ces remèdes justifie la réalisation de recherches plus approfondies.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Minist�re Fran�ais des Affaires sociales et de la Sant�, Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Laienverständliche Zusammenfassung

Vorbeugende Maßnahmen nach der Geburt der Plazenta, um nachgeburtliche Blutungen zu verringern

Eine starke Blutung nach der Geburt (postpartale Hämorrhagie) ist eine der Hauptursachen für mütterliche Todesfälle und gesundheitliche Probleme in einem unterversorgten Umfeld, sowohl in Ländern mit niedrigem als auch mit hohem Einkommen. Als postpartale Hämorrhagie wird ein Blutverlust von mehr als 500 ml aus der Vagina definiert. Dieser tritt meist innerhalb der ersten 24 Stunden nach Geburt der Plazenta auf, gelegentlich zwischen 24 Stunden und 6 bis 12 Wochen. Mögliche Ursachen sind Folgende: der Uterus (die Gebärmutter) zieht sich nach der Geburt nicht genügend zusammen (Uterusatonie), die Nachgeburt (Plazenta) wird nicht vollständig geboren, der Uterus ist umgestülpt oder gerissen und Risse am Gebärmutterhals, an der Vagina oder am Damm. Um diese Probleme anzugehen, empfehlen die gemeinsamen Stellungnahmen der International Confederation of Midwives, der International Federation of Gynecology and Obstetrics sowie der Weltgesundheitsorganisation ein „aktives Management in der Nachgeburtsphase". Dies umfasst die Verabreichung von wehenfördernden Mitteln (intravenös verabreichtes Oxytocin) kurz vor oder nach der Geburt, um die Kontraktion der Gebärmutter zu unterstützen. Die Verwendung von oralen Kontraktionsmitteln, wie Methylergometrin, zur Vorbeugung von postpartalen Blutungen nach Geburt der Plazenta wird von den gemeinsamen Stellungnahmen nicht empfohlen. Doch oral verabreichte Kontraktionsmittel, wie Mutterkornalkaloide (inklusive Methylergometrin), pflanzliche Therapien oder homöopathische Arzneimittel sind einfach anzuwendende Mittel und könnten als mögliche Alternativen nach der Geburt der Plazenta in Entwicklungsländern berücksichtigt werden, sowie in Japan. Wir untersuchten, ob solche Mittel wirksam sind, um Blutungen nach der Geburt vorzubeugen. Wir haben insgesamt fünf randomisierte klinische Studien mit 1466 Frauen gefunden. In drei dieser Studien (mit 1268 Frauen) wurde orales Methylergometrin mit Placebo (zwei Studien) oder dem traditionellen japanischen pflanzlichen Heilmittel Kyuki-chouketsu-in (eine Studie) verglichen. Die beiden anderen Studien mit 198 Teilnehmerinnen haben keine relevanten Endpunkte für diesen Review berichtet. Insgesamt gab es keine klare Evidenz dafür, dass prophylaktisch oral eingenommenes Methylergometrin wirksam ist, um Blutungen nach der Geburt zu reduzieren. Die Studien waren von ungenügender Qualität und unerwünschte Ereignisse wurden nicht gut berichtet. Wir haben keine abgeschlossenen Studien gefunden, die sich mit der Wirksamkeit von homöopathischen Heilmitteln zur Verminderung von Blutungen nach der Geburt beschäftigen. Die mögliche Wirksamkeit solcher Heilmittel erfordert weitere Untersuchungen.

Anmerkungen zur Übersetzung

J. Honegger, C. Loytved, freigegeben durch Cochrane Deutschland.

Background

Description of the condition

Postpartum haemorrhage (PPH), or excessive bleeding at or after childbirth is a leading cause of maternal mortality and morbidity worldwide, accounting for approximately a quarter of deaths that occur as a consequence of complicated pregnancy (WHO 2005). Although the majority of these deaths occur in developing countries, industrialised countries also suffer from direct cause-related maternal mortality such as PPH. Several recent publications have documented an increasing incidence in PPH over time in resource-affluent settings (Cameron 2006; Ford 2007; Joseph 2007), including Australia, Canada, the UK, and the USA (Knight 2009).

The postpartum period is generally deemed to start after delivery of the infant. PPH is generally defined as blood loss from the genital tract in excess of 500 mL with severe postpartum haemorrhage (SPPH) being a loss of 1000 mL or more, and very SPPH being a loss of 2500 mL or more. PPH in the third stage of labour and PPH within the first 24 hours following delivery of the placenta (so called immediate PPH or primary PPH) form the majority of postpartum complications (Cunningham 2010). PPH or SPPH, however, occasionally develop even in the postpartum period between 24 hours and six to 12 weeks (so called delayed/late PPH or secondary PPH) (ACOG 2006). Therefore, the postpartum period between 24 hours and six to 12 weeks can also be a potentially hazardous period during childbirth. The dominant cause of primary PPH is uterine atony, whereas, secondary PPH can be associated with various causes. Secondary PPH is caused due to subinvolution of the placental site, retained products of conception, infection and inherited coagulation defects (ACOG 2006). Clinically problematic uterine haemorrhage develops within one to two weeks in 1% of women. Such bleeding predominantly occurs due to the abnormal involution of the placental site (Cunningham 2010).

Common causes of primary or secondary PPH include failure of the uterus to contract adequately after birth (atonic PPH), genital tract trauma (traumatic PPH), bleeding due to retention of placental tissue and coagulation disorders. Atonic PPH is the most prevalent among all of these conditions. In an effort to prevent uterine atony and associated bleeding, administering oxytocin soon after delivery is a routine management therapy (ACOG 2006). The joint policy statements between the International Confederation of Midwives (ICM) and the International Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization (WHO) have recommended active management of the third stage of labour that includes the administration of oxytocin or another uterotonic drug within one minute after the birth of the child, early umbilical cord clamping and cutting, controlled cord traction, and uterine massage after delivery of the placenta, as deemed appropriate. However, use of uterotonic drugs for the prevention of PPH after delivery of the placenta was not recommended in the statements (ICM-FIGO 2003; ICM-FIGO 2006; WHO 2009).

The use and management of drug therapies to prevent PPH after delivery of the placenta remains unclear. However, some studies (Andersen 1998; De Groot 1996a; Van Selm 1995) have reported different types of ergot alkaloids, and varying routes and timing of administration of prophylactic measures. Oral ergometrine or methylergometrine were considered as possible alternative prophylactic oxytocics that were easy to administer and suitable for use in developing countries (De Groot 1996b). Likewise, in a resource-affluent country such as Japan, the use of these prophylactic medications following delivery of the placenta is routinely administered (Okada 2005).

According to the published reviews investigating the role of oral ergometrine or methylergometrine, these medications are not satisfactory alternatives to parenteral prophylactic oxytocic drugs for the prevention of PPH for at least three reasons: using the tablets orally, they are less effective, unstable, and pharmacokinetically unreliable (De Groot 1996b; De Groot 1998). Therefore, effectiveness and safety of the prophylactic use of ergometrine following delivery of the placenta needs to be backed up by clear evidence.

Moreover, a varying number of agents are administered either in herbal forms or as homeopathic remedies for the third stage of labour management (Brucker 2001). Therefore, it can be assumed that apart from ergot alkaloids, numerous prophylactic interventions (e.g. herbal therapies, homeopathic remedies, and other oxytocic drugs) do exist to help with the prevention of PPH after delivery of the placenta. However, the effectiveness and safety of these prophylactic interventions are yet to be investigated.

Description of the intervention

Intramuscular or intravenous ergometrine and methylergometrine are, in general, used in the management of the third stage of labour and for the prevention of puerperal haemorrhage (WHO 2009). Oral ergometrine or methylergometrine were considered to be possible alternative oxytocics that were easy to administer and suitable for use in developing countries (De Groot 1996b). In Japan, methylergometrine is administered orally for the prevention of secondary PPH in women in the postnatal period after delivery of the placenta (Okada 2005).

Furthermore, herbal medicines or homeopathic remedies in the forms of tablets, tea or other preparations can also be used during the third stage of labour (Brucker 2001).

How the intervention might work

There are three groups of uterotonic agents: ergot alkaloids, oxytocin, and prostaglandins. The mechanisms through which these uterotonic agents work for the prevention of PPH are however, different. Oxytocin and prostaglandin function through oxytocin/prostaglandin receptors in the myometrium leading to fast and long-lasting rhythmic contractions. Ergometrine and methylergometrine are the most common types of ergot alkaloids and increase the muscle tone of the uterus with continuous (not rhythmic) tetanic contractions resulting in compressed myometrial blood vessels (De Groot 1998).

Ergometrine and methylergometrine improve uterine involution contributing to secondary PPH prevention, in which uterine subinvolution of the placental site is likely to be the underlying cause (ACOG 2006; Cunningham 2010). However, administration of ergometrine and methylergometrine may increase the risk of hazardous side effects in mothers such as hypertension and other complications of vasoconstriction. Moreover, intoxicated cases with severe complications including apnoea, coma, and convulsions in newborns have also been documented (Aeby 2003).

Prescribing herbal or homeopathic medicines on the other hand, depends on the characteristics of individual patients. Therefore, the overall concept of administering herbal or homeopathic medicines for PPH prevention is different to conservative Western medication therapies. Yet, herbal or homeopathic medicines must be considered as drug therapies, and therefore, evaluating the effectiveness of the usage of these non-conventional agents is equally important.

Why it is important to do this review

PPH continues to be a challenge in the prevention of maternal morbidity and mortality. Establishing useful methods for preventing PPH that are effective and safe are of vital importance. Administration of ergometrine or methylergometrine in the postpartum period might be one such useful method. Several Cochrane reviews investigating PPH prophylaxis in the third stage of labour (i.e., before or after the delivery of the placenta) looked at both of these drugs (Begley 2011; Cotter 2010; Liabsuetrakul 2011; McDonald 2009; Mori 2012; Novikova 2011; Oladapo 2012; Rohwer 2012; Su 2012; Tunçalp 2012) as well as other measures (Hofmeyr 2010; Peña-Martí 2010; Soltani 2011). Another Cochrane review examined the timing of prophylactic uterotonics in the third stage of labour (Soltani 2010). Current evidence provided from these Cochrane reviews, in general, favours active management over passive management of this stage of labour, involving administration of a prophylactic oxytocic before delivery of the placenta. However, there are no Cochrane reviews looking at the use of prophylactic interventions given purely after delivery of the placenta. In addition, there are no Cochrane reviews investigating herbal therapies or homeopathic remedies for the prevention of PPH after delivery of the placenta.

Existing evidence indicates that ergometrine or methylergometrine are used for the prevention of PPH in the postpartum period after delivery of the placenta in developing countries, including a high-income country, Japan. However, the effectiveness and safety of prophylactic usage of these drugs are not clear and must therefore be systematically assessed. Furthermore, understanding the balance between the risks and benefits of such an intervention is crucial.

Objectives

To assess the effectiveness of available prophylactic interventions for PPH including prophylactic use of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, administered after delivery of the placenta, compared with no uterotonic agents as well as with different routes of administration for prevention of PPH after delivery of the placenta.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised or quasi-randomised (such as alternate allocation or allocation by health insurance number, hospital record, etc.) controlled trials comparing prophylactic ergometrine, methylergometrine, or other agents (using any route and timing of administration) with no uterotonic agents during the postpartum period after delivery of the placenta, or comparing different routes or timing of administration of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies during the postpartum period after delivery of the placenta. We included well-conceptualised studies that provided sufficient information for the targeted evaluation. Studies that did not provide sufficient information for the targeted evaluation were incorporated into the 'Studies awaiting classification' category until they are published as full reports.

Types of participants

Women who have had a spontaneous vaginal delivery.

Types of interventions

Ergometrine, methylergometrine, or other agents administered by any route or timing of administration for the prevention of postpartum haemorrhage after delivery of the placenta.

Comparisons
  1. Ergometrine/methylergometrine versus placebo/no treatment.

  2. Ergometrine/methylergometrine administration via different routes: oral versus intravenous, oral versus intramuscular or subcutaneous, intravenous versus intramuscular or subcutaneous.

  3. Herbal medicine versus ergometrine/methylergometrine (any route or dosage), or versus placebo/no treatment.

  4. Homeopathic remedy versus one of the following: ergometrine/methylergometrine (any route or dosage), herbal medicine, placebo/no treatment.

  5. Other agents versus ergometrine/methylergometrine (any route or dosage), or versus placebo/no treatment.

Types of outcome measures

Primary outcomes
  • Blood loss of 1000 mL or more over the period of observation (as determined by the trial investigator)

  • Maternal death or severe morbidity (e.g., major surgery, organ failure, hyperpyrexia, intensive care unit admission, hysterectomy, compression sutures, artery ligations, or as defined by trial authors)

Secondary outcomes
  • Maternal death; individual components of severe morbidity (as listed above or as defined by the trial authors)

  • Blood loss of 500 mL or more over the period of observation (as determined by the trial investigator)

  • Blood transfusion

  • Use of therapeutic uterotonics

  • Additional treatment for postpartum haemorrhage (uterine tamponade, X-ray, embolisation)

  • Side effects reported either individually or combined, when appropriate, e.g., vomiting, nausea, elevation of diastolic blood pressure, shivering, headache, chest pain, shortness of breath, pyrexia, and diarrhoea

  • Postnatal anaemia (defined by trial authors, absolute or relative drop in haemoglobin)

  • Thromboembolic events

  • Cost involved in the treatment sought

  • Amount of lochia (vaginal discharge after giving birth) during the first 72 hours postpartum (outcome not prespecified)

  • Amount of lochia by four weeks postpartum (outcome not prespecified)

  • Duration of lochia of more than four weeks (outcome not prespecified)

  • Endometritis (outcome not prespecified)

  • Pain requiring analgesia (outcome not prespecified)

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register by contacting the Trials Search Co-ordinator (30 April 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.  

To find clinical trials for approval of new drugs, we also searched the following databases through 30 April 2013:

  • The Food and Drug Administration (FDA) in the USA

  • The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK

  • The European Medicines Agency (EMA) in the EU

  • The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan

  • The Therapeutic Goods Administration (TGA) in Australia

For ongoing trials, we searched the following trial registers through 30 April 2013:

Searching other resources

We checked references cited in papers identified through the above search strategy to retrieve additional relevant studies. 

We also considered abstracts for inclusion, if sufficient information was provided.

We did not apply any language restrictions.

Data collection and analysis

Selection of studies

The inclusion of studies identified through the search strategy was independently assessed by two review authors, Yukari Yaju (YY) and Yaeko Kataoka (YK). We resolved any disagreement through discussion among the review authors.

Data extraction and management

We designed a form that would enable us to extract data. For eligible studies, two review authors (YY, YK) used the form to extract the data independently. We resolved discrepancies through discussion among the review authors. We used the Review Manager software (RevMan 2011) for data entry and checked the accuracy of the data entry. When information about the studies was unclear, we contacted the authors of the original reports to obtain further details. We contacted the authors of two studies (Andersen 1998; Arabin 1986) to request details on random sequence generation and prespecified outcomes and received a satisfactory answer from the author of one study (Arabin 1986). We contacted the author of one study (Ushiroyama 2003) to ask about inconsistency in blood haemoglobin concentrations reported in his article and he provided an appropriate answer. Further, we contacted the author of one study (Grünberger 1983) to request details of outcomes but received no reply. The review authors were not blinded to the names of authors, journals, or institutions.

Assessment of risk of bias in included studies

Two review authors (YY, YK) independently assessed risk of bias in each included study using The Cochrane Collaboration's tool for assessing risk of bias, outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and contained in RevMan (RevMan 2011). Any disagreement was resolved by discussion.

(1) Sequence generation (checking for possible selection bias)

For each included study, we described the method used in the sequence generation process in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the methods as:

  • yes (low risk of bias) (any truly random process, e.g. referring to a random number table, using a computer random number generator, minimisation method);

  • no (high risk of bias) (any non-random process, e.g. odd or even date of birth, some rule based on date or day of admission, some rule based on hospital or clinic record number); or

  • unclear (uncertain risk of bias) (insufficient information about the sequence generation process to permit judgement of 'yes' or 'no').

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

For each included study, we described the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

  • yes (low risk of bias) (e.g. central allocation including telephone, web-based and pharmacy-controlled randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes);

  • no (high risk of bias) (using an open random allocation schedule such as a list of random numbers, assignment envelopes without appropriate safeguards [e.g., unsealed or non-opaque], alternation or rotation, date of birth, case record number, any other explicitly unconcealed procedure); or

  • unclear (uncertain risk of bias) (insufficient information to permit judgement of 'yes' or 'no').

(3) Blinding of participants, personnel and outcome assessors (checking for possible performance bias)

For each included study, we described the methods used, if any, to blind study participants, personnel, and outcome assessors from knowledge of which intervention a participant received. We judged studies to be at low risk of bias if they were blinded, or if we judged that the outcome and the outcome measurement were not likely to be influenced by lack of blinding (e.g. for certain outcomes such as haemoglobin concentration, non-blinding of outcome assessors could not have affected the results). We assessed the methods for blinding under the headings: study participants, personnel and outcomes.

We assessed the methods as:

  • yes (low risk of bias) (blinding of participants and key study personnel was ensured, and it was unlikely that the blinding could have been broken; either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others was unlikely to introduce bias; or there was no blinding, but we judged that the outcome and the outcome measurement were not likely to be influenced by the lack of blinding);

  • no (high risk of bias) (there was no blinding or incomplete blinding, and the outcome or outcome measurement was likely to be influenced by lack of blinding; either participants or some key study personnel were not blinded, and the non-blinding of others was likely to introduce bias; or blinding of key study participants and personnel was attempted, but it was likely that the blinding could have been broken); or

  • unclear (uncertain risk of bias) (there was insufficient information to permit judgement of 'yes' or 'no'; or the study did not address the method of blinding).

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, and protocol deviations)

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

We assessed the methods as:

  • yes (low risk of bias) (no missing outcome data; reasons for missing outcome data were unlikely to be related to true outcome; missing outcome data were balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data the proportion of missing outcomes compared with the observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, the plausible effect size among missing outcomes was not enough to have a clinically relevant impact on the observed effect size; or missing data were imputed using appropriate methods);

  • no (high risk of bias) (the reason for missing outcome data was likely to be related to the true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with the observed event risk was enough to induce clinically relevant bias in the intervention effect estimate; for continuous outcome data, the plausible effect size among missing outcomes was enough to induce clinically relevant bias in the observed effect size; 'as-treated' analysis was done with substantial departure in the intervention received from that assigned at randomisation; or there was potentially inappropriate application of a simple imputation); or

  • unclear (uncertain risk of bias) (there was insufficient reporting of attrition/exclusions to permit judgement of 'yes' or 'no', e.g., the number randomised was not stated; or no reasons for missing data were provided; or the study did not address this outcome).

(5) Selective reporting bias

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • yes (low risk of bias) (the study protocol was available, and all of the study's prespecified primary and secondary outcomes of interest were reported in the prespecified way; or the study protocol was not available but it was clear that the published reports included all expected outcomes, including those that were prespecified);

  • no (high risk of bias) (not all of the study's prespecified primary outcomes were reported; one or more primary outcomes were reported using measurements, analysis methods or subsets of the data that were not prespecified; one or more reported primary outcomes were not prespecified; one or more outcomes of interest were reported incompletely so that they could not be entered in a meta-analysis; or the study report failed to include results for a key outcome that would be expected to have been reported for such a study); or

  • unclear (uncertain risk of bias) (there was insufficient information to permit judgement of 'yes' or 'no').

(6) Other potential threats to validity

For each included study, we described any important concerns we had about other possible sources of bias. We assessed whether each study was free of other problems that could put it at a risk of bias (e.g., issues with the specific study design, trial stopped early, or extreme baseline imbalance):

  • yes (low risk of bias) (the study was free of other sources of bias);

  • no (high risk of bias) (the study had a potential source of bias related to the specific study design used; was stopped early due to some data-dependent process that included a formal-stopping rule; had extreme baseline imbalance; has been claimed to have been fraudulent; or had some other problem); or

  • unclear (uncertain risk of bias) (there was insufficient information to assess whether an important risk of bias existed; or there was insufficient rationale or evidence that an identified problem will introduce 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 Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and considered whether it was likely to impact the findings. We planned to explore the impact of the bias by undertaking sensitivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CIs).

Continuous data

For continuous data, we used the mean difference where outcomes were measured in the same way between trials. In future updates of this review we will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster-randomised trials

We did not identify any cluster-randomised trials, such as trials involving randomisation by clinician or practice. In future updates, if we identify any cluster-randomised trials for inclusion, we will include them in the analyses along with individually-randomised trials. Their sample sizes will be adjusted using the methods described in Gates 2005 using an estimate of the intra-cluster correlation coefficient (ICC) derived from the trial (if possible) or from another source. If ICCs from other sources are used, we will report and conduct sensitivity analyses to investigate the effect of variation in them. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and an interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We will seek statistical advice for this part of the analysis.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit. Therefore, the meta-analysis will be performed in two parts.

Cross-over trials

We did not include cross-over trials because the cross-over design is not applicable for testing the effectiveness of interventions for PPH.

Studies with multiple treatment groups
1. Multiple dose groups

We expected that some studies would address the effects of different doses of ergometrine or methylergometrine compared with, for example, a placebo (e.g., methylergometrine at 0.125 mg/day versus placebo, or methylergometrine at 0.25 mg/day versus placebo). Therefore, we planned to sum up the sample sizes and the number of people with events across both (methylergometrine) experimental groups. However, we did not identify any such studies.

2. Multiple medications

We also expected that some other studies would combine several interventions into one comparison group (e.g., a three-arm study comparing methylergometrine and oxytocin with placebo). In this case, we planned to analyse the effects of methylergometrine and oxytocin versus placebo separately but to divide up the total number of participants in the placebo group. However, we did not identify any such studies.

Dealing with missing data

For included studies, we planned to note levels of attrition whenever this was an issue. Furthermore, we planned to explore the impact of included studies having high levels of missing data in the overall assessment of treatment effect using sensitivity analysis.

For all outcomes, analyses were performed on an intention-to-treat (ITT) principle when possible, i.e., we attempted to include all participants randomised to each group in the analyses, and participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The ITT principle is conservative for outcomes related to response to treatment. Since it is not necessary to be conservative for adverse event outcomes, we planned to perform both an ITT analysis and a 'per protocol' analysis for such outcomes.

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 the P value was low (less than 0.10) in the Chi² test.

Assessment of reporting biases

If there had been 10 or more studies in the meta-analysis, we planned to investigate reporting biases (such as publication bias) using funnel plots. In future updates, if more than 10 studies are included, we will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2011). We used fixed-effect and random-effects models for combining data. If there had been no statistical heterogeneity and no significant differences in the pooled estimates between the fixed-effect and random-effects models, we addressed only the results obtained using the fixed-effect model.

Whenever we suspected clinical or methodological heterogeneity between studies sufficient to expect that treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we addressed the results with the random-effects model.

Subgroup analysis and investigation of heterogeneity

We planned to carry out prespecified subgroup analysis but this was not possible due to the limited number of studies, all having a small sample size. In future updates we will carry out the following subgroup analyses on the primary outcomes.

  1. Spontaneous versus operative vaginal birth.

  2. Deliveries with the use of oxytocics versus without the use of oxytocics.

  3. Deliveries with the use of epidural analgesia versus without the use of epidural analgesia.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2011). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We planned to carry out the following sensitivity analyses if there had been a clear risk of bias associated with the quality of any of the included studies.

  1. Excluding quasi-randomised trials and trials with unclear concealment of random allocation and/or unclear double blinding.

  2. Excluding trials whose drop-out rate was greater than 20%.

We did not, however, conduct sensitivity analyses because no such studies were available.

Results

Description of studies

This review included five randomised trials (involving 1466 women). Oral methylergometrine was compared with a placebo in two studies conducted in Denmark (Andersen 1998) and Germany (Arabin 1986). In one trial (Ushiroyama 2003) conducted in Japan, oral methylergometrine was compared with Kyuki-chouketsu-in, a Japanese traditional herbal medicine. Ergometrine tartrate tablets administered after intramuscular injection of methylergometrine were compared with no ergot derivatives in one study (Jolivet 1978) conducted in France. In the remaining study (Klug 1983), conducted in Austria, oral methylergometrine was compared with no medication. See table of Characteristics of included studies.

Results of the search

The search of the Cochrane Pregnancy and Childbirth Group's Trials Register retrieved 11 trial reports. These included two studies in which oral methylergometrine was compared with a placebo (Andersen 1998; Arabin 1986), three studies in which oral methylergometrine was compared with no treatment (Arabin 1982; Del Pozo 1975; Klug 1983), three studies (Grünberger 1983; Ushiroyama 2003; Vogel 2004) in which head-to-head comparisons were made (oral methylergometrine versus oral prostaglandin E2; oral methylergometrine versus Kyuki-chouketsu-in; oral methylergometrine versus oral misoprostol), one study (Jolivet 1978) in which intramuscular methylergometrine plus oral ergotamine tartrate was compared with no rye ergot derivatives, and one study (two reports) (Oberbaum 2005) in which a homeopathic remedy (Arnica montana plus Bellis perennis) was compared with a placebo. We evaluated the full texts of the 11 trial reports and excluded two of these (Del Pozo 1975; Vogel 2004) for reasons described in the Excluded studies section below. Two trials were considered studies awaiting classification (Arabin 1982; Grünberger 1983), and the last two reports were of one ongoing trial (Oberbaum 2005). We did not identify any additional studies by searching through the Japanese clinical trial registers: UMIN-CTR, Japic-CTI, and JMACCT CTR. We therefore reviewed three remaining randomised trials.

Included studies

Five randomised studies (Andersen 1998; Arabin 1986; Jolivet 1978; Klug 1983; Ushiroyama 2003) involving 1466 women met our inclusion criteria. Of these, two studies (Andersen 1998; Arabin 1986) compared methylergometrine with a placebo. One study (Ushiroyama 2003) compared methylergometrine with Kyuki-chouketsu-in, a Japanese traditional herbal medicine. The remaining two studies (Jolivet 1978; Klug 1983) did not explore the effects of the intervention on postpartum haemorrhage and did not report on the outcomes of interest of this review. Therefore, the two studies did not contribute any data towards the analyses. There were no included studies that compared different routes of administration of ergometrine or methylergometrine.

(1) Settings

All studies included in this review were carried out in developed countries where maternal mortality was low, namely Denmark (Andersen 1998), Germany (Arabin 1986), France (Jolivet 1978), Austria (Klug 1983), and Japan (Ushiroyama 2003).

(2) Participants

The criteria for inclusion were defined in four of the studies (Andersen 1998; Jolivet 1978; Klug 1983; Ushiroyama 2003). In the Denmark study (Andersen 1998), participants were women who had a single pregnancy with no evidence of pregnancy complications, and had no contra-indications for methylergometrine (hypertension and vascular diseases). The authors did not report exclusion criteria. In two studies (Jolivet 1978; Klug 1983), participants were postpartum women who had given birth at full term. In the Japanese study (Ushiroyama 2003), participants were women who had spontaneous labour pain followed by a normal delivery. Pregnant women were excluded from the study if they required special management due to pregnancy complications such as breech presentation, gestational toxicosis, diabetes mellitus, multiple conception, or premature rupture of membranes. The remaining study (Arabin 1986) did not clearly report the inclusion/exclusion criteria.

(3) Interventions

Two studies (Andersen 1998; Arabin 1986) compared oral methylergometrine with a placebo. Oral methylergometrine with Kyuki-chouketsu-in, a Japanese traditional herbal medicine, were compared in a trial (Ushiroyama 2003) executed in Japan. In the Denmark study (Andersen 1998), the effect of 0.125 mg oral methylergometrine three times a day for three consecutive days following intravenous 0.2 mg methylergometrine after delivery of the placenta was investigated. In the two other studies (Arabin 1986; Ushiroyama 2003), the experimental intervention involved the administration of 0.125 mg of oral methylergometrine three times a day. The administration period of the oral methylergometrine varied from one day to four weeks (Andersen 1998: three days; Arabin 1986: four weeks; Ushiroyama 2003: one day). One study (Ushiroyama 2003) administered cefditoren pivoxil, an antibiotic, at a dose of 300 mg/day and serapeptase, an anti-inflammatory enzyme preparation, at a dose of 30 mg/day to all women enrolled in the study.

In two studies (Jolivet 1978; Klug 1983), methylergometrine was compared with no medication. In the study Jolivet 1978, the experimental intervention comprised of an intramuscular injection of 0.2 mg methylergometrine immediately after delivery, followed by 1.0 mg ergotamine tartrate tablets three times a day for the first six days postpartum. In the study Klug 1983, the experimental intervention involved the administration of 0.125 mg of methylergometrine orally three times a day for eight days.

(4) Outcomes

One prespecified outcome, clinically estimated blood loss of at least 500 mL, was reported in two studies (Andersen 1998; Arabin 1986). Another prespecified outcome, postnatal anaemia, or a postnatal absolute drop in haemoglobin, was reported in the third study (Ushiroyama 2003). The following outcomes were not prespecified but were reported in the review: amount of lochia during the first 72 hours of the puerperium (Andersen 1998), amount of lochia by four weeks postpartum (Arabin 1986), duration of lochia of more than four weeks (Arabin 1986), endometritis (Andersen 1998; Arabin 1986), and pain requiring analgesia (Andersen 1998).

Two studies (Jolivet 1978; Klug 1983) did not report on the outcomes of interest of this review.

Excluded studies

We excluded two studies because: one (Del Pozo 1975) lacked a clear study design; and in the other (Vogel 2004), eligibility criteria of the participants did not meet the review criteria. Descriptions of the excluded studies along with the reasons for exclusion are reported in the Characteristics of excluded studies tables.

Studies awaiting classification

We contacted five authors (Arabin 1982; Del Pozo 1975; Grünberger 1983; Klug 1983; Ushiroyama 2003) and asked for supplementary information. Two of these studies (Arabin 1982; Grünberger 1983) are awaiting classification pending further information because we have received no reply from the authors. (see Characteristics of studies awaiting classification).

Ongoing studies

We classified one study (Oberbaum 2005) as an ongoing study because the trial reports provided an interim analysis of the trial and a conference abstract. (see: Characteristics of ongoing studies).

Risk of bias in included studies

Allocation

Sequence generation

Two studies (Andersen 1998; Ushiroyama 2003) reported the use of blinded envelopes to allocate women to treatment groups and they did not provide any information on how the random numbers for the envelopes were generated. In the study by Arabin 1986, there was insufficient information to make a judgement as to whether the sequence allocation was adequate due to a lack of detailed information on sequence generation. We asked each author of these three studies to provide further information about the random sequence generation process and received a satisfactory answer from only one author (Arabin 1986). The author verified that they performed block randomisation using a computer-generated sequence number. Hence, we assessed two studies (Andersen 1998; Ushiroyama 2003) as 'unclear risk of bias' and one study (Arabin 1986) as 'low risk of bias' for sequence generation.

One study (Jolivet 1978) reported that two groups were set up randomly, but no information was provided on how random allocation was performed. In one study (Klug 1983), alternate allocation in a consecutive series was performed.

Allocation concealment

In all the included studies, the method used to conceal allocation was unclear.

In two studies (Andersen 1998; Ushiroyama 2003), there was no information regarding how the envelopes were prepared and managed. Therefore, we concluded that the absence of adequate allocation concealment could lead to selection bias in these two studies. In the study by Arabin 1986, there was insufficient information to make the judgement of adequate or inadequate allocation concealment as the allocation concealment method was not provided in detail. We asked the author of Arabin 1986 about the concealment process but received no satisfactory answers. Therefore, we assessed all three studies (Andersen 1998; Ushiroyama 2003; Arabin 1986) as 'unclear risk of bias' for allocation concealment.

In two studies (Jolivet 1978; Klug 1983), no information was provided on how alternate allocation was performed. We assessed these two studies (Jolivet 1978; Klug 1983) as 'unclear risk of bias' for allocation concealment.

Blinding

Method of blinding (participants and clinicians) was reported in two studies (Andersen 1998; Arabin 1986) that compared oral methylergometrine with a placebo. The study led by Ushiroyama 2003 compared oral methylergometrine tablets with Kyuki-chouketsu-in granules, a Japanese traditional herbal medicine, with no blinding. However, how outcome assessors were blinded was not presented in any of these studies. Therefore, in the identification for performance bias, we classified two studies (Andersen 1998; Arabin 1986) as 'low risk of bias', and one study (Ushiroyama 2003) as 'high risk of bias'. In addition, we assessed all studies as 'unclear risk of bias' for detection bias.

In two studies (Jolivet 1978; Klug 1983), we assessed these two studies as 'high risk of bias' for blinding as the control group was no medication.

Incomplete outcome data

We assessed loss of participants to follow-up, missing outcomes and lack of intention-to-treat analyses in one included study (Andersen 1998): four women in the methylergometrine group and two women in the placebo group were excluded. Each proportion of missing data was 3.8% in the methylergometrine group and 1.9% in the placebo group. The proportions of missing outcomes compared with observed events risk, e.g. incidence of endometritis were two (1.87%) in the treatment group and one (0.96%) in the placebo group, and this might be enough to have a clinically relevant impact on the intervention effect estimate. Furthermore, the analysis was not intention-to-treat and it was not possible that the data could be re-included.

In the study by Arabin 1986, all participants entered in the study were accounted for in the prespecified outcome measure, postpartum haemorrhage (PPH), which was evident from the number of allocated participants given in the tables and figures. Therefore, the study appeared to perform the analyses on an intention-to-treat principle. In the study by Ushiroyama 2003, it was not possible to assess the completeness of the follow-up as the study did not describe the number of the outcome measured participants.

In summary, two studies (Andersen 1998; Arabin 1986) were assessed as 'low risk of bias' and the remaining study (Ushiroyama 2003) was assessed as 'unclear risk of bias' for attrition bias.

Two studies (Jolivet 1978; Klug 1983), which did not report on the outcomes of interest of this review, were assessed for this risk of bias domain. Jolivet 1978 did not provide any information about incomplete outcome data (unclear risk of bias) but Klug 1983 appears to be free of attrition bias.

Selective reporting

We did not have access to the study protocols and therefore, formal assessment of reporting bias was not possible. In the "protocol" section of the study by Ushiroyama 2003, it was stated that evaluation was performed between days one and six postpartum to determine the height of the uterine fundus, anxillary temperature was taken at 6:00 in the morning and a blood sample was obtained to determine blood haemoglobin, plasma total protein, albumin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), alkaline phosphatase, leucine aminopeptidase (LAP), total cholesterol, triglyceride and C-reactive protein (CRP). We did not suspect selective reporting in this trial as all of these outcomes were reported. Therefore, this study (Ushiroyama 2003) was assessed as being free of selective reporting bias. We assessed the two other studies (Andersen 1998; Arabin 1986) as being 'unclear risk of bias'.

We did not assess reporting bias for two studies (Jolivet 1978 ; Klug 1983), as they did not report on the outcomes of interest of this review.

Other potential sources of bias

We considered the risk of other bias to be 'unclear' for all five included studies. Full details of 'Risk of bias' assessments are included in the Characteristics of included studies tables. We have also included figures which summarise our 'Risk of bias' assessments (Figure 1; Figure 2).

Figure 1.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Figure 2.

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

Effects of interventions

This review includes data from three studies comparing oral methylergometrine with either a placebo or a Japanese traditional herbal medicine with a total of 641 women in the methylergometrine group and 627 in the placebo or Japanese traditional herbal medicine group. None of the included studies reported the following outcomes that were prespecified in the review protocol (primary outcomes: blood loss of 1000 mL or more over the period of observation, maternal death or severe morbidity; secondary outcomes: maternal death, individual components of severe morbidity, blood transfusion, use of therapeutic uterotonics, additional treatment for PPH, side effects reported either individually or as a composite where appropriate, thromboembolic events, and cost). Non-prespecified outcomes relating to PPH were reported in some included studies. We therefore have included some non-prespecified outcomes and performed meta-analyses for the following outcomes: (1) prespecified secondary outcomes: PPH (PPH: blood loss of 500 mL or more over the period of observation); blood haemoglobin concentration at day one postpartum; (2) non-prespecified outcomes: amount of lochia during the first 72 hours of the puerperium; amount of lochia by four weeks postpartum; duration of lochia more than four weeks; endometritis; and post-birth pain requiring analgesia (requests for paracetamol).

(1) Oral methylergometrine versus placebo

Secondary outcome
Blood loss of 500 mL or more over the period of observation

Oral methylergometrine was not associated with a decrease in PPH: risk ratio (RR) 1.45, 95% confidence interval (CI) 0.39 to 5.47, two studies (Andersen 1998; Arabin 1986), involving 1097 women, with a random-effects model. We observed significant heterogeneity (Tau2 = 0.72, I2 = 75%) (Analysis 1.1).

Non-prespecified outcomes

Results were quoted from only one study (Andersen 1998 or Arabin 1986) except for 'Endometritis'.

Amount of lochia during the first 72 hours postpartum (g)

In the Denmark study (Andersen 1998), no statistically significant decrease was demonstrated in the amount of lochia during the first 72 hours of the puerperium (Analysis 1.2) when methylergometrine was compared with placebo (mean difference (MD) -25.00, 95% CI -69.79 to 19.79).

Amount of lochia by four weeks postpartum (g)

In the German study (Arabin 1986), the mean amount of lochia by four weeks postpartum was not significantly low in the methylergometrine group (MD -7.00, 95% CI -23.99 to 9.99) (Analysis 1.3).

Duration of lochia of more than four weeks

Arabin 1986 reported that the incidence of prolonged length of duration of lochia for more than four weeks postpartum was increased in the methylergometrine group and was statistically significant (RR 1.26, 95% CI 1.13 to 1.40) (Analysis 1.4).

Endometritis

No significant difference was seen in the incidence of endometritis between the two groups (RR 1.60, 95% CI 0.76 to 3.36) (Andersen 1998; Arabin 1986) and there was no heterogeneity observed (I2 = 0%) (Analysis 1.5).

Pain requiring analgesia (requests for paracetamol)

The risk of pain after birth requiring analgesia was slightly increased in one study (Andersen 1998); however, it was not statistically significant (RR 1.19, 95% CI 0.87 to 1.62) (Analysis 1.6).

(2) Oral methylergometrine versus oral Kyuki-chouketsu-in

Secondary outcome
Blood haemoglobin concentration at day one postpartum (g/dL)

In one study (Ushiroyama 2003) comparing methylergometrine with Kyuki-chouketsu-in, methylergometrine significantly increased the blood haemoglobin concentration at day one postpartum (MD 0.50, 95% CI 0.11 to 0.89) (Analysis 2.1).

Discussion

Summary of main results

This systematic review aimed to evaluate the effectiveness and safety of all prophylactic interventions for postpartum haemorrhage (PPH), including ergometrine, methylergometrine, herbal therapies and homeopathic remedies, in the postpartum period after delivery of the placenta. Five randomised or quasi-randomised studies were eligible to be included in this review. Three of them reported outcomes of interest of this review. The three studies that contributed data towards the analyses were of moderate quality and compared methylergometrine with either a placebo or Kyuki-chouketsu-in, a Japanese traditional herbal medicine. Evidence from these studies suggests that the use of oral methylergometrine did not significantly reduce the incidence of moderate PPH, or the amount of lochia during the first 72 hours postpartum, and the amount of lochia by four weeks postpartum when compared with a placebo. In two of these studies (Andersen 1998; Arabin 1986), an insignificantly higher incidence of endometritis was found in the methylergometrine group. On the contrary, one study demonstrated that the use of oral methylergometrine was significantly associated with higher postnatal haemoglobin concentration when compared with oral Kyuki-chouketsu-in, a Japanese traditional herbal medicine. In terms of adverse reactions to methylergometrine, one study found an non-significant increasing trend in requests for paracetamol. We identified one study, reported in two publications, that compared homeopathic remedies with a placebo; however, we did not include it in this review because it is an interim analysis report of an ongoing clinical trial. Therefore, any evidence on the effectiveness of the prophylactic use of homeopathic remedy for PPH was not possible to obtain.

Overall completeness and applicability of evidence

This review included five randomised trials published since 1978. The results suggested that oral methylergometrine administered after delivery of the placenta may not prevent PPH.

In two of the studies (Andersen 1998; Arabin 1986), oral methylergometrine did not reduce the risk of postpartum blood loss of at least 500 mL. In these two studies, heterogeneity was substantially high (75%), and the confidence interval was wide. In one of these studies (Arabin 1986), there was a trend toward higher risk of PPH in the oral methylergometrine group. The definition of PPH, however, was not clearly described in the study. Furthermore, there were caesarean section cases among the participants: 85 in the Methergin group and 77 in the placebo group. Therefore, the results should be interpreted with caution. In contrast, Andersen 1998 showed a trend toward a lower incidence of moderate PPH (blood loss 500 mL or more) in the group that received methylergometrine (a combination of intravenous and oral). A previous Cochrane review on prophylactic use of ergot alkaloids in the third stage of labour (Liabsuetrakul 2011) showed that intravenous or intramuscular ergot alkaloids administered in the third stage of labour significantly lowered the mean blood loss and reduced the incidence of postpartum blood loss of at least 500 mL. However, oral ergot alkaloids had no effects on either mean blood loss or the incidence of postpartum blood loss of at least 500 mL. Hence, it would be reasonable to consider that oral methylergometrine has no additional effects on moderate PPH after the administration of intravenous or intramuscular methylergometrine following delivery of the placenta.

In the study by Andersen (Andersen 1998), a non-significant trend was seen in favour of oral methylergometrine decreasing the amount of lochia during the first 72 hours of the puerperium. In the study by Arabin (Arabin 1986), oral methylergometrine showed a non-significant trend towards reduction in the amount of lochia during the first four weeks postpartum. These results agree with the findings of an earlier Cochrane review (Liabsuetrakul 2011) assessing the effectiveness and safety of prophylactic use of ergot alkaloids in the third stage of labour, and that concluded that oral ergot alkaloids had no effect on PPH.

In the study by Arabin (Arabin 1986), there was a statistically significantly higher increase in the incidence of a lochia duration of more than four weeks in the methylergometrine group than in the placebo group. The proportion of women who had this prolonged lochia duration was 305/444 in the methylergometrine group and 238/436 in the placebo group. These proportions of women who experienced prolonged duration of lochia more than four weeks did not appear to be clinically relevant. This result, therefore, requires careful interpretation.

Two studies (Andersen 1998; Arabin 1986) suggested that oral methylergometrine might increase the incidence of endometritis. However, the strength of the evidence is limited by a relatively low pooled estimate of the risk ratio (RR) (1.60), a wide confidence interval (CI), and low heterogeneity. Therefore, cautious interpretation of these findings are warranted. We concluded that there is no clear evidence on whether oral methylergometrine increases the incidence of endometritis.

In the study by Ushiroyama (Ushiroyama 2003), the authors found that oral methylergometrine was associated with a significantly higher postnatal haemoglobin concentration than was oral Kyuki-chouketsu-in. However, the difference in the postnatal haemoglobin concentration between the groups did not appear to be clinically relevant. There have been no published randomised studies comparing Kyuki-chouketsu-in with a placebo or 'no treatments'. Thus, we have insufficient information to determine the effectiveness of the Kyuki-chouketsu-in as a treatment for postnatal anaemia relative to that of a placebo or no treatments.

The Andersen 1998 study showed a non-significant trend towards increased risk of post-birth pain requiring analgesia. The RR, however, was 1.18, which was not statistically significant. The statistical insignificance could be explained by the small study sample size resulting in insufficient power to detect any difference. It is noteworthy that the trend towards increased risk of pain after birth requiring analgesia documented in Andersen 1998 was in accordance with the result of a previous Cochrane review (Liabsuetrakul 2011), in which the authors demonstrated that intravenous or intramuscular ergot alkaloids increased the risk of post-birth pain requiring analgesia.

Quality of the evidence

Overall, the methodological quality of the studies included in this review was moderate, and all studies were classified as having an unclear risk of bias.

In all three included studies, the methods used to generate random sequence and allocation concealment were not clearly described. We classified two of the studies (Andersen 1998; Arabin 1986) as having a low risk of performance bias, due to placebo-controlled blinding, and the other study (Ushiroyama 2003), which compared oral methylergometrine with a Japanese traditional herbal medicine, as having a high risk of performance bias.

Regarding detection bias, blinding of outcome assessors was not attempted in all studies.

The study by Ushiroyama (Ushiroyama 2003) was weakened by an attrition issue, namely, a lack of information of the number of participants whose outcome were measured. In the study by Andersen (Andersen 1998), some participants were excluded after randomisation. The reasons for the exclusions were clearly described, and the excluded participants appeared to have no impacts on the study findings, which indicated no differences between the groups. The Arabin 1986 study was free of attrition bias.

None of the three included studies reported the primary outcomes prespecified in the review protocol. However, all three reported a prespecified secondary outcome, and two of them (Andersen 1998; Arabin 1986) also reported non-prespecified outcomes relating to PPH. This led us to add some non-prespecified outcomes to this review and allowed us to perform meta-analyses. Results for most of the outcomes did not suggest any benefits of oral methylergometrine. However, results for blood haemoglobin concentration at day one postpartum did show a benefit of the oral methylergometrine compared to oral Kyuki-chouketsu-in. Nevertheless, this effect was found only in a single study with a high risk of performance bias and unclear risks of selection, detection, and attrition biases.

Potential biases in the review process

We believe that there were no other potential biases in the process of writing this review. All authors of this review declared no conflict of interest on this issue.

Agreements and disagreements with other studies or reviews

In all three studies (Andersen 1998; Arabin 1986; Ushiroyama 2003) that contributed data towards review analyses, it was suggested that oral methylergometrine did not significantly reduce the incidence of postpartum haemorrhage or the amount of lochia postpartum. This finding was consistent with the findings of a Cochrane review (Begley 2011) that compared active management in the third stage of labour with expectant management. The review found no statistically significant reduction in severe PPH for women at low risk of bleeding. Our findings were also similar to the findings of another Cochrane review (Liabsuetrakul 2011) that compared the effectiveness of ergot alkaloids with no uterotonic agents in the third stage of labour. Liabsuetrakul 2011 reported that one study compared oral ergometrine with a placebo and showed no significant benefit of ergometrine over a placebo in terms of mean blood loss, blood loss of at least 500 mL and 1000 mL. The authors also found that there was a significantly higher incidence of post-birth pain requiring analgesia in the intravenous or intramuscular ergot alkaloids group than in the placebo group. In our review, however, the risk of pain after birth requiring analgesia was slightly higher in the methylergometrine group than in the placebo group in one study (Andersen 1998) and it was not statistically significant.

Authors' conclusions

Implications for practice

We could not find any quality evidence to support the prophylactic usage of methylergometrine, Kyuki-chouketsu-in (a Japanese traditional herbal medicine) administered via oral routes following delivery of the placenta for the reduction of postpartum haemorrhage. There is insufficient evidence to recommend the use of oral methylergometrine or Kyuki-chouketsu-in after delivery of the placenta.

Implications for research

Due to the weak methodological quality of the included studies, well-designed studies with sample sizes sufficient for the estimation of the intervention (methylergometrine or herbal medicine) effects are essential. This review is also limited by the fact that we did not find any studies that assessed the effectiveness of homeopathic remedies, administered after delivery of the placenta, for the prophylaxis of PPH. This therefore warrants well-designed, randomised controlled studies that address this issue.

Acknowledgements

We would like to thank Dr Pisake Lumbiganon, Convenor of the Thai Cochrane Network, as well as Dr Malinee Laopaiboon, and Dr Chetta Ngamjarus for their help with and advice on writing the protocol.

We would like to thank Dr Sadequa Shahrook and Dr Emma Barber for their help with writing the review.

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

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. Oral methylergometrine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PPH (blood loss of 500 mL or more over the period of observation)21097Risk Ratio (M-H, Random, 95% CI)1.45 [0.39, 5.47]
2 Amount of lochia during the first 72-hour of the puerperium (g) (outcome not prespecified)1211Mean Difference (IV, Fixed, 95% CI)-25.0 [-69.79, 19.79]
3 Amount of lochia by 4 weeks postpartum (g) (outcome not prespecified)1880Mean Difference (IV, Fixed, 95% CI)-7.0 [-23.99, 9.99]
4 Duration of lochia of more than 4 weeks (outcome not prespecified)1880Risk Ratio (M-H, Fixed, 95% CI)1.26 [1.13, 1.40]
5 Endometritis (outcome not prespecified)21097Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.76, 3.36]
6 Pain requiring analgesia (requests for paracetamol) (outcome not prespecified)1217Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.87, 1.62]
Analysis 1.1.

Comparison 1 Oral methylergometrine versus placebo, Outcome 1 PPH (blood loss of 500 mL or more over the period of observation).

Analysis 1.2.

Comparison 1 Oral methylergometrine versus placebo, Outcome 2 Amount of lochia during the first 72-hour of the puerperium (g) (outcome not prespecified).

Analysis 1.3.

Comparison 1 Oral methylergometrine versus placebo, Outcome 3 Amount of lochia by 4 weeks postpartum (g) (outcome not prespecified).

Analysis 1.4.

Comparison 1 Oral methylergometrine versus placebo, Outcome 4 Duration of lochia of more than 4 weeks (outcome not prespecified).

Analysis 1.5.

Comparison 1 Oral methylergometrine versus placebo, Outcome 5 Endometritis (outcome not prespecified).

Analysis 1.6.

Comparison 1 Oral methylergometrine versus placebo, Outcome 6 Pain requiring analgesia (requests for paracetamol) (outcome not prespecified).

Comparison 2. Oral methylergometrine versus oral Kyuki-chouketsu-in
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Blood haemoglobin concentration at day 1 postpartum (g/dL)1171Mean Difference (IV, Fixed, 95% CI)0.5 [0.11, 0.89]
Analysis 2.1.

Comparison 2 Oral methylergometrine versus oral Kyuki-chouketsu-in, Outcome 1 Blood haemoglobin concentration at day 1 postpartum (g/dL).

Appendices

Appendix 1. Search terms used for pharmaceutical databases and trial registries

ergonovine, ergometrine, methylergometrine, ergotamine, "ergot alkaloids", metenarin, methergin, kyuki-chouketsu-in, arnica, bellis.

Contributions of authors

Y Yaju (YY) prepared all parts of the protocol and the review. YY wrote the first drafts of the protocol and the review. YY and Yaeko Kataoka assessed studies for inclusion, extracted data, and assessed risk of bias. The other co-authors (Rintaro Mori, Hiromi Eto, Shigeko Horiuchi) commented on the draft review. All authors approved the final manuscript.

Declarations of interest

None known.

Sources of support

Internal sources

  • St Luke's College of Nursing, Japan.

  • National Center for Child Health and Development, Japan.

External sources

  • Ministry of Health, Labour and Welfare, Japan.

Differences between protocol and review

The included studies did not report on a number of this review's prespecified outcomes: (primary outcomes: blood loss of 1000 mL or more over the period of observation, maternal death or severe morbidity; secondary outcomes: maternal death, individual components of severe morbidity, blood transfusion, use of therapeutic uterotonics, additional treatment for postpartum haemorrhage, side effects reported either individually or as a composite where appropriate, thromboembolic events, and cost). Consequently, we included data from the following non-prespecified outcomes relating to postpartum haemorrhage that were reported in the included studies:

  • amount of lochia during the first 72 hours of the puerperium;

  • amount of lochia by four weeks postpartum;

  • duration of lochia of more than four weeks;

  • endometritis;

  • pain after birth requiring analgesia (requests for paracetamol).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Andersen 1998

MethodsA prospective, double-blind, randomised trial using blinded envelopes. Individual randomisation was stratified in blocks of 50.
Participants

Setting: The Department of Obstetrics and Gynecology, Kolding Hospital, Kolding, Denmark.

Participants: 217 pregnant women admitted between November 16, 1992 and December 4, 1993. 

Inclusion criteria: women with a single pregnancy and no evidence of maternal pregnancy complications and no contraindications for methylergometrine (hypertension and vascular diseases).

Exclusion criteria: not mentioned.

Interventions

Experimental intervention: IV methylergometrine (Methergin (R) Sandoz, 0.2 mg) after delivery of the placenta and oral Methergin(R) (0.125 mg) tablet 3 times a day for 3 days.

Control/comparison intervention: IV methylergometrine (Methergin (R) Sandoz, 0.2 mg) after delivery of the placenta and placebo 3 times a day for 3 days.

Outcomes

Primary outcome: the amount of lochia (g) during the first 72 hours of puerperium. Lochia was measured by collecting and weighing sanitary towels.

Secondary outcomes: postpartum haemorrhage (loss of more than 600 mL/day) and curettage underwent the 10th day after delivery to remove placental fragments; postpartum endometritis diagnosed when body temperature was 38.0 degrees Celsius or higher on 2 readings in an 8-hour interval and there was uterine tenderness, foul-smelling lochia and no other apparent cause of fever; paracetamol consumption on request (g); length of hospital stay (days).

NotesThis study did not report details of other interventions for prevention of bleeding. We requested from the first author of the study further information about the random sequence generation process and prespecified outcomes, but received no reply.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Randomisation, using blinded envelopes, was stratified in blocks of 50".

Comment: insufficient information about the sequence generation process to permit judgement of "Yes" or "No". We inquired with the first author of the study about the random sequence generation process and prespecified outcomes, but received no reply.

Allocation concealment (selection bias)Unclear risk

Quote: "Randomisation, using blinded envelopes, was stratified in blocks of 50".

Comment: insufficient information to permit judgement of "Yes" or "No" as the method of concealment is not described. The absence of adequate allocation concealment can lead to selection bias because the envelope method was used for randomisation and there was no information about how the envelopes were managed.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "A prospective double-blind randomised trial". "Each woman received 0.2 mg methylergometrine (Methergin (R) Sandoz) intravenously after delivery of the placenta and was randomised to either tabl. Methergin(R) 0.125 mg or placebo."

Comment: blinded.

Participant: low risk of bias.

Clinician (Caregiver): low risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Comment: insufficient information to permit judgement of "Yes" or "No" as the blinding method for outcome assessors is not described.

Outcome assessor: unclear risk of bias.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "During the study period 111 women were randomised to the methylergometrine group. Four women in this group were excluded: one because of hypertension; one wished to go home early; two forgot to take their tablets". "A total of 106 women were randomised to the placebo group. Two women in this group were excluded: one forgot to collect sanitary towels and one wished to go home early."

Comment: according to the reasons for exclusion, there is no evidence of attrition bias. Each proportion of missing outcomes was, however, 3.8% in the methylergometrine group and 1.9% in the placebo group. Those proportions of missing outcomes compared with observed events risk, e.g. incidence of endometritis was 2 (1.87%) in the treatment group and 1 (0.96%) in the placebo group, may be enough to have a clinically relevant impact on the intervention effect estimate, but it is not unclear. The analysis was not intention-to-treat and the data were not able to be re-included.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement of "Yes" or "No" as information of expected outcomes prespecified for the study were not described.
Other biasUnclear riskThere was a difference in the need for oxytocin augmentation of labour between the participants in the intervention group (20%) and those in the control group (30%). Other baseline characteristics were quite similar.

Arabin 1986

MethodsA prospective, randomised, placebo-controlled trial.
Participants

Setting: University Hospital, Frauenklinik Heidelberg, Germany.

Participants: 880.

Inclusion criteria: not reported.

Quote: "The sample used in this study contained 880 women." "The aim of the prospective randomised trial reported here was to study in detail the effects of the routine administration of Methergin, with particular reference to uterine involution, puerperal morbidity and lactation".

Comment: according to the study aim quoted above, the intervention of interest of the study was the routine administration of methylergometrine. Therefore, we inferred that participants of the study were mainly women with normal delivery.

Exclusion criteria: not reported.

Quote: "The sample used in this study contained 880 women".

Interventions

Experimental intervention: 1 tablet of Methergin (0.125 mg methylergometrine maleate) 3 times a day for 4 weeks.

Control/comparison intervention: placebo 3 times a day for 4 weeks.

Outcomes

Main outcomes

Uterine involution

The height of the fundus between day 2 and day 5 postpartum

The size of the uterus measured using ultrasound at 4 weeks postpartum

Quantity of the lochia within 4 weeks postpartum

The number of women with the duration of lochia shorter than 4 weeks

Postpartum haemorrhage (blood loss of 500 mL or more over 2 days or more during the first week after birth)

Puerperal morbidity

Intensity of the after-pains on a scale from 0-36

Incidence of infection with lochiostasis and endometritis between day 1 and day 10 postpartum

Allergic reactions to Methergin(R)

Lactation

Daily quantity of milk produced

Notes

Authors did not report details of other interventions for prevention of bleeding.

There were 85 caesarean section cases in the Methergin group and 77 in the placebo group.

We inquired with the first author of the study about the prespecified outcomes, and received a satisfactory answer. The author verified that the definition of PPH was blood loss of 500 mL or more and the observational period was at least 2 days during the first week after birth.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "The aim of the prospective randomised trial reported here was to study in detail the effects of routine administration of Methergin, with particular reference to uterine involution, puerperal morbidity and lactation".

Comment: no information was provided on how random allocation was performed. We inquired with the first author of the study about the random sequence generation process and received a satisfactory answer. The author verified that they performed the block randomisation using a computer-generated sequence number.

Allocation concealment (selection bias)Unclear risk

Quote: "The aim of the prospective randomised trial reported here was to study in detail the effects of routine administration of Methergin, with particular reference to uterine involution, puerperal morbidity and lactation".

Comment: no information was provided on how random allocation was performed. We inquired with the first author of the study about the concealment process, but we received no satisfactory answers.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "The control group of 436 mothers were given a placebo three times daily for the same period of time".

Comment: blinded.

Participant: low risk of bias.

Clinician (Caregiver): low risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on how outcome assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe number of participants lost to follow-up varied across outcomes. All participants who enrolled in the study were accounted for in the prespecified outcome measure PPH. Although there was no mention of the exclusion after randomisation and intention-to-treat analysis, the study appeared to be free of attrition bias.
Selective reporting (reporting bias)Low riskInsufficient information to permit judgement of "Yes" or "No" as information of expected outcomes prespecified for the study were not described. We inquired with the first author of the study about the prespecified outcomes, and received a satisfactory answer.
Other biasUnclear riskBaseline characteristics, i.e. maternal age, parity and birthweight of the baby were reported in the study; however, frequency of the labour induction, augmentation, and breast-feeding were not reported. Inference on prophylactic effect of Methergin may be confounded by such baseline imbalances if not properly accounted for. Furthermore, the definition of 'postpartum haemorrhage' in the study was not reported. We inquired with the first author of the study about the prespecified outcomes, and received a satisfactory answer. The author verified that the definition of PPH was blood loss of 500 mL or more and the observational period was at least 2 days during the first week after birth.

Jolivet 1978

MethodsA randomised study.
Participants

Setting: not reported.

Participants: 58.

Inclusion criteria: women who had given birth at full term to a healthy child and then initiated breast feeding.

Exclusion criteria: not reported.

Interventions

Experimental intervention: an intramuscular injection of 0.2 mg methylergometrine immediately after delivery, followed by 1.0 mg ergotamine tartrate tablets 3 times a day for the first 6 days postpartum.

Control/comparison intervention: no rye ergot derivatives, either at delivery or in the following 6 days.

OutcomesAverage birthweight, infant weight gain during the first 6 days postpartum (breast-fed infants) and quantity of milk consumed in 24 hours during the first 5 days after birth.
NotesThe aim of the trial was to study the possible effects of ergot derivatives on lactation. The outcome measures prespecified in the study were average birthweight, infant weight gain during the first 6 days postpartum (for breast-fed infants) and quantity of milk consumed in 24 hours during the first 5 days after birth. This study did not explore the effects of the intervention on postpartum haemorrhage. Hence, we did not ask the author about the other outcomes.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Two groups were set up randomly".

Comment: no information was provided on how random allocation was performed.

Allocation concealment (selection bias)Unclear risk

Quote: "Two groups were set up randomly".

Comment: no information was provided on how random allocation was performed.

Blinding of participants and personnel (performance bias)
All outcomes
High risk

Quote: 28 women did not receive rye ergot derivatives.

Comment: not blinded.

Participant: high risk of bias.

Clinician (Caregiver): high risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on how the outcome assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information was provided on the number of participants lost to follow-up.
Selective reporting (reporting bias)Unclear risk

Quote: "The aim of the present trial is to study the possible effects on lactation of using rye ergot alkaloids in the first days post partum".

The outcome measures prespecified in the methods of the study were average birthweight, infant weight gain during the first 6 days postpartum (for breast-fed infants) and quantity of milk consumed in 24 hours during the first 5 days after birth. Outcomes of interest for this review were not available.

Other biasUnclear riskAuthors did not report any details of interventions except for methylergometrine and ergotamine tartrate.

Klug 1983

MethodsA quasi-randomised controlled study.
Participants

Setting: Austria.

Participants: 140.

Inclusion criteria: postpartum women who had given birth at full term.

Exclusion criteria: not reported.

Interventions

Experimental intervention: 0.125 mg methylergometrine (Methergin) orally 3 times a day for 8 days.

Control/comparison intervention: no medication nor methylergometrine.

OutcomesLength of the uterus in mm, duration of hospital stay, puerperal morbidity related to infections (unexplained febrile response, expulsion of matter and/or foetid lochia with fever, need for antibiotic treatment, and foetid lochia only) at day 8 postpartum.
NotesWe asked the author about the randomisation methods. According to the author's reply, alternate allocation in a consecutive series of 140 postpartum women was used. Therefore, we defined the study as a quasi-randomised trial. The outcome measures prespecified in the methods of the study were the length of the uterus, the duration of the hospital stay, puerperal morbidity related to infections (unexplained febrile response, expulsion of matter and/or foetid lochia with fever, need for antibiotic treatment, and foetid lochia only) at day 8 postpartum. According to the study title "Influence of methyl-ergometrine on early puerperal involution of the uterus" and the prespecified outcomes, we concluded that the study did not explore the effects of methylergometrine on postpartum haemorrhage. Hence, we did not ask the author about the other outcomes.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk

Description: alternate allocation in a consecutive series was performed.

Comment: quasi-randomisation.

Allocation concealment (selection bias)Unclear riskComment: no information was provided on how alternate allocation was performed.
Blinding of participants and personnel (performance bias)
All outcomes
High risk

Quote: 71 women were not given the medication nor any methylergometrine.

Comment: not blinded.

Participant: high risk of bias.

Clinician (Caregiver): high risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on how the outcome assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Description: the number of analysed participants was the same as the number of participants allocated.

Comment: although there was no mention of the number of participants lost to follow-up, the study appeared to be free of attrition bias.

Selective reporting (reporting bias)Unclear riskOutcomes of interest of this review were not available.
Other biasUnclear risk

Quote: a group of 69 puerperal women, which is matched with an untreated group of 71.

Comment: baseline characteristics might be similar in 2 groups.

Ushiroyama 2003

  1. a

    IV: intravenous
    PPH: postpartum haemorrhage

MethodsA prospective, randomised, open-label, trial.
Participants

Setting: Osaka Medical College Hospital and its affiliated clinics, Japan.

Participants: 171.

Inclusion criteria: women who had spontaneous labour pain followed by a normal delivery.

Exclusion criteria: women who had complicated pregnancy symptoms requiring special management such as breech presentation, gestational toxicosis, diabetes mellitus, multiple conception, or premature rupture of the membrane.

Interventions

Experimental intervention: Ergometrine (methylergometrine maleate) at an oral dose of 0.375 mg, on the day of delivery.

Control/Comparison intervention: Kyuki-chouketsu-in granules (Kanebo Pharmaceutical Co., Ltd., Tokyo, Japan) at an oral dose of 6.0 g/day (2.0 g 3 times a day) on the day of delivery.

Outcomes

Main outcomes

Height of the uterine fundus (cm) on days 1 and 6 postpartum

Blood haemoglobin concentration on days 1 and 6 postpartum

Axillary temperature at 6:00 am on days 1 and 6 postpartum

Others: plasma total protein, albumin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), alkaline phosphatase, leucine aminopeptidase (LAP), total cholesterol, triglyceride and C-reactive protein (CRP)

Notes

All women enrolled in the trial received cefditoren pivoxil, an antimicrobial agent commonly administered to puerperal women, at a dose of 300 mg/day, and serapeptase, an anti-inflammatory enzyme preparation, at a dose of 30 mg/day. Authors did not report details of other interventions for prevention of bleeding.

We requested the study author, Dr Ushiroyama, to provide further information about blood haemoglobin concentrations, and it was provided.

We found that the blood haemoglobin concentrations presented in Table 3 are inconsistent with those in the text. We contacted one of the authors, Dr Ushiroyama, who verified that the blood haemoglobin concentrations written in the text were correct.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Using the envelope method, the women were randomly assigned to a group of 85 women receiving Kyuki-chouketsu-in or a group of 86 women receiving ergometrine".

Comment: insufficient information about the sequence generation process because no information was provided on how the envelopes for random allocation were prepared and managed.

Allocation concealment (selection bias)Unclear risk

Quote: "Using the envelope method, the women were randomly assigned to a group of 85 women receiving Kyuki-chouketsu-in or a group of 86 women receiving ergometrine".

Comment: insufficient information to permit judgement of "Yes" or "No" as the method of concealment was not described. The absence of adequate allocation concealment could lead to selection bias when the envelope method was used for randomisation because there was no information about how the envelopes were managed.

Blinding of participants and personnel (performance bias)
All outcomes
High risk

Quote: "The women were randomly assigned to a group of 85 women receiving Kyuki-chouketsu-in (Kanebo Pharmaceutical Co., Ltd., Tokyo, Japan) granules at an oral dose of 6.0 g/day (2.0 g three times a day), on the day of delivery, or a group of 86 women receiving ergometrine (methylergometrine maleate) at an oral dose of 0.375 mg/day on the day of delivery".

Comment: not blinded.

Participant: high risk of bias.

Clinician (Caregiver): high risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on how outcome assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIt was not possible to assess the completeness of the follow-up as the number of outcome measured participants was not mentioned.
Selective reporting (reporting bias)Low risk

Quote: (in the 'protocol section') Evaluation was performed between days 1 and 6 postpartum to determine the height of the uterine fundus, axillary temperature at 6:00 am and blood sample were obtained to determine blood haemoglobin, plasma total protein, albumin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), alkaline phosphatase, leucine aminopeptidase (LAP), total cholesterol, triglyceride and C-reactive protein (CRP).

Comment: no selective reporting in this study was suspected as all of these outcomes were reported.

Other biasUnclear riskBaseline blood haemoglobin concentrations were not available because the data of the blood haemoglobin on the day before delivery were not shown. Therefore, it was not possible to assess differences in the baseline haemoglobin concentrations between the 2 study groups.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Del Pozo 1975

20 postpartum women were enrolled in the study and were divided into 2 groups: 10 women were treated with oral methylergometrine (0.2 mg) 3 times a day for 7 days, and the remaining 10 women received no medication. We asked one of the authors for further information on the points below, but we received no reply.

・Randomisation methods

・Intervention methods

・Participant inclusion/exclusion criteria

Vogel 2004The study is a prospective open-labelled randomised trial. Treatments were allocated in a computer-generated random sequence with sealed opaque envelopes to either 0.25 mg oral methylergometrine or 0.2 mg misoprostol orally. Eligible patients were healthy, lactating women with the postpartum complication of uterine atony (putrid lochia, soft uterus < 3 fingerbreadth below the umbilicus) who were normally treated with methylergometrine on postpartum days 3 through 6. The eligibility criteria of the participants did not meet the review criteria. Furthermore, the outcome data did not meet the review inclusion criteria as the outcome measures prespecified in the methods of the study were milk and maternal plasma levels of misoprostol and methylergometrine.

Characteristics of studies awaiting assessment [ordered by study ID]

Arabin 1982

MethodsA prospective randomised study.
ParticipantsMothers who gave birth vaginally or underwent caesarean section.
InterventionsMethylergometrine (0.125 mg/tablet), 3 tablets/day for 4 weeks.
OutcomesUterine involution, frequency of puerperal infection, reddish lochia, amount of breastfeeding, and consultation a doctor because of severe bleeding.
NotesThis is an abstract that was presented in the congress proceedings of the 8th European Congress of Perinatal Medicine, Brussels, Belgium, September 7-10, 1982. A prospective, randomised study was performed at 1 clinic and included 860 mothers: 438 who were treated with methylergometrine (0.125 mg/tablet, 3 tablets/day) for 4 weeks, and 422 who did not receive treatment. The methods, however, were not described in detail. Furthermore, there was no information on baseline characteristics and follow-up rate: only outcome data were available. According to the information reported in the abstract, this appeared to be the same study as Arabin 1986. We approached one of the authors of the study to verify this information, but did not receive a reply.

Grünberger 1983

MethodsA prospective, randomised trial using consecutively numbered sealed opaque envelopes.
ParticipantsUncomplicated pregnancies with spontaneous term delivery.
Interventions0.125 mg methylergometrine or 0.5 mg prostaglandin-E2, 3 times a day from day 1 to day 5 postpartum.
OutcomesUterine involution (amount, intensity and painfulness of contractions, and fundal height), lochia flow, bowel function, pulse, blood pressure, temperature, onset of lactation and amount of breast milk produced.
NotesThe study is self-described as a prospective randomised trial using consecutively numbered sealed opaque envelopes, in which totally 80 parturients were allocated to either 0.125 mg methylergometrine 3 times a day or to 0.5 mg prostaglandin-E2 3 times a day from day 1 to day 5 postpartum. The outcome measures in the study were uterine involution (amount, intensity and painfulness of contractions, and fundal height), lochia flow, bowel function, pulse, blood pressure, temperature, onset of lactation and amount of breast milk produced. 3 of the outcomes, lochia flow, blood pressure, and temperature, met the criteria for review inclusion. However, no data on blood pressure and temperature were reported, and lochia flow was determined and given as scores for which no interpretation or reference was provided. We contacted the author of the study regarding the data on blood pressure and temperature but did not receive a reply.

Characteristics of ongoing studies [ordered by study ID]

Oberbaum 2005

Trial name or titleThe effect of the homeopathic remedies Arnica montana and Bellis perennis on mild postpartum bleeding. A randomised, double-blind, placebo-controlled study.
MethodsA double-blind trial in which participants were randomised into 3 intervention arms using block randomisation lists.
ParticipantsWomen aged 20-35, at 37-43 weeks' gestation, singleton, scheduled for spontaneous vaginal delivery.
Interventions(1) Arnica montana and Bellis perennis, both at a dilution of 10-6 in a stem solution; (2) Arnica and Bellis, both at a dilution of 10-60; and (3) identical placebos.
OutcomesMean haemoglobin levels at 48 and 72 hours following delivery.
Starting dateFebruary 2003.
Contact informationCorresponding author: Menachem Oberbaum; E-mail address: oberbaum@szmc.org.il; Tel: +972-2-6666-395; Fax: +972-2-6666-975.
Notes

1 report presents preliminary results based on the interim analysis of an ongoing clinical trial, in which the total sample size was calculated to be 210 eligible patients. Patients were randomly allocated in a double-blinded manner using block randomisation lists into 3 groups: (1) Arnica montana and Bellis perennis, both in a dilution of 10-6 of the stem solution; (2) Arnica montana and Bellis perennis, both in a dilution of 10-60; and (3) identical placebos. The interim analysis was based on the results of the first 45 patients who were enrolled in the study. The reported outcome data were the mean haemoglobin levels at 48 and 72 hours following delivery. There was no information on blood loss.

The other report is the abstract of the ongoing study and was reported in 'Abstracts of the 12th Annual Symposium on Complementary Health Care 19th –21st September 2005, Exeter, UK'.