CURRENT REVIEW * ACTUALITES

Effectiveness of intrapartum penicillin prophylaxisin preventing early-onset group B streptococcalinfection: results of a meta-analysis

Upton D. Allen,* MB, BS, FRCPC, FAAP; Lissette Navas,t MD; Susan M. King,t MDCM, FRCPC, FAAP

Objective: To determine the effectiveness of intrapartum penicillin prophylaxis in prevent-ing early-onset group B streptococcal (GBS) infection in neonates of women whose birthcanals are colonized by group B streptococci.Data sources: Articles published between 1966 and 1992 identified from MEDLINE,EMBASE, the Science Citation Index and the Oxford Perinatal Database; the bibliographiesof primary studies, textbooks and review articles and published abstracts from major confer-ences and symposia.Data selection: Studies were selected if four criteria were met: (a) the target population wasintrapartum women and neonates, (b) the intervention was penicillin prophylaxis, (c) inva-sive early-onset GBS infection was an outcome measure, and (d) the studies were controlledtrials or cohort studies. Seven primary studies were identified, four of which were random-ized controlled trials.Data extraction: Explicit methodologic criteria were used by two of the authors to assess in-dependently the study quality; one of the reviewers was blind as to author, institution andjournal. The baseline characteristics of the population, intervention and outcome were sum-marized twice and checked for accuracy by two of the authors.Data synthesis: Five of the studies showed a trend toward a beneficial effect of penicillinprophylaxis, and two showed a statistically significant effect. The pooled odds ratio indicateda 30-fold reduction (95% confidence interval 0.0013 to 0.17) in the incidence of early-onsetGBS infection with intrapartum penicillin prophylaxis. Subgroup analyses did not changethese results. The magnitude of improvement observed did not differ between women withprenatal risk factors (premature rupture of the membranes and premature labour) and thosewithout these risk factors.Conclusions: There is accumulative evidence that intrapartum penicillin prophylaxis is ef-fective in preventing early-onset GBS infection. Such therapy is beneficial to women whosebirth canals are colonized with group B streptococci. Further studies are needed to determinethe optimum timing and method of detecting vaginal colonization during pregnancy.

Objectif: Determiner l'efficacite de la penicillino-prophylaxie intra-partum pour prevenirI'apparition precoce d'infection par streptocoque de groupe B (SGB) chez les nouveau-nes defemmes dont la filiere pelvi-genitale abrite des colonies de streptocoques de groupe B.

From *the Division of Infectiouis Diseases, Department of Pediatrics, Children 's Hospital ofEastern Ontario, Ottawa, Ont., and tthe DivisionofInfectious Diseases, Department of Pediatrics, Hospitalfor Sick Children, Toronto, Ont.

Reprint requests to: Dr. Upton D. Allen, Division of Infectious Diseases, Department of Pediatrics, Children s Hospital ofEastern Ontario,401 SmVth Rd., Ottawa, ON KJH 8LI

DECEMBER 1, 1993 CAN MED ASSOC J 1993; 149 (I 1) 1659

Sources de donnees: Articles publies entre 1966 et 1992, identifies 'a partir de MEDLINE,d'EMBASE, du Science Citation Index et de l'Oxford Perinatal Database; des bibliographiesd'detudes primaires, des manuels universitaires et des rapports de synthese; et des resumespublies de grandes conferences et symposiums.Selection d'etudes : Les etudes selectionnees repondaient 'a quatre criteres: (a) la populationcible etait constituee de femmes en intra-partum et de nouveau-nes, (b) la penicillino-prophy-laxie servait d'intervention, (c) l'apparition precoce d'une infection invasive par SGB etaitune mesure des re'sultats et (d) les etudes constituaient des essais controles ou des etudes decohorte. On a identifie sept etudes primaires; quatre d'entre elles etaient des essais ran-domises contr6les.Extraction de donnees: Deux des auteurs ont utilise des criteres methodologiques formelspour evaluer de fa,on independante la qualite de l'etude; l'un des evaluateurs a travaille al'insu de l'auteur, de l'institution et du journal. Deux des auteurs ont resume 'a deux repriseset verifie la precision des caracteristiques de base de la population, de l'intervention et des re-sultats.Synthese des donnees: Cinq des etudes indiquaient que la penicillino-prophylaxie tendait 'aavoir un effet benefique et deux demontraient un effet significatif sur le plan statistique. Lerisque relatif commun indiquait une reduction par 30 (intervalle de confiance de 95 % entre0,0013 et 0,17) de l'incidence de l'apparition precoce d'infection par SGB avec penicillino-prophylaxie intra-partum. Les analyses des sous-groupes n'ont pas modifie ces resultats.L'ampleur des ameliorations observees ne differait pas entre les femmes comportant des fac-teurs de risque prenataux (rupture des membranes et travail prematures) et celles ne compor-tant pas ces facteurs de risque.Conclusions: Les preuves s'accumulent pour demontrer que la penicillino-prophylaxieintra-partum est efficace pour prevenir l'apparition precoce de l'infection par SGB. Cettetherapie est benefique pour les femmes dont la filiere pelvi-genitale abrite des colonies destreptocoques de groupe B. Il faudra realiser d'autres etudes pour determiner le moment opti-mal et la methode de detection des colonies vaginales en cours de grossesse.

G roup B streptococci remain a major cause of se-rious bacterial infection in newborns.' Diseaseof early onset (less than 7 days after birth) is

more frequently seen than disease of late onset (7 daysor later) and is associated with a higher death rate (over50% v. 25%).2 Although an improved outcome has beenreported in recent years3 this was not confirmed whenthe death rates were corrected for maturity and birthweight.4

Early-onset group B streptococcal (GBS) infectionis thought to occur before or during birth.5 Various ap-proaches have been aimed at reducing or eliminatingvertical transmission between mother and child; one ofthese involves the use of intrapartum penicillin prophyl-axis in women whose birth canals are colonized bygroup B streptococci.

Many clinicians are not convinced by the strengthof the evidence supporting intrapartum chemoprophyl-axis. In addition, there is disagreement on when screen-ing for GBS infection should be done and whether se-lective (according to prenatal risk factors) or non-selective chemoprophylaxis should be used. As a firststep toward resolving some of these issues we usedmeta-analysis to address the effectiveness of intra-partum penicillin prophylaxis in preventing early-onsetGBS infection.

Meta-analysis is characterized by quantitative aswell as qualitative components and is especially usefulwhen results from several studies differ regarding thesize or direction of the effect or when samples are indi-

vidually too small to detect statistically significant dif-ferences.6

Methods

Identification of existing meta-analyses

An extensive literature search was done to detectexisting review articles. Recent articles (published from1985 to 1992) that reached a conclusion about the effec-tiveness of penicillin in the chemoprophylaxis of perina-tal GBS infection were identified'15,-8 and criticallyappraised according to established guidelines'9 before weproceeded further.

Identification ofprimary studies

MEDLINE was searched to identify primary stud-ies published from 1966 to 1992 on GBS infection. Twolibrarians and one clinician made three independentsearches using the following MeSH headings (medicalsubject headings of the National Library of Medicine):"Streptococcus agalactiae" and "penicillin G" and ("in-fant, newborn" or "pregnancy" or "prenatal care" or"perinatology"). "Pregnancy" and "penicillin G" were"exploded" to enable a search of the subheadings underthese broad headings. The term "Streptococcus agalac-tiae" was not used to search for articles published before1972; thus, for the years 1966 to 1972 "streptococcus"was truncated and used as a text word.

1660 CAN MED ASSOC J 1993; 149 (11) LE ler DECEMBRE 1993

Three well-known and frequently quoted articles2"22were used in a search of the Science Citation Index toidentify all other articles citing them. In addition, theOxford Perinatal Database and the Excerpta Medicadatabase (EMBASE) were searched. One of us (U.D.A.)conducted a thorough manual search of the bibliogra-phies of the selected studies for other pertinent articles.

As well as searching the Oxford Perinatal Databasefor studies in progress we made a systematic effort toidentify unpublished studies by writing to several ex-perts in the field. Recent abstracts (published from 1985to 1992) from the Interscience Conference on Antimi-crobial Agents and Chemotherapy were reviewed. Pub-lished abstracts from several other major conferencesand symposia were also reviewed.

After the search one of us (U.D.A.) selected articlesaccording to whether the wording of the titles suggestedthat the studies addressed prophylaxis against GBS in-fection. If the titles were ambiguous the abstracts werereviewed for relevance. The other two of us were eachgiven a sample of 35 articles to determine overall agree-ment on which ones to retrieve; we two were blind to theauthors and journals from which the articles came.

Study selection

Studies were selected if they met all of the follow-ing four criteria: (a) the target population was intra-partum women and neonates, (b) the intervention waspenicillin prophylaxis, (c) invasive early-onset GBS in-fection was an outcome measure, and (d) the studieswere controlled trials or cohort studies. Abstracts wereconsidered only if the data were available to enablemeaningful study evaluation and statistical analysis. Alog of rejected articles was kept, and those retrieved butrejected by a first reviewer were subsequently reviewedby another. Disagreement was resolved by consensus. Asample of 10 eligible and ineligible studies were re-viewed by all three of us to test agreement. Two of uswere blind to the authors and journals from which the ar-ticles came.

Study evaluation and data extraction

The methodologic validity of the studies was as-sessed according to specific criteria arrived at by con-sensus; the criteria for prospective studies are shownin Table 1. Studies that used retrospective controls hada maximum possible score of 10 on the basis of fivecriteria: case definition, baseline comparison ofgroups, method of outcome assessment, method usedto determine therapy and completeness of outcome as-sessment.

Weighting scores were applied such that studieswith a methodologically superior design had a poten-tially higher total rating than ones with an inferiordesign. In addition, criteria that were thought to be

relatively more important than others were weightedmore highly. If there was insufficient information in thearticles to determine whether specific criteria were sat-isfied, such criteria were regarded as not being satis-fied.

Methodologic validity was assessed independentlyby two of us, one of whom was blind to the authors, in-stitutions and journals. Interobserver agreement wasmeasured, and disagreement was resolved by consensus.

Data were extracted twice with a specified protocol;the second extraction was done 1 week after the first,with a fresh data extraction form. The data were then re-viewed for accuracy by two of us.

Analytic techniques

The level of agreement between reviewers was de-termined by a measurement of percentage agreement anda calculation of the kappa (K) statistic.23 The most impor-tant characteristics of the research design, patient popu-lation(s), intervention and outcome were identified andsummarized. The population group was intrapartumwomen; in the context of the risk of their having an in-fant with GBS infection the findings of the studies wereanalysed by a calculation of risk reduction and odds ra-tios (ORs). The results of different studies were com-bined if there were complete data and non-zero marginaltotals in 2 x 2 tables and if the group receiving penicillincomprised intrapartum women only.

The analyses of 2 x 2 tables were done with an iter-ative computer program (Jim Julian, McMaster Univer-sity, Hamilton, Ont.). The weighted Mantel-Haenszel

Crteron Maximum score

AAllocation methodRandomized (R) 2.0Quasirandomized 1.5Nonrandomized (NR) 0.5

Baseline comparison of groupsData documented 2.0Mertioned, but data not provided 1.5Not mentioned 0.5

Diagnosftic cteriaExplicit 2.0Not explicit 0.5

Blind outcome assessmentYes 2.0No 0.5

% of patients followed up. 90 2.0> 80-< 90 1.5S 80 or unknown 0.5

Blind administration of drugYes 2.0No 0.5

Total 12.0

CAN MED ASSOC J 1993; 149 (11) 1661DECEMBER 1, 1993

estimate was used to determine the overall OR;24 this esti-mate is not affected by zero cell entries. Cornfield'smethod,25 which is an approximation to the exact method,was used to determine confidence intervals (CIs).

To help formulate inferences from our study we

analysed the data on colonization rates between treat-ment and control groups by calculating p values.

Sensitivity analyses

To conduct subgroup analyses studies were pooledaccording to study design: prospective treatment andcontrol groups only, and randomized studies only.

The "Fail Safe N" was determined for the pooledOR according to the method described by Rosenthal.26 Inthe event of a publication bias whereby studies show-ing a null result were not published the "Fail Safe N"represents the number of unpublished studies with nullresults that would be needed to overturn the results ofthis meta-analysis.26

The effect of varying the choice of statisticalmethod for the estimation of the pooled OR was exam-

ined: the Mantel-Haenszel estimate was comparedwith the crude pooled OR and the asymptotic maxi-mum likelihood estimate, the latter being an approxi-mation to the exact conditional maximum likelihoodestimate.

A regression analysis was performed in which thevalidity criteria were weighted and the respectivescores related to outcome (ORs) in order to establishwhether there was a relation between study quality andoutcome.

Results

Seven relevant studies were obtained from six ref-erences2027-3' (one reference20 including two studies).There were no abstracts and no unpublished studies.Four additional studies addressing intrapartum penicillinprophylaxis satisfied three of the four inclusion criteriaand were rejected"because (a) even though colonizationdata were reported, invasive disease was not specificallyaddressed,3233 (b) intrapartum screening was done, no

prophylaxis was given, but symptomatic infants were

treated34 and (c) prophylaxis was antepartum and intra-partum.35

The reject log included studies that were even lessacceptable.2'22,3" These dealt with penicillin prophylaxisfor GBS infection but met two or fewer inclusion cri-teria.

There was excellent interobserver agreement at dif-ferent stages of the study selection and validity assess-

ment. The lowest level of agreement between any pair ofobservers was 80%, and the K values were generally inthe region of 0.8 to 0.9. The validity scores ranged from6.0 to 8.5 (maximum score possible 12) (Table 1).

Primary studies

The results are summarized in Table 2. There were

five studies in which both the treatment and controlgroups were followed prospectively;2029-3' in two the dataon control groups were obtained retrospectively.2728 Fourstudies were randomized controlled trials.2029-3' Five

studies demonstrated a trend toward a beneficial effect

Validityscore (and

Design maximum)Selection Dctiboncreria method

R 8.5112 .Colonized,PROM, PL

NR 6.0/12 Colonized,PROM, PL

NR 6.0/10 Colonized

NR 7.25/10 Heavy and

nizationF,. L-

R 8.5/12 Heavyandlight co.nization

R 7.0/12 Coloni

R 8.0/12 Heavy qolo

.izt. ;o

*C-

C

C

Group; no. ofwomen (and no.of infants withGBS infection) ORt

(andDrug Control 95% Cl)

83 (0) 77 (5) 0.0(0-1.53)

80 (0) 228 (7) 0.0

* ~~~(03.03)57 (O) 136 (9) 0-.0

_ (0-1.82)

ue.

(

'LS_ _ 4. i.:

. ' ;

-0.25

0.11

RAT 36 (0) 48 (13) 0.0 0.0027

RAT :135 (0) 128 (3) 0.0 0.28

R as .11. p..C 57 (0) 84 (3)( 0.'i;- , -o

RAT 88 (1) 111 (10) 0.12i k; 0i04.@~S-w ~~~~~~(0.01-0.91)- -;aal

1662 CAN MED ASSOC J 1993; 149 (11)

St edy-

BoyerBt at3

Aliardiceet aPB

Moraleset' '17

etaP

Matto,ras

Tppurinent'ap'.

.*Dat.on pait, prevous 08GBnon, nmtemna pyliad aei ee tion idi Tfo I iwas _fpcurnanted In. rerelces2026 and 28. In 1a but he ub inen dte4 nis amnlollib6 n th lasktstudyp as penicdn Was grien and the ri i oe Ws In i

ture qf* terine n ,P; = peatibure labow, C = ure,RT *d aClige lstR odrati =confidein;tevtThecommon OR was 0.03 (95% cf 0.0013 to 0.17); > 0.5 wa tocawth Oto g an OR of slighly more than 0.

LE ler DtCEMBRE 1993

of penicillin, as indicated by the ORs,20'27"29-3' and twostudies demonstrated a statistically significant effect, inthat the upper limit of the 95% CI was less than 1 (Table2).28,31

An estimate of the overall effectiveness of intra-partum penicillin prophylaxis was obtained from a pool-ing of the ORs of all seven studies: the overall OR was0.03 (95% CI 0.0013 to 0.17). Thus, such prophylaxisresulted in an overall 30-fold reduction in the incidenceof early-onset GBS infection, a reduction that could beas small as 6-fold or as large as 800-fold according tothe 95% CI.

The significant association across strata (p <0.0001) indicated that the risk of GBS infection de-pended on the treatment group. The test of homogeneitydid not reject the null hypothesis of homogeneity acrossstudies (p = 0.77); thus, the studies had enough similari-ties to justify pooling their results.

Results ofsensitivity analyses

The first subgroup analysis was of the data from thetotally prospective studies;20'29-31 the common OR was0.04 (95% CI 0.002 to 0.30), the test of association re-sulted in a p value of less than 0.0001 and the test of ho-mogeneity in a p value of 0.81. The second analysis, ofthe data from the randomized study from reference 20and the three other randomized studies,29-31 gave an over-all OR of 0.05 (95% CI 0.002 to 0.35); this confirmedthe benefit of penicillin.

The "Fail Safe N" for the overall result was 47.This high number suggests that unpublished studies withnull results would have been unlikely to overturn the re-sults of the meta-analysis.

The effect of varying the choice of statisticalmethod for the estimation of pooled OR was examined.The Mantel-Haenszel estimate was similar to the crudepooled OR and the asymptotic maximum likelihood esti-mate (OR = 0.03).

There was no indication that the validity scoreswere systematically related to outcome (ORs) (p = 0.87);the studies with the lowest ORs did not also have thelowest validity scores.

Magnitude of risk reduction relative to other riskfactors

In three of the studies premature rupture of themembranes (PROM) was an entry criterion,20'28 whereasin the remaining four studies patients with and withoutPROM were selected.27'29 31 In three studies patientswhose labour began before 37 weeks' gestation werealso enrolled.20'28 A regression analysis conducted to testthe null hypothesis that the magnitude of the risk reduc-tion when intrapartum penicillin is given prophylacti-cally would not differ among women with and thosewithout PROM or premature labour indicated that the

null hypothesis was not rejected (p = 0.21). Thus, al-though failure to reject the null hypothesis does not al-ways imply that it is correct, our result suggests thatwomen without PROM or premature labour also benefitfrom intrapartum penicillin prophylaxis.

Heavy versus light colonization

In four studies culture was used20'27'30 and in threestudies a rapid antigen detection system was used28 -' toidentify women infected with group B streptococci. Thelatter strategy enabled the identification of women withlight versus heavy colonization. In one study in whichthe rapid antigen test was used, only women with heavycolonization were included,3' whereas in the remainingtwo studies both heavily and lightly colonized womenwere involved. In the randomized trial by Morales, Limand Walsh29 all three of the untreated term women whosenewborns had GBS infection had heavy colonization. Inthe subsequent trial by Morales and Lim28 the risk ofneonatal sepsis among the infants of untreated pretermwomen with heavy colonization was 64%, as comparedwith 16% among those of women with light coloniza-tion.

Discussion

Our analyses show convincing evidence that intra-partum penicillin prophylaxis in women whose birthcanals are colonized by group B streptococci is effectivein reducing the incidence of early-onset GBS infectionin their infants.

The impact of such prophylaxis on late-onset GBSinfection was not specifically addressed. AlthoughMorales and associates29 noted that none of the infantsborn to the 135 women in their treatment group requiredreadmission because of late-onset GBS infection, the ef-fect of intrapartum prophylaxis on late-onset infectionhas not been studied.45

Our findings suggest that women given intrapartumpenicillin prophylactically who have PROM or prema-ture onset of labour benefit from a risk reduction similarto that for women without these risk factors. Thus, intra-partum prophylaxis of all colonized women would bedesirable. However, costs have an important bearing onthe choice of option. Cost-effectiveness was not ad-dressed in this study. In addition, there are concerns thatintrapartum prophylaxis of all colonized women couldlead to increased antimicrobial resistance and adversedrug events.20 Neither of these proved to be an importantproblem in the study by Boyer and Gotoff.20

The issue of heavy versus light colonization is ofinterest. Although in the study by Morales and Lim28 therisk of early-onset GBS infection appeared to be higheramong the offspring of heavily colonized women, therate of infection (16%) among the newborns of lightlycolonized women was still substantial. This suggests that

CAN MED ASSOC J 1993; 149 (11) 1663DECEMBER 1, 1993

the stratification of women into those with heavy andthose with light colonization is not ideal.

Because all of the studies showed at least a benefi-cial trend of penicillin, there is concern about the possi-bility of publication bias. However, we made extensiveefforts to locate unpublished papers, and in any event thehigh "Fail Safe N" makes it unlikely that the results ofthe meta-analysis would be overturned by unpublishedstudies with null results.

The quality of studies in a meta-analysis is impor-tant," but there is no consensus on the most appropriateway to assess quality. Explicit and reproducible criteriawere used in our meta-analysis. The validity scores sug-gested that most of the studies were of satisfactory qual-ity.

The issue of important articles being missed is ofconcern in a meta-analysis, but our comprehensivesearch strategy made this possibility unlikely. The list ofstudies identified was comparable to the key articles inthe bibliography of two recent expert consensus state-ments."447

Our meta-analysis was not affected by selectionbias. The inclusion criteria were explicit and would beeasily accepted by content experts. They were the logicaland obvious criteria to use to answer the study question.The four studies that came close to being accepted didnot address the specific issue of the effect of intrapartumpenicillin prophylaxis on the incidence of early-onsetGBS infection.

Two studies that did not meet our relevance criteria,because they addressed colonization rather than invasivedisease in newborns, supported our results:3233 Yow andassociates32 demonstrated that intrapartum ampicillinprophylaxis interrupted vertical transmission of groupB streptococci to newborns; a similar finding was re-ported by Easmon and collaborators.33 Also, in our meta-analysis all of the studies with analysable colonizationdata2027-29 showed a statistically significant difference be-tween the treatment and control groups (p < 0.05).

Although this study was concerned primarily withintrapartum penicillin prophylaxis, antepartum prophyl-axis is generally regarded as not likely being effectiveand therefore would not be preferred.27'28'35 With respectto postnatal prophylaxis the strength of the evidencerests with two studies that had conflicting findings,which were related to differences in eligibility cri-teria.2'22 Clearly, postnatal prophylaxis would not pre-vent many cases of GBS infection, since newborns oftenhave symptoms of infection at birth.2'

Our findings support the evidence that intrapartumpenicillin prophylaxis prevents early-onset GBS infec-tion when given to women whose birth canals are colo-nized by group B streptococci. The optimum timing andmethod of detecting vaginal colonization were not ad-dressed in this study. However, given the apparent ben-efit of intrapartum chemoprophylaxis and the lack of areliable, rapid diagnostic test it seems appropriate to

identify colonized women in the third trimester beforethe onset of labour. This would facilitate intrapartumchemoprophylaxis in those women who go into prema-ture labour and whose offspring are likely to be at in-creased risk of GBS-related illness and death.

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