Intrapartum antibiotic prophylaxis to prevent Group B streptococcal infections in newborn infants: a systematic review and meta-analysis comparing various strategies

Early-onset Group B Streptococcus (EOGBS) leads to substantial morbidity and mortality in newborn infants. Intrapartum antibiotic prophylaxis (IAP) prevents EOGBS infection, but IAP strategies vary. The approach to the provision of IAP can be risk-based, universal or a combination of the two strategies. Previous systematic reviews reported that universal strategies might be most optimal in lowering EOGBS infection, but there is no consensus. Therefore, we aimed to provide up-to-date evidence on effectiveness of different strategies by comparing perinatal outcomes.

A systematic search for EOGBS prevention strategies was performed in MEDLINE, Embase and Web of Science. Studies were included if they reported on different strategies and outcomes of interest, including EOGBS infection, IAP administration and antimicrobial resistance. Summary data was extracted from published reports. Study quality was assessed using the ROBINS-I tool. Random-effects meta-analyses were used to determine risk ratios (RR) and 95%-confidence intervals. PROSPERO registration CRD42023411806. Findings A total of 6050 records were identified, of which 72 observational studies were included for synthesis with more than 10 million live births. Meta-analysis demonstrated that implementation of any strategy (n=34 studies, RR 0.46 (0.36-0.60)), risk-based strategies (n=11 studies, RR 0.65 (0.48-0.87)), or universal strategies (n=16 studies, RR 0.37 (0.25- 0.55)) was associated with a reduced risk of EOGBS infection compared to no strategy. In direct comparison, universal strategies were associated with a reduced risk of EOGBS All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 3 compared to a risk-based strategy (n=17 studies, RR 0.41 (0.30-0.55)), while the proportion of women receiving IAP did not differ between risk-based (16%) and universal (21%) strategies (n=9 studies, RR 1.29 (0.95-1.75)). There was no antimicrobial resistance of EOGBS isolates to penicillin or ampicillin (n=11 studies). Interpretation Any IAP strategy could reduce the risk of EOGBS infection without evidence of increasing antimicrobial resistance. Universal strategies give the largest reduction in the EOGBS burden, while not exposing a significantly higher proportion of pregnancies to IAP compared to risk-based strategies. Funding UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction, a cosponsored programme executed by the World Health Organisation. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 4

Early-onset Group B Streptococcus (EOGBS) infection, comprising sepsis, pneumonia and meningitis, are a leading cause of neonatal morbidity and mortality, with a worldwide incidence of 0.41 per 1000 live births and a mortality rate of 4-10% in high-income countries. 1,2 EOGBS infections are defined as the presence of Group B Streptococcus (GBS) within 7 days of birth in normally sterile fluids, such as blood and cerebrospinal fluid.3,4 Infants may be infected antenatally by vertical transmission in colonised pregnant women.5 Globally, GBS colonisation of the recto-vaginal tract is 18% among all pregnant women at any point during pregnancy.6 Therefore, prevention of the sequelae of GBS colonisation contributes importantly to perinatal health. Currently, prevention of vertical transmission consists of administration of intrapartum antibiotic prophylaxis (IAP) at least 4 hours before birth, which is associated with a reduced risk of EOGBS infection. 7,8 IAP is administered according to various screening strategies applied in different settings. Risk-factor based screening (‘risk-based’) strategies are used in some settings, where IAP is administered according to the presence of any risk factor for EOGBS during pregnancy.9 In universal microbiology-based screening (‘universal’) strategies GBS colonisation is determined in all pregnant women antenatally and IAP is administered to women with GBS colonisation.7 In addition, IAP can be administered with any combination of elements from risk-based and universal strategies (‘other’).10,11 Previous systematic reviews and meta-analyses reported that universal strategies were associated with a lower incidence of EOGBS infection compared to risk-based strategies or having no strategy. 12,13 However, IAP strategies still vary considerably around the world, which is partly due to discussion concerning increased antibiotic use, antimicrobial resistance All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 5 development and risk of a possible increase in non-GBS early-onset sepsis (EOS), caused by pathogens like E. coli.14-16 Moreover, even when implementing universal strategies, there is no consensus of timing of GBS determination. In order to contribute to consensus on GBS prevention strategies, this review elaborates on previous work, while incorporating up-to-date evidence on a variety of outcomes needed for evidence-based and nuanced policy-making. We evaluated the effectiveness of different prevention strategies, by comparing maternal and neonatal infectious morbidity and mortality, the frequency of IAP administration, and the presence of antimicrobial resistance. Furthermore, we evaluated timing of GBS determination in universal strategies to prevent EOGBS infection in newborns.

Protocol and Registration The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane Handbook for Systematic Reviews were used to conduct and report this systematic review and meta-analysis.17,18 The protocol was registered in PROSPERO, with ID CRD42023411806.19 Eligibility criteria Study designs We included any randomised and non-randomised study with human participants that reported on any of the outcomes of interest (specified below) when comparing/describing at least two different strategies for IAP administration to prevent EOGBS infections, including All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 6 no strategy. Non-randomised studies included non-randomised interventional studies (e.g. quasi-randomised controlled trials) and uncontrolled observational studies (e.g. cohort studies). Studies were eligible regardless of sample size, year, country or language of publication and temporal data collection. Studies were excluded when: - only qualitative data was presented; - strategies coincided; - data was already published in other articles 1; - data was based on models, not actual cases; - the full-text article could not be obtained, or; - the article was categorised as case report, case series, letter to the editor, commentary, or conference abstract. Participants Participants were pregnant women and neonates. Interventions The intervention consisted of strategies for IAP administration (including no strategy). Risk- based strategies were defined as strategies where IAP was administered according to the presence of any risk factor for EOGBS during pregnancy, such as a history of an infant with EOGBS infection, presence of GBS bacteriuria during pregnancy, or presence of intrapartum fever, preterm labour or prolonged rupture of membranes >18 hours. 9 Universal strategies 1 If data was already published in other articles, then the study with the largest sample size was chosen and included. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 7 were defined as strategies where GBS colonisation was determined using microbiological testing and IAP was administered to all women positive for GBS colonisation.7 Other strategies were defined as strategies where IAP was administered based any combination of elements from risk-based and universal strategies. ‘Other’ strategies usually consisted of strategies where both risk-based and universal strategies were implemented in parallel and selective strategies that only treat pregnant women positive for GBS colonisation with the presence of least one risk factor. 10,11 Lastly, IAP was sometimes found to be administered without any official screening (‘no’) strategy on an individual basis and at the discretion of the attending physician.12,20 Outcome measures Review outcomes were selected based on the critical and important outcomes used in the WHO recommendations on the prevention and treatment of maternal peripartum infections.21 Outcomes listed below were used as primary outcomes for the review. Protocol outcomes were specified into the following outcomes: - Incidence of EOGBS infection per 1000 live births or pregnant women (as defined by study authors). - Incidence of non-GBS early-onset sepsis (EOS) per 1000 live births or pregnant women. - Incidence of all EOS per 1000 live births or pregnant women. - EOGBS-related mortality rate per 1000 live births or pregnant women. - IAP administration (%). - Antimicrobial resistance in EOS isolates (%). - Maternal peripartum infection (%). (Supplementary file 2 ) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 8 Information sources Records were obtained through a systematic search of MEDLINE, Embase, and Web of Science databases. Additional publications were obtained manually by searching reference lists of relevant records and reviews. Search strategy The full search strategy used in MEDLINE is presented in Supplementary file 1 . Search terms used included pregnancy, newborn, infant, Group B streptococcus, screening, culture- based, polymerase chain reaction, risk-based, prevention, guidelines, and early onset. In the final search, articles (regardless of language) were included until 2024. The last queries were run in May 2024. Selection process Potential studies were identified from the search strategy by double (independent) review (TJRP, GFH, TL, CA, YC, VB). Any disagreements were resolved by a third author (TJRP, GFH, TL, CA, YC, VB, respectively) and reviewers were not blinded. All titles and abstracts were placed in EndNote version X20 (Clarivate Analytics, Philadelphia, PA, USA) to automatically and manually deduplicate the list of studies. Afterwards, all articles were screened for eligibility via title and abstract in COVIDENCE (Veritas Health Innovation, Melbourne, Australia). Selected studies were subject to full-text screening. Full-text screening was done using aforementioned selection criteria. Data collection process Two authors (TJRP, GFH) independently extracted the following data: study design, study population and outcome measures using a preformed data extraction sheet. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 9 Data items Data items consisted of general information about the article, on the study population, IAP strategies, and outcome information. Outcome measures were manually calculated using raw data from the article. Missing data were reported as ‘No data’ in the tables. Study risk of bias assessment Risk of bias was assessed via the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool. 22 Studies were assessed by two independent reviewers (TJRP, GFH), and any discrepancies were handled through discussion until consensus. Seven domains of bias were assessed: confounding, selection of participants into the study, classification of interventions, deviations from intended intervention, missing data, measurement of outcomes and selection of the reported results. Each domain was scored as low, moderate, serious, critical, or unknown risk of bias. Confounding factors relevant to this review were specified before the studies were assessed for risk of bias. Effect measures EOGBS infection, non-GBS EOS and all EOS incidences were presented as cases per 1000 live births or pregnant women. EOGBS-related mortality rate was presented as deaths per 1000 live births or pregnant women. IAP administration incidence was presented as the percentage of pregnant women receiving IAP. Antimicrobial resistance incidence was presented as the percentage of resistance with respect to all EOS isolates examined. Incidence rates were calculated using the data provided in the studies. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 10 Incidence of all early-onset infections and administration of IAP were compared between strategies with pooled risk ratios (RR) and 95%-Confidence intervals (CIs). EOGBS-related mortality rate (per 1000 live births or pregnant women) and IAP administration (%) incidence were also reported as a pooled incidence of the random-effects meta-analyses with a random intercept logistic regression model. Individual study 95%-CIs were reported with normal approximation confidence intervals. Meta-regression output was presented as β -coefficient and corresponding p-value. Synthesis methods Studies were only included in data synthesis if they reported on at least two different strategies (including no strategy) and if raw data was provided on the incidence of the outcomes of interest. The category ‘other strategies’ was not included in the meta-analysis due to heterogeneity in the strategies used, but these studies were included in the ‘any’ vs. ‘no’ strategy comparison. We used R version 4.2.1 (R: The R Project for Statistical Computing (r-project.org)) within Studio version 4.2.1 (R Studio, Boston, MA, USA, 2022) to combine studies, synthesize data, and create funnel plots. Heterogeneity was assessed by i) a Chi 2-test for variation between studies and ii) the I2 statistic, which described the proportion of variation that is due to heterogeneity. As we anticipated marked heterogeneity between studies that might influence treatment effect, in terms of study population, baseline infection incidence and timing of GBS determination, we performed subgroup analyses in addition to random-effects meta- regression. Subgroup analyses included comparisons in EOGBS infection incidence in studies that reported on term case incidence. Meta-regression analyses were performed post- hoc with an inverse variance method for all EOGBS comparisons that included at least 10 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 11 studies. We sought to delineate baseline EOGBS infection incidence (in cases per 1000 live births or pregnant women) and timing of GBS determination. Meta-regression analyses for timing of GBS determination were performed with two different methods in two different comparisons. In the comparison between universal and no strategy, the timing of GBS determination was compared between early determination before 33 weeks’ gestation and late determination at 33-37 weeks’ gestation. In the comparison between universal and risk-based strategies, timing of determination was compared between (antepartum) determination at 35- 37 weeks’ gestation and (intrapartum) GBS colonisation determined within two days of birth. We performed sensitivity analyses to assess the robustness of the synthesised results by excluding all studies with a serious risk of bias in the comparisons for EOGBS infection incidence. A p-value <0.05 was considered significant. Reporting bias assessment Publication bias analyses were carried out via visual inspection of the funnel plots and an Egger’s test for funnel plot asymmetry for meta-analyses, including at least ten studies. 23 Certainty assessment Certainty of the outcomes was assessed using the GRADE approach of the Cochrane Handbook for Systematic Reviews of Interventions. 24 We critically evaluated study limitations, consistency of effect, imprecision, indirectness, and publication bias in the outcomes. An overall judgement of certainty assessment ranged from very low to high certainty evidence. Study limitations were evaluated with degree of risk of bias. Inconsistency was based on I 2 and overlap of 95%-CI estimates. Indirectness was not relevant All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 12 to this review. Imprecision was based on 95%-CI estimate of outcome. Publication bias was assessed as listed above. Role of the funding source This review was commissioned by the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of HRP, SRH to inform WHO recommendations for Prevention and treatment of peripartum infections. Author TL is a staff of WHO, has access to the dataset and contributed to the decision to submit for publication.

Study selection The selection process is illustrated in a flow diagram in Figure 1. The three databases overall provided 11,025 records, which were reduced to 6,613 after removing duplicates. Title and

screening was done in all 6,613 records: 5,624 did not meet inclusion criteria, and the remaining 669 articles were reviewed in full-text. Ultimately, data on 82 articles 25-106 were presented and 72 articles25-96 were included in the synthesis of the systematic review. Reasons for exclusions are listed in Figure 1. No randomised controlled trials on this subject were found. Study characteristics Overall, the 72 included studies included more than 10 million live births/deliveries from 20 different countries (Table 1) . A total of 55 observational studies reported on EOGBS infection incidence, 18 on non-GBS EOS, 19 on all EOS, 2 on timing of GBS determination, 19 on EOGBS-related mortality, 16 on IAP administration and 16 on antimicrobial resistance. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 13 Two studies reported on timing of GBS determination. Study characteristics and results of individual studies are displayed in Table 1 and Supplementary file 2. Risk of bias within studies Overall risk of bias was critical in 3 studies, serious in 43 studies, moderate-serious in 3 studies, moderate in 22 studies and low in 1 study (Supplementary file 3). Many studies had problems in the domain of confounding due to a lack of data on the demographics for the total population or issues with retrospective outcome measurements, which were not standardised. Synthesis of results EOGBS infection Any strategy (i.e. risk-based, universal or ‘other’) was associated with a reduced risk of EOGBS infection compared to no strategy (n=34 studies, RR 0.46 (0.36-0.60), I2=93%, Chi2- test p<0.001) (Figure 2 and Supplementary files 4, 5 and 6). Similarly, risk-based (n=11 studies, RR 0.65 (0.48-0.87)) and universal strategies (n=16 studies, RR 0.37 (0.25-0.55)) were also associated with reduced risk of EOGBS infection as compared to no strategy (Figure 3, 4 and Supplementary file 4, 5 and 6). In direct comparison, universal strategies were significantly associated with a reduced risk of EOGBS infection compared to risk-based strategies (n=17 studies, RR 0.41 (0.30-0.55), Figure 5 and Supplementary file 4, 5 and 6).

were similar for studies reporting on term incidence and after excluding studies with a serious risk of bias (sensitivity analyses) (Supplementary file 3, 4, 5 and 6). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 14 Meta-regression demonstrated that there was a correlation between the baseline EOGBS infection incidence and the differences between any strategy and no strategy (β =-0.463, p<0.001) and between universal and no strategy (β =-0.746, p<0.001). This indicates that the effect of any or universal strategies compared to no strategy is increased if the incidence in the population is higher. This was not the case in the comparison between risk-based and no strategy ( β =-0.328, p=0.082). Timing of GBS determination Vergani et al.2 reported no significant differences in EOGBS infection between early and late antepartum determination (RR 1.24 (0.25-6.12)), while El Helali et al. reported that intrapartum determination significantly reduced EOGBS infection compared to antepartum determination (RR 0.21 (0.07-0.64)) (Supplementary file 2, 4 and 5 ).43,92 Meta-regression demonstrated that there was no correlation between timing of GBS determination and the differences between universal and no or risk-based strategies. Additional early-onset infection Any strategy was associated with a reduced risk of non-GBS EOS compared to no strategy, but individual strategies did not significantly impact non-GBS EOS (Supplementary file 2, 4, 5). Similar to EOGBS infection comparisons, any, risk-based and universal strategies were all significantly associated with a reduced risk of all EOS compared to no strategy (Supplementary file 2, 4, 5 ). Universal strategies were associated with a reduced risk of all EOS compared to risk-based strategies (Supplementary file 2, 4, 5). 2 Vergani et al. used a combination strategy consisting of IAP administration to pregnant women with GBS colonisation and to those with risk-factors. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 15 EOGBS-related mortality The pooled EOGBS-related mortality rate during periods with no strategy (0.089 (0.047- 0.17), n=15 studies, I2=86%) was reduced by more than half after implementation of any strategy (0.028 (0.022-0.036, n=19 studies, I2=0%) (Table 2). EOGBS-related mortality rate was similar in periods with risk-based (0.026 (0.019-0.037), n=6 studies, I2=36%) and universal strategies (0.028 (0.015-0.054, n=10 studies, I2=0%) (Table 2). IAP administration Pooled IAP administration rate during periods with no strategy (8 (3-17) %, n=3 studies, I2=100%) more than doubled with any strategy (19 (16-22) %, n=16 studies, I2=100%). In the comparison of risk-based (16 (12-20) %, n=11 studies, I2=97%) and universal strategies (21 (18-24) %, n=12 studies, I2=98%) no significant difference in the rate of IAP administration was found (n=9 studies, RR 1.29 (0.95-1.75), I2=99%, Chi2-test p<0.001) (Table 3, and Supplementary file 4, 6). Antimicrobial resistance In the 11 studies reporting on antimicrobial resistance of EOGBS isolates, there was no resistance to ampicillin, penicillin or other β -lactams but varying resistance to other second- line antimicrobials, including erythromycin and clindamycin, but not vancomycin (Supplementary file 2). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 16

Our study adds to the data from previous reviews by expanding the number of included studies and thus the population size, as well as by exploring outcomes not previously reported (non-GBS early-onset sepsis (EOS), mortality and maternal peripartum infection).12,13 In this systematic review and meta-analysis of 72 studies that included more than 10 million live births and pregnant women, all strategies (i.e. any, risk-based, universal and ‘other’ strategies) were associated with a lower risk of early-onset Group B Streptococcal (EOGBS) infection. Universal strategies were associated with a lower risk of EOGBS infection compared to risk-based strategies, while intrapartum antibiotic prophylaxis (IAP) rate was not significantly different between strategies without report of antimicrobial resistance of EOGBS isolates to penicillin or ampicillin. Pooled EOGBS-related mortality was halved in periods with any strategy compared to periods with no strategy and non-GBS EOS incidence decreased after implementation of any strategy. This systematic review and meta-analysis confirms the findings of two previous reviews that universal strategies are more effective in preventing EOGBS infection compared to having no strategy or risk-based strategies. 12,13 In this review, evidence was mostly derived from observational studies conducted in high- and high-middle-income countries with historical controls (pre-post implementation studies). These study limitations are reflected in serious risks of bias, often due to potential confounding and potential time bias 3. Regardless, after sensitivity analyses, results were similar with respect to EOGBS infection incidence, in which the data was graded as moderate-level certainty evidence. Other limitations included heterogeneity of the strategies used, which led to classifying all that did not fit the terms ‘risk-based’ or ‘universal’ into an 3 The time bias could consist of possible improvements in care over time, but is contrasted by increased viability of premature infants and subsequent survival that could increase the amount of EOGBS cases. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 17 ‘other’ category. This category consisted of at least 10 different strategies, which could not be pooled. The results of this systematic review and meta-analysis need to be seen in context, by including consideration with regard to cost, feasibility and providers’ and women’s views. Universal strategies appear to be optimal in preventing EOGBS, with most protocols determining GBS colonisation between 35 and 37 weeks’ gestation.4,7,107 However, inherently, these protocols do not take into account preterm birth occurring before determination, in which EOGBS morbidity and mortality are higher.4 It is known that GBS diagnostics with regard to GBS colonisation lose accuracy as time progresses between diagnosis and birth (>6 weeks), indicative of possible transient colonisation.108 Earlier screening would, therefore, signify a less accurate prediction of EOGBS infection risk for infants, but our findings do not support this theory. Although intrapartum determination might lower EOGBS infection compared to antenatal determination, intrapartum testing is not yet widely available and more research to understand the potential harms and benefits is needed.

concerning the potential for IAP strategies to contribute to harm, such as increased non-GBS neonatal sepsis have featured prominently in this space, in addition to possible overtreatment and rising antimicrobial resistance with universal strategies, on account of associations between early antibiotic exposure and altered gut microbiome, asthma and obesity. 14-16,109,110 Interestingly, instead of an increase in non-GBS EOS, we observed that implementation of any strategy was associated with a lower risk of non-GBS EOS. The studies reporting an increasing incidence of gram-negative sepsis (particularly E. coli) primarily focused on very low-birthweight infants, while studies in premature and term infants (not included in our meta-analysis) did not observe such an increase, similar to our findings. 16,30,109,111 Our findings also suggest that antimicrobial resistance in EOGBS isolates All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 18 is confined to second-line antimicrobials. Hence, penicillin and ampicillin might still be the best choice for IAP in preventing vertical transmission of GBS, especially since recent evidence suggests that clindamycin is less effective than ampicillin against vertical transmission of GBS.112 Moreover, our findings provide some reassurance that universal strategies are not likely to result in significantly higher antibiotic exposure compared to risk- based strategies. Despite evidence for this systematic review and meta-analysis predominantly deriving from studies conducted in high and high-middle-income countries, GBS prevention strategies might also lower the high EOGBS burden in low- and lower-middle income countries. Low and lower-middle-income countries more commonly have no strategy for IAP, partly due to lack of resources and inadequate infrastructure for diagnostic screening and testing, while they have higher EOGBS morbidity and mortality. 113-115 In our review, we included one study that reported on the adoption of a strategy in a lower-middle-income country4 (India).83 After the adoption of a risk-based strategy, EOGBS infection incidence significantly decreased, particularly in premature infants, without any antimicrobial resistance for penicillin and ampicillin in EOGBS isolates. 83 As these results are similar to the findings in this review, IAP strategies might prove beneficial in these settings, though more research in low- and lower-middle income countries is necessary. Worldwide annual EOGBS burden is about 205 000 affected newborn infants, of which a significant proportion results in death.115 Any IAP strategy aimed to lower this EOGBS burden could reduce risk of EOGBS infection and non-GBS sepsis, while also lowering EOGBS-related mortality. Specifically, universal strategies likely lead to a larger reduction in 4 This study was not included in the synthesis of EOGBS infection, because no raw data was available. The study characteristics and results are mentioned in the corresponding tables. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 19 EOGBS infection compared to risk-based strategies while a similar proportion of pregnant women receive IAP. Considering that EOGBS isolates were not resistant to ampicillin or penicillin, altogether, our findings do not support evidence that IAP strategies, and in particular, universal strategies, are associated with explicit harm, though data was derived from observational studies. Currently, the randomised multicentre GBS3 (ISRCTN49639731) trial is being conducted in the United Kingdom comparing risk-based and universal strategies (antepartum and intrapartum). It is the first trial to concurrently investigate (cost)-effectiveness of the different strategies and will provide valuable insight into the optimal GBS prevention strategy. Contributors Conceptualisation: TJRP, GFH, CA, TL, ABtP, VB and TvdA. Data curation: TJRP. Formal analysis: TJRP. Investigation: TJRP, GFH, YC, CA, TL and VB. Methodology: TJRP, GFH, CA, TL, ABtP, VB and TvdA. Project administration: TJRP, TL, TvdA. Resources and software: Not relevant for this review. Supervision: TL and TvdA. Validation: GFH. Visualisation: TJRP. Writing – original draft: TJRP and GFH. Writing – review & editing: YC, CA, TL, ABtP, VB and TvdA. All authors reviewed and approved the final version before submission. All authors had access to all data used in this study, approved the final version of the manuscript, and accepted the responsibility for the decision to submit the manuscript for publication. Declarations of interests Authors have no competing or conflicts of interests to declare. Data sharing All data were presented in the manuscript and supplementary files. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 20

This work was funded by the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research (SRH), a co-sponsored programme executed by the World Health Organization. We want to acknowledge the support of MA Claudia Pees, whom assisted in search strategy formation. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 21

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The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint 28 Legends to Figures Figure 1: PRISMA study inclusion flowchart PRISMA flowchart of retrieved and included studies. Figure 2: Forest plot of EOGBS infection: any vs no strategy Forest plot of risk ratio (with 95%-CI) of EOGBS infection in any strategy versus no strategy. Figure 3: Forest plot of EOGBS infection: risk vs. no strategy Forest plot of risk ratio (with 95%-CI) of EOGBS infection in risk-based strategies versus no strategy. Figure 4: Forest plot of EOGBS infection: universal vs. no strategy Forest plot of risk ratio (with 95%-CI) of EOGBS infection in universal strategies versus no strategy. Figure 5: Forest plot of EOGBS infection: universal vs. risk strategies Forest plot of risk ratio (with 95%-CI) of EOGBS infection in universal strategies versus risk- based strategies. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint Table 1: Early-onset infection uthor Year Study design Time analys is Country Country Income Study setting/ Data source IAP criteria: Universal strategies IAP criteria: Risk-based strategies IAP criteria: Other strategies IAP agent EOS definition Incidence per 1000 live births or pregnant women (95%-CI) No strategy Risk strategy Universal strategy Other strategies delmaaboud & hammed 2011 Retrospective observational study Hi stori cal Qatar High Principal pub lic hospita l in State IAP to: i) carriers of rectovaginal and urine GBS culture at 35-37 weeks' gestation, and ii) carriers of GBS culture at presentation for all high-risk cases (preterm labour (PTL), prolonged rupture of membranes (PROM), intrapartum fever (fever), clinical chorioamnionitis or GBS colonisation). IAP to: PTL, PROM, fever, and a previous infant with GBS disease. Ampicillin initially 2 g intravenously (IV) and 1 g every 6 hours (h). Penicillin allergy, 900 mg clindamycin every 8 h. GBS: <72 hours blood or cerebrospinal fluid (CSF) 1.9 (no data) 0.57 (0.36-0.86) 0.48 (0.30-0.71) Luhidan et al. 2019 Retrospective cohort study Hi stori cal Saudi Arabia High Tertiary care hospital CDC 2002: IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation, ii) previous baby with invasive GBS infection, iii) GBS bacteriuria, and iv) if unknown carrier state, presence of PTL, PROM and fever. RCOG 2012: IAP to: PTL, PROM, fever, previous infant with invasive GBS infection, and GBS bacteriuria. CDC 2002: Penicillin G 5 million units IV initially and 2.5-3 million units every 4 h. Ampicillin as alternative. Penicillin allergy not at high risk of anaphylaxis, cefazolin 2g IV and 1 g every 8 h. Penicillin allergy high risk of anaphylaxis and susceptibility available, clindamycin 900 mg IV every 8 h, or erythromycin 500 IV every 6 h. If susceptibility not possible or unknown or isolates resistant to clindamycin or erythromycin, vancomycin 1 g IV every 12 h. RCOG 2012: Penicillin G 3 g IV initially and 1.5 g every 4 h. If allergy not risk of anaphylaxis, then cephalosporin (e.g. cefuroxime 1.5g IV initially and 750 mg every 8 h). If allergy high risk of anaphylaxis, vancomycin 1g every 12 h. GBS: <7 days in sterile body site (blood, CSF, suprapubi c catheter and lungs). 1.02 (0.59-1.66) 0.24 (0.15-0.36) dreu et al. 2003 Retrospective cohort study Hi stori cal Spain High Ten hospita ls, 5 public, 2 private and 3 with financing agreements with public sector IAP to: carriers of GBS colonisation. Hospitals used different timing of determination, but became uniform near end of study and most determined GBS colonisation between 35-37 weeks’ gestation. NI. GBS: <7 days in sterile product (blood, CSF, etc). 1.92 (1.34-2.67) 0.27 (0.098-0.58) gstetra et al. 2007 Prospective cohort study Hi stori cal Australia High Tertiary obstetric unit No information (NI). Rectovaginal swab at 34–37 weeks gestation , IAP to i) c arr ie rs of rectovaginal GBS colonisation at 34-37 weeks’ gestation, ii) PTL, fever previous infant with GBS infection, and GBS bacteriuria regardless of GBS status, and iii) if unknown carrier state, presence of PROM. Penicillin G 1.2 g IV initially then 600 mg 4 h. Peni cillin-sensitive individual s either cephalothin 2 g IV initially and 1 g every 6 h or clindamycin 600 mg IV. every 8 h. GBS: 1 Non-GBS: 2 All: 3 <7 days in blood or CSF, admission to neonatal unit for treatment with antibi otics and ventilation, and signs of sepsis. 0.84 (0.55-1.23) 1 0.94 (0.63-1.34) 2 1.78 (1.34-2.31) 3 0 0.72 (0.32-1.61) 0.72 (0.32-1.61) userman et al. 2013 Retrospective cohort study Hi stori cal United States of America (USA) High Three hundred twenty-two NICUs managed by the Paediatric Medical G roup CDC 2002. CDC 2002. GBS: <3 days in blood, urine or CSF. 3.5 (no data) 2.6 (No data) kker et al. 2014 Retrospective nationwide surveillance study Hi stori cal The Netherlands High The Netherlands Reference Laboratory for Bacterial Meningitis Dutch guidelines 1999: IAP to: i) previous infant with GBS infection, GBS bacteriuria or urinary tract infection and fever, and ii) GBS colonisation and PTL, (premature) PROM, previous infant with EOS without known pathogen. Co nsider IAP to : i) GBS co lon isation without risk-factors, and ii) if unknown carrier state, presence of PTL and (premature) PROM. Dutch guidelines 1999: Penicillin G 2 million international units (IU) IV initially and every 4 h. Alternatively amoxicillin or ampicillin 2g IV initially and 1g every 4 hours. Penicillin allergy, clindamycin 900 mg every 8 h. Alternatively, erythromycin 500 mg every 6 h. GBS: <7 days in blood or CSF. 0.11 (0.10-0.13) 0.18 (0.16-0.20) rkl und et al. 2017 Retrospective cohort study Hi stori cal Fi nland High Public financed tertiary delivery unity IAP to: i) carriers of rectovaginal GBS polymerase chain reaction at admission, and ii) if carrier state unknown on presence of risk-factors. IAP to: PROM, GBS bacteriuria, GBS colonisation, and previous infant with EOGBS. Penicillin G 5 million IU IV initially and 2.5 million IU every 4 h. Penicillin allergy, cefuroxime 1.5 g IV initially and 750 mg every 8 h or clindamycin 900 mg IV every 8 h. GBS: <3 days in clinical records databased with ICD code for GBS sepsis. 0.98 (0.20-2.87) 0 rnsdóttir et al. 2019 Retrospective and descriptive case study Hi stori cal Iceland High Iceland IAP to: PTL, fever, PROM, and positive GBS cultures in late pregnancy or earlier deliveries. NI. GBS: <7 days. 0.7 (no data) 0.2 (no data) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint zanski et al. 2000 Retrospective observational study Hi stori cal USA High Tertiary referral hospital CDC 1996 (similar to CDC 2002). AAP 1992 and no strategy IAP to: i) carriers of rectovaginal GBS colonisation at 26-28 weeks’ gestation or at admission with PTL, (premature) PROM, fev er, mul tiple births, and ii ) previous infant with invasive GBS infection. Ampicillin, penicillin, clindamycin, or erythromycin. GBS: <48 hours in blood or CSF. 0.14 (0.038-0.36) 1.16 (0.81-1.60) an et al. 2023 Retrospective cohort study Hi stori cal China High-Middl e Eight public hospitals and 31 health centres IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation, and ii) carrier state known before 35 weeks' gestation, GBS bacteriuria or history previous infant affected by GBS disease. IAP to: previous infant with invasive GBS disease, PTL, GBS colonisation, and GBS bacteriuria. Penicillin G 5 million IU IV initially and 2.5 million IU every 4 hours. Penicillin allergy, erythromycin, clindamycin, or vancomycin according to sensitivity. GBS 1 : Non-GBS 2 : All 3 : <8 days in blood or CSF. 1.03 1 (0.87-1.22) 2.21 2 (1.97-2.48) 3.25 3 (2.95-3.57) 0.26 1 (0.21-0.32) 2.00 2 (1.85-2.16) 2.27 3 (2.11-2.43) et al. 2019 Retrospective cohort study Hi stori cal Taiwan High Tertiary obstetric unit CDC 2010 (similar to CDC 2002). Penicillin, ampicillin, or cefazolin. GBS: <7 days in sterile site (blood, CSF or urine) with signs of clinical disease 2.8 (no data) 0 (no data) mens & Gable 2002 Retrospective cohort study Hi stori cal USA High Nonacademically affiliated commun ity hospita l CDC 1996 (similar to CDC 2002). EOGBS 1.93 (no data) 0.4 (no data) rlow et al. 2016 Prospective and retrospective surveillance study Hi stori cal New Zealand High New Zealand Paediatric Surveillance Unit (all hospitals) IAP to: PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria. Penicillin or amoxycillin. GBS: <3 days in blood, CSF or pleura wi th clinical and laboratory evidence of spesis 0.50 (0.38-0.65) 0.23 (0.15-0.33) erly & Rajnik 2009 Retrospective cohort study Hi stori cal USA High Hospitals withing the Department of Defence CDC 2002. CDC 1996 IAP to: i) PTL, PROM and fever, ii) carriers of rectovaginal GBS screening at 35-37 weeks' gestation, iii) if unknown carrier state, presence of risk- factors, iv) previous infant with GBS infection, and v) GBS bacteriuria. CDC 1996: Penicillin G 5 million IU IV initially and 2.5 million IU IV every 4 h. Alternatively, ampicillin 2 g IV initially and 1 g IV every 4 h. Penicillin allergy not at high risk of anaphylaxis, cefazolin 2 g IV initially and 1 g every 8 h. Peni cillin allergy at high ri sk of anaphyl axi s and susceptibility available, clindamycin 900 mg IV every 8 h, or erythromycin 500 IV every 6 h. If susceptibility not possible or unknown or isolates resistant to clindamycin or erythromycin, vancomycin 1 g IV every 12 h. CDC 2002. GBS: <7 days with possession of diagnosis group codes and lack of other diagnosis group codes that refer to non-GBS bacteria. 1.95 (1.78-2.14) 0.47 (0.39-0.56) 0.72 (0.64-0.82) ker et al. 2013 Retrospective cohort study Hi stori cal USA High Regional tertiary care centre CDC 2002. NI. Penicillin or ampicillin. GBS 1 : Non-GBS 2 : All 3 : ≤ 7 days in blood, urine or CSF with appropriate treatment. 2.06 (1.46-2.81) 1 3.48 (2.74-4.43) 2 5.54 (4.53-6.70) 3 0.96 (0.51-1.64) 1 4.28 (3.32-5.53) 2 5.24 (4.09-6.60) 3 1.11 (0.55-1.98) 1 3.33 (2.29-4.67) 2 4.44 (3.30-5.96) 3 wards et al. 2003 Retrospective cohort study Hi stori cal USA High General hospital CDC 1996. Ampicillin prior to march 1995 and penicillin thereafter. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood. 1.69 (0.92-2.83) 1 2.41 (1.47-3.72) 2 4.10 (2.84-5.73) 3 1.01 (0.46-1.92) 1 3.60 (2.46-5.07) 2 4.62 (3.49-6.25) 3 enberg 2005 Retrospective cohort study Concurrent USA High All acute care hospitals in four major counties of Tennessee IAP to: carriers of GBS culture at least 2 days before delivery. IAP to: no GBS culture <2 days and PTL, PROM, fever, GBS bacteriuria, or previous infant with invasive GBS disease. NI. GBS: <7 days in blood or CSF. 0.85 (0.56-1.25) 0.40 (0.19-0.74) tor et al. 1998 Retrospective cohort study Hi stori cal USA High Non-profit, tertiary care hospital ACOG 1992: IAP to: PTL, PROM, or fever. Ampicillin, cefazolin, cefoxitin, vancomycin, cephalothin, erythromycin, and oxacillin GBS: <7 days in blood or CSF. 1.70 (0.99-2.73) 0.15 (0.038-0.84) itas & Romero 2017 Retrospective cohort study Hi stori cal Brazil High-Middl e Regional maternity hospital Based on CDC 2010: IAP to i) carriers rectovaginal GBS colonisation at ≥ 24 weeks' pregnancy with PTL or ROM, ii) GBS bacteriur ia and previous infant with GBS sepsis, and iii) if unknown carrier state, presence of PTL, PROM and fever (majority of patients). Ampicillin 2g IV initially and 1 g every 4 h. Penicillin allergy, clindamycin 900 mg IV every 8 hours GBS 1 : Non-GBS 2 : All 3 : <72 hours in blood and antibiotic treatment ≥ 5 days or death <5 days while on antibiotic treatment. 0.51 (0.21-1.06) 1 1.40 (0.89-2.18) 2 1.91 (1.25-2.79) 3 0 1 1.32 (0.71-2.45) 2 1.32 (0.71-2.45) 3 rland 1991 Retrospective observational study Concurrent Australia High Public teaching hosp ital IAP to: carriers vaginal GBS culture at 32 weeks' gestation. Penicillin 1 million IU IV every 6 h. Penicillin allergy, erythromycin 500 mg every 6 h. EOGBS: in blood, CSF, surface swabs or urine 1.00 (0.66-1.46) 0.53 (0.30-0.86) bs et al. 1994 Retrospective cohort study Hi stori cal USA High University hospital IAP to: i) carriers of rectovaginal GBS culture at 26-28 weeks' gestation, ii) PTL, (premature) PROM, fever, chorioamnionitis with negative carrier status that turned positive, iii) previous Ampicillin 2g IV initially and 1g every 4 h. Penicillin allergy, erythromycin 500 mg every 6 h. EOGBS sepsis: 1.50 (0.72-2.75) 1.03 (0.34-2.41) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint infant with EOGBS infection, and iv) GBS bacteriuria. son et al. 2000 Retrospective cohort study Concurrent USA High Academic medical centre IAP to: i) carriers of GBS colonisation at 35-37 weeks' gestation, and ii) if unknown carrier state, presence of risk- factors. IAP to: PTL, fever, PROM, and previous infant with GBS infection. Before march 1995, ampicillin 2 g IV every 6 h. After march 1995, penicillin G 5 million IU initially and 2.5 million IU every 4 h. Penicillin allergy, clindamycin 900 mg every 8 h. GBS: <7 days in blood, CSF, uri ne or suprapubic aspiration. 1.49 (0.41-3.81) 0 pal Rao et al. 2017 Retrospective observational study Hi stori cal UK High General hospital IAP to: carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation NICE 2012. IAP to: previous infant with GBS infection, GBS bacteriuria, GBS colonisation, and fever. Penicillin G 3 g IV initially and 1.5 g every 4 h. Penicillin allergy, clindamycin. GBS: <7 days in blood, CSF or other sterile flui ds. 1.12 (0.78-1.57) 0.33 (0.068-0.96) sling et al. 2002 Questionnaire survey Concurrent New Zealand High Nineteen public hospitals IAP to: i) carriers antenatal GBS culture, and ii) PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria, and iii) a combination of strategy i) and ii). Amoxicillin and penicillin. Penicillin allergy, erythromycin, clindamycin or cephalosporins. 1.44 (0.47-3.36) 0.46 (0.26-0.76) fner et al. 1998 Retrospective and prospective cohort study Hi stori cal Austr ia High Sociomedical centre IAP to: carriers of rectovaginal GBS culture at 33-35 weeks' gestation. IAP to: (premature) PTL, PROM, fever, previous infant with GBS infection, and maternal diabetes mellitus. Amoxicillin with clavulanic acid 2.2 g every 6 h. Penicillin allergy, 600 mg clindamycin. GBS: in throat, umbilicus, ears or blood and signs of sepsis. 5.41 (3.31-8.34) 1.01 (0.28-2.59) kansson et al. 2017 Retrospective cohort study Hi stori cal Sweden High National health registers of all hospitals in Sweden IAP to: PTL, PROM, fever, GBS bacteriuria, and previous infant with GBS infection. NI. GBS: <7 days in blood or CSF. 0.40 (0.33-0.48) 0.30 (0.24-0.36) ng et al. 2019 Retrospective cohort study Hi stori cal South-Korea High Tertiary hospital CDC 2010. IAP to: PROM, fever, GBS bacteriuria, and previous infant with GBS sepsis. Cefazolin 2 g IV initially and 1 g every 8 h. Cephalosporin allergy, ampicillin 2 g IV initially and 1 g every 4 h. Penicillin allergy, vancomycin and clindamycin. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood. 0.77 (0.019-4.28) 1 1.54 (0.19-5.54) 2 2.31 (0.48-6.72) 3 0 1 0 2 0 3 rv áth et al. 2013 Prospective cohort study Hi stori cal Hungary High University hospital IAP to i) carriers of rectovaginal GBS colonisation at 30-32 weeks’ gestation, and ii) PTL, (premature) PROM, fever, multiple gestation, diabetes and polyhydramnios. Ampicillin 2 g IV initially and 1 g ampicillin every 4 h. Penicillin allergy, erythromycin or clindamycin in equivalent dosage. GBS: <7 days in blood or CSF with clinical signs of GBS. 1.57 (1.07-2.23) 0.31 (0.13-0.61) ng et al. 2018 Retrospective cohort study Hi stori cal Taiwan High National Health Insurance database (all hospital s) IAP to: carriers of rectovaginal GBS colonisation at 35-37 weeks’ gestation. GBS: <7 days in hospital record with ICD-9 codes for GBS sepsis, meningitis and pneumonia. 1.0 (no data) 0.16 (0.10-0.23) acs & Royle 1999 Prospective observational study Hi stori cal Australia High Australian neonatal units of the Australasian Study Group for Neonatal Infection Different strategies in hospitals comprising no, risk-based, universal and other strategies. Usually ampicillin or penicillin. GBS 1 : Non-GBS 2 : All 3 : <48 hours in blood, CSF or urine with clinical sepsis. 2.86 (2.22-3.60) 1 1.22 (0.86-1.75) 2 4.08 (3.32-4.96) 3 0.54 (0.39-0.73) 1 0.50 (0.36-0.69) 2 1.04 (0.83-1.30) 3 fery & Moses Lahra Prospective cohort study Hi stori cal Australia High Tertiary referral hospital IAP to: i) carriers of vaginal GBS colonisation at 28 weeks' gestation withou t risk-factors or 24 weeks if known risk-factor for preterm birth, ii) GBS bacteriuria, iii) previous infant with EOGBS infection, and iv) if unknown carrier state, presence of preterm labour. Ampicillin 1 g every 6 hours. Penicillin allergy, cephalosporin. GBS: <48 hours in blood and clinical signs of sepsis. 1.40 (0.60-2.75) 0.22 (0.095-0.43) ansson Gudjónsdóttir 2019 Retrospective cohort study Hi stori cal Sweden High University hospital, largest in Sweden IAP to: PTL, PROM, fever, previous infant with EOGBS infection, and GBS bacteriuria. NI. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood or CSF. 0.47 (0.34-0.64) 1 0.90 (0.72-1.12) 2 1.37 (1.13-1.64) 3 0.44 (0.32-0.59) 1 0.48 (0.35-0.64) 2 0.92 (0.74-1.13) 3 rdan-da Silva et al. Retrospective observational study Hi stori cal France High Epibac; a network of hospital microbiology laboratories involved in monitoring invasive bacterial infections IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks’ gestation, and ii) if carrier state unknown, presence of PTL, (premature) PROM, previous infant with GBS infection and GBS bacteriuria. NI. GBS: <7 days. 0.69 (0.63-0.75) (no data) 0.23 (0.19-0.26) (no data) tz et al. 1994 Retrospective cohort study Hi stori cal USA High Public academic tertiary care medical centre IAP to: i) carriers of rectovaginal GBS culture at 24-28 weeks' gestation, ii) GBS bacteriuria, and iii) if carrier state unknown, presence of PROM and PTL. Ampicillin 2 g IV every 6 hours. Penicillin allergy, cefazolin 500 mg or clindamycin 600 mg every 6 h. GBS: in blood 2.02 (0.55-5.17) 0 tz et al. 1999 Retrospective cohort study Historical USA High Urban tertiary centre IAP to: i) carriers of rectovaginal GBS culture at 28 weeks' gestation and PTL, and ii) (premature) PROM, fever and previous infant with GBS infection. Ampicillin 2 g IV every 6 h. Penicillin allergy, clindamycin 600 mg every 6 h. GBS: <7 days in blood or CSF with clinical signs of sepsis. 2.15 (1.50-2.99) 2.19 (1.34-3.38) et al. 2021 Retrospective cohort study Hi stori cal Taiwan High Two referral hospitals with level 3 NICUs IAP to: carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation. IAP to: PTL, PROM, fever, previous infant with invasive GBS infection and GBS bacteriuria. Ampi cillin, peni cillin or cefazoli n. GBS 1 : Non-GBS 2 : All 3 : <3 days in blood or CSF. 0.62 1 (no data) 1.44 2 (no data) 2.06 3 (no data) 0.38 1 (no data) 1.01 2 (no data) 1.39 3 (no data) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint et al. 2021 Retrospective cohort study Hi stori cal China High-Middl e Tertiary university hospital IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation. IAP to: i) PTL, PROM and fever. Ampicillin 2 g IV initially and 1 g every 4 h. GBS: <7 days in blood. 0.27 (0.12-0.51) 0 vine et al. 1999 Retrospective observational study Hi stori cal USA High The Infection Control Surveillance Database CDC 1996. Ampicillin or cefoxitin. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood or CSF. 1.74 (1.17-2.48) 1 0.99 (0.61-1.59) 2 2.72 (2.00-3.62) 3 0 1 2.14 (1.07-4.28) 2 2.14 (1.07-4.28) 3 et al. 2011 Retrospective cohort study Hi stori cal Taiwan High Private hospital IAP to: i) carriers of rectovaginal GBS culture at 35-37 weeks' gestation, ii) GBS bacteriuria, iii) previous infant with GBS infection, and iv) if unknown carrier state, presence of PTL, PROM and fever. Ampicillin 2 g IV initially and 1 g every 4 h. Alternative ly, penicillin G. Ampicillin allergy, cefazolin. Penicillin allergy, clindamycin or erythromycin. GBS 1 : Non-GBS 2 : All 3 : <72 hours in blood. 0.66 (0.32-1.21) 1 0.79 (0.45-1.39) 2 1.45 (0.91-2.19) 3 0.23 (0.063-0.59) 1 0.92 (0.53-1.49) 2 1.15 (0.74-1.78) 3 cksmith et al. 1999 Retrospective cohort study Hi stori cal USA High University tertiary care centre CDC 1996. Until 1993, IAP to: carriers of GBS colonisation at hospital with PTL, premature PROM and another risk- factor (unspecified). Until 1995, ampicillin 2 g IV initially and 1 g every 6 h. After 1995, penicillin 5 million IU and 2.5 million IU every 4 h. Amoxicillin for premature PROM and GBS colonisation. GBS: <7 days in blood or CSF. 1.35 (0.49-2.93) 2.95 (1.87-4.42) cksmith et al. 1999 Retrospective cohort study Hi stori cal USA High University tertiary care centre CDC 1996. After 1993, ACOG guidelines but unknown which ones. IAP to: i) if unknown carrier state, presence of PTL, PROM, fever, and previous infant with GBS sepsis, and ii) strategy above. Until 1995, ampicillin 2 g IV initially and 1 g every 6 h. After 1995, penicillin 5 million IU and 2.5 million IU every 4 h. Amoxicillin for premature PROM and GBS colonisation. GBS: <7 days in blood or CSF. 1.35 (0.49-2.93) 1.90 (1.06-3.12) pez Sastre et al. 2005 Prospective surveillance study Hi stori cal Spain High Twenty eight acute care teaching hospitals IAP to: i) carriers of rectovaginal GBS culture at 35-37 weeks' gestation, ii) GBS bacteriuria, and iii) previous infant with GBS infection. Societies of Clinical Microbiology and Infectious Disease and Chemotherapy 1998: Ampicillin 2 g IV initially and 1 g every 4 h or penicillin G 5 million IU IV initially and 2.5 million IU every 4 h. Beta-lactam allergy, clindamycin 900 mg every 8 h, or erythromycin 500 mg every 6 h. GBS 1 : Non-GBS 2 : All 3 : <3 days in blood with one clinical sign and at least one laboratory abnormality consistent with infection. 1.11 (0.89-1.37) 1 1.11 (0.89-1.37) 2 2.22 (1.90-2.57) 3 0.70 (0.54-0.90) 1 1.03 (0.83-1.26) 2 1.73 (1.48-2.02) 3 et al. 2022 Retrospective cohort study Hi stori cal Taiwan High University hospital with a level 3 NICU IAP to: carriers of rectovaginal GBS culture at 35-37 weeks' gestation. NI. GBS: <72 hours in blood or CSF. 1.1 (no data) 0.32 (no data) kacs & Schrag 2012 Cross sectional study Hi stori cal USA High National Centre for Health Statistics’ National Hospital Discharge Survey data CDC 2002 IAP to: i) carriers of rectovaginal GBS culture at 35-37 weeks' gestation, ii) previous baby with invasive GBS infection, iii) GBS bacteriuria, and iv) if GBS carrier rate unknown, PTL, PROM and fever. ACOG 2002 endorses CDC 2002 guidelines CDC 1996. AAP 1997 IAP to: i) GBS bacteriuria, ii) previous infant with GBS infection, iii) carriers of rectovaginal GBS culture at 35-37 weeks’ gestation, iv) if unknown carrier state, presence of risk-factors, and iv) PTL, PROM and fever. ACOG 1996 guidelines endorse CDC 1996. CDC 1996, ACOG 1996 (penicillin), ACOG 2002, CDC 2002, and AAP 1997: Penicillin G 5 million IU IV initially and 2.5 million IU every 4 h. Alternatively, ampicillin 2 g IV initially and 1 g every 4 h. Penicillin allergy, clindamycin or erythromycin IV. All: <7 days with ICD- 9 codes for infection in perinatal period or septicaemia. 14.51 (14.28- 14.74) 10.30 (10.05- 10.56) 11.40 (11.17- 11.64) in & Slagle 2000 Prospective observational study Hi stori cal USA High Tertiary perinatal referral centre CDC 1996 =ACOG 1996. IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation, ii) term patients with fever >38 ºC, iii) previous infant with GBS infection, and iv) if unknown carrier state, presence of PTL. ACOG 1992 and CDC 1996. IAP to: PTL, (premature) PROM, fever, previous infant with EOGBS infection, and GBS bacteriuria. ACOG 1992 and CDC 1996, but in reality: Ampicillin 2 g IV initially and 1 g every 4 h. Penicillin allergy, 900 mg clindamycin every 8 h. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood or CSF. 1.17 (0.51-2.31) 1 1.17 (0.51-2.31) 2 2.35 (1.34-3.80) 3 1.13 (0.63-1.86) 1 0.30 (0.082-0.77) 2 1.43 (0.86-2.24) 3 0.071 (0.0018- 0.40) 1 0.35 (0.12-0.83) 2 0.43 (0.19-0.95) 3 tsubara et al. 2013 Retrospective nationwide questionnaire surveillance Hi stori cal Japan High One hundred fifty-four hospital, 14 managed only outborn infants in absence of obstetric department, 62 NICUs and 76 regional centres IAP to: i) carriers of GBS colonisation at 33-37 weeks' gestation except for elective caesarean deliveries, ii) previous infant GBS disease, and iii) if unknown carrier state, at delivery irrespective of gestational age. NI. GBS: <7 days in blood, CSF or joint aspirate. 0.075 (0.048-0.11) 0.098 (0.052-0.17) tsubara et al. 2007 Multicentre questionnaire survey Japan High Twenty-eight regional hospitals with 9 NICUs 23 hospitals routine antenatal determination (likely 33-37 weeks’ gestation in Japan according to JSOG guidelines). Ampicillin, piperacillin, or cefotiam. Loading doses of antibiotics varied from 0.5-2 g and interval differed from every 4 h until every 12 h. EOGBS 0.11 (0.013-0.40) 0.10 (0.033-0.24) et al. 2018 Retrospective cohort study Hi stori cal China High-Middl e Eight public hospitals and 27 maternal and child health centres IAP to carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation. IAP to: PTL, PROM, fever, previous infant GBS disease, and GBS bacteriuria. NI. GBS: <7 days in blood or CSF. 1 (0.7-1.1) (no data) 0.24 (0.16-0.34) ullivan et al. 2019 Prospective active national surveillance study Hi stori cal UK and Ireland High Active surveillance (all paediatricians) and laboratory databases (all) RCOG 2003: IAP to: PTL, fever, previous infant with GBS infection, GBS bacteriur ia, GBS colonisation, and suspected chori oamni onitis. NICE 2012 Penicillin G, cephalosporin or vancomycin. GBS: <7 days in blood, CSF or joint flu id. 0.48 (0.43-0.53) 0.57 (0.52-0.62) tersen et al. 2014 Retrospective cohort study Hi stori cal Denmark High Public referral centre Denmark recommendation 2004: IAP to: PTL, PROM, fever, GBS bacteriuria, and previous infant with NI. GBS: <7 days in blood, CSF or tracheal 2.04 (1.09-3.48) 1.50 (0.99-2.18) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint in vasive GBS infection. swab. ares et al. 2008 Retrospective cohort study Hi stori cal USA High Database Active Bacterial Core surveillance/ Emerging Infections Program Network CDC 2002. CDC 1996, ACOG 1996, AAP 1997. CDC 1996, ACOG 1996, AAP 1997, CDC 2002. GBS: <7 days in blood or CSF. 0.34 (0.31-0.37) 0.47 (0.44-0.51) ulain et al. 1997 Prospective cohort study Hi stori cal France High University hospital regional

century IAP to: i) carriers of rectovaginal GBS colonisation at 28 weeks’ gestation, GBS bacteriuria and one of the foll owing risk-factors: PTL, PROM, fever, twin pregnancies, maternal diabetes, and ii) previous infant with GBS. Amoxicillin 2 g IV initially and 1 g every 4 h. GBS: Immediate in blood or CSF. 4.48 (1.65-9.73) 1.63 (0.44-4.17) opolo & Eichenwald Retrospective cohort study Hi stori cal USA High University hospital IAP to: carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation. IAP to: PTL, PROM, fever. Ampicillin or clindamycin for risk-factor strategy. Penicillin G for universa l strategy. Penicillin allergy, clindamycin, cefazolin, erythromycin and vancomycin. GBS 1 : Non-GBS 2 : All 3 : <72 hours in blood and neonatologist considered infant infected. Surviving infants treated with appropriate course of antibiotics ≥ 7 days. 2.16 (1.66-2.80) 1 1.54 (1.13-2.10) 2 3.72 (3.00-4.52) 3 1.12 (0.79-1.53) 1 1.12 (0.79-1.53) 2 2.24 (1.77-2.79) 3 0.43 (0.32-0.58) 1 1.16 (0.96-1.38) 2 1.59 (1.36-1.86) 3 nner et al. 2006 Retrospective observational study Hi stori cal Switzerland High University hospital IAP to: i) carriers of GBS screening at 35-37 weeks + PROM, fever or PTL, ii) unknown carriers state when risk-factor present, and iii) previous infant with GBS sepsis. NI. GBS: <7 days in blood. 0.99 (0.57-1.61) 0.53 (0.17-1.24) ttenstreich et al. 2019 Retrospective cohort study Hi stori cal Israel High University affiliated medical centre IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation, and ii) if unknown carrier state, presence of risk-factors. IAP to: PTL, PROM, fever, previous infant EOGBS, and GBS bacteriuria. NI. GBS: <7 days in normally sterile site. 0.36 (0.21-0.57) 0.19 (0.12-0.30) rera et al. 2001 Retrospective cohort study Hi stori cal Spain High Private hospital IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks' gestation, ii) unknown carrier state, and iii) previous child GBS and GBS bacteriuria during pregnancy IAP: PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria at end of pregnancy. IAP to: i) carriers of intrapartum GBS colonisation with PTL, PROM, fever, GBS bacteriuria and previous infant with GBS infection. Ampicillin 2 g IV initially and 1 g every 4 h. Penicillin allergy, erythromycin or clindamycin. GBS: <7 days in blood, CSF or in urine with clinical symptoms. 1.12 (0.54-2.06) 2.44 (1.53-3.69) ata et al. 2012 Retrospective cohort study Hi stori cal Japan High Public hospital JSOG and JAOG 2008 IAP to: i) carriers of rectovaginal GBS colonisation at 33-37 weeks' gestation, ii) earlier infant GBS infection, and iii) unknown carrier state. Sulbactam or ampicillin 1.5 g. GBS: <3 days in blood or CSF with signs of infection. 0.51 (0.10-1.48) 0.40 (0.010-2.23) rag et al. 2002 Retrospective cohort study Concurrent USA High Multiple hospitals of the Emerging Infections Program Network IAP to: carriers of GBS culture at least 2 days before delivery. IAP to: all pregnant women without documentation of test for GBS with PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria. NI. GBS: in normally sterile site. 0.68 (0.59-0.78) 0.33 (0.27-0.39) are et al. 2001 Retrospective cohort study Hi stori cal USA High University hospital AAP 1997, ACOG 1996. AAP 1997, ACOG 1996. GBS: <72h in blood or CSF. 2.66 (1.62-4.10) 0.70 (0.33-1.28) etka et al. 2010 Retrospective cohort study Hi stori cal Czech Republic High University hospital IAP to: i) carriers of rectovaginal GBS colonisation at 35-37 weeks, ii) GBS bacteriuria, iii) previous infant with invasive GBS, iii) if unknown carrier state, presence of PTL, PROM, fever or positive rapid test for GBS colonisation. Penicillin G 5 million IU IV and 2,5-3 million IU every 4 h. Alternatively, ampicillin 2 g IV initially and 1 g every 6 h. Penicillin allergy not at high risk of anaphylaxis, cephalosporins (cefazolin and cephalothin) 2 g IV initially and 1 g every 8 h. Penicillin allergy at high risk of anaphylaxis, clindamycin 900 mg IV every 8 h or vancomycin 1 g IV every 12 h. GBS: <7d in blood or CSF with clinical symptoms. 0.84 (0.17-2.45) 0.61 (0.13-1.79) rg et al. 2021 Retrospective cohort Hi stori cal Ge rmany High The scientific network of the Barmer Ersatzkasse (insurance providers) 10% of population of Germany IAP to: i) carriers of rectovaginal GBS culture at 35-37 weeks' gestation. or ii) if carrier state unknown, presence of risk-factors. IAP to 2 strategies: i) carriers of rectov agi nal GBS culture at 35-37 weeks’ gestation, and ii) PROM, PTL, fever, previous infant with GBS infection, and GBS bacteriuria. NI. GBS: <72 hours in blood, maternal cervical swab or other swabs. 0.5 (no data) 1.5 (no data) dhar et al. 2014 Retrospective cohort study Hi stori cal India Low-Middle Tertiary level neonatal unit of teaching hospital IAP to: PTL, (premature) PROM, fever, 3 or more gloved per vaginal examinations, chorioamnionitis, and GBS bacteriuria. Ampicillin. EOGBS 0.86 (0.59-1.13) (no data) 0.55 (0.36-0.72) (no data) tkin et al. 2005 Retrospective cohort study Hi stori cal USA High Tertiary referral hospital CDC 1996. AAP 1992 IAP to: carriers of rectovaginal GBS colonisation at 26-28 weeks’ gestation with one of the following risk-factors: PTL (premature) PROM, fever, previous infant with EOGBS disease, and GBS bacteriuria. Before 1993, there was no implemented strategy. Penicillin and clindamycin. Non-GBS 2 : All 3 : <48 hours in blood, CSF or other tissue. 1.11 (0.76-1.57) 2 1.25 (0.90-1.74) 3 1.16 (0.83-1.60) 2 1.77 (1.36-2.30) 3 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint pia et al. 2007 Retrospective cohort study Hi stori cal Chile High University hospital IAP to: i) carriers of GBS colonisation at 35-37 weeks' gestation, ii) previous infant with invasive GBS disease, iii) GBS bacteriuria, and iii) if carrier state unknown, presence of PTL, PROM and fever. NI. GBS 1 : Non-GBS 2 : All 3 : <72 hours in blood. 1.36 (0.54-2.79) 1 1.16 (0.52-2.58) 2 2.51 (1.34-4.30) 3 0.11 (0.0028- 1.79) 1 0.89 (0.38-1.75) 2 1.00 (0.52-1.92) 3 wers & Briggs 2002 Prospective cohort study Hi stori cal USA High Non-profit hospital IAP to: i) PTL, PROM and fever, and ii) carriers of inconsistent screening at 28 weeks' gestation or first prenatal visit. IAP to: carriers of GBS colonisation at 35-37-weeks’ gestation, or IAP to: PTL, PROM, fev er and; ii ) carri ers of inconsistent GBS screening at 28 weeks' gestation or first prenatal visit. Until 1998 ampicillin. After 1998, penicillin G. Also use of cefazolin and cephalexin in preterm population. Penicillin allergy, erythromycin and/or clindamycin. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood with clinically symptomatic infant. 1.53 (1.10-2.07) 1 0.67 (0.32-1.41) 2 1.44 (0.81-2.38) 3 0.36 (0.14-0.74) 1 1.02 (0.63-1.58) 2 1.38 (0.91-2.01) 3 0.50 (0.24-0.92) 1 0.80 (0.49-1.31) 2 1.31 (0.89-1.92) 3 llfors et al. 2022 Retrospective observational study Hi stori cal Sweden High All live births in southwest Sweden IAP: fever, PTL, PROM, previous infant with invasive GBS infection, and GBS bacteriuria. Penicillin. GBS: <7 days. 0.73 (no data) 0.34 (no data) et al. 2002 Retrospective population survey Hi stori cal USA High Tertiary care centre, division of university hospital. CDC 1996. Adhere to risk-based guidelines, but prescription left to individual practitioner. AAP 1992, ACOG 1992. AAP 1992: Ampicillin 2 g IV initially, 1-2 g every 4-6 h or penicillin G 5 million IU every 6 h. Penicillin a llergy, clindamycin or erythromycin. Also ACOG 1992 and CDC 1996. GBS: <7 days in blood or CSF. 1.5 (no data) 0.29 (no data) 0.67 (no data) den Hoogen et al. Retrospective cohort study Hi stori cal Netherlands High University hospital leve l 3 NICU unit Dutch guidelines 1999. Dutch guidelines 1999. Non-GBS 2 : All 3 : <48 hours in blood and clinical signs of infection. 0.28 (0.23-0.34) 2 0.54 (0.46-0.62) 3 0.10 (0.061-0.18) 2 0.23 (0.16-0.33) 3 Dyke et al. 2009 Retrospective cohort study Hi stori cal USA High Active Bacterial Core surveillance system 10 US states Any documented colonisation prenatally or at admission performed 2 days or more before delivery, IAP to carriers of GBS colonisation. Schrag et al. 2002: IAP to: i) carriers of GBS culture at least 2 days before delivery, and ii) all pregnant women without documentation of test for GBS with foll owing risk-factors: PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria. Penicillin, ampicillin, cefazolin, clindamycin or vancomycin. GBS: <7 days in normally sterile site. 0.31 (0.27-0.35) 0.50 (0.44-0.55) rgani et al. 2002 Retrospective cohort study Hi stori cal Italy High Tertiary referral centre IAP to: PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria. IAP to: i) carriers of rectovaginal GBS culture at 26-28 and 35-37 weeks’ gestation, and ii) PTL, PROM, fever, GBS bacteriuria, previous infant with GBS infection. Ampicillin 2 g IV initially and 1 g every 4 h. Penicillin allergy, erythromycin 500 mg every 6 h. GBS 1 : Non-GBS 2 : All 3 : <7 days in blood, CSF, auricular or pharyngeal culture with at least two inflammatory indices. 0.93 (0.40-1.84) 1 1.28 (0.71-2.32) 2 2.22 (1.33-3.46) 3 0.78 (0.34-1.53) 1 0.87 (0.40-1.66) 2 1.65 (0.96-2.64) 3 0.44 (0.16-0.95) 1 0.65 (0.34-1.26) 2 1.09 (0.66-1.81) 3 cker et al. 2019 Prospective surveillance study Hi stori cal Ge rmany High German Paediatric Surveillance Unit/ Survey of Rare Diseases and Robert Koch Institute IAP to: i) carriers of rectovaginal GBS culture at 35-37 weeks' gestation, and ii) if carrier state unknown, presence of risk-factors. IAP to 2 strategies: i) carriers of rectovaginal culture at 35-37 weeks’ gestation, or ii) PTL, PROM, fever, previous infant with GBS infection, and GBS bacteriuria. NI. GBS: <7 days in blood or CSF. 0.069 (0.055- 0.084) 0.14 (0.12-0.16) cesoy et al. 2004 Prospective, quasi- experimental study Concurrent Turkey High-Middl e Antenatal clinic ( in/i3 and out/i3 patient) IAP to: i) carriers of rectovaginal GBS culture at 35-37 weeks' gestation, and ii) if unknown carrier state, presence of risk-factors. CDC 1996. Ampicillin 2 g IV initially and 1 g every 4 h. GBS: <72 hours in blood. 3.33 (0.69-9.71) 5.00 (0.13-27.54) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint PRSIMA flow diagram Id ent ific ati on

from other sources (n = 7) Citation searching (n = 6) Grey literature (n = 1) Studies screened (n = 6293) Studies sought for retrieval (n = 669) Studies assessed for eligibility (n = 669)

removed (n = 327) Duplicates identified manually (n = 110) Duplicates identified by Covidence (n = 217) Marked as ineligible by automation tools (n = 0) Other reasons (n = 0) Studies excluded (n = 5624) Studies not retrieved (n = 0) Studies excluded (n = 597) Wrong/no comparator (n = 334) Wrong/no outcome data (n = 65) Wrong article type (e.g. conference abstract, guidelines or model analyses and no actual data) (n = 112) Cost-effectiveness (n=30) Wrong study design (n = 26) Full text not available (n = 27) Data published more extensive than other publication (n=2) In clu de d Studies included in review (n = 72) Sc ree ni ng Studies from databases/registers (n = 6613) MEDLINE (n = 3661) EMBASE (n = 2227) Web of Science (725) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted June 17, 2024. ; https://doi.org/10.1101/2024.06.17.24309017doi: medRxiv preprint