Hyaluronidase for reducing perineal trauma

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To access the effectiveness and safety of perineal hyaluronidase (HAase) injection for reducing spontaneous perineal trauma, episiotomy and perineal pain in vaginal deliveries.

Background

Description of the condition

Vaginal deliveries are associated with perineal trauma that may be spontaneous (tears) or surgical (episiotomy). Spontaneous tears are defined as first degree and involve the perineal skin only; second degree involves the perineal muscles; third degree involves the anal sphincter complex (classified as 3a where less than 50% of the external anal sphincter (EAS) is torn; 3b where more than 50% of the EAS is torn; 3c where there is injury to the EAS and the internal anal sphincter (IAS)); fourth degree involves the anal sphincter complex (EAS and IAS) and the anal epithelium (RCOG 2007).

The rates of perineal trauma reported after vaginal deliveries vary considerably, partly due to different definitions and reporting practices. The incidence of perineal trauma has been reported to be 85% (McCandlish 1998). Studies indicate that, in vaginal deliveries with limited episiotomy, 51% to 77% of women experienced some form of genital tract trauma that required suturing (Albers 2006; Dahlen 2007; Mayerhofer 2002; McCandlish 1998). The prevalence of severe perineal trauma (third and fourth degree lacerations) in vaginal deliveries is reported to be from 0.5% to 7.0% (Kudish 2008; RCOG 2007), and mostly between 0.5% and 2.5% (Byrd 2005). Perineal trauma, especially third and fourth degree lacerations can result in substantial short- and long-term morbidities that affect large numbers of women worldwide. The morbidities include blood loss (Albers 2006), anal sphincter tears (Andrews 2006), urinary dysfunction (Boyles 2009; Fenner 2003), faecal incontinence (Sultan 2002), sexual problems (Barrett 2000; Radestad 2008; Williams 2007), persistent perineal pain requiring surgical or psychological treatment (Andrews 2007; Macarthur 2004; McCandlish 1998). Moreover, 3% to 5% of all vaginal deliveries sustained anal sphincter tears (Ekeus 2008), and 8% of women experienced faecal incontinence (Eason 2002).

Episiotomy is the surgical enlargement of the vaginal outlet to facilitate the baby's birth during the last part of the second stage of labour. Episiotomy was thought to avoid severe perineal tears (Dannecker 2004; Rodriguez 2008) and easier to repair than a ragged laceration (Carroli 2009). Episiotomy had been introduced around the world without sufficient evidence of its benefits. The episiotomy rate ranged widely worldwide, from 9.70% in Sweden to as high as 100% in Taiwan (Graham 2005; Raisanen 2011). Episiotomy is an important risk factor for perineal trauma, restricting the liberal use of episiotomy can decrease the occurrence of perineal lactations as well as its complications (Carroli 2009; Dannecker 2004; Hartman 2005; Rodriguez 2008).

Furthermore, other risk factors that contribute to perineal lacerations include nulliparity, operative vaginal delivery (particularly forceps delivery), macrosomia (large baby), malposition, epidural anaesthesia, persistent occipitoposterior position, prolonged second stage of labour, induction of labour and shoulder dystocia (Andrews 2006; Carroll 2003; Christianson 2003; Edwards 2006; Eskandar 2009; Fitzpatrick 2003; Goldberg 2003; Hirayama 2012; Kudish 2008; Lowder 2007; Mayerhofer 2002; Nakai 2006; Raisanen 2009; Samarasekera 2009; Soong 2005). Ethnicity (Dahlen 2007; Goldberg 2003) and physical activity (Voldner 2009) may also be associated with perineal trauma.

Description of the intervention

Many perineal techniques are used to prevent perineal trauma. Antenatal perineal massage may lower rates of genital tract trauma (episiotomy, third degree and fourth degree) and ongoing perineal pain (Attarha 2009; Davidson 2000; Kalichman 2008; Stamp 2001). The use of warm compresses on the perineum could decrease the occurrence of perineal lacerations (third degree and fourth degree) (Dahlen 2007; Dahlen 2009) and increase comfort during the second stage of labour (Albers 2006; Sanders 2005). Using vacuum extraction rather than forceps for instrumental deliveries (Fitzpatrick 2003; Weerasekera 2002) could decrease the occurrence of perineal trauma. Perineal guarding (Mayerhofer 2002; McCandlish 1998), active directed pushing (Albers 2006), controlling the fetal head (Downe 2003), maternal position (Altman 2007; Brement 2007; Thies-Lagergren 2011), planned home birth (Radestad 2008), intravaginal use of obstetric gel during the first stage of labour (Schaub 2008) and midwifery model of care (Albers 2005) may also be associated with a reduced occurrence of perineal trauma (Radestad 2008). However, no systematic reviews have been published evaluating perineal hyaluronidase (HAase) injection during the second stage of labour for reducing perineal trauma.

Perineal HAase injection had been widely used to reduce the occurrence of perineal trauma and perineal pain, as well as the need for episiotomy in the 1950s to 1960s (Chatfield 1966; Mink 1955; O'Leary 1965). Reports suggested that the administration of HAase was a simple, low risk, low cost and effective way to produce perineum relaxation, and decrease the necessity of episiotomy without adverse effects (O'Leary 1965). The appropriate dose of HAase for reducing perineal trauma is uncertain. One study found that perineal HAase injection during the second stage of labour with a dose of 20,000 turbidity-reducing units, which was the same as applied in cervical ripening (Spallicci 2007), might significantly decrease the occurrence and severity of spontaneous perineal lactations (Scarabotto 2008). The injection region can be the anterior region of the perineum, the posterior region of perineum, or both.

How the intervention might work

The mechanism of action of HAase has been extensively studied (Menzel 1998), HAase is a enzymatic complex that has the capacity to dissolve (depolymerize and hydrolyze) Hyaluronic acid (HA), which is the major component of the extracellular cement substance of connective tissue, reduce the viscosity of HA and temporarily alter the intercellular cement without permanent damage (Girish 2007). HAase can increase the permeability of cellular membranes and blood vessels (Menzel 1998), relax the connective tissue around the skin or subcutaneous muscles, and render them less vulnerable to mechanical stress or extension during the passage of the fetus through the vaginal canal (Scarabotto 2008).

HAase has been used in many branches of medicine. Previous studies in obstetrics (Spallicci 2007) have revealed that intracervical HAase injections could ripen the uterine cervix, benefit vaginal deliveries, and shorten the labour time, and the use of HAase in the perineum region helps the tissue achieve the necessary relaxation for fetal passage, minimising the numbers of episiotomies.

Why it is important to do this review

Given the high rate of perineal lacerations in primiparas vaginal deliveries and the subsequent morbidities, it is of high importance to identify alternative perineal techniques in order to reduce the perineal trauma and potential associated morbidity during childbirth. The question whether perineal HAase injection can decrease the perineal lacerations has not been satisfactorily answered. Our review aims to evaluate the available evidence about the benefits and side effects of perineal HAase injection for reducing perineal trauma in vaginal deliveries. Perineal HAase may be an efficient and economic method; thus, our review is essential to provide evidence.

Objectives

To access the effectiveness and safety of perineal hyaluronidase (HAase) injection for reducing spontaneous perineal trauma, episiotomy and perineal pain in vaginal deliveries.

Methods

Criteria for considering studies for this review

Types of studies

We will consider for inclusion all published, unpublished and ongoing randomised controlled trials (RCTs), including cluster-randomised trials, quasi-RCTs and multi-armed studies ongoing comparing perineal HAase injection with placebo or no intervention in the second stage of labour in vaginal deliveries.

We will not include cross-over trials.

We will include studies reported only in abstract form in the studies awaiting classification category; we will include these in the analyses when published as full reports.

Types of participants

Women having a vaginal birth with a single fetus.

Types of interventions

Perineal HAase injection during the second stage of labour compared with placebo or no interventions.

Types of outcome measures

Primary outcomes
  1. Incidence of perineal trauma.

  2. Incidence of episiotomy.

  3. Perineal pain.

Secondary outcomes
  1. Third and fourth degree perineal trauma.

  2. Perineal trauma requiring suturing.

  3. Blood loss.

  4. Dyspareunia.

  5. Urinary incontinence.

  6. Assisted delivery rate.

  7. Women's satisfaction.

  8. Side effects.

  9. Apgar score less than seven at five minutes.

  10. Need for admission to special care baby unit.

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:

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

  2. weekly searches of MEDLINE;

  3. weekly searches of EMBASE;

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

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

Details of the search strategies for CENTRAL,  MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

Searching other resources

We will search the reference lists of retrieved studies.

We will not apply any language restrictions.  

Data collection and analysis

Selection of studies

Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2011) and check for accuracy.

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 risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

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

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

We will assess the method as:

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

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

  • unclear risk of bias.   

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

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

We will assess the methods as:

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

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

  • unclear risk of bias.   

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

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

We will assess the methods as:

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

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

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

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

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

We 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 and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

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

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

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

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

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

  • unclear risk of bias.

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

We 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:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(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 ( Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

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. We will adjust their sample sizes using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses 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 the intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.

Multi-armed trials

We will include multi-armed trials in the analyses along with individually-randomised trials. We will include the relevant intervention groups in a pair-wise comparison of intervention groups that meet the criteria for including studies in the review. We will combine groups to create a single pair-wise comparison using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions. We will address heterogeneity between studies in a random-effects meta-analysis, and investigate it through subgroup analyses or meta-regression.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

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

Assessment of heterogeneity

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

Assessment of reporting biases

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

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses.

  • Parity

  • Birthweight

  • Mode of delivery

  • Length of active second stage of birth

  • Different position in birth (vertical or backwards)

  • Trial quality

The following outcomes will be used in subgroup analysis.

  • Incidence of perineal trauma

  • Incidence of episiotomy

  • Perineal pain

  • Third and fourth degree perineal trauma

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

Sensitivity analysis

We will perform a sensitivity analyses to explore the effects of fixed- or random-effects analyses for outcomes with statistical heterogeneity and excluding studies with a high risk of bias, such as studies with more than 20% missing data.

Acknowledgements

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

Contributions of authors

Wang XD provided a clinical and policy perspective for the protocol, Li J provided a methodological perspective, Zhou F, Huang GQ and Gao BX wrote the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, IRT0935), China.

External sources

  • No sources of support supplied

Ancillary