Efficacy and safety of broad spectrum penicillin with or without beta-lactamase inhibitors vs first and second generation cephalosporins as prophylactic antibiotics during cesarean section: a systematic review and meta-analysis

Abstract This study assessed the efficacy and safety between broad spectrum penicillin (P2) with or without beta-lactamase inhibitors (P2+) versus first and second generation cephalosporins (C1&C2) in the prevention of post-cesarean infections. Relevant randomized controlled trials (RCTs) were searched in English and Chinese databases: nine RCTs were involved. Six trials compared P2+ vs C1&C2, no differences were found between interventions for endometritis, wound infection, urinary tract infection, febrile morbidity and maternal rashes. Four trials compared P2 vs C1&C2, no differences were found between interventions for endometritis, febrile morbidity, wound infection and urinary tract infection. Postoperative hospitalization was longer for women in P2 than C1&C2. Based on these results, P2/P2+ and C1&C2 may have similar efficacy on postoperative infections after cesarean section, there is no data on infant outcomes. PROSPERO Registration Number: CRD42022345721.


Introduction
Cesarean section is a routine surgery in critical obstetric cases.With the development of cesarean section, the rate of cesarean delivery continues to increase worldwide (Abdel Jalil et al. 2017).However, cesarean section is considered to be a clean-contaminated procedure and one of the most important risk factors for postpartum infection, with a global infection range of 2.5%-20.5% (Conroy et al. 2012), the risk of infections is 5-20-fold higher for women who have a cesarean delivery than for vaginal births (Van Schalkwyk and Van Eyk 2017).Good surgical technique is important for reducing infections.Additionally, guidelines of the American College of Obstetricians and Gynecologists (Committee on Practice Bulletins-Obstetrics 2018) recommend that the use of prophylactic antibiotics before cesarean section to reduce postoperative endometritis, wound infection, fever and severe infectious complications including pelvic abscess, bacteremia and sepsis, these more serious complications can lead to maternal deaths.Prophylactic antibiotics can decrease the risk of postoperative infections by >50% (Lamont et al. 2011).However, antibiotics can have adverse effects on the mother and infant.Antibiotics administered to women during delivery may have a direct impact on the offspring's microbiota and interfere with the development of the infant's immune system (Mutic et al. 2017, Stinson et al. 2018).
Therefore, the selection of effective and safe prophylactic antibiotics is particularly important.
During cesarean section, prophylactic antibiotics should be effective against the following pathogens: skin colonizers, primarily gram-positive cocci, particularly including Staphylococcus aureus and Streptococci; and vaginal colonizers, including anaerobes and, gram-negative bacilli (Gyte et al. 2014).Furthermore, such a ideally prophylactic antibiotics should be: (1) unrelated to the development of antimicrobial resistance; (2) able to attain adequate serum and tissue levels throughout the procedure; (3) lower cost and be welltolerated.Currently, guidelines for the clinical application of antimicrobial therapy in China recommend C1&C2 with or without metronidazole as prophylactic antibiotics (National Health and Family Planning Commission of China 2015).The American College of Obstetricians and Gynecologists and the Canadian Society of Obstetrics and Gynaecology (Van Schalkwyk and Van Eyk 2017, Committee on Practice Bulletins-Obstetrics 2018) have recommended C1 such as cefazolin as the first choice for prophylaxis.Despite there being clear guidelines regarding the recommendation of prophylactic antibiotics, differences in clinical practices remain: there are many interfering factors depending on variability in local policies or an obstetrician's preference.Several clinical studies (Gyte et al. 2014) have also reported the use of P2 or P2þ (eg ampicillin and ampicillin/sulbactam) as prophylaxis.Although P2 are similar in antibacterial spectrum to C1&C2, the use of P2 for antibiotic prophylaxis remains questionable, considering that ampicillin is prone to resistant to betalactamase-producing Staphylococcus, resulting in its ineffectiveness, and allergic reactions to penicillin under anesthesia are difficult to identify (Obstetrics and Gynecology Pharmacy Group, Hospital Pharmaceutical Committee, Chinese Pharmaceutical Association et al. 2021).Compared with C1&C2, the antimicrobial combination of ampicillin/sulbactam has a broader antibacterial spectrum including anaerobic bacteria and Enterococci (Dervisoglou et al. 2006).
It is not clear whether any one particular antibiotic is superior, and antibiotics given perinatally can also adversely affect the newborn's developing immune system and microbiome.Therefore, the aim of this study was to determine the efficacy and safety of the P2/P2þ vs C1&C2 in reducing postoperative infections in women and to investigate their adverse effects on mother and infant based on the best available evidence.

Protocol and registration
The protocol for this review is registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42022345721.

Eligibility criteria
Studies fulfilling the following criteria were included: (1) Type of study: RCTs; (2) Participants: pregnant women undergoing cesarean section, both elective and non-elective; (3) Intervention: the comparison of P2þ vs C1&C2; the comparison of P2 vs C1&C2.Exclusion criteria: (1) Non-RCTs; (2) Studies that were incomplete, outcome effects that were unclear, or data that could not be extracted.Main outcomes: endometritis, febrile morbidity, wound infection, urinary tract infection, maternal rashes and length of hospital stay.

Data collection and risk of bias assessment
Two investigators (Song and Yan) independently selected the literature according to the pre-established eligibility criteria, carried out data extraction using a standardized tool and assessed the risk of bias for each study using criteria outlined in the Cochrane Handbook.If there were discrepancies, they were resolved with a third investigator (Bu).Evaluation included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other possible biases.

Statistical analysis
Meta-analysis was performed using Rev Man 5.4 software.Enumeration data of outcome evaluation were statistically analyzed using the relative risk (RR).Continuous data were analyzed using mean difference (MD).The 95% confidence interval (95% CI) was used for interval estimation.Heterogeneity was assessed using the I2 test.If I 2 <50%, the fixed-effect model was used.If I 2 >50%, it indicated that there was statistical heterogeneity between trials.If there was no clinical or methodological heterogeneity, the random-effect model was preferred.

Search results
The database searches retrieved 418 records and 243 studies were retained after duplicates were removed, then 225 studies were excluded because the title/abstract did not meet the inclusion criteria or satisfied one of the exclusion criteria.After reading the full text, 9 articles were excluded and the final 9 RCTs were included (Figure 1).

Risk of bias assessment
Among the nine studies, three (Bracero 1997, Busowski et al. 2000, Spinnato et al. 2000) were randomized double-blind studies, two (Ziogos et al. 2010, Mivumbi et al. 2014) were randomized single-blind studies and four (Noyes et al. 1998, Jyothi et al. 2010, Zhang et al. 2010, Fang 2021) were described as RCTs.We assessed the included studies for risk of bias according to the Cochrane Handbook.Risk of bias of eligible studies is presented in Figures 2 and 3.

P2 vs C1&C2-outcome3: wound infection
Wound infection was reported in three studies (Zhang et al. 2010, Mivumbi et al. 2014, Fang 2021) involving 647 women were included in the meta-analysis.There was no evident difference in postoperative wound infection between groups (RR 1.19, 95% CI 0.20-6.97,I 2 ¼70%) (Figure 5(C)).Owing to the heterogeneity, subgroup analyses were carried out according to the subclasses of cephalosporins, region and

P2 vs C1&C2-outcome4: urinary tract infection
Only one RCT (Mivumbi et al. 2014) reported the incidence of urinary tract infection in pregnant women.There was no important difference between groups in postoperative urinary tract infection (RR 9.00, 95% CI 0.49-163.90).

P2 vs C1&C2-outcome5: length of postoperative hospitalization
Only one RCT (Mivumbi et al. 2014) reported length of postoperative stay in pregnant women.An increase was observed regarding length of postoperative stay in women who received P2 to C1 (MD 1.50, 95% CI 0.54-2.46).

Discussion
During cesarean section, causative agents that colonize the vagina and cervix may be transferred into the uterine cavity.Postoperative uterine tissue trauma, bleeding and exudate are also conducive to the generation of pathogens.Additionally, the surgical procedure changes the normal bacterial flora of the genital tract, resulting in an imbalance of the ratio of anaerobes to aerobes, which can lead to maternal infections when the postoperative immunity is decreased.
Therefore, the use of prophylactic antibiotics is recommended for all patients undergoing cesarean section.Clinical research practice has indicated (Committee on Practice Bulletins-Obstetrics 2018) that there is no significant difference between C1&C2 in reducing the post-cesarean infections, and a single dose regimen is usually recommended.
The most common pathogens isolated from wound infection included Ureaplasma, Staphylococcus and Enterococcus, these can contaminate the myometrium, uterine blood vessels and lymphatic vessels, leading to infections including endometritis during surgery (Jaiyeoba 2012).C1&C2 have been widely used as preventive measures in obstetrics and gynecology surgery.However, they are naturally resistant to Enterococcus but stable to the betalactamase-producing Staphylococci (Bratzler et al. 2013, Garc� ıa-Solache and Rice 2019).It is reported that Enterococcus are the most common pathogens in cases of endometritis following cephalosporins prophylaxis (Newton and Wallace 1998).Compared with C1&C2, P2 is effective against Enterococcus and other gramnegative bacteria, but not against Staphylococci.P2þ have a broader antimicrobial spectrum than C1&C2 and are active against gram-positive, gram-negative and anaerobic bacteria, including S.aureus, Enterococci, Streptococci, many Enterobacterales and Bacteroides spp.The aim of the present analysis was to evaluate the efficacy of P2/P2þ which are routinely used clinically vs C1&C2 which are the first choices as prophylactic antibiotics during cesarean delivery.
Cesarean section is the most important risk factor for postpartum endometritis (Olsen et al. 2010).The incidence of Wound infection Cefuroxime 1.5 g postoperative endometritis as high as 70% before prophylactic antibiotic therapy became standard practice (Pierson et al. 2018).This was especially common in pregnant women with high risk factors of infection, such as rupture of membranes, excessive vaginal examinations before cesarean section, maternal anemia, obesity and poor hygiene, the use of prophylactic antibiotics can reduce the incidence of endometritis (Leth et al. 2009, Valent et al. 2017).The results revealed that there was no significant difference between P2/P2þ and C1&C2 for postoperative endometritis.In terms of P2 vs C1&C2, however, our results were inconsistent with a review by Cochrane (Alfirevic et al. 2010), which indicated that P2 were more effective than C1&C2 in preventing postcesarean endometritis (RR 2.18, 95% CI 1.30 to 3.66).The source of difference owing to the inclusion of a recent RCT (Mivumbi et al. 2014), which reported a significant difference in the incidence of endometritis between the ampicillin and the cefazolin (15.2% vs 1.5%; p ¼ .009),where cephalosporins were more effective in preventing endometritis.
Wound infection refers to infection of the skin and subcutaneous tissue at the surgical site that can complicate cesarean section (Scholz et al. 2021).In addition, wound infection at the surgical site will result in therapeutic antibiotic use, prolonged hospital stay, higher hospitalization costs and burden to health care system (Blumenfeld et al. 2015).The results showed that there was no difference between P2/P2þ and C1&C2 for postoperative wound infection.Concerning the comparison of P2þ vs C1&C2, there was only one study (Jyothi et al. 2010) comparing amoxycillin/clavulanic acid (AMX/CL) with cefazolin and there was no significant difference between the two groups in preventing wound infection.Although AMX/CL had activity against potential pathogens, it was not superior to cefazolin in preventing infection.Regarding the cost, the use of AMX/CL was more expensive.Furthermore, RCOG guidelines had indicated that AMX/CL is not recommended owing to the increased risk of necrotizing enterocolitis (National Collaborating Centre for Women's and Children's Health (UK) 2011).Because of a substantial heterogeneity in P2 group, the three articles, we according to the subclasses of cephalosporins, region, dosage regimen subgroup analyses, the results showed:   were single-dose regimens, while only one study (Zhang et al. 2010) was a multiple-day dose regimen.Depending on the results, the dosage regimen may be a source of heterogeneity.In support of our hypothesis, the study of Zhang was removed, leaving two studies with homogeneity.We conducted a meta-analysis on the remaining two articles (Figure 6(B)).Although there was no statistical difference, C1&C2 were slightly superior to P2 in preventing wound infection (RR 3.00, 95% CI 0.84-10.73,I 2 ¼3.0%, p ¼ .09).At present, it is generally accepted that a single-dose regimen is better utilized for prevention.
The results showed that there were no differences between the P2/P2þ and C1&C2 for preventing post-cesarean urinary tract infection and febrile morbidity.Concerning  postpartum urinary tract infection, in addition to the prophylactic antibiotics, post-cesarean bacteriuria may be further reduced by avoiding routine catheterization.
In terms of safety, two articles (Bracero 1997, Noyes et al. 1998) reported the events of maternal rashes, there was no evident difference between groups regarding antibioticrelated rashes.Three patients were found in the ampicillin/sulbactam group and one in the cefotetan group.Patients developed a rash that resolved following two doses of diphenhydramine hydrochloride.Based on the available evidence, the safety of drugs in each group was good.However, we have no data on late infections (up to 30 days) in the mother, which is important gap in the evidence that warrant further investigate.
Intrapartum antibiotics exposure may adversely affect the newborn's developing immune system and microbiome.Studies have shown that antibiotics can cross the placenta and impact the newborn even short courses of intrapartum antibiotics (Zachariassen et al. 2016).In perioperative animal models, O 'Connor's et al. (2021) team observed that early life exposure to maternal antibiotics (a single, low-dose penicillins) led to persistent alterations in anxiety, sociability and cognitive behaviors.They suggest that change in the gut microbiome is a potential mechanism for behavioral and physiological changes.Additionally, antibiotics in the perinatal period may be a factor that contributes to the association of cesarean delivery with childhood infection, allergy, inflammatory bowel disease and respiratory problems (Stinson et al. 2017, Auger et al. 2021).This evidences support the view that there are potential long-term detrimental consequences of maternal antibiotic use in the perinatal period.Nevertheless, unfortunately, no neonatal adverse effects nor any longer-term effects on children were reported in the included studies, we suggest that this information needs to be assessed by collecting long-term data.So far, there is relatively little research in this area, these are important evidence for evaluating antibiotic safety that warrant further research.
Limitations of this analysis: (1) some of the studies lacked information on study design which may have increased the risk of deviation; (2) some outcome indicators were reported in only one study that was not available for meta-analysis; (3) earlier trials in this study administered antibiotics at or immediately after the umbilical cord clamping, with a difference in timing from the currently supported administration prior to skin incisions, so the results may influence the recommendations for prophylaxis.

Conclusions
This meta-analysis included relatively new, comprehensive studies that provide a more appropriate recommendation for the prophylactic use of antibiotics during cesarean section.P2/P2þ and C1&C2 may have similar efficacy in the prevention of post-cesarean infections.P2 such as ampicillin and C1&C2 are good choices as prophylactic antibiotics for cesarean section, they were found to be equally effective, safe and inexpensive.However, the use of a wider spectrum of antimicrobials, including ampicillin/sulbactam, was not superior to the narrower spectrum C1&C2, and may promote antimicrobial resistance.Impact on newborns need to be assessed through the collection of long-term data and the late maternal infections warrants further study, which are important evidence for assessing antibiotic safety.
(1) the comparison of P2 versus C1 remained heterogeneous, the comparison of P2 versus C2 is too few to analyze, and the subclasses of cephalosporins may not have been a source of heterogeneity; (2) the region was not a source of heterogeneity; (3) the studies ofMivumb et al. (2014)  andFang (2021)

Figure 5 .
Figure 5. Forest plots of the incidence of endometritis (A), febrile morbidity (B) and wound infection (C) comparing P2 with C1&C2.

Figure 6 .
Figure 6.Subgroup analysis of the incidence of wound infection comparing P2 with C1&C2 according to subclasses of cephalosporins, region, dosage regimen (A) and a forest plot was obtained after the removal of one article from heterogeneous sources (B).

Table 1 .
Characteristics of the nine studies included in the systematic review.