Early-Onset Group B Streptococcal Disease in the Era of Maternal Screening
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《小儿科》
Department of Newborn Medicine Channing Laboratory
Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Background. With the widespread implementation of intrapartum antibiotic prophylaxis (IAP), the rate of early-onset neonatal sepsis and meningitis caused by Streptococcus agalactiae (group B streptococcus [GBS]) has decreased dramatically, especially in term infants. However, cases of GBS disease continue to occur despite IAP and incur significant morbidity and mortality. Inaccurate screening results, improper implementation of IAP, or antibiotic failure all may contribute to persistent disease.
Objective. To determine if clinical, procedural, or microbiologic factors influenced persistent early-onset GBS disease (EOGBS) cases in a single large maternity service after the institution of a screening-based protocol for IAP.
Methods. Retrospective review of all cases of culture-proven EOGBS at the Brigham and Women's Hospital (Boston, MA) from 1997 to 2003. Serotyping and surface protein analyses were performed on available disease isolates.
Results. A total of 67260 infants were live-born during this period. Twenty-five cases of EOGBS (0.37 of 1000 live births) were identified. The overall incidence of EOGBS progressively decreased with different approaches to IAP. Of the 25 cases identified after institution of a screening-based protocol, 17 (68%) occurred in term infants (1 death), and 8 (32%) occurred in preterm infants (3 deaths). Among the mothers of term infants, 14 of 17 (82%) had been screened GBS negative; 1 was GBS unknown. More than half of the mothers of term infants who had screened GBS negative (8 of 14) had intrapartum risk factors for neonatal infection but did not receive antibiotics before delivery. Ten of the 17 term infants were evaluated for infection because of clinical signs of illness, and the remainder were evaluated because of intrapartum sepsis risk factors. Of the mothers of preterm infants, by the time of delivery 3 of 8 had been documented as GBS positive, 2 of 8 had been documented GBS negative, and 3 of 8 remained unknown. Only 1 of 25 women received adequate IAP, but the isolate was resistant to the administered antibiotic (clindamycin). Antibiotic resistance was not a factor in any other case, and no dominant serovariant was identified among tested isolates. Procedural errors (lack of recognition of documented GBS colonization or failure to evaluate infants at risk for sepsis) were identified in 4 cases.
Conclusions. The majority of the remaining cases of EOGBS occurred in infants whose mothers screened negative for GBS colonization. Even in the setting of a maternal GBS-screening program, efforts to evaluate and treat infants with intrapartum clinical risk factors for early-onset sepsis remain important. Until effective vaccines against GBS are available for clinical use, development and implementation of rapid and sensitive techniques for screening for GBS status and antibiotic susceptibility at presentation may help prevent additional cases of invasive GBS disease.
Key Words: neonatal infectious diseases neonatal infection neonatal sepsis neonatology group B streptococcus
Abbreviations: GBS, group B streptococcus EOGBS, early-onset neonatal group B streptococcus disease CDC, Centers for Disease Control and Prevention IAP, intrapartum antibiotic prophylaxis EOS, early-onset sepsis PCR, polymerase chain reaction WBC, white blood cell VLBW, very low birth weight
Streptococcus agalactiae (group B streptococcus [GBS]) was first recognized as a significant cause of neonatal sepsis and meningitis in the United States in the 1970s.1 Multiple clinical trials have demonstrated that the use of intrapartum penicillin or ampicillin significantly reduces the rate of neonatal colonization with GBS and the incidence of early-onset neonatal GBS disease (EOGBS).2–4 In 1996, the Centers for Disease Control and Prevention (CDC) published consensus guidelines for the prevention of neonatal GBS disease that endorsed the use of either a maternal screening-based or risk factor–based approach to intrapartum antibiotic prophylaxis (IAP).2 A 2001 case-control study comparing the efficacy of the 2 approaches demonstrated the superiority of the screening-based approach to IAP in the prevention of EOGBS.5 In 2002, the CDC issued revised guidelines that endorsed the screening-based approach to IAP for GBS and reserved the risk factor–based approach for cases in which maternal GBS status was unknown.6
Several epidemiologic studies conducted since the consensus statement in 1996 have assessed the overall impact of IAP and monitored for any unintended, adverse consequences. The national incidence of EOGBS has declined from an estimated 1.8 cases per 1000 live births in 1990 to 0.32 cases per 1000 live births in 2003.7,8 Overall mortality from EOGBS, as high as 50% in the 1970s, fell to 5% to 6% in 1993–2003 primarily because of advances in neonatal care.8,9 Among preterm infants, however, mortality remains substantially higher, with case/fatality rates of 22.7% reported in CDC surveillance data from 2000–2003.8 There are conflicting reports concerning the impact of IAP on early-onset sepsis (EOS) caused by organisms other than GBS,10–16 as well as on the incidence of macrolide resistance among both colonizing and invasive isolates of GBS.17,18
Despite the considerable effort and economic resources spent on IAP for EOGBS, cases continue to occur. The reasons for continued disease are unclear. There are no published reports evaluating EOGBS cases that occurred despite the implementation of a screening-based approach to IAP. The purpose of this study was to determine if clinical, procedural, or microbiologic factors influenced persistent EOGBS cases in a single large maternity service after institution of a screening-based protocol for IAP and if there were missed opportunities for prevention.
METHODS
Case Ascertainment and Chart Review
A screening-based protocol for IAP was implemented at the Brigham and Women's Hospital (Boston, MA) in 1997. During the period of 1993–1996, a risk-based protocol was in place at this hospital. Before 1993, IAP was not routinely used. Cases of EOGBS disease from January 1, 1997, through December 31, 2003, were identified by a search of the microbiology laboratory's computerized database. The database was queried to identify any blood or cerebrospinal fluid culture positive for GBS obtained from an infant before 72 hours of age. Maternal and infant clinical data were obtained from a review of medical records. Annual live birth, birth weight, and neonatal intensive care admission data were obtained from hospital summary statistics. The incidence of EOGBS from 1997 to 2003 was compared with previously reported incidence data from the Brigham and Women's Hospital for the years 1990–1996.13
Capsular Polysaccharide and Surface Protein Serotyping of Disease Isolates
Beginning in 1999, invasive GBS disease isolates were obtained from the hospital microbiology laboratory for additional study. Of the subsequent 15 isolates, 12 were available for study. Capsular polysaccharide serotyping was performed by using Channing Laboratory GBS reference strains and reference antisera.19 Protein typing was performed by using a polymerase chain reaction (PCR)-based method to detect the genes for the -like surface proteins (L.C.M., unpublished data, 2004).
Maternal GBS-Screening Culture Methods
All obstetricians who deliver infants at the Brigham and Women's Hospital obtain rectovaginal screening swabs for GBS culture, following a hospital protocol that was instituted in 1997. This protocol is available for reference through the hospital computer system and is in compliance with CDC guidelines. All screening cultures are processed at either the hospital microbiology laboratory or a single commercial laboratory. Both sites use procedures (Amies transport media, incubation in Lim broth, subculture on selective blood agar) that are in compliance with CDC guidelines.6
Blood Culture Methods and Antibiotic Susceptibility
Blood cultures were performed in the Brigham and Women's Hospital microbiology laboratory with an automated BACTEC system. Both aerobic and anaerobic bottles are used for routine infant culture. Antibiotic susceptibility testing was performed by the microbiology laboratory, using standard methods for Kirby-Bauer diffusion testing. Each isolate was tested for susceptibility to ampicillin, chloramphenicol, clindamycin, erythromycin, gentamicin, penicillin, oxacillin/cephalosporins, tetracycline, vancomycin, trimethoprim/sulfamethoxazole, and a fluoroquinolone.
Infant Sepsis Evaluation
1997 to 2003, infants born at the Brigham and Women's Hospital were evaluated for EOS according to established guidelines, as described previously.20 The guidelines applied only to well-appearing infants. A complete blood count, white blood cell (WBC) count differential, and blood culture were obtained if the infant was judged at significant risk for EOS on the basis of a variety of clinical risk factors including maternal GBS colonization, inadequate IAP, maternal intrapartum fever, duration of rupture of membranes, clinical diagnosis of chorioamnionitis, preterm delivery, multiple gestation, sustained fetal tachycardia, and the mother having had a previous infant with GBS disease. A lumbar puncture was not performed as part of the routine evaluation for sepsis in well-appearing infants. Empiric antibiotic therapy was instituted if the WBC count or WBC count differential was abnormal, which was defined by (1) total WBC count of <5.0, (2) ratio of immature to total neutrophil forms on the WBC count differential of 0.20, or (3) absolute neutrophil count of <1500.21,22 Empiric antibiotic therapy was also instituted if >1 clinical risk factor for sepsis was present. Term infants with signs of illness and all premature infants were evaluated with a complete blood count, differential, and blood culture. Lumbar puncture was performed (if clinically feasible) on ill-appearing infants and any infant with a positive blood culture.
Statistical Methods
The incidence of EOGBS disease over the period of 1990–2003 was evaluated by using the Mantel-Haenszel test for trends.23
Approval
This study was approved by the Brigham and Women's Hospital Human Research Committee.
RESULTS
Incidence of EOGBS
January 1, 1997, through December 31, 2003, a total of 67260 live births were recorded at the Brigham and Women's Hospital. Of these births, 1502 were very low birth weight (VLBW) infants (birth weight 400–1499 g). Twenty-five cases of EOGBS were identified; 5 cases occurred in VLBW infants. The annual incidence of EOGBS from 1997–2003 is shown in Fig 1A. The overall incidence during this period was 0.37 cases per 1000 live births. The incidence among VLBW infants was 3.3 cases per 1000 VLBW births. We previously reported the incidence of EOGBS at our hospital from 1990 to 1996.13 Before the use of IAP (1990–1992), the overall incidence of EOGBS was 2.2 cases per 1000 live births and 10.1 cases per 1000 VLBW births. From 1993 to 1996, during which a risk-based approach to IAP was used, the overall incidence was 1.1 cases per 1000 live births and 3.1 cases per 1000 VLBW births. The overall incidence of EOGBS decreased significantly between each of the time periods (Fig 1B). The incidence of EOGBS in VLBW infants also decreased significantly with the institution of a risk-based protocol for IAP, but no additional decline was seen with the change to a screening-based protocol.
Maternal Clinical Characteristics
Maternal GBS-screening results are summarized in Table 1. Of the 25 mothers of the infants in this study, 21 were screened for GBS colonization: 16 of the 25 mothers screened (64%) were GBS negative. Of the mothers of term infants, 14 of 17 (82%) screened negative. Rectovaginal screening cultures were obtained and processed by using methods recommended by the CDC. The cultures were performed routinely at 35 weeks' gestation in the mothers of term infants. The exact timing of culture in relation to delivery could be determined in 8 of the 21 women whose screening cultures were performed at the hospital microbiology laboratory. The mean interval between screening and delivery was 20.2 (±6.8) days (range: 10–28 days) for these 8 women; the interval was slightly shorter for the preterm infants and slightly longer for the term infants.
Nineteen of the 25 mothers (76%) had deliveries complicated by 1 identifiable risk factors for EOGBS in their infants: delivery at <37 weeks' gestation, intrapartum fever of >100.4°C, clinical chorioamnionitis, or GBS colonization (Table 1). Despite the presence of intrapartum risk factors for neonatal sepsis, only 4 mothers received intrapartum antibiotic therapy. In only one instance was intrapartum antibiotic therapy administered >4 hours before delivery as prophylaxis for recognized maternal GBS colonization. Clindamycin and gentamicin were administered in this case because of maternal penicillin allergy, but the GBS later isolated from the infant blood culture was found to be resistant to clindamycin and, like most GBS isolates, was resistant to gentamicin. In the remaining 3 cases, maternal intrapartum antibiotic therapy was administered <4 hours before delivery because of the onset of maternal fever or other signs and symptoms of chorioamnionitis. Neither of the 2 GBS-positive mothers of term infants received IAP: one because of clinical error and the second because a precipitous delivery precluded use of IAP.
Infant Clinical Characteristics
The clinical characteristics of the infants with EOGBS disease are summarized in Table 1. Seventeen of the 25 EOGBS cases occurred in term infants, with a mean gestational age and birth weight of 39.7 (±1.5) weeks and 3738 (±456) g, respectively. Among the term cases, 12 infants either had no signs of illness or were only mildly ill, and 5 were critically ill. One of these infants died despite maximal intensive care support that included extracorporeal membrane oxygenation therapy. Eight cases occurred in preterm infants, with a mean gestational age of 29.8 (±3.8) weeks (range: 26–35 weeks) and birth weight of 1671 (±742) g (range: 890–2722 g). Of the 8 preterm infants, 7 were ill from birth, and 6 of the 8 required mechanical ventilation. Three preterm infants died, for a mortality rate of 37%. Lumbar punctures were performed in 21 of 25 cases, and 2 infants had meningitis. Lumbar punctures were not performed in 4 cases because of death or early transfer of the infant for extracorporeal membrane oxygenation. Taken together, the majority of infants (19 of 25) had signs of illness ranging from mild respiratory distress to multisystem organ failure, and all became ill before 24 hours of life.
Seven well-appearing term infants were evaluated shortly after birth because of intrapartum risk factors for sepsis according to our hospital's guidelines. Five of the 7 were treated with antibiotics because of an abnormal WBC count or multiple clinical risk factors for sepsis. The 5 infants who received empiric antibiotic therapy all remained clinically well. Of the 2 infants who did not receive empiric therapy, 1 later became clinically ill, and the other remained well-appearing but was persistently bacteremic 24 hours after the first blood culture.
Five term infants and 1 preterm infant appeared well at birth but were evaluated for infection after developing signs of illness in the first 24 hours of life. In 3 of these cases, the mothers were screened GBS negative, and there were no other intrapartum risk factors for sepsis. In the other 3 cases, the infants should have been evaluated based on our guidelines because of intrapartum risk factors for sepsis, but by error they were not.
Microbiology and Antibiotic Susceptibility
Polysaccharide serotyping and surface protein molecular typing was performed on the available clinical isolates to determine if a single virulent strain was responsible for all or most of the invasive disease cases. No dominant serovariant of GBS was identified among the isolates (data not shown). Antibiotic sensitivity testing was performed on all isolates. Five of the 25 isolates (20%) were resistant to clindamycin and/or erythromycin. Another 5 isolates were partially resistant to erythromycin or clindamycin as indicated by intermediate-sized (ie, neither fully sensitive nor fully resistant) zones on disk testing. We identified only 1 case in which the infant blood isolate was resistant to the antibiotic administered to the mother. None of the invasive isolates were resistant to penicillin, ampicillin, cephalosporins, or vancomycin, the antibiotics currently recommended for IAP.6
DISCUSSION
The overall incidence of EOGBS in our large maternity center has progressively dropped coincident with adoption of specific policies for IAP for the prevention of invasive GBS disease (Fig 1B). The incidence of EOGBS in VLBW (<1500-g) infants also fell significantly with the implementation of a risk-based approach to IAP. No additional decrease was observed with the change to a screening-based approach; this is not surprising, because most mothers have not yet been screened for GBS colonization when a significantly preterm birth occurs. Cases of EOGBS continued to occur despite routine screening for GBS and incurred significant morbidity and mortality. We sought to identify any clinical, procedural, or microbiologic factors that contributed to these cases, with the hope that changes in practice could further decrease our rate of EOGBS.
Two studies published before the 2002 CDC recommendation for routine screening of pregnant women for GBS colonization addressed some of the reasons for continued EOGBS disease in the era of prophylaxis. Pinto et al24 reported a series of 92 infants with EOGBS disease referred from 23 different centers with inconsistent policies for IAP over their study period (1992–2001). The majority of the mothers (62 of 92) had not been screened for GBS colonization, and most (68 of 92) did not receive IAP. In another study, Velaphi et al25 reported on 32 cases of EOGBS that occurred from 1995 to 1999 in a hospital with a risk-based approach to maternal IAP. This hospital also routinely administered intramuscular penicillin to all newborns immediately after birth, a practice not endorsed by the CDC. Of the 32 cases, 13 infants were born to mothers without risk factors who did not receive intrapartum antibiotics, and 12 infants were born to mothers who received IAP only after the development of intrapartum fever. In both of these reports, the authors concluded that the risk factor–based approach to GBS prophylaxis led to missed opportunities for GBS prevention.
Our study is the first to address continued EOGBS disease in a single maternity service with use of a screening-based approach to IAP. We speculated that continued cases of EOGBS might be caused by problems in several aspects of prenatal and perinatal clinical practice, including the accuracy of GBS screening, communication of GBS-screening results, administration of IAP, or the identification and treatment of infants at risk for EOS. In addition, we sought to determine if microbiologic factors including antibiotic resistance contributed to ongoing EOGBS.
Hospital system or procedural errors in the communication of GBS-screening results or the administration of IAP when indicated did not contribute significantly to ongoing EOGBS in this series. Only 3 cases could be attributed to a failure to administer IAP to a mother known to be GBS positive. We also examined whether failure to recognize and evaluate infants with intrapartum risk factors for infection might have contributed to EOGBS. The majority of well-appearing infants with significant risk factors for sepsis were promptly evaluated, treated with antibiotics, and remained well. The apparent protective effect of empiric antibiotic therapy in preventing clinical illness underscores the importance of ongoing efforts to evaluate infants at risk for EOS even in the setting of a GBS-screening program. We attributed antibiotic resistance as contributing to only 1 case of EOGBS. We were able to obtain the GBS isolates for the majority of cases that occurred after 1999. The combination of polysaccharide capsule and C-protein typing demonstrated that no dominant serovariant accounted for the cases of EOGBS in our hospital during this period.
The most surprising finding of this study is that the majority of cases of continued EOGBS disease in term infants occurred in those delivered to mothers with negative GBS-screening culture results. In addition to precluding the use of effective IAP, the negative prenatal GBS-screening results may have contributed to intrapartum management in a way that increased the risk of sepsis in the infant. Antibiotics are frequently administered to women in labor with signs and symptoms suggestive of chorioamnionitis. The majority of mothers who screened GBS negative had labors complicated by at least 1 established risk factor for sepsis (Table 1), yet only 4 women received intrapartum antibiotic therapy. It is possible that the negative GBS screens provided a false sense of reassurance to obstetrical providers. If the mothers in these cases had an unknown GBS status, it is likely that antibiotics for IAP in the presence of risk factors, or for treatment for chorioamnionitis, would have been given and perhaps prevented some of the cases of EOGBS.
Whether these negative cultures were false-negative results or the mothers acquired GBS in the interval between the screening culture and the time of delivery is unknown. Technical factors known to contribute to false-negative GBS-culture results are specifically addressed in the 1996 and 2002 CDC recommendations,6 including the use of cervical or vaginal swabs rather than rectovaginal sampling, poor swab storage and transfer practices, and use of inappropriate culture media.6,26–30 Obstetricians who deliver infants at the Brigham and Women's Hospital are required by protocol to obtain rectovaginal swabs for GBS screening. The GBS cultures are performed in only 2 laboratories: either the hospital microbiology laboratory or a single private laboratory. Both are experienced laboratories that handle thousands of cultures yearly and use culture-transport and processing practices that strictly adhere to CDC laboratory-practice guidelines for GBS-screening culture. One limitation of this study, however, is that it is difficult to assess in retrospect the possible contribution of poor obstetrical technique to the negative screening results. Failure to culture GBS even with ideal sampling and culture techniques may also be caused by maternal factors. The use of oral antibiotics or a variety of feminine hygiene products (including douches, vaginal candidiasis medications, and inert lubricants) before specimen collection may inhibit GBS growth in culture31 and contribute to false-negative results.
It is possible that some of the mothers in our study who screened negative were indeed not colonized with GBS at the time of screening but colonized at the time of delivery. Recent longitudinal data suggest that the prevalence of GBS colonization among American women is higher than is obvious from prenatal screening data, with up to 75% of women colonized with GBS at some time over a 12-month period.32 Multiple studies have also demonstrated that GBS colonization varies during pregnancy.33–35 Boyer et al28 first evaluated the concordance of prenatal GBS colonization status with colonization at the time of delivery. In this study, 8.5% of women with negative GBS cultures at 26 to 28 weeks' gestation were found to have acquired GBS colonization by the time of delivery. The results of this study prompted the CDC to recommend a shift from obtaining GBS-screening cultures at 26 to 28 weeks' gestation to closer to term at 35 to 37 weeks' gestation.2 To determine the predictive value of screening later in gestation, Yancey et al36 performed rectovaginal cultures on 826 women at 33 to 39 weeks' gestation and again at presentation for delivery. In this study, 4% of women with negative antenatal cultures were found to be colonized at delivery.
A 4% false-negative GBS-screening rate could have a significant impact on continued EOGBS. Seventy-two percent of women delivering at term at the Brigham and Women's Hospital screened GBS negative in 2002 (E. Lieberman, MD, DrPH, written communication, 2004). Assuming that 72% of pregnant women during our entire study period screened GBS negative, and 4% of these were false negative, 20 infants would have developed EOGBS in our delivery population (assuming an attack rate of 1%), which is consistent with our findings. Multiple epidemiologic studies demonstrate that the overall rate of GBS colonization among American women ranges from 20% to 30%.37 Given this range of colonization, a 4% false-negative rate in GBS screening alone could account for 0.3 of 1000 cases of EOGBS per year.
A potential alternative to antenatal GBS-screening culture is the identification of GBS colonization at presentation for delivery. Antigen-based and DNA-probe–based methods to detect GBS carriage have failed to demonstrate adequate sensitivity when compared with standard culture techniques.38 Recent data suggest that real-time PCR-based methodology can equal or surpass the sensitivity of antenatal culture at 35 to 37 weeks' gestation. Bergeron et al39 demonstrated that a real-time, fluorogenic PCR assay compared favorably to standard culture methods for the detection of GBS colonization at presentation for delivery. This assay has been developed commercially (IDI-Strep B test, Cepheid, Sunnyvale, CA) and was approved for use by the Food and Drug Administration in 2003.40 Using culture at presentation for delivery as the reference, a recent study demonstrated that the IDI-Strep B test had greater sensitivity than standard antepartum culture and equivalent specificity for the identification of colonization at delivery.41 It is unclear, however, whether similar results would occur with actual clinical use, and questions of costs and logistics remain unanswered.
CONCLUSIONS
The implementation of a screening-based approach to the management and prevention of GBS disease has been accompanied by a dramatic decrease in the overall rate of neonatal EOGBS in our large maternity service. Cases of EOGBS continue to occur, with significant morbidity and mortality, particularly in preterm infants. Although procedural errors may have contributed to a few cases, the majority of cases of EOGBS occurred in infants whose mothers had screened negative for GBS colonization. Our results demonstrate that prompt intrapartum antibiotic treatment of women with signs and symptoms of chorioamnionitis regardless of their GBS-screening results and the evaluation of well-appearing infants for possible sepsis because of intrapartum clinical risk factors remain imperative. Until effective GBS vaccines are available for clinical use, rapid and accurate diagnostic screening of women when they present for delivery may be the most effective approach to additional prevention of neonatal GBS disease in the current era of screening-based IAP. A large-scale, multicenter, controlled trial designed to evaluate the accuracy of real-time PCR-based diagnostics compared with antenatal culture-based screening in predicting maternal GBS colonization at delivery is warranted.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health grants HD041534 and AI38424, National Institutes of Health contract N01-AI-25495, and a grant from the Children's Hospital, Boston Office of Faculty Development.
We thank Meaghan Gilmore, Laura Stulgis, and Christopher Jordan for technical assistance; Dr Andrew Onderdonk and the staff of the Brigham and Women's Hospital Microbiology Laboratory for providing the group B streptococcus disease isolates; Nancy Jeffery Harrison for performing the microbiology database computer searches; Dr Ellice Lieberman for statistical analyses; Dr Cynthia Cole for critical review of the manuscript; Dr William Tarnow-Mordi for helpful discussion; and Dr Dennis Kasper for ongoing support of our work.
FOOTNOTES
Accepted Feb 7, 2005.
No conflict of interest declared.
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Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Background. With the widespread implementation of intrapartum antibiotic prophylaxis (IAP), the rate of early-onset neonatal sepsis and meningitis caused by Streptococcus agalactiae (group B streptococcus [GBS]) has decreased dramatically, especially in term infants. However, cases of GBS disease continue to occur despite IAP and incur significant morbidity and mortality. Inaccurate screening results, improper implementation of IAP, or antibiotic failure all may contribute to persistent disease.
Objective. To determine if clinical, procedural, or microbiologic factors influenced persistent early-onset GBS disease (EOGBS) cases in a single large maternity service after the institution of a screening-based protocol for IAP.
Methods. Retrospective review of all cases of culture-proven EOGBS at the Brigham and Women's Hospital (Boston, MA) from 1997 to 2003. Serotyping and surface protein analyses were performed on available disease isolates.
Results. A total of 67260 infants were live-born during this period. Twenty-five cases of EOGBS (0.37 of 1000 live births) were identified. The overall incidence of EOGBS progressively decreased with different approaches to IAP. Of the 25 cases identified after institution of a screening-based protocol, 17 (68%) occurred in term infants (1 death), and 8 (32%) occurred in preterm infants (3 deaths). Among the mothers of term infants, 14 of 17 (82%) had been screened GBS negative; 1 was GBS unknown. More than half of the mothers of term infants who had screened GBS negative (8 of 14) had intrapartum risk factors for neonatal infection but did not receive antibiotics before delivery. Ten of the 17 term infants were evaluated for infection because of clinical signs of illness, and the remainder were evaluated because of intrapartum sepsis risk factors. Of the mothers of preterm infants, by the time of delivery 3 of 8 had been documented as GBS positive, 2 of 8 had been documented GBS negative, and 3 of 8 remained unknown. Only 1 of 25 women received adequate IAP, but the isolate was resistant to the administered antibiotic (clindamycin). Antibiotic resistance was not a factor in any other case, and no dominant serovariant was identified among tested isolates. Procedural errors (lack of recognition of documented GBS colonization or failure to evaluate infants at risk for sepsis) were identified in 4 cases.
Conclusions. The majority of the remaining cases of EOGBS occurred in infants whose mothers screened negative for GBS colonization. Even in the setting of a maternal GBS-screening program, efforts to evaluate and treat infants with intrapartum clinical risk factors for early-onset sepsis remain important. Until effective vaccines against GBS are available for clinical use, development and implementation of rapid and sensitive techniques for screening for GBS status and antibiotic susceptibility at presentation may help prevent additional cases of invasive GBS disease.
Key Words: neonatal infectious diseases neonatal infection neonatal sepsis neonatology group B streptococcus
Abbreviations: GBS, group B streptococcus EOGBS, early-onset neonatal group B streptococcus disease CDC, Centers for Disease Control and Prevention IAP, intrapartum antibiotic prophylaxis EOS, early-onset sepsis PCR, polymerase chain reaction WBC, white blood cell VLBW, very low birth weight
Streptococcus agalactiae (group B streptococcus [GBS]) was first recognized as a significant cause of neonatal sepsis and meningitis in the United States in the 1970s.1 Multiple clinical trials have demonstrated that the use of intrapartum penicillin or ampicillin significantly reduces the rate of neonatal colonization with GBS and the incidence of early-onset neonatal GBS disease (EOGBS).2–4 In 1996, the Centers for Disease Control and Prevention (CDC) published consensus guidelines for the prevention of neonatal GBS disease that endorsed the use of either a maternal screening-based or risk factor–based approach to intrapartum antibiotic prophylaxis (IAP).2 A 2001 case-control study comparing the efficacy of the 2 approaches demonstrated the superiority of the screening-based approach to IAP in the prevention of EOGBS.5 In 2002, the CDC issued revised guidelines that endorsed the screening-based approach to IAP for GBS and reserved the risk factor–based approach for cases in which maternal GBS status was unknown.6
Several epidemiologic studies conducted since the consensus statement in 1996 have assessed the overall impact of IAP and monitored for any unintended, adverse consequences. The national incidence of EOGBS has declined from an estimated 1.8 cases per 1000 live births in 1990 to 0.32 cases per 1000 live births in 2003.7,8 Overall mortality from EOGBS, as high as 50% in the 1970s, fell to 5% to 6% in 1993–2003 primarily because of advances in neonatal care.8,9 Among preterm infants, however, mortality remains substantially higher, with case/fatality rates of 22.7% reported in CDC surveillance data from 2000–2003.8 There are conflicting reports concerning the impact of IAP on early-onset sepsis (EOS) caused by organisms other than GBS,10–16 as well as on the incidence of macrolide resistance among both colonizing and invasive isolates of GBS.17,18
Despite the considerable effort and economic resources spent on IAP for EOGBS, cases continue to occur. The reasons for continued disease are unclear. There are no published reports evaluating EOGBS cases that occurred despite the implementation of a screening-based approach to IAP. The purpose of this study was to determine if clinical, procedural, or microbiologic factors influenced persistent EOGBS cases in a single large maternity service after institution of a screening-based protocol for IAP and if there were missed opportunities for prevention.
METHODS
Case Ascertainment and Chart Review
A screening-based protocol for IAP was implemented at the Brigham and Women's Hospital (Boston, MA) in 1997. During the period of 1993–1996, a risk-based protocol was in place at this hospital. Before 1993, IAP was not routinely used. Cases of EOGBS disease from January 1, 1997, through December 31, 2003, were identified by a search of the microbiology laboratory's computerized database. The database was queried to identify any blood or cerebrospinal fluid culture positive for GBS obtained from an infant before 72 hours of age. Maternal and infant clinical data were obtained from a review of medical records. Annual live birth, birth weight, and neonatal intensive care admission data were obtained from hospital summary statistics. The incidence of EOGBS from 1997 to 2003 was compared with previously reported incidence data from the Brigham and Women's Hospital for the years 1990–1996.13
Capsular Polysaccharide and Surface Protein Serotyping of Disease Isolates
Beginning in 1999, invasive GBS disease isolates were obtained from the hospital microbiology laboratory for additional study. Of the subsequent 15 isolates, 12 were available for study. Capsular polysaccharide serotyping was performed by using Channing Laboratory GBS reference strains and reference antisera.19 Protein typing was performed by using a polymerase chain reaction (PCR)-based method to detect the genes for the -like surface proteins (L.C.M., unpublished data, 2004).
Maternal GBS-Screening Culture Methods
All obstetricians who deliver infants at the Brigham and Women's Hospital obtain rectovaginal screening swabs for GBS culture, following a hospital protocol that was instituted in 1997. This protocol is available for reference through the hospital computer system and is in compliance with CDC guidelines. All screening cultures are processed at either the hospital microbiology laboratory or a single commercial laboratory. Both sites use procedures (Amies transport media, incubation in Lim broth, subculture on selective blood agar) that are in compliance with CDC guidelines.6
Blood Culture Methods and Antibiotic Susceptibility
Blood cultures were performed in the Brigham and Women's Hospital microbiology laboratory with an automated BACTEC system. Both aerobic and anaerobic bottles are used for routine infant culture. Antibiotic susceptibility testing was performed by the microbiology laboratory, using standard methods for Kirby-Bauer diffusion testing. Each isolate was tested for susceptibility to ampicillin, chloramphenicol, clindamycin, erythromycin, gentamicin, penicillin, oxacillin/cephalosporins, tetracycline, vancomycin, trimethoprim/sulfamethoxazole, and a fluoroquinolone.
Infant Sepsis Evaluation
1997 to 2003, infants born at the Brigham and Women's Hospital were evaluated for EOS according to established guidelines, as described previously.20 The guidelines applied only to well-appearing infants. A complete blood count, white blood cell (WBC) count differential, and blood culture were obtained if the infant was judged at significant risk for EOS on the basis of a variety of clinical risk factors including maternal GBS colonization, inadequate IAP, maternal intrapartum fever, duration of rupture of membranes, clinical diagnosis of chorioamnionitis, preterm delivery, multiple gestation, sustained fetal tachycardia, and the mother having had a previous infant with GBS disease. A lumbar puncture was not performed as part of the routine evaluation for sepsis in well-appearing infants. Empiric antibiotic therapy was instituted if the WBC count or WBC count differential was abnormal, which was defined by (1) total WBC count of <5.0, (2) ratio of immature to total neutrophil forms on the WBC count differential of 0.20, or (3) absolute neutrophil count of <1500.21,22 Empiric antibiotic therapy was also instituted if >1 clinical risk factor for sepsis was present. Term infants with signs of illness and all premature infants were evaluated with a complete blood count, differential, and blood culture. Lumbar puncture was performed (if clinically feasible) on ill-appearing infants and any infant with a positive blood culture.
Statistical Methods
The incidence of EOGBS disease over the period of 1990–2003 was evaluated by using the Mantel-Haenszel test for trends.23
Approval
This study was approved by the Brigham and Women's Hospital Human Research Committee.
RESULTS
Incidence of EOGBS
January 1, 1997, through December 31, 2003, a total of 67260 live births were recorded at the Brigham and Women's Hospital. Of these births, 1502 were very low birth weight (VLBW) infants (birth weight 400–1499 g). Twenty-five cases of EOGBS were identified; 5 cases occurred in VLBW infants. The annual incidence of EOGBS from 1997–2003 is shown in Fig 1A. The overall incidence during this period was 0.37 cases per 1000 live births. The incidence among VLBW infants was 3.3 cases per 1000 VLBW births. We previously reported the incidence of EOGBS at our hospital from 1990 to 1996.13 Before the use of IAP (1990–1992), the overall incidence of EOGBS was 2.2 cases per 1000 live births and 10.1 cases per 1000 VLBW births. From 1993 to 1996, during which a risk-based approach to IAP was used, the overall incidence was 1.1 cases per 1000 live births and 3.1 cases per 1000 VLBW births. The overall incidence of EOGBS decreased significantly between each of the time periods (Fig 1B). The incidence of EOGBS in VLBW infants also decreased significantly with the institution of a risk-based protocol for IAP, but no additional decline was seen with the change to a screening-based protocol.
Maternal Clinical Characteristics
Maternal GBS-screening results are summarized in Table 1. Of the 25 mothers of the infants in this study, 21 were screened for GBS colonization: 16 of the 25 mothers screened (64%) were GBS negative. Of the mothers of term infants, 14 of 17 (82%) screened negative. Rectovaginal screening cultures were obtained and processed by using methods recommended by the CDC. The cultures were performed routinely at 35 weeks' gestation in the mothers of term infants. The exact timing of culture in relation to delivery could be determined in 8 of the 21 women whose screening cultures were performed at the hospital microbiology laboratory. The mean interval between screening and delivery was 20.2 (±6.8) days (range: 10–28 days) for these 8 women; the interval was slightly shorter for the preterm infants and slightly longer for the term infants.
Nineteen of the 25 mothers (76%) had deliveries complicated by 1 identifiable risk factors for EOGBS in their infants: delivery at <37 weeks' gestation, intrapartum fever of >100.4°C, clinical chorioamnionitis, or GBS colonization (Table 1). Despite the presence of intrapartum risk factors for neonatal sepsis, only 4 mothers received intrapartum antibiotic therapy. In only one instance was intrapartum antibiotic therapy administered >4 hours before delivery as prophylaxis for recognized maternal GBS colonization. Clindamycin and gentamicin were administered in this case because of maternal penicillin allergy, but the GBS later isolated from the infant blood culture was found to be resistant to clindamycin and, like most GBS isolates, was resistant to gentamicin. In the remaining 3 cases, maternal intrapartum antibiotic therapy was administered <4 hours before delivery because of the onset of maternal fever or other signs and symptoms of chorioamnionitis. Neither of the 2 GBS-positive mothers of term infants received IAP: one because of clinical error and the second because a precipitous delivery precluded use of IAP.
Infant Clinical Characteristics
The clinical characteristics of the infants with EOGBS disease are summarized in Table 1. Seventeen of the 25 EOGBS cases occurred in term infants, with a mean gestational age and birth weight of 39.7 (±1.5) weeks and 3738 (±456) g, respectively. Among the term cases, 12 infants either had no signs of illness or were only mildly ill, and 5 were critically ill. One of these infants died despite maximal intensive care support that included extracorporeal membrane oxygenation therapy. Eight cases occurred in preterm infants, with a mean gestational age of 29.8 (±3.8) weeks (range: 26–35 weeks) and birth weight of 1671 (±742) g (range: 890–2722 g). Of the 8 preterm infants, 7 were ill from birth, and 6 of the 8 required mechanical ventilation. Three preterm infants died, for a mortality rate of 37%. Lumbar punctures were performed in 21 of 25 cases, and 2 infants had meningitis. Lumbar punctures were not performed in 4 cases because of death or early transfer of the infant for extracorporeal membrane oxygenation. Taken together, the majority of infants (19 of 25) had signs of illness ranging from mild respiratory distress to multisystem organ failure, and all became ill before 24 hours of life.
Seven well-appearing term infants were evaluated shortly after birth because of intrapartum risk factors for sepsis according to our hospital's guidelines. Five of the 7 were treated with antibiotics because of an abnormal WBC count or multiple clinical risk factors for sepsis. The 5 infants who received empiric antibiotic therapy all remained clinically well. Of the 2 infants who did not receive empiric therapy, 1 later became clinically ill, and the other remained well-appearing but was persistently bacteremic 24 hours after the first blood culture.
Five term infants and 1 preterm infant appeared well at birth but were evaluated for infection after developing signs of illness in the first 24 hours of life. In 3 of these cases, the mothers were screened GBS negative, and there were no other intrapartum risk factors for sepsis. In the other 3 cases, the infants should have been evaluated based on our guidelines because of intrapartum risk factors for sepsis, but by error they were not.
Microbiology and Antibiotic Susceptibility
Polysaccharide serotyping and surface protein molecular typing was performed on the available clinical isolates to determine if a single virulent strain was responsible for all or most of the invasive disease cases. No dominant serovariant of GBS was identified among the isolates (data not shown). Antibiotic sensitivity testing was performed on all isolates. Five of the 25 isolates (20%) were resistant to clindamycin and/or erythromycin. Another 5 isolates were partially resistant to erythromycin or clindamycin as indicated by intermediate-sized (ie, neither fully sensitive nor fully resistant) zones on disk testing. We identified only 1 case in which the infant blood isolate was resistant to the antibiotic administered to the mother. None of the invasive isolates were resistant to penicillin, ampicillin, cephalosporins, or vancomycin, the antibiotics currently recommended for IAP.6
DISCUSSION
The overall incidence of EOGBS in our large maternity center has progressively dropped coincident with adoption of specific policies for IAP for the prevention of invasive GBS disease (Fig 1B). The incidence of EOGBS in VLBW (<1500-g) infants also fell significantly with the implementation of a risk-based approach to IAP. No additional decrease was observed with the change to a screening-based approach; this is not surprising, because most mothers have not yet been screened for GBS colonization when a significantly preterm birth occurs. Cases of EOGBS continued to occur despite routine screening for GBS and incurred significant morbidity and mortality. We sought to identify any clinical, procedural, or microbiologic factors that contributed to these cases, with the hope that changes in practice could further decrease our rate of EOGBS.
Two studies published before the 2002 CDC recommendation for routine screening of pregnant women for GBS colonization addressed some of the reasons for continued EOGBS disease in the era of prophylaxis. Pinto et al24 reported a series of 92 infants with EOGBS disease referred from 23 different centers with inconsistent policies for IAP over their study period (1992–2001). The majority of the mothers (62 of 92) had not been screened for GBS colonization, and most (68 of 92) did not receive IAP. In another study, Velaphi et al25 reported on 32 cases of EOGBS that occurred from 1995 to 1999 in a hospital with a risk-based approach to maternal IAP. This hospital also routinely administered intramuscular penicillin to all newborns immediately after birth, a practice not endorsed by the CDC. Of the 32 cases, 13 infants were born to mothers without risk factors who did not receive intrapartum antibiotics, and 12 infants were born to mothers who received IAP only after the development of intrapartum fever. In both of these reports, the authors concluded that the risk factor–based approach to GBS prophylaxis led to missed opportunities for GBS prevention.
Our study is the first to address continued EOGBS disease in a single maternity service with use of a screening-based approach to IAP. We speculated that continued cases of EOGBS might be caused by problems in several aspects of prenatal and perinatal clinical practice, including the accuracy of GBS screening, communication of GBS-screening results, administration of IAP, or the identification and treatment of infants at risk for EOS. In addition, we sought to determine if microbiologic factors including antibiotic resistance contributed to ongoing EOGBS.
Hospital system or procedural errors in the communication of GBS-screening results or the administration of IAP when indicated did not contribute significantly to ongoing EOGBS in this series. Only 3 cases could be attributed to a failure to administer IAP to a mother known to be GBS positive. We also examined whether failure to recognize and evaluate infants with intrapartum risk factors for infection might have contributed to EOGBS. The majority of well-appearing infants with significant risk factors for sepsis were promptly evaluated, treated with antibiotics, and remained well. The apparent protective effect of empiric antibiotic therapy in preventing clinical illness underscores the importance of ongoing efforts to evaluate infants at risk for EOS even in the setting of a GBS-screening program. We attributed antibiotic resistance as contributing to only 1 case of EOGBS. We were able to obtain the GBS isolates for the majority of cases that occurred after 1999. The combination of polysaccharide capsule and C-protein typing demonstrated that no dominant serovariant accounted for the cases of EOGBS in our hospital during this period.
The most surprising finding of this study is that the majority of cases of continued EOGBS disease in term infants occurred in those delivered to mothers with negative GBS-screening culture results. In addition to precluding the use of effective IAP, the negative prenatal GBS-screening results may have contributed to intrapartum management in a way that increased the risk of sepsis in the infant. Antibiotics are frequently administered to women in labor with signs and symptoms suggestive of chorioamnionitis. The majority of mothers who screened GBS negative had labors complicated by at least 1 established risk factor for sepsis (Table 1), yet only 4 women received intrapartum antibiotic therapy. It is possible that the negative GBS screens provided a false sense of reassurance to obstetrical providers. If the mothers in these cases had an unknown GBS status, it is likely that antibiotics for IAP in the presence of risk factors, or for treatment for chorioamnionitis, would have been given and perhaps prevented some of the cases of EOGBS.
Whether these negative cultures were false-negative results or the mothers acquired GBS in the interval between the screening culture and the time of delivery is unknown. Technical factors known to contribute to false-negative GBS-culture results are specifically addressed in the 1996 and 2002 CDC recommendations,6 including the use of cervical or vaginal swabs rather than rectovaginal sampling, poor swab storage and transfer practices, and use of inappropriate culture media.6,26–30 Obstetricians who deliver infants at the Brigham and Women's Hospital are required by protocol to obtain rectovaginal swabs for GBS screening. The GBS cultures are performed in only 2 laboratories: either the hospital microbiology laboratory or a single private laboratory. Both are experienced laboratories that handle thousands of cultures yearly and use culture-transport and processing practices that strictly adhere to CDC laboratory-practice guidelines for GBS-screening culture. One limitation of this study, however, is that it is difficult to assess in retrospect the possible contribution of poor obstetrical technique to the negative screening results. Failure to culture GBS even with ideal sampling and culture techniques may also be caused by maternal factors. The use of oral antibiotics or a variety of feminine hygiene products (including douches, vaginal candidiasis medications, and inert lubricants) before specimen collection may inhibit GBS growth in culture31 and contribute to false-negative results.
It is possible that some of the mothers in our study who screened negative were indeed not colonized with GBS at the time of screening but colonized at the time of delivery. Recent longitudinal data suggest that the prevalence of GBS colonization among American women is higher than is obvious from prenatal screening data, with up to 75% of women colonized with GBS at some time over a 12-month period.32 Multiple studies have also demonstrated that GBS colonization varies during pregnancy.33–35 Boyer et al28 first evaluated the concordance of prenatal GBS colonization status with colonization at the time of delivery. In this study, 8.5% of women with negative GBS cultures at 26 to 28 weeks' gestation were found to have acquired GBS colonization by the time of delivery. The results of this study prompted the CDC to recommend a shift from obtaining GBS-screening cultures at 26 to 28 weeks' gestation to closer to term at 35 to 37 weeks' gestation.2 To determine the predictive value of screening later in gestation, Yancey et al36 performed rectovaginal cultures on 826 women at 33 to 39 weeks' gestation and again at presentation for delivery. In this study, 4% of women with negative antenatal cultures were found to be colonized at delivery.
A 4% false-negative GBS-screening rate could have a significant impact on continued EOGBS. Seventy-two percent of women delivering at term at the Brigham and Women's Hospital screened GBS negative in 2002 (E. Lieberman, MD, DrPH, written communication, 2004). Assuming that 72% of pregnant women during our entire study period screened GBS negative, and 4% of these were false negative, 20 infants would have developed EOGBS in our delivery population (assuming an attack rate of 1%), which is consistent with our findings. Multiple epidemiologic studies demonstrate that the overall rate of GBS colonization among American women ranges from 20% to 30%.37 Given this range of colonization, a 4% false-negative rate in GBS screening alone could account for 0.3 of 1000 cases of EOGBS per year.
A potential alternative to antenatal GBS-screening culture is the identification of GBS colonization at presentation for delivery. Antigen-based and DNA-probe–based methods to detect GBS carriage have failed to demonstrate adequate sensitivity when compared with standard culture techniques.38 Recent data suggest that real-time PCR-based methodology can equal or surpass the sensitivity of antenatal culture at 35 to 37 weeks' gestation. Bergeron et al39 demonstrated that a real-time, fluorogenic PCR assay compared favorably to standard culture methods for the detection of GBS colonization at presentation for delivery. This assay has been developed commercially (IDI-Strep B test, Cepheid, Sunnyvale, CA) and was approved for use by the Food and Drug Administration in 2003.40 Using culture at presentation for delivery as the reference, a recent study demonstrated that the IDI-Strep B test had greater sensitivity than standard antepartum culture and equivalent specificity for the identification of colonization at delivery.41 It is unclear, however, whether similar results would occur with actual clinical use, and questions of costs and logistics remain unanswered.
CONCLUSIONS
The implementation of a screening-based approach to the management and prevention of GBS disease has been accompanied by a dramatic decrease in the overall rate of neonatal EOGBS in our large maternity service. Cases of EOGBS continue to occur, with significant morbidity and mortality, particularly in preterm infants. Although procedural errors may have contributed to a few cases, the majority of cases of EOGBS occurred in infants whose mothers had screened negative for GBS colonization. Our results demonstrate that prompt intrapartum antibiotic treatment of women with signs and symptoms of chorioamnionitis regardless of their GBS-screening results and the evaluation of well-appearing infants for possible sepsis because of intrapartum clinical risk factors remain imperative. Until effective GBS vaccines are available for clinical use, rapid and accurate diagnostic screening of women when they present for delivery may be the most effective approach to additional prevention of neonatal GBS disease in the current era of screening-based IAP. A large-scale, multicenter, controlled trial designed to evaluate the accuracy of real-time PCR-based diagnostics compared with antenatal culture-based screening in predicting maternal GBS colonization at delivery is warranted.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health grants HD041534 and AI38424, National Institutes of Health contract N01-AI-25495, and a grant from the Children's Hospital, Boston Office of Faculty Development.
We thank Meaghan Gilmore, Laura Stulgis, and Christopher Jordan for technical assistance; Dr Andrew Onderdonk and the staff of the Brigham and Women's Hospital Microbiology Laboratory for providing the group B streptococcus disease isolates; Nancy Jeffery Harrison for performing the microbiology database computer searches; Dr Ellice Lieberman for statistical analyses; Dr Cynthia Cole for critical review of the manuscript; Dr William Tarnow-Mordi for helpful discussion; and Dr Dennis Kasper for ongoing support of our work.
FOOTNOTES
Accepted Feb 7, 2005.
No conflict of interest declared.
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