Gomella's Neonatology, 8th Edition 2020, Edith

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Diseases and Disorders,
S E CT I O N V I .
General
85 ABO Incompatibility

I. Definition. Isoimmune hemolytic anemia may result when ABO incompatibility
occurs between the mother and the newborn infant. This disorder is most common
with blood type A or B infants born to type O mothers. The hemolytic process begins
in utero and is the result of active placental transport of maternal isoantibody. In type
O mothers, isoantibody is predominantly 7S-IgG (immunoglobulin G) and is capable
of crossing the placental membranes. Because of its larger size, the mostly 19S-IgM
(immunoglobulin M) isoantibody found in type A or type B mothers cannot cross.
Symptomatic clinical disease, which usually does not present until after birth, is a
compensated mild hemolytic anemia with reticulocytosis, microspherocytosis, and
early-onset unconjugated hyperbilirubinemia.
II. Incidence. Risk factors for ABO incompatibility are present in 12% to 15% of pregnan-
cies, but evidence of fetal sensitization (positive direct Coombs test) occurs in only
3% to 4%. Symptomatic ABO hemolytic disease occurs in <1% of all newborn infants
but accounts for approximately two-thirds of observed cases of hemolytic disease in
the newborn.
III. Pathophysiology. Transplacental transport of maternal isoantibody results in an
immune reaction with the A or B antigen on fetal erythrocytes, which produces char-
acteristic microspherocytes. This process eventually results in complete extravascular
hemolysis of the end-stage spherocyte. The ongoing hemolysis is balanced by com-
pensatory reticulocytosis and shortening of the cell cycle time, so that there is overall
maintenance of the erythrocyte indices within physiologic limits. A paucity of A or B
antigenic sites on the fetal (in contrast to the adult) erythrocytes and competitive bind-
ing of isoantibody to a myriad of other antigenic sites in other tissues may explain the
often mild hemolytic process that occurs and the usual absence of progressive disease
with subsequent pregnancies.
IV. Risk factors
A. A1 antigen in the infant. Of the major blood group antigens, the A1 antigen has the
greatest antigenicity and is associated with the greater risk of symptomatic disease.
However, the hemolytic activity of anti-B antibodies is higher than that of anti-A
antibodies and may produce a more severe disease, in particular among infants of
African American descent.
B. Elevated isohemagglutinins. Antepartum intestinal parasitism or third-trimester
immunization with tetanus toxoid or pneumococcal vaccine may stimulate isoan-
tibody titer to A or B antigens.
C. Maternal immune serum globulin anti-A/B titers. Anti-A/B titers >512% are
significantly associated with the risk of ABO hemolytic disease of the newborn and
may be an early indicator for therapy.
D. Birth order. Birth order is not considered a risk factor. Maternal isoantibody exists
naturally and is independent of prior exposure to incompatible fetal blood group
antigens.
V. Clinical presentation
A. Jaundice. Icterus is often the sole physical manifestation of ABO incompatibility
with a clinically significant level of hemolysis. The onset is usually within the first
24 hours of life. The jaundice evolves at a faster rate over the early neonatal period
than nonhemolytic physiologic pattern jaundice.
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802 DISEASES AND DISORDERS, GENERAL
B. Anemia. Because of the effectiveness of compensation by reticulocytosis in

response to the ongoing mild hemolytic process, erythrocyte indices are main-
tained within a physiologic range that is normal for asymptomatic infants of the
same gestational age. Additional signs of clinical disease (eg, hepatosplenomegaly
or hydrops fetalis) are extremely unusual but may be seen with a more progressive
hemolytic process (see Chapter 119). Exaggerated physiologic anemia may occur
at 8 to 12 weeks of age, particularly when treatment during the neonatal period
required phototherapy or exchange transfusion.
VI. Diagnosis. Obligatory screening for infants with unconjugated hyperbilirubinemia
includes the following studies:
A. Blood type and Rh factor in the mother and the infant. These studies establish
risk factors for ABO incompatibility. Noninvasive prenatal typing can now be done
using cell-free fetal DNA genotyping.
B. Reticulocyte count. Elevated values after adjustment for gestational age and degree
of anemia, if any, support the diagnosis of hemolytic anemia. For term infants,
normal values are 4% to 5%; for preterm infants of 30 to 36 weeks’ gestational age,
values are 6% to 10%. In ABO hemolytic disease of the newborn, values range
from 10% to 30%.
C. Direct Coombs test (direct antiglobulin test). Because there is very little antibody
on the red blood cell (RBC), the direct Coombs test is often only weakly positive
at birth and may become negative by 2 to 3 days of age. A strongly positive test is
distinctly unusual and would direct attention to other isoimmune or autoimmune
hemolytic processes.
D. Blood smear. The blood smear typically demonstrates microspherocytes, poly-
chromasia proportionate to the reticulocyte response, and normoblastosis above
the normal values for gestational age. An increased number of nucleated RBCs in
the cord blood could be a sign of ABO incompatibility.
E. Bilirubin levels (fractionated or total and direct). Indirect hyperbilirubinemia is
mainly present and provides an index of the severity of disease. The rate at which
unconjugated bilirubin levels are increasing suggests the required frequency of test-
ing, usually every 4 to 8 hours until values plateau.
F. Additional laboratory studies. Supportive diagnostic studies may be indicated on
an individual basis if the nature of the hemolytic process remains unclear.
1. Antibody identification (indirect Coombs test). The indirect Coombs test is
more sensitive than the direct Coombs test in detecting the presence of maternal
isoantibody and identifies antibody specificity. The test is performed on an eluate
of neonatal erythrocytes, which is then tested against a panel of type-specific
adult cells.
2. Maternal IgG titer. The absence in the mother of elevated IgG titers against
the infant’s blood group tends to exclude a diagnosis of ABO incompatibility.
VII. Management
A. Antepartum treatment. Because of the low incidence of moderate to severe ABO
hemolytic disease, invasive maneuvers before term is reached (eg, amniocentesis
or early delivery) are usually not indicated.
B. Postpartum treatment
1. General measures. The maintenance of adequate hydration and evaluation for
potentially aggravating factors (eg, sepsis, drug exposure, or metabolic distur-
bance) should be considered.
2. Phototherapy. Once a diagnosis of ABO incompatibility is established, photo-
therapy may be initiated before exchange transfusion is given. Because of the
usual mild to moderate hemolysis, phototherapy may entirely obviate the need
for exchange transfusion or may reduce the number of transfusions required. For
guidelines on phototherapy, see Table 63–1 and Figure 99–2.
3. Exchange transfusion. See Table 63–1 and Figure 99–3 for guidelines on
exchange transfusion and Chapter 34 for exchange transfusion procedure.

86: Acute Kidney Injury 803
4. Tin porphyrin. This can decrease the production of bilirubin and reduce the
need for exchange transfusion and duration of phototherapy. It is an inhibitor
of heme oxygenase, which is the enzyme that allows the production of bilirubin
from heme. The dose of stannsoporfin is 6 µmol/kg intramuscularly as a single
dose given within 24 hours of birth with severe hemolytic disease, and it is
available via compassionate use protocol. (Note: In May 2018, the US Food and
Drug Administration advisory committee recommended that the risk–benefit
profile of stannsoporfin does not support the approval for treatment of newborns
≥35 weeks of gestational age at risk for hyperbilirubinemia.)
5. Intravenous immunoglobulin. By blocking neonatal reticuloendothelial Fc
receptors and thus decreasing hemolysis of the antibody-coated RBCs, high-
dose intravenous immunoglobulin (IVIG; 1 g/kg over 4 hours) reduces serum
bilirubin levels and the need for blood exchange transfusion with ABO or Rh
hemolytic diseases. AAP recommends IVIG 0.5 to 1 g/kg over 2 hours if the TSB
is rising despite intensive phototherapy or if the TSB level is within 2 to 3 mg/dL
of the exchange level, can be repeated in 12 hours. Cochrane review (2018) does
not recommend routine use of IVIG in alloimmune HDN because of low quality
of evidence. Caution should be used when considering treatment with IVIG as
there are emerging reports of increased incidence of necrotizing enterocolitis in
term and late preterm infants with hemolytic disease of the newborn and isoim-
mune neonatal thrombocytopenia who were treated with IVIG.
VIII. Prognosis. For infants with ABO incompatibility, the overall prognosis is excellent.
Timely recognition and appropriate management of the rare infant with aggressive
ABO hemolytic disease may avoid any potential morbidity or severe hemolytic anemia
and secondary hyperbilirubinemia and the inherent risks associated with exchange
transfusion with the use of blood products.
86 Acute Kidney Injury

I. Definition. There is no unified definition of acute kidney injury (AKI), previously
termed acute renal failure, in neonates. Historically, neonatal AKI is defined as absolute
serum creatinine ≥1.5 mg/dL, regardless of age or urine output, with normal maternal
renal function. In 2013, a panel of experts at a National Institutes of Health-sponsored
workshop proposed the adaptation of the categorical modified Kidney Disease: Improv-
ing Global Outcomes (KDIGO) definition to predict neonatal clinical outcomes
(Table 86–1). According to neonatal KDIGO definition, AKI is defined as an absolute
rise of ≥0.3 mg/dL or a ≥50% rise from lowest baseline serum creatinine. AKI can be
anuric (absence of urinary output by 24–48 hours of age), oliguric (urine output of
<1.0 mL/kg/h over 24 hours), or nonoliguric (>1.0 mL/kg/h). AKI can present with nor-
mal urinary output (seen in asphyxiated neonates). Normal urine output is approximately
1 to 3 mL/kg/h with almost all infants voiding within 24 hours of birth. See Table 73–1.
II. Incidence. In some studies, as many as 30% of neonatal intensive care unit–admitted
neonates have some degree of renal failure. Prerenal is the most common type in
the neonate, which may be identified in up to 85% of cases. Intrinsic renal disease
incidence is 11%, and postrenal incidence is 3% to 5%.
III. Pathophysiology. The normal newborn kidney has poor concentrating ability (maxi-
mum urine concentration is approximately 700 mOsm/L in the first few days after
birth as compared to 1200 mOsm/L at 1 year of age). Renal injury leads to problems

132: Cytomegalovirus 1117
VIII. Prognosis. Infants who are diagnosed and treated early generally recover. Experimen-
tal studies suggest that neonatal chlamydial pneumonia, especially in preterm neo-
nates, may cause airway hyperreactivity and respiratory dysfunction that continues
into adulthood.
132 Cytomegalovirus
I. Definition. Human cytomegalovirus (CMV), also known as human herpesvirus 5, is
a DNA virus and a member of the herpesvirus family (Herpesviridae).
II. Incidence. CMV is the most common cause of congenital infection in the United
States and occurs in approximately 0.5% to 1.3% of all live births. This results in approx-
imately 40,000 new cases in the United States per year.
III. Pathophysiology. CMV is highly species specific, and only human CMV has been
shown to infect humans and cause disease. CMV is a ubiquitous virus that is transmit-
ted in secretions, including saliva, tears, semen, urine, cervical secretions, blood (white
blood cells), and breast milk. The seroprevalence increases with age and is influenced
by many factors, such as hygienic circumstances, socioeconomic factors, breast feed-
ing, and sexual contacts. In addition to transplacental infection, CMV may also be
transmitted to the infant intrapartum (through exposure to CMV in cervical secre-
tions), via breast milk, and via blood transfusion. CMV infection acquired during
delivery or via breast milk is often asymptomatic in full-term infants with no effect on
future neurodevelopmental outcome; however, a sepsis-like illness has been described
in premature infants.
In developed countries, CMV seroprevalence varies inversely with socioeconomic
status, with 40% to 80% of women of childbearing age in the United States having
serologic evidence of past CMV infection. Seroconversion and initial infection can
occur around the time of puberty, and shedding of the virus may continue for a long
time. CMV can also become latent in white blood cells and reactivate periodically. In
addition, a seropositive individual can be infected by a different strain of CMV. Reac-
tivation and reinfection are grouped as a “nonprimary” infection.
CMV is capable of penetrating the placental barrier as well as the blood–brain
barrier. During early pregnancy, CMV has a teratogenic potential in the fetus. CMV
infections may result in neuronal migration disturbances in the brain. Both primary
and nonprimary maternal CMV infection can lead to transmission of the virus to
the fetus. When primary maternal infection occurs during pregnancy, the virus is
transmitted to the fetus in approximately 35% of cases. The rate of fetal transmission
appears to increase with advancing gestation; however, infection in early pregnancy
causes more severe fetal infection with significant central nervous system (CNS)
sequelae compared to infection acquired later. During nonprimary infection, trans-
mission rate is low (only 0.2% to 1.8%), except for human immunodeficiency virus
(HIV)-infected women, who show higher transmission despite receiving antiretro-
viral prophylaxis. Even though the risk for congenital infection is high after primary
maternal infection, nonprimary infection is responsible for 75% of the overall burden
of congenital CMV disease.
More than 85% of infants born with congenital CMV have a subclinical infec-
tion. Symptomatic infants are usually born to women with a primary infection.
When the placenta becomes infected with CMV after a primary maternal infec-
tion, its ability to provide oxygen and nutrients to the developing fetus becomes

1118 INFECTIOUS DISEASES
impaired. This leads to placental enlargement due to viral placentitis and revascu-
larization. Although not completely elucidated, placental tissue damage occurs due
to direct tissue injury by persistent CMV replication, ischemic tissue damage due
to vasculitis with viral infection of endothelial cells, and tissue damage by immune
complex deposition. Eventual fetal viremia leads to fetal multiorgan involvement.
The primary target organs are the CNS, eyes, liver, lungs, and kidneys. Character-
istic histopathologic features include focal necrosis, inflammatory response, for-
mation of enlarged cells with intranuclear inclusions (cytomegalic cells), and the
production of multinucleated giant cells.
IV. Risk factors. CMV infection in neonates is associated with nonwhite race, lower socio-
economic status, drug abuse, and neonatal intensive care unit admittance. Premature
infants are more often affected than full-term infants. Transfusion with unscreened
blood is an additional risk factor for neonatal disease. Risk factors for primary CMV
infection during pregnancy include prolonged exposure to young children (daycare
workers, multiparous women) and sexual contact (young maternal age, greater num-
bers of sexual partners, abnormal cervical cytology, and having a sexually transmitted
infection during pregnancy).
A. Prenatal presentation. Pregnant women who acquire primary CMV may develop
a mononucleosis-like illness with mild hepatitis (<25% of the time). Maternal
screening is currently not recommended routinely. Fetal anomalies consistent with
congenital CMV infection that can be detected on prenatal ultrasound examina-
tion include fetal growth restriction, cerebral periventricular echogenicity or cal-
cifications, cerebral ventriculomegaly, microcephaly, polymicrogyria, cerebellar
hypoplasia, hyperechogenic fetal bowel, hepatosplenomegaly, hepatic calcifica-
tions, amniotic fluid abnormalities, ascites and/or pleural effusion, and placental
enlargement. Prenatal magnetic resonance imaging (MRI), especially to evaluate
brain anomalies, is increasingly being used. Amniocentesis to perform polymerase
chain reaction (PCR) for CMV DNA in amniotic fluid is the preferred diagnos-
tic approach for identifying an infected fetus. Amniocentesis is most sensitive
when done after 21 weeks of gestation and after 6 weeks from maternal infection/
exposure.
B. Postnatal presentation
1. Subclinical infection. Occurs in 85% to 90% of cases. Despite being asymp-
tomatic at birth, these infants are at risk for sensorineural hearing loss (SNHL)
during the first 6 years of life. Universal CMV screening at birth is not recom-
mended in the United States at this time; however, some authorities suggest a
targeted approach that focuses on newborns who fail their universal hearing
screening.
2. Low birthweight. Maternal CMV infection is associated with low birth-
weight and small for gestational age infants, even when the infant is not
infected.
3. Classic cytomegalovirus inclusion disease. Occurs in 10% to 15% of the cases
and consists of fetal growth restriction, hepatosplenomegaly with jaundice,
transaminitis, thrombocytopenia with or without purpura, and severe CNS
involvement. CNS complications include microcephaly, intracerebral calci-
fications (most characteristically in the subependymal periventricular area),
chorioretinitis, and progressive SNHL. Other symptoms include hemolytic
anemia and pneumonitis. The most severely affected infants have a mortal-
ity rate of approximately 30%. Deaths are usually due to hepatic dysfunc-
tion, bleeding, disseminated intravascular coagulation, or secondary bacterial
infection.
4. Late sequelae. SNHL occurs in 33% to 50% of symptomatic and in 10% to
15% of asymptomatic infants. CMV-related SNHL may be present at birth or
occur later in childhood. Approximately 55% and 75% of symptomatic and

132: Cytomegalovirus 1119
asymptomatic infants, respectively, who ultimately develop congenital CMV-

associated SNHL will not have hearing loss detectable within the first month
of life. Therefore, repeated auditory evaluation during the first 6 years of life
is strongly recommended. Visual impairment and strabismus are common in
children with clinically symptomatic CMV infection. Visual complications usu-
ally occur secondary to chorioretinitis, pigmentary retinitis, macular scarring,
optic atrophy, and central cortical defects.
VI. Diagnosis
A. Laboratory studies
1. Culture for demonstration of the virus. The gold standard for the diagnosis
of congenital CMV is urine or saliva culture obtained before 3 weeks of age.
Most urine specimens from infants with congenital CMV are positive within 48
to 72 hours, especially if shell vial tissue culture techniques are used. Shell vial
assay detects CMV-induced antigens by monoclonal antibodies, allowing for
identification of the virus within 48 hours compared with the standard tissue
culture, which takes 2 to 4 weeks.
2. Polymerase chain reaction. PCR for CMV DNA is as sensitive as a urine or
saliva culture for the detection of CMV infection. Studies evaluating saliva for
rapid detection of CMV (PCR or shell vial assay) have shown it to be at least
as sensitive as urine for detecting congenital CMV infection, although there
is risk of contamination of the saliva sample with retained breast milk in the
mouth of the newborn. PCR has been used successfully in retrospective diag-
nosis of congenital CMV beyond 3 weeks of age through CMV DNA analysis
of dried blood spots (Guthrie cards). The sensitivity of CMV DNA detection by
PCR assay of dried blood spots is low, limiting use of this type of specimen for
widespread screening for congenital CMV. A positive PCR assay result from a
neonatal dried blood spot confirms congenital infection, but a negative result
does not rule it out.
3. Serologic tests. Serologic tests based on the detection of immunoglobulin
M (IgM) should not be used to diagnose congenital CMV because they are
less sensitive and more subject to false-positive results than culture or PCR.
Only 70% of neonates infected with congenital CMV have IgM antibodies
at birth.
4. Other laboratory tests. Other lab tests that are indicated in the workup include
complete blood count, liver function tests, coagulation panel and cerebrospinal
fluid analysis, culture, and PCR.
B. Imaging and other studies. Ultrasound or computed tomography scans of the
head may demonstrate characteristic periventricular calcifications in addition to
other abnormalities (see prenatal presentation earlier). Brain MRI is preferred over
other modalities because it is likely to identify most of the brain anomalies associ-
ated with congenital CMV.
VII. Management
A. Prevention and treatment of maternal infection during pregnancy. These
include changes in hygienic behavior for seronegative pregnant women, admin-
istration of CMV hyperimmune globulin (CMV-HIG) to pregnant women with
a primary infection, administration of antiviral therapy to women with primary
infection, and administration of vaccines to girls or women well before or dur-
ing pregnancy. With regard to hygienic measures, epidemiologic studies have
shown that instructing mothers who are pregnant on frequent hand washing;
wearing gloves for specific childcare tasks; avoiding kissing children under age
6 on the mouth or cheek; not sharing food, drinks, or oral utensils (eg, fork,
spoon, toothbrush, pacifier) with young children; and cleaning toys, counter-
tops, and other surfaces that come into contact with children’s urine or saliva
reduces their chances of acquiring congenital CMV infection. CMV-HIG given
to women with primary congenital infection before 20 weeks’ gestation has shown

promise in reducing congenital CMV infection in the fetus in observational and

small randomized trials; however, the benefits need to be confirmed in large
randomized controlled studies (a trial is underway by the National Institute of
Child Health and Human Development; trial identifier NCT01376778; avail-
able at https://clinicaltrials.gov; accessed February 11, 2018). Use of antiviral
therapy for the infected pregnant woman has been studied recently in a multi-
center, open-label, phase II trial using high-dose (8 g daily) oral valacyclovir in
women carrying CMV-infected fetuses with measurable extracerebral or mild
cerebral ultrasound findings starting at a median gestational age of 25 weeks until
delivery. The study found that the use of valacyclovir increased the proportion of
asymptomatic neonates from 43% without treatment to 82% with treatment. The
benefit of valacyclovir needs to be confirmed in large randomized trials before
it can be recommended. The most effective preventive strategy is developing a
vaccine against CMV. A vaccine targeted toward CMV envelope glycoprotein B, an
antigen that typically induces a serum antibody response, was tested in phase II
clinical trials in adult women as well as adolescent girls. This vaccine has been
shown to be immunogenic with an acceptable risk profile with the potential to
decrease incident cases of maternal and congenital CMV infection. Phase III
trials are underway.
B. Prevention of cytomegalovirus transmission in the neonatal intensive care
unit. Neonatal intensive care unit infants requiring packed red cell transfusion
should be transfused from CMV antibody-negative donors, and the blood should
be filtered to remove white blood cells. Pasteurization or freezing of donated human
milk can decrease the likelihood of CMV transmission. Short-term pasteurization
(72°C for 5 seconds) of milk appears to inactivate CMV; this short-term pasteuri-
zation is less harmful to the beneficial constituents of human milk compared to
Holder pasteurization. If pasteurization is not available, freezing milk at –20°C
for 24 hours will decrease viral titers but does not eliminate CMV reliably. Breast
feeding is recommended for CMV antibody–positive mothers as benefits outweigh
risks of potential postnatal CMV infection.
C. Antiviral agents. Neonates with symptomatic congenital CMV disease with or
without CNS involvement have improved audiologic and neurodevelopmental
outcomes at 2 years of age when treated with oral valganciclovir (a prodrug
for ganciclovir) at 16 mg/kg/dose, given orally twice a day for 6 months. The
dose should be adjusted each month to account for weight gain. If the infant is
unable to absorb the medication due to gastrointestinal illness (eg, necrotizing
enterocolitis), intravenous ganciclovir at 6 mg/kg/dose is an alternative. Signif-
icant neutropenia occurs in 20% of infants treated with oral valganciclovir and
in 67% of infants treated with ganciclovir. Absolute neutrophil counts should
be performed weekly for 6 weeks, then at 8 weeks, and then monthly for the
duration of antiviral treatment; serum aminotransferase concentration should
be measured monthly during treatment. Some authorities also recommend
monitoring viral load (CMV DNA PCR in the blood) to document response
to therapy and check for ganciclovir resistance. Antiviral therapy should be
limited to patients with symptomatic congenital CMV disease who are able to
start treatment within the first month of life. Preterm infants with perinatally
or nosocomially acquired CMV infection can have significant symptomatic
disease with end-organ dysfunction (eg, pneumonitis, hepatitis, thrombocyto-
penia). Antiviral treatment has not been studied in this population; however,
these patients are reasonable candidates for oral valganciclovir or intravenous
ganciclovir treatment for 2 to 4 weeks, depending on responsiveness of symp-
toms. The antivirals foscarnet and cidofovir are reserved for cases of refractory
CMV disease, ganciclovir resistance, ganciclovir toxicity, and co-infection with
adenovirus. Infants with asymptomatic congenital CMV infection should not
receive antiviral treatment.
133: Dengue Infection, Neonatal 1121
VIII. Prognosis. Congenital CMV is the leading cause of nonhereditary SNHL. Overall

mortality rate among infants with congenital CMV infection is approximately 4% to
8% within the first year of life. For symptomatic infants with fulminant disease at birth,
mortality is up to 30%, and late complications including intellectual or developmental
impairment, progressive hearing loss, and spasticity develop in 70% to 80% of cases.
Visual impairment develops in 10% to 20% of symptomatic newborns. With asymp-
tomatic, congenitally infected infants, the prognosis is uncertain, but they are at risk
for SNHL (up to 20% by 6 years of age).
133 Dengue Infection, Neonatal

I. Definition. Dengue fever (DF) is a worldwide infection caused by 4 related RNA
viruses of the genus Flavivirus, dengue viruses (DENV) DENV-1, DENV-2, DENV-3,
and DENV-4. DENV is primarily transmitted to humans through the bite of infected
Aedes aegypti (and less commonly Aedes albopictus or Aedes polynesiensis) mosquitoes.
DENV causes asymptomatic infection, DF, or a severe syndrome (dengue hemor-
rhagic fever [DHF]/dengue shock syndrome [DSS]). The latter is characterized by
systemic capillary leakage, thrombocytopenia, and hypovolemic shock.
II. Incidence. Dengue is a major public health problem in the tropics and subtropics; an
estimated 50 to 100 million dengue cases occur annually in more than 100 countries,
and 40% of the world’s population lives in areas with DENV transmission. In the United
States, dengue is endemic in Puerto Rico, the Virgin Islands, and American Samoa.
Additionally, limited outbreaks with local DENV transmission have occurred in Texas,
Hawaii, and Florida in the past decade, but no neonatal cases have been reported from
the United States. Millions of US travelers, including children, are at risk. Neonatal
dengue has been described in case reports and case series from outside the United
States; therefore, its true incidence worldwide is unknown.
III. Pathophysiology. Viremia is usually detected about 6 to 18 hours before the onset of
symptoms and ends as the fever resolves. Both innate and adaptive immune responses
seem to play a role in the clearance of infection. Infection with 1 of the 4 DENVs
(primary infection) provides long-lasting immunity to infection with a virus of the
same serotype; however, immunity to the other dengue serotypes is transient. Individu-
als can subsequently be infected with another dengue serotype (secondary infection),
often with more severe manifestations. DHF can develop with any of the 4 DENVs,
but the risk is highest with DENV-2. DHF can usually be distinguished from DF as it
progresses through 3 predictable pathophysiologic phases:
A. Febrile phase: Viremia-driven high fevers.
B. Critical/plasma leak phase: Sudden onset of varying degrees of plasma leak into
the pleural and abdominal cavities. This phase probably occurs due to endothelial
cell dysfunction rather than injury.
C. Convalescence or reabsorption phase: Sudden arrest of plasma leak with con-
comitant reabsorption of extravasated plasma and fluids.
Neonates can be infected through mosquito bites but also as a vertical infection
from the mother. The highest risk period is when the mother becomes acutely ill with
dengue at or near the time of delivery. It has been hypothesized that there is an insuf-
ficient level of protective maternal antibodies (immunoglobulin [Ig] G) transferred to
the fetus, and therefore, the newborn can manifest serious disease. Endothelial damage
and plasma leakage may enable the virus an easy access across the placental barrier.

(50%–100%). Fetal loss or early neonatal mortality is also significant. Commercial kits are
available to detect anti-HEV IgG and IgM. Definitive diagnosis may be made by demonstrating
viral RNA in serum or stool by RT-PCR. The only treatment is supportive. It is unclear if breast
feeding is a potential route of HEV transmission. A recombinant HEV vaccine evaluated in a
phase III clinical trial was demonstrated to be effective in preventing disease and is approved
for use by the Chinese Food and Drug Administration.
137 Herpes Simplex Viruses

I. Definition. Herpes simplex viruses (HSV-1 and HSV-2) are enveloped, double-
stranded DNA viruses. They are part of the herpes group, which also includes cyto-
megalovirus, Epstein-Barr virus, varicella-zoster virus, and human herpes viruses
(HHV-6 and HHV-7). HSV infection is among the most prevalent of all viral infections
encountered by humans.
II. Incidence. The incidence of neonatal HSV infection is estimated to range from 1 in
2000 to 1 in 3000 live births. As of 2014, seroprevalence of HSV-1 and HSV-2 in preg-
nant women in the United States was approximately 59.3% and 21.1%, respectively.
III. Pathophysiology. HSV enters the human host through inoculation of oral, genital,
or conjunctival mucosa or breaks in skin, infects the sensory nerve endings, and
then passes via retrograde axonal flow to the dorsal root ganglia, where it remains
for the life of the host. Two serologic subtypes can be distinguished by antigenic
and serologic tests: HSV-1 (usually affects face and skin above the waist) and HSV-2
(genitalia and skin below the waist). Three quarters of neonatal herpes infections are
secondary to HSV-2. HSV-1, however, can be the cause of maternal genital herpes
infections in 9% of the cases, and its rate appears to be increasing (eg, HSV-1 is the
major serotype causing neonatal disease in Australia). HSV infection of the neonate
can be acquired at 1 of 3 times: intrauterine, intrapartum, or postnatal. Most infections
(85%) are acquired in the intrapartum period as ascending infections with ruptured
membranes (the period of 4–6 hours is considered a critical period for this to occur)
or by delivery through an infected cervix or vagina. An additional 10% of infected
neonates acquire the virus postnatally (eg, from someone shedding HSV from the
mouth who then kisses the infant). The final 5% of neonatal HSV infections occur in
utero. In utero infection is acquired transplacentally and occurs only in women with
primary HSV infection. It is usually associated with placental infarcts and necrotizing
funisitis and may result in miscarriage, congenital anomalies, preterm birth, and/or
fetal growth restriction. The incubation period is from 2 to 20 days. Three general
patterns of neonatal HSV infection are recognized: disease localized to the skin,
eyes, and mouth (SEM); central nervous system (CNS) disease (with or without
SEM involvement); and disseminated disease (which also may include signs of the
first 2 groups). Maternal infection can be classified as either first-episode or recur-
rent infections. First-episode infections are further classified as either primary or
first-episode nonprimary based on type-specific serologic testing. Primary infections
are those in which the mother is experiencing a new infection with either HSV-1
or HSV-2 and has not already been infected with the other virus type. First-episode
nonprimary infections are those in which the mother has a new infection with 1 virus
type, usually HSV-2, but has antibodies to the other virus type, usually HSV-1. Infants
born vaginally to mothers with a true primary infection are at highest risk, with a
transmission rate of approximately 60%. Those born to a mother with a first-episode

137: Herpes Simplex Viruses 1137
nonprimary infection are at a somewhat lower risk of 25%. The lowest risk infants
(2%) are those born to mothers with recurrent infections. Maternal antibody is not
always protective in the fetus.
IV. Risk factors. The risk of genital herpes infection varies with maternal age, socioeco-
nomic status, and number of sexual partners. Only approximately 12% of pregnant
women who test seropositive for HSV-2 give a clinical history suggestive of the disease.
The first-episode infection may stay “active” with asymptomatic cervical shedding for
as long as 2 months. Besides a first-episode infection (primary or nonprimary), addi-
tional risk factors for neonatal HSV infection include acquisition of HSV shortly before
labor, viral genital shedding in labor, genital shedding of HSV-1 rather than HSV-2, the
use of a fetal-scalp electrode, preterm birth, and maternal age <21 years.
V. Clinical presentation. Congenital in utero HSV infection is rare and is associated with
high rate of fetal demise; it shares clinical features such as microcephaly, hydrocepha-
lus, and chorioretinitis with other congenital infections. In addition, skin ulcerations
or scarring and eye damage are commonly noted. The neonatal disease is commonly
acquired intrapartum. It may be localized or disseminated. Humoral and cellular
immune mechanisms appear important in preventing initial HSV infections or limit-
ing their spread. Infants with disseminated and SEM disease generally present at 10
to 12 days of life, whereas patients with CNS disease usually present at 16 to 19 days
of life. More than 20% of infants with disseminated disease and 30% to 40% of infants
with encephalitis never have skin vesicles (see Figure 80–10).
A. Skin, eyes, and mouth disease. HSV disease localized to the skin, eyes, or oral
cavity accounts for approximately 45% of the cases. Skin lesions vary from discrete
vesicles to large bullous lesions and denuded skin. It typically involves the present-
ing part (eg, vertex) and sites of skin trauma (eg, scalp electrodes). There is skin
involvement in 80% to 85% of SEM cases. Ulcerative mouth lesions (∼10% of SEM
cases) with or without cutaneous involvement can be seen. Ocular findings include
keratoconjunctivitis and chorioretinitis (see Chapter 58). Without treatment, there
is a high risk of progression to encephalitis or disseminated disease.
B. Disseminated disease accounts for 25% of neonatal HSV disease and carries the
worst prognosis with respect to mortality. Patients commonly present with fever,
lethargy, apnea, and a septic shock–like picture, including respiratory collapse
(hemorrhagic pneumonitis), liver failure, neutropenia, thrombocytopenia, and dis-
seminated intravascular coagulation (DIC). Approximately half of these cases also
have SEM manifestations, and 60% to 75% have CNS involvement. Skin involve-
ment may appear late, but approximately 20% of infants with disseminated disease
will not develop any cutaneous vesicles during the course of their illness. Recogni-
tion of the disseminated HSV disease is often delayed. It should be suspected in
any infant presenting with a sepsis-like picture associated with thrombocytopenia,
elevated liver enzymes, consumptive coagulopathy, and cerebrospinal fluid (CSF)
pleocytosis.
C. Central nervous system disease accounts for approximately 30% of neonatal
HSV infection. It may develop as a result of localized retrograde spread from the
nasopharynx and olfactory nerves to the brain or through hematogenous spread
in neonates with disseminated disease. Clinical manifestations include seizures
(focal and generalized), lethargy, irritability, tremors, poor feeding, temperature
instability, and a bulging fontanelle. These infants usually present at 16 to
19 days of age, and 30% to 40% have no herpetic skin lesions. CSF findings are
variable and typically show a mild pleocytosis, increased protein, and a slightly
low glucose. Abnormalities of the CSF may be more pronounced as CNS disease
progresses.
VI. Diagnosis. Diagnosis of neonatal HSV infection can be challenging, and the diagnosis
is often delayed. Early manifestations are subtle and nonspecific (especially for the
disseminated form). The maternal history is often not helpful (negative in 80% of the
cases).

1. Surface viral cultures. Isolation of HSV by culture remains the definitive diag-
nostic method of documenting infection. Skin or mucous membrane lesions
or surfaces (mouth, nasopharynx, conjunctivae, and anus) are scraped and
transferred in appropriate viral transport media on ice. Swab specimens from
mouth, nasopharynx, conjunctivae, and anus can be obtained with a single
swab starting with the eyes and ending with the anus and placed in 1 viral
transport media tube. With the exception of CNS involvement, the important
information gathered from such cultures is the presence or absence of the rep-
licating virus, rather than its precise location. Preliminary results may become
available in 24 to 72 hours. Positive cultures obtained from any of these sites
more than 12 to 24 hours after birth indicate viral replication and, therefore,
are suggestive of infant infection rather than mere contamination after intra-
partum exposure.
2. Polymerase chain reaction. Polymerase chain reaction (PCR) is an important
tool in the diagnosis of HSV infection. PCR has been used to detect HSV DNA
in CSF and blood specimens. PCR is especially useful for the diagnosis of
HSV encephalitis. Overall sensitivities of CSF PCR in neonatal HSV disease
have ranged from 75% to 100%, with overall specificities ranging from 71% to
100%. Negative CSF PCR does not exclude the diagnosis of HSV CNS disease;
it may be negative early in the course of the disease or if the test is done after
antiviral therapy has been given for a few days. PCR is especially important
in monitoring therapy of CNS disease, with discontinuation of therapy only
when PCR is negative. Blood PCR assay should not supplant surface cultures
or be used to classify disease because viremia can be present in any of the 3
forms of disease. The performance of PCR assay on skin and mucosal speci-
mens from neonates has not been studied; if used, surface or skin PCR assays
should be performed in addition to (and not instead of) the gold standard
surface culture.
3. Immunologic assays. Immunologic assays to detect HSV antigen in lesion
scrapings, usually using monoclonal anti-HSV antibodies in either an enzyme-
linked immunosorbent assay or direct fluorescent antibody staining, are very
specific and 80% to 90% sensitive.
4. Liver function tests. Measuring serum liver function tests, especially alanine
aminotransferase (ALT), is recommended. HSV characteristically invades the
liver and causes hepatocellular damage.
5. Serologic tests. These are not helpful in the diagnosis of neonatal infection
but are helpful in diagnosing and classifying maternal disease (primary vs
secondary).
6. Lumbar puncture should be performed in all suspected cases including SEM
disease. CSF may be normal early in the course of the disease but typically will
show a mononuclear cell pleocytosis, normal or moderately low glucose, and
mildly elevated protein. Contrary to the historical suggestion, erythrocytes are
not notably increased in HSV CNS disease. HSV PCR should always be per-
formed on CSF.
B. Imaging and other studies
1. Brain imaging with computed tomography or preferably magnetic reso-
nance imaging is recommended in all infants with HSV CNS disease. Findings
include parenchymal brain edema or attenuation, hemorrhage, and destructive
lesions, especially in the temporal lobe.
2. Electroencephalogram. Should be performed in all neonates suspected to have
CNS involvement (seizures, abnormal CSF, abnormal neurologic examination).
Electroencephalogram is often abnormal very early in the course of the CNS
disease; it may show focal or multifocal epileptiform discharges before abnormal
changes are detected by computed tomography or magnetic resonance imaging.

137: Herpes Simplex Viruses 1139
VII. Management
A. Antepartum. The history of genital herpes in a pregnant woman or in her
partner(s) should be solicited and recorded in the prenatal record. If a positive
history is obtained, the following steps may be taken:
1. Antiviral therapy. Acyclovir or valacyclovir may be given to pregnant women
who have a primary episode of genital HSV as well as to women with an active
infection (primary or secondary) near or at the time of delivery. Multiple tri-
als showed that prophylactic acyclovir beginning at 36 weeks’ gestation, given
to women who present with a genital HSV lesion anytime during pregnancy,
reduces the risk of clinical HSV recurrence at delivery, cesarean delivery, and
HSV viral shedding at delivery. Valacyclovir also demonstrated similar results
in randomized studies. These studies did not identify any neonatal side effects
from maternal suppressive therapy. These infants will need to be monitored
closely because the risk of neonatal HSV infection is not totally eliminated. See
dosing in Chapter 155.
2. If there are no visible lesions at the onset of labor or prodromal symptoms,
vaginal delivery is acceptable.
3. Cesarean delivery is recommended in women with a history of HSV who have
genital HSV lesions or prodromal HSV symptoms at the time of labor. Some
experts also recommend cesarean delivery for women who had a primary or
nonprimary first episode genital infection during the latter weeks of pregnancy
(eg, within 6 weeks of delivery) even with no active genital lesions at the time
of labor, due to significant and prolonged viral shedding. Debate exists if mem-
branes have already been ruptured for >4 hours in the presence of active lesion;
most experts still recommend cesarean delivery in this situation. All neonates
delivered by cesarean section should be monitored closely because neonatal
HSV infections have occasionally occurred despite delivery before the mem-
branes rupture.
B. Neonatal treatment
1. Infants born to mothers with a genital lesion. The American Academy of
Pediatrics has published an algorithm (Figures 137–1 and 137–2) addressing
management of asymptomatic neonates following vaginal or cesarean delivery
to women with active genital HSV lesions. The algorithm calls for obtaining
HSV surface cultures and HSV blood PCR (in addition to CSF cell count, chem-
istries, and HSV PCR, as well as serum ALT when maternal history for HSV
is negative) in all exposed infants at approximately 24 hours of age. Because of
the high transmission rate after primary or first episode nonprimary maternal
infection (25%–60%), the algorithm recommends preemptive therapy for those
exposed infants with acyclovir at 60 mg/kg/d for 10 days. Infants exposed to
active lesions with maternal recurrent infection have 2% risk of acquiring the
neonatal HSV disease; those infants can be monitored clinically with education
of the family about signs and symptoms of the disease and treatment only if the
infant becomes symptomatic.
2. Infants born to mothers with a history of genital herpes but no active genital
lesions at delivery. Should be observed for signs of infection but no surface
cultures or parenteral acyclovir is needed. Education of parents and caregivers
about the signs and symptoms of neonatal HSV infection during the first
6 weeks of life is prudent.
3. Pharmacologic therapy for established herpes simplex virus disease.
a. Intravenous acyclovir. Neonates with HSV disease should be treated with
intravenous acyclovir at 60 mg/kg/d, divided every 8 hours (20 mg/kg/dose).
The dosing interval of intravenous acyclovir may need to be increased in
premature infants, based on their creatinine clearance. Duration of therapy
is a minimum of 21 days for patients with disseminated or CNS disease and
14 days for those with SEM disease. All patients with CNS involvement should

1140
Asymptomatic neonate following vaginal or cesarean delivery to mother
with visible genital lesions that are characteristic of HSV
Obstetric provider obtains swab of lesion for HSV PCR assay and culture
Type all positive results
Gomella_Sec07_p1115_1224.indd 1140
Maternal history of genital HSV preceding pregnancy?
No Yes
Send maternal type specific serology for HSV-1 and HSV-2 At ~24 hours of age* obtain from the neonate:
antibodies, if assays are available at the delivery hospital • HSV surface† cultures (and PCRs if desired)
• HSV blood PCR‡
If infant remains asymptomatic, do not start acyclovir

At ~24 hours of age* obtain from the neonate:
• HSV surface† cultures (and PCRs if desired)
• HSV blood PCR‡
• CSF cell count, chemistries, and HSV PCR
• Serum ALT Neonatal surface cultures Neonatal surface cultures
negative, AND blood and positive, OR blood and
Start IV acyclovir at 60 mg/kg/day in 3 divided doses surface PCRs negative surface PCRs positive
Determine Maternal HSV Infection Classification (Table 2) Obtain CSF for cell count,
chemistries, and HSV PCR.
Send serum ALT. Start IV
acyclovir at 60 mg/kg/day
in 3 divided doses
First-Episode Primary or Recurrent infection Educate family on signs and Go to Figure

First-Episode Nonprimary symptoms of neonatal HSV 137–2
disease and follow closely§
18/10/19 3:18 pm
Neonatal Neonatal PCRs *Evaluation and treatment is indicated prior to 24 hours of
virology studies or viral age if the infant develops signs and symptoms of neonatal
negative (PCRs cultures HSV disease. In addition, immediate evaluation and
negative; viral positive treatment may be considered if:
cultures • There is prolonged rupture of membranes (>4–6 hours)
negative at • The infant is premature (≤37 weeks’ gestation)
48–72 hours)
†Conjunctivae, mouth, nasopharynx, and rectum, and scalp
electrode site, if present.
Go to Figure Stop acyclovir. Go to Figure ‡HSV blood PCR is not utilized for assignment of disease
137–2 Educate family for 137–2 classification.
signs and symptoms
of neonatal HSV §Discharge after 48 hours of negative HSV cultures (and
disease and follow negative PCRs) is acceptable if other discharge criteria
closely§ have been met, there is ready access to medical care, and
a person who is able to comply fully with instructions for
TABLE 2. Maternal Infection Classification by Genital HSV Viral Type and Maternal Serologya home observation will be present. If any of these conditions
Classification of Maternal Infection PCR/Culture from Genital Lesion Maternal HSV-1 and HSV-2 IgG Antibody Status is not met, the infant should be observed in the hospitaI until
Documented first-episode primary infection Positive, either virus Both negative HSV cultures are finalized as negative or are negative for 96
hours alter being set up in cell culture, whichever is shorter.
Documented first-episode nonprimary Positive for HSV-1 Positive for HSV-2 AND negative for HSV-1
infection Positive for HSV-1 AND negative for HSV-2
Positive for HSV-2
This algorithm should be applied only in facilities where
Assume first-episode (primary or Positive for HSV-1 OR HSV-2 Not available access to PCR and type type-specific serologic testing is
nonprimary) infection readily available and turnaround time for test results is
Negative OR not availableb Negative for HSV-1 and/or HSV-2 OR not available
appropriately short. In situations where this is not
Recurrent infection Positive for HSV-1 Positive for HSV-1 possible, the approach detailed in the algorithm will have
limited and perhaps no applicability.
Positive for HSV-2 Positive for HSV-2
a
To be used for women without a clinical history of genital herpes.
b
When a genital lesion is strongly suspicious for HSV, clinical judgment should supersede the virological test results for the conservative purposes of this neontal
management algorithm. Conversely, if in retrospect, the genital lesion was not likely to be caused by HSV and the PCR assay result or culture is negative, departure
from the evaluation and management in this conservative algorithm may be warranted.
FIGURE 137–1. Algorithm for the evaluation of asymptomatic neonates following vaginal or cesarean delivery to women with active genital herpes lesions.
ALT, alanine aminotransferase; D/C, discontinue; HSV, herpes simplex virus; IV, intravenous; PCR, polymerase chain reaction. (Reproduced with permission
from Kimberlin DW, Baley J; Committee on infectious diseases, et al: Guidance on management of asymptomatic neonates born to women with active genital
herpes lesions, Pediatrics. 2013 Feb;131(2):e635-e646.)
1141
18/10/19 3:18 pm
Patient remains asymptomatic, CSF indices not indicative of infection, CSF and blood
PCR negative, and normal serum ALT*
No Yes
Treatment of Infection and Proven Preemptive Therapy of Infection but

Disease No Proven Disease
Treat with intravenous acyclovir at 60 Treat with intravenous acyclovir at
mg/kg/day in 3 divided daily doses for 60 mg/kg/day in 3 divided daily doses
14 days (SEM) or 21 days (CNS or for 10 days
disseminated)
Additional evaluation may be indicated
*Serum ALT values in neonates may be
elevated due to noninfectious causes
(delivery-related perfusion, etc). For this
Repeat CSF HSV PCR algorithm, ALT values more that 2 times the
near end of 21 day upper limit of normal may be considered
course of treatment† suggestive of neonatal disseminated HSV
disease for HSV-exposed neonates.
†
If evidence of CNS disease at beginning of
therapy.
Positive Negative
Continue D/C
intravenous intravenous
acyclovir acyclovir
for 7 days after 21-day
more treatment
course
FIGURE 137–2. Algorithm for the treatment of asymptomatic neonates following vaginal or
cesarean delivery to women with active genital herpes lesions. ALT, alanine aminotransferase;
CNS, central nervous system; CSF, cerebrospinal fluid; D/C, discontinue; HSV, herpes sim-
plex virus; PCR, polymerase chain reaction; SEM, skin, eyes, and mouth. (Reproduced with
permission from Kimberlin DW, Baley J; Committee on infectious diseases, et al: Guidance
on management of asymptomatic neonates born to women with active genital herpes lesions,
Pediatrics. 2013 Feb;131(2):e635-e646.)
have a repeat lumbar puncture near the end of acyclovir therapy to determine
whether CSF HSV PCR is negative. Infants who remain PCR positive should
receive intravenous acyclovir therapy for another week, with repeat CSF HSV
PCR assay performed near the end of the extended treatment period. Par-
enteral acyclovir therapy should be extended in 1-week intervals until the
CSF HSV PCR negativity is achieved. Absolute neutrophil counts should be
followed twice weekly during the course of therapy. If IV acyclovir is not
available, IV ganciclovir is considered a first-line alternative at a dose
of 6 mg/kg every 12 hours for infants ≤90 days of age and 5 mg/kg every
12 hours for infants >90 days old.
b. Infants with ocular HSV involvement should receive a topical ophthal-
mic drug (1% trifluridine, 0.1% iododeoxyuridine, or 0.15% ganciclovir) as
well as parenteral acyclovir. An ophthalmologist should be involved in the
management.

138: Human Immunodeficiency Virus 1143
c. Oral acyclovir suppressive therapy is recommended for 6 months after

treatment of acute neonatal HSV disease. In particular, improved neuro-
developmental outcome has been observed with suppressive therapy after
HSV CNS disease. Moreover, suppressive therapy has been associated with
reduced recurrences of skin lesions after other forms of HSV. The oral acy-
clovir dose is 300 mg/m2/dose, 3 times per day for 6 months; the dose should
be adjusted each month to account for growth. Absolute neutrophil counts
should be assessed at 2 and 4 weeks after initiating suppressive therapy and
then monthly during the treatment period.
C. Breast feeding. The infant may breast feed as long as no breast lesions are pres-
ent on the mother, and the mother should be instructed in good hand washing
technique.
D. Parents with orolabial herpes. Parents should wear a mask when handling the
newborn and should not kiss or nuzzle the infant.
VIII. Prognosis. High-dose acyclovir (60 mg/kg/d) therapy has greatly reduced mortality
for neonatal HSV infection. Twelve-month mortality has been reduced to 29% for
disseminated disease and 4% for CNS disease. Predictors of mortality include disease
severity (pneumonia, DIC, seizures, and hepatitis), virus type (HSV-1 in systemic dis-
ease, HSV-2 in CNS disease), and prematurity. Systemic infection in premature infants
is associated with near 100% mortality. Improvements in morbidity rates have not been
as dramatic as with mortality. The proportion of survivors of disseminated neonatal
HSV disease who have normal neurologic development has increased to 83%. In the
case of CNS disease, morbidity in survivors has not changed, with only approximately
30% developing normally by 12 months of age. Seizures at or before the initiation of
antiviral therapy and persistently positive CSF PCR after 4 weeks of acyclovir therapy
are associated with poor neurodevelopmental outcome. The outcome for infants with
SEM disease is excellent, with <2% of acyclovir recipients experiencing developmental
delays. Survivors of neonatal HSV infections should undergo developmental assess-
ments regularly. Cutaneous recurrences are relatively common (∼50%), especially for
SEM disease, and those can be reduced by suppressive oral acyclovir therapy.
138 Human Immunodeficiency Virus

I. Definition. Two types of human immunodeficiency virus (HIV) cause disease in
humans: HIV-1 and HIV-2. These are enveloped RNA cytopathic lentiviruses belong-
ing to the family Retroviridae. Infection is most commonly secondary to HIV-1. HIV-2
is rare in the United States but more common in West Africa. Unless otherwise speci-
fied, this chapter addresses HIV-1 infection. HIV results in a broad spectrum of disease,
with acquired immunodeficiency syndrome (AIDS) representing the most severe
end of the clinical spectrum.
II. Incidence. The Joint United Nations Program on HIV/AIDS estimated that
36.7 million people worldwide were infected with HIV at the end of 2015. More than
95% of the total cases reside in developing countries. In the same year, an estimated
150,000 children contracted HIV, down from 290,000 in 2010 (down 50%). This drop
reflects the fact that access to services for preventing the mother-to-child transmission
(MTCT) of HIV has significantly increased. The estimated number of children living
with HIV declined to 1.8 million worldwide in 2015. Among infants born in the United
States, the overall annual rate of perinatally acquired HIV infections decreased from
3.6 per 100,000 live births in 2008 to 1.8 per 100,000 live births in 2013.

III. Pathophysiology. Rubella typically has an epidemic seasonal pattern of increased

frequency in the spring. In developing countries with no vaccination programs, epi-
demics have occurred at 4- to 7-year intervals, with major pandemics every 10 to
30 years. Humans are the only known hosts, with an incubation period of 14 to 21 days
after contact. Virus is spread by respiratory secretions and also from stool, urine, and
cervical secretions. A live virus vaccine has been available since 1969. In places with
no vaccination, 15% to 20% of women of childbearing age are susceptible to rubella.
There is a high incidence of subclinical infections. Maternal viremia is a prerequisite
for placental infection, which may or may not spread to the fetus. Most cases occur
after primary disease, although few cases (2%) have been described after reinfection.
Rubella infection can have catastrophic effects on the developing fetus, resulting in
spontaneous abortion, fetal infection, stillbirth, or intrauterine growth restriction. The
fetal infection rate varies according to the timing of maternal infection during preg-
nancy. If infection occurs at 1 to 12 weeks and is associated with maternal rash, there
is an 81% risk of fetal infection; at 13 to 16 weeks, 54%; at 17 to 22 weeks, 36%; at 23 to
30 weeks, 30%. There is a rise to 60% at 31 to 36 weeks and to 100% in the last month of
pregnancy, but late infection is not associated with CRS. No correlation exists between
the severity of maternal rubella and teratogenicity. However, the incidence of fetal
effects is greater the earlier in gestation that infection occurs, especially at 1 to 12 weeks,
when 85% of infected fetuses will have congenital defects. Infection during weeks 13 to
16 results in 35% of fetuses having congenital defects; infection at later gestational ages
rarely causes deafness or congenital malformations. Spontaneous abortion may occur
in up to 20% of cases when rubella occurs in the first 8 weeks of pregnancy. The disease
involves angiopathy as well as cytolytic changes. Other viral effects include chromo-
some breakage, decreased cell multiplication time, induction of programmed cell death
(apoptosis), and mitotic arrest in certain cell types. There is little inflammatory reaction.
IV. Risk factors. Women of childbearing age who are rubella nonimmune or foreign born
are at risk.
V. Clinical presentation. Congenital rubella infection has a wide spectrum of presenta-
tions, ranging from asymptomatic infection to acute disseminated infection to deficits
not evident at birth.
A. Systemic transient manifestations include low birthweight, hepatosplenomegaly,
meningoencephalitis, thrombocytopenia with or without purpura, and bony radio-
lucencies. These are probably a consequence of extensive viral infection and usually
resolve spontaneously within days or weeks. Infants with these abnormalities usu-
ally fail to thrive during infancy.
B. Systemic permanent manifestations include heart defects (eg, patent ductus arteri-
osus [PDA], pulmonary artery stenosis or hypoplasia), eye defects (eg, cataracts, iris
hypoplasia, microphthalmos, and retinopathy), central nervous system (CNS) prob-
lems (eg, intellectual disability and psychomotor developmental delay, speech and
language delay), microcephaly, and sensorineural deafness (unilateral or bilateral).
More than half of children infected during the first 8 weeks of gestation have heart
defects; branch pulmonary artery stenosis (78%) and PDA (62%) are the most
common. Of the eye defects, a “salt and pepper” retinopathy is the most common.
Cataract occurs in approximately 30% of cases of CRS (∼50% bilateral); rubella virus
is recovered in high titer from lens aspirates in children with congenital cataracts
for several years. Deafness is a major disabling abnormality and may occur alone.
C. Developmental and late-onset abnormalities. Rubella is a progressive disease due
to the persistence of the viral infection and the defective immune response to the
virus. Existing manifestations, such as deafness and CNS disease, may progress, and
some abnormalities may not be detected until the second year of life or later. These
include hearing, developmental and eye defects, diabetes mellitus (DM), thyroid
disorders, behavioral and educational difficulties, and progressive panencephalitis.
Insulin-dependent DM is the most frequent endocrine abnormality, occurring in
approximately 20% of cases.

145: Rubella 1173
VI. Diagnosis. Timely diagnosis of congenital rubella infection is important both for man-
agement of the individual patient and for prevention of secondary infection because
these infants may remain infectious for 1 year. The diagnosis may be suspected
clinically but needs to be confirmed with laboratory tests. The Centers for Disease
Control and Prevention (CDC) has published an elaborate case definition for congenital
rubella infection that is updated regularly (https://wwwn.cdc.gov/nndss/conditions/
rubella-congenital-syndrome/; accessed September 6, 2018). According to the most
recent update available at the time of publication (2010), cases of CRS are classified as
suspected, probable, confirmed, or infection only, depending on clinical findings and
laboratory criteria for diagnosis.
A. Centers for Disease Control and Prevention case definition
1. Suspected. An infant who has 1 or more of the following findings (but does
not meet the criteria for a confirmed or probable case): cataracts or congenital
glaucoma, congenital heart disease (most commonly PDA or peripheral pulmo-
nary artery stenosis), hearing impairment, pigmentary retinopathy, purpura,
hepatosplenomegaly, jaundice, microcephaly, developmental delay, meningo-
encephalitis, or radiolucent bone disease.
2. Probable. An infant who has at least 2 of the following findings (but does
not have laboratory confirmation of rubella infection or a more plausible
etiology): either cataracts or congenital glaucoma or both (counts as 1), con-
genital heart disease (most commonly PDA or peripheral pulmonary artery
stenosis), hearing impairment, or pigmentary retinopathy.
OR
An infant who has at least 1 or more of the following (but does not have
laboratory confirmation or an alternative more plausible etiology): either
cataracts or congenital glaucoma or both (counts as 1), congenital heart dis-
ease (PDA or peripheral pulmonary artery stenosis), hearing impairment, or
pigmentary retinopathy
AND
1 or more of the following of the following: purpura, hepatosplenomegaly,
microcephaly, developmental delay, meningoencephalitis, or radiolucent bone
disease.
3. Confirmed. An infant with at least 1 symptom (listed previously) that is
clinically consistent with CRS and laboratory evidence of congenital rubella
infection as demonstrated by: isolation of rubella virus, or detection of rubella-
specific immunoglobulin (Ig) M antibody, or infant rubella antibody level that
persists at a higher level and for a longer period than expected from passive
transfer of maternal antibody (ie, rubella titer that does not drop at the expected
rate of a 2-fold dilution per month), or a specimen that is polymerase chain
reaction (PCR) positive for rubella virus.
4. Infection only. An infant with laboratory evidence of infection but with no
clinical symptoms or signs. Laboratory evidence is as shown in Section VI.A.3.
If any signs or symptoms are identified later such as hearing loss, then the
diagnosis is reclassified as confirmed.
5. Congenital rubella syndrome cases are further classified epidemiologically
as internationally imported or United States acquired, according to the source
of infection in the mother.
B. Laboratory studies
1. Open cultures. The virus can be cultured for up to 1 year despite measurable
antibody titer. The best specimens for viral recovery are from nasopharyngeal
swabs, conjunctival scrapings, urine, and cerebrospinal fluid (CSF), in decreas-
ing order of usefulness.
2. Serologic studies. These are the mainstay of rubella diagnosis. CRS is diagnosed
by the detection of rubella-specific IgM in a serum or oral fluid taken before
3 months of age. IgM testing is less reliable after 3 months of age as levels of
specific IgM decline. However, if sensitive assays are used, specific IgM may
be detected in 85% of symptomatic infants at 3 to 6 months and >30% at 6 to
12 months of age. A negative result by IgM-capture enzyme immunosorbent
assay in the first 3 months of age virtually excludes congenital infection. It is
also possible to make a diagnosis by demonstrating persistence of rubella IgG
in sera taken between 6 and 12 months of age. It is difficult to make a serologic
diagnosis of congenital rubella after rubella vaccination. Testing of oral fluid
samples (IgM, IgG, and PCR) as an alternative to serum has been used and
standardized. It offers many advantages for surveillance of CRS in developing
countries. A false-positive IgM test result may rarely occur; this is caused by a
number of factors including rheumatoid factor, parvovirus IgM, and heterophile
antibodies. If false-positive IgM results are suspected, IgG avidity assay in a
reference laboratory (eg, CDC) can be used to confirm or refute the diagnosis.
IgG avidity and IgG response to the 3 viral structural proteins (E1, E2, and C),
reflected by immunoblot fluorescent signals may help to establish the diagnosis
of CRS in older school-aged children.
3. Rubella virus polymerase chain reaction. CRS may also be diagnosed by detec-
tion of viral RNA by nested reverse transcriptase (RT)-PCR in nasopharyngeal
swabs, urine, oral fluid, CSF, lens aspirate, and ethylenediaminetetraacetic acid
(EDTA)-blood.
4. Cerebrospinal fluid examination. This may reveal encephalitis with an
increased protein and cell count.
C. Imaging studies. Long-bone films may show metaphyseal radiolucencies that
correlate with metaphyseal osteoporosis.
VII. Management. Prenatal serologic screening for rubella immunity should be undertaken
for all pregnant women. Those without antibody concentrations above the standard
positive cutoff or those with equivocal test results should receive rubella vaccine dur-
ing the immediate postpartum period before discharge. Cases of CRS (suspected or
confirmed) in the United States should be reported to the CDC through local and state
health departments. All newborns who fail hearing screening and born to mothers
who are rubella nonimmune should undergo evaluation for rubella (measurement of
rubella-specific IgM antibodies) and other intrauterine infections. There is no spe-
cific treatment for rubella. Long-term follow-up is needed secondary to late-onset
symptoms. Prevention consists of vaccination of the susceptible population (especially
young children). Vaccine should not be given to pregnant women. Pregnancy should
be avoided for 28 days after vaccination. Inadvertent vaccination of pregnant women
does not cause CRS, although there is a 3% chance of congenital infection. Passive
immunization (with immune globulin [IG]) does not prevent rubella infection after
exposure and is not recommended. Administration of IG should be considered only if
a pregnant woman who has been exposed to rubella will not consider termination of
pregnancy under any circumstance. Administration of IG eliminates the value of IgG
antibody testing to detect maternal infection; however, IgM antibody can still be used
to detect maternal infection after exposure. Children with congenital rubella should be
considered contagious until they are at least 1 year of age, unless 2 cultures of clinical
specimens (nasopharyngeal and urine cultures) obtained 1 month apart are negative
for rubella virus after 3 months of age. Rubella vaccine virus can be isolated from breast
milk in lactating women who have received the vaccine. However, breast feeding is
not a contraindication to vaccination because no evidence indicates that the vaccine
virus is in any way harmful to the infant.
VIII. Prognosis. Infection in the first or second trimester can cause growth restriction, deaf-
ness, and other congenital malformations (CRS, discussed earlier). Congenital rubella
is a progressive disease, some of its consequences may not present until the second
decade of life (motor and mental retardation, hearing and communication disorders, DM).
Natural rubella infection in pregnancy is 1 of the few known causes of autism.

146: Sepsis 1175
146 Sepsis
Neonatal sepsis is a clinical syndrome of systemic illness accompanied by bacteremia occurring
in the first month of life. It can be classified into 2 relatively distinct syndromes based on the age
of presentation: early-onset and late-onset sepsis. These 2 entities will be discussed separately.
NEONATAL EARLY ONSET SEPSIS

I. Definition. Early-onset sepsis (EOS) is defined by the Centers for Disease Control and
Prevention (CDC) as blood and/or cerebrospinal fluid (CSF) culture–proven infection
occurring in the newborn at <7 days of age. For the continuously hospitalized very
low birthweight (VLBW; <1500 g) infant, EOS is defined as culture-proven infection
occurring at <72 hours of age.
II. Incidence. The overall incidence of EOS in the United States is estimated at 0.77 to
0.98 per 1000 live births. Incidence is strongly influenced by gestational age (GA) at
birth. Among infants born at ≥37 weeks’ gestation, the incidence is around 0.53 per
1000 live births, whereas in the preterm population, the incidence is 3.7 per 1000 live
births (7 times higher), and among VLBW infants, it is approximately 11 per 1000 live
births (20 times higher).
III. Pathophysiology
A. Infants usually present with a multisystem, sometimes fulminant, illness with
prominent respiratory symptoms. Typically, the infant has acquired the organ-
ism during the antepartum or intrapartum period from the maternal genital tract.
Several infectious agents, notably treponemes, viruses (eg, herpes simplex virus,
enteroviruses, and parechoviruses), Listeria, and probably Candida, can be acquired
transplacentally via hematogenous routes. Acquisition of other organisms is asso-
ciated with the birth process. With rupture of membranes, vaginal flora or other
bacterial pathogens may ascend to reach the amniotic fluid and the fetus. Cho-
rioamnionitis develops, leading to fetal colonization and infection. Aspiration of
infected amniotic fluid by the fetus or neonate may play a role in the resultant
respiratory symptoms. Finally, the infant may be exposed to vaginal flora as it passes
through the birth canal. The primary sites of colonization tend to be the skin, naso-
pharynx, oropharynx, conjunctiva, and umbilical cord. Trauma to these mucosal
surfaces may lead to infection. The disease may present suddenly with a fulminant
course that can progress rapidly to septic shock and death.
B. Microbiology. The principal pathogens involved in EOS have tended to change
with time. Before 1965, Staphylococcus aureus and Escherichia coli used to be the
most commonly isolated organisms. In the late 1960s and early 1970s, group B
Streptococcus (GBS) emerged as the most common microorganism. Currently,
most centers continue to report GBS as the most common microorganism, even
though the incidence has decreased considerably after the widespread adoption of
universal antenatal screening for GBS colonization at 35 to 37 weeks’ gestation and
intrapartum antibiotic prophylaxis (IAP) with penicillin or ampicillin for colonized
women. The incidence of EOS secondary to GBS decreased from 1.7 per 1000
live births in 1993 to 0.22 per 1000 in 2016 (>85% reduction). The second most
common bacteria are gram-negative enteric organisms, especially E coli. An increase
in the incidence of E coli has been noted in EOS in VLBW infants to the extent that
E coli is currently the predominant microorganism in this group of patients. GBS
and E coli account for two-thirds of all cases of EOS. Other pathogens causing
EOS include Listeria monocytogenes, S aureus, enterococci, other gram-negative
bacteria (Klebsiella, Citrobacter, Serratia, and Enterobacter), anaerobes (especially
Bacteroides fraglis), Haemophilus influenzae, and Streptococcus pneumoniae.

IV. Risk factors for neonatal early-onset sepsis

A. Prematurity and low birthweight. Prematurity (especially if <35 weeks’ gestation)
is the single most significant factor correlated with sepsis. The risk increases in
proportion to the decrease in birthweight and GA.
B. Rupture of membranes ≥18 hours. The risk for proven sepsis increases 10-fold.
C. Maternal peripartum infection. Infections such as chorioamnionitis manifesting
as maternal fever, urinary tract infection (UTI) especially GBS bacteriuria,
rectovaginal colonization with GBS, and perineal colonization with E coli are
well-recognized risk factors for EOS. Chorioamnionitis is an imprecise and
heterogeneous disorder; the National Institute of Child Health and Human
Development (NICHD) convened a group of experts in 2015 to a workshop that
issued evidence-based recommendations with regard to this issue. The group
proposed to replace the term chorioamnionitis with a more general descriptive
term: “intrauterine inflammation or infection or both,” abbreviated as “triple I.”
However, this terminology has not been widely accepted yet. The American College
of Obstetricians and Gynecologists (ACOG) endorsed the recommendations of
the NICHD workshop but chose to use the term “intraamniotic infection” instead.
D. Previous delivery of a neonate with group B streptococcal disease.
E. Fetal and intrapartum distress. Infants who had intrapartum fetal tachycardia,
meconium-stained amniotic fluid, were born by traumatic delivery, or were severely
depressed at birth and required intubation and resuscitation are either infected in
utero or at significant risk for EOS.
F. Multiple gestation.
G. Metabolic factors. Hypoxia, acidosis, inherited metabolic disorders (eg, galacto-
semia predisposing to E coli sepsis), and immune defects (eg, asplenia) are factors
that predispose to, as well as increase the severity of, sepsis.
H. Other factors. Males are affected 4 times more often than females, and the possibil-
ity of a sex-linked genetic basis for host susceptibility is postulated. Black African
descent is an independent risk factor for EOS with GBS. Reasons for the dispropor-
tionately high disease burden among black populations cannot be fully explained
by prematurity or socioeconomic status. However, Black African descent is known
to be associated with higher rates of GBS colonization.
V. Clinical presentation of neonatal early-onset sepsis. Because the initial diagnosis of
sepsis is, by necessity, a clinical one, it is crucial to begin treatment before the results
of cultures are available. Clinical signs and symptoms of sepsis are nonspecific, and the
differential diagnosis is broad. Some signs are subtle or insidious, and therefore, a high
index of suspicion is required to identify and evaluate infected neonates. Clinical signs
and symptoms most often mentioned include the following:
A. Temperature irregularity. Hypothermia is more common than fever as a presenting
sign for bacterial sepsis in premature infants. Hyperthermia is more common in full-
term infants beyond the first 24 hours of life and if viral agents (eg, herpes) are involved.
B. Change in behavior. Lethargy, irritability, seizures, or change in tone.
C. Skin. Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes,
sclerema, and jaundice singularly or in combinations are known signs of sepsis.
D. Cardiopulmonary. Tachypnea, respiratory distress (grunting, flaring, and retrac-
tions), apnea within the first 24 hours of birth, tachycardia, and hypotension singu-
larly or in combinations should suggest sepsis. Hypotension tends to be a late sign.
E. Metabolic. Metabolic findings include hyperkalemia, hyponatremia, hyperglyce-
mia, or metabolic acidosis. There is no evidence that hypoglycemia occurring in
isolation is a risk factor or manifestation of EOS.
VI. Diagnosis
A. Differential diagnosis. Because signs and symptoms of neonatal sepsis are
nonspecific, noninfectious etiologies need to be considered. If the infant is presenting
with respiratory symptoms, respiratory distress syndrome, transient tachypnea of the
newborn, meconium aspiration, and aspiration pneumonia are considered. If the

146: Sepsis 1177
infant is showing central nervous system (CNS) symptoms, then meningitis, intracranial
hemorrhage, drug withdrawal, and inborn errors of metabolism are considered.
B. Laboratory studies
1. Cultures. Blood and other normally sterile body fluids (eg, tracheal aspi-
rate and CSF) should be obtained for culture. Body surface cultures are not
recommended.
a. Blood cultures. Modern, computer-assisted automated blood culture systems use
optimized enriched culture media with antimicrobial neutralization properties;
they provide continuous-read detection and are able to identify up to 94% to
96% of all microorganisms by 36 hours of incubation. Results may vary because
of a number of factors, including maternal antibiotics administered before birth,
organisms that are difficult to grow and isolate (ie, anaerobes), and sampling
error with small sample volumes (the minimum volume for blood culture is
1 mL). The concerns about low-level bacteremia and the effect of intrapartum
antibiotic administration are not substantiated as these systems have been
shown to reliably detect bacteremia at a level of 1 to 10 colony-forming units
per mL if a minimum blood volume of 1 mL is inoculated. Additionally, several
studies have reported no effect of intrapartum antibiotic therapy on time to
positivity since the culture media contains antimicrobial neutralization elements
that efficiently neutralize β-lactam antibiotic agents as well as gentamicin. One
aerobic blood culture is typically obtained in cases of EOS, however, the use of 2
separate culture bottles (1 aerobic and 1 anaerobic) may provide the opportunity
to determine if commensal species are true infections by comparing growth in
the 2 cultures. In some clinical situations where the infant is critically ill, it may
be appropriate to treat for “presumed” sepsis despite negative cultures.
b. Lumbar puncture. Some controversy currently exists regarding whether a
lumbar puncture (LP) is needed in asymptomatic newborns being worked up
for presumptive EOS. Many institutions perform LPs only on infants who are
clinically ill, infants who have CNS symptoms such as apnea or seizures, or
in cases of documented positive blood cultures or if the decision is made to
extend antibiotics beyond 48 hours for presumptive clinical sepsis.
c. Urine cultures. In neonates <24 hours of age, a sterile urine specimen is not
recommended given that the occurrence of UTIs is exceedingly rare in this
age group.
d. Tracheal cultures may be obtained shortly after intubation (within 3 hours)
in ill neonates with a clinical picture suggestive of early-onset pneumonia or
if the mother developed intraamniotic infection with overwhelming EOS of
the newborn. Tracheal aspirates done after several hours or days of intubation
are of limited value.
2. Gram stain. Gram staining is especially helpful for the study of CSF. Gram-
stained smears and cultures of amniotic fluid are helpful in diagnosing intraam-
niotic infection. A Gram stain of tracheal aspirate can show the infecting
microorganism in EOS/pneumonia.
3. Molecular testing. Molecular methods for detection of neonatal sepsis in blood
include polymerase chain reaction (PCR) and DNA microarray–based meth-
ods. Most of these tests hold the promise of rapid detection directly from blood
without prior culture combined with high sensitivity and specificity in relation
to cultures and with using small volume of blood. A recent Cochrane review
that evaluated 35 studies found a summary estimate of sensitivity of 0.90 and
specificity of 0.93 and concluded that molecular assays have the advantage of
producing rapid results and may perform well as add-on tests.
4. Other laboratory tests
a. Complete blood count with differential. These values alone are very non-
specific. There are reference values for total white blood cell (WBC) count
and absolute neutrophil counts as a function of postnatal age in hours

(they peak during the first 12–14 hours of age; see Chapter 78, particularly
Tables 78–1 and 78–2). Neutropenia may be a significant finding with an
ominous prognosis when associated with EOS. The presence of immature
forms is more specific but still rather insensitive. Ratio of immature to total
polymorphonuclear cells (I/T) >0.2 has good predictive value, if present. The
diagnostic yield of WBC count improves when testing is done after 6 hours
of age. A variety of conditions other than sepsis can alter neutrophil counts
and ratios, including maternal hypertension and fever, neonatal asphyxia,
maternal intrapartum oxytocin, hypoglycemia, stressful labor, meconium
aspiration syndrome, pneumothorax, and even prolonged crying. Serial WBC
counts obtained several hours apart may be helpful in establishing a trend.
Decreased platelet count can be associated with EOS; however, this is usually
a late sign and very nonspecific.
b. Acute-phase reactants (APRs). APRs are complex multifunctional group
comprising complement components, coagulation proteins, protease inhibi-
tors, C-reactive protein (CRP), and others that rise in concentration in the
serum in response to inflammation. The inflammation may be secondary
to infection, trauma, or other processes of cellular destruction. An elevated
APR does not distinguish between infectious and noninfectious causes of
inflammation. Except for CRP and procalcitonin (PCT), most APRs are not
commercially available for routine testing.
i. C-reactive protein is an APR that increases the most in the presence of
inflammation caused by infection or tissue injury. The highest concentra-
tions of CRP are reported in patients with bacterial infections, whereas
moderate elevations typify chronic inflammatory conditions. Synthesis of
CPR by hepatocytes is modulated by cytokines. Interleukin (IL)-1β, IL-6,
IL-8, and tumor necrosis factor (TNF) are the most important regulators
of CRP synthesis. CRP secretion starts within 4 to 6 hours after the inflam-
matory stimulus and peaks at approximately 36 to 48 hours. The biologic
half-life of CRP is 19 hours, with a 50% reduction daily after the acute-
phase stimulus resolves. A single normal value (<1 mg/dL) cannot rule out
infection because the sampling may have preceded the rise in CRP; if a
single value is obtained, it needs to be done after 18 hours of age. If CRP is
obtained, serial determinations are better than a single value. Two normal
CRP determinations (8–24 hours after birth and 24 hours later) have been
shown to have a negative predictive value of 99.7% for proven neonatal
sepsis. CRP elevations in noninfected neonates have been seen with fetal
hypoxia, respiratory distress syndrome (RDS), and meconium aspiration;
after trauma/surgery; and after immunizations. Serial abnormal CRP val-
ues alone should not be used to decide whether to administer antibiotics
in the absence of a culture-confirmed infection. A false-positive rate of
8% has been found in healthy neonates. Nonetheless, CRP is a valuable
adjunct in the diagnosis of sepsis (ruling it out when serial CRPs are low),
monitoring the response to treatment, and guiding duration of treatment.
ii. Procalcitonin is a propeptide of calcitonin that is released by paren-
chymal cells in response to bacterial toxins. A recent systematic review
showed a sensitivity of 0.85 and specificity of 0.54 for detection of neo-
natal sepsis (EOS and late-onset sepsis [LOS]) at the PCT cutoff of 2.0
to 2.5 ng/mL. A recent multicenter randomized controlled trial showed
that PCT seems to have some utility in guiding the duration of antibiotic
therapy in neonates with suspected EOS. A physiologic increase in the
PCT concentration occurs within the first 24 hours of birth.
iii. Cytokines interleukin-6, interleukin-8, and tumor necrosis factor are
produced primarily by activated monocytes and macrophages and are
major mediators of the systemic response to infection. Studies have shown
that combining cytokines with CRP may be better than using CRP alone.

146: Sepsis 1179
iv. Neutrophil surface antigens CD11, CD14, and CD64 are promising

markers of early infection that correlate well with CRP but peak earlier.
Presepsin (soluble CD14 subtype) has attracted recent attention because
of its utility as a sepsis marker in adults. Preliminary studies in neonates
have shown that most variables commonly affecting CRP and PCT values
do not affect presepsin levels, which suggests that presepsin could become
an effective sepsis marker in neonates.
C. Imaging studies. Chest radiograph should be obtained in cases with respiratory
symptoms, although it is often impossible to distinguish GBS or Listeria pneumonia
from uncomplicated RDS. One distinguishing feature is the presence of pleural
effusion, which occurs in 67% of cases of pneumonia.
D. Other studies. Examination of the placenta and fetal membranes may disclose evi-
dence of chorioamnionitis and thus an increased potential for neonatal infection.
VII. Management. Isolation precautions for all infectious diseases, including maternal and
neonatal precautions, breast feeding, and visiting issues, can be found in Appendix F.
Chapter 78 (on call problem “Post-delivery Antibiotics”) discusses which infants
should be considered for antibiotics.
A. Prevention: group B Streptococcus prophylaxis. Because of the widespread use of
IAP, EOS secondary to GBS has been reduced by >85%. Fortunately, GBS preven-
tion efforts have not led to an increasing burden of early-onset E coli infections.
Approximately 20% to 30% of pregnant women are colonized with GBS in the
vaginal or rectal area. Consensus guidelines regarding management of GBS were
published by the CDC in 1996 and were later revised in 2002 and in 2010. In 2017,
representatives from the CDC, AAP, ACOG, and other stakeholder organizations
agreed to review and revise the 2010 GBS guidelines. It was decided that the AAP
would revise neonatal care recommendations and ACOG would revise obstetric
care guidelines. These separate but congruent clinical reports were published in
July 2019 and replaced the CDC 2010 GBS perinatal guidelines. They recommend
that all pregnant women should be screened at 36 0/7 to 37 6/7 weeks’ gestation
for vaginal and rectal GBS colonization. At the time of labor or rupture of mem-
branes, IAP should be given to all pregnant women identified as GBS carriers.
Women with GBS isolated from the urine (GBS bacteriuria, any colony count)
during their current pregnancy should receive IAP because such women usually
are heavily colonized with GBS and are at increased risk of delivering an infant with
EOS. Women who have previously given birth to an infant with invasive GBS
disease should receive IAP as well. Additionally, women who were GBS colonized
during a previous pregnancy have a 50% likelihood of GBS carriage in the cur-
rent pregnancy, therefore, ACOG guidelines recommend that if a woman with
unknown GBS status presents in labor and is known to have had GBS colonization
in a previous pregnancy, IAP should be considered for such woman. Penicillin
is the drug of choice, but ampicillin is an acceptable alternative. First generation
cephalosporins (ie, cefazolin) are recommended for women whose reported peni-
cillin allergy indicates a low risk of anaphylaxis or is of uncertain severity. Penicillin
allergy skin testing, if available, is safe during pregnancy and can be recommended
to “penicillin-allergic” women to ascertain their true risk of anaphylaxis. Clindamy-
cin is the recommended alternative to penicillin only if the GBS isolate is known to
be susceptible to clindamycin. Vancomycin is used when there is a high-risk penicil-
lin allergy and when GBS isolate is not susceptible to clindamycin. The risk-based
approach is not acceptable except for circumstances in which screening results are
not available before labor and delivery. In these circumstances, IAP should be given
to women <37 weeks’ gestation, those with rupture of membranes ≥18 hours, and
women who have a fever ≥38°C (100.4°F). Women with GBS colonization in one
pregnancy have an estimated 50% risk of colonization in a subsequent pregnancy,
therefore GBS IAP may be considered for such women. The guidelines recognize the
availability of commercial nucleic acid amplification tests (NAAT) such as PCR
for rapid detection of GBS. If available, NAAT intrapartum rectovaginal testing can

be performed on women with unknown GBS status and no intrapartum GBS risk
factors. IAP should be given if the NAAT testing returns positive or an intrapartum
risk factor develops regardless of NAAT results. In addition, the guidelines specifi-
cally addressed threatened preterm labor (PTL) and preterm prelabor rupture of
membranes (pPROM) with detailed algorithms. Briefly, women with threatened
PTL or pPROM should be screened for GBS colonization on admission unless a GBS
culture was obtained within the preceding 5 weeks. In both of these situations, women
should receive GBS prophylaxis (typically for 48 hours) unless the screening results
are negative. The recommendations also provide clarification on optimal GBS cultur-
ing methods. On the neonatal side, the GBS guidelines (published by AAP) review the
epidemiology of neonatal GBS disease and provide specific algorithms for neonatal
management based on risk assessment and gestational age (see next sections).
B. Neonatal risk assessment for infants born at ≥35 weeks’ gestation. The AAP
report acknowledges and endorses 3 commonly used approaches to risk assessment
among infants born at ≥35 weeks’ gestation as follows:
1. Categorical risk assessment. This approach uses risk factor (mainly maternal
intrapartum fever–oral temperature >38°C) to identify infants at increased
risk for EOS due to GBS (Figure 146–1A). Different versions of this approach
A B C
Categorical Risk Assessment Neonatal Early-Onset Enhanced Observation
Sepsis Calculator
Yes Blood culturesa Yes Blood culturesa

https://neonatalsepsiscalculator.kaiserpermanente.org
Signs of Predictor Scenario Signs of

clinical illness Empiric clinical illness Empiric
Incidence of
antibiotics Early–Onset antibiotics
Yes
Sepsis ? No
Gestational weeks
age ?
Maternal • Serial physical
Maternal days Yes examination
Yes Blood culturesa intrapartum
intrapartum and vital sign
Empiric
Highest Fahrenheit temperature
temperature maternal
for 36–48 hours
antibiotics antepartum ≥38°C (100.4°F)
≥38°C (100.4°F) temperature
? or inadequate • Blood culturesa
indicated GBS and empiric
Yes ROM
(Hours) ? IAP? antibiotics if
Maternal No infant develops
GBS IAP No GBS status
Negative
Routine ? signs of clinical
indicated for Positive
Routine illness
newborn care
mother? Unknown
newborn care
Yes Type of
Broad spectrum
Clinical intrapartum
antibiotics
antibiotics > 4 hrs prior to
birth
No observation ?
Adequate GBS
for 36–48 Broad spectrum
IAPb given? antibiotics 2-3.9 hrs prior
hours to birth
Yes after birth GBS specific antibiotics >

2 hrs prior to birth
No antibiotics or any
Routine antibiotics < 2 hrs prior
to birth
newborn care
FIGURE 146–1. Options for EOS risk assessment among infants born ≥35 weeks’ gestation.
(A) Categorical risk assessment. (B) Neonatal Early-Onset Sepsis Calculator. (The screenshot
of the Neonatal Early-Onset Sepsis Calculator [https://neonatalsepsiscalculator.kaiserpermanente
.org/] was used with permission from Kaiser-Permanente Division of Research.) (C) Enhanced
observation. aConsider lumbar puncture and CSF culture before initiation of empiric
antibiotics for infants who are at the highest risk of infection, especially those with critical
illness. Lumbar puncture should not be performed if the infant’s clinical condition would be
compromised, and antibiotics should be administered promptly and not deferred because
of procedure delays. bAdequate GBS IAP is defined as the administration of penicillin G,
ampicillin, or cefazolin ≥4 hours before delivery. (Reproduced with permission from Puopolo KM,
Lynfield R, Cummings JJ, et al: Management of Infants at Risk for Group B Streptococcal Disease,
Pediatrics. 2019 Aug;144(2). pii: e20191881.)
146: Sepsis 1181
have been published previously including the algorithm published by CDC in

2010. For the purpose of categorical risk assessment, maternal intrapartum
temperature >38°C is used as a surrogate for intraamniotic infection (called
chorioamnionitis in the 2010 CDC algorithm). The administration of penicillin
G, ampicillin, or cefazolin >4 hours before delivery is considered adequate GBS
IAP; other antibiotics or other durations of treatment <4 hours are considered
inadequate for this approach. It has been recognized that the risk of EOS is highly
variable when maternal fever (any degree) is used alone as the principal cat-
egorical risk. Other important factors that modify the risk substantially include
gestational age, duration of ROM, and timing and content of administered intra-
partum antibiotics. Adopting this approach may result in many relatively low
risk infants receiving empirical antibiotic treatment unnecessarily, especially if
their only risk is exposure to low-grade maternal fever.
2. Multivariate risk assessment (the Neonatal Early-Onset Sepsis Calculator):
Multivariate risk assessment integrates the individual infant’s combination of
objective quantifiable risk factors and his/her clinical examination to estimate
the individual infant’s risk of EOS (including EOS secondary to GBS). Predictive
models based on gestational age at birth (weeks and days), highest maternal
intrapartum temperature (centigrade or Fahrenheit), maternal GBS colonization
status (positive, negative, uncertain), duration of ROM (hours), and type and
duration of intrapartum antibiotic therapies (1 of 4 categories) have been
developed and validated. The models are available as web-based Neonatal
Early-Onset Sepsis Calculator (Figure 146–1B) (neonatalsepsiscalculator
.kaiserpermanente.org). The calculator begins with the previous probability of
EOS (typically of 0.5/1000 in the United States, unless local incidence of EOS
is known to differ). When using the calculator, only penicillin, ampicillin, or
cefazolin should be considered as “GBS-specific antibiotics.” The administration
of clindamycin or vancomycin alone for intrapartum GBS prophylaxis for any
duration is currently recommended to be entered as “no antibiotics.” Entering
the data listed above in the calculator produces risk estimate of EOS per 1000
births and recommends further action based on infant’s examination ranging
from enhanced clinical observation to blood culture and empirical antibiotic
therapy. Using the original dataset, if the hypothetical risk of sepsis ranged from
0.65 to 1.54 per 1000 live births (based solely on objective risk factors), 823 well-
appearing neonates born to women with maternal fever/possible intraamniotic
infection would need treatment to capture the one truly infected neonate (the
number needed to treat). Such newborns account for 11% of all live births. For
example, if a well-appearing newborn infant is born at 39 2/7 weeks’ gestation
to a GBS positive mother with maximum intrapartum temperature of 38.5°C
(called by obstetricians as chorioamnionitis), with ROM for 18 hours and IAP
with Penicillin G, one dose 3 hours prior to delivery, this infant’s sepsis risk score
is calculated at 1.13. The management of the infant in this scenario would be
different if categorical risk assessment is used (blood culture followed by empirical
antibiotics) compared to Neonatal Sepsis Calculator (no culture, no antibiotics;
vitals every 4 hours for 24 hours). Several retrospective and prospective studies
have demonstrated the utility of the sepsis calculator in substantially reducing
laboratory testing and exposure to antimicrobial agents (compared to categorical
risk strategy) in populations of well-appearing neonates with gestational age
≥35 weeks without missing EOS, provided that these neonates receive continued
observation for 48 hours after birth. Centers that opt for this approach will need
to develop a structured method for close clinical observation of infants at specific
levels of estimated risk.
3. Risk assessment based on clinical condition (enhanced observation): This
approach relies on clinical signs of illness to identify infants with EOS
(including that secondary to GBS) regardless of neonatal or maternal
risk factors (Figure 146–1C). Infants who appear ill at birth and those
who develop signs of illness over the first 48 hours after birth are treated
empirically with antibiotic agents (after blood culture is obtained). Among
term infants, “good clinical condition” at birth is associated with a reduction
in risk for EOS of approximately 60% to 70%. Researchers at 1 center in Italy
reported a cohort of 7628 term infants who were managed with a categorical
approach to risk identification and compared the outcomes with a cohort of
7611 infants who were managed with serial physical examinations every 4 to
6 hours through 48 hours of age. Significant decreases in the use of laboratory
tests, blood cultures, and empirical antibiotic agents were observed in the
second cohort. Two infants who developed EOS in the second cohort were
identified as they developed signs of illness. This approach is embraced by
the NICHD workshop on chorioamnionitis. Centers that adopt this approach
need to establish processes to ensure serial, structured, documented physical
assessments and develop clear criteria for additional evaluation and empirical
antibiotic administration. Physicians and families must understand that the
identification of initially well-appearing infants who develop clinical illness is
not a failure of care, but rather an anticipated outcome of this approach to EOS
(including EOS due to GBS). Additionally, it may be reasonable to consider
supplementing the structured clinical examination with a limited evaluation
(eg, CBC, CRP) at 6 hours of age.
The AAP guidelines stop short of recommending one approach over
the other. Instead, they recommend that birth centers consider the devel-
opment of locally tailored, documented guidelines for EOS risk assessment
and clinical management. They also recommend ongoing surveillance once
guidelines are implemented.
C. Neonatal risk assessment for infants born at ≤ 34 6/7 weeks’ gestation. The AAP
report on GBS addresses infants born at ≤34 6/7 weeks’ gestation at risk for GBS
in a similar fashion to infants at risk from all other causes of EOS. It indicates that
those infants can be categorized by level of risk for EOS by the circumstances of
their preterm birth as follows (Figure 146–2):
1. Preterm infants at highest risk for EOS. Infants born preterm because of
maternal cervical incompetence, preterm labor, pPROM, clinical concern for
intraamniotic infection, and/or acute onset of unexplained nonreassuring fetal
status are at the highest risk for EOS. Such neonates should undergo EOS evalu-
ation with a blood culture and empiric antibiotic treatment.
2. Preterm infants at lowest risk for EOS. Preterm infants at lowest risk for EOS
(including EOS due to GBS) are those born under circumstances that include all
of these criteria: (1) maternal and/or fetal indications for preterm birth (such as
maternal preeclampsia or other noninfectious medical illness, placental insuffi-
ciency, or fetal growth restriction), (2) birth by cesarean delivery, and (3) absence
of labor, attempts to induce labor, or any ROM before delivery. Acceptable initial
approaches to these infants include (1) no laboratory evaluation and no empiri-
cal antibiotic therapy or (2) blood culture and clinical monitoring. For infants
who do not improve after initial stabilization and/or those who have severe
systemic instability, the administration of empirical antibiotics may be reason-
able but is not mandatory.
3. Preterm infants delivered for maternal and/or fetal indications but who are
ultimately born by vaginal or cesarean delivery after efforts to induce labor
and/or with ROM before delivery. Those infants are subject to factors associ-
ated with the pathogenesis of EOS due to GBS or other bacteria. If the mother
has an indication for GBS prophylaxis and appropriate treatment (penicillin,
ampicillin, or cefazolin >4 hours before delivery) is not given or if any other
concern for infection arises during the process of delivery, the infant should
be managed as recommended above for preterm infants at higher risk for EOS

146: Sepsis 1183
Infant born in association Infant born by induction of Infant born by cesarean

with any of: preterm labor; No labor with or without cervical No section for maternal/fetal
prelabor ROM; or any concern ripening (resulting in either indications with ROM at
for intraamniotic infectiona vaginal or cesarean delivery) time of delivery
Yes Yes Yes
Blood culturesb Any of the following are present: Approaches included:

Empiric antibiotics • Indication for GBS prophylaxis No • No laboratory evaluation and
and inadequate GBS IAPc no empiric antibiotic therapy
• Concern for intraamniotic • Blood culture and clinical
infection monitoring
• Infant with respiratory and/or
cardiovascular instability
Yes
Blood culturesb
Empiric antibiotics
FIGURE 146–2. EOS risk assessment among infants born ≤34 weeks’ gestation. aIntraamniotic
infection should be considered when a pregnant woman presents with unexplained decreased
fetal movement and/or there is sudden and unexplained poor fetal testing. bLumbar
puncture and CSF culture should be performed before initiation of empiric antibiotics for
infants who are at the highest risk of infection unless the procedure would compromise the
infant’s clinical condition. Antibiotics should be administered promptly and not deferred
because of procedural delays. cAdequate GBS IAP is defined as the administration of
penicillin G, ampicillin, or cefazolin ≥4 hours before delivery. dFor infants who do not
improve after initial stabilization and/or those who have severe systemic instability, the
administration of empiric antibiotics may be reasonable but is not mandatory. (Reproduced
with permission from Puopolo KM, Lynfield R, Cummings JJ, et al: Management of Infants at
Risk for Group B Streptococcal Disease, Pediatrics. 2019 Aug;144(2). pii: e20191881.)
(Section VII.C.1). Otherwise, an acceptable approach to these infants is close

observation for those infants who are well appearing at birth and to obtain a
blood culture and initiate antibiotic therapy for infants with respiratory and/or
cardiovascular instability after birth.
D. Empiric antibiotic therapy. Treatment for EOS is often begun before a definite
causative agent is identified. It usually consists of ampicillin and gentamicin.
(Dosages are presented in Chapter 155.) This empirical regimen covers the most
commonly encountered microorganisms, namely GBS and E coli, and has proved
to be efficacious over the years. Third-generation cephalosporins should be avoided
as an empirical therapy for EOS because they are associated with increased risk for
antibiotic resistance and invasive fungal infections. Third-generation cephalosporins
may be considered for infants suspected to have meningitis or who have renal
impairment. According to recent CDC surveillance studies, approximately 1.7% of
all E coli EOS cases were resistant to both ampicillin and gentamicin; therefore, the
empirical addition of broader spectrum antibiotics should be considered in critically
ill newborns who deteriorate despite being on ampicillin and gentamicin, or in
preterm infants exposed to prolonged antepartum maternal antibiotic treatment.
When blood cultures are sterile, antibiotic therapy should be discontinued by 36
to 48 hours of incubation, unless there is clear evidence of site-specific infection or
unexplained persistent cardiorespiratory instability. Laboratory test abnormalities
alone rarely justify prolonged empirical antibiotic administration, particularly
among preterm infants at a lower risk for EOS.
E. Continuing therapy is based on culture and sensitivity results, clinical course, and
occasionally other serial laboratory studies (eg, CRP and PCT). Monitoring for

antibiotic toxicity is important, as is monitoring levels of aminoglycosides. When

GBS is documented as the causative agent, penicillin G is the drug of choice; however,
an aminoglycoside is often added for a few days because of documented synergism
in vitro.
F. Complications and supportive therapy
1. Respiratory. Ensure adequate oxygenation with blood gas monitoring, and initi-
ate oxygen therapy or ventilator support if needed.
2. Cardiovascular. Support blood pressure and perfusion to prevent shock. Use
volume expanders such as normal saline, and monitor the intake and output of
fluids. Inotropes such as dopamine or dobutamine may be needed (see Chapter 70).
3. Hematologic
a. Disseminated intravascular coagulation. With disseminated intravascular
coagulation (DIC), one may observe generalized bleeding at puncture sites,
the gastrointestinal tract, or CNS. In the skin, large-vessel thrombosis may
cause gangrene. Laboratory parameters consistent with DIC include thrombo-
cytopenia, increased prothrombin time, and increased partial thromboplastin
time. There is an increase in fibrin split products or d-dimers. Treatment
options include fresh-frozen plasma, 10 mL/kg; vitamin K (see Chapter 155);
platelet infusion; and possible exchange transfusion (see Chapter 34).
b. Neutropenia. Multiple factors contribute to the increased susceptibility of
neonates to infection, including developmental quantitative and qualitative
neutrophil defects. Colony-stimulating factors comprise a group of cyto-
kines that are central to the hematopoiesis of blood cells, as well as to the
maintenance of homeostasis and overall immune competence. Granulocyte
colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-
stimulating factor (GM-CSF) have been used in neonates with established
sepsis associated with neutropenia, in neutropenic infants without sepsis,
and prophylactically in neonates at risk for sepsis. Limited data suggest that
colony-stimulating factor administration may reduce mortality when sys-
temic infection is accompanied by severe neutropenia. Intravenous immuno-
globulin does not appear useful either as a prophylactic agent or as an adjunct
to antibiotic therapy in serious neonatal infection.
4. Central nervous system. Implement seizure control measures using pheno-
barbital, and monitor for the syndrome of inappropriate antidiuretic hormone
(decreased urine output, hyponatremia, decreased serum osmolarity, and
increased urine specific gravity and osmolarity).
5. Metabolic. Monitor for and treat hypoglycemia or hyperglycemia. Metabolic acidosis
may accompany sepsis and is treated with bicarbonate and fluid replacement.
G. Future developments. Intensive research continues in the development of vaccines
(especially for GBS). Research is also ongoing into blocking some of the body’s own
inflammatory mediators that result in significant tissue injury, including endotoxin
inhibitors, cytokine inhibitors, nitric oxide synthetase inhibitors, and neutrophil
adhesion inhibitors.
VIII. Prognosis. With early diagnosis and treatment, most infants will recover and not have
long-term complications. However, the mortality rate is still significant for EOS, especially
in VLBW infants. For term and late preterm infants, the reported mortality is approxi-
mately 3%, whereas EOS mortality for VLBW infants is approximately 16%. Neonatal
EOS is a risk factor for long-term neurodevelopmental impairment in premature infants.
NEONATAL LATE-ONSET SEPSIS

I. Definition. Neonatal LOS is defined by the CDC as blood and/or CSF culture–proven
infection occurring in the newborn after 7 days of age caused by a postnatal acquisition
(nosocomial or community sources). For the continuously hospitalized VLBW infant,
LOS is defined as culture-proven infection occurring at >72 hours of age.

146: Sepsis 1185
II. Incidence of neonatal late-onset sepsis. The overall incidence of primary sepsis (EOS
and LOS) is 1 to 2 per 1000 live births. The incidence of LOS in term infants is hard
to know; however, a study that looked at late preterm infants hospitalized in the first
3 months of life identified LOS in 6.3 per 1000 admissions. According to the CDC,
late-onset GBS infection rates have remained relatively stable over the past 20 years
and are not impacted by intrapartum antibiotics prophylaxis (0.32 per 1000 live births
in 2015). Incidence of LOS is much higher for VLBW infants; according to data from
the NICHD Neonatal Research Network (NICHD-NRN), the incidence is 32% and
appears to be decreasing in recent years (37% in 2005, 27% in 2012).
III. Pathophysiology of neonatal late-onset sepsis. LOS is usually more insidious
(compared to EOS), but it can be fulminant at times. It is usually not associated with
early obstetric complications. In addition to bacteremia, these infants may have an
identifiable focus, most often meningitis in addition to sepsis. Bacteria responsible
for LOS and meningitis include those acquired after birth from the maternal genital
tract (vertical transmission) as well as organisms acquired after birth from human
contact or from contaminated equipment/environment (nosocomial). Therefore,
horizontal transmission appears to play a significant role in LOS. The reasons for
the delay in development of clinical illness, the predilection for CNS disease, and
the less severe systemic and cardiorespiratory symptoms are unclear. Transplacental
transfer of maternal antibodies (also in breastmilk) to the mother’s own vaginal flora
may play a role in determining which exposed infants become infected, especially in
the case of GBS infections. In case of nosocomial spread, the pathogenesis is related
to the underlying illness and debilitation of the infant, the flora in the neonatal
intensive care (NICU) environment, and invasive monitoring and other techniques
used in the NICU, especially the use of peripherally inserted central catheters
(PICCs). Breaks in the natural barrier function of the skin and intestine allow
opportunistic organisms to invade and overwhelm the neonate. Infants, especially
the premature, have an increased susceptibility to infection because of underlying
illnesses and immature immune defenses that are less efficient at localizing and
clearing bacterial invasion.
A. Microbiology. The pathogens that cause LOS or nosocomial sepsis tend to vary
in each nursery; however, coagulase-negative staphylococci (CONS), especially
Staphylococcus epidermidis, are the most predominant (53% of cases in NICHD-
NRN). Other microorganisms causing LOS include gram-negative rods (including
Pseudomonas, Klebsiella, Serratia, E coli, and Proteus), S aureus (both methicillin-
susceptible and methicillin-resistant), GBS, and fungal microorganisms.
B. Antibiotic resistance. Antibiotics resistance, especially to Enterobacteriaceae
such as E coli, is an emerging problem in many NICUs. Multiple mechanisms
of resistance may be present simultaneously. Resistance resulting from produc-
tion of chromosomally encoded or plasmid-derived AmpC β-lactamases or from
plasmid-mediated extended-spectrum β-lactamases (ESBLs) occurs primarily in
E coli, Klebsiella species, and Enterobacter species but has been reported in many
other gram-negative species. Resistant gram-negative infections have been associ-
ated with nursery outbreaks, especially in VLBW infants. Organisms that produce
ESBLs typically are resistant to penicillins, cephalosporins, and monobactams and
can be resistant to aminoglycosides. Carbapenemase-producing Enterobacteriaceae
(CPE) also have emerged, especially Klebsiella pneumoniae, Pseudomonas aeru-
ginosa, and Acinetobacter species. ESBL- and carbapenemase-producing bacteria
often carry additional plasmid-borne genes that encode for high-level resistance to
aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole.
IV. Risk factors of neonatal late-onset sepsis
A. Prematurity and low birthweight. Prematurity (<37 weeks’ gestation) is the single
most significant factor correlated with sepsis. The risk increases in proportion to
the decrease in birthweight and GA (GA <25 weeks: 41%; GA 25–28 weeks: 21%;
GA 29–32 weeks: 10%). Being small for gestational age increases the risk further.

B. Invasive procedures/devices. Intravascular catheterization (PICC and umbilical

catheters) and respiratory (endotracheal intubation) or metabolic support (total
parenteral nutrition) are important risk factors for LOS. Mechanical ventilation
and continuous positive airway pressure have been associated with an increased
risk of LOS in VLBW infants.
C. Risk factors for extended-spectrum β-lactamase infection and carbapenemase-
producing Enterobacteriaceae. Additional risk factors associated with neonatal
ESBL infection include prolonged mechanical ventilation, extended hospital stay,
use of invasive devices, and use of antimicrobial agents. Infants born to mothers
colonized with ESBL-producing E coli are themselves at an increased risk of acquir-
ing colonization with ESBL-producing E coli.
D. Other factors. Bottle feeding (as opposed to breast feeding) predisposes to infec-
tion. Black African descent has been found as an independent risk factor for GBS
sepsis (both EOS and LOS). Reasons for the disproportionately high disease burden
among black populations cannot be fully explained by prematurity or socioeco-
nomic status. NICU staff and family members are often vectors for the spread of
microorganisms, primarily as a result of improper or lack of hand washing. The
risk of infection correlates with length of stay in the NICU.
V. Clinical presentation of neonatal late-onset sepsis. Because the initial diagnosis of
sepsis is, by necessity, a clinical one, it is crucial to begin treatment before the results
of cultures are available. Clinical signs and symptoms of sepsis are nonspecific, and the
differential diagnosis is broad. Some signs are subtle or insidious, and therefore, a high
index of suspicion is required to identify and evaluate infected neonates. Clinical signs
and symptoms most often mentioned include the following:
A. Temperature irregularity. Hypothermia is more common than fever as a present-
ing sign for bacterial sepsis in premature infants. Hyperthermia is more common
in full-term infants beyond the first 24 hours of life and if viral agents (eg, herpes)
are involved.
B. Change in behavior. Lethargy, irritability, or change in tone.
C. Skin. Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes,
sclerema, and jaundice singularly or in combinations are known signs of sepsis.
D. Feeding problems. Feeding intolerance, vomiting, diarrhea, or abdominal disten-
tion with or without visible bowel loops.
E. Cardiopulmonary. Tachypnea, respiratory distress (grunting, flaring, and retrac-
tions), new onset of apnea, bradycardia and desaturation episodes (ABD [apnea,
bradycardia, desaturation] spells), tachycardia, and hypotension singularly or in
combinations should suggest sepsis. Hypotension tends to be a late sign.
Reduced variability and transient decelerations in heart rate (HR) may be present
in the hours to days before diagnosis of LOS. These abnormal HR characteristics
(HRC) in response to systemic infection and inflammation have been character-
ized mathematically, and the resulting HRC index can be computed in real time
and displayed continuously at the bedside. Some studies suggest that monitoring
the HRC index in high-risk premature infants may result in improved outcomes
and decreased mortality (through early warning with diagnosing early sepsis and
prompt treatment with antibiotics).
F. Metabolic. Metabolic findings include hypoglycemia, hyperglycemia, or metabolic
acidosis.
G. Focal infections. These may precede or accompany LOS. Look for cellulitis, impe-
tigo, soft tissue abscesses, omphalitis, conjunctivitis, otitis media, meningitis, or
osteomyelitis.
VI. Diagnosis of neonatal late-onset sepsis
A. Differential diagnosis. Because signs and symptoms of neonatal sepsis are nonspe-
cific, noninfectious etiologies need to be considered. If the infant is presenting with
cardiorespiratory symptoms, aspiration pneumonia, patent ductus arteriosus, or
other congenital heart diseases need to be considered. If the infant is showing CNS

146: Sepsis 1187
symptoms, then intracranial hemorrhage, drug withdrawal, and inborn errors of

metabolism are considered. Patients with feeding intolerance and bloody stool may
have necrotizing enterocolitis (NEC), gastrointestinal perforation, or obstruction.
Some nonbacterial infections such as disseminated herpes simplex virus can be
indistinguishable from bacterial sepsis and should be considered in the differential
diagnosis, especially if the infant has fever. Postnatal cytomegalovirus (acquired
through breast milk or blood transfusion) is another agent that is increasingly being
recognized as a cause of sepsis-like illness in extremely low birth weight infants
beyond the first week of life. Other viral agents that need to be considered include
respiratory syncytial virus (RSV) and Enterovirus/Parechovirus.
B. Laboratory studies of neonatal late-onset sepsis
1. Cultures. Blood and other normally sterile body fluids (urine, spinal fluid, and
occasionally tracheal aspirate) should be obtained for culture. Body surface cul-
tures are not recommended unless the infant has pustules or a characteristic
rash (eg, candida).
a. Blood cultures. Computer-assisted automated blood culture systems identify
up to 94% to 96% of all microorganisms by 36 to 48 hours of incubation. The
minimum volume for blood culture is 1 mL (some have suggested weight-
based criteria; 1 mL for infants weighing <1.5 kg, 2 mL for infants weighing
1.5–3 kg, and 3 mL for infants >3 kg). Two blood cultures (1 from PICC
and 1 peripheral) are recommended. In many clinical situations, infants
are treated for “presumed” sepsis despite negative cultures, if clinical and
laboratory findings are suggestive of infection and no other etiology is found
to explain the clinical deterioration.
b. Lumbar puncture. LP should be part of the routine evaluation for LOS. Men-
ingitis is likely to happen without sepsis in VLBW infants, and therefore, LP
is mandatory.
c. Urine culture must be obtained as part of evaluation for LOS. Urine specimen
should be obtained by either a suprapubic tap (see Chapter 29) or catheterized
specimen (see Chapter 30). Bag urine samples should not be used to diagnose
UTI in neonates.
d. Tracheal cultures may be considered in intubated neonates with a clinical
picture suggestive of pneumonia, especially when the quality and volume of
tracheal secretions change substantially. However, it is often hard to differ-
entiate tube colonization from true infection.
2. Gram stain of various fluids. Gram staining is especially helpful for the study
of CSF. A Gram stain of tracheal aspirate fluid may suggest an inflammatory
process if numerous WBCs, together with bacteria, are identified.
3. Molecular testing. See prior discussion under EOS of this chapter (page 1177).
4. Other laboratory tests
a. Complete blood count with differential. See prior discussion under EOS
of this chapter. LOS is associated with both low and high WBC (<1000/mm3
and >50,000/mm3), high absolute neutrophil count (>17,670/mm3), elevated
I/T ratio (>0.2), and low platelet count (<50,000/mm3). It is also important to
note that neutropenia has been described commonly as an incidental finding
in otherwise healthy growing VLBW infants.
b. Acute-phase reactants. See prior discussion under EOS section of this
chapter. Serial CRP determinations are helpful in ruling out infection when
normal (high negative predictive value). PCT may be better than CRP in the
diagnosis and follow-up of neonatal sepsis secondary to CONS.
C. Imaging and other studies
1. Chest radiograph. A chest radiograph should be obtained in cases with respira-
tory symptoms, although it is often difficult to differentiate changes associated
with true bacterial pneumonia from those associated with bronchopulmonary
dysplasia, simple aspiration, or atelectasis.

2. Urinary tract imaging. Imaging with renal ultrasound, renal scan, and possibly
voiding cystourethrogram should be considered when UTI accompanies sepsis.
VII. Management of neonatal late-onset sepsis. Isolation precautions for all infectious dis-
eases, including maternal and neonatal precautions, breast feeding, and visiting issues,
can be found in Appendix F.
A. Prevention of neonatal nosocomial late-onset sepsis. A subset of nosocomial
sepsis is central line–associated bloodstream infections (CLABSIs). Although
primary prevention of CLABSI relies on minimizing the use of central lines, novel
technologies such as antiseptic- and antimicrobial-impregnated catheters in addition
to meticulous care during PICC insertion and maintenance are key factors in
preventing CLABSIs. Quality improvement initiatives that focus on adherence to best
practices of catheter insertion and maintenance (NICU Central Catheter Bundles)
have resulted in widespread reduction in CLABSIs across different NICUs. Some of
those bundles were adopted and disseminated through statewide collaboratives such
as the California Perinatal Quality Care Collaborative (CPQCC). Hand hygiene is the
single most important strategy for avoiding transmission of contagions in the NICU.
Fresh maternal milk contains a number of substances responsible for innate immune
and humoral responses against pathogens; therefore, promotion of breast feeding
is considered a key step in the prevention of NICU infections. Medical stewardship
of antibiotics, steroids, and H2 blockers is mandatory; indiscriminate use of these
agents has been associated with increased nosocomial sepsis. Enhancement of the
enteric microbiome composition with the possible use of probiotics may restore gut
immune function and help prevent NEC and sepsis. In a recent meta-analysis of 37
trials, probiotics were associated with a small, but statistically significant, reduction in
the risk of LOS compared with placebo or no treatment. Use of bioactive substances
with known anti-infective properties such as lactoferrin may be helpful. A recently
published Cochrane review that included 6 trials suggested that lactoferrin
supplementation to enteral feeds with or without probiotics may decrease LOS
and NEC in preterm infants. However, no recommendations can be made until
ongoing trials that enrolled >6000 preterm neonates are completed. Finally, specific
and targeted pharmacologic prophylactic interventions have been used with some
success. For example, specific antifungal prophylaxis with fluconazole has been
associated with significant reduction in invasive fungal infection; it is recommended
in NICUs that experience high rates of invasive candidiasis. However, the use of
pagibaximab, a recombinant monoclonal antibody targeting staphylococcal species,
does not appear to offer protection against gram-positive CLABSIs in the NICU.
B. Empiric antibiotic therapy. Treatment is most often begun before a definite caus-
ative agent is identified. In nosocomial sepsis, the flora of the NICU must be con-
sidered in choosing antibiotics; however, staphylococcal coverage with vancomycin
plus an aminoglycoside such as gentamicin or amikacin is usually begun. Some
NICUs use a cefazolin or nafcillin for staphylococcal coverage instead of vanco-
mycin. The empirical treatment for suspected LOS in a neonate admitted from the
community is ampicillin and gentamicin; cefotaxime can be added only when there
is a concern for meningitis. Dosages are presented in Chapter 155.
C. Continuing therapy is based on culture and sensitivity results, clinical course, and
other serial laboratory studies (eg, CRP or PCT). If an ESBL-producing organism,
such as K pneumoniae, is suspected or identified, then carbapenem is the drug
of choice (with aminoglycoside for double coverage). Of the aminoglycosides,
amikacin retains the most activity against ESBL-producing strains. An aminogly-
coside or cefepime can be used if the organism is susceptible, because cefepime
does not induce chromosomal AmpC enzymes. Monitoring for antibiotic toxicity
is important, as well as monitoring levels of aminoglycosides and vancomycin.
D. Complications and supportive therapy are reviewed under the EOS section of this
chapter (page 1184). In particular, administration of intravenous immunoglobulin
to neonates with suspected or proven LOS does not result in reduction in mortality

147: Syphilis 1189
during hospital stay or major disability at 2 years of age. Similarly, administration of

colony-stimulating factors, namely G-CSF and GM-CSF, does not result in reduced
mortality or better neurodevelopmental outcome at 2 and 5 years. However, there
might be a place for using G-CSF in cases of severe infection complicated by severe
neutropenia (absolute neutrophil count <500/mm3) and/or in the presence of
specific hematologic diseases causing severe neutropenia.
E. Future developments. Intensive research continues in the development of vac-
cines as well as synthetic monoclonal antibodies to the specific pathogens caus-
ing neonatal LOS. Research is also ongoing into blocking some of the body’s own
inflammatory mediators that result in significant tissue injury, including endotoxin
inhibitors, cytokine inhibitors, nitric oxide synthetase inhibitors, and neutrophil
adhesion inhibitors. Finally, recent research is showing prebiotics, probiotics, and
lactoferrin to be promising agents in the prevention of LOS and NEC.
VIII. Prognosis. Neonatal LOS remains a major cause of death in VLBW infants, with a
reported mortality rate of approximately 18%. Mortality due to gram-negative infections
is higher than that due to gram-positive infections. Risk factors for LOS mortality
include endotracheal intubation, administration of vasopressors, hypoglycemia,
thrombocytopenia, and development of NEC. VLBW infants who survive LOS are at
risk for long term neurodevelopmental impairment including cerebral palsy.
147 Syphilis
I. Definition. Syphilis is a sexually transmitted infection caused by Treponema pallidum,
which is a thin, motile spirochete that is extremely fastidious, surviving only briefly
outside the host. The Centers for Disease Control and Prevention (CDC) issued a
case definition of congenital syphilis (CS) in 2018 as follows: a condition caused by
infection in utero with T pallidum. A wide spectrum of severity exists, from inap-
parent infection to severe cases that are clinically apparent at birth. Laboratory cri-
teria for diagnosis entail demonstration of T pallidum by: (1) darkfield microscopy
of lesions, body fluids, or neonatal nasal discharge; or (2) polymerase chain reaction
(PCR) or other equivalent direct molecular methods of lesions, neonatal nasal dis-
charge, placenta, umbilical cord, or autopsy material; or (3) immunohistochemistry or
special stains (eg, silver staining) of specimens from lesions, placenta, umbilical cord,
or autopsy material. Cases are classified as confirmed (by laboratory diagnosis) or
probable. Probable CS is a condition affecting an infant whose mother had untreated
or inadequately treated syphilis at delivery, regardless of signs in the infant, or an infant
or child who has a reactive nontreponemal test for syphilis (Venereal Disease Research
Laboratory [VDRL], rapid plasma reagin [RPR], or equivalent serologic methods) and
any 1 of the following: (1) any evidence of CS on physical examination; (2) any evidence
of CS on radiographs of long bones; (3) a reactive cerebrospinal fluid (CSF) VDRL test;
(4) an elevated CSF leukocyte (white blood cell [WBC]) count or protein (without other
cause) in a nontraumatic lumbar puncture. Suggested parameters for abnormal CSF
WBC and protein values include the following: during the first 30 days of life, a CSF
WBC count of >15 WBC/mm3 or a CSF protein >120 mg/dL is abnormal; after the
first 30 days of life, a CSF WBC count of >5 WBC/mm3 or a CSF protein >40 mg/dL is
abnormal, regardless of CSF serology. Adequate treatment is defined as completion of
a penicillin-based regimen, in accordance with CDC treatment guidelines, appropriate
for stage of infection, initiated ≥30 days before delivery.

II. Incidence. According the CDC, from 2013 through 2017, there was a 76% increase in
cases of syphilis in the United States (from 17,375 to 30,644 cases). The incidence of
CS parallels that of primary and secondary syphilis in the general population. In the
United States, in 2016, there were a total of 628 reported cases of CS, including 41 syphi-
litic stillbirths, with a national rate of 15.7 cases per 100,000 live births. This rate represents
an increase of 86.9% relative to 2012. Worldwide, syphilis continues to represent a serious
public health problem; a World Health Organization analysis showed that in 2012, an esti-
mated 930,000 maternal syphilis infections caused 350,000 adverse pregnancy outcomes
including 143,000 early fetal deaths and stillbirths, 62,000 neonatal deaths, 44,000 preterm
or low-weight births, and 102,000 infected infants worldwide. The rate of CS is increased
among infants born to mothers with human immunodeficiency virus (HIV) infection.
III. Pathophysiology. Treponemes are able to cross the placenta at any time during preg-
nancy, thereby infecting the fetus. Syphilis can cause stillbirth (30% to 40% of fetuses
with CS are stillborn), preterm delivery, congenital infection, or neonatal death,
depending on the stage of maternal infection and duration of fetal infection before
delivery. Untreated infection in the first and second trimesters often leads to significant
fetal morbidity, whereas with third-trimester infection, many infants are asymptomatic.
The most common cause of fetal death is placental infection associated with decreas-
ing blood flow to the fetus, although direct fetal infection also plays a role. Infection
can also be acquired by the neonate via contact with infectious lesions during passage
through the birth canal. Kassowitz’s law states that the risk of vertical transmission of
syphilis from an infected, untreated mother decreases as maternal disease progresses.
Thus, transmission ranges from 70% to 90% in primary and secondary syphilis, to 40%
for early latent syphilis, and to 8% for late latent disease. CS can cause placentomegaly
and congenital hydrops. T pallidum is not transferred in breast milk, but transmission
may occur if the mother has an infectious lesion (eg, chancre) on her breast.
IV. Risk factors. At-risk group include infants whose mothers received no or inadequate
treatment (dose was unknown, inadequate, or undocumented), whose mother received
a nonpenicillin treatment during pregnancy for syphilis, or whose mother was treated
within 30 days of the infant’s birth. Infants of high-risk mothers (drug use, especially
cocaine use; low socioeconomic levels; HIV infection; teen pregnancy; commercial sex
work; and lack of prenatal care) are at increased risk for syphilis. Lack of early prenatal
care is the strongest predictor of CS.
V. Clinical presentation. CS is a multiorgan infection that may cause neurologic or skel-
etal disabilities or death in the fetus or newborn. However, when mothers with syphilis
are treated early in pregnancy, the disease is almost entirely preventable. The risk of
fetal infection increases with advancing gestation. Approximately two-thirds of live-
born neonates with CS are asymptomatic at birth but have low birthweight. Clinical
manifestations after birth are arbitrarily divided into early CS (<2 years of age) and
late CS (>2 years of age).
A. Early manifestations include nasal discharge (snuffles) and maculopapular or
vesiculobullous rash that appears on the palms and soles. The rash may be associ-
ated with desquamation. Other early stigmata include fever, abnormal bone radio-
graphs, hepatosplenomegaly, petechiae, lymphadenopathy, jaundice, pneumonia,
osteochondritis, pseudoparalysis, hemolytic anemia, leukocytosis, thrombocytope-
nia, and central nervous system (CNS) involvement. Skin lesions and moist nasal
secretions in infected babies are highly contagious. However, organisms are rarely
found in lesions >24 hours after treatment has begun.
B. Late manifestations develop in untreated infants and are characterized by chronic
granulomatous inflammation. The sites most often involved include bones and joints,
teeth, eyes, and the nervous system. Hutchinson triad (blunted upper incisors, inter-
stitial keratitis, and eighth nerve deafness) and saddle nose are distinct complications.
Some of these consequences may not become apparent until many years after birth,
such as interstitial keratitis (5–20 years of age) and eighth cranial nerve deafness
(10–40 years of age). A poor response to antibiotic treatment is often noted.

147: Syphilis 1191
VI. Diagnosis. Diagnosis relies on active surveillance and laboratory studies. Maternal

testing during pregnancy to treat the mother and identify the at-risk newborn is crucial.
Most infants are asymptomatic at birth. Besides testing for syphilis, these infants should
be tested for HIV infection as well.
A. Laboratory studies. Patients with congenital or acquired syphilis produce several
different antibodies that can be tested in the laboratory. These are grouped as non-
specific nontreponemal antibody (NTA) tests and specific treponemal antibody
(STA) tests. NTA tests (including VDRL, RPR, and automated reagin test) are inex-
pensive, rapid, and convenient screening tests that may indicate disease activity.
These tests measure the antibody directed against lipoidal antigen from T pallidum,
antibody interaction with host tissues, or both. They are used as initial screening
tests and quantitatively to monitor a patient’s response to treatment and to detect
reinfection and relapse. False-positive reactions can be secondary to autoimmune
disease, intravenous drug addiction, aging, pregnancy, and many infections, such
as hepatitis, mononucleosis, measles, and endocarditis. The interpretation of NTA
and STA tests can be confounded by maternal immunoglobulin (Ig) G antibodies
that are passed transplacentally to the fetus.
1. Nonspecific nontreponemal antibody tests. The 2 most often used of these
nonspecific screening tests are VDRL and RPR. A titer of at least 2 dilutions
(4-fold) higher in the infant than in the mother signifies probable active infection.
Titers should be monitored and repeated every 2 to 3 months after therapy. A
sustained 4-fold decrease in titer, equivalent to a change of 2 dilutions (eg, from
1:16 to 1:4), of the NTA test result after treatment usually demonstrates adequate
therapy, whereas a sustained 4-fold increase in titer (eg, from 1:8 to 1:32) after
treatment suggests reinfection or relapse. The NTA test titer usually decreases
4-fold within 6 to 12 months after therapy for primary or secondary syphilis and
usually becomes nonreactive within 1 year. VDRL (not RPR) should be used on
CSF. A normal test result is negative, and any positive test should be followed up
with a specific treponemal test. When NTA tests are used to monitor treatment
response, the same test (eg, VDRL or RPR) must be used throughout the follow-up
period, preferably by the same laboratory, to ensure comparability of results.
2. Specific treponemal antibody tests. These tests verify a diagnosis of current or
past infection and should be performed if NTA test results are positive. These
antibody tests do not correlate with disease activity and are not usually quantified.
They are useful for diagnosing a first episode of syphilis and for distinguishing a
false-positive result of NTA tests. However, they have limited use for evaluating
response to therapy and possible reinfections. Once the STA test is positive, it will
stay positive for life. In addition, STA tests are not 100% specific for syphilis; positive
reactions variably occur in patients with other spirochetal diseases, such as yaws,
pinta, leptospirosis, rat-bite fever, relapsing fever, and Lyme disease. NTA tests
can be used to differentiate Lyme disease from syphilis, because the VDRL test is
nonreactive in Lyme disease. Examples of STA tests include the T pallidum particle
agglutination (TP-PA) test, T pallidum enzyme immunoassay (TP-EIA), T pallidum
chemiluminescent assay (TP-CIA), and fluorescent treponemal antibody absorption
(FTA-ABS) test. T pallidum–specific IgM immunoblot testing in the newborn
is able to identify infants with CS with high sensitivity; however, the test is not
commercially available. Recently, some clinical laboratories and blood banks have
begun to screen samples using TP-EIA, rather than beginning with an NTA test; the
reasons for this change in sequence of the screening relate to cost and manpower
issues. However, this “reverse sequence screening” approach is associated with
high rates of false-positive results, and in 2011, the CDC recommended against
adopting it. Despite that, an increasing number of laboratories are adopting it and
the Committee on Infectious Diseases of the American Academy of Pediatrics
modified its diagnostic algorithm to CS to include the “reverse sequence
screening approach” (see Section VII, “Management,” and Figure 147–1).

1192
Conventional Diagnostic Approach Reverse-Sequence Screening Approach
Initial reactive maternal RPR/VDRL Initial positive maternal treponemal EIA/CIA screening
Nonreactive maternal treponemal testa Reactive maternal treponemal testa,b Reactive maternal RPR/VDRL Nonreactive maternal RPR/VDRL
Reactive alternative maternal Nonreactive alternative maternal

treponemal testa,b treponemal testa
False-positive reaction: Evaluate mother’s treatment history for syphilis Consider maternal risk factors
no further evaluation for possible recent infection—
(if pregnant, treponemal prudent to repeat serologic
repeat testing may testing in 4 wks to differentiate
be appropriate) Adequate maternal early primary infection from
Maternal treatment: Maternal penicillin treatment
treatment before pregnancy false positive, especially in
• none, OR during pregnancy AND more
with low stable (serofast)d or higher-prevalence community
• undocumented, OR than 4 wks before delivery,
• 4 wks or less before delivery, AND no evidence/concern of negative titer AND infant
OR maternal infection or relapse examination normal; if infant
• nonpenicillin drug, OR examination abnormal,
• maternal evidence/concern proceed with evaluatione Reactive maternal RPR/VDRL
of reinfection/relapse
(fourfold or greater increase
in maternal titers)c
• partner recently diagnosed
with syphilis Evaluatee
Infant RPR/VDRL Infant RPR/VDRL not

fourfold or greater than fourfold or greater than
Evaluatee maternal RPR/VDRLc maternal RPR/VDRL titerc
18/10/19 3:19 pm
Infant physical Infant physical Infant physical Infant physical Infant physical Infant physical
examination examination examination examination examination examination
normal; AND abnormal; OR abnormal normal normal; AND abnormal; OR
evaluation evaluation evaluation evaluation
normal; AND abnormal or normal; AND abnormal or
infant incomplete; OR infant incomplete; OR
RPR/VDRL RPR/VDRL at RPR/VDRL RPR/VDRL at
same or less least fourfold same or less least fourfold
than fourfold greater than than fourfold greater than
the maternal maternal the maternal maternal
RPR/VDRL RPR/VDRLc RPR/VDRL RPR/VDRL c
titerc titer c
Possible Proven or Proven or Congenital Congenital Possible Proven or

congenital highly probable highly probable syphilis syphilis congenital highly probable
syphilis congenital congenital less likely unlikely syphilis congenital
See Mgt. syphilis syphilis See Mgt. See Mgt. See Mgt. syphilis
VII.B.2.a See Mgt. VII.B.1 See Mgt. VII.B.1 VII.B.2.b VII.B.2.c VII.B.2.a See Mgt. VII.B.1
RPR indicates rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.
aTreponema pallidum particle agglutination (TP-PA) (which is the preferred treponemal test), fluorescent treponemal antibody absorption (FTA-ABS), or microhemagglutination
test for antibodies to T pallidum (MHA-TP).
bTest for human immunodeficiency virus (HIV) antibody. Infants of HIV-infected mothers do not require different evaluation or treatment for syphilis.
cA fourfold change in titer is the same as a change of 2 dilutions. For example, a titer of 1:64 is fourfold greater than a titer of 1:16, and a titer of 1:4 is fourfold lower than a
titer of 1:16. When comparing titers, the same type of nontreponemal test should be used (eg, if the initial test was a RPR, the follow-up test should also be an RPR).
dStable VDRL titers 1:2 or less or RPR 1:4 or less beyond 1 year after successful treatment are considerd low serofast.
eComplete blood cell (CBC) and platelet count; cerebrospinal fluid (CSF) examination for cell count, protein, and quantitative VDRL; other tests as clinically indicated
(eg, chest radiographs, long-bone radiographs, eye examination, liver function tests, neuroimaging, and auditory brainstem response).
FIGURE 147–1. Algorithm for diagnostic approach of infants born to mothers with reactive serologic tests for syphilis. (Reproduced with permission from
Kimberlin DW, Long SS, Brady MT, et al: Red Book: 2018 Report of the Committee on Infectious Diseases, 31st ed. Elk Grove Village, IL: American Academy
of Pediatrics; 2018.)
1193
18/10/19 3:19 pm
3. Direct identification of T pallidum. Microscopic darkfield examination

can be performed on appropriate specimens (lesion exudate, nasal discharge,
or tissue, such as placenta, umbilical cord, or autopsy specimens) to detect
spirochetes. Specimens from mouth lesions can contain nonpathogenic
treponemes that can be difficult to distinguish from T pallidum by darkfield
microscopy. Direct fluorescent antibody tests are no longer available in the
United States. T pallidum can be detected by PCR assay, but clinical diagnostic
PCR assays cleared by the US Food and Drug Administration (FDA) are not
yet available.
4. Lumbar puncture. CNS disease may be detected by examining CSF and
finding positive serologic tests (VDRL or FTA-ABS), darkfield examination
positive for spirochetes, positive syphilis PCR, elevated monocyte count, or
elevated spinal fluid protein levels. VDRL is most commonly used, but some
experts recommend the FTA-ABS test as well. FTA-ABS may be more sensitive
but less specific than VDRL. Results from the VDRL test should be interpreted
cautiously because a negative result on a VDRL test of CSF does not exclude
a diagnosis of neurosyphilis. Alternatively, a reactive VDRL test in the CSF
of neonates can be the result of nontreponemal IgG antibodies that cross the
blood–brain barrier. PCR testing of CSF may prove very useful for the diag-
nosis of CNS syphilis. The CDC has included age-appropriate definitions of
abnormal CSF cell count and protein levels in the 2018 case definition of CS
(see Section I).
B. Histopathologic examination of the placenta and umbilical cord. The
placenta of neonates with CS is often large, thick, and pale. The umbilical cord is
edematous and may resemble a “barber’s pole” with spiral stripes of red and light
blue discoloration alternating with streaks of chalky white. It may be significantly
inflamed with micro-abscesses and necrotizing funisitis. The placenta and the
cord should be carefully examined with darkfield microscopy and special stains
looking for spirochetes.
C. Imaging studies. Radiographic abnormalities may be noted in 65% of the cases.
These manifestations noted on long bones include periostitis, osteitis, and sclerotic
metaphyseal changes. Infants may also present with pseudoparalysis or pathologic
fractures.
VII. Management. Isolation precautions for all infectious diseases, including maternal
and neonatal precautions, breast feeding, and visiting issues, can be found in
Appendix F.
A. Maternal testing during pregnancy. CDC recommends serologic syphilis testing
for all pregnant women at the first prenatal visit. In communities and populations
in which the risk for CS is high, serologic testing and a sexual history also should
be obtained at 28 to 32 weeks’ gestation and at delivery. Any woman who delivers
a stillborn infant after 20 weeks’ gestation should be tested for syphilis. An NTA
test (RPR or VDRL) is recommended for screening, followed by a treponemal (eg,
TP-PA) test if the screening result is positive. If the reverse-sequence screening
algorithm is used, pregnant women with reactive treponemal TP-EIA/TP-CIA
screening test results should have confirmatory testing with a quantitative NTA
test. If the NTA test result is negative (discordant result), a second treponemal test
using a different T pallidum antigen should be obtained to determine whether the
initial treponemal test result was a false positive. If the second treponemal test result
is positive, it may be attributable to a prior infection adequately treated in the past or
to untreated syphilis in a late stage. For women treated during pregnancy, follow-up
serologic testing is necessary to assess the effectiveness of therapy. Treated pregnant
women with syphilis should have quantitative NTA serologic tests repeated at 28
to 32 weeks of gestation, at delivery, and according to recommendations for the
stage of disease. Serologic titers may be repeated monthly in women at high risk of
reinfection or in geographic areas where the prevalence of syphilis is high. Rapid

147: Syphilis 1195
point-of-care prenatal syphilis screening using an immunochromographic strip

has been used in several resource-limited countries.
B. Evaluation and treatment of infants. No newborn infant should be discharged
from the hospital without determination of the mother’s serologic status for
syphilis at least once during pregnancy and also at delivery in communities and
populations in which the risk for CS is high. Testing of umbilical cord blood
or an infant serum sample is inadequate for screening, because these can be
nonreactive if the mother’s serologic test result is of low titer or she was infected
late in pregnancy. All infants born to seropositive mothers require a careful
examination and a quantitative NTA test. The test performed on the infant should
be the same as that performed on the mother to enable comparison of titer results.
The diagnostic and therapeutic approach to infants being evaluated for CS is
summarized in Figure 147–1.
1. Infants with proven or highly probable congenital syphilis (abnormal
physical examination consistent with CS or a serum quantitative NTA titer
that is 4-fold higher than the mother’s titer or a positive darkfield microscopy
or PCR of a lesion or body fluid). The recommended treatment according to
the CDC guidelines is aqueous crystalline penicillin G 50,000 U/kg/dose
intravenously every 12 hours during the first 7 days of life and every 8 hours
thereafter for a total of 10 days (preferred treatment) or procaine penicillin G
50,000 U/kg/dose intramuscularly (IM) in a single daily dose for 10 days. If
>1 day of therapy is missed, the entire course should be restarted. Data are
insufficient regarding the use of other antimicrobial agents (eg, ampicillin).
A full 10-day course of penicillin is needed, even if ampicillin was initially
provided for possible sepsis. These patients always should be treated with
penicillin, even if desensitization for penicillin allergy is necessary (extremely
rare in the newborn period).
2. Asymptomatic infants who have normal physical examination and a
serum quantitative nonspecific nontreponemal antibody titer ≤4-fold
the maternal titer should be managed according to the status of maternal
treatment:
a. Maternal treatment uncertain (possible congenital syphilis). The mother
was not treated, was inadequately treated, or has no documentation of hav-
ing received treatment; the mother was treated with erythromycin or other
nonpenicillin regimen; or the mother received treatment <4 weeks before
delivery. These infants should be fully evaluated and treated as described
in Section VII.B.1. Alternatively, benzathine penicillin G, 50,000 U/kg as a
single IM dose, is acceptable provided that all components of the evaluation
are obtained and are normal, including normal CSF results, and follow-up
is ensured.
b. Maternal treatment during pregnancy is adequate (congenital syphilis less
likely). (Penicillin therapy given >4 weeks before delivery and the mother has
no evidence of reinfection or relapse.) No evaluation is needed; however, a
single IM dose of benzathine penicillin G, 50,000 U/kg, is recommended.
Alternatively, infants whose mother’s NTA titers decreased at least 4-fold
after appropriate therapy for early syphilis or remained stable at low titer
(eg, VDRL ≤1:2; RPR ≤1:4) may be followed every 2 to 3 months without
treatment until the NTA test becomes nonreactive.
c. Maternal treatment before pregnancy is adequate, and mother’s
nonspecific nontreponemal antibody titer remained low and stable
before and during pregnancy and at delivery (eg, VDRL <1:2; RPR <1:4;
congenital syphilis is unlikely). No evaluation or therapy is needed for
the infant. Infants with reactive NTA tests should be followed serologically
to ensure test result returns to negative. Benzathine penicillin G, 50,000 U/kg
IM as single dose, can be considered if follow-up is uncertain and infant

has a reactive test. Neonates with a negative NTA test result at birth
and whose mothers were seroreactive at delivery should be retested at
3 months to rule out serologically negative incubating CS at the time
of birth.
C. Isolation procedures. Precautions regarding drainage, secretions, and blood and
body fluids are indicated for all infants with suspected or proven CS until therapy
has been given for 24 hours.
D. Follow-up care. The infant should have repeated quantitative NTA tests at 3, 6, and
12 months. Most infants will have a negative titer with adequate treatment. A rising
titer requires further investigation and retreatment.
VIII. Prognosis. Infants infected early in the pregnancy are usually stillborn. Infants
infected in the second and third trimesters are at risk for premature delivery,
low birthweight, neonatal death, and symptomatic congenital infection. In the
United States, the case fatality rate for CS is 6% to 8%. Late manifestations of CS
such as interstitial keratitis and anterior tibial bowing (“saber shins”) may occur
despite appropriate treatment. Infants infected through the birth canal and treated
early have excellent prognosis.
148 TORCH (TORCHZ) Infections

TORCH is an acronym that denotes a chronic nonbacterial perinatal infection. It stands
for toxoplasmosis, other infections, rubella virus, cytomegalovirus (CMV), herpes simplex
virus (HSV). The Zika virus (ZIKV) infection during pregnancy results in a congenital
infection syndrome in the fetus and the newborn similar to other TORCH infections;
manifestations include fetal growth restriction (FGR), microcephaly, craniofacial
disproportion, ventriculomegaly, intracranial calcification, optic nerve hypoplasia, and
chorioretinal atrophy, among others. Thus, it has been suggested that ZIKV be added
to the TORCH acronym to become TORCHZ. “Other” infections include syphilis,
hepatitis B, coxsackievirus, Epstein-Barr virus, varicella-zoster virus (VZV), Enterovirus/
Parechovirus, human immunodeficiency virus (HIV), tuberculosis, and parvovirus B19.
HSV disease in the neonate does not fit the pattern of chronic intrauterine infection but is
traditionally grouped with TORCH. This group of infections may present in the neonate
with similar clinical and laboratory findings (ie, IUGR, hepatosplenomegaly, rash, central
nervous system [CNS] manifestations including calcifications, early jaundice, and low
platelets), hence the usefulness of the TORCHZ concept. However, because the “other
infections” category of responsible pathogens is growing and becoming diverse, the
validity of indiscriminate screening of neonates presenting with findings compatible with
congenital infection using “TORCH titers” has been questioned. Additionally, some of
this serologic testing yields both false-positive and false-negative results. An alternative
approach involves testing of infants with suspected congenital infections for specific
pathogens based on their clinical presentation (see Table 148–1 and individual chapters
on each pathogen). A high index of suspicion for congenital infection and awareness of
the prominent features of the most common congenital infections help to facilitate early
diagnosis and possible therapy. Clinicians are getting away from the acronym TORCHZ;
therefore, each of these chapters has been separated and listed as a single chapter. See
Chapter 149 for toxoplasmosis, Chapter 145 for rubella, Chapter 132 for cytomegalovirus,
Chapter 137 for herpes simplex viruses, Chapter 154 for ZIKV, and other disease-specific
chapters. See Appendix F for isolation precautions for all infectious diseases, including
maternal and neonatal precautions, breast feeding, and visiting issues.

149: Toxoplasmosis 1197
Table 148–1. SIGNS SUGGESTIVE OF A SPECIFIC CONGENITAL INFECTION IN THE NEONATE

Toxoplasmosis Intracranial calcifications (diffuse), hydrocephalus, chorioretinitis
Syphilis Snuffles, maculopapular rash (on palms and soles), skeletal abnormalities
(osteochondritis and periostitis)
Rubella Blueberry muffin lesions,a eye findings (cataracts, congenital glaucoma,
pigmentary retinopathy), congenital heart disease (most commonly
patent ductus arteriosus), radiolucent bone disease
Cytomegalovirus Periventricular intracranial calcifications, microcephaly
Herpes simplex virus Mucocutaneous vesicles or scarring, conjunctivitis or keratoconjunctivitis,
elevated liver transaminases
Zika virus Microcephaly, craniofacial disproportion, ventriculomegaly, intracranial
calcification, optic nerve hypoplasia
a
See Figure 80–18.
149 Toxoplasmosis
I. Definition. Toxoplasmosis is caused by Toxoplasma gondii, a protozoan and obli-
gate intracellular parasite capable of causing intrauterine infection (part of TORCH
[toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex virus] infections; see
Chapter 148).
II. Incidence. The incidence of congenital toxoplasmosis (CT) is 0.23 to 0.91 per 10,000
live births based on published data from the New England Newborn Screening Pro-
gram; the true incidence might be higher, because the sensitivity of the newborn
screening test (blot-spot immunoglobulin [Ig] M test) is approximately 50% to 75%,
and fetal losses attributable to severe CT are not counted. Seroprevalence of T gondii
among women of childbearing age (15–44 years) has declined over time (15%, 11%,
and 9% in 1988–1994, 1999–2004, and 2009–2010, respectively).
III. Pathophysiology. T gondii is a coccidian parasite ubiquitous in nature. Members of the
feline family are the definitive hosts. The organism exists in 3 forms: oocyst, tachyzo-
ite, and tissue cyst (bradyzoites). Cats generally acquire the infection by feeding on
infected animals such as mice or uncooked household meats. The parasite replicates
sexually in the feline intestine. Cats may begin to excrete oocysts in their stool for 7
to 14 days after infection. During this phase, the cat can shed millions of oocysts daily
for 2 weeks. After excretion, oocysts require a maturation phase (sporulation) of 24
to 48 hours before they become infective by the oral route. Intermediate hosts (sheep,
cattle, and pigs) can have tissue cysts within organs and skeletal muscle. These cysts
can remain viable for the lifetime of the host. The pregnant woman usually becomes
infected by consumption of raw or undercooked meat that contains cysts or by the
accidental ingestion of sporulated oocysts from soil or contaminated food. Ingestion
of oocysts (and cysts) releases sporozoites that penetrate the gastrointestinal mucosa
and later differentiate into tachyzoites. Tachyzoites are ovoid unicellular organisms
characteristic of the acute infection. Tachyzoites spread throughout the body via the
bloodstream and lymphatics. It is during this stage that vertical transmission from
mother to the child (MTCT) occurs. In the immunocompetent host, the tachyzoites

are sequestered in tissue cysts and form bradyzoites. Bradyzoites are indicative of the
chronic stage of infection and can persist in the brain, liver, and skeletal tissue for
the life of the individual. There are reports of transmission of toxoplasmosis through
contaminated municipal water, blood transfusion, organ donation, and occasionally
as a result of a laboratory accident.
Acute infection in the pregnant woman is often subclinical (90% of the cases). If
symptoms are present, they are generally nonspecific: mononucleosis-like illness with
fever, painless lymphadenopathy, fatigue, malaise, myalgia, fever, skin rash, and sple-
nomegaly. Placental infection occurs and persists throughout pregnancy. The infec-
tion may or may not be transmitted to the fetus. The later in pregnancy that infection
is acquired, the more likely is MTCT (first trimester, 17%; second trimester, 25%;
and third trimester, 65% transmission). In women who are screened routinely dur-
ing pregnancy and treated once primary infection is diagnosed, the MTCT rate is
<5%. Infections transmitted earlier in gestation are likely to cause more severe fetal
effects (abortion, stillbirth, or severe disease with teratogenesis). Those transmitted
later are more likely to be subclinical. Factors associated with an increased risk of
MTCT are as follows: (1) acute T gondii infection during pregnancy, (2) immuno-
compromising conditions, (3) lack of antepartum treatment, (4) high T gondii strain
virulence, and (5) high parasite load. Infection in the fetus or neonate usually involves
the central nervous system (CNS) or the eyes with or without disseminated sys-
temic infection. Approximately 60% to 80% of infants with congenital infection are
asymptomatic at birth; however, visual impairment, learning disabilities, or mental
impairment becomes apparent in a large percentage of children months to several
years later.
IV. Risk factors. Epidemiologic risk factors for acquiring toxoplasmosis during
pregnancy include eating or contact with raw or undercooked meat, cleaning
the cat litter box, eating unwashed raw vegetables or fruits, exposure to soil, and
travel outside the United States, Europe, or Canada. Interestingly, cat ownership
by itself is not linked to toxoplasmosis (except having ≥3 kittens). One study found
that eating raw oysters, clams, or mussels was a novel risk factor for acquiring
toxoplasmosis. Premature infants have a higher incidence of CT than term infants
(25%–50% of cases in most series).
A. Antenatal detection. Fetuses that are infected early in pregnancy may become
symptomatic in utero with abnormalities detected on fetal ultrasound. These
include intracranial hyperechogenic foci or calcifications and ventricular dilata-
tion. Other abnormalities include anemia, hydrops, and ascites.
B. Subclinical neonatal infection. Occurs in 60% to 80% of infected newborns,
where no manifestations are found on routine physical examination. These infants
are typically identified by routine maternal or newborn screening. When more spe-
cific tests are performed (eg, cerebrospinal fluid [CSF] tap, CNS imaging, and reti-
nal eye examinations), up to 40% have abnormalities such as macular retinal scars,
focal cerebral calcifications, and elevations of CSF protein and mononuclear cell
count. Infants born to mothers known to be infected with both human immuno-
deficiency virus (HIV) and T gondii should be tested for CT. There is an increased
risk for intrauterine reinfection after maternal reactivated T gondii disease.
C. Clinical neonatal disease. Those with evident clinical disease may have dissemi-
nated illness or isolated CNS or ocular disease. Late sequelae are primarily related
to ocular or CNS disease. Obstructive hydrocephalus, chorioretinitis, and diffuse
intracranial calcifications form the classic triad of toxoplasmosis, which is found
in <10% of the cases. Beside the classic triad, other prominent features in symptom-
atic infants include abnormalities of CSF (high protein), anemia, seizures, direct
hyperbilirubinemia, fever, hepatosplenomegaly, lymphadenopathy, eosinophilia,
bleeding diathesis, hypothermia, rash, and pneumonitis. Some of these symptoms
may develop in the first few months of life.

D. Late manifestations may develop in congenitally infected infants, especially in

those who do not receive extended antiparasitic therapy. Chorioretinitis is the
most common late manifestation. The lifetime incidence for untreated infants
approaches 90%, and the risk extends into adulthood. Treated patients may have
episodic recurrences of chorioretinitis. Associated ophthalmologic findings may
include microphthalmia, strabismus, cataract, glaucoma, and nystagmus. These
complications can lead to vision loss and retinal detachment. Other late CNS mani-
festations include microcephaly, seizures, motor and cerebellar dysfunction, mental
retardation, and sensorineural hearing loss.
VI. Diagnosis. CT should be suspected in infants born to mothers who had primary infection
during pregnancy, infants born to women who are immunosuppressed, infants who have
suggestive clinical findings, and infants who test positive (toxoplasma IgM) through
universal newborn screening (in regions where it is done). Infants suspected of the
disease should undergo detailed evaluation that includes eye examination, CNS imaging,
spinal tap, and detailed laboratory evaluation. In early 2017, the American Academy of
Pediatrics issued an elaborate report discussing the diagnosis, treatment, and prevention
of CT in the United States (Maldonado et al. Pediatrics 2017;139[2]:e20163860).
A. Laboratory studies. Laboratory tools for the diagnosis of T gondii infection include
serologic tests, such as the Toxoplasma IgG, IgM, IgA, IgE, or IgG avidity and dif-
ferential agglutination (AC/HS) tests; polymerase chain reaction (PCR) assays;
histologic and cytologic examination of tissue and body fluids; and attempts to
isolate the parasite with mice subinoculation (this test is only performed in ref-
erence laboratories). Commercial laboratories in the United States usually offer
Toxoplasma IgG and IgM testing; some of them also offer Toxoplasma IgA and
IgG avidity tests (approved by the US Food and Drug Administration [FDA] since
2011) and PCR assays. In reference laboratories for toxoplasmosis, like the one at
Palo Alto Medical Foundation (Palo Alto Medical Foundation Toxoplasma Serology
Laboratory [PAMF-TSL], http://www.pamf.org/serology/; phone: 650-853-4828; fax:
650-614-3292; e-mail: [email protected]), panels of serologic tests are offered. The
majority of the tests in those panels are not available in nonreference laboratories
(NRL), including the Toxoplasma IgG dye test, the Toxoplasma IgM immunosor-
bent agglutination assay (ISAGA), the Toxoplasma IgE enzyme-linked immunosor-
bent assay, and the AC/HS differential agglutination test. The reference laboratories
offer expert advice on the interpretation of these results.
1. Diagnosis of T gondii infection during pregnancy. When there is clinical
suspicion of acute toxoplasmosis during pregnancy, serologic samples should
be sent to a reference laboratory to avoid any unnecessary delays in the estab-
lishment of diagnosis and initiation of prenatal treatment. Prompt initiation of
prenatal treatment has been recently shown to decrease MTCT and ameliorate
the severity of clinical manifestations. In a recent publication from PAMF-TSL
involving 451 patients with positive toxoplasmosis IgM and IgG from NRL, 335
of patients (74%) had a chronic infection, 100 (22%) had an acute infection, and
7 (2%) were not infected, and for 9 patients (2%), results were indeterminate.
Positive Toxoplasma IgM and IgG test results obtained at NRLs cannot accurately
distinguish between acute and chronic infections. To do so, testing at reference
laboratories is required, as mandated by a 1997 letter from the FDA to clinicians
and laboratories in the United States.
2. Prenatal diagnosis of congenital T gondii infection in the fetus. CT can occur
in 3 ways: (1) transmission of T gondii infection to the fetus from a mother
who acquired acute primary infection during pregnancy or shortly before
conception; (2) reactivation of a Toxoplasma infection in an immune woman
who became immunocompromised during gestation (eg, due to HIV infection
or immunosuppressive medications); and (3) reinfection of a previously immune
mother with a new, more virulent strain (eg, after international travel). Amplification
of Toxoplasma DNA by PCR assay in amniotic fluid sample (AF PCR) is the
preferred method to diagnose fetal infection. The sensitivity and negative predictive
value (NPV) for AF PCR is influenced by the gestational age at which infection
is acquired. NPV of AF PCR assay for early maternal primary infections (first or
second trimester) is very high (92%–99%). However, for infections acquired in the
third trimester, the NPV is lower. Explanations for poor NPV include a dilution
effect attributable to a larger amount of AF in the third trimester and/or maternal
treatment before AF PCR testing. Moreover, it probably takes several weeks for the
infection to cross the placenta from the mother to the fetus in large enough quantities
to spill into the AF. The positive predictive value of an AF PCR at any time during
pregnancy is very high (95%–100%). In general, AF PCR assay should be performed
at least 4 weeks after acute primary maternal infection and at ≥18 weeks of gestation.
3. Diagnosis of T gondii infection in the infant. Persistence of positive
Toxoplasma IgG in the child beyond 12 months of age is considered as the
gold standard for the diagnosis of CT. In general, any maternal Toxoplasma IgG
antibodies transferred transplacentally are expected to decrease by 50% per
month after birth and usually disappear by 6 to 12 months of age. Maternal
treatment during pregnancy and/or postnatal treatment of the infant could
affect the production and kinetics of Toxoplasma IgG antibodies in the infant.
A positive Toxoplasma IgM ISAGA result (at or after 5 days of age) and/or a
positive Toxoplasma IgA test result (at or after 10 days of age) are considered
diagnostic of CT in infants with a positive Toxoplasma IgG. Because IgM
and IgA antibodies do not cross the placenta, they reflect the infant’s response
to T gondii infection. Of note, positive results before 5 or 10 days of age could
represent false-positive results from contamination of the infant’s blood with
maternal blood (maternal–fetal blood leak). Moreover, false-positive Toxoplasma
IgG and IgM test results can occur after recent transfusion of blood products or
receipt of immunoglobulin intravenously. False-negative results occur in 13% of
patients with IgM ISAGA, 23% with IgA, and 7% with both IgM and IgA. Infants
with negative Toxoplasma IgM and IgA antibodies but with positive neonatal
Toxoplasma IgG, serologic evidence of acute maternal T gondii infection during
pregnancy, and evidence of clinical manifestations suggestive of CT should be
regarded as having CT and treated as such. Positive PCR assay results from
peripheral blood, CSF, urine, or other body fluid in symptomatic patients are
also diagnostic of CT. One study showed that the sensitivity is 29% for blood
PCR assay, 46% for CSF PCR assay, and 50% for urine PCR assay. The CSF PCR
assay result was positive in 71% of infants with CT and hydrocephalus, in 53% of
infants with CT and intracranial calcifications, and in 51% of infants with CT eye
disease. Placentas can be examined with PCR assay as well; however, a positive
placental PCR assay result may suggest CT but is not diagnostic of CT per se.
B. Cerebrospinal fluid examination should be performed in suspected cases. The
most characteristic abnormalities are xanthochromia, mononuclear pleocytosis,
and a very high protein level (sometimes >1 g/L). Tests for PCR and CSF IgM to
toxoplasmosis should also be performed.
C. Imaging studies. Fetal ultrasound every month until delivery is recommended in
a mother with definite seroconversion during pregnancy. Postnatal imaging stud-
ies include:
1. Computed tomography of the head should be considered when there is suspi-
cion of CT to evaluate for the presence of intracranial calcifications, ventriculo-
megaly, hydrocephalus, and other findings. Computed tomography is superior
to ultrasound or magnetic resonance imaging in identifying calcifications.
2. Abdominal ultrasonography at birth for intrahepatic calcifications and/or
hepatosplenomegaly is also indicated.
3. Long-bone films may show abnormalities, specifically metaphyseal lucency and
irregularity of the line of calcification at the epiphyseal plates without periosteal
reaction.

D. Ophthalmologic examination (preferably by retinal specialist) characteristically

shows chorioretinitis. It may also show other findings such as microphthalmia,
cataract, macular scarring, and optic nerve atrophy.
VII. Management
A. Antepartum management of pregnant women. Initiating treatment of the preg-
nant woman as soon as possible after seroconversion helps to prevent MTCT. The
odds of MTCT decrease by 52% when treatment is promptly initiated within
3 weeks after seroconversion. Additionally, antepartum treatment is associated with
lower odds of severe neurologic sequelae in infants with CT. Spiramycin is recom-
mended for women who acquire their infection at <18 weeks of pregnancy. It should
be continued until delivery to prevent MTCT. Spiramycin is not teratogenic and is
available in the United States only through the Investigational New Drug process at
the FDA (phone: 301-796-1600). Spiramycin is not recommended when fetal infec-
tion is established (it should be stopped if AF PCR or fetal ultrasound is suggestive
of CT). For established fetal infections (based on AF PCR or fetal ultrasound),
maternal treatment with pyrimethamine, sulfadiazine, and folinic acid should
be instituted after 18 weeks of gestation. Pyrimethamine is potentially teratogenic
and should not be used before the 18th week of pregnancy.
B. Postnatal management of the infant with congenital toxoplasmosis. Antipara-
sitic therapy is indicated for infants in whom a diagnosis of CT is confirmed or
probable based on serology, PCR, or clinical symptoms. The typical course consists
of sulfadiazine (50 mg/kg, twice daily), pyrimethamine (2 mg/kg/d for 2 days, then
1 mg/kg/d for 2–6 months, then 1 mg/kg/d 3 times a week), and folinic acid
(10 mg, 3 times weekly) for a minimum of 12 months. Serial follow-up to gauge
the response of the infant to therapy should include neuroradiology, ophthalmo-
logic examinations, and CSF analysis if indicated. Corticosteroids in the form of
prednisone (1 mg/kg/d in 2 divided doses) should be given when CSF protein is
>1 g/dL and when active chorioretinitis threatens vision. Prednisone is continued
until resolution of CSF protein elevation and active chorioretinitis. Infants treated
with pyrimethamine and sulfadiazine require weekly blood counts (complete blood
count [CBC] including platelets) and urine microscopy to detect any adverse drug
effects. CBC can be spaced to every 2 weeks if counts remain stable.
C. Prevention
1. Primary prevention should be done through education. Pregnant women
should be counseled that toxoplasma infection can be prevented in large part
by cooking meat to a safe temperature (152°F); peeling or thoroughly washing
fruits and vegetables before eating; avoiding drinking unfiltered water in any
setting; cleaning cooking surfaces and utensils after they have contacted raw
meat, poultry, seafood, or unwashed fruits or vegetables; avoiding ingestion of
raw shellfish such as oysters, clams, and mussels; avoiding ingestion of raw goat
milk; avoiding changing cat litter or, if necessary, using gloves, and then washing
hands thoroughly; not feeding raw or undercooked meat to cats; and keeping
cats inside to prevent acquisition of Toxoplasma by eating infected prey.
2. Secondary prevention. Only approximately 50% of mothers of infants with CT
had clinical symptoms suggestive of acute toxoplasmosis during pregnancy or
had reported risk factors for T gondii exposure (eg, exposure to undercooked
meat or to cat feces). Therefore, only routine serologic screening during preg-
nancy would have identified the other 50%. Secondary prevention by routine
serologic screening of the pregnant woman is done in some countries (France
and Austria) but is not widely used in the United States.
VIII. Prognosis. Maternal toxoplasmosis acquired during the first and second trimesters is asso-
ciated with stillbirth (35%) and perinatal death (7%). Infants with CT have a mortality
rate as high as 12% and are at risk for many other problems later in life (seizures, visual
impairment, learning disabilities, deafness, mental retardation, and spasticity). Adults who
were treated as infants for CT appear to have reasonable quality of life and visual function.

150 Tuberculosis
I. Definition. Tuberculosis (TB), an infection caused by the organism Mycobacterium
tuberculosis, can be congenital or acquired in the postnatal period.
II. Incidence. The World Health Organization (WHO) estimates an incidence of 10.4
million new TB cases and 1.3 million TB deaths in 2016. Although congenital TB is
rare, with about 350 cases reported in the English literature, the mortality rate is as
high as 50%.
III. Pathophysiology. M tuberculosis transmission occurs via inhalation of airborne drop-
let nuclei, which are carried by alveolar macrophages through the lymphatic system to
hilar lymph nodes. The infection can either be contained or lead to primary progres-
sive TB. Infected macrophages interact with T lymphocytes to release cytokines that
promote phagocytosis of M tuberculosis, leading to granuloma formation within 2 to
8 weeks in most individuals. Young children and immunosuppressed individuals lack
host immunity and instead develop active primary progressive disease in the lung
parenchyma and hilar lymph nodes. In these individuals, the characteristic fibrous
granuloma capsule becomes disrupted, causing liquefactive necrosis of the central
caseous material. The necrotic material can then flow into adjacent vasculature and
disseminate systemically or to adjacent bronchi and spread externally via respiratory
droplets. Immunosuppression and malnutrition are risk factors for reactivation of
latent infection.
Vertical transmission causing congenital TB can occur due to hematogenous spread
via the umbilical vein leading to a primary tuberculous lesion in the liver or lung. Alter-
natively, fetal aspiration or ingestion of infected amniotic fluid can lead to pulmonary
or gastrointestinal TB.
IV. Risk factors. The highest risk of transmission to newborns occurs via respiratory trans-
mission from untreated mothers during the postnatal period. This is more common
than congenital TB, and diagnosis of neonatal TB can lead to identification of previ-
ously unrecognized diagnosis of TB in the mother. Maternal extrapulmonary TB, such
as miliary TB or tuberculous endometritis, increases the risk of congenital infection.
Maternal treatment for 2 to 3 weeks in the antenatal period reduces the risk of post-
natal infection. Human immunodeficiency virus (HIV) is a risk factor for maternal
TB, which in turn increases the risk of mother-to-child transmission of HIV. Living in
endemic areas or crowded conditions also increases the risk of TB.
A. Pregnancy. Pregnant women with TB tend to have fewer of the typical symptoms
associated with TB. Active TB symptoms and signs include fever, cough, night
sweats, anorexia, weight loss, general malaise, and weakness. Extrapulmonary TB
can affect the genitourinary tract, bones and joints, meninges, lymph nodes, pleu-
ral lining, and peritoneum. Extrapulmonary TB is more common when there is
co-infection with HIV. The natural history of TB is thought to be unaffected by
pregnancy. Maternal TB, especially extrapulmonary disease, does increase preg-
nancy and perinatal complications such as preeclampsia, vaginal bleeding, early
pregnancy loss, preterm labor, and low birthweight.
B. Neonatal period. Congenital TB can mimic neonatal sepsis, or the infant may pres-
ent in the first 90 days of life with bronchopneumonia and/or hepatosplenomeg-
aly. Symptoms are usually present by the second or third week of life. As neonates
tend to present with atypical signs, the diagnosis of TB must be considered in the
differential diagnosis of other congenital infections (syphilis, cytomegalovirus, and
toxoplasmosis). Beside bronchopneumonia and/or hepatosplenomegaly, congeni-
tal TB can present with fever, lymphadenopathy, abdominal distention, lethargy
or irritability, ear discharge, and papular skin lesions. Less common symptoms

150: Tuberculosis 1203
include vomiting, apnea, cyanosis, jaundice, seizures, and petechiae. Respiratory

signs include cough, wheezing, tachypnea, stridor, and crepitation, which is thought
to result from obstruction of bronchi by enlarged hilar lymph nodes. Young infants
are at increased risk for meningeal involvement and disseminated or miliary TB due
to their immature immune systems. Meningeal presentations include meningoen-
cephalitis, basal arachnoiditis, and intracranial tuberculomas. TB of the spine (Pott
disease) has also been described in congenital infection. Clinical signs of congenital
or postnatally acquired TB are typically occult and delayed in presentation because
of the immaturity of the newborn and infant immune system.
VI. Diagnosis
A. Clinical criteria. Congenital infection is diagnosed if the infant has the primary
criterion and meets 1 of the secondary criteria for congenital TB (Cantwell criteria).
Otherwise, postnatally acquired TB is diagnosed based on known exposure and a
proven tuberculous lesion.
1. Primary criterion. The infant must have proven tuberculous lesions.
2. Secondary criteria
a. Lesions in the first week of life.
b. A primary hepatic complex or caseating hepatic granulomas.
c. Tuberculous infection of the placenta or the maternal genital tract.
d. Exclusion of postnatal transmission by a thorough investigation.
B. Acid-fast Bacillus smear and culture. M tuberculosis can be identified by culture
from the following specimens: gastric aspirates, sputum, bronchial washings, pleu-
ral fluid, cerebrospinal fluid (CSF), urine, or other body fluids. A biopsy specimen
can also be obtained from lymph node, pleura, mesentery, liver, bone marrow,
or other tissues. The best specimen in neonates and infants who may have an
absent or nonproductive cough is an early-morning gastric aspirate, obtained
by a nasogastric tube before feeding. Aspirates should be collected on 3 separate
days. Gastric aspirates usually yield negative acid-fast Bacillus (AFB) smears, with
an overall diagnostic yield of <50%. Fluorescent staining methods increase the sen-
sitivity of gastric aspirates. The presence of nontuberculous mycobacteria can result
in a false-positive smear. Liquid media culture facilitates growth of M tuberculosis,
which can take between 3 and 6 weeks to grow.
C. Nucleic acid amplification test. Nucleic acid amplification tests for rapid diagnosis
of TB are available but have varying sensitivity and specificity. False-positive and
false-negative results have also been reported.
D. Tuberculin skin testing. A negative tuberculin skin test (TST) result should be
considered unreliable in infants <3 months of age. The definition of a positive
Mantoux skin test is as follows:
1. Reaction ≥5 mm
a. Infants in close contact with known or suspected infectious cases of TB.
b. Infants suspected to have tuberculous disease based on clinical evidence or
abnormal chest radiograph.
c. Infants with an immunosuppressive condition, including HIV, or receiving
immunosuppressive therapy.
2. Reaction ≥10 mm
a. Age <4 years.
b. Medical risk factors such as chronic renal failure or malnutrition.
c. Increased environmental exposure.
E. Interferon-γ release assays. Interferon-γ release assays (IGRAs) measure
interferon-γ production from T lymphocytes in response to antigens specific to
M tuberculosis. Because these antigens are not found on Mycobacterium bovis–
bacille Calmette-Guérin (BCG) vaccine or most nontuberculous mycobacteria,
IGRAs are more specific tests than the TST, yielding fewer false-positive results.
IGRAs may be used in conjunction with TST, but a negative test is unreliable in
newborns due to low sensitivity.

F. Chest radiograph. Chest imaging may initially be normal, but most infants present
with abnormal findings, including miliary TB, multiple pulmonary nodules, lobar
pneumonia, bronchopneumonia, interstitial pneumonia, pleural effusion, and
mediastinal adenopathy. The upper lobes and posterior lung segments are thought
to be the most common sites for TB in infants.
G. Imaging. Other imaging modalities include abdominal sonography for hepatic
involvement and thoracic computed tomography (CT) for adenopathies. Central
nervous system (CNS) imaging includes ultrasonography, CT, and magnetic reso-
nance imaging.
H. Laboratory markers. Leukocytosis with neutrophil predominance and elevation
of C-reactive protein has been reported in congenital TB due to the inflamma-
tory response associated with M tuberculosis. Thrombocytopenia has also been
observed, although it is a nonspecific finding.
I. Cerebrospinal fluid. A lumbar puncture should promptly be performed when con-
genital or postnatally acquired TB is suspected. CSF findings can include lympho-
cytic pleocytosis, increased protein levels, and decreased CSF–to–serum glucose
ratio.
J. Human immunodeficiency virus testing. All individuals with TB should be evalu-
ated for HIV infection due to the increased incidence of TB co-infection.
K. Placental pathology. The placenta may demonstrate evidence of granulomas, and
an AFB smear and culture should be sent from placental specimen.
VII. Management
A. Antimicrobial therapy during pregnancy
1. Latent infection. The Centers for Disease Control and Prevention (CDC) rec-
ommends deferring treatment of pregnant women with latent infection until the
postpartum period except in high-risk situations. Isoniazid therapy for 9 months
should be considered for latent TB (positive TST and normal chest radiographic
findings) in pregnant women with HIV, recent contagious contact, and skin
test conversion within the prior 2 years. Pyridoxine supplementation should be
administered for the duration of pregnancy and breast feeding.
2. Active infection. The CDC recommends an initial treatment regimen with
isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and
rifampin for a total of 9 months. Isoniazid, rifampin, and ethambutol are con-
sidered relatively safe for the fetus. Streptomycin should not be administered to
the mother due to ototoxic effects in the fetus. Although pyrazinamide is used in
some regimens, its safety during pregnancy has not been established.
B. Antimicrobial therapy during the neonatal period
1. Active maternal and congenital or neonatal acquired infection. In cases
in which the maternal physical examination and chest radiographic findings
are diagnostic of active TB, the infant should be treated promptly with iso-
niazid, rifampin, pyrazinamide, and an aminoglycoside such as amikacin.
Pyridoxine (to prevent neurotoxicity) supplementation in infants receiving iso-
niazid therapy is recommended in the following instances: exclusively breast-
fed infants, malnourished infants, and those with symptomatic HIV infection.
Hepatotoxic effects of isoniazid therapy are rare but can be life threatening.
2. Active maternal infection without congenital infection. If the mother has
active TB disease but the neonate is not affected, isoniazid should be given until
3 or 4 months of age. If a negative TST result is obtained at the end of therapy
and the mother demonstrates successful response to therapy, the infant’s isonia-
zid can be discontinued. A positive TST at 3 to 4 months of age necessitates a
reevaluation for TB disease in the infant and continued isoniazid therapy for a
total of 9 months with monthly evaluation.
3. Latent maternal infection. Neonatal evaluation and therapy are not required
in cases where the mother is asymptomatic and is diagnosed with latent TB
infection.

150: Tuberculosis 1205
4. Postnatal tuberculosis infection. For infants with pulmonary disease, pulmo-

nary disease with hilar adenopathy, and hilar adenopathy disease, a 6-month
4-drug regimen is recommended as follows: isoniazid, rifampin, pyrazinamide,
and ethambutol for 2 months followed by isoniazid and rifampin for 4 months.
The duration of therapy is extended to 9 months if there is evidence of cavitary
pulmonary lesions or sputum culture remains positive after 2 months of therapy.
The risks and benefits of using ethambutol in infants need to be considered due
to a dose- and duration-dependent risk of optic neuritis. An infectious disease
consultation is essential for managing infants who are co-infected with HIV due
to drug interactions and overlapping drug toxicities, especially between antiret-
rovirals and rifampin.
5. Extrapulmonary tuberculosis. For tuberculous meningitis, treatment is initi-
ated with isoniazid, rifampin, pyrazinamide, and ethionamide/aminoglycoside.
Pyrazinamide is given for a total of 2 months, and isoniazid and rifampin are
given for a total of 9 to 12 months. Ethionamide or aminoglycoside is discon-
tinued after drug susceptibility is established. Corticosteroids should be added
in confirmed cases of TB meningitis as they reduce mortality rates and long-
term neurologic impairment. Corticosteroids can also be considered for pleural
and pericardial effusions, severe miliary disease, endobronchial disease, and
abdominal TB. Surgical therapy for lymphadenitis, bone and joint abscesses, and
hydrocephalus complicating CNS disease may be indicated.
C. Isolation precautions/breast feeding
1. Maternal latent infection. No separation or restrictions on breast feeding are
required.
2. Maternal active disease. In suspected or proven cases of maternal TB, the
mother and infant should be separated pending evaluation and appropriate
maternal and infant therapy. Separation is not necessary once the infant begins
isoniazid and the mother adheres to treatment, wears a mask, and follows infec-
tion control measures. In cases of multidrug-resistant TB or maternal nonad-
herence to therapy, the infant should be separated, and BCG vaccine should be
considered in consultation with an infectious disease specialist. Breast-feeding
restrictions can be removed after the mother has been treated appropriately for
≥2 weeks and is not considered contagious.
D. Hospital control measures. Restriction to an airborne infection isolation room is
indicated in the following cases: neonates with congenital or acquired TB undergo-
ing manipulation of the oropharyngeal airway, infants with cavitary lesions, positive
sputum AFB smears, and laryngeal or extensive pulmonary involvement. Noso-
comial transmission from infants to healthcare workers and between infants via
contaminated respiratory equipment has been reported.
E. Prevention. The BCG vaccine contains a live attenuated strain of M bovis. The
WHO recommends that a single dose of BCG vaccine should be given to all infants
soon after birth in countries with a high TB burden. BCG vaccine should not be
given to symptomatic HIV-positive or immunosuppressed infants. If the neonate is
exposed to smear-positive pulmonary TB shortly after birth, BCG vaccine should
be delayed pending completion of isoniazid therapy. The CDC does not recom-
mend routine use of BCG vaccine in the United States due to the low burden of
disease and interference of the vaccine with TST reactivity.
VIII. Prognosis. Information on prognostic factors is not well defined for infants with either
congenital or acquired disease. Survival rate is not influenced by the following factors:
specific signs or symptoms, birthweight, the nature or severity of maternal disease,
timing of maternal diagnosis, prematurity, hepatic dysfunction, or thrombocytopenia.
An improved survival rate has been seen in infants with the following: presentation
of symptoms after 3 weeks of age, no CNS TB disease, appropriate anti-TB therapy,
higher leukocyte count, and absence of miliary or multiple pulmonary nodules pattern
on chest radiograph.

151 Ureaplasma Infection

I. Definition. Ureaplasma belongs to the Mycoplasmataceae family. These are small
pleomorphic bacteria that characteristically lack a cell wall. The genus Ureaplasma
contains 2 species capable of causing human infection, Ureaplasma urealyticum and
Ureaplasma parvum.
II. Incidence. Ureaplasma species are frequently present in the lower genital tract of sexu-
ally active women with a colonization rate ranging between 40% and 80%. Vertical
transmission to the newborn is high, especially in premature infants <1000 g birth-
weight, in whom the transmission rate approaches 90%.
III. Pathophysiology. U urealyticum has been implicated in a variety of obstetric and
neonatal diseases including preterm labor, preterm premature rupture of membranes
(pPROM), chorioamnionitis, postpartum fever and endometritis, congenital
pneumonia, bacteremia, meningitis, intraventricular hemorrhage (IVH), necrotizing
enterocolitis (NEC), and bronchopulmonary dysplasia (BPD). The presumed
mechanisms of infection include fetal exposure to ascending intrauterine infection,
passage through an infected birth canal, and hematogenous dissemination through the
placenta into umbilical vessels. This exposure leads to colonization of the skin, mucosal
membranes, gastrointestinal and respiratory tract, and sometimes dissemination into the
bloodstream and central nervous system (CNS). Phospholipases and cytokines produced
through the inflammatory response can trigger uterine contractions and premature birth.
Ureaplasma infection of the respiratory tract in the newborn promotes a proinflammatory
cytokine cascade with increase in tumor necrosis factor-α, interleukin (IL)-1β, and IL-8.
These cytokines recruit neutrophils to the lungs and intensify the inflammatory cascade,
which damages the premature lung and impairs future alveolar development. The same
mechanisms may be involved in Ureaplasma-mediated intestinal injury and NEC.
IV. Risk factors. Ureaplasma colonization is associated with preterm labor, chorioamnio-
nitis, birthweight <1000 g, and gestational age (GA) <30 weeks. Respiratory coloniza-
tion is inversely related to GA at birth (65% in infants <26 weeks vs 31% in infants
≥26 weeks).
A. Preterm labor, preterm premature rupture of membranes, and chorioamnio-
nitis. Ureaplasma can invade the amniotic fluid early in pregnancy and are the
single most common organisms that can be isolated from inflamed placentas.
Ureaplasma can persist in the amniotic fluid subclinically for several weeks.
Detection of Ureaplasma in second-trimester amniotic fluid by polymerase chain
reaction (PCR) correlates with subsequent preterm labor and delivery (58.6%
for those with positive PCR vs 4.4% for those with negative results). In addition,
Ureaplasma cord blood infections (identified by cultures) are far more common
in spontaneous than indicated preterm deliveries and are strongly associated with
markers of acute placental inflammation. Positive cord cultures are also associated
with neonatal systemic inflammatory response syndrome.
B. Congenital pneumonia. Evidence that suggests Ureaplasma as a cause of congeni-
tal pneumonia includes isolation of the organism in pure culture from amniotic
fluid and tracheal aspirate of neonates <24 hours after birth with specific immu-
noglobulin M (IgM) response in the midst of an acute inflammatory reaction and
radiographic changes. These infants develop early interstitial pulmonary infiltrates
with cystic/dysplastic changes as early as 7 to 10 days of age.
C. Meningitis and intraventricular hemorrhage. Multiple studies have shown
Ureaplasma to be isolated from cerebrospinal fluid (CSF) of premature infants
with meningitis, IVH, and hydrocephalus. The contribution of Ureaplasma to the
outcome of these newborns is uncertain.

152: Urinary Tract Infection 1207
D. Association with necrotizing enterocolitis. One study showed that the incidence

of NEC was 3.3-fold higher in Ureaplasma-positive, ≤28 weeks preterm infants with
higher cord blood IL-6 and IL-1β.
E. Predisposition to bronchopulmonary dysplasia. Multiple cohort studies have
linked the development of BPD with colonization of the airways with Ureaplasma.
VI. Diagnosis
1. Culture. Specimens for culture require specific transport media with refrigeration
at 4°C. Dacron or calcium alginate swabs should be used instead of cotton swabs.
2. Other tests. Several sensitive PCR assays have been developed, but they are not
available routinely. Serologic assays are of limited value.
A. Treatment of the colonized pregnant mother. Treatment of pregnant women
who present with pPROM with a 7-day course of erythromycin has been shown
to prolong pregnancy, reduce neonatal treatment with surfactant, decrease infant
oxygen dependency at ≥28 days of age, and result in fewer major cerebral abnor-
malities on ultrasonography before discharge. A recent study showed that a single
oral dose of azithromycin (1 g) is comparable to a 7-day regimen of erythromycin.
Those same benefits are not accrued if the mother presents with preterm labor but
with intact membranes.
B. Treatment of the colonized newborn infant is controversial. For infants with
congenital pneumonia with radiographic evidence of early interstitial pneumonitis
and when Ureaplasma is the only microorganism isolated from the respiratory tract,
some experts recommend treatment with a 3-day course of intravenous azithromy-
cin (20 mg/kg/d). Treatment may also be considered when Ureaplasma is isolated
from a normally sterile site such as the bloodstream or CSF. Azithromycin has
both anti-inflammatory and anti-infective properties; limited evidence suggests
that azithromycin significantly reduces the risk of BPD in preterm neonates irre-
spective of Ureaplasma colonization. However, given the limited information on
pharmacokinetics and potential harmful effects including risk of pyloric stenosis,
its routine use for the prevention of BPD cannot be recommended.
VIII. Prognosis. In utero exposure to Ureaplasma is associated with reactive airway disease
and wheezing in the first 2 to 3 years of life. It is also associated with adverse neuro-
developmental outcome and cerebral palsy at 2 years of adjusted age in these infants.
152 Urinary Tract Infection

I. Definition. A urinary tract infection (UTI) is the presence of pathogenic bacteria or
fungus in the urinary tract. It is the most common bacterial infection in febrile neo-
nates, although it is very uncommon in the first few days of life.
II. Incidence. UTI incidence in all neonates is approximately 0.1% to 2%. However, in
preterm and low birthweight infants, the incidence is as high as 20%. In infants younger
than 3 months, boys have a higher prevalence of UTI than girls.
III. Pathophysiology. See Table 152–1 for the most common pathogens isolated in neona-
tal UTI. Nosocomial infections occur more often due to indwelling urinary catheters.
A. Term infants. Ascending infection through the urethra is the most common source
of infection in term infants. Escherichia coli is the most common bacterial pathogen,
followed by other gram-negative bacilli (Klebsiella, Proteus, Enterobacter).

Table 152–1. COMMON ORGANISMS ISOLATED IN NEWBORN AND

NEONATAL UTI
Organism Incidence (%)

Gram-negative rods
E. coli 40–72
Klebsiella spp 7–40
Enterobacter cloacae 3–8
Proteus vulgaris 3
Serratia marcescens 1–7
Pseudomonas aeruginosa 1
Gram-positive cocci
Enterococcus spp 10–16
Staphylococcus aureus 1–5
Group B streptococcus 1–3
Staphylococcus, coagulase negative 1
Viridans streptococcus 1
Yeast
Candida spp 25–42
Reproduced with permission from Arshad M, Seed PC: Urinary tract infections
in the infant, Clin Perinatol. 2015 Mar;42(1):17-28.
B. Preterm infants. Hematogenous spread of infection plays a bigger role in preterm

infants. Klebsiella and coagulase-negative Staphylococcus are more commonly iden-
tified than E coli. Candida UTIs are also common in this group.
C. Fungal urinary tract infections. Most often caused by Candida species and are
more common in nosocomial infections. Fungal UTIs are also more common in
extremely low birthweight babies.
IV. Risk factors
A. Congenital anomalies of the kidney and urinary tract (CAKUT) such as urinary
tract dilatation (eg, ureteropelvic junction obstruction, ureterovesical junction
obstructions, ureterocele, ectopic ureter), posterior urethral valves, and vesicoure-
teral reflux can predispose to UTIs.
B. Alteration in normal bladder function (eg, neurogenic bladder) predisposes the
infant to UTI.
C. Recent urinary tract instrumentation or indwelling catheters are the most com-
mon risk factors for nosocomial infections.
D. Uncircumcised males have a 10-fold increased risk for UTI compared to
circumcised males. This is presumably due to increased bacterial adherence to
the mucosal surface of the foreskin and bacterial colonization under the foreskin.
E. Prematurity is a risk factor for UTI because premature infants are relatively
immunocompromised compared to term infants. Risk increases with decreasing
gestational age and birthweight.
F. Prolonged unexplained jaundice can be a marker for UTI in infants and warrants
screening with a urinalysis and culture. Indirect (unconjugated) hyperbilirubine-
mia is thought to be secondary to hemolysis caused by E coli infection. Direct
(conjugated) hyperbilirubinemia-associated UTI is secondary to cholestasis, but
the mechanism is not known.

152: Urinary Tract Infection 1209
G. Maternal urinary tract infection during pregnancy and premature rupture of

membranes are potential risk factors for UTI. These were reported in 2 small case
series. The increased incidence may be because these mothers harbor pathogens
transmitted to the infant during birth.
H. White race is risk factor for urinary tract infection. Febrile white infants have
a higher probability of being diagnosed with UTI compared to black infants or
infants of other ethnic groups. This is especially the case in female white infants.
In 1 study, African American infants were much less likely to be diagnosed with
UTI than white or Hispanic infants.
V. Clinical presentation. Infants may appear acutely toxic, similar to neonatal sepsis, or
present with nonspecific findings of fever, lethargy, irritability, poor feeding, vomit-
ing, jaundice secondary to cholestasis, loose stools, or failure to thrive. Fever does not
always occur. Newborns with UTI are at higher risk for bacteremia than older infants.
Preterm infants have the same signs as term infants but can also have apnea, bradycar-
dia, and hypoxia. Term infants usually present in the second to third week with a UTI.
VI. Diagnosis
1. Urinalysis. Positive leukocyte esterase suggests inflammation in the urinary
tract; it has a sensitivity of 84% and specificity of 78%. Positive nitrite suggests
the presence of gram-negative bacteria and is 98% specific; sensitivity is only
50%. Detection of bacteria by microscopy adds specificity to other urine findings.
Hemocytometer white blood cell (WBC) counts in the urine specimen may be of
value in diagnosing UTI. A recent study stated that a minimum of 3 to 6 WBCs per
high-power field depending on urine concentration is required for a presumptive
diagnosis of UTI. Although no single finding on urinalysis is diagnostic of UTI,
neonates without pyuria or bacteriuria have a very low likelihood of UTI.
2. Urine culture. A urine culture is no longer recommended in infants <72 hours
of age in an early-onset sepsis workup and is more appropriately done for late-
onset sepsis workup.
a. Suprapubic aspiration and bladder catheterizations are the only truly reli-
able methods to obtain urine cultures in neonates (see Chapters 29 and 30).
Cultures obtained from a suprapubic bladder aspiration that grow >1000
colony-forming units (CFU)/mL are significant. The optimal definition for
UTI from catheter-obtained specimens in neonates has not been established.
However, >50,000 CFU/mL or 10,000 to 50,000 CFU/mL with pyuria on the
urinalysis are generally accepted definitions.
b. Clean-catch or collection bag specimens often are inaccurate due to con-
tamination and are only clinically reliable if the culture demonstrates no
growth. Due to high false-positive rates, this type of collection is not
recommended.
c. Rapid culture techniques using reverse transcriptase–polymerase chain reac-
tion and next-generation sequencing to identify organisms are available in
many facilities.
3. Serum tests. Complete blood count, blood cultures, serum creatinine, C-reactive
protein, and erythrocyte sedimentation rate may be clinically useful in guiding
management.
4. Sepsis evaluation should be done in all infants suspected of a UTI (see
Chapter 146). The risk of sepsis is about 4% to 7% in term newborns and young
infants and is greater in preterm infants. Blood culture is mandatory in all infants
with a suspected UTI and prior to starting antibiotics. The risk of bacterial men-
ingitis is approximately 1% to 3% in infants with a UTI; therefore, the decision
to perform a lumbar puncture depends on the severity of illness of the infant.
VII. Management
A. Initial antibiotic treatment. For the majority of neonatal cases, initial treatment
with broad-spectrum intravenous (IV) antibiotics is appropriate (usually ampicillin
and gentamicin). It is also important to consider maternal use of antibiotics prior to

delivery (which increases the risk of a neonatal UTI with β-lactamase–producing

E coli) and local antibiotic resistance patterns. Antibiotics can be tailored according to
susceptibility testing on urine culture. Ideal duration of therapy is not completely
known but is usually 10 to 14 days. For an infant in the hospital who is older than
7 days, consider vancomycin and gentamicin. Oral antibiotics can be initiated for
mature infants who are able to tolerate oral intake and who are not ill appearing.
A delay in initiation of antibiotic treatment of 72 hours or more was a risk factor
for permanent renal scars after the first febrile UTI. There is no difference in renal
scarring between oral and IV antibiotic therapy.
B. Imaging after urinary tract infection
1. Renal ultrasound. Because of the high rate of congenital anomalies of the kidney
and urinary tract, all neonates with a documented UTI should undergo renal
ultrasound. The timing of this study remains under debate. Hydronephrosis or
upper urinary tract dilatation is the most common finding.
2. Voiding cystourethrogram. Children younger than 2 months of age and any child
with an abnormal renal ultrasound should also have a voiding cystourethrogram
(VCUG) to look for vesicoureteral reflux, obstructive lesions (eg, ureterocele, pos-
terior urethral valve), or signs of neurogenic bladder. VCUG for children older
than 2 months of age with normal renal ultrasound after first febrile UTI is contro-
versial and is currently not recommended by the American Academy of Pediatrics
(AAP). Any child with a history of >1 febrile UTI should undergo a VCUG.
3. Watchful waiting without voiding cystourethrogram. In children 0 to
3 months of age with E coli UTI (first, febrile UTI) and normal renal ultrasound,
watchful waiting without VCUG can be considered. This is based on evidence
that the probability of high-grade vesicoureteral reflux was low in children with
E coli UTIs and normal renal ultrasounds (1%). The presence of non–E coli UTI
increased the probability of high-grade vesicoureteral reflux to 26%, and adding
an abnormal renal ultrasound further increased the probability to 55%.
4. Other imaging studies. Ultrasound of the spine or magnetic resonance imaging
(MRI) of the spine may be considered if there is evidence of neurogenic bladder.
MRI of the urinary tract is rarely done but can provide excellent anatomic detail
of the urinary tract. Diuretic renogram can be done to localize and quantify the
degree of urinary tract obstruction.
C. Antibiotic prophylaxis. Use and efficacy of antibiotic prophylaxis are debated sub-
jects in the fields of pediatrics and urology. Although prophylactic antibiotics may
reduce the incidence of UTI, they may not reduce the risk of renal scarring. The use
of prophylactic antibiotics may also increase the risk of acquiring pathogens with
antibiotic resistance. The AAP Red Book states that “data do not support the use
of antimicrobial prophylaxis to prevent febrile recurrent UTIs in infants without
vesicoureteral reflux.” For neonates with vesicoureteral reflux, moderate to severe
hydronephrosis, or other abnormalities such as posterior urethral valves, antibiotic
prophylaxis should be considered. Amoxicillin (10 mg/kg/d) is the most commonly
used. If vesicoureteral reflux is present, prophylaxis is continued. Trimethoprim-
sulfamethoxazole is contraindicated because of liver and kidney immaturity in
neonates.
D. Circumcision should be considered in uncircumcised males with a history of
recurrent UTIs. Newborn circumcision is a common procedure with relatively few
associated complications. Pathogenic bacteria may be more adherent to the mucosal
surface of the foreskin than the keratinzed surface of the penis after circumcision.
In theory, circumcision also reduces the bacterial colonization of the periurethral
area, thereby reducing the risk of UTIs. The AAP feels that the potential benefits of
male circumcision outweigh the risks; therefore, the procedure should be accessible
to families who choose it. There is insufficient evidence to recommend routine
circumcision in all newborns. The risks and potential benefits of the procedure
should be outlined to parents to help them make an informed decision.

153: Varicella-Zoster Infections 1211
E. American Academy of Pediatrics Urinary Tract Infection Guidelines. In 2011,

the AAP revised its practice parameters for diagnosis and management of ini-
tial UTI in febrile infants and children age 2 to 24 months. This report did not
include infants younger than 2 months of age due to insufficient data in this age
group. Therefore, there is no consensus on evaluation and management in infants
<2 months old.
153 Varicella-Zoster Infections

Varicella-zoster virus (VZV) is a member of the herpesvirus family. Primary maternal
VZV infection (chickenpox) can result in fetal or neonatal infection. Other rare complications
include spontaneous abortion, fetal demise, and premature delivery. Reactivation infection
(zoster, shingles) does not result in fetal infection. Primary maternal VZV infection during
the last trimester can cause maternal pneumonia with significant morbidity and mortality. The
overall incidence of maternal and neonatal varicella has decreased over the past 15 to 20 years,
presumably due to varicella vaccination. Active surveillance among adults has shown that
the incidence of varicella declined 74% during 1995 to 2005, despite vaccination rates among
adults of only 3%. Herd immunity is the likely explanation for this phenomenon. As of 2013,
more than 78% of 13- to 17-year-old adolescents have received 2 doses of varicella vaccine.
Varicella immunization is recommended for all nonimmune women as part of prepregnancy
and postpartum care. Varicella vaccine should not be administered to pregnant women,
because the possible effects on fetal development are unknown, although no cases of con-
genital varicella syndrome or patterns of malformation have been identified after inadvertent
immunization of pregnant women. When postpubertal females are immunized, pregnancy
should be avoided for at least 1 month after immunization. Reporting of instances of inadver-
tent immunization to the US Food and Drug Administration with a varicella-zoster–containing
vaccine during pregnancy is encouraged (1-877-888-4231).
There are 3 forms of varicella-zoster infections involving the fetus and neonate: fetal, con-
genital (early neonatal), and postnatal.
FETAL VARICELLA SYNDROME

I. Definition. VZV is a teratogen that can cross the placenta and cause a pattern of con-
genital malformations called fetal varicella syndrome (FVS). This form occurs when the
mother has her first exposure to VZV during the first half of pregnancy. The syndrome
is also recognized in the literature as congenital varicella syndrome (CVS).
II. Incidence. Only approximately 5% of women of childbearing age are susceptible to
VZV. The incidence of varicella during pregnancy is estimated at 1 to 5 cases per 10,000
pregnancies. The incidence of embryopathy and fetopathy (FVS) after maternal vari-
cella infection in the first 20 weeks is 1% to 2%.
III. Pathophysiology. Maternal acquisition of the virus probably occurs via respiratory
droplets or direct contact with chickenpox or zoster lesions. The virus replicates in the
oropharynx, and viremia results, before the onset of rash, with transplacental passage
to the fetus. Almost all cases reported have involved exposure between the 8th and
20th weeks of pregnancy. The pathogenesis of FVS may reflect disseminated infec-
tion in utero or be a consequence of failure of the virus–host interaction to result
in establishment of latency, as normally occurs in postnatal VZV infection. Because
VZV is a lymphotropic virus, it has the potential to spread to all fetal organs by the

hematogenous route. Pathology specimens from aborted fetuses with VZV infection
have shown the virus to be distributed throughout fetal tissues. Microcephaly can be
attributed to VZV encephalitis and irreversible damage to the developing brain. Of
interest, the virus does not appear to cause intrauterine damage to the lungs or liver
in infants with FVS, as it does in perinatal varicella or in other immunocompromised
hosts. Fulminant infection involving these organs may result in fetal demise, rather
than birth of an infant with FVS. VZV is also a neurotropic virus; many of the defects
have been postulated to be a direct result of spinal cord and ganglia infection, which
causes destruction of the plexi during embryogenesis, leading to denervation of the
limb bud and subsequent hypoplasia. Failure of muscle development has consequences
for limb bone formation. The cutaneous defects are also likely to reflect VZV infec-
tion of sensory nerves. VZV infection of cells in developing optic tracts also explains
the optic atrophy and chorioretinitis. From the pattern of dermatomal distribution
of the skin defects seen in FVS, particularly the scarring and limb hypoplasia, it has
been suggested that FVS is the result of intrauterine zoster. The extremely short latent
period between fetal infection and reactivation, if latency is established at all, is the
consequence of the lack of cell-mediated immunity in the fetus before 20 weeks’ gesta-
tion. Infants exposed to VZV in utero also can develop zoster (shingles) early in life
without having had extrauterine varicella (chickenpox).
IV. Risk factors. A pregnant woman with no history of varicella infection or vaccination
who becomes exposed to VZV between the 8th and 20th weeks of gestation is at risk.
V. Clinical presentation. The main symptoms of FVS are:
A. Skin lesions (60%–70%). Cicatricial scars and skin loss.
B. Central nervous system defects or disease (60%). Microcephaly, seizures, enceph-
alitis, cortical atrophy and spinal cord atrophy, mental retardation, and cerebral
calcifications.
C. Ocular abnormalities (60%). Microphthalmia, chorioretinitis, cataracts, optic
atrophy, nystagmus, and Horner syndrome (ptosis, miosis, and enophthalmos).
D. Limb abnormalities, which often include hypoplasia of bone and muscle (50%).
E. Prematurity and intrauterine growth restriction (35%).
VI. Diagnosis. Alkalay et al proposed the following criteria for the diagnosis of FVS in
the newborn:
A. Appearance of maternal varicella during pregnancy.
B. Presence of congenital skin lesions in dermatomal distribution and/or neurologic
defects, eye disease, or limb hypoplasia.
C. Proof of intrauterine varicella-zoster virus infection by detection of viral DNA
in the infant by polymerase chain reaction (PCR), presence of VZV-specific immu-
noglobulin (Ig) M, persistence of VZV IgG beyond 7 months of age, or appearance
of zoster (shingles) during early infancy.
Prenatal diagnosis is most often done by detailed ultrasound, searching for typi-
cal anomalies and VZV-specific PCR in amniotic fluid. At least a 5-week interval is
advised between onset of maternal rash and obtaining of the ultrasound. An initial
ultrasound is recommended at 17 to 21 weeks of gestation with a follow-up study
done 4 to 6 weeks later. The role of prenatal magnetic resonance imaging for assess-
ment of the fetus after maternal varicella is only beginning to be delineated, but it
may provide improved specificity, particularly for central nervous system damage.
A. Mother. If the mother is exposed to VZV infection in the first or second trimester,
treat the mother with varicella-zoster immune globulin (VariZIG) if her past
history of varicella infection or vaccination is negative or uncertain. For dosage,
see Chapter 155. VariZIG should be given as soon as possible after exposure (pref-
erably within 72 hours, but up to 10 days), and it appears to protect both mother
and fetus. If VariZIG is not available, intravenous immunoglobulin (IVIG) can be
used. If chickenpox is diagnosed during pregnancy, antiviral therapy with acyclovir

153: Varicella-Zoster Infections 1213
or valacyclovir should be strongly considered. Acyclovir and valacyclovir therapy

during pregnancy appears to be safe; it has not been associated with increased
congenital abnormalities compared with the general population.
B. Infant. Supportive care of the infant is required because there is usually profound
neurologic impairment. Acyclovir therapy may be helpful to stop the progression
of eye disease or to treat recurrent zoster (shingles), which is common in the first
2 years of life.
C. Isolation. Isolation is not necessary.
VIII. Prognosis. Approximately 30% of these infants with FVS die in the first months of life,
often because of intractable gastroesophageal reflux, severe recurrent aspiration pneu-
monia, and respiratory failure. Survivors usually suffer profound mental retardation
and major neurologic disabilities. These infants are also at risk for developing zoster
(shingles) in the first 2 years of life.
CONGENITAL (EARLY NEONATAL) VARICELLA INFECTION

I. Definition. This is the form of the disease that occurs when a pregnant woman suffers
chickenpox during the last 3 weeks of pregnancy or within the first few days postpar-
tum. Disease begins in the neonate just before delivery or within the first 10 to
12 days of life.
II. Incidence. Although the congenital (early neonatal) form is more common than the
teratogenic form, it is still rare, with recent estimates of 0.7 per 100,000 live births per
annum. The introduction of varicella vaccination in 1995 greatly reduced the incidence
of varicella infection in all age groups (herd immunity).
III. Pathophysiology. Maternal chickenpox near term or soon after delivery may cause
severe or fatal illness in the newborn. Maternal varicella can affect the baby through
transplacental viremia, ascending infection during birth, or respiratory droplet/direct
contact with infectious lesions after birth. Neonatal chickenpox occurring in the first
10 to 12 days of life is typically caused by intrauterine transmission of VZV (incuba-
tion period 10–21 days). Chickenpox after the 12th day of life is most likely acquired
by postnatal VZV exposure. If the onset of maternal disease is between 5 days before
delivery or 2 days postpartum, there is a high attack rate (up to 50%) with significant
associated mortality (up to 30%). Those babies present with the classic skin lesions, but
can disseminate with pneumonia, hepatitis, meningoencephalitis, and severe coagu-
lopathy (disseminated intravascular coagulation [DIC]) resulting from liver failure
and thrombocytopenia. If the maternal rash happens >5 days before delivery, there is
enough maternal anti-VZV IgG production with subsequent transplacental transfer to
protect the newborn, which results in a milder case of chickenpox.
IV. Risk factors. Primarily a mother with chickenpox during the last 3 weeks of pregnancy
or within the first few days postpartum. There is a higher risk of mortality if the onset
of maternal disease is 5 days before delivery or 2 days postpartum. Premature infants,
especially those <28 weeks, are extremely susceptible.
V. Clinical presentation is variable. There may be only mild involvement of the infant,
with vesicles on the skin, or the following may be seen:
A. Skin. A centripetal rash (beginning on the trunk and spreading to the face and
scalp, sparing the extremities) begins as red macules and progresses to vesicles and
encrustation. Lesions are more common in the diaper area and skin folds. There
may be 2 or 3 lesions or thousands of them. The differential diagnosis includes
herpes simplex virus and enterovirus. The main complication is staphylococcal and
streptococcal secondary skin infections.
B. Lungs. Lung involvement is seen in all fatal cases. It usually appears 2 to 4 days
after the onset of the rash but may be seen up to 10 days after. Signs include fever,
cyanosis, rales, and hemoptysis. Chest radiograph shows a diffuse nodular-miliary
pattern, especially in the perihilar region.

C. Other organs. Focal necrosis may be seen in the liver, adrenals, intestines, kidneys,
and thymus. Glomerulonephritis, myocarditis, encephalitis, and cerebellar ataxia
are sometimes seen.
VI. Diagnosis. The diagnosis of varicella usually is made clinically based on the charac-
teristic appearance of skin lesions.
A. Polymerase chain reaction is the most sensitive and specific method for detec-
tion of VZV DNA in clinical specimens. This is the diagnostic method of choice
for investigation of vesicular fluid or scabs, biopsies, and amniotic fluid. This test-
ing also can be used to distinguish between wild-type and vaccine-strain VZV
(genotyping). Viral culture and direct fluorescent antibody assay are less sensitive
than PCR and are not usually recommended.
B. Serum testing of varicella-zoster virus antibody. Serologic tests may help to
document acute infection in difficult cases. IgM antibody may be detected as
soon as 3 days after the appearance of VZV symptoms, but the test may not
be reliable.
VII. Management
A. VariZIG. Infants of mothers who develop VZV infection (rash) within 5 days
before or 2 days after delivery should receive 125 U (62.5 U if <2 kg) of VariZIG
as soon as possible and no later than 10 days. IVIG (400 mg/kg) should be used if
VariZIG is not available. Infants treated with immune globulins should be placed
in strict respiratory isolation for 28 days because immunoglobulin treatment may
prolong the incubation period. VariZIG is not expected to reduce the clinical attack
rate in treated newborns; however, these infants tend to develop milder infections
than the untreated neonates. Prophylactic administration of oral acyclovir begin-
ning 7 days after exposure also may prevent or attenuate varicella disease in exposed
infants. Infants born to mothers with rash occurring >5 days before delivery do not
need VZIG, unless they are born at <28 weeks’ gestation; it is believed that these
infants should have received protective transplacental antibodies.
B. Acyclovir therapy 15 mg/kg/dose every 8 hours for 7 days should be considered for
postexposure prophylaxis as well as a treatment in symptomatic neonates.
C. Antibiotics. Use antibiotics if secondary bacterial skin infections occur.
D. Breast feeding. Neither wild-type VZV nor Oka vaccine strain virus has been
shown to be transmitted by human milk; expressed/pumped milk from a mother
with varicella or zoster can be given to the infant, provided no lesions are on
the breast.
VIII. Prognosis. If the mother has onset of disease within 5 days before delivery or 2 days
after, the infant is exposed with no antibodies and will be at risk for severe disease.
Overwhelming sepsis and multiple organ failure can lead to a mortality rate as high
as 30%. The usual causes of death are pneumonia, fulminant hepatitis, and DIC. With
the use of VariZIG, the mortality rate is reduced to 7%. There is an increased risk of
developing zoster (shingles) in the first 2 years of life.
POSTNATAL CHICKENPOX
I. Definition. This form of the disease presents after the 12th day of life. It does not
represent transplacental infection from the mother.
II. Incidence. There has been a significant decline in the incidence since the introduction
of the varicella vaccine in 1995 (by 90%). The incidence of neonatal varicella in the
vaccine era is approximately 0.7 per 100,000 live births.
III. Pathophysiology. Postnatal VZV infection occurs by droplet transmission. This dis-
ease is usually mild because of passive protection from maternal antibodies. Placental
antibody transfer is lower in preterm infants, which makes them more susceptible
compared with term infants. Horizontal transmission in neonatal intensive care units
has been well documented. Neonatal vaccine-strain VZV infection after maternal post-
partum vaccination has been reported.

154: Zika Virus (Congenital Zika Syndrome) 1215
IV. Risk factors. Seronegative mother, delivery before 28 weeks, birthweight <1.5 kg, post-
natal age >2 months (maternal transplacental immunity has waned), immunocompro-
mised neonates (eg, sepsis, steroids).
V. Clinical presentation. The typical chickenpox rash is seen with centripetal spread,
beginning on the trunk and spreading to the face and scalp and sparing the extremities.
All stages of the rash may appear at the same time, from red macules to clear vesicles
to crusting lesions. Complications of this form of the disease are rare but may include
secondary infections and varicella pneumonia. In older children, necrotizing fasciitis
secondary to group A streptococcal infections is particularly worrisome and may be
associated with ibuprofen use (see Figure 80–11).
VI. Diagnosis. Same as for congenital varicella (see the previous section). Diagnosis is
usually made based on clinical grounds.
VII. Management. For the full-term infant in the community setting, the disease is usually
mild. Therefore, acyclovir therapy is controversial. For nosocomial chickenpox in the
intensive care nursery (exposure):
A. Varicella-zoster immune globulin. Recommended for all exposed infants of
<28 weeks’ gestational age or weighing ≤1000 g regardless of their mothers’ evi-
dence of immunity to varicella. It is also recommended in older premature infants
(28–36 weeks) whose mothers do not have a history of chickenpox or varicella
vaccination (seronegative). Some experts recommend administration of VariZIG
to term infants who have been exposed to varicella in the first 2 weeks after birth
and whose mothers do not have evidence of immunity.
B. Infants ≥28 weeks’ gestation born to seropositive (immune) mothers. These
infants should have sufficient transplacental antibodies to protect them from the
risk of complications.
C. Isolation. Exposed infants should be placed in strict isolation (airborne and con-
tact precautions) from 8 until 21 days after the onset of the rash in the index case.
Exposed infants who receive VariZIG/IVIG should be in strict respiratory isolation
for 28 days.
D. Breast feeding. Expressed/pumped milk from a mother with varicella or zoster
can be given to the infant, provided no lesions are on the breast. Breast feeding is
encouraged in infants exposed to or infected with varicella because antibody in
breast milk may be protective.
E. Acyclovir. Recommended for infants who develop breakthrough lesions or prophy-
lactically beginning 7 days after exposure. Therapy should be continued for 7 days
(if used prophylactically) or for 48 hours after the last new lesions have appeared.
VIII. Prognosis. This form of the disease is mild, and death is extremely rare. Normal term
infants who develop postnatal chickenpox have the same risk of complications of chick-
enpox as older children. Premature infants are at increased risk for nosocomial acquisi-
tion of VZV. The risk of complications for infants <28 weeks who develop postnatal
chickenpox is unknown.
154 Zika Virus (Congenital Zika Syndrome)

I. Definition. Congenital Zika syndrome (CZS) is a constellation of central nervous sys-
tem (CNS), ocular, and neuromuscular abnormalities seen in newborns after in utero
exposure to Zika virus, a member of the Flaviviridae virus family (which includes
dengue, yellow fever, and West Nile viruses).

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Gomella_Sec05_p0427_0800.

indd 800 18/10/19 3:23 pm

85 ABO Incompatibility

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B. Anemia. Because of the effectiveness of compensation by reticulocytosis in

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86 Acute Kidney Injury

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asymptomatic infants, respectively, who ultimately develop congenital CMV-

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promise in reducing congenital CMV infection in the fetus in observational and

VIII. Prognosis. Congenital CMV is the leading cause of nonhereditary SNHL. Overall

133 Dengue Infection, Neonatal

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137 Herpes Simplex Viruses

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If infant remains asymptomatic, do not start acyclovir

First-Episode Primary or Recurrent infection Educate family on signs and Go to Figure

Treatment of Infection and Proven Preemptive Therapy of Infection but

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c. Oral acyclovir suppressive therapy is recommended for 6 months after

138 Human Immunodeficiency Virus

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III. Pathophysiology. Rubella typically has an epidemic seasonal pattern of increased

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NEONATAL EARLY ONSET SEPSIS

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IV. Risk factors for neonatal early-onset sepsis

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iv. Neutrophil surface antigens CD11, CD14, and CD64 are promising

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Yes Blood culturesa Yes Blood culturesa

Signs of Predictor Scenario Signs of

Yes after birth GBS specific antibiotics >

have been published previously including the algorithm published by CDC in

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Infant born in association Infant born by induction of Infant born by cesarean

Yes Yes Yes

Blood culturesb Any of the following are present: Approaches included:

(Section VII.C.1). Otherwise, an acceptable approach to these infants is close

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antibiotic toxicity is important, as is monitoring levels of aminoglycosides. When

NEONATAL LATE-ONSET SEPSIS

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B. Invasive procedures/devices. Intravascular catheterization (PICC and umbilical

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symptoms, then intracranial hemorrhage, drug withdrawal, and inborn errors of

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during hospital stay or major disability at 2 years of age. Similarly, administration of

154 Zika Virus (Congenital Zika Syndrome)