Early-onset sepsis (EOS) is a leading cause of neonatal death.1 Group B streptococcus (GBS) is the leading pathogen of EOS, accounting for approximately one-third of all cases.2,3 In 1996, the Centers for Disease Control and Prevention of the United States implemented a risk-based strategy to determine the candidates of intrapartum antibiotics prophylaxis (IAP) for the prevention of GBS-EOS4 and common risk factors included delivery at <37 weeks of gestation, rupture of the membranes >18 hours duration, intrapartum temperature >38.0°C, GBS bacteriuria during this pregnancy, and previous infant with invasive GBS disease. This strategy was revised to a screening-based strategy in 2002, known as GBS screening by vaginal or rectovaginal microbiologic culture or molecular tests at 35–37 weeks, which is still in use today.4 This change was made given that the screening-based strategy may more accurately identify the population for IAP and therefore increase compliance, compared with the risk-based strategy.1,5 The Royal College of Obstetricians and Gynaeologists Guideline of Britain, however, still recommends a risk-based strategy, considering that the difference between the 2 prophylaxis strategies may not be clinically significant when the incidence is below 1 case per 1000 live births.6
Although there have been variable policies in the application of the 2 strategies, the incidence of GBS-EOS, since the introduction of IAP, has declined drastically.2,7 Growing concerns, however, have been raised over the antibiotic resistance in the community,8–10 and several studies have shown a suggestive trend towards increased risk of neonatal sepsis with Gram-negative bacteria (such as Escherichia coli) and first-line and second-line antibiotic-resistant bacteria, especially among very low birth weight (VLBW) infants.4,11–13 Since E. coli, the second cause of EOS, accounts for about 25% of all cases with high mortality, it would be an issue of concern if antibiotic-resistant E. coli emerged to a large scale, especially β-lactam-resistant E. coli. But whether the incidence of antibiotic resistance EOS differs between the 2 strategies remains undetermined because of the modest statistical power of available studies in the literature.
In 2011, Taminato et al14 conducted a systematic review and meta-analysis of the effectiveness of screening-based versus risk-based strategy. Then, Kurz et al15 conducted an updated systematic review and meta-analysis 4 years later. Taminato et al14 compared the incidence of GBS-EOS among participants under screening-based strategy, risk-based strategy, and no strategy, and Kurz et al15 compared the incidence of GBS-EOS between screening-based and risk-based strategy. Both reviews only include studies before 2007, and the outcome measures only include GBS-EOS. Several studies have been published thereafter, and evidence beyond GBS-EOS has become available, including the incidence of E. coli-EOS and antibiotic-resistant bacteria-EOS.16,17 In this systematic review and meta-analysis, we aimed to provide updated and more comprehensive information regarding the prophylactic effects of the 2 strategies on the incidence of GBS-EOS. We also aimed to examine the impacts of the 2 strategies on other outcomes like non-GBS-EOS including E. coli-EOS and ampicillin resistant E. coli-EOS. This systematic review and meta-analysis was conducted after the reporting guidelines of the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols 2015.18
Since the risk-based strategy was introduced in 1996, we searched for articles published between January 1, 1996, and December 31, 2018, from PubMed, Embase, Web of Science, and The Cochrane Central Register of Controlled Trials. The search was conducted by using the combination of text words (newborn, EOS, antibiotic, IAP, risk-based, screening-based, and antibiotic resistant) and the expansion terms for newborn and EOS, and the language was limited to English (see List, Supplemental Digital Content 1, http://links.lww.com/INF/D900). We also manually searched the studies included by previous systematic reviews and meta-analyses.14,15
Eligibility Criteria and Study Selection
Eligible studies should be original research articles or correspondences containing original data; use an acceptable design (ie, randomized controlled trials, prospective cohort studies, retrospective cohort studies, or ambispective cohort studies); involve both risk-based and screening-based strategies; include the number of live births or mothers; and contain at least one of the following outcome measures: the number of live births infected with EOS, GBS-EOS, non-GBS-EOS, E. coli-EOS, β-lactam-resistant EOS, antiampicillin E. coli-EOS, and antierythromycin GBS-EOS. The risk-based strategy refers to the method of IAP based on prenatal risk factors (ie, delivery at <37 weeks of gestation, rupture of the membranes >18 hours duration, intrapartum temperature >38.0°C, GBS bacteriuria during this pregnancy, previous infant with invasive GBS disease, etc.) that may increase the risk of EOS, and the screening-based strategy refers to the method of IAP when observing GBS colonization by using either molecular tests (ie, polymerase chain reaction testing) or microbiologic methods [ie, detecting pathogen colonization by using Columbia colistin-nalidixic acid agar plate and selective medium inoculated with sample from vaginal or vaginal-rectal swabs in the third trimester (≥28 weeks of gestation)]. EOS refers to sepsis determined by positive blood, cerebrospinal fluid, or other sterile fluids culture, which should be defined as occurring within the first 72 hours or 7 days after birth. If more than one publication was identified for the same study population, only the one with the largest sample size was retained. Studies were excluded if there were (1) no comparison between the 2 strategies (ie, only involving risk-based or screening-based strategy), (2) no data on the number or incidence of outcomes of interest or (3) antibiotic application to newborns but not to their mother. Moreover, case series, case reports, abstracts, editorials, letters and opinion containing no original data, algorithmic model and animal experiments were also excluded. Literature search and study selection were conducted independently by 2 reviewers (D.W. and Q.L.), and discrepancies were resolved by discussion with a third reviewer (H.L. or J.L.).
Evaluation of the Study Quality
The quality of the included studies was critically and independently assessed by 2 reviewers (D.W. and Q.L.) based on the Newcastle-Ottawa Scale (NOS).19 Any disagreements regarding the assessments were resolved by a consensus discussion between the 2 reviewers or with a third reviewer (H.L. or J.L.). We defined a NOS score of 4 or lower as low quality and a score of 5 or higher as high quality; all studies were ultimately included in the meta-analysis.
Two reviewers (D.W. and Q.L.) independently extracted the following information from the included studies: the name of the first author, publication year, study design, study location, number of neonates and mothers, key characteristics of study participants (eg, the distribution of gestational age at delivery, birth weight, ethnicity, incidence of chorioamnionitis, incidence of premature rupture of membranes, and cesarean delivery rate) and all the outcomes of interest as well as the specific number of EOS cases.
To provide an estimate of the comparative effects of the 2 strategies, we calculated the pooled relative risks (RRs) by using random effects model with the Mantel–Haenszel method for all the outcomes of interest. The statistical heterogeneity across individual studies was qualitatively assessed by using Cochrane Q test (P < 0.10 indicates presence of heterogeneity) and quantitatively assessed by using the I2 statistic.20 We examined the presence of publication bias through both visual inspection of the funnel plots and the Egger’s linear regression test (P < 0.05 indicates significance).
In addition to the main analysis, we performed sensitivity analyses to examine the robustness of the pooled results to the study carrying the greatest weight. Besides, we performed meta-regression analyses21 to explore whether the pooled results differed across levels of key characteristics of study participants (ie, the rate of preterm birth and VLBW) as well as the time when the study was undertaken.
We used Endnote, version X9 (ISI ResearchSoft, Carlsbad, CA), for the management of literature, and used R software, version 2.10.0 (R Foundation for Statistical Computing, Vienna, Austria), for all the statistical analyses.
Study Selection and Quality Assessment
We identified 1867, 2359, 2863, and 70 publications from PubMed, Embase, Web of Science and The Cochrane Central Register of Controlled Trials, respectively, and 2 additional studies from manual search of the reference list of previous systematic reviews,14,15 resulting in a total of 3486 nonduplicate records (Fig. 1). Of these nonduplicate records, the full texts of 73 potentially relevant publications were retrieved for further evaluation (see Table, Supplemental Digital Content 2, http://links.lww.com/INF/D901), and 18 studies met the inclusion criteria. Of these 18 studies, 3 had a NOS score of 7,5,22,23 4 scored 6 points,24–27 4 scored 5 points16,17,28,29 and 7 scored 4 points.30–36 According to the prespecified rules, the 7 studies scored 4 points were considered as low quality, primarily because they did not report baseline data. Table 1 shows the detailed information of the 18 studies included in the meta-analysis, comprising 4 prospective cohort studies (3 used a historical control and 1 parallel control) and 14 retrospective cohort studies (10 used historical control and 4 parallel control).
Total EOS was used as an outcome measure in 4 retrospective cohort studies,16,17,32,33 involving a total of 187,994 neonates (127,754 from screening-based group and 60,240 from risk-based group). The total number of newborns with EOS was 524, including 300 from the screening-based group and 224 from the risk-based group. The pooled analysis showed that the incidence of total EOS for screening-based strategy was significantly lower than that for risk-based strategy [RR = 0.78; 95% confidence interval (CI): 0.62–0.98; I2 =38%] (Table 2).
A total of 18 studies compared the incidence of GBS-EOS between the 2 strategies, including 4 prospective cohort studies23,25,26,29 and 14 retrospective cohort studies.5,16,17,22–24,27,28,30,32–36 There were totally 604,869 neonates from the 18 studies, including 327,213 from the screening-based group and 277,656 from the risk-based group, and the corresponding number of newborns with GBS-EOS was 268 and 523, respectively. Of note, the number of cases for studies conducted by Abdelmaaboud and Mohammed27 and Schrag et al5 was calculated based on the number of newborns, the incidence of GBS-EOS and the RR of GBS-EOS for screening-based versus risk-based group reported by the authors. Besides, in the studies conducted by Eisenberg et al34 and Reisner et al,29 we used the number of women to calculate the value of RR because of the unavailable number of neonates. The pooled analysis showed that the incidence of GBS-EOS for screening-based strategy was significantly lower than that for risk-based strategy (RR = 0.45; 95% CI: 0.34–0.59; I2 = 45%) (Fig. 2). In subgroup analyses according to NOS score, the RR showed lower incidence of GBS-EOS in screening-based group when the analysis was restricted to high-quality studies (RR = 0.44, 95% CI: 0.32–0.62; I2 = 46%) (Fig. 2). The RR for low score studies showed similar results (RR = 0.45; 95% CI: 0.28–0.75; I2 = 51%) (Fig. 2). Further sensitivity analyses showed that the pooled results remained almost unchanged when excluding the study5 carrying the greatest weight (RR = 0.43; 95% CI: 0.31–0.60; I2 = 48%) (see Figure, Supplemental Digital Content 3, http://links.lww.com/INF/D902). Both visual inspection of the funnel plot and Egger’s test (P = 0.188) (Fig. 3) indicated no obvious publication bias. Further meta regression analyses revealed that there was no significant difference in the RR of GBS-EOS for screening-based versus risk-based strategy over time and across populations with different rates of preterm birth and VLBW (see Figures, Supplemental Digital Content 4a–c, http://links.lww.com/INF/D903).
Non-GBS-EOS was used as an outcome measure in 7 studies, including 3 prospective cohort studies23,25,29 and 4 retrospective cohort studies.17,32,33,36 There were totally 280,896 neonates, including 161,379 in screening-based group and 119,517 in risk-based group, and the corresponding number of newborns with non-GBS-EOS was 305 and 272, respectively. In the study conducted by Reisner et al,29 we used the number of women to calculated the value of RR because of the unavailable number of neonates. Pooled analysis indicated no significant difference in the incidence of non-GBS-EOS for screening-based strategy compared with risk-based strategy (RR = 0.91; 95% CI: 0.74–1.11; I2 = 18%) (Table 2).
Four retrospective cohort studies16,17,32,33 reported the incidence of E. coli-EOS, involving 127,754 neonates from screening-based group and 60,240 from risk-based group, and the corresponding number of E. coli-EOS cases was 86 and 52, respectively. The pooled analysis indicated no significant difference of E. coli-EOS between risk-based strategy and screening-based strategy (RR = 0.98, 95% CI: 0.69–1.40; I2 = 0%) (Table 2).
Ampicillin-resistant E. coli-EOS
Three retrospective cohort studies16,17,32 reported the incidence of ampicillin resistant E. coli-EOS, involving 118,854 neonates from screening-based group and 51,953 from risk-based group, and the corresponding number of cases was 45 and 22, respectively. The pooled analysis showed that the incidence of ampicillin resistant E. coli-EOS was higher in screening-based group compared with risk-based group, but the difference did not reach statistical significance (RR = 1.28; 95% CI: 0.74–2.21; I2 = 0%) (Table 2).
In this meta-analysis, we present updated evidence on the prophylactic effects of GBS-EOS for screening-based versus risk-based strategy as well as their impacts on non-GBS including ampicillin resistant E.coli-EOS. We found that the incidence of GBS-EOS and total EOS was significantly lower under screening-based strategy compared with risk-based strategy, and there was no significant difference in the incidence of non-GBS-EOS, E. coli-EOS, and ampicillin resistant E. coli-EOS between the 2 strategies.
We identified totally 18 studies on GBS-EOS that met prespecified inclusion criteria of meta-analysis and had moderate statistical heterogeneity. Similar pooled results were observed in several sets of sensitivity analyses, including a confirmatory analysis by using the fixed effect model (see Table, Supplemental Digital Content 5, http://links.lww.com/INF/D905). The pooled RR of these 18 studies was similar to 2 previous meta-analyses based on studies published before 2007,14,15 suggesting that the relative effectiveness of the 2 strategies did not change over time. In subgroup analyses, the RR between high and-low quality studies was comparable. In meta-regression analysis, we confirmed that the magnitude of the RR for screening-based versus risk-based strategy did not change with the time when the study was undertaken as well as the rate of preterm delivery and that of VLBW neonates.
Besides GBS-EOS, we also conducted pooled analyses for total EOS and non-GBS-EOS. The point estimate of the pooled RR for total EOS was 0.78, intermediate between that of GBS-EOS (0.45) and non-GBS-EOS (0.91). For ampicillin resistant E. coli-EOS, a subgroup of non-GBS-EOS, we observed a tendency of increasing disease rate for screening-based strategy compared with risk-based strategy, but the difference did not reach statistical significance. Of note, some countries chose penicillin in their screening-based strategy because of its narrower spectrum with an anticipation of causing less β-lactam antibiotic-resistant organisms33; however, a clinical trial found that penicillin and ampicillin administered intravenously intrapartum prophylaxis had no difference with respect to the presence of ampicillin-resistant Gram-negative organisms on postpartum vaginal-perineal culture.37 Because the screening-based strategy was associated with increased use of antibiotic prophylaxis,38 the current findings deserve further investigation.
The present meta-analysis has several limitations. First, although several major databases were searched for potentially eligible studies, we may have missed studies that were not collected in the searched databases, especially those published in languages other than English. Most studies included in the meta-analysis were from Europe and United States, where the main pathogen of EOS in neonates is GBS,3,39 a pathogen less common in many developing countries.40 Therefore, the generalization of the study findings should be made with caution. Second, it should be noted that most of the included studies used a retrospective design without parallel control and their quality was at a moderate to high level. The prevalence of the microbial flora in the community level may change over time,41 indicating the importance of using a parallel control to draw more robust conclusions. Third, for the majority of studies the RR was derived based on the number of neonates, but for 2 studies that did not provide the number of neonates,42,43 we calculated the RR using the number of mothers as an approximation of the number of neonates. However, this may have little influence on the pooled results, because these 2 numbers are expected to be very similar. Fourth, the studies included in the meta-analysis were conducted in settings with inherent clinical and practical heterogeneity (eg, timing of swabs in culture-based screening, use of vaginal vs vaginal-rectal swabs, and policies on neonatal antibiotic use), so again generalization of the study conclusion should be made with caution. Fifth, 2 studies5,27 did not report the exact number of the cases, 3 studies22,25,27 did not report all the baseline data as needed and 7 studies30–36 did not provide baseline data; the corresponding information was calculated by using other relevant data. Last, as noted above some countries used penicillin rather than ampicillin for IAP in screening-based strategy,44 which may affect comparisons concerning ampicillin-resistant E. coli-EOS. Despite these limitations, the present meta-analysis synthesized currently available best evidence regarding the 2 major prophylaxis strategies for EOS, which may facilitate the understanding of the updated progress in the field and improve the design of future studies.
In conclusion, the screening-based strategy as proposed in the 1990s was associated with a reduced risk of EOS in the neonates, particularly GBS-EOS, compared with the risk-based strategy. However, our study indicates a possibility of an increased risk of ampicillin resistant E. coli-EOS of the screening-based strategy. It is worthy of noting that although only 1 of the 18 studies included in the meta-analysis used polymerase chain reaction in detecting GBS, molecular tests (eg, polymerase chain reaction testing), in comparison with the traditional microbiologic methods, have been found to have greater throughput, higher efficiency and potentially greater sensitivity.45,46 Further studies are warranted to assess the potential risks as well as cost-benefits of the 2 prophylaxis strategies.
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