Group B Streptococci Perinatal Infections: A Comprehensive Review
Dr. Ronald S. Gibbs, MD
Professor and Chair
Department of Obstetrics and Gynecology
E. Stewart Taylor Professor
University of Colorado Health Sciences Center
Denver, Colorado (USA)
Group B streptococci (GBS) emerged dramatically in the 1970s as the leading cause of neonatal infection and as an important cause of maternal uterine infection. In 2002, new national guidelines were released recommending: 1) solely a screen-based prevention strategy, 2) a new algorithm for patients with penicillin allergy, and 3) more specific practices in certain clinical scenarios. In the pre-prevention era, active surveillance for invasive neonatal GBS disease estimated that approximately 6,100 early-onset cases and 1,400 late-onset cases occurred annually in the United States. As prevention implementation increased in the mid 1990s, disease incidence declined by 70% to a rate of 0.5 cases per 1,000 live birth. Based on active multi-state surveillance data of 2002, 1,570 early-onset cases (0.4 cases/1,000 live births) and 110 deaths occurred nationally.
The purpose of this document is to address clinical issues of group B streptococci (GBS) perinatal infection, implementation of new diagnostic techniques, management of preterm rupture of membranes, use of alternative antibiotic approaches, improvement of compliance, prevention of low birthweight infants, emergence of resistant organisms and vaccine development.
The Group B Streptococci:
In 1933, Lancefield reported her classic taxonomic classification of beta-hemolytic streptococci. The most common groups causing human infection are: A (Streptococcus pyogenes), B (S. agalactiae), and, D which include enterococci. Groups C and G are occasional causes of infection in humans. Group B streptococci are facultative, gram-positive diplococci, with approximately 99% of strains showing beta (complete) hemolysis on blood agar plates. Several serotypes of GBS have been identified. The predominant types causing disease are Ia, Ib, II, III, and more recently, V. Among genital isolates from pregnant women, the distribution has been reported as Ia -- 38%, Ib-11%, II-7%, III-26%, and V-18%. In cases of late-onset neonatal disease, isolates are predominantly type III.
Maternal Colonization: The lower gastrointestinal tract and vagina are often colonized with GBS. Transient, intermittent, or chronic colonization of GBS can occur and it can be isolated from swabs of the vagina, rectum or both sites, and swabbing both lower vagina and rectum is recommended to increase the sensitivity of prenatal screening. An estimated 20-30% of all pregnant women are GBS carriers, and it is likely that GBS colonizes virtually every female at some point. Because colonization can be intermittent or transient, culture status can vary between pregnancies, and screening during each subsequent pregnancy is advised. The predictive value of perinatal screening improves with shorter intervals between culture and delivery, so that prenatal screening at 35-37 weeks of gestation is currently recommended in the United States. Chemoprophylaxis at delivery should be based upon the 35-37 week culture even if early cultures were obtained.
Neonatal Disease: In newborns, GBS can cause sepsis, pneumonia, meningitis, and less frequently, focal infection such as osteomyelitis, septic arthritis, or cellulites. Early-onset disease occurs within the first week of life, with most of these cases evident on the day of birth or within 72 hours. Late-onset disease occurs after the first week, and cases are relatively evenly distributed through 90 days of age. Now that early-onset disease rates have declined, the ratio of early- to late-onset GBS neonatal disease is approximately 1:1. Clinical presentations of early-and late-onset disease overlap, although 24% of late-onset disease presented as meningitis compared with only 6% of early-onset disease. Although survival has improved in recent years it remains lowest for preterm infants. For infants at more than 37 weeks with GBS sepsis, survival is very good at 98%, but for preterm infants the survival is lower, at 90% for cases at 34-36 weeks and 70% for cases at less than 33 weeks. It is these suboptimal outcomes that prompted the search for effective prevention strategies. Since meningitis can occur in up to one third of late-onset cases, risk of long-term neurologic sequelae seems to be higher among survivors of late-onset disease compared with early-onset.
Maternal Disease: In the mother, GBS can cause urinary tract infection, chorioamnionitis, endometritis, bacteremia, and most likely stillbirth. In urinary tract infections in pregnant and non-pregnant women, the most common isolates are E. coli and then other aerobic, gram-negative rods collectively accounting for 80-90% of cases. Gram-positive infections, including enterococci, Staphylococcus saprophyticus, and GBS are responsible for the remainder. When amniotic fluid has been cultured from such cases, polymicrobial results are usually reported. GBS is isolated in about 15% of these cases. Among postpartum women with GBS infection, fever occurred early, with 80% being evaluated within 24 hours of delivery. A recent review identified GBS as a "common cause of stillbirth." Although stillbirths due to GBS seem to have decreased substantially in the United States, in other countries such as Sweden, GBS are the most common bacterial infections associated with stillbirth.
Although definite microbiologic identification is done by serologic detection of the group B antigen, presumptive tests are used in clinical laboratories and include the Christie, Atkins, and Munch-Peterson (CAMP) test, bile esculin reaction and bacitracin sensitivity. Presumptive identification of GBS, based upon colonial morphology and gram stain, can often be made within 24 hours of plating on blood agar. A final report is usually available within 48 hours.
To optimize yield of GBS from recto-genital tract specimens, it is necessary to use selective media to suppress the growth of competing bacteria. In 2002, CDC Guidelines provided directions for collecting and processing these specimens. These guidelines continue to recommend a recto-vaginal specimen to obtain optimal yield of GBS.
Following are the recommended procedures for collecting and processing clinical specimens for group B streptococcal (GBS):
- 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. Culture should be collected in the outpatient setting by the health-care provider or the patient herself, with appropriate instruction. Cervical cultures are not recommended and a speculum should not be used for culture collection.
- Place the swab(s) into a non-nutritive transport medium. Appropriate transport systems (e.g., Amies or Stuart's without charcoal) are commercially available. If vaginal and rectal swabs were collected separately, both swabs can be placed into the same container of medium. Transport media will maintain group B streptococcus (GBS) viability for up to 4 days at room temperature or under refrigeration.
- Specimen labels should clearly identify that specimens are for group B streptococcal culture. If susceptibility testing is ordered for penicillin-allergic women, specimen labels should also identify the patient as penicillin-allergic and should specify that susceptibility testing for clindamycin and erythromycin should be performed if GBS is isolated.
Because of its uniform activity, penicillin G remains the drug of choice for clinically evident maternal infection with GBS for GBS prophylaxis. In clinical practice, therapy of genitourinary infection in pregnant and puerperal women is most often initiated empirically before culture results are available. In view of 1) the polymicrobial nature of chorioamnionitis and 2) the lack of a rapid, reliable test to detect specific organisms in a given case, treatment recommendations for this common infection are for empiric, broad-spectrum (usually combination) intravenous antibiotic therapy and for delivery.
Following are the recommended regimens for intrapartum antimicrobial prophylaxis for perinatal group B streptococci disease prevention:
Penicillin G, 5 million units intravenously (IV) initial dose, then 2.5 million units IV every 4 hours until delivery.
Ampicillin, 2 gm IV initial dose, then 1 gm IV every 4 hours until delivery.
If Penicillin Allergic:
(Patients not at high risk for anaphylaxis)
Cefazolin, 2 gm IV initial dose, then 1 gm IV every 8 hours until delivery.
(Patients at high risk for anaphylaxis and isolate shown to be susceptible to erythromycin and clindamycin.
Clindamycin, 900 mg IV every 8 hours until delivery
(GBS resistant to clindamycin or erythromycin or susceptibility unknown
Vancomycin, 1 gm IV every 12 hours until delivery.
Briefly, newborns with suspected sepsis are initially treated empirically, with intravenous ampicillin and an intravenous aminoglycoside, a combination that includes activity against GBS as well as other common neonatal pathogens. If there is bacteremia without meningitis, this initial treatment is recommended for 48-72 hours (until culture results are available). If GBS are the sole isolate, then therapy with intravenous penicillin G is continued to complete a total course of 10 days. If meningitis complicates the picture, then intravenous ampicillin and intravenous gentamicin are continued until the cerebrospinal fluid is sterile, and then intravenous penicillin G is continued to complete the minimum course of 14 days.
Prevention of perinatal GBS infection:
Several clinical trials have demonstrated that use of intravenous antibiotics during the intrapartum period is highly effective at preventing early-onset neonatal GBS infections. Use of intrapartum prophylaxis has also been shown to be cost-effective in the United States. Universal prophylaxis for deliveries is not advisable, because only a small percentage of women in labor are at risk of transmitting GBS to their newborns, and universal prophylaxis would lead to vast overuse of intrapartum antibiotics. Indications for intrapartum antibiotics prophylaxis to prevent perinatal GBS disease under a universal prenatal screening strategy based on combined vaginal and rectal cultures collected at 35-37 weeks of gestation from all pregnant women are:
- Intrapartum prophylaxis indicated
- Previous infant with invasive GBS disease
- GBS bacteriuria during current pregnancy
- Positive GBS screening culture during current pregnancy (unless a planned cesarean delivery, in the absence of labor or amniotic membrane rupture, is performed)
- Unknown GBS status (culture not done, incomplete, or results unknown) and any of the following: Delivery at <37 weeks of gestation; amniotic membrane rupture >18 hours and intrapartum temperature >100.4 F (>38.0C)
- Intrapartum prophylaxis not indicated
- Previous pregnancy with a positive GBS screening culture (unless a culture was also positive during the current pregnancy)
- Planned cesarean delivery performed in the absence of labor or membrane rupture (regardless of maternal GBS culture status)
- Negative vaginal and rectal GBS screening culture in late gestation during the current pregnancy, regardless of intrapartum risk factors
Preterm Premature Rupture of Membranes (PROM):
Preterm premature rupture of the membranes places the fetus or newborn at double risk for GBS sepsis, based upon the combination of prematurity and prolonged membrane rupture. Although the 2002 CDC Guidelines provide rationale of the antibiotics use, specifics of the management are left to the individual providers to prevent maternal or neonatal complications such as chorioamnionitis, neonatal infection, and neonatal sepsis.
Onset of labor or rupture of membranes at <37 weeks of gestation with significant risk for imminent preterm delivery:
- No GBS culture -- obtain vaginal and rectal GBS culture and initiate IV penicillin. If there is no growth at 48 hours, discontinue penicillin. If GBS positive, give penicillin IV for >48 hours and intrapartum antibiotic prophylaxis at delivery.
- GBS Positive -- penicillin IV for >48 hours (during tocolysis) and intrapartum antibiotic prophylaxis.
- GBS Negative -- no GBS prophylaxis.
Detailed sample antibiotic algorithm for PROM:
- PROM before viability less than approximately 24 weeks -- no GBS prophylaxis and no antibiotics to prolong gestation.
- PROM between 25 to 33 weeks:
- Obtain GBS ano-rectal culture; begin ampicillin 2 gm IV initially, then 1-2 gm IV intravenously every 4-6 hours plus erythromycin 250 mg IV every 6 hours for 48 hours. Then if patient is still undelivered, give amoxicillin 250 mg every 8 hours plus erythromycin 333 mg orally every 8 hours until labor or to complete 7 days.
- If the GBS ano-rectal culture was negative before start of the antibiotic regimen, there is no need to give intrapartum antibiotics to prevent GBS perinatal infection.
- If the GBS ano-rectal culture was positive before the start of the antibiotic regimen, then our approach is to re-culture for GBS while the patient is taking the ampicillin plus erythromycin regimen to determine whether colonization was suppressed. If the GBS culture remains positive, we restart with the rationale of preventing ascending GBS infection and chorioamnionitis. There is no standard regimen, but our recommendation is to give IV ampicillin for an additional 5-7 days.
- PROM greater than 33 weeks:
- Do not give antibiotic regimen to prolong delivery.
- If GBS ano-genital culture status is unknown (i.e., gestation is less than 35-37 weeks), obtain GBS ano-rectal culture.
- If the GBS culture status is positive or unknown, give IV penicillin G for 48 hours. Approximately 48 hours after completion of this, re-culture, and if GBS remains positive, treat for another 48 hours to prevent ascending infection and chorioamnionitis.
- If GBS culture result is negative, then discontinue antibiotics at this juncture.
- General Recommendations:
- Regardless of the management strategy used, patients (greater than or equal to 24 weeks gestation) with positive GBS culture or unknown GBS status should also receive intrapartum antibiotic chemoprophylaxis for GBS when labor ensues.
- If clinical chorioamnionitis develops, broad-spectrum therapy should be started empirically in recognition of the polymicrobial cause of this infection.
- The accuracy of GBS ano-rectal cultures in predicting colonization status at delivery is most predictive if collected within 5 weeks of delivery. If a patient remains undelivered for 4 weeks after her screening culture, she should be screened again, especially if the initial culture was negative.
Clinical Questions and Situations:
The 2002 CDC Guidelines recommend not treating GBS-colonized women in antepartum period, because it has no benefit and would expose approximately 1 million pregnant women per year in the United States to unnecessary antibiotics. Maternal anaphylaxis to penicillins or cephalosporins is possible, but the rate of life-threatening reactions is relatively low. The ecologic impact of large increases in antibiotic use in labor and delivery on the maternal and newborn bacterial flora remains a central concern, particularly that reductions of GBS cases would be followed by increased occurrence of other species, especially gram-negative organisms and penicillin- or ampicillin- resistant bacteria.
Emergence of Resistant Organisms
Although group B streptococci remain uniformly susceptible to penicillin, concerns have centered on whether increased use of penicillin or ampicillin for intrapartum prophylaxis will lead to increases in illness associated with antibiotic-resistant organisms other than group B streptococci. Recent studies have shown, vaginal colonization with Enterobacteriaceae among women randomly assigned to either intrapartum benzyl-penicillin or ampicillin found that either agent led to significant increases in colonization with ampicillin-resistant organisms 36 hours postpartum.
Obstetric Procedures in a GBS Positive Woman
Analysis of available studies found no significant increase in overall perinatal or peripartum infection when women who had membrane sweeping were compared with those who did not have this procedure. Nevertheless, because the benefits of membrane sweeping are limited, we suggest avoiding membrane sweeping in GBS-positive women. If there is an indication for delivery, there are many alternative interventions to membrane sweeping such as vaginal prostaglandin preparations. Frequent vaginal examinations in labor and intrauterine-fetal monitoring have been associated with chorioamnionitis and endometritis. In GBS-positive women, the obstetrician should not avoid appropriate vaginal examinations nor avoid indicated intrauterine fetal monitoring.
Because the vast majority of maternal and neonatal GBS disease is caused by a small number of GBS serotypes, researchers began to explore development of vaccines shortly after GBS emerged. Immunization strategies hold promise to prevent a larger burden of disease, protecting against both early- and late- onset infections. Moreover, vaccination may prevent some adverse pregnancy outcomes associated with GBS, such as preterm delivery, spontaneous abortion, or stillbirth, particularly if vaccination of adolescent girls before pregnancy is a viable strategy. Additionally, immunization strategies would not contribute to emerging antimicrobial resistance among GBS. Liability concerns of researching a vaccine with an indication for use in pregnant women pose perhaps the larger obstacle, and to date, pharmaceutical company backing for phase III trials has not been obtained.
CDC Resources for GBS Prevention
Suggested Reading: Ronald S. Gibbs, Stephanie Schrag, Anne Schuchat. Perinatal Infections Due to Group B Streptococci. Obstetrics & Gynecology. Vol. 104, No. 5, Part 1, November 2004. Publication of The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.
We, at Women's Health & Education Center (WHEC) express gratitude to Dr. Ronald S. Gibbs for sharing his work and research with us. His priceless work has helped many women all over the world. We look forward to work with him for a long time to come. Thanks again, Dr. Gibbs.
Dedicated to Women's and Children's Well-being and Health Care Worldwide