Arie Alkalay, MD

In the newborn period, group B         streptococcus agalactiae infection is the leading cause of sepsis in the         United States.[1] The overall attack rate of early onset GBS infection         (EOGBSI) per 1000 deliveries ranges from 0.72 to 5.5.[3] In term         infants, the attack rate ranges from 0.5 to 1.5 per 1000 deliveries.[1]         In premature infants, the attack rate (in parenthesis) correlates         inversely with the birth weight; the estimates are: <1000 g (7.6 [4]         - 26.2 [5]), 1001-1500 g (1.7-18.8) , 1501-2000 g (6.7- 11.0), and         2001-2500 g (3.2-4.8).[4]

Early onset GBS infection (less than 7         days of age) and late onset GBS infection (7 days to three months) has         estimated mortality rates of 15% and 10%, respectively.[1] Term infants         have mortality rates of 2% to 8% and premature infants 25%-30%.[1] Each         year, of 3.5 million babies born in the United States[5], approximately         12,000 infants develop morbidity or mortality from GBS infection, 1600         have neurologic sequelae following meningitis, and 1600 die.[1]

Epidemiology and Clinical         Manifestations

When both lower vaginal and anorectal         sites are sampled and inoculated into selective broth media (Todd-Hewitt         broth containing 5% defibrinated sheep blood, 8 mcg/mL gentamicin and 15         mcg/mL nalidixic acid), virtually 100% of the GBS carriers are         detected.[6] Culturing the cervix alone, or not using selective broth         media may fail to identify as many as 50% of the GBS carriers.[6]         Colonization can be chronic (40%), intermittent or transient.[7]         Although overal colonization rates do not vary by trimester, only 4% to         7% of women who had negative vaginal and anorectal cultures late in         second trimester will have positive GBS culture at delivery [7,8], and         approximately 33% of the women who had positive GBS cultures during the         second trimester (weeks 15 to 28) have negative cultures at delivery.[9]

Approximately 20% of pregnant women         harbor group B streptococci in the lower genital tract.[10] Two studies         involving 2040 and 327 pregnant women, employing combined vaginal and         rectal cultures using selected broth media and performed in the third         trimester, showed colonization rates of 16.3% and 21%,         respectively.[11,12] Vertical transmission from GBS colonized mothers         results in colonization of 40% to 73% of their newborns; but only 1% to         2% will develop invasive disease (EOGBSI).[13]

In pregnant women, GBS infection may         cause urinary tract infection, sepsis, chorioamnionitis, postpartum         endometritis, pelvic thrombophlebitis, and endocarditis . In newborns,         the major manifestations of GBS infection are congenital pneumonia,         sepsis and meningitis.

The American Academy of Pediatrics (AAP)         [1] and American College of Obstetricians and Gynecologists (ACOG) [14]         have identified the following intrapartum risk factors as indications         for antibiotic prophylaxis to prevent EOGBSI:

Prematurity ( < 37 weeks             gestation).

Premature rupture of membranes (             <37 weeks gestation).

Prolonged rupture of membranes (             >18 hours) at all gestational ages. When membranes have been             ruptured for 12 hours, an assessment of the likely duration of labor             should be made so that chemoprophylaxis can be initiated if rupture             is considered likely to extend 18 hours.

Maternal fever ( >37.5 C or             >99.5 F).

In contrast to ACOG, the AAP considers         previous delivery of a sibling with GBS infection an indication for         intrapartum maternal chemoprophylaxis regardless of maternal GBS status.

Screening and Chemoprophylaxis         Strategies

Currently, no universal maternal GBS         screening is mandated. As many as seven percent of the GBS negative         mothers cultured late in the second trimester (by combined vaginal and         rectal cultures in selective broth media) will be positive at         delivery.[8] Conversely, approximately 33% of the GBS positive mothers         identified late in the second trimester, will be negative at         delivery.[9] Thus, intrapartum identification of the carriers would be         desirable. It would avoid exposure of women who are GBS positive and         their infants to antibiotics if the mothers become negative at delivery.         At least as important, intrapartum testing will identify GBS positives         women who were negative earlier in pregnancy. Unfortunately, reliable         rapid diagnostic tests, which would be ideally suited for this         situation, are not available at the present time.

The American Academy of Pediatrics         recommends screening of all pregnant women for GBS at 26-28 weeks         gestation.[1] The GBS cultures should be obtained from two sites (lower         vagina and anorectum) using separate swabs, and placed into a single         tube of selective broth media. If carrier mother has symptoms of GBS         infection, has GBS bacteriuria or requires cerclage during antepartum         period, she should be treated. At the present time, the ACOG and AAP do         not recommend chemoprophylaxis of carrier mothers in labor who have no         risk factors. Chemoprophylaxis would place many mothers at risk of         reaction to penicillin. Additionally, in many cases the carrier state         will not be eradicated by penicillin, and approximately 33% of the         carrier mothers will not be colonized at the time of delivery in absence         of prophylaxis.

If the mother is a carrier, with one or         more risk factors at the onset of labor or at the time of rupture of         membranes, intrapartum intravenous ampicillin should be administered.         Two grams are given initially followed by 1-2 g every 4-6 hours until         delivery. Alternatively, penicillin G can be used, at a dose of 5         million Units every 6 hours. If there is a history of penicillin         allergy, erythromycin 500 mg every 6 hours or clindamycin 900 mg every 8         hours should be given intravenously. Ideally, chemoprophylaxis should be         administered at least 4 hours prior to delivery. This allows sufficient         time for the antibiotics to achieve optimal concentrations in placental         circulation and amniotic fluid.[15] If the mother has had premature         labor, or has had premature rupture of membranes and her GBS status is         unknown, the mother should be cultured by one of the rapid cultures if         available, or by selective broth cultures. Those who are positive should         be treated. Whether those for whom no results are available should be         treated should be left to the discretion of the treating obstetrician.         Mothers who develop chorioamnionitis should receive therapy rather than         chemoprophylaxis. Therapy for chorioamnionitis consists of intravenous         ampicillin 2 g every 4 hours and gentamicin 1.3-1.6 mg/kg every 8 hours,         or an equivalent regimen. Therapy should be continued until symptoms and         signs resolve and the patient is afebrile for at least 24 hours.

Maternal chemoprophylaxis decreases the         incidence of EOGBSI when risk factors for GBS infection are present at         delivery.[16,2] However, it is estimated that chemoprophylaxis fails to         prevent up to 30% of EOGBSI and 10% of the fatalities.[16,17]

Management of Infants of GBS Carrier         Mothers

Attempts to eradicate maternal vaginal and         rectal colonization with antibiotics during the antepartum period have         been unsuccessful.[18] Thus, intrapartum antibiotic therapy of GBS         carriers mothers has been promoted to prevent GBS infection of the fetus         and newborns. Prophylactic antibiotics given to newborns whose mothers         are GBS carriers may be ineffective because some neonates which became         infected in utero are already septic at birth.[19] Even if the fetus         becomes infected in utero, she or he may have sterile blood cultures         (BC) due to maternal chemoprophylaxis and transplacental transfer.

Antepartum chemoprophylaxis of GBS         colonized mothers with risk factors for neonatal GBS infection at         delivery has reduced the risk of EOGBSI.[16,2] No studies regarding         management of infants born to mothers who received antepartum         chemoprophylaxis have been published. Thus, the recommendations are         empirical.[18]

In newborn infants, we identified the         following risk factors for the purposes of this management guideline:

Prematurity with gestational age             <34 weeks

Prolonged rupture of membranes (             >18 hrs)

Multiple births if gestational age             is <37 wks

Intrapartum maternal fever (38.0 C             or 100.4 F)

The AAP includes multiple gestations in         the list of risk factors without specifying the gestational age.         However, we limited this risk factor to only infants of <37 wks         gestation as we anticipate that full term infant products of multiple         gestation are not at high risk for infection. Even though a lower         intrapartum temperature (37.5 C) was defined as a risk factor by ACOG,         we elected to chose a higher temperature to avoid unnecessary inclusion         of many newborns in the high risk group, as we feel that it is very         common to have an intrapartum temperature of 37.5 C in healthy women.

Infants who have one of the listed risk         factors should have a complete blood cell count and differential (CBC)         and blood culture (BC) drawn, a chest radiograph (CXR) if respiratory         symptoms are present, and should receive intravenous ampicillin +         gentamicin therapy (150 mg/kg/d ampicillin or 200,00 U/kg/d penicillin G         divided TID, and 5 mg/kg/d gentamicin if <=7 days old or gentamicin         7.5 mg/kg/d if >7 days old divided BID).[20] Penicillin G or         ampicillin alone may be given when GBS infection has been identified and         the sensitivity of GBS organism has been determined.[21] Lumbar puncture         (LP) is recommended in all infants who have neurological symptomps or         signs of impaired cardiac output and/or infants who have positive blood         cultures. When the CBC or CXR are abnormal, it is up to the discretion         of the treating physician whether or not to perform an LP. If the LP is         positive for GBS infection, a minimal course of 14 days intravenous         antibiotic therapy is indicated [150-200 mg/kg/d ampicillin or         250,000-400,000 U/kg/d penicillin G divided TID (if <=7days old) and         300-400 mg/kg/d ampicillin or 400,000 U/kg/d penicillin G divided to         four doses (if >7 days old).[20,21]

Asymptomatic newborns without any risk         factors whose mothers received chemoprophylaxis do not require any         further work up or therapy. At-risk infants whose mothers did not         receive chemoprophylaxis, on the other hand, are more problematic since         the rapid discharge policies now in effect may not allow sufficient time         to observe the infant for development of symptoms. Therefore, in these         infants we recommend obtaining a screening CBC. If the CBC is normal, no         therapy is indicated. If mildly abnormal, the CBC may be repeated, and         if the repeat CBC is normal or normalizing, no therapy is indicated. If         the CBC is very abnormal, obtain a blood culture and give antibiotic         therapy for at least two days, until the blood culture is known to be         negative. If the repeat CBC is markedly abnormal, longer antibiotic         therapy may be warranted. Obtaining a CBC in these asymptomatic infants         is optional, if medical supervision can be maintained for >24 hrs.

If newborns are symptomatic, a CBC,         blood culture, and CXR should be obtained. If the CBC or chest         radiograph is abnormal, antibiotic therapy should be continued for five         to ten days. If the blood culture is positive, it should be repeated, a         lumbar puncture (LP) should be performed, and antibiotic therapy should         be continued for ten days. If the LP is positive, antibiotic therapy         should be continued for 14-21 days.

         for managing newborns born to GBS colonized mothers is presented along         with this document. The recommendations are empirical, and provide         guidelines that will include majority of the clinical situations.         However, inevitably, there will be some cases in which further         discretion of the treating physician will be needed. These guidelines         are intended to guide medical practice and not to replace clinical         judgment.

Signs of bacterial sepsis are not         specific. A study of clinical signs of sepsis of 455 newborn infants at         four medical centers [22-25] showed the following prevalence:

In addition to these signs, the following         clinical signs were observed in infants with neonatal sepsis: lethargy,         poor feeding, persistent signs of impaired cardiac output, bloody stools         and meconium stained amniotic fluid.[26] Of course, many of these signs         can also be present in sick newborns who do not have bacterial         infection.

Almost all infants with bacterial         infection in the first few hours after birth will have one of the         following symptoms: lethargy, apnea, seizures, hypothermia,         hyperthermia, impaired cardiac output, respiratory distress, or poor         feeding. Additional signs or symptoms such as abdominal distension,         vomiting, bloody stool, non-physiologic jaundice and meconium stained         amniotic fluid, in the abscence of any of the above signs, may not         suggest infection. In these circumstances, discretion should be used by         the treating physician regarding whether or not to pursue a sepsis         workup.

White Blood Cell Count and         Differential

Neutropenia, an increased ratio of         immature forms to mature neutrophils (I:T ratio), or an increase in the         absolute immature neutrophil count have a better predictive value than         increased absolute neutrophils count (ANC) and absolute white blood cell         count.

In term infants and premature infants         >1500 grams, the following parameters for neutropenia, neutrophilia         and absolute immature neutrophil count are considered abnormal (adopted         from Manroe [27]):

* Mature neutrophils =         polymorphonuclears (PMNs or "polys"); immature neutrophils =         bands + metamyelocytes + myelocytes + promyelocytes.

In very-low-birth-weight infants         (<1500 g), the following parameters of neutropenia and neutrophilia         are considered abnormal (adopted from Mouzinho [27]):

In term and premature infants the         following parameters of I:T ratio are considered abnormal (adopted from         Maroe [27]):

Increased ANC may be found in infants         in the following conditions: Maternal fever (healthy newborn), oxytocin         therapy (6 hours or more), stressful labor, asphyxia, meconium         aspiration syndrome, pneumothorax, seizures, prolonged crying (4         minutes), hypoglycemia, hemolytic disease and surgery. Decreased ANC may         be found infants whose mothers have hypertension, or who themselves have         periventricular hemorrhage and hemolytic disease.[27,29] The total white         cell count is the least helpful in the diagnosis of neonatal infection         and was dismissed by some investigators as a diagnostic tool.[30]

The majority of the decisions regarding         workup and management of neonatal GBS infection are made within the         first 24 hours postnatally. In the first day of life, the following CBC         values (reference values at 12 hours of age), are considered abnormal:

Neutropenia <7200 in term infants             or preterm infants >1500 g, and <2200 in preterm infants             <1500 g.

I:T ratio > 0.16 (for both term             and preterm infants).

Immature neutrophils >1400 (for             both term and preterm infants).

The sensitivity (probability that the test         will be abnormal in a presence of the disease) for neutropenia is 87%,         for increased absolute immature neutrophil count is 42%, and for an I:T         ratio of >0.3 is 91%.[31] In premature infants less than 32 weeks         gestation during the first five days of life, an I:T ratio of <0.2 is         associated with no infection in 96%.[32] Neutrophilia of >14400 (term         infants) and >12600 (preterm infants) and leukocytosis >31000         (term infants) and >21000 (preterm infants) are much less sensitive         parameters than those mentioned above.

The latex agglutination urine test for GBS         antigen by CIE method is an unreliable screening test for GBS sepsis         because of the high false positive rate. In most instances positive         urine CIE for GBS is due to contamination of bagged specimens from         perineal colonization[33], or due to absorption of GBS antigen from         gastrointestinal tract[34]. As few as 100 group B streptococcal         organisms contaminating a specimen may result in a false positive         results.[35] Therefore, urine CIE testing is usually not recommended as         a part of GBS infection work-up.

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In the newborn period, group B streptococcus agalactiae infection is the leading cause of sepsis in the United States. The overall attack rate of early onset GBS infection (EOGBSI) per 1000 deliveries ranges from 0.72 to 5.5.

Arie Alkalay, MD

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Group B Streptococcal Infection in Newborns