SYMPOSIUM: Perinatal GBS: Guidelines worth following

SYMPOSIUM

Perinatal GBS: Guidelines worth following

Moderator: Philip B. Mead,MD, Professor and Chair, Department of Obstetrics and Gynecology, Universityof Vermont College of Medicine, Burlington, VT

Panelists: Anne Schuchat, MD,Chief of the Respiratory Diseases Branch, The Centers for Disease Controland Prevention, Atlanta, GA. Carol J. Baker, MD, Professorof Pediatrics and Microbiology and Immunology, Baylor College of Medicine,Houston, TX

This discussion was held last August at the 1998 AnnualMeeting of the Infectious Diseases Society for Obstetrics and Gynecology(IDSOG), Jackson Hole, WY.

In this symposium, two obstetricians and a pediatricianreflect on more than two years of experience with the CDC guidelines forprevention of perinatal Group B streptococcal disease. They address theeffectiveness of prophylaxis, unforeseen problems with the guidelines, andmore.

The guidelines for prevention of perinatal Group B streptococcal (GBS)disease released by the Centers for Disease Control and Prevention (CDC)in the spring of 1996 representeda hard-won consensus between the obstetricaland pediatric communities on how to prevent the leading cause of neonatalinfection. Before that time, the American Academy of Pediatrics (AAP) andAmerican College of Obstetricians and Gynecologists (ACOG) had recommendeddifferent strategies to identify pregnant women for GBS prophylaxis. TheAAP approach relied on both risk factors and anogenital cultures, whileACOG rejected cultures and recommended deciding who should be treated solelyon the basis of risk factors. The CDC guidelines, which are supported byboth the AAP and ACOG, offer physicians a choice between these two strategies.¹

The following discussion--held more than two years after the revisedguidelines were introduced--provides some insight into which of these twoapproaches is most popular and why, the efficacy of prophylaxis in reducingGBS disease, the practical problems in implementing the guidelines, andan update on vaccination strategies for preventing GBS disease. Participantsin the interchange are experts on GBS. Dr. Anne Schuchat was the primaryauthor of the guidelines, and Dr. Carol Baker, a pediatrician, is knownfor her many years of work on a GBS vaccine. Dr. Baker also was a key figurein developing consensus guidelines. Dr. Mead,an expert on infectious diseases,facilitates the discussion.

Mead: Dr. Schuchat, what disease trends have become apparent since therelease of the CDC's 1996 recommendations on prevention of GBS infectionin newborns?

Schuchat: We actually have seen significant declines in early-onset disease.In some areas of the United States, the decline has been as much as 35%to 50%. Unfortunately, late-onset disease is not declining, and diseasein adults might actually be increasing.

Mead: The CDC guidelines offer physicians two options for the preventionof GBS (Figures 1 and 2). Do physicians show a preference for either option?

Schuchat:Most hospitals in our surveillance areas have adopted a policyusing one of the two recommended approaches. A few hospitals allow theirclinicians to choose their own strategy. The culture-based screening approachappears to be more popular than thesolely risk-based approach, though notby a wide margin.

Baker: The approach using cultures as well as risk factors also seemsto be more popular in the Houston area. This preference may have developedafter that option was adopted two decades ago for research purposes.

Culture-based screening approach

Mead: What trends have you noticed regarding the use of the culture-basedscreening approach?

Schuchat: Clinicians are adhering to our newest recommendation that culturesbe collected at 35 to 37 weeks' gestation. In addition, more vaginal-rectalcultures are being used to find GBS colonization, whereas, in the past,clinicians used cervical cultures or urine tests. However, we are stillconcerned about how laboratories process these samples. While data suggestthat more labs are using selective broth media, almost half of them stilldo not. Improvement in this area is essential to ensure compliance withthe screening approach as described in the guidelines.

Mead: How are data being managed? When the correct cultures are obtainedand laboratory tests performed, are the data always recorded on charts?

Schuchat: This is one compliance issue that we are currently evaluating.We have found that medical records often don't clearly reflect whether womenwere screened prenatally and the results of the screening. Further, somehealth-care providers have reported that they have this information butthat it wasn't noted on the chart. Anecdotal information needs to be documentedwith better studies.

Baker: We find that data management varies among institutions. In hospitalsand practices that use the screening-based approach and want to receiveresults quickly, clinicians have developed protocols to record results withother screening data contained in the obstetric records.

Schuchat: It's more complicated for clinicians who have to send teststo multiple labs because of managed-care directives. One nurse-midwife whois developing a policy for her practice sidestepped the managed care plan'srequirements for specimens by sending all prenatal cultures to the hospitallab. She finds it easier to communicate with its personnel and transferinformation than to send the test outside her facility to multiple labs.

Risk-based approach

Mead: It seems that the issues that have emerged with the screening-basedstrategy are the failure of many labs to use the proper culture media, theproblem of information transfer, and managed-care requirements to use differentlabs, compounding problems of setting up a consistent and efficient system.

What kinds of compliance issues are associated with the risk-based approach?

Schuchat: While all clinicians should be able to recognize risk factorsfor GBS in labor, the chaos of multiple events occurring at once may hindertotal compliance. We know it can be difficult to have a sufficient proportionof preterm women actually receive antibiotics. In cases of women who havefever, there's probably good compliance, but the question of howlong theinfection has been present by the time antibiotics are administered is stilla concern.

Baker: Two risk factors always necessitate action: (1) previous deliveryof an infant with GBS sepsis, and (2) known GBS bacteriuria during the pregnancy.To avoid delay, some obstetricians prepare antibiotic instructions and intrapartumchemoprophylaxis as part of their admission orders for the delivery.

Imminent delivery

Mead: Fleming recently published an interesting paper about compliancewhen risk factors are present in a patient.² As expected, 100%of women with a previously affected child received the prophylaxis, butthe rate decreased to 87% for women with fever, 73% with prolonged ruptureof the membranes, and only 51% with preterm delivery. Clearly, there needsto be more effort in those areas.

One circumstance that can complicate compliance is imminent delivery.A major study on the timing of prophylaxis indicates that it is essentialto recognize the risk of GBS infection earlier than four hours before delivery.³However, this doesn't always happen. Dr. Schuchat, what are your findingsregarding imminent delivery?

Schuchat: There definitely are cases where there just isn't time to intervene.Nevertheless, we were struck by Dr. Nancy Rosenstein's review in 1997 thatshowed most women with GBS had sufficient time in the hospital to get antibiotics.⁴Few cases were difficult to prevent in the group she studied.

Baker: To protect infants affected by imminent delivery, the infant managementalgorithm (Figure 3) recommends that the baby have limited laboratory studies--CBC,differential, and blood culture--and at least 48 hours' hospitalizationif intravenous prophylaxis was given less than four hours before delivery.If two or more doses of maternal antibiotics were given before delivery,these precautions are probably unnecessary.

Mead: Dr. Stanley Gall's group at Louisville approaches imminent deliveriesby administering long-acting benzathine penicillin weeks before the expecteddelivery date.⁵ Pharmacokinetic studies show that you can achieveadequate serum levels for several weeks with this approach, but I'm notsure if there is proven efficacy in cases of imminent delivery. Obviously,the downside is that the mother and child have prolonged exposure to antibioticsand therefore increased time for microbial selection.

Dr. Baker, what do you think about this approach?

Baker: From a pharmacologic point of view, it's not ideal. The serumlevels are sufficient to prevent diseases such as rheumatic fever, but groupA streptococci are inhibited by concentrations of penicillin that are abouttenfold less than for GBS. Therefore, instead of the patient benefitingfrom high blood and amniotic fluid levels of penicillin G achieved afterIV administration, you would have insufficient blood levels and undetectableamniotic fluid concentrations of penicillin.

Ideally, chemoprophylaxis would provide both high amniotic fluid levelsand effective serum levels for the baby. However, one study reported thatbenzathine penicillin failed to eradicate GBS colonization.⁶Similar failures have been reported for orally administered penicillin,ampicillin, cephalosporins, and erythromycin prescribed antenatally.

Cesarean section

Mead: A related issue is GBS prophylaxis for the scheduled or emergentcesarean section. One approach for emergent cesarean section is to giveall of those women prophylaxis, 2 g of cefazolin, as soon as the decisionis made to perform cesarean section. That doesn't follow the four-hour guideline,but I believe it's the best you can do for women who are known carriersor who have risk factors and need immediate delivery.

Scheduled cesarean section is more problematic because the risk of apatient undergoing elective cesarean section and having a baby develop early-onsetsepsis is theoretical and presumably extremely remote. Further, it's notrealistic to think the patient can be admitted at 3 a.m. to begin GBS prophylaxisfor a scheduled 8 a.m. cesarean. Dr. Schuchat, what do you advise for thesesituations?

Schuchat: The risk of early-onset disease is extremely low for a womanwith a scheduled cesarean section who's a known carrier and has no labor,intact membranes, and no fever. In our surveillance areas, there haven'tbeen any babies who developed early-onset disease after that scenario. However,since GBS theoretically can cross intact membranes, the clinician shouldat least discuss the situation with a pregnant woman. There are no conclusivedata that indicate a need for two doses of antibiotics before the cesareansection, but it seems reasonable to offer the woman one dose before surgery.

Baker: It also isn't practical to bring in women having elective cesareansection hours before delivery because it won't happen in most circumstances--whetherwe recommend it or not. At least one dose of antibiotic administered a coupleof hours prior to delivery might be a reasonable compromise in this low-risksituation. Cefazolin should be appropriate as a chemoprophylactic agent,although efficacy trials with this drug have not been conducted.

Clindamycin use in penicillin-allergic patients

Mead: The CDC guidelines also recommend that clindamycin be used as analternate therapy for penicillin-allergic patients. However, increasingevidence shows that clindamycin and other macrolides are less effectivethan penicillin against group B streptococci. I've always been puzzled thatcefazolin was not the alternative for patients who had only rash as theirhistory of penicillin allergy. What is your opinion on this issue, Dr. Schuchat?

Schuchat: It's a good time to reevaluate the alternative agent for prophylaxisin women who are allergic to penicillin. Reports of macrolide resistancein GBS strains have occurred in surveillance reports as well as in somecase studies. A cephalosporin is probably a very reasonable alternative,particularly with low cross-reactivity for real anaphylaxis.

Baker: In the 1950s, Max Finland and his associates at the Boston CityHospital evaluated the susceptibility of GBS strains and found that about5% were resistant to erythromycin.⁷ This phenomenon has beenprevalent for a long time, and it may be increasing. Since this phenomenondoes not occurinfrequently, I thinkwe should reassess whether cephalosporinswould be an appropriate alternative for the woman with a history of nonthreateningallergy to penicillin. My personal choice in this instance always has beencefazolin.

Mead: One of the most contentious issues is related to the newborn ofa mother colonized with GBS who has received penicillin prophylaxis in labor.The current approach is to observe these newborns in the hospital for 48hours because some data suggest there is a later time of onset. As a pediatrician,Dr. Baker, what is your opinion?

Baker: The 48-hour recommendation was based on two things. One was theepidemiologic information about age at onset. We know that most early-onsetdisease begins in the first 24 hours and that another small percentage ofbabies develop GBS in the second 24 hours. Second, the AAP drafted theseGBS recommendations to be consistent with the 1997 Perinatal Guidelines,which state that certain infants--including those of mothers who had beengiven chemoprophylaxis for GBS--require a mandatory 48-hour observation.However, the academy based its management strategy on available data andexpert opinion; the infant management algorithm is not exclusive, and itallows physicians and hospitals to modify it as appropriate for their patients'circumstances. Until we have additional data assessing the effectivenessof the algorithm, it should be used as a guide to care, keeping in mindthat minor adaptations, while acceptable, are unlikely to be based on strongevidence.

I think the infant management algorithm also should consider each clinician'spatient population. At one of my hospital affiliates, for example, morethan half of the maternity patients cannot speak English and most of themdon't have a telephone or access to transportation. We have decided thatin groups such as these, the infant should be observed for 48 hours; inother groups the infant can be discharged after a shorter period, if appropriate,and observed further at home.

Mead: In essence, do you believe that all babies need the observationbut that in some cases observation can be performed at home by a very observantmother, as long as she has easy access to her pediatrician?

Baker: Absolutely.

Vaccination strategies

Mead: As we grow more concerned about the increasing resistance of bacteriato antibiotics, we're considering more non-antibiotic strategies. What canyou tell us about vaccination strategies for GBS, Dr. Baker?

Baker: The rationale for vaccination is based on 20 years of researchin the landmark studies by Lancefield.⁸ This research showedthat antibody against the capsules of GBS is protective against invasivedisease in experimentalmodels. One major risk factor in early-onset disease,as well as in late-onset infant disease and possibly maternal invasive disease,is low concentrations of antibodies against these capsular polysaccharides.Thus the rationale for immunization is that a suitable vaccine would elicitenough antibodies to block invasion of these organisms into the bloodstream.

Dr. Dennis Kasper, at Channing Laboratory and Harvard Medical School,and his colleagues have worked for the past 10 years to conjugate theseGBS capsular polysaccharides--which aren't sufficiently antigenic as vaccineson their own--with a protein, tetanus toxoid. Phase I and II clinical trialshave shown these GBS conjugate vaccines to be well tolerated in healthynonpregnant women, and they are much more antigenic than the unconjugatedpolysaccharides. Ninety percent or more of vaccinated women develop a fourfoldor greater increase in IgG antibodies to the capsular polysaccharide componentof the vaccines within two weeks, with a peak between four and eight weeks.

Therefore, if you immunize a pregnant woman early in the third trimester,these IgG class antibodies to GBS polysaccharides would be transferred tothe fetus and protect against early- and late-onset disease. I and my colleaguesin Houston plan to launch a type III GBS conjugate vaccine phase I studyin pregnant women in the future, aiming to immunize them at approximately30 to 32 weeks' gestation.

Ultimately, a multivalent GBS vaccine will be required to prevent diseasecaused by most GBS strains. Based on recent surveillance data, types Iaand III together account for about 75% of cases in infants and types II(5% to 10%) and V (10% to 15%) bring the total to nearly 95%. This suggeststhat a quadravalent (Ia, II, III, and V) GBS conjugate vaccine might beideal for future development, but further data are needed.

Schuchat: We consider this the "honeymoon" period. Right now,we feel the current CDC guidelines are an interim approach that is providinggood results in reducing early-onset disease. However, we don't know howlong that is sustainable. Thus, we're very excited about the developmentof vaccines as a long-term solution to the problem.

Baker: Although I am excited about the scientific progress in GBS vaccinedevelopment, I think there are substantial obstacles to their use in pregnantwomen for prevention of GBS in women and infants. One obstacle has beenthe lack of willingness by obstetricians to immunize pregnant women evenin the third trimester, though this is beginning to change. This obstaclecan be overcome by leadership from obstetricians who promote vaccinationin pregnant women where it's appropriate and suitable. For example, pregnantwomen in the US born in countries where vaccination against tetanus is notroutine need to be vaccinated for tetanus with tetanus toxoid. Influenzaimmunization also is recommended for pregnant women. Another obstacle, litigationliability concerns, overshadows all others, despite insufficient evidenceof serious adverse outcome in either the pregnant woman or her fetus. Thesebarriers must be overcome so that the benefits of maternal immunizationto prevent perinatal GBS disease may be realized.

Mead: I'd like to conclude by saying that early-onset GBS neonatal sepsisclearly has been one of the major concerns of the past 20 years. Both ofyou have had an enormous impact on developments in managing and preventingthis devastating disease. I thank you both for sharing your knowledge andinsight.

REFERENCES

1. American Academy of Pediatrics, Committee on Infectious Disease andCommittee on Fetus and Newborn: Revised guidelines for prevention of eary-onsetGroup B streptococcal (GBS) infection. Pediatrics 1997;99(3):489

2. Fleming MT, McDuffie RS, Russell K, et al: Compliance with a risk-factorbased guideline in the prevention of neonatal group B streptococcal sepsis.Infant Disease in Obstet Gynecol 1997;5:345

3. Cueto M, Sanchez M, Sampedro A, et al: Timing of intrapartum ampicillinand prevention of vertical transmission of group B streptococcus. ObstetGynecol 1998;91:112

4. Rosenstein NE, Schuchat A: Opportunities for prevention of perinatalgroup B streptococcal disease: A multistate surveillance analysis. The NeonatalGroup B Streptococcal Disease Study Group. Obstet Gynecol 1997;90(6):901

5. Weeks JW, Myers SR, Lasher L, et al: Persistance of penicillin G benzathinein pregnant group B streptococcus carriers. Obstet Gynecol 1997;90:240

6.Lewin EB, Amstey MS: Natural history of group B streptococcus colonizationand its therapy during pregnancy. Am J Obstet Gynecol 1981;139:512

7. James WF, Feldman HA, Finland M: Susceptibility of hemolytic streptococciother than those of group D to eleven antibiotics in vitro. Am J Clin Pathol1957;27:159

8. Lancefield RC: Cellular antigens of group B streptococci, in WanamakerLW, Matsen JM (eds): Streptococci and Streptococcal Diseases. Academic Press,New York, 1972, pp 57­64



SYMPOSIUM. Contemporary Pediatrics 1999;0:067.