Comparing different types of antibiotics given routinely to women at caesarean section to reduce infections

What is the issue?

We wanted to find out if giving specific types of antibiotics routinely at caesarean sections reduced the number of women and babies with infections, when compared with other types of antibiotics. We also looked to see if there were differences in adverse effects. The main types of antibiotics we considered were ones which target infections most commonly seen after giving birth, so we looked mainly at cephalosporins versus penicillins. We collected and analysed all relevant studies (randomised controlled trials) to answer this question (date of latest search 2 December 2019).

Why is this important?

Women undergoing caesarean section have an increased likelihood of infection compared with women giving birth vaginally. These infections can come from the urine, the surgical incision, or occur in the lining of the womb (endometritis). Infections can be serious, causing, for example, an abscess in the pelvis or infection in the blood. Very occasionally they can lead to a mother's death, particularly in low-resource settings. Good surgical techniques are important to reduce infection, along with the use of skin antiseptics and giving antibiotics before the initiation of the caesarean section. Antibiotics can, however, cause adverse effects in the mother, such as nausea, vomiting, skin rash and in some rare cases allergic reactions. The mother and the baby can develop thrush (candida). Antibiotics given to women around the time of giving birth can also change the baby's gut flora and may interfere with the baby's developing immune system.

What evidence did we find?

We included 39 studies, of which 33 studies involving 8073 women and their babies provided data. The quality of the individual studies was generally unclear, which led to overall low or very low certainty of the evidence. Three of the 33 studies were undertaken with drug company funding. Most of the studies administered antibiotics at or after cord clamping, although practice now often gives antibiotics before skin incision.

Eight studies with data on 1540 women reported on antistaphylococcal cephalosporins (first and second generation) versus broad spectrum penicillins plus betalactamase inhibitors. We found that these antibiotics may be as effective as each other in reducing endometritis and maternal fever. We were uncertain which antibiotic performed better for wound infection, urinary tract infection, and maternal adverse effects such as nausea, vomiting, diarrhoea and skin rash. We did not find any evidence on longer-term outcomes for mothers once they left hospital, or on any outcomes for babies. Only one small study (75 women) reported on blood infection (sepsis) in mothers, with too few events to identify any clear differences between the antibiotics.

We identified no studies with evidence on antistaphylococcal cephalosporins versus lincosamides, nor antistaphylococcal cephalosporins versus lincosamides plus aminoglycosides. The other studies looked at a very large number of different comparisons with insufficient data to come to any firm conclusions about specific comparisons.

What does this mean?

At caesarean sections, antistaphylococcal cephalosporins and penicillins plus betalactamase inhibitors may be similarly effective at preventing infections for the mother, although we did not find clear evidence for many important outcomes. In particular, we found no evidence describing the effects of these antibiotics on babies, nor any longer-term effects on women and children. This is particularly concerning for the studies giving the antibiotics prior to the surgical incision, as these antibiotics may reach the baby. For the other comparisons included in this review, data were sparse. Many studies were old and lacked information on study design and important outcomes, often including small numbers of women and few events. Research on drug-resistant antibiotics needs to be considered as well.

Authors' conclusions: 

Based on the best currently available evidence, 'antistaphylococcal cephalosporins' and 'broad spectrum penicillins plus betalactamase inhibitors' may have similar efficacy at caesarean section when considering immediate postoperative infection, although we did not have clear evidence for several important outcomes. Most trials administered antibiotics at or after cord clamping, or post-operatively, so results may have limited applicability to current practice which generally favours administration prior to skin incision. We have no data on any infant outcomes, nor on late infections (up to 30 days) in the mother; these are important gaps in the evidence that warrant further research. Antimicrobial resistance is very important but more appropriately investigated by other trial designs.

Read the full abstract...
Background: 

Caesarean section increases the risk of postpartum infection for women and prophylactic antibiotics have been shown to reduce the incidence; however, there are adverse effects. It is important to identify the most effective class of antibiotics to use and those with the least adverse effects. 

Objectives: 

To determine, from the best available evidence, the balance of benefits and harms between different classes of antibiotic given prophylactically to women undergoing caesarean section, considering their effectiveness in reducing infectious complications for women and adverse effects on both mother and infant.

Search strategy: 

For this 2020 update, we searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (2 December 2019), and reference lists of retrieved studies.

Selection criteria: 

We included randomised controlled trials (RCTs) comparing different classes of prophylactic antibiotics given to women undergoing caesarean section.  RCTs published in abstract form were also included. We excluded trials that compared drugs with placebo or drugs within a specific class; these are assessed in other Cochrane Reviews. We excluded quasi-RCTs and cross-over trials. Cluster-RCTs were eligible for inclusion but none were identified.

Data collection and analysis: 

Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We assessed the certainty of the evidence using the GRADE approach.

Main results: 

We included 39 studies, with 33 providing data (8073 women). Thirty-two studies (7690 women) contributing data administered antibiotics systemically, while one study (383 women) used lavage and was analysed separately.

We identified three main comparisons that addressed clinically important questions on antibiotics at caesarean section (all systemic administration), but we only found studies for one comparison, 'antistaphylococcal cephalosporins (1st and 2nd generation) versus broad spectrum penicillins plus betalactamase inhibitors'.   We found no studies for the following comparisons: 'antistaphylococcal cephalosporins (1st and 2nd generation) versus lincosamides' and 'antistaphylococcal cephalosporins (1st and 2nd generation) versus lincosamides plus aminoglycosides'.

Twenty-seven studies (22 provided data) included comparisons of cephalosporins (only) versus penicillins (only). However for this update, we only pooled data relating to different sub-classes of penicillins and cephalosporins where they are known to have similar spectra of action against agents likely to cause infection at caesarean section.

Eight trials, providing data on 1540 women, reported on our main comparison, 'antistaphylococcal cephalosporins (1st and 2nd generation) versus broad spectrum penicillins plus betalactamase inhibitors'. We found data on four other comparisons of cephalosporins (only) versus penicillins (only) using systemic administration: antistaphylococcal cephalosporins (1st and 2nd generation) versus non-antistaphylococcal penicillins (natural and broad spectrum) (9 studies, 3093 women); minimally antistaphylococcal cephalosporins (3rd generation) versus non-antistaphylococcal penicillins (natural and broad spectrum) (4 studies, 854 women); minimally antistaphylococcal cephalosporins (3rd generation) versus broad spectrum penicillins plus betalactamase inhibitors (2 studies, 865 women); and minimally antistaphylococcal cephalosporins (3rd generation) versus broad spectrum and antistaphylococcal penicillins (1 study, 200 women). For other comparisons of different classes of antibiotics, only a small number of trials provided data for each comparison, and in all but one case data were not pooled.

For all comparisons, there was a lack of good quality data and important outcomes often included few women. Three of the studies that contributed data were undertaken with drug company funding, one was funded by the hospital, and for all other studies the funding source was not reported.

Most of the studies were at unclear risk of selection bias, reporting bias and other biases, partly due to the inclusion of many older trials where trial reports did not provide sufficient methodological information. We undertook GRADE assessment on the only main comparison reported by the included studies, antistaphylococcal cephalosporins (1st and 2nd generation) versus broad spectrum penicillins plus betalactamase inhibitors, and the certainty ranged from low to very low, mostly due to concerns about risk of bias, wide confidence intervals (CI), and few events.

In terms of the primary outcomes for our main comparison of 'antistaphylococcal cephalosporins (1st and 2nd generation) versus broad spectrum penicillins plus betalactamase inhibitors': only one small study reported sepsis, and there were too few events to identify clear differences between the drugs (risk ratio (RR) 2.37, 95% CI 0.10 to 56.41, 1 study, 75 women, very low-certainty evidence). There may be little or no difference between these antibiotics in preventing endometritis (RR 1.10; 95% CI 0.76 to 1.60, 7 studies, 1161 women; low-certainty evidence). None of the included studies reported on infant sepsis or infant oral thrush. For our secondary outcomes, we found there may be little or no difference between interventions for maternal fever (RR 1.07, 95% CI 0.65 to 1.75, 3 studies, 678 women; low-certainty evidence). We are uncertain of the effects on maternal: wound infection (RR 0.78, 95% CI 0.32 to 1.90, 4 studies, 543 women), urinary tract infection (average RR 0.64, 95% CI 0.11 to 3.73, 4 studies, 496 women), composite adverse effects (RR 0.96, 95% CI 0.09 to 10.50, 2 studies, 468 women), and skin rash (RR 1.08, 95% CI 0.28 to 4.1, 3 studies, 591 women) (all very low certainty evidence). Although maternal allergic reactions were reported by two studies, there were no events. There were no infant outcomes reported in the included studies.

For the other comparisons, the results for most outcomes had wide CIs, few studies and few women included. None of the included trials reported on longer-term maternal outcomes, or on any infant outcomes.

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