Prophylactic antibiotics for manual removal of retained placenta in vaginal birth

Abstract

Background

Retained placenta is a potentially life‐threatening condition because of its association with postpartum hemorrhage. Manual removal of placenta increases the likelihood of bacterial contamination in the uterine cavity.

Objectives

To compare the effectiveness and side‐effects of routine antibiotic use for manual removal of placenta in vaginal birth in women who received antibiotic prophylaxis and those who did not and to identify the appropriate regimen of antibiotic prophylaxis for this procedure.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014).

Selection criteria

All randomized controlled trials comparing antibiotic prophylaxis and placebo or non antibiotic use to prevent endometritis after manual removal of placenta in vaginal birth.

Data collection and analysis

There are no included trials. In future updates, if we identify eligible trials, two review authors will independently assess trial quality and extract data

Main results

No studies that met the inclusion criteria were identified.

Authors' conclusions

There are no randomized controlled trials to evaluate the effectiveness of antibiotic prophylaxis to prevent endometritis after manual removal of placenta in vaginal birth.

Plain language summary

Prophylactic antibiotics for manual removal of retained placenta in vaginal birth

We did not identify any trials to say if women with retained placenta after giving birth would benefit from routine antibiotics prior to manual removal of placenta.

Following the birth of her baby, a mother normally delivers the placenta with further pushing and support from her caregivers. Sometimes the placenta gets stuck on the wall of the womb (retained placenta) and does not deliver. These women usually require manual removal of the placenta under anesthesia (either a general or regional). Infection and bleeding are the important complications of manual removal. The review found no trials to determine whether antibiotics given routinely (prophylactically) to all women with retained placenta reduced the incidence of problems. Future trials need to address the risk of contributing to drug resistant bacterial strains.

Background

Description of the condition

Retained placenta is a potentially life‐threatening condition because of the associated risk of hemorrhage, shock and infection, as well as complications related to its removal (Chhabra 2002). This condition continues to be responsible for a high number of maternal fatalities worldwide (WHO 1989). Some studies have reported a maternal mortality of 5.6% to nearly 10% in rural areas because of retained placenta (Chhabra 2002; Weeks 2001). Mortality due to retained placenta accounted for 3.33% of all mortality from vaginal deliveries (Chhabra 2002). The main clinical consequence of retained placenta is massive: uncontrolled postpartum hemorrhage, requiring immediate intervention (Stones 1993). This consequence may occur in about 10% of cases (Tandberg 1999).

The reported incidence of retained placenta varied from 1% to 5.5% depending on the definition of prolonged third stage of labor, which ranges from 10 to 60 minutes in various reports (Ely 1995; Selinger 1986; Thomas 1983; Weeks 2001). Retained placenta has been reported with an incidence of 3.3% when 30 minutes was used as the cut‐off point (Combs 1991). There is still no definite agreement about the length of time that should elapse in the absence of bleeding before the placenta is removed manually (Cunningham 2001). When the third stage of labor nears 30 minutes or more, the risk of hemorrhage increases (Combs 1991). Therefore, 30 minutes is generally used as a criterion to diagnose retained placenta. When the placenta is not separated promptly after delivery of the baby, and if at any time there is a risk bleeding, the placenta can be removed by applying pressure to the body of the uterus and lifting the uterus cephalad by the hand over abdomen. This maneuver is repeated until the placenta reaches the introitus. Pressure on the uterus is then stopped, allowing the placenta to pass through (Prendiville 1988). If this technique is not possible, manual removal is indicated (Cunningham 2001). There is a Cochrane review indicating that an injection of oxytocin into the umbilical vein may reduce the need for manual removal of retained placenta (Carroli 2001). Even after this effective intervention, about 50% of women with retained placenta require manual removal (Carroli 2001).

Description of the intervention

Manual removal of the placenta involves inserting one hand through the vagina into the uterus. This procedure increases the likelihood of bacterial contamination in the uterine cavity. There is controversy whether manual removal of the placenta increases the risk of infection in the uterus. Some believe that it does (Ely 1995), but others believe it does not (Gibbs 1980; MacLean 1990). Ely 1995 reported that 6.7% of women with manual removal of placenta while 1.8% of women with normal placental delivery developed endometritis, adjusted odds ratio 2.9, 95% confidence interval 1.7 to 4.9. However, Tandberg 1999 and Thomas 1983 found no increased risk of infection following this procedure. All these studies were from developed countries. One report from a low‐income country did not give the incidence of endometritis among women undergoing manual removal of placenta (Chhabra 2002). Prophylactic antibiotics after manual removal of placenta are routinely recommended by some (Carroli 1991; Loeffler 1995; Mathai 2000), but not by others (Ely 1995; Tandberg 1999).

How the intervention might work

Antibiotic prophylaxis significantly affects the composition of the indigenous vaginal microflora (Gilstrap 1997).Therefore, it might decrease postpartum infection.

Why it is important to do this review

Inappropriate use of antibiotics could have potential adverse effects including hypersensitivity, drug‐resistant strains, etc. Using the best current available data from randomized controlled trials, this review aims to determine whether prophylactic antibiotics reduce the incidence of endometritis which cause maternal morbidity (such as prolonged hospital stays, increased cost etc.) and/or mortality.

Objectives

1. To compare the effectiveness and side‐effects of routine antibiotic use for manual removal of the placenta in vaginal birth in women who received antibiotic prophylaxis and those who did not.

2. To identify the appropriate regimen of antibiotic prophylaxis for this procedure by comparing the incidence of postpartum endometritis after manual removal of placenta in vaginal birth in women who received different antibiotic regimens (if antibiotic prophylaxis is found to be effective).

Methods

Criteria for considering studies for this review

Types of studies

All randomized controlled trials comparing antibiotic prophylaxis and placebo or non antibiotic use to prevent endometritis in the manual removal of placenta after vaginal birth.

Types of participants

All pregnant women undergoing manual removal of placenta after vaginal birth with gestational age more than 22 weeks, or birthweight greater than 500 g (delivery regarded as birth not an abortion according to the International Classification of Diseases, 10th revision (ICD‐10)) (WHO 1992).

Types of interventions

Antibiotic prophylaxis for manual removal of the placenta in vaginal birth.

Types of outcome measures

Primary outcomes

1. Postpartum endometritis (as defined by authors).

Secondary outcomes

1. Puerperal morbidity (defined as temperature 38.0 °C (100.4 °F) or higher, the temperature to occur on any two of the first 10 days postpartum, exclusive of the first 24 hours, and to be taken orally by a standard technique at least four times daily (Cunningham 2005).

2. Perineal infection.

3. Duration of hospital stay.

4. Sepsis.

5. Any infection.

6. Blood loss.

7. Hemorrhage greater than 1000 mL.

8. Secondary postpartum hemorrhage.

9. Readmission to hospital.

10. Side‐effects of drugs: drug‐resistance, women's satisfaction, etc.

11. Neonatal outcomes: jaundice, sepsis, neonatal intensive care unit admission, etc.

Search methods for identification of studies

The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (31 July 2014).

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.

We did not apply any language restrictions.

For details of additional searching carried out for the initial version of the review, please see Appendix 1.

Data collection and analysis

For methods used in the previous version of this review, see Chongsomchai 2006. In future updates, if new reports are identified, we will use the full methods outlined in Appendix 2.

Results

Description of studies

Results of the search

No studies that met the inclusion criteria were identified. One study (Lamnerg 2013) is ongoing; see Characteristics of ongoing studies.

Included studies

No studies that met the inclusion criteria were identified.

Excluded studies

None.

Risk of bias in included studies

Not relevant as there are no included studies.

Allocation

Not relevant as there are no included studies.

Blinding

Not relevant as there are no included studies.

Incomplete outcome data

Not relevant as there are no included studies.

Selective reporting

Not relevant as there are no included studies.

Other potential sources of bias

Not relevant as there are no included studies.

Effects of interventions

No results were obtained as there are no included studies.

Discussion

It is disappointing that no randomized controlled trials are available to assess the effectiveness of antibiotic prophylaxis in manual removal of placenta after vaginal birth.

Summary of main results

Not relevant as no included studies were identified.

Overall completeness and applicability of evidence

Not relevant as there are no included studies.

Quality of the evidence

Not relevant as rhere are no included studies.

Potential biases in the review process

Not relevant as there are no included studies.

Agreements and disagreements with other studies or reviews

Not relevant as there are no included studies.

Authors' conclusions

Implications for practice.

There are no randomized controlled trials that have determined whether prophylactic antibiotics reduce the incidence of endometritis. Healthcare providers may consider following the World Health Organization's recent suggestion of a single dose of ampicillin 2 g given intravenously plus metronidazole 500 mg intravenously or cefazolin 1 g intravenously plus metronidazole 500 mg intravenously for manual removal of placenta in vaginal birth. The basis for this recommendation is that the antibiotics recommended cover the aerobic and anaerobic flora commonly seen in the genital tract; they are widely available; they are inexpensive and safe; and are used only at the time of the procedure to reduce the bacterial load during the procedure ‐ in line with the principles of antibiotic prophylaxis for surgery.

Implications for research.

Multicenter randomized controlled trials comparing antibiotic prophylaxis and placebo or no antibiotic use to prevent endometritis after manual removal of placenta in vaginal birth are urgently needed. The sample size for detecting the decreased incidence of endometritis from 6% to 3% with 80% power and two tailed significant level of 0.05 is approximate 780 for a two‐group comparison.

What's new

Date	Event	Description
31 July 2014	New search has been performed	Search updated. One report of an ongoing trial identified (Lamnerg 2013). Methods updated.
31 July 2014	New citation required but conclusions have not changed	Review updated. No trials included. One ongoing trial (Lamnerg 2013).

History

Protocol first published: Issue 3, 2004
 Review first published: Issue 2, 2006

Date	Event	Description
22 March 2011	New search has been performed	Search updated. No trials identified.
28 April 2009	New search has been performed	Search updated. No new trials identified.
1 May 2008	Amended	Converted to new review format.

Appendices

Appendix 1. Search methods for the previous version of the review

Authors searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2005) using the following search strategy:
 #1 PLACENTA, RETAINED (MeSH)
 #2 placenta* AND (retained or retention or remov*)
 #3 ANTIBIOTICS (MeSH)
 #4 antibiotic*
 #5 #1 or #2
 #6 #3 or #4
 #7 #5 and #6

We also searched MEDLINE (from 1966 to January 2005), EMBASE (from 1980 to January 2005), CINAHL (from 1982 to January 2005) and LILACS (from 1982 to January 2005), adapting the search strategy by selecting appropriate subject headings and/or free text terms.

We planned to review abstracts and letters to the editor to identify randomized controlled trials that have not been published. If we had identified a randomized controlled trial, we would have contacted the primary investigator directly to obtain further data. We applied no language restrictions.

Appendix 2. Methods to be used in future updates

The following methods will be used for the next update.

Selection of studies

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

We will create a Study flow diagram to map out the number of records identified, included and excluded.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2014) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

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

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

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

We will assess the method as:

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

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

• unclear risk of bias.

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

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

We will assess the methods as:

• low risk of bias (e.g. telephone or central randomization; 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 randomized 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 randomization);

• 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.

The quality of the evidence will be assessed using the GRADE approach (Schunemann 2009) in order to assess the quality of the body of evidence relating to the following key outcomes for the main comparison (antibiotic prophylaxis versus placebo or no antibiotic prophylaxis):

1. Postpartum endometritis (metritis)

2. Puerperal morbidity

3. Perineal infection

GRADE profiler (GRADE 2008) will be used to import data from Review Manager 5.3 (RevMan 2014) in order to create ’Summary of findings’ tables. A summary of the intervention effect and a measure of quality for each of the above outcomes will be produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

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 standardized mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster‐randomized trials

We will include cluster‐randomized trials in the analyses along with individually‐randomized trials. We will adjust their sample sizes using the methods described in the Handbook [Section 16.3.4 or 16.3.6] using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomized trials and individually‐randomized trials, we plan to synthesize 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 randomization unit is considered to be unlikely.

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

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 randomized to each group in the analyses, and all participants will be analyzed 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 randomized minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either a Tau² 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 2014). 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 of the 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 Tau² 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 :

• ruptured membranes more than 24 hours;

• ruptured membranes less than 24 hours.

The following outcomes will be used in subgroup analysis:

• postpartum endometritis.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2014). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We plan to carry out sensitivity analyses to explore the effect of trial quality assessed by concealment of allocation, high attrition rates, or both, with poor quality studies being excluded from the analyses in order to assess whether this makes any difference to the overall result.

Characteristics of studies

Characteristics of ongoing studies [ordered by study ID]

Lamnerg 2013.

Trial name or title	Prophylactic antibiotics for manual removal of retained placenta in vaginal birth.
Methods	Randomized intervention.
Participants	Women with retained placenta after vaginal birth.
Interventions	Antibiotic prophylaxis (gentamicin, ampicilin, clindamycin).
Outcomes	Puerperal fever, endometritis, length of hospitalization after labor, recurrent hospitalization in the first 2 weeks after discharge.
Starting date	January 2014
Contact information	Dr. Hadas Lamnerg (lhadas@hadassah.org.il)
Notes	Recruitment ongoing (NCT01945450) September 2016 (for final data collection date for primary outcome measure)

Contributions of authors

Chompilas Chongsomchai (CC) and Pisake Lumbiganon (PL) selected the topic. CC drafted the protocol and review. PL reviewed the protocol and review. CC, PL and Malinee Laopaiboon (ML) approved the final version of the protocol and review.

For the 2014 update, CC and PL updated the review. PL and ML approved the edits made for publication.

Sources of support

Internal sources

• Khon Kaen University, Thailand.

• Thai Cochrane Network, Thailand.

External sources

• Thailand Research Fund (Distinguised Professor Award), Thailand.

Declarations of interest

None known.

New search for studies and content updated (no change to conclusions)