Results

Recruitment and retention

Between March 2016 and June 2018, 3427 women were randomised: 1719 to the antibiotic arm and 1708 to the placebo arm (Figure 2).

FIGURE 2 Flow of participants. Figure modified from Knight et al.30 This article is available under the terms of the Creative Commons Attribution License (CC BY). You may copy and distribute the article, create extracts, abstracts and new works from the article, alter and revise the article, text or data mine the article and otherwise reuse the article commercially (including reuse and/or resale of the article) without permission from Elsevier. You must give appropriate credit to the original work, together with a link to the formal publication through the relevant DOI and a link to the Creative Commons user license above. You must indicate if any changes are made but not in any way that suggests the licensor endorses you or your use of the work. (Figure not reproduced here; see the original article.)

The number of participants recruited at each site varied from 22 to 388 (Table 1).

Characteristics of participants

Characteristics of participants were similar between the two trial arms (Table 2) and appeared to be representative of the general population of women undergoing operative vaginal birth. Women had a mean age of 30 years, approximately half were of normal BMI and more than four-fifths were of white ethnicity. Overall, 77% of women were primiparous, and 49% had labour induced. Sixty-five per cent of births were assisted by forceps and 35% were assisted by vacuum extraction. Eighty-eight per cent of women had an episiotomy, 31% had a perineal tear and > 99% of women had suturing of a perineal wound.

Outcomes

Primary outcome data were available for 3225 out of 3420 women (94.3%). There were no substantive differences between women for whom primary outcome data were available (Table 3). Questionnaires were received for 2593 women (75.8%).

Primary outcomes

There was a 42% reduction in the risk of the overall primary outcome (risk difference 7.9%, 95% CI 5.5% to 10.4%) among the antibiotic arm compared with the placebo arm, noting that the overall primary outcome rate was substantially higher in the placebo arm than we had hypothesised (19% vs. an estimated 4%) (Table 4). The primary outcome was principally driven by one of the three components of the primary outcome: new prescription of antibiotics with specific indication. However, all components of the primary outcome showed the same direction of effect, and there was a statistically significant 56% reduction in confirmed systemic infection on culture from 1.5% (25/1606) in the placebo arm to 0.6% (11/1619) in the antibiotic arm.

Secondary outcomes

There were statistically significant reductions in the secondary outcomes superficial perineal infection and deep perineal wound infection in the antibiotic arm. There was no significant difference in the incidence of systemic sepsis according to the modified SIRS criteria for pregnancy (see Table 4).

Considering the secondary outcomes reported on the postal/online questionnaire (Table 5), women in the antibiotic arm reported significantly lower levels of perineal pain, less use of pain relief for perineal pain, a less frequent need for additional perineal care and lower rates of wound breakdown than those in the placebo arm. There were no differences in reported dyspareunia between the groups, noting that only 41% of women had resumed intercourse at the time of returning their questionnaire. There was no statistically significant difference in breastfeeding rates between the two groups, but a greater proportion of women in the placebo arm reported times at which their perineum was too uncomfortable to feed their baby. Women in the antibiotic arm had fewer primary care or home visits, or hospital outpatient visits, in relation to their perineum than women in the placebo arm. There was no statistically significant difference in hospital re-admissions between the two arms, and no difference in mean EQ-5D-5L score (using the significance level p < 0.01 for secondary outcomes).

Adverse events and side effects

Only three women reported side effects of the intervention: 2 out of 1715 in the antibiotic arm (0.12%) and 1 out of 1705 (0.06%) in the placebo arm (risk difference 0.06%, 95% CI –0.14% to 0.25%). The woman in the placebo arm reported a skin rash, and the women in the antibiotic arm reported other reactions (e.g. itching, swollen throat). There were no cases of anaphylaxis. Three SAEs were reported (Table 6), but only one was thought to be causally related to the intervention.

Adherence

The intervention was administered a median of 3 hours after women had given birth (Table 7). Thirty-three women (1.0%) received the intervention > 6 hours after giving birth. Overall, 33 telephone follow-up interviews (1.0%) were conducted by staff who had prepared or checked the ANODE intervention and may, theoretically, have been unblinded to allocation. Similarly, as antibiotic prescription was part of the primary outcome, we checked whether or not the person prescribing antibiotics was also the person who had checked or prepared the ANODE intervention and would therefore have been unblinded. Only one woman, in the antibiotic arm, was prescribed further antibiotics by a member of staff who may have been unblinded.

Sensitivity analyses

There were no material changes to the primary outcome with any of the sensitivity analyses (Tables 8–11 and Figure 3).

FIGURE 3 Forest plot showing the results of the sensitivity analyses. (Figure not reproduced here; see the original article.)

Health-care resource use and cost analysis

Among the 2593 women who returned the questionnaire, we found evidence that, at 6 weeks post delivery, women randomised to the antibiotic arm consumed fewer NHS health-care resources than those in the placebo arm (Table 12). The mean difference in all categories of resource use favoured the antibiotic arm, with the number of visits to the GP (p < 0.001), nurse or midwife home visits (p < 0.001) and outpatient hospital visits (p < 0.001) being statistically significantly different between groups. No statistically significant mean differences were detected in the length of stay for all-cause hospital re-admissions.

Similar results were found for costs. Among different health-care categories, the highest cost was estimated for hospital re-admissions, followed by nurse or midwife home visits and outpatient hospital visits (Table 13). Compared with the women allocated to the placebo arm, the health-care costs for women in the antibiotic arm were, on average, a significant £0.40 (99% CI £0.20 to £0.50) less for new prescriptions of antibiotic, £3.90 (99% CI £1.60 to £6.20) less for GP visits, £12.10 (99% CI £4.00 to £20.10) less for nurse or midwife home visits and £15.40 (99% CI £5.20 to £25.50) less for outpatient hospital visits. The mean cost of hospital re-admissions was also found to be lower in the antibiotic arm (£50.30 vs. £81.60), but the difference was not statistically significant (p = 0.164). The total mean cost at 6 weeks following delivery was estimated to be £102.50 (SD £652.40) per woman in the antibiotic arm and £155.10 (SD £497.40) per woman in the placebo arm. The mean difference in the total health-care cost was –£52.60 (99% CI –£115.10 to £9.90) per woman, which was not statistically significantly different at the 1% level (p = 0.030).

On the basis of the estimated number of doses of co-amoxiclav used for the costs analysis (see Table 13), we estimated the potential effect of a policy of universal prophylaxis with a single dose of co-amoxiclav after operative vaginal birth on overall antibiotic use. In the placebo arm, 19% of women had a confirmed or suspected infection and 1297 women received an estimated 5166 doses of co-amoxiclav to treat infection (three daily doses for 7 days in 246 women). In the antibiotic arm, 11% of women had a confirmed or suspected infection and 1296 women received an estimated 3003 doses of co-amoxiclav to treat infection (three daily doses for 7 days in 143 women), as well as 1296 prophylactic doses; therefore, a total of 4299 doses. A policy of universal prophylaxis would therefore be associated with an estimated net reduction of 867 doses of antibiotic (17% reduction).

There were statistically significant differences in the characteristics of women who had missing secondary resource outcomes compared with those who did not (Table 14). However, the comparisons of post-delivery health-care resource use and costs after multiple imputation were similar to those generated by using complete cases (Tables 15 and 16). Compared with women allocated to the placebo arm, women in the antibiotic arm had significantly fewer GP visits, nurse or midwife visits at home, and outpatient hospital visits. The total mean costs after multiple imputation were estimated to be £117.30 (SE £20.23) in the co-amoxiclav group and £168.30 (SE £15.07) in the placebo group. The mean difference in the total cost was –£50.90 (99% CI–£114.70 to £12.90; p = 0.040).