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.
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.
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.
- Ergometrine/methylergometrine versus placebo/no treatment.
- Ergometrine/methylergometrine administration via different routes: oral versus intravenous, oral versus intramuscular or subcutaneous, intravenous versus intramuscular or subcutaneous.
- Herbal medicine versus ergometrine/methylergometrine (any route or dosage), or versus placebo/no treatment.
- Homeopathic remedy versus one of the following: ergometrine/methylergometrine (any route or dosage), herbal medicine, placebo/no treatment.
- Other agents versus ergometrine/methylergometrine (any route or dosage), or versus placebo/no treatment.
Types of outcome measures
- 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)
- 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
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:
- monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
- weekly searches of MEDLINE;
- weekly searches of Embase;
- handsearches of 30 journals and the proceedings of major conferences;
- 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:
- The 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)
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
For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CIs).
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
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.
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.
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.
- Spontaneous versus operative vaginal birth.
- Deliveries with the use of oxytocics versus without the use of oxytocics.
- 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.
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.
- Excluding quasi-randomised trials and trials with unclear concealment of random allocation and/or unclear double blinding.
- Excluding trials whose drop-out rate was greater than 20%.
We did not, however, conduct sensitivity analyses because no such studies were available.
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.
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.
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).
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.
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.
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).
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).
Risk of bias in included studies
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.
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.
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.
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.
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.
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'.
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
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 (Tau
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)
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).
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 (I
Pain requiring analgesia (requests for paracetamol)
(2) Oral methylergometrine versus oral Kyuki-chouketsu-in
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).
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.
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.
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
- Top of page
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
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
Sources of support
- St Luke's College of Nursing, Japan.
- National Center for Child Health and Development, Japan.
- 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;
- pain after birth requiring analgesia (requests for paracetamol).
Medical Subject Headings (MeSH)
*Labor Stage, Third; Drugs, Chinese Herbal [therapeutic use]; Ergonovine [therapeutic use]; Ergotamine [therapeutic use]; Homeopathy [methods]; Methylergonovine [therapeutic use]; Phytotherapy [methods]; Postpartum Hemorrhage [*prevention & control]; Randomized Controlled Trials as Topic; Vasoconstrictor Agents [therapeutic use]
MeSH check words
Female; Humans; Pregnancy