Antibiotics prior to amniotomy for reducing infectious morbidity in mother and infant

  • Protocol
  • Intervention

Authors


Abstract

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

To study the effects of the use of antibiotics versus placebo or no treatment prior to amniotomy on maternal and perinatal morbidity and mortality.

Background

Amniotomy

Amniotomy is the deliberate rupture of the fetal membranes. It was first described over 200 years ago by Thomas Denman of the Middlesex Hospital in the United Kingdom) (Calder 1999). This procedure involves feeling the membranes vaginally and rupturing or piercing them either by fingers or instruments (Bricker 2000; Frigoletto 1995). Amniotomy has been used alone, or in combination with other interventions, both for induction and for shortening of labour (Bricker 2000). It is thought to act by releasing prostaglandins and increasing oxytocin levels (Busowski 1995; Wolomby 2009).

Induction and augmentation of labour are common obstetric practices. Trends have shown a rise in the induction rate over the last decade with rates varying from 9.5% to 33.7% of all pregnancies annually (Mackenzie 2006; Tenore 2003). Data claim that the rate of labour inductions are rising faster than the rate of pregnancy complications (Agency for Healthcare Research and Quality 2009).

There is a myriad of methods for both labour induction and augmentation including pharmacological, mechanical, complementary and alternative medicine (Hofmeyr 2009). Even though the pharmacological methods of induction of labour have become more common in recent years, amniotomy alone or amniotomy with oxytocin still remain the most common approach to induce or augment labour, particularly in resource-constrained settings (Bricker 2000; Janes 2001; Mozurkewich 2011; Tinelli 2003).

Description of the condition

Amniotomy for induction of labour

Many studies  have utilised amniotomy as a method for induction of labour. This has been studied with and without the use of oxytocin (Busowski 1995; Cooley 2010; Mozurkewich 2011; Nachum 2010). Some evidence is present that amniotomy alone may necessitate the use of oxytocin more often than pharmacological methods (Bricker 2000; Mozurkewich 2011; Tinelli 2003).

Amniotomy to shorten first stage of labour

Besides induction of labour, amniotomy is commonly used to shorten labour both singly or in combination with oxytocin (Smyth 2007) and is a part of "active management of labour". Studies and reviews looking at the safety and efficacy profiles report insufficient data for the use of amniotomy alone. When considering a combination of amniotomy with oxytocin establishment of active labour, a shorter amniotomy-delivery interval, lesser maternal fever and greater maternal satisfaction has been reported (Howarth 2001; Nachum 2010; Pisal 2009).

Risks of amniotomy (infectious morbidity associated with intra-amniotic infection)

Rupture of membranes can lead to ascending infection from the vagina to the uterine cavity and, in the majority of instances is the reason for intra-amniotic infections (Heinemann 2008; Hopkins 2002). Intra-amniotic infections in turn can lead to significant maternal and fetal morbidity (Gibbs 1982; Gilstrap 1988).

Even though the actual incidence of chorioamnionitis is not known, it would be expected to be higher in the developing countries where women may receive sub-optimal care and have poor nutrition during pregnancy (Katona 2008; Naeye 1977; Reilly 2008). It is in these resource-poor settings that amniotomy would be more commonly used, either as a method of augmentation or induction (Bricker 2000; Janes 2001). The implications for the neonate too would be graver as universal Group B Streptococcus screening would not be available in these settings.

Intra-amniotic infection can lead to early onset neonatal sepsis (EONS) (Escobar 1999). Newborns who develop EONS, defined as proven infection at less than 72 hours of life, have a higher mortality rate (Dutta 2010).

Infection would also be related to the time between amniotomy and delivery. It is likely the length of time would be quite short in most cases (especially amniotomy to shorten the first stage of labour), therefore, the potential for infection might be unlikely. On the other hand, amniotomy for induction may not follow the same pattern and may result in greater infectious morbidity (Cooley 2010; Hofmeyr 2009).

Apart from the risks of amniotomy per se, there are other associated procedures that contribute to the risks of amniotomy when used either for labour augmentation or induction. These include intravenous line, electronic fetal monitoring by scalp electrode, intrauterine pressure catheters, pain-relieving drugs, immobilisation and regional anaesthesia, each of which contribute to the risks or benefits of amniotomy for induction or augmentation (Hofmeyr 2009).

Besides infectious morbidity, early amniotomy has also been associated with fetal heart abnormalities (Goffinct 1982).

Description of the intervention

The organisms commonly isolated in intra-amniotic infections are ascending genital microbes and chorioamnionitis is often poly-microbial. Ureaplasma urealyticum and Mycoplasma hominis are the most commonly isolated organisms (Kron 1995; Romero 1989; Silver 1989; Tita 2010). Besides, Gardenella vaginalis, Bacteroides species, Escherichia coli and Group B streptococci lead to intra-amniotic infection with significant maternal and neonatal morbidity (Hopkins 2002). Additionally, methicillin-resistant Staphylococcus aureus (MRSA) has been identified as a common cause of nosocomial infection in maternity and neonatal units (Bratu 2005; Zanella 2010). Listeria monocytogenes infection of the neonate has also been reported, presumably due to hematogenous spread (originating or transported in the blood) rather than ascending vaginal infection (Hopkins 2002; Schuchat 1992).

The antibiotics commonly used to combat intra-amniotic infections are targeted against these organisms (Hopkins 2002; Verani 2010).

How the intervention might work

Comparison of different antibiotic regimens for intra-amniotic infections has not given any conclusive results (Hopkins 2002; Lamont 2006; Yoon 2001). Since the optimal antibiotic regimen is not established, most of the recommendations for antibiotic usage are based on consensus. A combination regimen is mostly used which combines a penicillin and an aminoglycoside. For anaerobic coverage, either clindamycin or metronidazole is often used as a third drug. Intravenous administration of ampicillin (2 g) or aqueous penicillin G (5 million Units) intravenously every six hours and gentamicin every eight to 24 hours until delivery is the typical regimen (Edwards 2005; Hopkins 2002; Locksmith 2005). Vancomycin, extended spectrum penicillins or cephalosporins such as piperacillin-tazobactam or cefotetan have also been used (Edwards 2005). In penicillin-allergic patients, vancomycin (1 g intravenously every 12 hours) may replace ampicillin (Duff 2002). For the purpose of this review, we will consider any antibiotic or combination of antibiotics used by the trial authors.

Mode of action and side effects of the commonly used antibiotics

Ampicillin is a semisynthetic derivative of penicillin used as a broad spectrum bactericidal agent against gram-positive bacteria and acts by inhibiting cell wall synthesis. As with all of the penicillin group of drugs hypersensitivity and sometimes serious anaphylaxis is reported. Antibiotic-associated diarrhoea is a common side effect (Katzung 2007; Thomas 2003; US FDA 2009). Gentamicin is an aminoglycoside, bactericidal antibiotic, which is particularly active against infections caused by gram-negative organisms. It acts by binding to ribosomes and preventing bacterial protein synthesis. Gentamycin acts as a vestibulo toxin as well as a nephrotoxin and this action is dose-related. Therefore, dosage of gentamycin has to be titrated by body weight (Falco 1969; Katzung 2007; Merck 2005). Like gentamycin,Clindamycin inhibits bacterial protein synthesis by binding to ribosomes. It has bacteriostatic action against gram-positive aerobes and anaerobes and gram-negative anaerobes. Antibiotic-associated diarrhoea is a common side effect and hypersensitivity can also occur. In the event of long-term use, liver and renal function tests should be checked (Merck 2006; Rossi 2006; Thomas 2003; US FDA 2009).

Metronidazole acts by producing intermediates that cause DNA damage (Muller 1983). Sharp, unpleasant metallic taste, furry tongue glossitis and stomatitis, reversible neutropenia (reduction in the number of white cells (neutrophils) and rarely reversible thrombocytopenia (reduction in the numbers of platelets) are the common side effects of metronidazole.

Vancomycin acts by inhibiting cell wall synthesis in gram-positive bacteria and is reserved for infections by these bacteria that do not respond to less toxic antibiotics. A common side effect of vancomycin when given intravenously is thrombophlebitis (Katzung 2007; Levine 2006; Moellering 2006; Sundin 2001).

Why it is important to do this review

Amniotomy was, and still is, a common obstetric intervention both for induction and as a part of active management of labour. This is particularly true in settings where pharmacological agents that have become more popular in the recent years cannot be used due to cost and availability constraints.

Amniotomy is an invasive procedure and often accompanied by other invasive ones giving lower genital tract organisms access to the amniotic cavity (Hopkins 2002). This could well be the argument for use of prophylactic antibiotics. Countries where screening for Group B streptococci is available are using prophylactic antibiotics in women testing positive for this organism. But this universal screening is not available in many countries, which again speaks in favour of antibiotic use. Other predisposing factors for intra-amniotic infections are: abnormal vaginal flora, obesity, drug abuse, smoking, immunodeficiency states, any of which could be present in any setting (Newton 1993).

With the use of antibiotics come other concerns. The chief being the side effects of these antibiotics on the mother and baby and also the graver issue of emergence of antibiotic-resistant strains. Administering antibiotics prior to amniotomy would prevent or lessen maternal morbidity but could lead to delay in the diagnosis of neonatal sepsis. Besides this, there is the issue of cost, again more so in low-resource settings.

We will evaluate the use of antibiotics prior to amniotomy in terms of the beneficial and harmful effects for the mother and the neonate

Objectives

To study the effects of the use of antibiotics versus placebo or no treatment prior to amniotomy on maternal and perinatal morbidity and mortality.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials comparing antibiotics prior to amniotomy versus placebo or no treatment. Quasi-randomised trials will not be included. If a trial has multiple arms, we will only include the arm which has antibiotic versus either placebo or no treatment, not the arm of antibiotic versus another antibiotic.

Types of participants

Pregnant women with live fetuses, regardless of parity and gestation undergoing amniotomy for either induction or augmentation of labour.

Types of interventions

Antibiotics versus placebo or no treatment.

Types of outcome measures

Primary outcomes
  1. Chorioamnionitis, which will be considered if any of these definitions are satisfied and also if stated as chorioamnionitis by trial authors.

    1. Clinical (presence of typical clinical findings).

    2. Pathological in the presence of maternal leucocytosis (variously defined as white blood cell count (WBC) > 12,000/mm3 or > 15,000/mm3), or high levels of C-reactive protein (CRP), culture of the amniotic fluid (which is the gold standard) (Tita 2010).

    3. Histopathological (microscopic evidence of infection or inflammation on examination of the placenta or chorioamnionic specimens) (Yoon 2001).

  2. Early onset neonatal sepsis, which by definition manifests within the first 24 hours of life and which will be considered if any of the following conditions are satisfied and also if stated as neonatal sepsis by trial authors.

    1. Clinical features of: respiratory distress (ranging from tachypnoea ( increased rate of respiration) to respiratory failure), disseminated intravascular coagulation (DIC), irritability, lethargy, temperature instability, hypotension, poor feeding, vomiting and ileus (obstruction of the bowel) (Cloherty 2010).

    2. Pathological features: WBC counts either < 5000/mm3 or > 24,000/mm3 with predominance of immature granulocytes (immature to total white blood cells (I:T) ratio > 0.2), hyperglycaemia > 130 mg/dL, metabolic acidosis, thrombocytopenia, positive blood cultures (gold standard) and positive chest X-ray (Cloherty 2010).

Secondary outcomes
Maternal
  1. Wound infection.

  2. Septic shock.

  3. Adverse effects of antibiotics as defined by the trial authors.

Neonatal
  1. Neonatal death.

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. 

In addition to this, we plan to search International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing unpublished trials (See: Appendix 1)

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

Three review authors (S Ray (SR), A Ray (AR), A George (AG)) will independently screen all citations and abstracts identified by the search strategy to select potentially eligible studies. We will obtain full texts of potentially eligible studies for inclusion in the review based on the inclusion and exclusion criteria. If eligibility is unclear due to inadequate or unclear information, we will attempt to contact the authors for details. If a trial report is published in a different language, we will seek translation. We will resolve any disagreements through discussion. We will exclude studies that do not meet the criteria and document the reason for exclusion. In multi-armed studies we will only consider the arms comparing amniotomy and antibiotics against amniotomy alone .

Data extraction and management

We will design a form to extract data. For eligible studies, three review authors (AR, SR, AG) will extract the data using the agreed form. We will resolve discrepancies through discussion. 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

Three review authors (AR, SR, AG) 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.

(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 Handbook (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 size using the methods described in the Handbook 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 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.

Other unit of analysis issues
Multiple pregnancies

In case of multiple pregnancies, we will consider for each outcome whether the appropriate denominator is the number of babies or the number of women (depending on neonatal or maternal outcomes). If we are dealing with pregnancy outcomes then each woman can be considered as a randomised cluster. If we are not able to calculate the ICC from the data included in the paper then we might use an ICC from another trial or review that included multiple pregnancies, involving a similar population. If it is not possible to make these adjustments and provided the number of multiple pregnancies in the study population is low, then the data must be analysed as if babies from multiple pregnancies are independent using the number of infants as the denominator.

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 an I² is greater than 30% and either the 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:

  • parenteral versus oral antibiotics;

  • augmentation versus induction;

  • high-income versus low-income settings;

  • use of fetal scalp electrode versus non use;

  • use of intrauterine pressure gauges versus no use;

  • use of other methods (e.g. oxytocin) in addition to amniotomy versus no use.

Subgroup analysis will be restricted to the review’s first primary outcome, i.e. chorioamnionitis.

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 conduct sensitivity analyses to investigate the robustness of the results for the primary outcomes by evaluating outcomes in trials that have low risk of bias versus those with high risk or unclear risk of bias. High risk or unclear risk of bias will be those studies where randomisation, allocation concealment, blinding of outcomes has not been stated or if stated, the methods have not been specified. We will also undertake sensitivity analyses if trials report dropout rates of 10% or greater, to ascertain differences in outcomes of intention-to-treat analysis and analysis of completers.This analysis will be restricted to the primary outcome of chorioamnionitis.

Acknowledgements

This document is an output of a workshop organised by the South Asian Cochrane Network at Christian Medical College, Vellore, India.

As part of the pre-publication editorial process, this protocol has been commented on by four peers (an editor and three referees who are external to the editorial team) and the Group's Statistical Adviser.

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

Appendices

Appendix 1. Search terms for ClinicalTrials.gov and ICTRP

Amniotomy AND Antibiotic*

Contributions of authors

Amita Ray conceptualising the review topic, developing and drafting the initial version of the protocol, searching for additional references and approving the final version of the protocol.

Sujoy Ray: initiating the review, searching for additional references, developing the protocol and writing the final version of protocol and providing citations and full-text articles for the background,

Amita Ray, Sujoy Ray, Aneesh Thomas George: approving the final version of the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • South Asian Cochrane Network, India.

Ancillary