Discussion and conclusions

Summary of main findings

This trial showed clear evidence of benefit of a single dose of intravenous co-amoxiclav administered to women a median of 3 hours after operative vaginal birth. Women in the antibiotic arm had a 42% relative reduction, from 19% to 11%, in the risk of suspected or confirmed infection. This was principally driven by the prescription of antibiotics for presumed perineal wound-related infection, endometritis or uterine infection, urinary tract infection with systemic features or other systemic infection, but women in the antibiotic arm also had a statistically significant 56% reduction in the risk of confirmed systemic infection on culture, from 1.5% to 0.6%. Secondary outcomes also favoured the active (co-amoxiclav) arm, with significant reductions in rates of both deep and superficial perineal infection, perineal pain, wound breakdown and the need for additional perineal care.

At 6 weeks post delivery, women who were randomised to the antibiotic arm consumed fewer NHS health-care resources than women randomised to the placebo arm, with significantly fewer visits to the GP, midwife/nurse home visits and outpatient hospital visits. The mean total health-care cost per woman was £52.60 lower in the antibiotic arm than in the placebo arm, but this was not statistically significantly different at the 1% level.

Limitations

We took the pragmatic approach in this trial of defining suspected or confirmed maternal infection using a composite outcome, including a new prescription of antibiotics for confirmed or suspected infection, which can be interpreted as equating to a clinical diagnosis of infection. This clinical diagnosis of infection drove the overall outcome and resulted in a substantially higher than anticipated event rate, which may suggest overprescription of antibiotics in the postnatal period. The use of this clinical definition rather than microbiologically confirmed infection could be regarded as a limitation; however, we observed a statistically significant decrease in the rate of microbiologically confirmed systemic infection following culture from a sterile site, which supports the assumption that the findings represent a genuine decrease in infection, despite our pragmatic primary outcome definition.

We achieved a 76% follow-up rate for the majority of our secondary outcomes, which represents the main limitation of this trial. There were statistically significant differences in the characteristics of the women who completed the 6-week questionnaire and those who did not. Most notably, a greater proportion of women who returned the 6-week questionnaire were primiparous. It is possible that their consultation behaviour differed from multiparous women; thus, rates of some of the reported secondary outcomes may be higher than would be seen in the general population. This difference in characteristics between those with follow-up data and those without is, however, unlikely to account for the magnitude of difference we observed between the antibiotic and placebo arms.

The population of women included in the trial was representative of the population of women undergoing operative vaginal birth and thus appear broadly generalisable. The trial was limited to women who were not penicillin-allergic and, therefore, is not directly applicable to women who are allergic to penicillin. However, it would be anticipated that another antibiotic with a similar spectrum of activity would have a similar protective effect in women for whom co-amoxiclav is contraindicated. Options for penicillin-allergic women that offer a comparable spectrum of activity to co-amoxiclav would include cefuroxime with metronidazole or clindamycin with gentamicin. Similarly, we included only women giving birth at ≥ 36 weeks’ gestation. However, there are no clear reasons why the results would not also be generalisable to women who had an instrumental vaginal birth at lower gestations than this.

We asked sites to administer the intervention as soon as possible after women had given birth, and no later than 6 hours after women had given birth. In practice, it was administered a median of 3 hours after women had given birth. It is possible that administration this length of time after women had given birth made the co-amoxiclav less effective than it might have been, given that caesarean section trials suggest that pre-delivery administration is more effective at preventing wound infection and endometritis.41 However, as noted earlier, the perineal wound, which is highly likely to become contaminated, is very different from the caesarean section wound, and later administration may have allowed for a longer duration of protective effect and greater efficacy. Further analyses are needed to investigate the mechanism of effect, as described in Implications for research.

Comparison with existing literature

The single previous trial of antibiotic prophylaxis after operative vaginal birth42 reported on endometritis only, noting a rate of 4% in the no antibiotic arm. This is considerably lower than the rate of suspected or confirmed infection we observed in the ANODE trial but, interestingly, using the strict CDC surveillance definition,31 we observed a lower endometritis rate. The estimate of effect we observed for endometritis (relative risk 0.65, 95% CI 0.34 to 1.24) in the ANODE trial is compatible with the effect estimate in the Heitmann and Benrubi trial42 (relative risk 0.07, 95% CI 0.00 to 1.17). Combining the results of the two trials using Mantel–Haenszel fixed-effect meta-analysis gives an overall relative risk 0.50 (95% CI 0.27 to 0.93) for endometritis.

Women in the ANODE trial who received placebo had a 19% rate of confirmed or suspected infection at 6 weeks post partum. This is higher than the infection rate reported in most other studies of complications following instrumental vaginal birth.29 As noted previously, very few of these observational studies followed women beyond discharge, yet post-partum wound infections and endometritis have been reported to occur at a peak of 7 days post discharge in large data-linkage studies.43 The ANODE trial shows very clearly a significant burden of confirmed or suspected infection and, most notably, both superficial and deep perineal wound infection after initial hospital discharge.

Although a single dose of co-amoxiclav almost halved the infection rate, 11% of women still had a confirmed or suspected infection after receiving antibiotic prophylaxis. The question therefore arises as to whether or not other, non-pharmaceutical interventions might reduce this further. We did not collect information about the aseptic techniques used at the time of operative vaginal birth, nor whether or not gloves and instrument trollies were changed between birth and perineal repair; the RCOG guidelines simply state that good standards of hygiene and aseptic technique are recommended.15 It is possible that further attention to aseptic technique at the time of birth may influence later outcomes. A Cochrane review identified no difference in infection rates in surgical wounds cleansed with water versus other solutions (saline, procaine spirit) or no cleansing.44 The review identified only one small trial of wound-cleansing post episiotomy, which randomised 100 women to cleanse their episiotomy wounds with either water or procaine spirit;45 the authors report no difference in infection rates, but did not give exact figures. They note that women cleaned their wounds an average of five times per day and that all wounds were healed well by 14 days post partum. Therefore, there may be a place for further investigation of wound-cleansing after operative vaginal birth to see if infection rates are lower.

There is an apparent discrepancy between the proportion of women who were diagnosed with systemic sepsis in the ANODE trial, defined by the modified SIRS criteria for pregnancy, and those with a microbiologically confirmed systemic infection. There are several possible reasons for this. The modified SIRS criteria in pregnancy3,32 have never been validated against microbiological or other diagnostic tests, and work is ongoing to establish a clear and actionable definition of maternal sepsis.46,47 It is possible that women with microbiologically confirmed systemic infection are false negative cases of maternal sepsis when using the modified SIRS criteria. Conversely, with the substantially raised awareness of maternal sepsis, which has followed the UK Confidential Enquiries into Maternal Deaths and Morbidity48 and the work of the UK Sepsis Trust [https://sepsistrust.org (accessed 12 December 2018)], women with microbiologically confirmed systemic infection may have been diagnosed and treated early, before progression to infection sufficiently severe to meet the modified SIRS criteria.

Women reported a range of other complications after operative vaginal birth, the majority of which were also less frequent among women who were randomised to receive antibiotic prophylaxis. A very high proportion of women reported perineal pain at 6 weeks after giving birth (46% in the antibiotic arm and 55% in the placebo arm), although a much lower proportion reported use of pain relief for their perineal pain (8% in the antibiotic arm vs. 11% in the placebo arm). A recent US study of women undergoing vaginal birth noted that operative vaginal birth was associated with opioid prescription in the 7 days after discharge (adjusted odds ratio 1.52, 95% CI 1.49 to 1.54), indicating a significant degree of pain. A trial of restrictive versus routine use of episiotomy at operative vaginal birth noted very similar rates of perineal pain at 6 weeks post partum (44%), but this had decreased to 18% at 1 year post partum.49 Notably, women reported higher levels of pain with restrictive use of episiotomy compared with routine use; however, almost 90% of women included in the ANODE trial had an episiotomy, suggesting that restricted use is unlikely to be a potential underlying reason for the high rates of perineal pain observed.

One in five women in the placebo arm and one in 10 in the antibiotic arm reported that they had experienced perineal wound breakdown. Although a previous feasibility study reported that most women whose perineal wound had dehisced had healed by 6–8 weeks,35 women described long-term impacts 6–9 months later,37 including psychosexual morbidity. It is therefore probable that the almost 50% reduction in wound breakdown reported in the antibiotic arm is associated with longer-term benefit on sexual function, even though we observed no difference in dyspareunia between the groups at 6 weeks post partum. Only 40% of women had resumed intercourse, which may also mask any potential beneficial effect of the active intervention, but our results highlight the high levels of ongoing maternal morbidity following childbirth.

The mean total health-care cost per woman was £52.60 lower in the antibiotic arm than in the placebo arm, but this was not statistically significantly different at the 1% level. However, considering the probable long-term persistence of some complications, and the likelihood that the intervention dominates, it is probable that co-amoxiclav prophylaxis will prove cost-effective as well as clinically effective in the longer term. In the light of current concerns over antimicrobial stewardship and the emergence of antimicrobial resistance,21 an assessment of the impact of the single prophylactic dose on overall antibiotic use is important. The additional health-care cost and resource analysis conducted for the ANODE trial estimates that, for each additional 100 doses of antibiotic used in prophylaxis, 168 treatment doses will be avoided, representing a 17% overall reduction in antibiotic use with a policy of universal prophylaxis.

Sensitivity analyses

None of the sensitivity analyses we conducted materially affected the assessment of the primary outcome. A number of women were prescribed antibiotics in labour, for indications such as prophylaxis against group B streptococcal infection or maternal pyrexia. Exclusion of these women from the analysis did not change the estimate of effect of antibiotic prophylaxis, indicating that the effect we observed was not caused by a protective effect of prior antibiotic administration. We additionally examined whether or not exclusion from the primary outcome of any women who were prescribed antibiotics within the first 24 hours after giving birth had any impact, to test if the effect was solely due to prevention of infection among women who were already infected at or around the time of giving birth. As this had no substantial effect on the results, it suggests that the protective effect of a single dose of antibiotic is not caused by treatment of early or already established infections alone.

We also examined whether or not the exclusion of data that were obtained < 6 weeks or > 10 weeks after women had given birth had an impact on the results. There was no major influence, suggesting that the results were not biased by any over-reporting of outcomes from data returned at a later time point or under-reporting of outcomes in data returned at an earlier time point.

As a final sensitivity analysis we included site as a random effect; there was no suggestion that the results differed by site.

Implications for practice

Current national guidance on operative vaginal birth in the UK,15 the USA,50 Australia and New Zealand51 either do not mention or do not recommend antibiotic prophylaxis after instrumental vaginal birth. The WHO guidelines on prevention of maternal infection explicitly state that antibiotic prophylaxis is not recommended after instrumental vaginal birth based on a lack of evidence of effectiveness. The ANODE trial provides clear evidence of effectiveness of a single dose of prophylactic intravenous co-amoxiclav on prevention of confirmed or suspected maternal infection, a range of secondary outcomes and a potential impact on health service costs. On the basis of this evidence, reconsideration of official policy/guidance about whether or not routine prophylaxis with a single dose of intravenous antibiotic after operative vaginal birth should be considered.

Implications for research

Further analyses of the ANODE trial data

A number of questions remain that could be addressed by further analyses of the ANODE trial data:

1. The intervention was given a median of 3 hours after women had given birth; as discussed earlier, theoretically, either earlier or later intervention may have been more effective. Further investigation of whether or not the efficacy of prophylaxis varied with timing of administration is warranted to further guide advice on how rapidly antibiotic prophylaxis should be administered, and to assess whether or not there is any evidence to suggest that pre-delivery or repeated administration may be more effective.
2. The ANODE trial intervention showed clear evidence of benefit in reducing incidence of suspected or confirmed maternal infection. Nevertheless, it is possible that it had different effects among different groups of women, for example, women who had a forceps birth compared with those having a ventouse birth, or those who had an episiotomy compared with those who did not. Further investigation of these subgroups is important.
3. Eleven per cent of women in the antibiotic arm had confirmed or suspected maternal infection. Investigation of the factors associated with maternal infection may give additional indications as to future preventative interventions, or specific risk groups towards whom preventative interventions may be focused.
4. Similarly, detailed examination of the microorganisms causing infection in the ANODE trial cohort, together with their resistance patterns, would provide further information about the mechanism of action, and the optimal spectrum of antibacterial activity, of this single prophylactic antibiotic dose.
5. A high proportion of women in the ANODE trial were prescribed antibiotics in the absence of a confirmed infection, or for non-infective indications. Further detailed examination of these prescription patterns may indicate areas of practice that could be the focus of future antimicrobial stewardship interventions.
6. A number of assumptions were made during the cost analysis, for example, in relation to the duration of antibiotic treatment and the type of antibiotic used in women who had infection or suspected infection. Further sensitivity analyses could be conducted to investigate the impact of these assumptions on the cost analysis.

Further research questions raised

1. In this trial, the prophylactic antibiotic was administered intravenously. The commonest reason for women not receiving the planned intervention was cannula failure. Similarly, a significant number of women declined to participate in the trial because it would require placement of a cannula to administer antibiotics. In other settings where operative vaginal delivery is undertaken, for example in low- and middle-income countries, intravenous administration of antibiotics may be difficult or impossible. This raises the question of whether or not oral antibiotic prophylaxis would be as effective as intravenous, either as a single dose or as multiple doses.
2. The substantial residual burden of infection after antibiotic prophylaxis indicates a need for investigation of additional preventative measures and/or early identification to prevent associated wound breakdown. It is possible that multiple doses of antibiotic may be more effective, but this needs to be carefully evaluated against the risk of driving emergence of antimicrobial resistance. This would also need to be robustly investigated in a future RCT if further analysis of the ANODE trial data suggests that there is a potential place for multiple doses. Currently, both 1- and 3-day courses are being prescribed with no clear evidence. Further investigation of cleansing/aseptic measures is also warranted.
3. The evidence from this trial suggests that there could be a change of policy to recommend universal antibiotic prophylaxis at operative vaginal birth. The effect of such a change of policy on patterns of infection and emerging antimicrobial resistance would, however, need careful evaluation.
4. The women participating in the ANODE trial reported high rates of perineal pain and wound breakdown as well as confirmed or suspected infection at 6 weeks postnatally. Nevertheless, it is unclear whether women will continue to have long-term morbidity or if these outcomes are problematic only in the short term. Assessment of the long-term costs and outcomes for women will be essential in assessing the cost-effectiveness of any prophylaxis policies.

Conclusions

The ANODE trial has shown clear evidence of the benefit of a single intravenous dose of prophylactic co-amoxiclav after operative vaginal birth; these results indicate the need for reconsideration of official policy/guidance. Further analysis of the mechanism of action of this single dose of antibiotic is needed to investigate whether earlier, pre-delivery or repeated administration could be more effective. Until these analyses are completed, there is no indication for administration of more than a single dose of prophylactic antibiotic, or for pre-delivery administration.