Congenital and Perinatal Infection

Congenital Infections: Presentation

• Intrauterine growth retardation• Microcephaly• Hydrocephalus• Intracranial calcifications• Thrombocytopenia• Blueberry muffin skin rash• Hepatosplenomegaly, conjugated hyperbilirubinemia

• Chorioretinitis • Cataracts

Blueberry Muffin Skin Rash

Etiologies of Congenital Infection

• Toxoplasmosis T• Syphilis Other• Rubella R• Cytomegalovirus C• Herpes simplex H• HIV• Lymphocytic choriomeningitis virus• Parvovirus B19• Varicella

Diagnosis of Congenital Infection:General Tests

• CBC

• Total/direct bilirubin, liver enzymes

• Total IgM

• Bone radiographs

• CSF exam

• Eye exam

• CNS imaging

Diagnosis of Congenital Infection:Specific Tests

• Toxoplasmosis IgM, IgG• RPR• Rubella IgM• Rubella culture: eye, urine, nasopharynx• Urine culture for CMV• Herpes simplex IgM, IgG• CSF: routine studies, quantitative VDRL, HSV PCR• Parvovirus B19 PCR

• Lymphocytic choriomeningitis virus: infant IgM and IgG, mother IgG

How Toxoplasmosis is Transmitted

Toxoplasmosis

• Toxoplasma gondii, protozoan, cats are host• 70-90% asymptomatic• Symptoms: maculopapular rash,

thrombocytopenia, lymphadenopathy, hepatomegaly, splenomegaly, jaundice, hydrocephalus, microcephaly, chorioretinitis, seizures, deafness

• Diagnosis: IgM, IgG, intracranial calcifications• Treatment: pyrimethamine, sulfadiazine

Toxoplasmosis: Chorioretinitis

Congenital Syphilis: Symptoms

• Asymptomatic 50%• Fever, lymphadenopathy, irritability, failure to thrive• Jaundice, hepatosplenomegaly• Mucocutaneous: palmar/plantar bullae, maculopapular

rash trunk/limbs, mucosal lesions, condylomata lata• Anemia (BM arrest, hemolysis), thrombocytopenia,

low/high WBCs• Meningitis• “Snuffles” (serous rhinitis)• Bone changes: osteochondritis of humerus, tibia

Congenital Syphilis: Snuffles

Congenital Syphilis: Diagnostic Studies

• Quantitative RPR

• CSF exam: cell count, protein, VDRL

• CBC, platelets, liver enzymes

• Long bone radiographs

• Demonstration of spirochetes: tissue/fluid

• HIV testing

Congenital Syphilis: Bone Changes

Congenital Syphilis: Treatment and Follow-up of the Newborn

• Choice of regimens for confirmed or probable congenital syphilis:– Penicillin G 100-150,000 unit/kg/day x 10-14 days

(50,000 unit/kg/dose IV BID x 7 days, then TID for a total of 10 days)

– Procaine penicillin G 50,000 unit/kg/day IM once daily x 10 days (may not adequately treat CNS)

– ampicillin is not a suitable alternative

• RPR at 3, 6, 12 months• Complicated cases should be referred to specialist

Congenital Rubella: Clinical Findings

• Asymptomatic: 50% at birth• Sensorineural hearing loss• Mental retardation• PDA, peripheral pulmonic stenosis• Ocular: cataracts, chorioretinitis, glaucoma• Microcephaly• Blueberry muffin rash• Metaphyseal radiolucencies

Congenital Rubella: Vertical Transmission

• Transplacental passage of virus• Greatest risk for congenital defects and hearing

loss early in the pregnancy• Non-immune pregnant women

– do not immunize during pregnancy– no cases of malformation due to rubella vaccine

in women immunized during pregnancy– avoid exposure to rubella– post-partum vaccine

Congenital Rubella: skin Lesions

Congenital Rubella Syndrome

Congenital Rubella: Diagnosis and Treatment

• Diagnosis:– Rubella specific IgM

– culture: nasopharynx, blood, urine, CSF, throat

• Treatment: supportive

Cytomegalovirus: Transmission

• Vertical transmission– transplacental and perinatal acquisition

– maternal primary and reactivated CMV

• Incidence: – 2.5%

– most are asymptomatic - 95%

Cytomegalovirus: Clinical Findings In Symptomatic Infants

• Microcephaly, intracranial calcifications• Thrombocytopenia, petechiae, purpura• Conjugated hyperbilirubinemia, elevated liver enzymes,

liver failure• Interstitial pneumonitis• Hearing loss• Mental retardation• Neurologic impairment, cerebral palsy• Chorioretinitis • Intestinal pseudo-obstruction like illness

CMV: Calcifications

CMV: Hydrocephalus, Calcifications

Cytomegalovirus: Diagnosis

• CMV titers: – IgM, IgG

– Acute and convalescent

• Urine culture for CMV– Excretion may be intermittent

• CNS imaging

• Eye exam

Cytomegalovirus: Treatment

• Supportive– Platelet transfusion

• Anti-viral treatment– Ganciclovir may reduce sequelae, but of

limited efficacy

• CMV hyperimmune globulin

• Infectious disease consultation

Lymphocytic choriomeningitis virus

• Arenavirus, shed by rodents• Symptoms in adults: influenza like illness - fever,

malaise, myalgia, retro-orbital headache, photophobia

• Congenital infection: hydrocephalus, chorioretinitis, intracranial calcifications, microcephaly, mental retardation, neurologic sequelae, visual loss

• Diagnosis: culture, acute and convalescent titers• Treatment: supportive

Lymphocytic Choriomeningitis Virus -

Hydrocephalus

Parvovirus B19

• Associated with multiple disorders:– Erythema infectiosum (fifth disease)– Aplastic crisis (hemolytic disorders, sickle cell)– Chronic anemia in immunosuppressed– Acute arthritis

• Fetal hydrops and death due to anemia– (?)Efficacy of intrauterine transfusion– Spontaneous recovery of fetal hydrops can

occur

Varicella

• Maternal varicella before 20 weeks: congenital anomalies reported to be 1-2%– Cicatricial skin lesions– Limb hypoplasia– CNS, ocular, neurologic

• Maternal varicella in last 5 days of pregnancy to 2 days post partum:– VZIG 125 units IM indicated in exposed infants– Skin lesions, pneumonitis, dissemination reported– Add acyclovir if signs or symptoms develop

Congenital varicella

Varicella: perinatally acquired

Perinatally Acquired Infection: Basic Principles

• Maternal colonization or infection: – Amniotic fluid– Blood– Genital tract secretions– Breast milk– Direct skin contact, environment

• Timing and duration of exposure

• Interventions, prophylaxis

Herpes Simplex: Epidemiology

• Vertical transmission most common– perinatal exposure with ROM and delivery– 50% risk if infant exposed to primary maternal HSV– <1-5% risk if infant exposed to recurrent maternal HSV– increased risk in premature infants (reduced IgG)– C-section reduces risk if ROM < 4-6 hour

• Horizontal transmission reported– nursery outbreaks

• Time of onset: 2 days - several weeks

Herpes Simplex: Clinical Presentation

• Fever

• skin vesicles

• encephalitis

• seizures

• respiratory distress, pneumonia

• hepatitis

• septic shock like syndrome

Herpes Simplex Skin Lesions

Herpes Simplex Skin Lesions

Herpes Simplex Skin Lesions

Herpes Simplex Conjunctivitis

Herpes Simplex Oral Lesions

Herpes Simplex: Encephalitis

Neonatal Herpes Simplex: Treatment

• Acyclovir 60 mg/kg/day divided q 8 hr x 14 days (21 days for systemic or CNS)

• Ocular HSV: add ophthalmic trifluridine, iododeoxyuridine, or vidarabine

• Supportive: control seizures, respiratory and cardiovascular support

• Reduce cutaneous or ocular spread• High mortality rate for CNS or systemic HSV, even

with treatment

Management of HSV Exposure

• Recurrent maternal HSV– risk is very low; observation only

• Primary maternal disease– risk is high

– viral throat culture at 24-48 hr of age

– empiric therapy is controversial

• Premature infant - risk may be greater

HIV

• Transmission is vertical– In utero, intrapartum (most common), and

postnatal (breastfeeding)

• Risk factors

Zidovudine (AZT) for reduction of perinatal HIV transmission

• pregnancy: begin 200 mg PO 3x/day at 14-34 wk, continue throughout pregnancy

• intrapartum: 2 mg/kg x 1 h, then 1 mg/kg/h IV until delivery

• newborn: 2 mg/kg 4x/day PO begining at 8-12 h of age until 6 weeks of age

• referral to pediatric HIV center

HIV: perinatal prophylaxis

• Reduction of vertical transmission with AZT as compared to placebo in women with mildly symptomatic disease– Connor EM et al. NEMJ 1994;331:1173

• placebo 25.5%

• prenatal, intrapartum, postnatal8.3%

HIV: Benefit persists even with abbreviated prophylaxis

• DNA PCR on HIV exposed infants with incomplete prophylaxis.– Wade NA et al. NEJM 1998;339:1409

• prenatal 6.1%

• intrapartum 10.0%

• < 48 h postnatal 9.3%

• > 48 h postnatal 18.4%

HIV: mode of delivery

• Metanalysis of 15 NA/European studies

• 8533 mother-child pairs

• adjusted for antiretroviral Rx, maternal stage of disease and birth weight

• elective C-section: prior to labor or ROM

• International Perinatal HIV Group

– NEJM 1999;340:977

HIV: mode of delivery

• other mode (vag, non-elective C/S) 16.7%

• elective C-section 8.4%

• other mode, complete retroviral Rx 7.3%

• elective C/S, complete retroviral Rx 2.0%

• International Perinatal HIV Group

– NEJM 1999;340:977

Hepatitis B

• Vertical transmission– Blood exposure during labor and delivery

– In utero transmission: < 2% of cases

• Maternal HBsAg+ HBeAg+70-80%

• Maternal HBsAg+ HBeAg- 5-20%

• Chronic carrier, hepatitis, cirrhosis, hepatocellular carcinoma

Infant born to HBsAg + mother: management

• Avoid skin to skin until infant bathed• Hepatitis B vaccine within 12 hr• HBIG given at separate site• Complete standard HBV schedule

– Preterm < 2 kg: 1st dose not counted, total 4 doses

• HBsAg and anti-HBsAg at 9-15 months of age• Breast feeding not precluded: controversial

Infant born to HBsAg unknown mother: management

• Avoid skin to skin until infant bathed• HBV within 12 hours• If mother HBsAg +, HBIG within 7 days• Premature infant < 2 kg: give both HBV and HBIG

within 12 hours, if unable to determine maternal status by 12 hours.

• Complete standard HBV schedule– Preterm < 2 kg: 1st dose not counted, total 4 doses

Hepatitis C

• Prevalence in adults in U.S. - 1.8%• Vertical transmission - 5% of infants born to

mothers with hepatitis C• No specific preventive measures• Breast feeding is allowed

– Transmission not proven– Cracked or bleeding nipples: may be risk

• Test infant at 18 months: anti-HCV– Earlier testing with HCV RNA PCR

Enterovirus

• Commonly occurs in summer and fall seasons• History of maternal illness late in pregnancy• Perinatal vertical transmission from mother to infant• Outbreaks reported in NICU’s• Presents in the first 2 weeks• Neonatal symptoms: fever, lethargy, poor feeding,

respiratory distress• Clinical syndromes: aseptic meningitis, “sepsis,”

cardiomyopathy, hepatitis, pneumonia, pulmonary hypertension

Etiology of Early Onset Sepsis

• Group B Strep (GBS): 67%

• Non-GBS organisms– E Coli: 25%

– Others: 8%• Enterococcus, staph aureus, strep

pneumonia, candida.

Epidemiology of Group B Strep

• Maternal Colonization:15-40%

• 50-75% of newborns born to colonized mothers become colonized during birth

• Attack Rate (# infected nb/# colonized mothers): 1-2%

• Neonatal Early Onset Disease:– 1-4 per 1000

Risk Factors for Neonatal Infection in Colonized Mothers• Prolonged rupture of membranes > 18 hr

• Premature birth esp < 34 weeks

• Intrapartum fever

• African-American Race

• Maternal age < 20 yr

• Previous birth of GBS infected infant

• Heavy maternal colonization, e.g. bacteruria

• Low levels of anti-GBS capsular antibody

Maternal GBS Disease

• UTI

• amnionitis

• endometritis

• wound infection

Neonatal GBS Disease

• Early Onset Disease– symptomatic infection occurring during 1st

week– results from vertical transmission during labor

or delivery– constitutes 80% of neonatal GBS infection– pneumonia and overwhelming sepsis more

common

Prevention of early onset group B strep

• GBS is sensitive to Ampicillin and Penicillin

• Failure of prenatal administration of Amp/PCN to eradicate colonization

• Failure of immediate postnatal treatment with Penicillin– Lack of treatment efficacy in several studies– increased morbidity from Penicillin resistant

organisms in one study

Prevention of early onset group B strep

• Only success at maternal treatment is intrapartum antibiotic prophylaxis– Boyer and Gottof, 1986

• Reduces maternal colonization• Reduces neonatal colonization• Reduces attack rate of GBS by 80-95%

– Allen et al, meta-analysis, 1993: 30 fold decrease in neonatal infection

Strategies to Reduce GBS Disease

• AAP, 1992– 26-28 week cultures of all pregnant women– intrapartum prophylaxis for:

• positive cultures• ROM > 12 hr• onset of labor or ROM < 37 wks• intrapartum fever• previous birth of an infant with GBS disease

– Will treat approx 3.4% of all mothers, to prevent 50% of Early Onset GBS disease

Strategies to Reduce GBS Disease

• ACOG– Prophylaxis for:

• preterm labor < 37 wks• PROM < 37 wks• ROM > 18 hr• previous child with GBS disease• maternal fever during labor

– Note: cultures not included in decision – Will treat approximately 18.3% of mothers and

prevent 68.8% of early onset GBS disease

Risks of Maternal Treatment - Why not treat all mothers?

• Fatal anaphylaxis to Ampicillin: 1 per 100,000

• Pseudomembraneous enterocolitis (Clostridium dificile)

• incidence of other less severe maternal reactions

• risk of antibiotic resistance among GBS or other organisms

Failures of GBS Prophylaxis

• Late administration of intrapartum antibiotic prophylaxis (< 4 hr before birth)

• Inadequate dosing

• Failure to recognize mothers at risk

Prophylaxis Failures

• Importance of hospital guidelines

• Surveillance study, 1997– 165 hospitals surveyed– 96 (58%) had established departmental

guidelines for maternal prophylaxis– Lower early onset GBS incidence in hospitals

with guidelines• .58/1000 vs 1.29/1000 (p=.006)

Factor SE, et al, OB GYN 2000;95:377-82)

Failures of Intrapartum Prophylaxis

• CDC study 1998-1999; 629,912 births• 312 infants with GBS early onset

sepsis (0.5/1000 births)– 62% had no maternal risk factors– 52% of women were screened for GBS

• Relative Risk of neonatal GBS in screened vs risk based approach was 0.48 (0.38-0.61)

Schrag SJ, et al, NEJM 2002;347:233-9.

Failure of Intrapartum Prophylaxis

• Reasons for failure of risk-based approach:– Incidence of GBS colonization in mothers

who have no risk factors on presentation

– Failure of identification of risk factors when present

CDC Guidelines Updated 2002

• All pregnant women should be cultured at 35-37 weeks gestation

• Penicillin prophylaxis preferred, due to narrow spectrum• Prophylaxis recommended for

– Positive cervical culture for GBS– GBS bacteruria during gestation– Previous infant born with invasive GBS disease– Risk factors in absence of culture results

• Gestation < 37 wks• Fever• ROM > 18 hr

• Prophylaxis not needed for Cesarean sections for culture positive mothers with intact membranes

Change in Epidemiology of Early Onset Sepsis

• Does widespread use of Intrapartum Antibiotic Prophylaxis lead to emergence of resistant organisms?

Stoll B, et al, Changes in Pathogens Causing Early Onset Sepsis in Very Low Birthweight

Infants, NEJM 2002;347:240-7

• 5447 VLBW infants born 1998-2000

• Compared to 7606 VLBW infants born 1991-93

15.4NS

19.3Total early onset

6.8P=.004

3.2E. Coli

1.7P<.001

5.9GBS

98-00Inf./1000 live births

91-93Inf./1000 live births

Explanations for Ampicillin Resistance

• Selection of resistant organisms from maternal GU tract– Especially in preterm infants

• Change in NICU resistance patterns

• Change in resistance patterns of ambulatory patients

• Change in general resistance patterns

Hyde T, et al, Trends in Incidence and Antimicrobial Resistance of Early-onset Sepsis: Population Based

Surveillance in San Francisco and Atlanta, Ped 2002;110:690-5.

• CDC Emerging Infection Program Network, 1998-2000– All hospitals with a delivery service in 3

county area of San Francisco (39,768)

– All 10 birthing hospitals in the 8 county Atlanta area (42, 960)

Hyde et alEarly Onset Sepsis

(positive blood culture in 1st 7 days of life)

• N = 408

• 166/408 (40.7%) were GBS

• 70/409 (17.2%) were E. Coli

• No change in E. Coli or GBS rates over the 3 yr period

• 78% of ampicillin resistant organisms were in prematures

Changing Epidemiology of Early Onset Sepsis

• Term deliveries – 3.9 million per year

– Incidence of early onset sepsis: 1/1000 live births

– 3,900 term infants per year

• Antibiotic resistance does not appear to be a problem in term infants

Changing Epidemiology of Early Onset Sepsis

• VLBW Infants– 48,000 births/yr < 1500 gm– Incidence of Early Onset Sepsis: 15/1000 (Stoll data)– 720 preterm infants/yr

• Antibiotic resistance is a problem in VLBW infants– Due to GBS prophylaxis vs background changes in

microbial resistance patterns?• Strategies to prevent GBS must address the majority of

susceptible infants (5 out of every 6 susceptible infants is term)

• Strategies must reflect the potential for resistance in preterm infants

Management of Newborn Whose Mother Received Prophylaxis

• Diagnostic evaluation and empiric antibiotics if:– signs and symptoms of sepsis– < 35 weeks gestation

• Limited Evaluation and 48 hr observation if:– Duration of prophylaxis < 4 hr before delivery– Asymptomatic infant

• No evaluation, but 48 hr observation if: > 4 hr antibiotics prophylaxis

Diagnostic Eval: CBC, Diff, Bld Cult, plus CXR, LP etc, as indicated Limited Eval: CBC, diff and Bld Cult.

Maternal IAP for GBSMaternal antibiotics

for suspectedchorioamnionitis

Signs of neonatalsepsis

Gestational age< 35 weeks

Duration of IAP beforedelivery < 4 hr

No evaluationNo therapy

Observe 48 hr

Full diagnosticevaluation

Empiric therapy

Limited evaluationObserve 48 hr

If sepsis is suspected, fulldiagnostic evaluation and empiric

therapy

Yes

No

No

No

Yes

Yes

Yes

Yes

Is an LP necessary in evaluation for sepsis in the newborn?

• Pro– Risk of meningitis in absence of positive blood

cultures or CNS symptoms– Wiswell et al:

• 5 yr review of U.S. Army Hospitals; 169,849 births• Incidence of meningitis: 0.25/1000 live births• 8/43 (19%) were term infants with no CNS

symptoms and negative blood cultures

Wiswell TE et al, Ped 1995;95:803-6

Is an LP necessary in evaluation for sepsis in the newborn?

• Con:– Metanalysis of 6 papers excluding Wiswell et al

• 4913 LP’s successfully performed• 19 cases of culture positive meningitis (259 LP’s per

case of meningitis)• 16/19 cases had positive blood cultures• Thus, 1638 successful LP’s are needed to diagnose

one case of meningitis in the absence of a positive blood culture

• Better blood culture technique lessens the need for LP’s

Blood Culture Technique

• Appropriate prep:– 30 seconds vs 10 seconds x 2

• Appropriate volume:– At least 1 ml

• Obtain from peripheral stick and central line if line is in more than 12 hr

Duration of Antibiotics

• Are negative blood cultures conclusive when the mother has received IAP?

• Ancillary tests– CBC:

• Neutropenia• I:T ratio

– CRP

C-Reactive Protein in Suspected Sepsis

• CRP performed on 2 successive days in early onset sepsis:– Sensitivity: 88.9%– Specificity: 73.8%– Positive predictive ability: 6.0%– Negative predictive ability: 99.7%

• Conclusions: – In episodes where CRP was positive, only 6% turned out to

have sepsis– In episodes where CRP was negative, 99.7% did not have

sepsis

Benitz et al, Ped, 1998

Decision to stop antibiotics

• Negative blood cultures at 48-72 hr

• Symptoms of mild severity (tachypnea, brief O2 dependency, poor feeding)– D/C antibiotics and observe 24-48 hr

• If moderate-severe symptoms – decision to D/C or continue antibiotics depends on other factors:– Presence of chorioamniotis?– Elevated CRP?– Neutropenia or elevated I:T ratio?

Nosocomial infection in the NICU:Common organisms

• Coagulase negative staphylococcus

• Coagulase positive staphylococcus

• Gram negatives: E coli, Klebsiella, Enterobacter, Serratia, Pseudomonas

• Candida albicans, parapsilosis

Risk factors for nosocomial infection

• Central lines– Duration of insertion– Type of catheter: Broviac, silastic

• Ventilation, endotracheal intubation

• Exposure to antibiotics

• Surgical procedures: intestinal

• Use of intravenous lipids

Strategies to reduce nosocomial infection

• Remove central lines ASAP

• Limit entries into central lines

– Medications via PIV

– Limit number of ports into central line

– Use ports rather than stopcocks

• Good handwashing

• Respiratory care, suctioning techniques

• Limit use of IV lipids

Empiric treatment of suspected nosocomial sepsis

• Ampicillin and gentamicin

• Ampicillin and cefotaxime

• Vancomycin and gentamicin

• Vancomycin and cefotaxime