Active versus expectant management for women in the third stage of labour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
-
To compare the effects of active versus expectant management of the third stage of labour on severe primary postpartum haemorrhage, blood loss and other maternal and infant outcomes.
-
To compare variations in the packages of active and expectant management of the third stage of labour on severe primary postpartum haemorrhage, blood loss and other maternal and infant outcomes.
Background
Description of the condition
The third stage of labour is the time from the birth of the baby to the expulsion of the placenta and membranes. Once the baby is born the uterus continues to contract and reduces in size. There is a lack of full understanding of the physiology of the third stage of labour but recent work using ultrasonography has demonstrated that the process of placental separation has three distinct phases (Herman 2002). The first, or latent phase, consists of strong uterine contraction, which leads to thickening of the uterine muscle, thus causing a shearing force to occur between the elastic uterine wall and the more rigid placenta (Herman 2002). Continued contraction leads to gradual separation of the placenta, commencing at one of the poles (most commonly the lower) and spreading slowly during the contraction or detachment phase until full separation occurs. This is followed by delivery of the placenta in the expulsion phase (Herman 2002). Muscle fibres surrounding the maternal vessels contract to prevent excessive bleeding (Inch 1985) and the mother's coagulation system is temporarily activated (Bonnar 1970).
There is always some blood loss during the third stage of labour as the placenta separates and is delivered but what might be considered a normal amount of loss is the subject of debate (Gyte 1992). Nevertheless, some women can suffer from considerable blood loss during or after the third stage of labour. This can be a primary haemorrhage (within the first 24 hours) (Mousa 2007) or a secondary haemorrhage (between 24 hours and six weeks) (McDonald 2003). Postpartum haemorrhage (PPH) is generally defined as a blood loss in excess of 500 ml (WHO 2003), with severe haemorrhage being loss of 1000 ml or more and very severe haemorrhage being a loss of 2500 ml or more (Bloomfield 1990; Greer 1998; Penney 2005). However, the impact of blood loss on an individual woman at birth can vary considerably and will depend not only on the volume of blood lost but also on her general state of health, the speed of the loss, her haemoglobin levels at the time and her coagulation system. In well‐nourished women, there is generally little impact from a loss of 500 ml, but in women in low‐income countries who may be poorly nourished and anaemic, this loss can cause considerable morbidity or mortality. It has been estimated that at least 25% of maternal deaths in a number of countries are due to haemorrhage ‐ the majority due to PPH (Abouzaher 1998). The vast majority of these happen in the developing world, and PPH is the leading cause of maternal mortality in sub‐Saharan Africa (Lazarus 2005). The seriousness with which PPH is viewed by professionals is evidenced in joint policy statements between the International Confederation of Midwives (ICM) and the International Federation of Gynaecology and Obstetrics (FIGO) (ICM‐FIGO 2003; ICM‐FIGO 2006), and the World Health Organization (WHO 2003), all of which recommend active management of the third stage of labour; however, definitions differ, in particular in relation to whether or not early cord clamping is recommended. Despite this, debate continues among women and practitioners on the optimum method of management of the third stage of labour to balance the benefits and harms.
Description of the intervention
There are two distinct approaches to the clinical management of the third stage of labour, expectant and active management. However, a third approach is sometimes used that consists of a combination of components of both expectant and active management: this has been referred to as 'mixed management' or the 'piecemeal approach' (Prendiville 1989). Expectant, active and mixed management approaches, and comparisons of different types of active management, have been the subject of a number of critical reviews (Elbourne 1995; Gyte 1994; Maughan 2006; McDonald 2007; Prendiville 1989; Prendiville 1996).
(a) Expectant management of third stage of labour
Expectant management is also known as conservative or physiological management and is popular in some northern European countries (Nordstrom 1997). It is also practised on occasion in midwifery‐led units and home births in the United Kingdom and Ireland (Blackburn 2008; Fry 2007; Kanikosmay 2007), and is the usual practice in domiciliary care in the developing world.
The main principle of expectant management is a 'hands off' approach, where signs of placental separation are awaited and the placenta is delivered spontaneously or with the aid of gravity, maternal pushing or, sometimes, nipple stimulation (Inch 1985; Prendiville 1989), hence:
-
a prophylactic uterotonic agent is not administered;
-
ideally the umbilical cord is neither clamped nor cut until the placenta has been delivered but, as a minimum, caregivers have waited until cord pulsation has ceased; and
-
the placenta is delivered spontaneously with the aid of gravity and sometimes by maternal effort (Rogers 1998).
There can be variations within expectant management. For example, some caregivers will wait for the placenta to be delivered before clamping and cutting the cord whilst others, for convenience, just wait until pulsation has finished. Breastfeeding or other means of stimulating the physiological release of oxytocin, such as nipple stimulation, is sometimes also used (Bullough 1989) but is not an essential component of expectant management.
(b) Active management of third stage of labour
In 'active' management of the third stage of labour, the clinician chooses to intervene by using the following package of interventions (Prendiville 1989):
-
the routine administration of a prophylactic uterotonic drug just before, with, or immediately after, the birth of the baby;
-
early cord clamping and cutting; and
-
controlled cord traction to deliver the placenta.
These interventions are implemented routinely and prophylactically in an attempt to reduce the blood loss associated with the third stage of labour and to reduce the risk of PPH. There are many possible variations with this package of interventions.
-
There are different uterotonic drugs that can be used, e.g. oxytocin (intravenous (IV) or intramuscular (IM)); syntometrine (IM); ergometrine (IV or IM); misoprostol (IM) (Cotter 2001; Gülmezoglu 2007; Liabsuetrakul 2007; McDonald 2004; Su 2007). There is also debate over the route of administration and dosage of the various drugs used. A recent change has been proposed in the UK with the National Institute for Health and Clinical Excellence guidelines now recommending the administration of oxytocin 10 units IM, rather than syntometrine (NICE 2007). Misoprostol is potentially the most important drug for use in low‐income countries because it is stable at ambient temperatures and is inexpensive (Parsons 2007). However, it does have adverse side‐effects (Mousa 2007) such as shivering, nausea and headaches, and it has been shown to be less effective than other agents (Gülmezoglu 2007).
-
There can be differing timings for giving the prophylactic uterotonic drug, e.g. with the crowning of the baby's head; with the birth of the anterior shoulder; immediately after the birth of the baby; after the birth of the baby but before the placenta is delivered (Harris 2004) and after the placenta is delivered (Winter 2007). The timing of administration of uterotonic drugs is currently under review (Soltani 2006).
-
There can be variation in the time when the cord is clamped and cut; this can be immediately the baby is born; within a set time after the birth, e.g. within 30 seconds, or a minute; or anytime before umbilical cord pulsation ceases (McDonald 2008; Rabe 2004).
-
There are also different timings for the initiation of controlled cord traction, such as, waiting for signs of placental separation or not (McDonald 2003).
-
There can also be a delay in using the whole package of active management until after cord pulsation ceases, which has been described as ‘delayed active management’ (Gyte 2006).
Placental cord drainage, which is an additional intervention, is sometimes used with active management of third stage. This involves releasing the maternal end of the clamped umbilical cord to allow the blood from the placental side to drain out, thus reducing the size of the placenta and thereby hoping to help separation and reduce the chance of a retained placenta (Prendiville 1989; Soltani 2005).
Some of these variations in the components of active management of the third stage of labour may no longer be considered good practice, but may, nonetheless, be used in included studies identified for this review.
(c) Mixed management of third stage of labour
Mixed management of the third stage of labour (or 'combined' or 'piecemeal' management) consists of a mixture of some of the components of both active and expectant management of third stage, but without exclusively containing all the components of either. Although active management of the third stage is usually recommended (ICM‐FIGO 2006; NICE 2007; WHO 2003), there are many variations, and in practice it may be that some women actually received mixed management (Harris 2006; Mercer 2000). Mixed management of third stage might include, for example: (1) early uterotonic administration, cord clamping after pulsation ceases and controlled cord traction; or (2) delayed uterotonic administration until cord pulsation ceases, then cord clamping and controlled cord traction. These forms of mixed management of third stage have become of interest because of the evidence of benefits from delayed cord clamping for the baby (McDonald 2008; Mercer 2008; Rabe 2004).
How the intervention might work
Expectant management
Expectant management of the third stage relies on the natural contractions of the uterus, stimulated by a surge of oxytocin at birth, and anything that interferes with this oxytocin release may reduce the effectiveness of the physiological process in the third stage (Inch 1985). Release of oxytocin can, for example, be inhibited by anxiety through the excess release of adrenaline (Buckley 2004).
Hence, expectant management of the third stage of labour is only considered appropriate following a labour where there has been no interference with the natural release of oxytocin, e.g. where oxytocin augmentation, induction, epidural or narcotic analgesia, or both, have not been used (Buckley 2004; Fry 2007), but some will consider that these aspects still need to be assessed in well‐designed studies. This type of labour is more likely when the woman has positive psychological support from her midwife, or other trained supporter, who encourages her to listen to her body's messages about movement, positioning, hydration and nutrition (Buckley 2004; Hodnett 2003).
Active management
In active management of the third stage of labour, it is suggested that the prophylactic administration of a uterotonic will reduce bleeding and the risk of haemorrhage (Greer 1998; Prendiville 1989). The role of early cord clamping and controlled cord traction in the reduction of bleeding and haemorrhage is less clear, but it is thought that once the uterotonic drug has been administered, it is important to deliver the placenta quickly to prevent it being retained. Applying a clamp to the cord thus gives the caregiver something to grasp in order to deliver the placenta quickly by applying controlled cord traction. 'Active' management of the third stage has been standard practice in many high‐income countries for many years (Prendiville 1989). Recently, however, arguments have been put forward for a delay in cord clamping, pointing out that it is not an evidence‐based part of the package of active management (Weeks 2007).
A number of Cochrane reviews have been conducted examining different aspects of active management of the third stage of labour. These include reviews on prophylactic oxytocin in the third stage of labour (Cotter 2001); prophylactic ergometrine‐oxytocin versus oxytocin for the third stage of labour (McDonald 2004); prophylactic use of ergot alkaloids in the third stage of labour (Liabsuetrakul 2007); prostaglandins for preventing PPH (Gülmezoglu 2007); oxytocin agonists for preventing PPH (Su 2007); timing of cord clamping in term infants (McDonald 2008) and timing of cord clamping in preterm infants (Rabe 2004).
Potential adverse effects
Interventions used in active management of third stage are known to cause adverse effects, mainly due to the uterotonic drugs used and to early clamping of the cord. Uterotonic drugs can increase the risk of hypertension, nausea, and vomiting for women (Maughan 2006). Early cord clamping has been shown to cause an increased risk of intraventricular haemorrhage and the need for blood transfusions for preterm babies (Rabe 2004). In term babies, the evidence is less clear, but early cord clamping has been shown to be associated with anaemia in the baby which can last for several months (Hutton 2007; McDonald 2008; Prendiville 1989; van Rheenen 2007). There is also concern that early cord clamping may be associated with decreased duration of early breastfeeding (Mercer 2001). A Cochrane review has shown that neither early nor late cord clamping showed any significant difference in PPH rates. However, in terms of neonatal outcomes, delayed cord clamping improved the iron status in infants up to six months of age, but there was an increase in jaundice requiring phototherapy, though this latter finding has been questioned in a feedback comment on the Cochrane review (McDonald 2008).
The potential consequences for the newborn infant of active versus expectant management of the third stage of labour also need to be considered. Broadly, these relate to the use of uterotonic drugs and the timing of cord‐clamping.
-
If uterotonic drugs are administered before delivery of the infant, for example, when the head is crowned, then disruption of the placental‐uterine wall interface and interruption of placental‐umbilical blood flow may cause acute perinatal asphyxia that compromises neonatal cardio‐respiratory transition. Newborn infants compromised at birth are more likely to need transition support (cardio‐respiratory resuscitation). If an asphyxial insult has been severe or prolonged (for example, if exacerbated by obstructed labour such as shoulder dystocia) then other potential consequences may include neonatal encephalopathy with its associated risk of mortality and long‐term neurodevelopmental morbidity.
-
The effects on the neonate of early versus delayed cord clamping have been explored in Cochrane and other systematic reviews (Hutton 2007; McDonald 2008; Rabe 2004). Early cord clamping reduces the volume of postnatal blood transfusion, resulting in lower blood haematocrit levels and haemoglobin concentrations after birth in term infants and higher numbers of neonatal blood transfusions in preterm infants. For term infants, indices of iron status remain lower at three to six months after birth. The clinical importance of this effect is unclear as systematic reviews of iron supplementation during infancy have not found evidence that enhancing iron stores has important effects on growth or development (Sachdev 2005; Sachdev 2006). Potentially, placental transfusion may be more important for infants born in low‐ and middle‐income settings where iron‐deficiency anaemia exacerbated by nutritional and infectious insults may have substantial and long‐term adverse effects on growth and development (van Rheenen 2007).
Early cord clamping also results in lower postnatal levels of plasma bilirubin and a lower incidence of neonatal jaundice that requires phototherapy (McDonald 2008; Rabe 2004). Treatment of neonatal jaundice may result in mother‐infant separation that delays the initiation and establishment of breastfeeding and disrupts early neonatal metabolic adaptation (Mercer 2001). For infants born in low‐ or middle‐income settings, or in rural or remote settings distant from healthcare facilities, the need for phototherapy (or its lack of availability) may be of greater clinical importance.
For preterm infants, another specific concern is the effect of postnatal placental transfusion on neonatal haemodynamic transition processes. The Cochrane review of early versus delayed cord clamping for preterm infants found some evidence that infants who had early cord clamping had a higher risk of hypotension treated with volume‐transfusion and of intraventricular haemorrhage (though no evidence of an effect on the incidence of 'severe' (grade III/IV) intraventricular haemorrhage that is associated with adverse neurological outcomes) (Rabe 2004).
Why it is important to do this review
It is important to undertake this systematic review because of the need to determine if active, expectant management, or a mixed management package, is most likely to be of overall benefit. It is important to assess the impact of all these forms of care on both the mother and baby. We believe that this review is highly relevant to families and clinicians, as women frequently enquire about the differences in third stage management during the antenatal period.
Objectives
-
To compare the effects of active versus expectant management of the third stage of labour on severe primary postpartum haemorrhage, blood loss and other maternal and infant outcomes.
-
To compare variations in the packages of active and expectant management of the third stage of labour on severe primary postpartum haemorrhage, blood loss and other maternal and infant outcomes.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised, and quasi‐randomised, controlled trials of active versus expectant management of the third stage of labour.
Types of participants
All women who expect a vaginal birth at 24 weeks' gestation or later.
Types of interventions
(a) Active management of the third stage of labour, which is here defined as the package of interventions comprising of:
-
the administration of a prophylactic uterotonic just before, with, or immediately after, the birth of the baby;
-
early cord clamping and cutting (from immediately after the birth of the baby's head in the case of a nuchal cord, or immediately after the birth of the baby to, usually, within a minute of birth);
-
controlled cord traction to aid the delivery of the placenta.
(b) Expectant management of the third stage of labour, which is here defined as:
-
no prophylactic administration of a uterotonic;
-
the umbilical cord is neither clamped nor cut until the placenta has been delivered or until cord pulsation has ceased; and
-
the placenta is delivered spontaneously with the aid of gravity and sometimes by maternal effort;
-
none of the components of active management, described above, are routinely employed.
(c) Mixed management of third stage of labour which consists of a mixture of some of the components of both active and expectant management of third stage, but without exclusively containing all the components of either (Table 1).
| Terms | Definitions used in this review | ||||||
| Expectant management of third stage of labour | 1. A prophylactic uterotonic agent is not administered; | ||||||
| Active management of third stage of labour | 1. The routine administration of a prophylactic uterotonic drug just before, with, or immediately after, the birth of the baby; | ||||||
| Mixed management of third stage of labour | A mixture of some of the components of both active and expectant management of third stage, but without exclusively containing all the components of either. There can be a number of different mixed third stage managements, for example: | ||||||
| Early prophylactic uterotonic | Prophylactic uterotonic drug administered just before, with, or immediately after, the birth of the infant. | ||||||
| Delayed prophylactic uterotonic | Prophylactic uterotonic drug administered after the cord pulsation has ceased. | ||||||
| Early cord claming | The application of a clamp to the umbilical cord within 60 seconds of the birth of the infant (McDonald 2008). | ||||||
| Delayed cord clamping | The application of a clamp to the umbilical cord greater than one minute after birth or when cord pulsation has ceased (McDonald 2008). | ||||||
| Sarnat staging for hypoxic ischaemic encephalopathy (Sarnat 1976) | Stage 1 (mild): hyperalertness, hyper‐reflexia, dilated pupils, tachycardia, absence of seizures. Stage 2 (moderate): lethargy, hyper‐reflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro reflexes. Stage 3 (severe): stupor, flaccidity, small to midposition pupils which react poorly to light, decreased stretch reflexes, hypothermia and absent Moro. | ||||||
Comparisons
-
Active versus expectant management of the third stage of labour.
-
Active versus mixed management with early prophylactic uterotonic administration, delayed cord clamping and controlled cord traction.
-
Active versus mixed management, with delayed prophylactic uterotonic administration, delayed cord clamping and controlled cord traction.
-
Active management with prophylactic uterotonic given before or with the birth of baby versus active management with prophylactic uterotonic drug given immediately after birth of the baby.
-
Expectant versus mixed management with early prophylactic uterotonic administration, delayed cord clamping and controlled cord traction.
-
Expectant versus mixed management with delayed prophylactic uterotonic administration, delayed cord clamping and controlled cord traction.
Comparisons two to six are included because of the review team's awareness of these different forms of clinical management of the third stage of labour and following the results of two reviews that indicated the benefits of delaying cord clamping for the baby (McDonald 2008; Rabe 2004).
Types of outcome measures
We selected outcome measures in order of importance with due recognition of the core data set of outcome measures identified by Devane et al (Devane 2007).
Maternal ‐ primary
-
Severe primary postpartum haemorrhage (PPH) (clinically estimated blood loss greater than or equal to 1000 ml at time of birth and up to 24 hours).
-
Very severe primary PPH (clinically estimated blood loss greater than or equal to 2500 ml at time of birth and up to 24 hours).
-
Maternal haemoglobin concentration (Hb) less than 9 gm/dl 24 to 48 hours postpartum.
-
Clinical signs of severe blood loss at the time of birth, e.g. woman feeling breathless, weak, faint, pale, exhausted.
-
Maternal mortality.
Maternal ‐ secondary
-
Primary PPH (clinically estimated blood loss greater than or equal to 500 ml at time of birth and up to 24 hours).
-
Mean blood loss (ml), measured or estimated at time of birth.
-
Use of blood transfusion.
-
Iron therapy during the puerperium.
-
Therapeutic uterotonics during the third stage or within the first 24 hours, or both.
-
Length of third stage greater than or equal to 60 minutes.
-
Mean length of third stage (minutes).
-
Manual removal of the placenta as defined by authors.
-
Diastolic blood pressure greater than 90 mmHg between birth of baby and discharge from the labour ward.
-
Vomiting between birth of baby and discharge from the labour ward.
-
Nausea between birth of baby and discharge from the labour ward.
-
Headache between birth of baby and discharge from the labour ward.
-
Administration of oral or rectal analgesia (e.g. paracetamol, codeine, non‐steroidals) between birth of the baby and discharge from the labour ward.
-
Administration of opiate analgesia between birth of the baby and discharge from the labour ward.
-
Maternal views of third stage management (assessed using a validated questionnaire).
-
Women's assessment of maternal pain during third stage as reported by authors.
-
Secondary PPH (clinically estimated blood loss greater than or equal to 500 ml after 24 hours and before six weeks).
-
Any vaginal bleeding needing treatment (after 24 hours and before six weeks).
-
Amount of lochia either estimated or measured after 24 hours and up to discharge from hospital.
-
Uterotonic treatment after 24 hours and before six weeks.
-
Surgical evacuation of retained products of conception.
-
Maternal haemoglobin concentration (Hb) less than 9 gm/dl postdischarge and up to six weeks.
-
Sequelae of PPH (length of stay; infection; re‐admission).
-
Afterpains ‐ abdominal pain associated with the contracting uterus in the postpartum period.
Infant ‐ primary
-
Cardio‐respiratory or neurological depression at birth, or both, as demonstrated by (a) an Apgar score less than seven less at five minutes, or (b) evidence of acidaemia indicated by a pH less than seven or base deficit greater than 12 mmol/L in umbilical arterial cord blood, or (c) neonatal blood sample in first hour of life, or both.
-
Incidence and severity of neonatal ('hypoxic ischaemic') encephalopathy assessed using Sarnat staging (Sarnat 1976; Table 1).
-
Perinatal mortality rate (stillbirth and neonatal deaths).
-
Death (postneonatal and up to or equal to 12 months of age) or severe neurodevelopmental disability in survivors (assessed aged greater than or equal to 12 months of age) defined as any one or combination of the following: non‐ambulant cerebral palsy, severe developmental delay assessed using validated tools, auditory and visual impairment (each component analysed individually as well as part of the composite outcome).
Infant ‐ secondary
-
Need for transition support at birth (neonatal resuscitation) with oxygen supplementation, positive‐pressure ventilation, cardiac compression, or drug therapy.
-
Incidence of admission to neonatal special care or intensive care unit.
-
Need for cardio‐respiratory support, e.g. mechanical ventilation (IPPV/continuous positive airways pressure) for more than four hours.
-
Neonatal jaundice requiring phototherapy (plasma bilirubin greater than 340 umol/L).
-
Neonatal jaundice requiring exchange transfusion (plasma bilirubin greater than 510 umol/L).
-
Severe neonatal polycythaemia treated with dilutional exchange transfusion (venous or arterial blood haematocrit greater than 70%).
-
Intraventricular haemorrhage (grade III/IV).
-
Birthweight.
-
Infant haemoglobin level (Hb) at 24 to 48 hours.
-
Transfusion requirements (preterm infants): (i) number of infants exposed to one or more red blood cell transfusions; (ii) number of transfusions per infant: (iii) number of donors to whom the infant was exposed.
-
Breastfeeding at discharge from hospital and at interval assessments until six months.
-
Infant haemoglobin level and iron indices beyond three months.
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
-
quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
-
weekly searches of MEDLINE;
-
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 and MEDLINE, 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.
Supplementary to the search by the Trials Search Co‐ordinator, we will search EMBASE (1980 to current), CINAHL (1982 to current), Dissertation Abstracts (1980 to current) and SIGLE (2000 to current). We will list the full search strategies for these databases in the review.
Searching other resources
We will retrieve any additional relevant references cited in papers identified through the above search strategy and assess their suitability for inclusion in the review.
We will not apply any language restrictions.
Data collection and analysis
The methodology for data collection and analysis is based on the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008).
Selection of studies
Two authors will assess for potential inclusion all studies we identify as a result of the search strategy. We will resolve any disagreement through discussion with at least one additional review author.
Data extraction and management
We will design a form to extract data. Two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion with at least one additional review author. We will use the Review Manager software (RevMan 2008) for data entry and check the accuracy of the data entry.
Assessment of risk of bias in included studies
We will assess risk of bias in included studies using the Cochrane Collaboration’s tool for assessing risk of bias as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) and contained in RevMan (RevMan 2008). This will be achieved by assigning a judgement to the following questions:
(1) Sequence generation (randomisation)
Was the allocation sequence adequately generated?
-
Yes (random‐number table, computer random‐number generator).
-
No (systematic non‐random approach, e.g. use of case record numbers, dates of birth or days of the week).
-
Unclear.
(2) Allocation concealment (selection bias)
Was allocation adequately concealed?
-
Yes (telephone or central randomisation, consecutively numbered, sealed opaque envelopes).
-
No (open list of random‐number tables, alternation or rotation).
-
Unclear.
(3) Blinding (checking for possible performance bias)
Was knowledge of the allocated interventions adequately prevented during the study?
It is not possible to blind participants or personnel in these trials, as the fact that a uterotonic has been given (rather than a placebo, or nothing) is usually apparent to both women (who feel a strong contraction or pain) and clinicians (who can see or feel a strongly contracted uterus following injection). However, for certain outcomes such as haemoglobin concentration, which could be assessed by a blinded outcome assessor, we will assess the methods for blinding under the headings: participants, personnel and outcomes.
We will assess the blinding for outcome assessors on these outcomes as:
-
adequate;
-
inadequate;
-
unclear.
(4) Incomplete data collection (checking for possible attrition bias through withdrawals, dropouts, protocol violations)
We will describe for each included study and for each outcome or class of outcomes the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake.
We will discuss whether missing data greater than 20% might (a) be reasonably expected (acknowledging that with long‐term follow up, complete data are difficult to attain), and (b) impact on outcomes.
(5) Selective reporting bias
We will describe for each included study how the possibility of selective outcome reporting bias was examined by us and what we found.
We will assess the methods as:
-
adequate (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
-
inadequate (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would be expected to have been reported);
-
unclear.
(6) Other sources of bias
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias (e.g. specific study design, trial stopped early; extreme baseline imbalances):
-
free from other problems;
-
not free from other problems (problems detailed);
-
unclear.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions with reference to (1) to (6) above (Higgins 2008). If considered appropriate by the team, we will explore the impact of the level of bias through undertaking sensitivity analyses ‐ see 'Sensitivity analysis'.
When information regarding any of the above (1) to (7) is unclear, we will attempt to contact authors of the original reports to provide further details
Measures of treatment effect
We will carry out statistical analysis using the Review Manager software (RevMan 2008).
Dichotomous data
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.
Continuous data
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. 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 will include cluster‐randomised trials 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 intracluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, this will be reported and sensitivity analyses conducted to investigate the effect of variation in the ICC. 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 the 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 separate meta‐analysis. Therefore, the meta‐analysis will be performed in two parts as well.
Dealing with missing data
We will analyse data on all participants with available data in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If, in the original reports, participants are not analysed in the group to which they were randomised, and there is sufficient information in the trial report, we will attempt to restore them to the correct group and analyse accordingly (i.e. intention‐to‐treat analysis).
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among outcomes contained in all comparisons. We will explore substantial heterogeneity (I2 greater than 50%) using sensitivity analyses.
Assessment of reporting biases
Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.
Data synthesis
We will carry out statistical analysis using RevMan 2008. We will use fixed‐effect inverse variance meta‐analysis for combining data where trials are examining the same intervention, and the trials' populations and methods are judged sufficiently similar. Where we suspect clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we will use random‐effects meta‐analysis.
If substantial heterogeneity is identified in a fixed‐effect meta‐analysis (I2 greater than 50%), this will be noted and the analysis repeated using a random‐effects method.
Subgroup analysis and investigation of heterogeneity
We will conduct planned subgroup analyses classifying whole trials by interaction tests as described by Deeks 2001.
We plan to carry out the following subgroup analyses on the primary outcomes:
-
Low risk of postpartum haemorrhage (PPH) versus high risk of PPH.
-
Spontaneous versus operative vaginal birth.
-
Nulliparous versus multiparous women.
-
Low‐income versus high‐income setting.
-
Full‐term versus preterm birth (we will also include outcomes specific to preterm babies).
Sensitivity analysis
We will perform sensitivity analysis based on trial quality, separating high‐quality trials from trials of lower quality. 'High quality' will, for the purposes of this sensitivity analysis, be defined as a trial having adequate allocation concealment and an 'unreasonably expected loss to follow up' classified as less than 20%, given the stated importance of attrition as a quality measure (Tierney 2005).
If some cluster‐randomised trials are included, other sensitivity analysis may also be desirable. If cluster trials have been incorporated with an estimate of the intra‐cluster correlation coefficient (ICC) borrowed from a different trial, a sensitivity analysis will be performed to see what the effect of different values of the ICC on the results of the analysis would be.
| Terms | Definitions used in this review | ||||||
| Expectant management of third stage of labour | 1. A prophylactic uterotonic agent is not administered; | ||||||
| Active management of third stage of labour | 1. The routine administration of a prophylactic uterotonic drug just before, with, or immediately after, the birth of the baby; | ||||||
| Mixed management of third stage of labour | A mixture of some of the components of both active and expectant management of third stage, but without exclusively containing all the components of either. There can be a number of different mixed third stage managements, for example: | ||||||
| Early prophylactic uterotonic | Prophylactic uterotonic drug administered just before, with, or immediately after, the birth of the infant. | ||||||
| Delayed prophylactic uterotonic | Prophylactic uterotonic drug administered after the cord pulsation has ceased. | ||||||
| Early cord claming | The application of a clamp to the umbilical cord within 60 seconds of the birth of the infant (McDonald 2008). | ||||||
| Delayed cord clamping | The application of a clamp to the umbilical cord greater than one minute after birth or when cord pulsation has ceased (McDonald 2008). | ||||||
| Sarnat staging for hypoxic ischaemic encephalopathy (Sarnat 1976) | Stage 1 (mild): hyperalertness, hyper‐reflexia, dilated pupils, tachycardia, absence of seizures. Stage 2 (moderate): lethargy, hyper‐reflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro reflexes. Stage 3 (severe): stupor, flaccidity, small to midposition pupils which react poorly to light, decreased stretch reflexes, hypothermia and absent Moro. | ||||||
