Neonatal Infections

Resident will become competent in the identification and management of newborns at risk for common neonatal infections

Clinical Questions:

1) How should an asymptomatic newborn with risk factors for sepsis be managed in the nursery?

2) How do you manage a baby at risk for Hepatitis B, Toxoplasmosis, CMV, Herpes infections?

Background Information:

HEPATITIS B

Admission maternal

HBsAg status Birth Weight > 2000gm

Negative Hep B vaccine before discharge

Positive Hep B vaccine and HBIG within 12 hours

Unknown Hep B vaccine within 12 hours and

HBIG within 7 days if HbsAg positive

Early Onset Neonatal Sepsis: is associated with an ascending infection through ruptured membranes, via the birth canal and uterus, and may be associated with exposure during the birth process itself. Organisms causing the sepsis include: Group B Streptococcus, Gram negative organisms and Listeria. Majority of infants presenting with early onset sepsis are premature and symptomatic at delivery. However, a minority do not develop symptoms until after delivery. Maternal antibiotics during labor (even when given late but before cord clamping) decrease the risk of sepsis.

Maternal Fever: during labor and delivery or during the post-partum period may be a major risk factor for neonatal sepsis. Maternal fever (T>100.4⁰F) may be caused by a variety of mechanisms including:

Stress of delivery
Dehydration
Environmental overheating
Epidural anesthesia
Medications or illicit drugs
Maternal intercurrent viral infection (URI)
Maternal bacterial infections (chorioamnionitis, pneumonia, UTI with possibility for hematogenous spread to baby or vertical transmission through ruptured membranes)

Group B Streptococcus (GBS)

is a major cause of morbidity and mortality in the perinatal period for women and for their newborn infants. Of the 15-30% of women who are vaginally or anorectally GBS colonized, most will be asymptomatic; however, some women may become bacteremic or have endometritis, amnionitis or urinary tract infections. Colonization can be transient, chronic or intermittent. Transmission of GBS from the mother to the infant occurs after onset of labor or ROM. Onset of GBS disease is either early (0-6 days) or late (3-4 weeks). Greater than 95% of infants with early-onset disease will have symptoms within 48 hours. Late-onset disease usually presents as occult bacteremia (fever, poor feeding, etc) or meningitis.

Guidelines for the prevention of perinatal Group B streptococci disease have been published by the CDC and endorsed by the AAP. Universal prenatal culture based screening with Intrapartum Antibiotic Prophylaxis (IAP) is 50% more effective than risk-based approach in preventing GBBS disease in newborns. This approach has reduced the risk of early onset GBS from 1.5-5.0 to 0.3 cases per 1000 live births. IAP has no impact on the prevention of late onset GBBS.

The following are risk factors for neonatal sepsis:

Preterm infants ≤37 weeks gestation
Maternal fever >100.4^oF (especially when >101^oF)
Rupture of membranes >18 hours
Colonization with GBS in maternal vaginal or anorectal cultures
GBS bacteriuria
Previous delivery of infant with invasive GBS disease
African-American descent
Maternal age <20 years
Maternal intra-amniotic infection (IAI) which is defined by ruptured membranes, fever (>100.4) AND at least two of the following:

Maternal tachycardia (HR>90/minute)
Fetal tachycardia (HR>170/minute)
Maternal leukocytosis (WBC>15,000)
Uterine tenderness
Foul-smelling amniotic fluid

Signs and symptoms of SEPSIS in a newborn (typically >1 symptom):

Respiratory distress or grunting Apnea

Lethargy or irritability Cyanotic spells

Fever or hypothermia Seizures

Hypo or hyperglycemia Poor perfusion

Acidosis Hypotension

Hypotonia Petechiae or purpura

Vomiting Cholestatic jaundice

Poor feeding Persistent pulmonary HTN

Risk Factors to consider for Neonatal Sepsis: **Risk factors are additive

Conditions Incidence of proven sepsis

PROM >18 hrs (some centers use >24 hrs) 1% (10 fold over baseline)

PROM >12 hrs in preemie 4-6%

PROM + low apgars 3-4%

Maternal + GBS (pre-prophylaxis era) 0.5-1.5%

Maternal + GBS (prophylaxis era) 0.2-0.4%

(0.3/1000 live births)

Maternal + GBS (no tx) and PROM, fever or preemie 4-7%

True Chorioamnionitis (T>100.4 +>2 factors:

fetal tachycardia, uterine tenderness,

foul vaginal d/c, maternal leukocytosis) 3-8%

Maternal +GBS and chorioamnionitis 6-20% (OR: 6.4 (2.3-18))

Maternal +GBS (no tx) and PPROM preemie 35-50%

FYI:

1) Neonatal sepsis is a low incidence, high severity disease

2) 90% of neonates with sepsis will develop symptoms within 12 hours of birth, 95% within 24 hrs and 98% within 48 hrs

3) Over 90% of newborns with sepsis will have at least one symptom of sepsis; majority will have three or more symptoms

4) **Intrapartum maternal fever or having previous infant with GBS disease are the factors associated with highest risk of early onset GBS disease

5) Antibiotics given to mother prior to delivery decreases the risk of sepsis

6) Decision to evaluate and treat a neonate for possible sepsis is a matter of clinical judgment relying on: careful history, physical examination, laboratory investigations and serial assessments of the clinical course and severity of symptoms.

Predictive values of adjunctive diagnostic tests

Lab test sensitivity specificity PPV NPV

ANC <1750 38-96% 61-92% 20-77% 96-99%

I:T > 0.2 90-100% 30-78% 11-51% 99-100%

CRP > 1.0mg/dl 70-93% 78-94% 7-43% 97-99.5%

WBC < 5000 29% 91% low 99%

WBC < 5000,

I:T > 0.2,

CRP > 1.0

(2 of 3 abnl) 100% 83% 27% 100%

FYI:

1) Perinatal conditions that may cause an inflammatory response without having a proven infection (elevating I/T ratio or CRP): maternal fever, PROM, fetal distress or stressful delivery, meconium aspiration

2) Total WBC can be higher in capillary than in arterial/venous samples

Sources: for above data

=Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002 Aug 16;51(RR-11):1-22.

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5111a1.htm

=Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am. 2004 Aug; 51(4):939-59.

http://intercambiolara.com/DUMA/Enero%202008/SEPSIS/sepsis%2013.pdf

Maternal fever (intrapartum and within 1 hr post delivery) or Maternal Chorioamnionitis: If either of these criteria are met, then newborn requires:

1) CBC/manual diff, CRP and blood culture, 2) close monitoring with vital signs Q4 hours for first 24 hrs, and 3) a minimum of 48 hours of antibiotics. Endpoint of antibiotics treatment depends upon clinical symptoms suggestive of sepsis and laboratory evaluation (initial labs and blood culture and possible use of serial CRP +/- CBC with manual diff). If newborn becomes symptomatic at any time, transfer to ICN for further management, and consider CSF cx if not done already.

Mothers with GBS Positive:

If at delivery, a) the baby is clinically stable, b) no maternal fever, and

c) adequate treatment (either appropriate antibiotics were given to the mother > 4 hrs prior to the delivery, or C/S with no labor or ROM at delivery), THEN, newborn can be managed with routine care and clinical observation for up to 48hrs (i.e. no work-up or treatment is necessary). Adequate treatment includes: 1) penicillin, ampicillin or cefazolin given four hours or more prior to delivery; or 2) (in PCN allergic mothers) clindamycin given four hours or more prior to delivery IF GBBS CULTURE IS SENSITIVE TO CLINDAMYCIN. Check with the lab for sensitivity of the mother’s GBBS culture to clindamycin.

If at delivery, a) the baby is clinically stable, b) no maternal fever, and

c) inadequate treatment (i.e. antibiotics were given less than 4hrs prior to the delivery, or no antibiotics were given to the mother), THEN, assess for additional risk factors for sepsis and obtain CBC/manual diff (for WBC count and I/T ratio), CRP and blood culture.

IF LABS ARE NORMAL and there are no additional risk factors for sepsis—clinically observe the baby for 48 hours with vitals every 4 hours for first 24hrs. Consider serial labs if medically indicated. Discharge home if clinically well after 48 hrs.

If LABS ARE ABNORMAL and/or there are multiple risk factors for sepsis: 1) consider starting antibiotics at birth or 2) consider starting antibiotics after abnormal serial labs (q12hrs). Clinically observe the newborn for at least 48 hours with more frequent vital signs (Q4hrs for first 24 hrs). Transfer to ICN at any time the newborn is symptomatic.

Mothers with GBS Unknown: If GBS status is unknown, infant looks well at delivery and there is no maternal fever: assess NB for additional risk factors for sepsis (GA less than 37 wks, ROM greater than 18hrs, previous child with invasive GBBS disease):

If there are no other risk factors for sepsis—no workup or treatment is necessary; routine care and observation for 48 hrs
If there are additional risk factors for sepsis: 1) do CBC/diff, CRP and blood culture 2) clinically observe infant for up to 48 hours. Management guidelines are listed above based on lab results and number of additive risk factors.

Note==NB with a history of a sibling with invasive GBBS disease merit the following: 1) cbc/diff, blood culture; 2) Antibiotics if a) intrapartum prophylaxis is inadequate (less than 4 hours prior to delivery), or b) abnormal birth labs or c) maternal fever occurs intrapartum or within one hour after delivery.

*ADEQUATE TREATMENT for GBBS prevention: 1) PNC, AMP or Cefazolin > 4 hrs prior to delivery; 2) Clindamycin=if GBBS culture is sensitive (call lab for mother’s cx sensitivity to clinda)

** Healthy NB may be discharged before 48 hrs if reliable parent/full instructions for home monitoring

***ABNORMAL LABS-birth: 1) WBC < 5,000 or > 30,000; or 2) I:T >0.2 (immature PMN’s/total of all PMN’s);

or 3) CRP > 1mg/dl

NOTE--Mothers with previous child with GBS disease: The infant should have a CBC/diff/BCX drawn and Start antibiotics IF: 1) Intrapartum antibiotics prophylaxis < 4hrs or 2) maternal fever or 3) abnormal labs

Key Readings:

**Guidelines 1-07: Evaluation and Management of Asymptomatic Newborns Born at ≥ 35 wks Gestation at Risk for Early Onset Neonatal Sepsis.

**Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002 Aug 16;51(RR-11):1-22.

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5111a1.htm

**Ottolini MC, Lundgren K, Mirkinson LJ, Cason S, Ottolini MG. Utility of complete blood count and blood culture screening to diagnose neonatal sepsis in the asymptomatic at risk newborn. Pediatr Infect Dis J. 2003 May;22(5):430-4. http://www.pidj.com/pt/re/pidj/abstract.00006454-200305000-00008.htm;jsessionid=HnrLQ1Pn3x0KvBQyynDgr7cQmPCGGvL4hLR7RpNb8yNqW8Kn1bHb!-1108188142!181195628!8091!-1?index=1&database=ppvovft&results=1&count=10&searchid=1&nav=search

**Puopolo KM et al., Early Onset Group B Streptococcal Disease in the Era of Maternal Screening. Pediatrics May 2005, Volume 115 (5): 1240-1245.

http://pediatrics.aappublications.org/cgi/content/full/115/5/1240

**Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am. 2004 Aug; 51(4):939-59.

http://intercambiolara.com/DUMA/Enero%202008/SEPSIS/sepsis%2013.pdf

Herpes Simplex: AAP Red Book Online. 2006 (1): 361-371. http://aapredbook.aappublications.org/cgi/content/full/2003/1/3.56?cookietest=yes

Syphillis: AAP Red Book Online. 2006 (1): 631-644. http://aapredbook.aappublications.org/cgi/content/full/2006/1/3.126?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=syphilis&searchid=1&FIRSTINDEX=0&fdate=1/1/2006&tdate=1/31/2006&resourcetype=HWCIT

Cytomegalovirus Infection: AAP Red Book Online. 2006: 273-277.

http://aapredbook.aappublications.org/cgi/content/full/2006/1/3.35?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=CMV&searchid=1&FIRSTINDEX=0&fdate=1/1/2006&tdate=1/31/2006&resourcetype=HWCIT

Toxoplasmosis: AAP Red Book Online. 2006: 666-671. http://aapredbook.aappublications.org/cgi/content/full/2006/1/3.136

Additional Readings:

Bhandari V, Wang C, Rinder C, Rinder H. Hematologic Profile of Sepsis in Neonates: Neutrophil CD64 as a Diagnostic Marker. Pediatrics, Jan 2008; 121 (1): 129-134

http://pediatrics.aappublications.org/cgi/content/abstract/121/1/129

Honest H, Sharma S and Khan K. Rapid Tests for Group B Streptococcus Colonization in Laboring Women: A Systemic Review. Pediatrics April 2006; 117(4): 1055-1066.

http://pediatrics.aappublications.org/cgi/content/full/117/4/1055

Ehl S, Gering B, Bartmann P., et al. C-Reactive Protein is a Useful Marker for Guiding Duration of Antibiotic Therapy in Suspected Neonatal Bacterial Infection. Pediatrics February 1997;99: 216-221. http://pediatrics.aappublications.org/cgi/content/full/99/2/216

Schrag SJ, Zell ER, Lynfield R., et al. A Population Based Comparison of Strategies to Prevent Early-Onset Group B Streptococcal Disease in Neonates. N Engl J Med July 25, 2002, 347(4): 233-239. http://content.nejm.org/cgi/content/full/347/4/233

Natarajan G, Johnson YR, Zhang F., et al. Real Time Polymerase Chain Reaction for the Rapid Detection of Group B Streptococcal Colonization in Neonates. Pediatrics July 2006; 118(1):14-22. http://pediatrics.aappublications.org/cgi/content/full/118/1/14