An overview of rapid screening and augmented screening techniques that impact sensitivity and a look at potential opportunities for appropriate antibiotic prophylaxis against neonatal infection.
Maternal screening and antibiotic prophylaxis guidelines for Group B Streptococcus (GBS) has significantly evolved over the past 2 decades. Gaps in current maternal screening and treatment remain, however, impacting efforts to prevent infection in the potentially at-risk neonate.
This review article provides an overview of screening and addresses rapid screening and augmented screening techniques that impact sensitivity. It also outlines other potential opportunities for appropriate antibiotic prophylaxis against neonatal infection.
GBS screening in pregnancy is focused on prevention of neonatal disease via transmission during vaginal delivery. GBS was first studied in the peripartum period in the 1930s in an attempt to explain frequent cases of maternal sepsis.1,2 It took another 30 years for studies to associate GBS infection in mothers with transmission to the neonate.3 Neonatal GBS sepsis is classified as early or late onset, with the former type occurring within the first week of life.
Disease incidence for early-onset GBS neonatal sepsis in the United States was as high as 2 per 1000 live births in the 1970s.4 In 2008, the Centers for Disease Control and Prevention (CDC) reported that the figure had fallen to approximately 0.3 per 1000 live births, which translates to an estimated 1200 cases per year (Figure 1). Antenatal screening and maternal antibiotic treatment during labor have primarily reduced the burden of disease. Advances in pediatric medicine also have significantly reduced the case fatality rate from an estimated 50% in the 1970s to 4% to 6% in recent years. Because intrapartum treatment does not impact late-onset GBS, the epidemiology has not changed.
The first formal screening guidelines for GBS in pregnancy were released in 1992, based on the joint efforts of The American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) (Figure 2).5 These guidelines supported GBS screening and treatment aimed at reducing early-onset GBS neonatal disease. In 1994, Rouse et al evaluated 19 different protocols for screening/treatment and the 2 most effective ones were endorsed in the CDC’s 1996 guidelines.6 Those guidelines included a screening-based approach of providing intrapartum antibiotic prophylaxis based on positive antepartum screening or risk-based treatment (that is, < 37 weeks’ gestation, duration of membrane rupture >18 hours, or temperature >100.4° F), defined the appropriate methods of collection from the lower vagina and rectum, and specified the time point for screening as 35 to 37 weeks’ gestation.7 This time point was based on the premise that standard culture had a negative predictive value of 95% to 98%, which dramatically fell to 80% after 5 weeks.8
In its 2002 revised guidelines, the CDC recommended universal antepartum screening between 35 and 37 weeks’ gestation.9 Evidence for that recommendation was based on a population study of more than 600,000 women that showed that the screening strategy prevented 54% more cases of early-onset GBS neonatal disease than the risk-based approach.10 In 2010, the CDC updated the 2002 guidelines and included additional information about preterm labor and preterm premature rupture of membranes (PPROM), elimination of erythromycin use, and optimal administration of intrapartum antibiotic prophylaxis for 4 hours prior to delivery, and provided an algorithm for the penicillin-allergic patient.11
Despite the positive impact of universal screening, GBS neonatal infections still occur, which suggests opportunities to further define those at risk of early-onset infection. A recent prospective cohort analysis of almost 400,000 infants from 2006 to 2009, showed that in 160 neonates diagnosed with early-onset GBS sepsis, only 63% of the term mothers and 44% of the preterm mothers were screened, clearly reinforcing the need for education regarding screening among patients and providers.12 Furthermore, in neonates with early-onset GBS disease, approximately 81% of the term mothers who were screened had a GBS-negative result, suggesting either suboptimal collection techniques or a true change in maternal colonization status.12
The most recent ACOG Committee Opinion on prevention of early-onset GBS in newborns, dated April 2011, outlines methods for specimen collection and handling:
Swab the lower vagina (vaginal introitus), followed by the rectum (i.e. insert swab through the anal sphincter) using the same swab or two different swabs. Cultures should be collected by the health care provider or, with appropriate instruction, the patient herself. Cervical, perianal, perirectal, or perineal specimens are not acceptable, and a speculum should not be used for culture collection.13
Cervical samples yield 40% fewer positive cultures than do single vaginal swabs.14 Studies have shown that sampling the vaginal and rectal regions in combination yields a significantly higher percentage of GBS colonization.15,16 Perianal swabs may be equivalent to rectal swabs.17,18 However, perianal collection may be suboptimal and therefore is not formally endorsed.13 Updates of CDC and ACOG bulletins have attempted to clarify the sampling methods in order to standardize provider practices and to minimize the likelihood of suboptimal collection and false-negative results.
Self-collection of GBS cultures, with appropriate instruction, is considered an acceptable alternative. A randomized crossover study of 330 women in Canada showed that the sensitivity for the self collection-87.5% (95% CI, 77.0-93.8)-was fairly high when compared with clinician-obtained sensitivity of 96.9% (95% CI, 88.7-99.8).19 A study involving 251 pregnant women found 98.4% sensitivity among those who self-collected GBS swabs.20
Laboratory testing with culture media, which typically requires 36 to 72 hours of incubation time, remains the gold standard. The most recent CDC guidelines recommend rapid testing, which takes < 30 minutes for results and has > 90% accuracy.11
The technical limitation with the original blood agar plates was overgrowth of other bacteria, which would limit the detection of GBS.21 Modifications to this technique included addition of agents to suppress other bacteria and an enrichment broth to promote GBS growth.22 The current gold standard after inoculation is to use selective enrichment broth (that is, Lim Broth, TransVag Broth or Carrot Broth) and incubate for 18 to 24 hours. That is followed by a subculture using selective media for another 18 to 24 hours. If colonies are present, they undergo extraction to determine if Group A or B streptococcus is present and, if necessary, susceptibility testing for antibiotics (another 12 to 24 hours).
The need for prolonged incubation does not allow for point-of-care testing in labor. Therefore, many forms of rapid testing have been tried during the past 30 years. Rapid testing was first examined, using latex agglutination methods, in the 1980s, but it had poor sensitivity in those lightly colonized.23 Optical immunoassay, enzyme immunoassay, and DNA hybridization all involved binding of GBS-unique antigens or RNA segments. Despite the dramatic reduction in processing time, these methods are suboptimal because of the wide range of sensitivity and specificity values.24
In the past 15 years, the use of polymerase chain reaction (PCR) or nucleic acid amplification tests (NAAT) has been intensely studied to improve speed and accuracy of GBS antepartum and intrapartum testing.25,26 The two main tests-Xpert GBS Assay and IDI-Strep-utilize primers targeting specific DNA regions unique to GBS and do not require incubation with broth media. The most recent versions of the tests consistently have sensitivities of greater than 90% (Table 1).27-33
PCR tests have not been universally implemented in hospitals and outpatient laboratories, primarily due to cost and inability to run susceptibility testing if a culture tests positive. However, as technology advances and costs are driven down by increased utilization, the high sensitivity values make PCR-based tests more attractive options for intrapartum and possibly even antepartum cultures. Cost/benefit analysis models have shown a potential $6 benefit per birth if intrapartum PCR testing were used, compared with standard culture at 35 to 37 weeks’ gestation.34
Rapid intrapartum GBS screening is ideal for women who have scant or no prenatal care, or those who present with preterm labor or PPROM. Utilizing PCR tests that give results in 1 to 2 hours for certain high-risk patients is more optimal than treatment according to risk factors. If a delay in receiving antibiotics is a concern, these patients may empirically receive 1 dose after the intrapartum screening. Then once the results are back, their care can be modified based on the results, thereby minimizing unnecessary exposure of the neonate to empiric antibiotic treatment.
The 2011 ACOG Committee Opinion provides an algorithm for women with unknown culture results and those with preterm labor or PPROM. While the Opinion does not suggest the use of rapid screening in these situations, it seems a logical alternative to empiric antibiotic prophylaxis or prolonged treatment in the neonatal period. Furthermore, a negative rapid test result has specific implications in a penicillin-allergic patient for whom clindamycin or vancomycin is the alternative antibiotic, in that such a drug would not be necessary under a negative-rapid-test scenario.
More recent work has been published using 35- to 37-weeks’ gestation antepartum cultures and correlating those results with intrapartum cultures. In contrast to the 87% sensitivity reported by Yancey et al,8 sensitivity values have been as low as 54.3% to 69.2% (Table 2).
As mentioned previously, interval conversion of maternal colonization also may contribute to the lower sensitivity values for standard antepartum cultures. However, suboptimal collection methods and lower levels of colonization also may be contributors to false-negative results. More sensitive DNA amplification assays may be beneficial in confirming a true positive in women with lower levels of colonization.
Improved sensitivity for GBS detection potentially can be achieved with available modified testing techniques. These GBS tests first utilize a broth enrichment step, and then incubation for 18 to 24 hours, followed by PCR amplification of a GBS-specific primer to Streptococcusagalactiae, which takes approximately 1 hour. Illumigene, an example of such a modified test, targets the highly conserved 213 base-pair sequence of the S agalactiae genome found in all 8 GBS strains. The combination of steps yields a sensitivity of 98.6% (95% CI, 96.5-99.5) and specificity of 93.2% (95% CI, 91.6-94.5). This test was designed to improve accuracy of antepartum GBS screening and is not intended for intrapartum use.
Data demonstrating greater sensitivity than standard culture are based on the fact that 64 culture-negative specimens were positive by both illumigene GBS and an independent molecular method. BD GeneOhm is another combination PCR test that has a somewhat wider range of sensitivity, depending on the culture media used for enrichment (92.5%-100%).26 Further studies will verify the potential benefits of these methods in confirming higher sensitivity in detecting antepartum GBS colonization.
Additional studies are needed to re-evaluate the optimal time for screening, because testing closer to the time of delivery may identify more women who are false-negative. Efforts at minimizing false-negatives are central to identifying women who should receive intrapartum antibiotic prophylaxis to prevent neonatal GBS disease.
--Early-onset GBS neonatal sepsis has significantly declined with widespread screening and treatment in labor over the past 20 years.
--ACOG defines proper sample collection to include a swab of the lower vagina (vaginal introitus) and the rectum (inside the anal sphincter).
--Rapid testing by PCR amplification will be increasingly useful in patients who are late entries to prenatal care or have preterm labor or PPROM and can potentially avoid overuse of neonatal antibiotics and prolonged neonatal hospital stay.
--Wider use of DNA amplification assays may provide a benefit of higher sensitivity and minimize false negatives.
--Further investigation is needed to re-evaluate the timing for antepartum screening.
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