Umbilical vein injection for the routine management of third stage of labour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to compare, from the best available evidence, the effects of umbilical vein injection of a saline solution alone or with any uterotonic drug versus an alternative solution with or without any other uterotonic agent or expectant management or any other method for routine management of the third stage of labour, on maternal and perinatal outcomes. We will only consider management of third stage of labour when the umbilical vein injection is administered within 15 minutes after the delivery of the baby.
Additional subgroup analyses for the main outcomes will be based on the following characteristics:
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total volume administered;
-
volume of oxytocin administered;
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method of injection (catheter, syringe, milked, etc).
Background
Global estimates of maternal mortality rates (MMR) show that around 530,000 women die annually across the world because of complications during pregnancy and childbirth. The true figure is, however, likely to lie somewhere between 227,000 and 817,000. More dramatic than MMR is the assessment of the risk of dying due to obstetric factors manifested by the lifetime risk of death. This is highest in sub‐Saharan Africa, with as many as 1 woman in 16 facing the risk of maternal death in the course of her lifetime, compared with 1 in 2800 in developed regions (that is, a 175‐fold difference), with a worldwide estimate of 1 in 74. Almost all of these maternal deaths (99%) occur in the developing world, showing one of the greatest differences between poor and rich countries of any health indicator (WHO 2004).
Among the different causes of maternal death, haemorrhage alone is responsible for at least 25% of these deaths, with the majority due to postpartum haemorrhage (PPH). PPH is therefore the most important maternal complication in labour and puerperium (AbouZahr 2003).
Traditionally, PPH following a vaginal delivery is defined as bleeding from the genital tract of 500 ml or more in the first 24 hours (WHO 1990), although alternative cut‐off levels for moderate and severe PPH have also been suggested elsewhere (Combs 1991a; Mousa 2001; Waterstone 2001). Underestimation of blood loss following delivery is a common problem. The diagnosis is usually made subjectively and many cases remain undetected (ACOG 1998). When blood loss after delivery is objectively measured, actively managed third stages following vaginal deliveries are associated with 3% to 5% prevalence of severe PPH (loss greater than 1000 ml) (Gulmezoglu 2001; Magann 2005) and 14% of moderate PPH (loss greater than 500 ml) (Gulmezoglu 2001). Without oxytocics, incidences as high as 51% for moderate PPH and 17% for severe PPH were found in a randomised double‐blind controlled trial in Guinea Bissau (compared to 45% and 11% respectively in those given prophylactic misoprostol) (Hoj 2005). Caesarean deliveries are associated with a prevalence of around 6% of severe PPH (Combs 1991b). Moderate blood loss is physiological and unlikely to lead to later problems except for women who are already anaemic. The most important consequences include hypovolaemic shock, disseminated intravascular coagulopathies, renal failure, hepatic failure and adult respiratory distress syndrome (Bonnar 2000). In developing countries, poor nutritional status, lack of easy access to treatment, and inadequate intensive care and blood bank facilities are additional contributing factors that lead to the high morbidity and mortality rates in these countries. The lack of a universally accepted definition of PPH means that its exact incidence and the incidence of its complications are unknown.
Aetiology of postpartum haemorrhage
Uterine atony is the most common cause of PPH. Other important causes are retained placental fragments, abnormal placentation (including placenta previa, abruptio placentae, placenta accreta, etc), trauma (that is, episiotomy, vulvar/vaginal/cervical lacerations, caesarean section extensions and uterine rupture) and coagulation defects (Ural 2000). Several predictors (risk factors) of PPH have been identified. Prolonged labour and oxytocin augmentation, prolonged third stage, prior history of postpartum haemorrhage, manual removal of placenta, large baby, multiple gestations, maternal obesity, nulliparity, age greater than 35 years, social exclusion and emergency caesarean section, have been found to be associated with an increased risk of PPH (Combs 1991a; Mousa 2001; Waterstone 2001). However, primary PPH still occurs unpredictably in low‐risk women (Prendiville 2000).
Although, traditionally, the length of the third stage of labour was not considered a risk factor until it exceeds at least 30 minutes (Combs 1991c; Dombrowski 1995), a recent study using objective quantification of blood loss showed a statistically significant increase in PPH when the placenta was not delivered after 18 minutes of the delivery of the baby (Magann 2005).
Management of postpartum haemorrhage
Uterotonic drugs are those that increase the uterine tone or contractility, or both. Different agents have been evaluated in several randomised controlled trials and some of them are the subject of published Cochrane systematic reviews (oxytocin, ergometrine‐ocytocin and prostaglandins) (Cotter 2001; Gulmezoglu 2004; McDonald 2004) or protocols (ergot alkaloids, oxytocin antagonists) (Liabsuetrakul 2005; Su 2005). Other systematic reviews focused on different interventions for the management of postpartum haemorrhage (Peña‐Martí 2005; Prendiville 2000; Soltani 2005). However, many of the results of this high‐quality evidence have not been incorporated into practice (Festin 2003).
The combined effects of uterotonics, and controlled cord traction with countertraction of the uterus, are sometimes summarised by the term 'active management of the third stage'. Early cord clamping is usually included in this definition (Prendiville 2000) but some suggest that it should be considered separately due to its effects on neonatal haematocrit levels (WHO 1996). Active management is shown to be associated with a two‐fold reduction in the risk of PPH and a reduction in the need for blood transfusion (Prendiville 2000). It is widely used in clinical practice in the UK, Australia, and several other developed and developing countries. Expectant management (also known as conservative or physiological management), on the other hand, involves waiting for signs of separation of the placenta and allowing the placenta to deliver spontaneously or aided by gravity or nipple stimulation. It is popular in some northern European countries and in some units in the USA and Canada. It is also the usual practice in domiciliary attendance in the developing world. According to a survey of the WHO in 2003, in 15 countries (Festin 2003) the overall use of the active management is low (25%), and there is a wide variation in the use of the components of the package recommended by WHO and described elsewhere (Prendiville 2000; WHO 1996), with a range of 0% to 100% in the use of prophylactic oxytocics (overall usage 44%) and 13% to 100% in the practice of controlled cord traction.
Umbilical vein injection
Umbilical (or intraumbilical) vein injection (UVI, IUVI) for the treatment of retained placenta was first described by Mojon and Asdrubali in 1826 (Koerting 1926). This technique allows the treatment to be directed specifically at the area with the contractile failure. In the early twentieth century, various authors reported on the use of umbilical vein injection of saline solution 0.9% with volumes that have varied widely between 200 ml and 400 ml (Gabaston 1914; Jarcho 1928). Recent studies have concentrated on smaller volumes of umbilical vein injection of 0.9% saline solution plus oxytocin, although most of these were uncontrolled (Golan 1983; Golan 1984; Hauksson 1986; Heinonen 1985; Neri 1966). A Cochrane review of UVI of saline solution plus oxytocin concludes that it is effective in the management of retained placenta. Saline solution alone however, does not appear be more effective than expectant management (Carroli 2001).
Routine umbilical vein injection has been suggested as an alternative way of managing the third stage of labour, as it directs the treatment to the placental bed and uterine wall, resulting in an earlier uterine contraction and placental separation (Neri 1966). It also allows higher doses to be used, and a reduction of systemic side‐effects. Balanced against this is a need for training in the technique and a possible higher cost of materials. There is a wide variety of UVI methods. The efficacy of any method will depend on the volume of fluid injected and the concentration of drug within that fluid as well as the rapidity of transfer of drugs across the placenta (Pipingas 1993).
The aim of this review is to evaluate the available evidence about the possible benefits and risks of this approach. The benefits and risks of different fluids and uterotonic drugs for umbilical vein injection are also evaluated.
Objectives
The objective of this review is to compare, from the best available evidence, the effects of umbilical vein injection of a saline solution alone or with any uterotonic drug versus an alternative solution with or without any other uterotonic agent or expectant management or any other method for routine management of the third stage of labour, on maternal and perinatal outcomes. We will only consider management of third stage of labour when the umbilical vein injection is administered within 15 minutes after the delivery of the baby.
Additional subgroup analyses for the main outcomes will be based on the following characteristics:
-
total volume administered;
-
volume of oxytocin administered;
-
method of injection (catheter, syringe, milked, etc).
Methods
Criteria for considering studies for this review
Types of studies
Any randomised controlled trial. Trials with inadequate concealment of allocation (see selection bias) or high loss of participants (more than 20%) (see attrition bias) will be excluded.
Types of participants
All women who expected a vaginal delivery.
Types of interventions
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Umbilical vein injection of saline solution versus expectant management
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Umbilical vein injection of saline solution versus active management
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Umbilical vein injection of saline solution versus umbilical vein injection of saline solution plus oxytocin
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Umbilical vein injection of saline solution versus umbilical vein injection of saline solution plus prostaglandin
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Umbilical vein injection of saline solution versus umbilical vein injection of plasma expanders
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Umbilical vein injection of saline solution plus oxytocin versus expectant management
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Umbilical vein injection of saline solution plus oxytocin versus active management
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Umbilical vein injection of saline solution plus oxytocin versus umbilical vein injection of saline solution plus prostaglandin
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Umbilical vein injection of saline solution plus oxytocin versus umbilical vein injection of plasma expanders
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Umbilical vein injection of saline solution plus prostaglandin versus expectant management
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Umbilical vein injection of saline solution plus prostaglandin versus active management
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Umbilical vein injection of saline solution plus prostaglandin versus umbilical vein injection of plasma expanders
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Umbilical vein injection of plasma expanders versus expectant management
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Umbilical vein injection of plasma expanders versus active management
(I) Umbilical vein injection
This technique allows the treatment to be directed specifically at the area with the contractile failure, whilst sparing the remainder. The objective is to deliver a solution (with or without the addition of uterotonic agents) directly to the retro‐placental myometrium by injecting it into the placental bed via the umbilical vein. Various methods of intraumbilical vein injection have been proposed. Injection of oxytocin diluted in saline solution and injected directly into the umbilical vein is the method most commonly used in clinical trials. Another proposed method suggests that the oxytocin should be diluted in saline solution and injected through a catheter (infant naso‐gastric feeding tube) passed along the umbilical vein deep into the placental bed. This has been shown to improve delivery of the dye to the placental bed (Pipingas 1993).
The total volume to be administered varies largely between studies, as does the volume of the uterotonic drug (if used). Finally, different groups of uterotonic agents could be added to either saline solution or plasma expanders to be administered together through the umbilical vein.
(II) Other
(a) Active management of the third stage of labour. The different components of the of active management are:
(i) administration of a prophylactic uterotonic with or immediately after delivery of the baby and usually;
(ii) early cord clamping and cutting;
(iii) controlled cord traction to deliver the placenta.
Note: the package consisting of the sum of all three above‐mentioned components is defined as 'active management' by WHO and recommended for the management of third stage of labour. For the purposes of this review, active management of third stage will be considered when (i) is used alone or in combination with (ii) or (iii), or both.
(b) Expectant management of the third stage of labour, which is defined as a 'hands off' policy, where signs of separation are awaited and the placenta allowed to deliver spontaneously or with the aid of gravity or nipple stimulation.
Types of outcome measures
Maternal and perinatal complications of the third stage of labour included in this review are listed below, for all women and for women at low risk of PPH.
Five primary outcomes were chosen as being most representative of the clinically important measures of ineffectiveness and complications.
Primary outcomes
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Severe PPH (defined as clinically estimated blood loss greater than or equal to 1000 ml)
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Blood transfusion
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Maternal postpartum anaemia (defined by the haemoglobin concentration according to local standards)
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Manual removal of the placenta
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Addition of therapeutic uterotonics
Secondary outcomes
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Maternal mortality
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Serious maternal morbidity (hysterectomy, admission to intensive care, renal or respiratory failure, and other additional surgical procedures to treat PPH other than manual removal of placenta, related to the randomised interventions )
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PPH (defined as clinically estimated or measured blood loss greater than or equal to 500 ml)
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Median blood loss (ml)
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Prolonged third stage of labour (according to individual trial definitions)
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Mean length of third stage (minutes)
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Drop in haemoglobin levels (defined as decrease in previous haemoglobin concentration levels by at least 10%)
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Iron tablets during the puerperium
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Subsequent surgical evacuation of retained products of conception
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Diastolic blood pressure greater than 100 mmHg between delivery of baby and discharge from the labour ward
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Vomiting between delivery of baby and discharge from the labour ward
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Shivering
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Nausea between delivery of baby and discharge from the labour ward
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Headache between delivery of baby and discharge from the labour ward
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Maternal pain during third stage of labour
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Maternal dissatisfaction with third stage management
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Secondary PPH (after 24 hours and before six weeks)
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Bleeding needing readmission
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Need for treatment with antibiotics
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Maternal fatigue
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Breastfeeding at discharge from hospital
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:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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monthly searches of MEDLINE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness search of a further 37 journals.
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 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co‐ordinator searches the register for each review using these codes rather than keywords.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
We will assess for inclusion all potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, consult an outside person.
Data extraction and management
We will design a form to extract data. At least two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion. We will use the Review Manager software (RevMan 2003) to double enter all the data or a subsample.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of methodological quality of included studies
Two review authors will assess independently the validity of each study using the criteria outlined in the Cochrane Reviewers' Handbook (Higgins 2005). Methods used for generation of the randomisation sequence will be described for each trial.
(1) Selection bias (randomisation and allocation concealment)
We will assign a quality score for each trial, using the following criteria:
(A) = adequate concealment of allocation: such as telephone randomisation, consecutively numbered, sealed opaque envelopes;
(B) = unclear whether adequate concealment of allocation: such as list or table used, sealed envelopes, or study does not report any concealment approach;
(C) = inadequate concealment of allocation: such as open list of random number tables, use of case record numbers, dates of birth or days of the week.
Only properly randomised controlled trials or those in which the randomisation process is unclear will be included; quasi‐random designs (C) will be excluded.
(2) Attrition bias (loss of participants, for example, withdrawals, dropouts, protocol deviations)
We will assess completeness to follow up using the following criteria:
(A) less than 5% loss of participants;
(B) 5% to 9.9% loss of participants;
(C) 10% to 19.9% loss of participants;
(D) more than 20% loss of participants.
Studies in group D will be excluded from the analysis.
(3) Performance bias (blinding of participants, researchers and outcome assessment)
We will assess blinding using the following criteria:
(A) blinding of participants (yes/no/unclear);
(B) blinding of caregiver (yes/no/unclear);
(C) blinding of outcome assessment (yes/no/unclear).
Measures of treatment effect
We will carry out statistical analysis using the Review Manager software (RevMan 2003). We will use a fixed‐effect meta‐analysis for combining data in the absence of significant heterogeneity if trials are sufficiently similar.
Dichotomous data
For dichotomous data, we will present results as summary relative risk with 95% confidence intervals.
Continuous data
For continuous data, we will use the weighted 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. If there is evidence of skewness, this will be reported.
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 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.
Intention‐to‐treat analysis
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.
Assessment of heterogeneity
We will apply tests of heterogeneity between trials, if appropriate, using the I‐squared statistic. If we identify high levels of heterogeneity among the trials (exceeding 50%) we will explore it by prespecified subgroup analysis (setting: developing and industrialised countries), method of measurement of blood loss (objective versus clinically estimated), selection of women) and perform sensitivity analysis. The use of a random‐effects model recommended by some authors to overcome the problem of heterogeneity is still debatable (Deeks 2001; Villar 2001); therefore, no summary estimator that could lead to wrong assumptions will be used in this situation.
Subgroup analyses
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:
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total volume administered;
-
volume of oxytocin administered;
-
method of injection (catheter, syringe, milked, etc).
Sensitivity analyses
We will carry out sensitivity analysis to explore the effect of trial quality. This will involve analysis based on an A, B, C, or D rating of selection bias and attrition bias. Studies of poor quality will be excluded in the analysis (those rating B, C, or D) in order to assess for any substantive difference to the overall result.
