Hyaluronidase for reducing perineal trauma

  • Review
  • Intervention

Authors


Abstract

Background

Perineal hyaluronidase (HAase) injection was widely used to reduce the occurrence of perineal trauma, pain and need for episiotomy in the 1950s to 1960s. Reports suggested that the administration of HAase was a simple, low risk, low cost and effective way to decrease perineal trauma without adverse effects.

Objectives

The objective of this review was to assess the effectiveness and safety of perineal HAase injection for reducing spontaneous perineal trauma, episiotomy and perineal pain in vaginal deliveries.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2013), the International Clinical Trials Registry Platform (ICTRP) and the Networked Digital Library of Theses and Dissertations (both on 1 April 2013), and reference lists of retrieved studies. We also contacted relevant organisations.

Selection criteria

Published and unpublished randomised and quasi-randomised controlled trials comparing perineal HAase injection with placebo injection or no intervention in vaginal deliveries.

Data collection and analysis

Two review authors independently assessed trials for inclusion, extracted data and evaluated methodological quality. Data were checked for accuracy.

Main results

The search strategy identified six potentially eligible studies. Two studies were excluded. We included four randomised controlled trials that randomised a total of 599 women (data were available for 595 women).

Two trials (283 women) compared the effects of perineal HAase injection during the second stage of labour with placebo injection and were at low risk of bias. Three trials (one three-armed trial was analysed twice) (373 women) compared the effects of perineal HAase injection during second stage of labour with no intervention and two out of the three trials were at high risk of bias. Data from four trials involving 599 women suggested that perineal HAase injection during second stage of labour had a lower incidence of perineal trauma (average risk ratio (RR) 0.69, 95% confidence interval (CI) 0.50 to 0.95,Tau² = 0.08, I² = 82% compared with women in the control group, but there was no clear evidence of a reduction in the incidence of episiotomy (average RR 0.74, 95% CI 0.43 to 1.29, Tau² = 0.17, I² = 66%), first and second degree perineal lacerations (average RR 0.54, 95% CI 0.38 to 1.33, Tau² = 0.30 , I² = 85%) and third and fourth degree perineal lacerations (RR 0.12, 95% CI 0.01 to 2.13). Data from two trials involving 283 women indicated that there was no clear evidence of a reduction in the incidence of perineal trauma (RR 0.90, 95% CI 0.77 to 1.06, Tau²=1.07, I² = 7%), episiotomy (RR 0.77, 95% CI 0.32 to 1.89, Tau² = 0.27, I² = 54%), first and second degree perineal lacerations (RR 1.08, 95% CI 0.83 to 1.40, Tau² = 1.11, I² = 10%) and third and fourth degree perineal lacerations (RR 0.12, 95% CI 0.01 to 2.13) with perineal HAase injection. Data from three trials involving 373 women suggested that perineal HAase injection during second stage of labour had a lower incidence of perineal trauma (RR 0.61, 95% CI 0.42 to 0.88, Tau² = 0.08, I² = 78%) compared with no intervention, but had no clear effect on in the incidence of episiotomy (RR 0.79, 95% CI 0.44 to 1.42, Tau² = 0.16, I² = 70%) and first and second degree perineal lacerations (RR 0.58, 95% CI 0.31 to 1.10, Tau² = 0.18, I² = 59%). No side effects were reported in the included trials.

No included trials reported on perineal pain and other pre-specified secondary outcomes: perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit.

Authors' conclusions

Perineal HAase injection during second stage of labour had a lower incidence of perineal trauma compared with control or no intervention, but there was no clear evidence of benefit compared with placebo injection. The difference in incidence of perineal trauma may probably be due to bias and confounding in the non-placebo controlled comparison, this result should be interpreted cautiously. The potential use of perineal HAase injection as a method to reduce perineal trauma were yet to be determined as there was no appropriate established dose for HAase, no evidence of follow up, and the number of high-quality trials and outcomes reported were too limited to draw conclusions on its effectiveness and safety. Further rigorous randomised controlled trials are required to evaluate the role of perineal HAase injection in vaginal deliveries.

Résumé scientifique

Hyaluronidase pour réduire les traumatismes périnéaux

Contexte

Les injections périnéales de Hyaluronidase (HAase) étaient largement utilisées pour réduire l'incidence des traumatismes du périnée, la douleur et le besoin de recourir à une épisiotomie dans les années 50 à 60. Des descriptions suggèrent que l'administration de HAase était simple, à faible risque et faible coût, et efficace pour réduire les traumatismes du périnée, ceci sans effets indésirables.

Objectifs

L'objectif de cette revue était d'évaluer l'efficacité et l'innocuité d’injections périnéales de HAase pour réduire les traumatismes spontanés du périnée, les épisiotomies et les douleurs périnéales lors des accouchements par voie basse.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais du groupe Cochrane sur la grossesse et la naissance (le 31 octobre 2013), dans l'International Clinical Trials Registry Platform ((ICTRP) et le Networked Digital Library of Theses and Dissertations (le 1 avril 2013), et dans les références bibliographiques des études trouvées. Nous avons également contacté des organisations compétentes.

Critères de sélection

Essais contrôlés randomisés et quasi-randomisés, publiés et non publiés, comparant l’injection de HAase au niveau du périnée à l'injection de placebo ou l'absence d'intervention lors d’accouchements par voie basse.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment évalué les essais à inclure, extrait les données et évalué la qualité méthodologique. L’exactitude des données a été vérifiée.

Résultats principaux

La stratégie de recherche documentaire a identifié six études potentiellement éligibles. Deux études ont été exclues. Nous avons inclus quatre essais contrôlés randomisés qui randomisaient un total de 599 femmes (les données étaient disponibles pour 595 femmes).

Deux essais (283 femmes) ont comparé les effets de l'injection périnéale de HAase pendant la deuxième phase du travail avec l'injection de placebo et étaient à faible risque de biais. Trois essais (un essai composé de trois bras a été analysé deux fois) (373 femmes) ont comparé les effets de l'injection de HAase au niveau du périnée pendant la deuxième phase du travail à l'absence d'intervention et deux des trois essais étaient à risque élevé de biais. Les données de quatre essais portant sur 599 femmes ont suggéré que l'injection périnéale de HAase pendant la deuxième phase du travail présentait une incidence plus faible de traumatisme périnéal (risque relatif moyen (RR) 0,69, intervalle de confiance à 95 % (IC) de 0,50 à 0,95, Tau² = 0,08, I² = 82 % par rapport aux femmes dans le groupe témoin, mais il n'y avait aucune preuve probante d'une réduction de l'incidence d’épisiotomies (RR moyen 0,74, IC à 95 % 0,43 à 1,29, Tau² = 0,17, I² = 66 %), de lacérations périnéales de premier et second degré (RR moyen 0,54, IC à 95 % 0,38 à 1,33, Tau² = 0,30, I² = 85 %) et de lacérations périnéale du troisième et quatrième degré (RR 0,12, IC à 95 % 0,01 à 2,13). Les données issues de deux essais portant sur 283 femmes ont indiqué qu'il n'y avait aucune preuve probante d'une réduction dans l'incidence des traumatismes du périnée (RR 0,90, IC à 95 % 0,77 à 1,06, Tau² = 1,07, I² = 7 %), des épisiotomies (RR 0,77, IC à 95 % 0,32 à 1,89, Tau² = 0,27, I² = 54 %), des lacérations périnéales de premier et second degré (RR 1,08, IC à 95 % 0,83 à 1,40, Tau² = 1,11, I² = 10 %) et des lacérations périnéale du troisième et quatrième degré (RR 0,12, IC à 95 % 0,01 à 2,13) avec l'injection périnéale de HAase. Les données de trois essais portant sur 373 femmes ont suggéré que l'injection de HAase au niveau périnéal pendant la deuxième phase du travail s’accompagnait d’une incidence plus faible de traumatisme périnéal (RR 0,61, IC à 95 % 0,42 à 0,88, Tau² = 0,08, I² = 78 %) par rapport à l'absence d'intervention, mais n'avait aucun effet évident sur l'incidence des épisiotomies (RR 0,79, IC à 95 % 0,44 à 1,42, Tau² = 0,16, I² = 70 %) et des lacérations périnéales de premier et second degré (RR 0,58, IC à 95 % 0,31 à 1,10, Tau² = 0,18, I² = 59 %). Aucun effet secondaire n'a été rapporté dans les essais inclus.

Aucun des essais inclus n'a rapporté d’éléments sur la douleur périnéale et d'autres critères de jugement secondaires prédéfinis : la survenue d’un traumatisme périnéal nécessitant une suture ; la perte de sang ; la dyspareunie ; l’apparition d’une incontinence urinaire ou fécale ; le taux d'accouchements assistés ; la satisfaction des femmes ; le score Apgar inférieur à sept à cinq minutes et la nécessité d’une admission en unité de soins intensifs néonataux.

Conclusions des auteurs

L’injection périnéale de HAase pendant la deuxième phase du travail s’accompagnait d’une incidence plus faible de traumatismes périnéaux par rapport au groupe témoin ou à l'absence d'intervention, mais il n'y avait aucune preuve claire de bénéfice par rapport à l'injection de placebo. La différence dans l'incidence des traumatismes du périnée pouvant être due à des biais et des facteurs de confusion au niveau des études comparatives contrôlées non-placebo, ce résultat doit être interprété avec précaution. L'éventuelle utilisation d'injections périnéales de HAase en tant que méthode pour réduire les traumatismes périnéaux est encore à déterminer, car il n’a pas été établi de dose appropriée de HAase, il n’y a aucune preuve de suivi, et le nombre d'essais de haute qualité et de résultats rapportés était trop limité pour tirer des conclusions sur son efficacité et son innocuité. D'autres essais contrôlés randomisés rigoureux sont nécessaires pour évaluer le rôle de l’injection périnéale de HAase dans les accouchements par voie basse.

Plain language summary

Hyaluronidase for reducing perineal trauma during vaginal birth

Vaginal deliveries are associated with perineal trauma that may be unexpected tears or surgical as a result of episiotomy. Many techniques have been used to prevent perineal trauma, such as antenatal perineal massage or perineum warm compresses. Their effectiveness in reducing perineal trauma has been identified by researchers. Perineal hyaluronidase (HAase) injection was widely used in the 1950s and 1960s to reduce the occurrence of perineal trauma, pain, and the need for episiotomy. The review authors searched the medical literature for randomised controlled trials that compared perineal HAase injection during the second stage of labour with perineal placebo injection or no intervention. They identified four randomised controlled trials involving 599 women (with data available for 595 women). The methodological quality of two out of the four trials included in this review was poor.

Two trials involving 283 women compared the effects of perineal HAase injection with placebo injection during second stage of labour and were at low risk of bias. Three trials (one three-armed trial was analysed twice) with 373 women compared the effects of perineal HAase injection during second stage of labour with no intervention. The overall results showed that perineal HAase injection had a significantly lower incidence of perineal trauma compared with control or no intervention, but there was no difference in the incidence of episiotomy, first and second degree and more severe (third and fourth degree) perineal tears.

There was no clear evidence that HAase injection lowered the incidence of perineal trauma, episiotomy, first and second degree and more severe (third and fourth degree) perineal tears when compared with placebo injection. No side effects were reported in the included trials. Other measures such as perineal pain and other pre-specified secondary outcomes were not measured by the included trials. The difference in the incidence of perineal trauma may be due to bias and confounding in the non-placebo controlled comparison, this result should be interpreted cautiously.

The potential use of this intervention as a method to reduce perineal trauma are yet to be determined as there was no appropriate established dose for HAase, no evidence of follow-up and side effects, and the number of high-quality trials and outcomes reported was too limited to draw conclusions on its effectiveness and safety. Further rigorous randomised controlled trials are required to evaluate the role of perineal HAase injection in vaginal deliveries.

Résumé simplifié

Utilisation de Hyaluronidase pour réduire les traumatismes du périnée pendant l'accouchement par voie basse

Les accouchements par voie basse sont associés à des traumatismes périnéaux pouvant être des déchirures inattendues ou chirurgicales comme en cas d’épisiotomie. De nombreuses techniques ont été utilisées pour prévenir les traumatismes du périnée, tels que le massage périnéal prénatal ou l'application de compresses chaudes. Leur efficacité pour réduire les traumatismes périnéaux a été identifiée par des chercheurs. L’injection de hyaluronidase au niveau périnéal était largement utilisée dans les années 50 et 60 pour réduire l'incidence des traumatismes du périnée, la douleur et la nécessité de recourir à une épisiotomie. Les auteurs de cette revue ont parcouru la littérature médicale à la recherche d’essais contrôlés randomisés comparant l'injection périnéale d’HAase pendant la deuxième phase du travail avec l’injection périnéale de placebo ou l'absence d'intervention. Ils ont identifié quatre essais contrôlés randomisés portant sur 599 femmes (avec des données disponibles pour 595 femmes). La qualité méthodologique de deux des quatre essais inclus dans cette revue était médiocre.

Deux essais portant sur 283 femmes comparaient les effets d’une injection d’HAase au niveau périnéal à ceux d’une injection de placebo, au cours de la deuxième phase du travail et ils étaient à faible risque de biais. Trois essais (un essai composé de trois bras a été analysé deux fois) incluant 373 femmes comparaient les effets de l'injection d’HAase au niveau du périnée, pendant la deuxième phase du travail, à l'absence d'intervention. Les résultats globaux ont montré que l'injection périnéale d’HAase s’accompagnait d’une incidence significativement plus faible de traumatismes du périnée, par rapport au témoin ou à l'absence d'intervention, mais il n'y avait aucune différence sur l'incidence des épisiotomies, et des déchirures périnéales de premier et second degré ou plus graves (troisième et quatrième degré).

Il n'y avait aucune preuve évidente que l'injection d’HAase ait réduit l’incidence des traumatismes périnéaux, des épisiotomies et des déchirures périnéales de premier et second degré et même plus graves (troisième et quatrième degré) par rapport à l'injection de placebo. Aucun effet secondaire n'a été rapporté dans les essais inclus. D'autres mesures telles que la douleur périnéale et d'autres critères de jugement secondaires prédéfinis n'ont pas été mesurés dans les essais inclus. La différence d'incidence concernant les traumatismes du périnée pouvant être due à des biais et des facteurs de confusion au niveau des études comparatives contrôlées sans placebo, ce résultat doit être interprété avec prudence.

L’utilisation potentielle de cette intervention en tant que méthode permettant de réduire les traumatismes du périnée est encore à déterminer, car il n’a pas été établi de dose d’HAase appropriée, il n’y avait pas de preuves de suivi ni d’effets secondaires, et le nombre d'essais de haute qualité et de résultats rapportés était trop limité pour tirer des conclusions sur son efficacité et son innocuité. D'autres essais contrôlés randomisés rigoureux sont nécessaires pour évaluer le rôle des injections périnéales de HAase dans les accouchements par voie basse.

Notes de traduction

Traduit par: French Cochrane Centre 6th July, 2014

Background

Description of the condition

Vaginal deliveries are associated with perineal trauma that may be unexpected tears or surgical as a result of episiotomy. Lacerations of the vagina and perineum are classified as first through fourth degree lacerations or perineal tears. First-degree lacerations involve the fourchette, perineal skin, and vaginal mucous membrane but not the underlying fascia and muscle. Second-degree lacerations involve, in addition, the fascia and muscles of the perineal body but not the anal sphincter. Third-degree lacerations extend farther to involve the anal sphincter (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)). A fourth-degree laceration extends through the anal sphincter complex (EAS and IAS) and the anal epithelium (RCOG 2007; Williams 2011).

The reported incidence of perineal trauma after vaginal deliveries varied considerably, partly due to the different definitions and reporting practices. Studies have indicated that in vaginal deliveries with restrictive use of episiotomy, 51% to 77% of women experienced some form of genital tract trauma that required suturing (Beckmann 2013; Mayerhofer 2002; McCandlish 1998). The prevalence of severe perineal trauma (third and fourth degree lacerations) in vaginal deliveries was reported to be from 0.5% to 7.0% (Aasheim 2011, 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, including blood loss, anal sphincter tears, urinary dysfunction, faecal incontinence, sexual problems and persistent perineal pain requiring surgical or psychological treatment (Albers 2006; Andrews 2007; Barrett 2000; Boyles 2009; Eason 2002; Ekeus 2008; Fenner 2003; Macarthur 2004; McCandlish 1998; Radestad 2008; Sultan 2002; Williams 2007).

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. Through the 1970s, it was common practice to cut an episiotomy for almost all women having their first delivery to get a straight surgical incision, which was easier to repair (Carroli 2009; Rodriguez 2008; Williams 2011). Although still a common obstetrical procedure, the use of episiotomy had decreased remarkably over the past 25 years and the rate ranged from 9.7% in Sweden to as high as 100% in Taiwan (Carroli 2009; Graham 2005). 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 have been used to prevent perineal trauma. Antenatal perineal massage may lower rates of perineal trauma (episiotomy, third degree and fourth degree tears) and ongoing perineal pain (Attarha 2009; Aasheim 2011; Davidson 2000; Kalichman 2008). The use of warm compresses on the perineum could decrease the occurrence of perineal lacerations (third degree and fourth degree) (Dahlen 2007; Aasheim 2011) and increase comfort during the second stage of labour (Dahlen 2009; 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 was widely used to reduce the occurrence of perineal trauma, pain, and 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 was 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, each sides of the perineum (left and right) and any previous episiotomy scars.

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, which is the major component of the extracellular cement substance of connective tissue, reduce the viscosity of hyaluronic acid 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 had 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 second stage of labour. The use of HAase in the perineum region helped the tissue achieve the necessary relaxation for fetal passage and minimised the numbers of episiotomies.

Why it is important to do this review

Given the high rate of perineal lacerations in vaginal deliveries, especially in women who were giving birth to their first child, and the subsequent morbidities, it is of high importance to identify alternative perineal techniques in order to reduce the perineal trauma and potential associated morbidities during childbirth. The question whether perineal HAase injection can decrease the perineal lacerations had not been satisfactorily answered. Our review aimed to evaluate the available evidence about the benefits and side effects of perineal HAase injection for reducing perineal trauma in vaginal deliveries. Perineal HAase injection may be an efficient and economic method to reduce perineal trauma. Our review was essential to provide evidence.

Objectives

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

We did not include cross-over trials.

We intended to include studies reported only in abstract form in the studies awaiting classification category and include them 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 injection or no intervention.

Types of outcome measures

Primary outcomes
  1. Incidence of perineal trauma.

  2. Incidence of episiotomy.

  3. Perineal pain.

Secondary outcomes
  1. Incidence of first and second degree perineal trauma.

  2. Incidence of third and fourth degree perineal trauma.

  3. Perineal trauma requiring suturing.

  4. Blood loss.

  5. Dyspareunia.

  6. Urinary incontinence.

  7. Faecal incontinence.

  8. Assisted delivery rate.

  9. Women's satisfaction.

  10. Side effects.

  11. Apgar score less than seven at five minutes.

  12. Need for admission to special care baby unit.

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2013)

The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

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

  2. weekly searches of MEDLINE;

  3. weekly searches of Embase;

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

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

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

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

In addition, we conducted a supplementary search of the International Clinical Trials Registry Platform (ICTRP) (1 April 2013), the Networked Digital Library of Theses and Dissertations (1 April 2013) (see: Appendix 1).

Searching other resources

We searched the reference lists of retrieved studies and also contacted relevant organisations (e.g. Chinese Medical Association) (1 April 2013).

We did not apply any language restrictions. 

Data collection and analysis

Selection of studies

Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted a third person.

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third person. We entered data into Review Manager software (RevMan 2012) and checked for accuracy.

When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

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

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

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

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

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

We assessed 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 have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated 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 was reported, or was supplied by the trial authors, we re-included missing data in the analyses which we undertook.

We assessed 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 have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

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

  • high risk of bias (where not all the study's pre-specified outcomes had been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so cannot be used; study failed 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 have described for each included study 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 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 made explicit judgments 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 whether we considered it was likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

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

Continuous data

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

Unit of analysis issues

Cluster-randomised trials

We did not identify any cluster-randomised trials for inclusion. However, if we identify any cluster-randomised trials in future updates, we will include them 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 intra-cluster 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 included multi-armed trials in the analyses along with individually-randomised trials. We included the relevant intervention groups in a pair-wise comparison of intervention groups that meet the criteria for including studies in the review. We combined groups to create a single pair-wise comparison using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions.

Dealing with missing data

For included studies, we noted levels of attrition. We explored 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 carried out analyses, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were 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 was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if the I² was greater than 30% and either the Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

In future updates of this review, 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 carried out statistical analysis using the Review Manager software (RevMan 2012). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials' populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random-effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials.

Where we used random-effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of  Tau² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity in future updates of this review, 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 planned to carry prespecified subgroup analyses but were unable to perform these analyses due to insufficient data. However, in future updates we will carry out the following prespecified subgroup analyses where possible.

  • Parity

  • Birthweight

  • Different birth positions (upright or supine)

  • Strength, frequency and position of injection

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 2012). We will report the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

In future updates of this review we will performed sensitivity analysis (where required) excluding studies with a high risk of bias, such as studies with more than 20% missing data.

Results

Description of studies

Results of the search

See:Figure 1. The search of the Pregnancy and Childbirth Group's Trials Register retrieved six reports. The additional author search retrieved no reports. Four randomised controlled trials involving 599 women (with data available from 595 women) who were giving birth to their first child have been included (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008) and two reports have been excluded (Giri 1969; Nashar 2011). One of the included studies (Chatfield 1966) was a three-armed trial and we included data from all three arms.

Figure 1.

Study flow diagram.

Included studies

Four randomised controlled trials had been included in this review. Two studies were quite old and were conducted during the 1960s (Chatfield 1966; O'Leary 1965). Another study was published in 2008 (Scarabotto 2008), the remaining in 2011 (Colacioppo 2011). The included trials were conducted in Sao Paulo, Brazil (Colacioppo 2011; Scarabotto 2008), Glasgow, The United Kingdom (Chatfield 1966) and Columbia-Presbyterian Medical Center, USA (O'Leary 1965). None of the included trials reported the characteristics of the participants in terms of ethnicity or skin pigmentation. The sample sizes from all the studies were small and ranged between 100 (O'Leary 1965) and 200 women (Chatfield 1966). Chatfield 1966 included primigravida women; in Colacioppo 2011 and Scarabotto 2008 women had had no previous vaginal birth; and O'Leary 1965 included both nulliparous and primiparous women.

Two trials compared perineal HAase injection with placebo injection (Chatfield 1966; Colacioppo 2011) and three trials (one three-armed trial was analysed twice) provided perineal HAase injection in comparison with no intervention (Chatfield 1966; O'Leary 1965; Scarabotto 2008). The perineal HAase or placebo injections were performed once at the onset of the second stage of labour. The dose of the HAase injection varied from 750 turbidity-reducing units to 2000 turbidity-reducing units. The injection regions were the perineal body, each sides of the perineum (left and right), anterior region of the perineum, the posterior region of perineum, and any previous episiotomy scars. Most of the outcomes were defined in the same way across the different trials.

Please refer to Characteristics of included studies table for a detailed description of the studies, including HAase injection doses used and regimens compared.

Excluded studies

Two studies (Giri 1969; Nashar 2011) were excluded from the review as they did not satisfy the inclusion criteria. Giri 1969 studied the effects of HAase injection before episiotomy on local anaesthesia oedema and pain, sepsis and healing of the episiotomy wound. Nashar 2011 examined the effectiveness of Cikatridina spray on aiding healing of episiotomy and spontaneous perineal ruptures after normal and operative vaginal deliveries.

Please refer to Characteristics of excluded studies table for more details.

Risk of bias in included studies

Full details of 'Risk of bias' assessments were included in the Characteristics of included studies table. We have also included figures that summarised our 'Risk of bias' assessments (Figure 2, Figure 3).

Figure 2.

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

Figure 3.

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

Allocation

One study used computer-generated random number sequences (Colacioppo 2011) and another used a random numbers table (Scarabotto 2008) to randomise the intervention groups; these were rated as low risk of bias. The other trials reported the trials as randomised but the methods used to generate the sequence were not described (Chatfield 1966; O'Leary 1965) and were rated as 'unclear' risk of bias.

One trial (Chatfield 1966) reported that the allocation was supervised by the resident anaesthetic staff who were not concerned with this delivery (sequence generated by an independent researcher), and prepared the "blind" solutions for injection (low risk of bias). One trial (Colacioppo 2011) was reported as double-blind (low risk of bias). Another trial (Scarabotto 2008) reported to be an open trial without concealment (high risk of bias). The remaining trial (O'Leary 1965) did not report the methods used to conceal the allocation (unclear risk of bias).

Blinding

Two trials (Chatfield 1966; Colacioppo 2011) were reported as double-blind (low risk of bias). Another trial (Scarabotto 2008) was reported as open (high risk of bias). The remaining trial (O'Leary 1965) was not reported as blinded (high risk of bias). While lack of blinding may not represent a serious source of bias for some outcomes (e.g. perineal pain, blood loss), other outcomes (i.e. incidence of perineal trauma, episiotomy and perineal trauma requiring suturing) may have been affected by knowledge of the treatment group.

Incomplete outcome data

Two trials (Chatfield 1966; O'Leary 1965) reported no participants lost to follow-up. The remaining trials reported an attrition rate of 2.5% (Colacioppo 2011) and 13.1% (Scarabotto 2008). All trials were rated as low risk of attrition bias.

Selective reporting

All four included randomised controlled trials were rated as 'unclear' risk of bias as they provided insufficient information, which limited us from making any judgment (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008).

Other potential sources of bias

No other potential sources of bias were identified and all four trials were rated as 'low risk'.

Effects of interventions

In this review, we included four randomised controlled trials, involving 599 women. Data were only available for 595 of the women. We organised the summary results by comparison. We analysed the perineal HAase injection in comparison with control (placebo injection and no intervention). The lack of blinding may affect some outcomes (e.g. incidence of perineal trauma, episiotomy and perineal trauma requiring suturing) and represent a serious source of bias. Any differences between perineal HAase injection and control were probably due to bias and confounding in the non-placebo controlled comparison. Thus, we decided to put the perineal HAase injection versus placebo injection and perineal HAase injection versus no intervention in separate comparisons and re-analysed the comparisons.

In the Data and analyses tables, we set up all three prespecified comparisons.

For each of the comparisons, we have indicated the number of studies contributing data and the number of women included in that analysis.

Comparison 1 - HAase injection versus control (four studies, 599 women)

Four studies (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008) involving 599 women were included in this comparison, 595 participants contributed data. Two trials (Chatfield 1966; Colacioppo 2011) were assessed as being at low risk of bias, the others (O'Leary 1965; Scarabotto 2008) were assessed as being at high risk of bias.

Primary outcomes
Incidence of perineal trauma

The data from four randomised controlled trials (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008) involving 595 women suggested a trend that women receiving perineal HAase injection during second stage of labour had a lower incidence of perineal trauma compared with control (average risk ratio (RR) 0.69, 95% confidence interval (CI) 0.50 to 0.95) (Analysis 1.1).There was some variation among trials in terms of the size of the treatment effect (Tau² = 0.08, I² = 82% and Chi² test for heterogeneity P = 0.0008).

Incidence of episiotomy

The data from four randomised controlled trials (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008) involving 595 women contributed data for this analysis. There was no difference in the incidence of episiotomy between women who received perineal HAase injection during second stage of labour and control. There was some variation among trials in terms of the size of the treatment effect (Tau² = 0.17 , I² = 66% and Chi² test for heterogeneity P = 0.03).The average RR between groups was 0.74 (95% CI 0.43 to 1.29) (Analysis 1.2).

Perineal pain

None of the included trials reported on this outcome.

Secondary outcomes
Incidence of first and second degree perineal trauma

The data from four randomised controlled trials (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008) involving 595 women contributed to this analysis. There was no difference in the incidence of first and second degree perineal trauma between women receiving perineal HAase injection during second stage of labour and control (average RR 0.71, 95% CI 0.38 to 1.33) (Analysis 1.3). There was some variation among trials in terms of the size of the treatment effect (Tau² = 0.30, I² = 85% and Chi² test for heterogeneity P = 0.0002).

Incidence of third and fourth degree perineal trauma

The data from four randomised controlled trials (Chatfield 1966; Colacioppo 2011; O'Leary 1965; Scarabotto 2008) involving 595 women contributed to this analysis. There was no difference in the incidence of third and fourth degree perineal trauma between women who received perineal HAse injection during second stage of labour and control (RR 0.12; 95% CI 0.01 to 2.13) (Analysis 1.4), but given the scarcity of data for this outcome, no firm conclusions can be drawn.

Side effects

No side effects were reported in the included trials.

None of the included trials reported on our other pre-specified secondary outcomes: perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit.

Comparison 2 - HAase injection versus placebo injection (two studies, 283 women)

Two randomised controlled trials involving 283 women were included in this comparison, 279 women contributed data. The two randomised controlled trials (Chatfield 1966; Colacioppo 2011) were assessed as being at low risk of bias.

Primary outcomes
Incidence of perineal trauma

The data from two randomised controlled trials (Chatfield 1966; Colacioppo 2011) involving 279 women suggested a trend that women receiving perineal HAase injection during the second stage of labour had no statistically difference in the incidence of perineal trauma compared with placebo injection (RR 0.90; 95% CI 0.77 to 1.06) (Analysis 2.1).There was little variation among trials in terms of the size of the treatment effect (Tau² = 1.07, I² = 7% and Chi² test for heterogeneity P = 0.30).

Incidence of episiotomy

The data from two randomised controlled trials (Chatfield 1966; Colacioppo 2011) involving 279 women contributed data for this analysis. There was no difference in the incidence of episiotomy between women who received perineal HAase injection and placebo injection during second stage of labour. There was some variation among trials in terms of the size of the treatment effect (Tau² = 0.27, I² = 54% and Chi² test for heterogeneity P = 0.14).The average RR between groups was 0.77 (95% CI 0.32 to 1.89) (Analysis 2.2).

Perineal pain

None of the included trials reported on this outcome.

Secondary outcomes
Incidence of first and second degree perineal trauma

The data from two randomised controlled trials (Chatfield 1966; Colacioppo 2011) involving 279 women contributed to this analysis. There was no difference in the incidence of first and second degree perineal trauma between women receiving perineal HAase injection and placebo injection during second stage of labour (RR 1.08; 95% CI 0.83 to 1.40) (Analysis 2.3). There was little variation among trials in terms of the size of the treatment effect (Tau² = 1.11, I² = 10% and Chi² test for heterogeneity P = 0.29).

Incidence of third and fourth degree perineal trauma

The data from two randomised controlled trials (Chatfield 1966; Colacioppo 2011) involving 279 women contributed to this analysis. There was no difference in the incidence of third and fourth degree perineal trauma between women who received perineal HAse injection and placebo injection during second stage of labour (RR 0.12; 95% CI 0.01 to 2.13) (Analysis 2.4), but given the scarcity of data for this outcome, no firm conclusions can be drawn.

Side effects

No side effects were reported in the included trials.

None of the included trials reported on our other pre-specified secondary outcomes: perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit.

Comparison 3 - HAase injection versus no intervention (three studies, 373 women)

Three randomised controlled trials involving 373 women were included in this comparison (Chatfield 1966; O'Leary 1965; Scarabotto 2008); all three studies contributed data. Only one trial (Chatfield 1966) was assessed as being at low risk of bias.

Primary outcomes
Incidence of perineal trauma

The data from three randomised controlled trials (Chatfield 1966; O'Leary 1965; Scarabotto 2008) involving 373 women suggested that women who received perineal HAase injection during second stage of labour had a lower incidence of perineal trauma compared with no intervention (RR 0.61; 95% CI 0.42 to 0.88) (Analysis 3.1). There was some substantial heterogeneity among trials in terms of the size of the treatment (Tau² = 0.08, I² = 78% and Chi² test for heterogeneity P = 0.01).

Incidence of episiotomy

Three randomised controlled trials (Chatfield 1966; O'Leary 1965; Scarabotto 2008) involving 373 women reported on this outcome. Results suggested that there was no difference in the incidence of episiotomy between women who received perineal HAase injection during second stage of labour in comparison with no intervention (RR 0.79; 95% CI 0.44 to 1.42) (Analysis 3.2). There was some substantial heterogeneity among trials in terms of the size of the treatment (T² = 0.16, I² = 70% and Chi² test for heterogeneity P = 0.03).

Perineal pain

None of the included trials reported on this outcome.

Secondary outcomes  
Incidence of first and second degree perineal trauma

The data from three randomised controlled trials (Chatfield 1966; O'Leary 1965; Scarabotto 2008) involving 373 women reported on this outcome. Results suggested that there was no difference in the incidence of first and second degree perineal trauma between women who received perineal HAase injection during second stage of labour in comparison with no intervention (RR 0.58; 95% CI 0.31 to 1.10) (Analysis 3.3). There was some substantial heterogeneity among trials in terms of the size of the treatment (Tau² = 0.18, I² = 59% and Chi² test for heterogeneity P = 0.09).

Incidence of third and fourth degree perineal trauma

The data from three randomised controlled trials (Chatfield 1966; O'Leary 1965; Scarabotto 2008) involving 373 women reported on this outcome. But no third or fourth degree of perineal trauma were reported in these trials, therefore, no firm conclusions can be drawn (Analysis 3.4).

Side effects

No side effects were reported in the included trials.

None of the included trials reported on our other pre-specified secondary outcomes: perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit.

Subgroup analysis

We attempted to conduct a subgroup analysis but in all the outcomes very few studies contributed data. Indeed, for several subgroups, all the trials were in the same subgroup category or only one trial was allocated to one of the subgroup categories impeding any judgements.

As more data become available, in updates of the review, we hope to explore possible subgroup differences by carrying out both visual exploration and formal statistical tests.

Discussion

Summary of main results

This review evaluated the effectiveness and safety of perineal HAase injection during the second stage of labour for reducing the incidence of spontaneous perineal trauma, the incidence of episiotomy and perineal pain in vaginal deliveries. It included four randomised controlled trials involving 599 women (with data available for 595 women). Two trials compared perineal HAase injection with perineal placebo injection and three trials (one three-armed trial was analysed twice) compared perineal HAase injection with no intervention.

In comparison with control (placebo injection or no intervention), perineal HAase injection during the second stage of labour resulted in a lower incidence of perineal trauma, but there was no difference in incidence of episiotomy, first and second degree and more severe (third and fourth degree) perineal lacerations. Meanwhile, in comparison with women who received placebo injection, perineal HAase injection during second stage of labour had no difference in the incidence of perineal trauma, episiotomy, first and second degree and more severe (third and fourth degree) perineal lacerations. In comparison with the group that received no intervention, women who received perineal HAase injection during second stage of labour had a significantly lower incidence of perineal trauma, but there was no significant difference in terms of incidence of episiotomy and first and second degree perineal lacerations.

Perineal HAase injection had a lower incidence of perineal trauma compared with control or no intervention, but had no difference compared with placebo injection. The difference in the incidence of perineal trauma between perineal HAase injection and control or no intervention may probably due to bias and confounding in the non-placebo controlled comparison; this result should be interpreted cautiously.

No side effects were reported in the included trials. No included trials reported on perineal pain and our other pre-specified secondary outcomes: perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit.

Overall completeness and applicability of evidence

Perineal HAase injection during the second stage of labour was given with the aim of reducing perineal trauma and improving gestational outcomes. However, the scarcity of data was evident, not only from the limited number of trials, but also from the small number of outcomes evaluated. Numerous gestational outcomes (perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit) were not reported. The clinical significance of perineal HAase injection is yet to be determined.

Quality of the evidence

The methodological qualities of two out of the four trials included in this review were poor after considered the methods for allocating the treatment, blinding and attrition rates (see Risk of bias in included studies).

Potential biases in the review process

We identified several potential biases in the review process. They were minimised in two ways: (1) eligibility for inclusion and data extraction were assessed independently by two review authors and (2) assessments of risk of bias and data entry were also assessed independently by two review authors. However, this type of review required that we made a number of subjective judgments and others may have reached different decisions regarding assessments of eligibility and risk of bias. We encourage readers to examine the Characteristics of included studies tables to assist in the interpretation of results.

Agreements and disagreements with other studies or reviews

Previous observational studies had suggested that perineum HAase injection was associated with reduced perineal trauma or increased intact perineum (Digonnet 1952; Mink 1955; Patrini 1956). The findings from this review suggested that perineal HAase injection during second stage of labour had a lower incidence of perineal trauma compared with control or no intervention, but this result should be interpreted cautiously due to the probably existence of bias and confounding.

Authors' conclusions

Implications for practice

Perineal HAase injection during second stage of labour had a lower incidence of perineal trauma compared with control or no intervention, but there was no clear evidence of a difference compared with placebo injection. The difference in incidence of perineal trauma between perineal HAase injection and control or no intervention may probably due to bias and confounding in the non-placebo controlled comparison, this result should be interpreted cautiously. The clinical significance of this finding was yet to be determined as there was currently insufficient high quality evidence relating to the effectiveness and safety of perineal HAase injection during the second stage of labour. Caution was needed as there has been no evaluation of acceptability and comfort by women. Good quality studies are needed to determine the effectiveness and feasibility of perineal HAase injection for reducing perineal trauma.

Implications for research

Further rigorous randomised trials are required to evaluate the role of perineal HAase injection for reducing perineal trauma. Future researches should evaluate if the perineal HAase injection is associated with reduced perineal trauma in populations with different parity, birthweight, birth positions (upright or supine) and strength, frequency and position of injection. Information on the most effective and safe dosage are also needed to inform policy-making.

Acknowledgements

The review authors would like to thank Lynn Hampson, Caroline Crowther, Rintaro Mori, Janet Wale, Denise Atherton of the Cochrane Pregnancy and Childbirth Group for their support in the production of this review.

As part of the pre-publication editorial process, this review 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.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

Comparison 1. HAase injection versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of perineal trauma4595Risk Ratio (M-H, Random, 95% CI)0.69 [0.50, 0.95]
2 Incidence of episiotomy4595Risk Ratio (M-H, Random, 95% CI)0.74 [0.43, 1.29]
3 Incidence of first and second degree perineal lacerations4595Risk Ratio (M-H, Random, 95% CI)0.71 [0.38, 1.33]
4 Incidence of third and fourth degree perineal lacerations4595Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 2.13]
Analysis 1.1.

Comparison 1 HAase injection versus control, Outcome 1 Incidence of perineal trauma.

Analysis 1.2.

Comparison 1 HAase injection versus control, Outcome 2 Incidence of episiotomy.

Analysis 1.3.

Comparison 1 HAase injection versus control, Outcome 3 Incidence of first and second degree perineal lacerations.

Analysis 1.4.

Comparison 1 HAase injection versus control, Outcome 4 Incidence of third and fourth degree perineal lacerations.

Comparison 2. HAase injection versus placebo injection
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of perineal trauma2279Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.77, 1.06]
2 Incidence of episiotomy2279Risk Ratio (M-H, Random, 95% CI)0.77 [0.32, 1.89]
3 Incidence of first and second degree perineal lacerations2279Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.83, 1.40]
4 Incidence of third and fourth degree perineal trauma2279Risk Ratio (M-H, Random, 95% CI)0.12 [0.01, 2.13]
Analysis 2.1.

Comparison 2 HAase injection versus placebo injection, Outcome 1 Incidence of perineal trauma.

Analysis 2.2.

Comparison 2 HAase injection versus placebo injection, Outcome 2 Incidence of episiotomy.

Analysis 2.3.

Comparison 2 HAase injection versus placebo injection, Outcome 3 Incidence of first and second degree perineal lacerations.

Analysis 2.4.

Comparison 2 HAase injection versus placebo injection, Outcome 4 Incidence of third and fourth degree perineal trauma.

Comparison 3. HAase injection versus no intervention
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of perineal trauma3373Risk Ratio (M-H, Random, 95% CI)0.61 [0.42, 0.88]
2 Incidence of episiotomy3373Risk Ratio (M-H, Random, 95% CI)0.79 [0.44, 1.42]
3 Incidence of first and second degree perineal lacerations3373Risk Ratio (M-H, Random, 95% CI)0.58 [0.31, 1.10]
4 Incidence of third and fourth degree perineal trauma3373Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 HAase injection versus no intervention, Outcome 1 Incidence of perineal trauma.

Analysis 3.2.

Comparison 3 HAase injection versus no intervention, Outcome 2 Incidence of episiotomy.

Analysis 3.3.

Comparison 3 HAase injection versus no intervention, Outcome 3 Incidence of first and second degree perineal lacerations.

Analysis 3.4.

Comparison 3 HAase injection versus no intervention, Outcome 4 Incidence of third and fourth degree perineal trauma.

Appendices

Appendix 1. Additional search strategy

Review authors searched the WHO International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned trials and the Networked Digital Library of Theses and Dissertations (NDLTD) for grey literature on 1 April 2013 using the terms hyaluronidase and perine*

Contributions of authors

Wang XD provided a clinical and policy perspective for the review, Li J provided a methodological perspective, Zhou F, Huang GQ and Gao BX prepared a draft of the protocol. All review authors discussed the document and provided edits and references and evaluated the references for eligibility. Wang XD and Zhou F evaluated the references for eligibility. Zhou F and Huang GQ extracted data from the included trials. All review authors contributed to the preparation of the review.

Declarations of interest

We certify that we have no affiliations or involvement in any organisation or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

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

Differences between protocol and review

In comparison with the protocol, this review has the following differences.

  • We searched the International Clinical Trials Registry Platform (ICTRP) (1 April 2013), the Networked Digital Library of Theses and Dissertations (1 April 2013) and also contacted relevant organisations (1 April 2013) in review to avoid missing important trials.

  • We added "Incidence of first and second degree of perineal lacerations" and "faecal incontinence" to the secondary outcomes of review because they were important outcome variables in evaluating the severity or prognosis of perineal lacerations.

  • The "mode of delivery" and "length of second stage of labour" occurred after intervention (i.e. outcome variables) and it would be inappropriate for making plans to conduct subgroup analyses based on them. As a result, We deleted the "mode of delivery" and "length of second stage of labour" in the subgroup analyses of our review. Given that our planned sensitivity analyses included excluding studies with a high risk of bias, it was considered unnecessary to perform subgroup analysis based on "trial quality".

  • The "strength, frequency and locations" have a major impact on the effectiveness and safety of HAase injection. We preferred to perform subgroup analyses based on "strength, frequency and locations" in the future update of review if sufficient new data become available.

  • We decided not to carry out planned sensitivity analyses to explore the effects of fixed- or random-effects analyses for outcomes with statistical heterogeneity. Where substantial statistical heterogeneity was present we used a random-effects model as stated in our methods.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Chatfield 1966

MethodsRandomised double-blind controlled trial; 3-arm design with individual randomisation.
Participants200 women were included. Inclusion criteria: primigravid patients having spontaneous vaginal vertex deliveries. Exclusion criteria: any patient requiring episiotomy for an indication other than a tight or rigid perineum.
Interventions

Participants were randomly allocated to 1 of the following groups.

Group 1 (n = 57): women received 5 mL sterile normal saline containing 1500 U.S.P units of HAase injected into perineal body at the onset of the second stage of labour.

Group 2 (n = 66): women received 5 mL sterile normal saline injected into perineal body at the onset of the second stage of labour.

Group 3 (n = 77): women received no intervention.

OutcomesPercentage of patients requiring episiotomy; percentage of patients with perineal tears; percentage of patients with intact perineum.
NotesThe perineum was infiltrated at the onset of the second stage of labour. 5 mL of the solution was injected into the perineal body and into the base of the hymen and fourchette. Labour was allowed to continue normally and the decision to perform an episiotomy was made on the usual indications, namely a rigid perineum preventing advance of the presenting part or a tight perineum showing signs of an impending tear.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskTrial reported random allocation to the groups, although the method of sequence generation was not described.
Allocation concealment (selection bias)Low riskThe allocation was supervised by the resident anaesthetic staff who were not concerned with this delivery, and prepared the "blind" solutions for injection.
Selective reporting (reporting bias)Unclear riskThere was insufficient information to permit judgement.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskTrial reported as double-blind. The participants did not know the solution injected.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskTrial reported as double-blind. The obstetrician did not know the identity of the solution injected by him and so was not influenced in his decision to perform episiotomy.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients completed the trial, no participants eliminated from the trial.
Other biasLow riskThe study appeared to be free of other sources of bias.

Colacioppo 2011

MethodsRandomised double-blind controlled trial; 2-arm design with individual randomisation.
Participants160 women were included. Inclusion criteria were: age 18 years or older; no prior record of vaginal birth; term, single, and live fetus; vertex fetal presentation; cervical dilation at least 8 cm on admission to the birth centre; no suspected or confirmed systemic infections or infections of the perineal or vulvovaginal region; and spontaneous birth in a semi sitting position without intradural or extradural anaesthesia.
Interventions

Participants were randomly allocated to 1 of the following groups.

Group 1 (n = 75 at the end of the trial): women received 5 mL sterile water containing 2000 turbidity-reducing units of HAase injected through the perineal subcutaneous tissue, with 1 mL injected in the centre of the perineum and 2 mL in each of the sides (left and right) at the onset of the second stage of labour.

Group 2 (n = 77 at the end of the trial): women received 5 mL sterile water containing placebo injected through the perineal subcutaneous tissue, with 1 mL injected in the centre of the perineum and 2 mL in each of the sides (left and right) at the onset of the second stage of labour.

OutcomesIntegrity or perineal trauma and its severity.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by using a computerised, random-numbers table previously generated by the statistician.
Allocation concealment (selection bias)Low riskDouble-blind.
Selective reporting (reporting bias)Unclear riskThere was insufficient information to permit judgement.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskA total of 160 women who met the inclusion criteria were recruited and enrolled in the study. None of them declined to participate, and 4 were excluded for the following reasons: 3 did not receive the intervention (2 flasks were broken during use, and 1 was discarded because of accidental introduction of a fragment of the rubber lid during the aspiration of the solution); the fourth was excluded because the providers conducted uterine fundal pressure to help birthing (Kristellermaneuver), and it was thought that this manoeuvre was not standard and may increase perineal trauma. The final sample consisted of 156 participants distributed into 2 groups, with 76 women in the experimental group and 80 in the control group.
Other biasLow riskThe study appeared to be free of other sources of bias.

O'Leary 1965

MethodsRandomised double-blind controlled trial; 2-arm design with randomised selection.
Participants100 term nulliparity or primiparity vaginal deliveries irrespective of age or nationality.
Interventions

Intervention group: 5-10 mL prepared HAase contained 750-1550 turbidity-reducing units of HAase (Wydase) injected into the perineal body, hymen, and any previous episiotomy scars before delivery.

Control group: no intervention.

OutcomesEpisiotomy; perineum lacerations.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation was not described.
Allocation concealment (selection bias)Unclear riskMethod of concealment was not described.
Selective reporting (reporting bias)Unclear riskThere was insufficient information to permit judgement.
Blinding of participants and personnel (performance bias)
All outcomes
High riskIt was not possible to blind the intervention for the participants.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot reported as blinded. Different interventions were used: HAase injection or no intervention.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients completed the trial, no participants eliminated from the trial.
Other biasLow riskThe study appeared to be free of other sources of bias.

Scarabotto 2008

  1. a

    HAase: hyaluronidase

MethodsRandomised controlled trial; 2-arm design with individual randomisation.
Participants139 women were included. Inclusion criteria: between 15 and 35 years of age; no previous record of vaginal birth; single, live fetus, vertex fetal presentation; spontaneous delivery in left lateral position; no intravenous oxytocin infusion during the first and second stages of labour; no previous perineal treatment during gestation; and no suspected or confirmed systemic infections or infections of the perineal or vulvo-vaginal region. Additionally, upon admission to the birth centre, study participants had a uterine height no greater than 36 cm, cervical dilatation of 8 cm or less, and intact amniotic membranes. Cases requiring medical interventions were excluded.
Interventions

Participants were randomly allocated to 1 of the following groups.

Group 1 (n = 71 at the end of the trial): women received 5 mL sterile water containing 2000 turbidity-reducing units of HAase injected 1 mL in the centre of the perineum and 2 mL in each of the sides in the shape of a fan during the second stage of labour.

Group 2 (n = 68 at the end of the trial): no intervention.

OutcomesIntact perineum, episiotomy, first and second degree laceration.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by computerised random numbers table previously generated by the statistician.
Allocation concealment (selection bias)High riskNo concealment.
Selective reporting (reporting bias)Unclear riskThere was insufficient information to permit judgement.
Blinding of participants and personnel (performance bias)
All outcomes
High riskIt was not possible to blind the intervention for the participants.
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot reported as blinded. Different interventions were used: HAase injection or no intervention.
Incomplete outcome data (attrition bias)
All outcomes
Low riskIn total, 160 women who met the eligibility criteria were enrolled in the study. During the first stage of labour, 9 women were excluded following intravenous infusion of oxytocin and 11 were excluded because of the need to perform caesarean delivery. During the second stage, 1 woman was excluded because of the use of forceps to deliver the fetus. The final sample consisted of 139 women distributed into 2 groups, with 71 women in the intervention group and 68 in the control group.
Other biasLow riskThe study appeared to be free of other sources of bias.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    HAase: hyaluronidase

Giri 1969This study aimed at studying the effects of HAase injection before episiotomy on local anaesthesia oedema and pain, sepsis and union of the episiotomy wound, and compared these effects with those of a control series.
Nashar 2011Aimed at determining the effectiveness of Cikatridina spray on aiding healing of episiotomy and spontaneous perineal ruptures after normal and operative vaginal delivery. This study did not compare the injection of hyaluronidase versus placebo or no intervention.

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