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Maternal Chorioamnionitis

Article Last Updated: Dec 20, 2006


AUTHOR AND EDITOR INFORMATION
Section 1 of 10

Author: Michael P Sherman, MD, Professor, Department of Pediatrics, Southern Illinois


University School of Medicine; Professor Emeritus, Department of Pediatrics, University of
California, Davis School of Medicine; Interim Director, Division of Neonatology, Southern
Illinois University School of Medicine; Interim Co-director, South Central Illinois Perinatal
Center, St John's Hospital, Springfield
Michael P Sherman is a member of the following medical societies: American Academy of
Pediatrics, American Association of Immunologists, American Pediatric Society, American
Society for Microbiology, American Thoracic Society, Perinatal Research Society, and
Society for Pediatric Research
Coauthor(s): Katsufumi Otsuki MD, PhD, Chief of Obstetrics, Associate Professor,
Department of Obstetrics and Gynecology, Showa University School of Medicine, Tokyo,
Japan
Editors: Ted Rosenkrantz, MD, Head, Division of Neonatal-Perinatal Medicine, Professor,
Departments of Pediatrics and Obstetrics/Gynecology, University of Connecticut School of
Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska
Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Arun K
Pramanik, MD, MBBS, Professor of Pediatrics, Director of Neonatal Fellowship,
Louisiana State University Health Sciences Center; Carol L Wagner, MD, Professor of
Pediatrics, Medical University of South Carolina; Ted Rosenkrantz, MD, Head, Division of
Neonatal-Perinatal Medicine, Professor, Departments of Pediatrics and
Obstetrics/Gynecology, University of Connecticut School of Medicine
Author and Editor Disclosure

Synonyms and related keywords: maternal chorioamnionitis, acute chorioamnionitis,


neonatal sepsis, maternal and fetal effects of amniotic fluid infection, pregnancy and fetal
infection with bacteria, preterm labor, premature rupture of membranes, epidural
anesthesia, intrapartum fever, abnormal bacterial colonization of the urogenital tract,
ascending amniotic fluid infection, symptomatic chorioamnionitis, early-onset neonatal
sepsis
INTRODUCTION
Section 2 of 10

Background
Newborn nursery personnel commonly call a family practitioner, pediatrician, or
neonatologist when a newborn is admitted and the mother has had an intrapartum fever.
This telephone call often prompts an evaluation to rule out sepsis. As a consequence of
this evaluation and local practice guidelines, each year, for every infant with proven
bacteremia, 10-20 newborns are evaluated and treated with antibiotics. The reason for
this clinical phenomenon is that newborns who develop an early-onset bacterial infection
(disease occurring <72 h after birth) have a high mortality rate.
Frequent clinical evaluations of neonates for early-onset sepsis began in the 1970s when
group B streptococcal (GBS) infections resulted in a neonatal mortality rate approaching
50%. In the past 30 years, a heightened awareness of bacterial infection in neonates,
chemoprophylaxis to prevent GBS infections, and improvements in supportive care have
considerably reduced the risk of neonatal infection and death from early-onset neonatal
sepsis. The dilemma for the physician is in determining whether the neonate is truly at risk
for localized (eg, bacterial pneumonia, meningitis) or systemic (eg, bacteremia) infection.
Early-onset bacterial infections in the newborn may occur when the mother has abnormal
bacterial colonization of the urogenital tract, an ascending but silent amniotic fluid
infection, or symptomatic chorioamnionitis. Thus, the physician cannot assume that
maternal symptoms may be used to identify all infected infants. Currently, two new
challenges face the physician who must diagnose and treat mothers and their infants with
infections. GBS infections are no longer the predominant cause of early-onset neonatal
sepsis; that honor now goes to gram-negative organisms (Stoll, 2005). In addition,
methicillin-resistant Staphylococcus aureus, already a common cause of nosocomial
infection in maternity and neonatal units (Bratu, 2005), looms as a major cause of earlyonset neonatal sepsis.
This review summarizes the history, physical examination, and laboratory findings in both
mother and infant to provide appropriate decision-making tools for cost-effective
management of the neonate born to a mother with suspected chorioamnionitis. For
readers who wish to read additional reviews, the September 2005 issue of Clinics in
Perinatology is devoted to infectious diseases in pregnancy (Hollier, 2005). Several

chapters in that monograph contain current information on the pathophysiology of


chorioamnionitis and its adverse consequences in the mother, fetus, and newborn.

Pathophysiology
Abnormal bacterial colonization of the rectum and anus during pregnancy may create an
abnormal vaginal and cervical microbial environment. More than 2 decades ago,
rectovaginal colonization with GBS during pregnancy was found to be associated with this
bacterium infecting either the fetus or the newborn. Studies have demonstrated that other
types of bacteria residing in the vagina, cervix, or both ascend through intact or ruptured
fetal membranes and initiate amniotic fluid infection.
Urinary tract infection during pregnancy can bathe the vagina with bacterial pathogens
and is a recognized risk factor for neonatal sepsis. Bacterial vaginosis has been
recognized as an important cause of premature labor, although overt infection of the
neonate with microbes causing bacterial vaginosis may occur infrequently. Treatment of
bacterial vaginosis may prevent preterm birth, but it has not yet been proven in clinical
studies.

Frequency
United States
Incidence of maternal chorioamnionitis in the US population cannot be stated with
accuracy. Studies from the United Kingdom, Australia, and the United States have
reported a 6-14% incidence of villitis. Villitis does not indicate placental infection, only
inflammation. Textbooks of obstetrics generally state that chorioamnionitis occurs in 1% of
all deliveries. This is likely a conservative incidence.
Among lower-income socioeconomic populations or certain groups with associated risk
factors (eg, illicit drug users) in the United States, incidence of maternal chorioamnionitis
is expected to be higher. Defining an exact incidence of maternal chorioamnionitis is also
problematic because histologic or microbiologic examination of the placenta and fetal
membranes may not confirm classic signs and symptoms of the disease. However,
maternal chorioamnionitis is a common problem that either initiates labor (and preterm
delivery) or occurs during the intrapartum period.
Maternal chorioamnionitis is more commonly observed in prolonged labor and prolonged
rupture of the fetal membranes. Prolonged rupture is considered the highest risk factor
related to the pathogenesis of maternal chorioamnionitis.
Most agree that infection is directly or indirectly associated with 40-60% of preterm births
(Newton, 2005).

International
Most Western countries probably have an incidence equal to or perhaps less than that
observed in the United States. In the 1970s, the classic studies of R. L. Naeye, MD,
demonstrated that malnourished pregnant women in Africa had a higher risk of ascending
urogenital infection with subsequent amniotic fluid infection. This process increased the
risk of fetal infection and perinatal death. The pathophysiology of the amniotic fluid
infection in these malnourished women was attributed to a decrease in host defense
factors regularly present in the amniotic fluid.
In developing countries where women receive suboptimal care and nutrition during
pregnancy, a higher incidence of maternal chorioamnionitis and amniotic fluid infection is
expected. Chorioamnionitis and amniotic fluid infection result in more fetal and neonatal
deaths from bacterial infection.

Mortality/Morbidity
Maternal mortality from chorioamnionitis is rare, but morbidity and hospital costs are
substantial in this disease. The same is not true for the neonate. In the 1970s, the
neonatal mortality rate from GBS infections approached 50%. Currently, Escherichia coli,
GBS, and other bacteria that cause early-onset infection in newborn infants carry a
mortality rate of 5-25%. A higher rate of death is associated with GBS infection in more
prematurely born infants.
Early-onset neonatal infection associated with ampicillin-resistant E coli disease carries a
high mortality rate. This appears to be an emerging problem as a consequence of
intrapartum ampicillin chemoprophylaxis to prevent GBS infections in the neonate. Thus,
for caregivers attempting to prevent neonatal GBS infection with intrapartum
chemoprophylaxis, obstetric infectious disease experts have recommended penicillin
rather than ampicillin.

Race
Race alone does not appear to increase the risk of maternal chorioamnionitis and
neonatal sepsis. This is not true if one considers environmental circumstances that result
in inadequate care (Berenson, 1994; Turner, 1996) or malnutrition (Scholl, 1998; Romero,
2003) during pregnancy. For more information on this issue, see the work of A. Prentice,
PhD, and colleagues, based in Gambia.

Sex
Sex plays an important role in neonatal infection (St Geme, 1984). Along with prematurity
and prolonged rupture of the fetal membranes, male sex is a known risk factor for
neonatal sepsis.

Age
Maternal age alone has not been identified as a risk factor for chorioamnionitis. However,
lifestyle activities associated with teenage pregnancy may increase the risk of bacterial
vaginosis, urinary tract infection, or ascending urogenital infection. The degree of
prematurity or birth at earlier gestational age increases the incidence of fetal and neonatal
bacterial infection when maternal chorioamnionitis is present.

CLINICAL
Section 3 of 10

History

The time-honored clinical signs and symptoms of chorioamnionitis include the


following:

o
o
o
o
o
o

Fever (an intrapartum temperature >100.4F or >37.8C)


Significant maternal tachycardia (>120 beats per minute [bpm])
Fetal tachycardia (>160 bpm)
Purulent or foul-smelling amniotic fluid or vaginal discharge
Uterine tenderness
Maternal leukocytosis (total blood leukocyte count >15,000-18,000 cells/L)
Of these criteria, intrapartum maternal fever appears to be the most frequent; other
findings, such as fetal tachycardia, may be less important in the absence of
maternal fever.
When at least 2 of the aforementioned criteria are present, the risk of neonatal
sepsis is increased.
An increasing total leukocyte count may be more important than a single
determination. Abnormalities in either umbilical vein interleukin-6 (IL-6) levels or an
increasing neonatal immature-to-total neutrophil ratio, along with clinical criteria for
chorioamnionitis, improve the sensitivity and predictive accuracy of identifying the
septic neonate.
Risk of neonatal infection increases as the duration of ruptured membranes
lengthens. Chorioamnionitis may initiate uteroplacental bleeding or a placental
abruption. Labor and delivery may be rapid in the presence of chorioamnionitis.
Alternatively, infection may cause uterine atony, requiring labor to be augmented
with oxytocin (Pitocin). Ultimately, a poor labor pattern may require an instrumented
delivery or a cesarean delivery. Each of these antepartum and intrapartum factors
must be considered when evaluating the newborn for the presence of bacterial
infection.

Physical
Physical examination of the pregnant woman with chorioamnionitis may reveal no signs or
symptoms of infection. Conversely, a pregnant woman with chorioamnionitis may appear
ill, even toxic.

Physical symptoms may include the following:

o
o
o
o
o
o
o

Fever
Tachycardia (>120 bpm)
Hypotension
Diaphoresis
Cool or clammy skin
Uterine tenderness
Foul-smelling or abnormal vaginal discharge
The fetus may also have tachycardia, and a biophysical profile (BPP) performed on
the fetus using ultrasonography may reveal a lower than normal score.
Conditions falsely simulating chorioamnionitis include the following:

Clinical signs and symptoms of chorioamnionitis are not always associated


with placental evidence of inflammation. This is particularly true if maternal
fever is the sole criterion for the diagnosis.
Epidural anesthesia during the intrapartum period has been
associated with fever in the mother and the neonate (Lieberman,
1997; Lieberman, 2000); however, the pathophysiology of the fever
and its adverse effects on the mother, fetus, or infant remains
controversial (Vallejo, 2001; Leighton, 2002; Goetzl, 2002; Alexander,
2005).
Epidural anesthesia and maternal and/or neonatal fevers result in
more evaluations for sepsis and antibiotic treatment in neonates,
although the incidence of sepsis compared with that in a neonatal
population whose mothers did not receive epidural anesthesia during
labor is unknown. Epidural anesthesia during labor is associated with
other types of neonatal morbidity that are also risk factors for sepsis.
Although the exact mechanisms for this phenomenon remain unclear,
nulliparity, dysfunctional labor, prolonged labor, maternal exhaustion,
dehydration, and/or prolonged rupture of membranes may result in
this condition.
In the setting of epidural anesthesia during labor, the following clinical course
has been observed. The fetus usually has tachycardia when the mother is
febrile during labor. At birth, the newborn may also have a fever
(temperature >37.8 C). If the neonate is not septic, the temperature
elevation dissipates rapidly following birth, and the newborn subsequently
exhibits normal behavior. Furthermore, these noninfected, febrile neonates
have normal Apgar scores and appear remarkably well following birth. Such

newborns can be observed for illness rather than undergoing a septic


workup and antibiotic therapy. However, judgment must be based on many
factors, including the intrapartum administration of broad-spectrum
antibiotics to the mother.
Maternal chorioamnionitis increases the potential that the following clinical
presentations may be evident in the neonate. Signs and symptoms of neonatal
sepsis are often nonspecific and subtle. The neonate may demonstrate behavioral
abnormalities such as lethargy, hypotonia, weak cry, and poor suck. Specific organ
involvement may manifest as follows:

Tachypnea, respiratory distress (eg, expiratory grunt, retractions), cyanosis,


pulmonary hemorrhage, and/or apnea (ie, pulmonary manifestations of
pneumonia, sepsis, or both), must be appreciated by caregivers
immediately. Nursery personnel must be aware that a neonate who is born
without respiratory distress but who develops signs and symptoms of
pulmonary disease in the first hours of life has a heightened risk for
infectious pneumonia.
o Tachycardia, hypotension, prolonged capillary refill time, cool and clammy
skin, pale or mottled appearance, oliguria (ie, cardiovascular manifestations
of sepsis), or a combination of these may be observed. Caregivers must also
consider other explanations for these physical findings, such as
developmental defects in the cardiovascular system or inborn errors of
metabolism.
o Abdominal distension, vomiting, diarrhea, bloody stools, or a combination of
these may be observed. GI symptoms may be nonspecific in patients with
early-onset bacterial disease.
o Thermal regulatory abnormalities (hypothermia or hyperthermia), behavioral
abnormalities, apnea, seizures (CNS manifestations), or a combination may
be seen. A bulging fontanel or nuchal rigidity is not a reliable sign of
meningitis in a neonate.
o Pallor, petechiae or purpura, and overt bleeding (hematopoietic involvement,
liver involvement, or both) may be seen.
As one physiologic system may affect another, signs and symptoms may originate
from more than one dysfunctional organ system. However, many neonatal
conditions resemble neonatal sepsis; thus, physician caregivers must have an open
mind regarding other clinical conditions that may involve signs and symptoms
resembling neonatal sepsis. Those conditions include, but are not limited to, the
following:

o
o

o
o

Cardiovascular malformations, especially left-sided obstructive lesions


causing poor systemic cardiac output
Endocrine disorders that may also cause shocklike states, such as different
types of congenital adrenal insufficiency or hypoglycemia associated with
hyperinsulinemia
Serious CNS trauma or dysfunction from any cause
Anemia caused by unrecognized isoimmunization or blood loss from

conditions such as fetomaternal transfusion syndrome

Causes
Maternal chorioamnionitis occurs when several protective mechanisms of the urogenital
tract and uterus fail during pregnancy (Otsuki, 1999; Hein, 2002; King, 2003; Akinbi, 2004)
or when increased numbers of microbial flora or highly pathogenic flora are introduced into
the genital environment.

Ascending infection into the vagina, then the cervix, and finally into the uterine
cavity, fetal membranes, and placenta is the consequence of many factors (ie,
innate host defenses, healthy bacterial flora, bacterial burden, bacterial
pathogenetic factors). Recently, a short cervix has been recognized as either a risk
factor or a surrogate for microbial invasion of the amniotic fluid (Gomez, 2005;
Hassan, 2006).
Urogenital hygiene is obviously important in establishing healthy bacterial flora.
Healthy bacteria (ie, lactobacilli; Wilks, 2004) and natural peptide antibiotics in the
vagina and cervix may have a role in preventing infections during pregnancy (Balu,
2003). Mucus, phagocytes, and humoral factors (ie, lactoferrin, lysozyme, beta
defensins) in the cervicovaginal secretions attempt to maintain a normal bacterial
flora (Hein, 2002). Bacterial interference, mainly produced via lactobacilli living in
an acid environment and producing bacteriocins, also helps to keep pathogenic
bacteria from gaining a foothold in the cervicovaginal secretions (Simoes, 2001;
Reid, 2002). These mechanisms of host protection may be altered in a significant
number of pregnant women who develop chorioamnionitis.
Oral hygiene may influence rectal and urogenital bacterial flora during pregnancy.
Although the theory is controversial, intense interest has focused on a connection
among periodontitis, abnormal rectal colonization, and preterm delivery (McGaw,
2002; Urban, 2006).
Rectal bacterial flora is believed to be important in establishing abnormal urogenital
colonization during pregnancy (Matorras, 1989; Sanchez, 1990; Spiegel, 1991).
Alterations in vaginal and cervical host defense mechanisms during pregnancy
cause vaginitis (Donder, 2002), bacterial vaginosis, urinary infections, and other
urogenital infections. Currently, researchers are thoroughly investigating host
defense mechanisms that prevent urogenital infection during pregnancy.
Orogenital contact may also alter either colonic or urogenital microbial flora and
ultimately cause ascending infection and chorioamnionitis (Dixon, 1994; Hansen,
1996). Similarly, coitus has been linked with chorioamnionitis (Naeye, 1982; Yost,
2006).
Clinical events associated with chorioamnionitis include the following:

o
o
o
o

History of premature birth (with increasing risk at earlier gestational age)


Presence of premature labor
Prematurely ruptured fetal membranes
Prolonged rupture of the fetal membranes
In a recent report of patients with clinical signs and symptoms of chorioamnionitis,

38% showed no histologic evidence of placental inflammation. Thus, other causes


of signs and symptoms that may resemble maternal chorioamnionitis must be
sought.
Epidural anesthesia during labor may be associated with maternal fever and fetal
tachycardia (see Special Concerns). Other conditions, such as dehydration or
maternal exhaustion during labor, may result in maternal fever and must be
considered as causes of the febrile state.

DIFFERENTIALS
Section 4 of 10

Herpes Simplex Virus Infection


Urinary Tract Infection

Other Problems to be Considered


Urinary tract infections (particularly cystitis)
Vaginitis and cervicitis
Sexually transmitted diseases that cause pelvic infection and inflammation
Viral infections (eg, urogenital disease caused by herpes simplex virus)
Pelvic inflammatory disease
Pelvic adenitis (eg, herpes simplex, enteroviral infections [eg, coxsackievirus])

WORKUP
Section 5 of 10

Lab Studies

During the intrapartum period, diagnosis of chorioamnionitis is usually based on the


clinical criteria. This is particularly true for pregnancies at term.
Bacteriologic cultures of amniotic fluid and urogenital discharge may be diagnostic
for causative pathogens. Investigators have suggested that obtaining cervical
cultures is associated with an increased risk of initiating amniotic fluid infection in
the presence or absence of ruptured membranes. Silent chorioamnionitis is
recognized as an important cause of premature labor.
The asymptomatic pregnant mother who presents with premature labor or
premature rupture of the membranes may require certain studies to exclude silent
chorioamnionitis. To diagnose silent or obvious amniotic fluid infection or
chorioamnionitis, the physician often uses laboratory examinations of the amniotic
fluid, maternal blood, maternal urine, or a combination.

Examination of amniotic fluid and urogenital secretions involves the following:

Amniotic fluid, obtained with amniocentesis, may be screened for leukocyte


count, Gram stain, pH, glucose concentration, endotoxin, lactoferrin,
cytokine levels (eg, IL-6), or a combination of these.
o The cytokines commonly quantified in either the amniotic fluid or the blood
include IL-6, tumor necrosis factor-alpha, interleukin-1 (IL-1), and interleukin8 (Figueroa, 2005; Hagberg, 2005). No consensus exists regarding which
cytokine offers the best sensitivity, specificity, and positive versus negative
predictive accuracy, although IL-6 is most often cited in the literature.
Elevated IL-6 levels in cord blood and amniotic fluid have been related to
adverse long-term neurologic outcomes in the neonate (Volante, 2004;
Kayem, 2005).
o Polymerase chain reaction (PCR) has rapidly developed as a diagnostic aid.
It is used to identify microbes such as human immunodeficiency virus,
cytomegalovirus, herpes simplex, parvovirus, toxoplasmosis, and bacterial
DNA in amniotic and other body fluids. PCR has been used for the diagnosis
of amniotic fluid infection caused by bacterial pathogens (Straka, 2004).
o Amniocentesis to obtain amniotic fluid carries the risk of rupturing the fetal
membranes. For this reason, screening tests that use cervicovaginal
secretions to indicate chorioamnionitis have been reported. Potential
markers of cervical or chorion inflammation include cervicovaginal secretion
concentrations of fetal fibronectin, insulinlike growth factor binding protein-1,
and sialidase. Significant association exists among levels of cervical IL-6,
fetal fibronectin, and amnionitis.
o Antenatal screening examinations demonstrate that the presence of GBS
colonization increases the risk of chorioamnionitis, and intrapartum
prophylaxis with antibiotics reduces the incidence of neonatal infection from
GBS. Intrapartum screening for GBS using the rapid Streptococcus B test on
vaginal secretions identifies more at-risk infants than any other test. The use
of the rapid screen for GBS to select mothers who would receive intrapartum
chemoprophylaxis may also reduce the cost by approximately $12,000 per
prevented case of neonatal infection.
Examinations of maternal blood

White blood cell (WBC) counts or C-reactive protein (CRP) levels in


maternal blood have commonly been used to predict acute chorioamnionitis
when maternal fever is present. Different studies have supported or refuted
the use of CRP to diagnose chorioamnionitis (Shim, 2005; Wiwanitkit, 2005).
The CRP level may be a better predictor of the risk of chorioamnionitis than
peripheral WBC counts, especially if the mother has received
corticosteroids, which may falsely increase the total WBC count.
Other investigators have suggested that the alpha1-proteinase inhibitor
complex in maternal blood is a better predictor of amniotic fluid infection than
either CRP or WBC count.
o

Analyzing amniotic fluid for leukocytes appears to be a better


predictor of amniotic fluid infection than levels of either CRP or total
WBC count in maternal blood. In fact, the combination of leukocytosis
and a low glucose concentration in the amniotic fluid is highly
indicative of chorioamnionitis and may be the best predictor of this
condition.
Analysis of maternal serum for either IL-6 or ferritin content may also
be helpful, because elevations in these mediators are associated with
maternal or neonatal infection. Serum IL-6 levels may be more
predictive than CRP concentrations in maternal blood.
Alpha1-proteinase inhibitor complex, cytokines, and ferritin in
maternal blood have not gained widespread use as markers of acute
chorioamnionitis.
The criterion standard for making a diagnosis of early-onset bacteremia,
pneumonia, or meningitis in the neonate is the growth of bacteria in an appropriate
specimen (ie, blood, tracheal secretions, cerebrospinal fluid [CSF]). Urinary tract
infection is an infrequent cause of early-onset bacterial disease in the neonate;
thus, suprapubic bladder taps are not usually required as part of the evaluation
(Visser, 1979; Sherman, 1984).

In recent years, controversy has arisen regarding the inclusion of the lumbar
puncture as part of the evaluation for sepsis. Some clinicians have argued
that the neonate with meningitis has obvious manifestations, and the
asymptomatic term neonate does not require a lumbar puncture as part of
the evaluation for sepsis.
o Other investigators have stressed that cases of meningitis may be missed
with this approach (Wiswell, 1995). The medical literature contains good
evidence that meningitis may exist in association with sterile blood cultures.
As meningitis can be such a devastating infection and sterile blood culture in
association with no lumbar puncture may result in inadequate therapy for
meningitis, a lumbar puncture should continue to be performed as part of the
evaluation for neonatal sepsis.
Studies that are also considered specific for infection include positive findings on
Gram stains of CSF or tracheal secretions (Sherman, 1980).

The tracheal secretions must be obtained shortly after birth (<4-8 h). Both
tracheal fluids and CSF should be sterile at birth. The presence of bacteria
upon microscopic analysis (Gram stain) indicates that more than 10,000
colony-forming units of bacteria are present per milliliter of specimen (body
fluid). However, the absence of bacteria in either CSF or tracheal secretions
does not exclude infection. A final diagnosis should be made after culture
results are available.
An absence of neutrophils in CSF or tracheal secretions is expected. The
presence of neutrophils in tracheal aspirates obtained after birth indicates
that the fetus has mounted an inflammatory response to infection in the
environment.

Studies by the primary author and separate studies by pathologists indicate


that neutrophils present in tracheal secretions shortly after birth originate
from the fetus or neonate and do not represent aspirated maternal
neutrophils found in infected amniotic fluid. This conclusion is based on
examining Y-body fluorescence of the neutrophils present in the tracheal
secretions of infected male neonates. In some studies, 50% of the
neutrophils present in tracheal secretions of infants with suspected
congenital pneumonia had Y-chromosome fluorescence, indicating a fetal
origin.
o Conversely, 10% of neutrophils in gastric aspirates from the same infants
had Y-chromosomal fluorescence. Thus, neutrophils in gastric aspirates are
primarily maternal neutrophils, and they represent WBCs present in infected
amniotic fluid that is swallowed by the fetus. Alternatively, the flux of fetal
airway fluid is outward from the lung. Maternal neutrophils can gain access
to the fetal lung only when gasping occurs during fetal asphyxia. The male
neutrophils observed in the gastric aspirates of these infants with congenital
pneumonia indicated that neutrophils were swallowed after they left the fetal
lung via the outward flux of airway fluid.
Bacterial antigen detection in CSF is also a useful test to indicate bacterial
infection. Bacterial antigen detection in the urine should not be a part of the
neonate's evaluation for sepsis. Many factors can cause false-positive or falsenegative test results in bacterial antigen detection in the urine. Surface cultures
have no role in decision-making regarding the diagnosis and treatment of the
neonate with early-onset bacterial infection.
All other tests used to diagnose early-onset bacterial infection in the neonate
should be considered screening tests. The most common laboratory studies used
to screen for neonatal sepsis are WBC profiles and CRP determinations. These
tests, at best, are presumptive indicators of infection.
o

WBC profiles (leukopenia [<5000/L], leukocytosis [>30,000/L], a markedly


diminished absolute neutrophil count [<500-1500/L], an immature-total
neutrophil ratio [>0.3-0.4]) are a commonly used screening test for the septic
neonate. Note that the immature-to-total neutrophil ratio of 0.3-0.4 is higher
than the previous value of 0.2 reported in the classic studies of Manroe
(1977, 1979). Clinical pathologists have been less accepting of the
immature-to-total neutrophil ratio as a diagnostic aid in neonatal sepsis
(Cornbleet, 2002). Other diagnostic tests (eg, inflammatory factors, adhesion
molecules, cytokines, neutrophil surface antigens, or even bacterial DNA)
may be superior alternatives to this test.
WBC profiles and kinetics are influenced by the genetic makeup of the
patient, the gestational age, maternal noninfectious disorders such as
pregnancy-induced hypertension (PIH), medications administered to the
mother, fetal disease, and many other factors. Reference-range WBC counts
in the neonate do not exclude infection, and serial studies of WBC indices at
approximately 6-hour intervals may be more useful in detecting sepsis. A
continued assessment of WBC kinetics offers more information regarding

decision making. For example, a physician should be particularly concerned


when a falling total WBC count, a declining absolute neutrophil count, and a
rising immature-to-total neutrophil ratio are observed. This finding may
indicate depletion in the bone marrowrelated storage pool of neutrophils.
The predictive accuracy of WBC indices for the diagnosis of the septic
neonate is poor. Likewise, the accuracy of CRP determinations to predict
neonatal infections shortly after birth is low. However, persistently negative
findings on CRP may be useful in the decision to stop antibiotic therapy after
48 hours (Benitz, 1998).
Akin to maternal diagnostic studies for infection, alpha1-proteinase inhibitor
complex, cytokines (eg, IL-1 and IL-6 in particular, IL-1 receptor antagonist),
and detection of bacterial products in neonatal blood have not gained
widespread use as markers of neonatal sepsis. However, they may prove to
have better predictive accuracy than WBC tests or CRP. Procalcitonin may
have better sensitivity, specificity, and positive and negative predictive value
than CRP in the diagnosis of early-onset neonatal sepsis (Joram, 2006).

Imaging Studies

Ultrasonography may be used to ascertain fetal well-being. A BPP provides


information about the status of the fetus. A low BPP score, and especially the loss
of fetal breathing movements, has been associated with fetal bacterial infection
after premature rupture of membranes (Vintzileos, 1985; Vintzileos, 1986). Other
investigations have not confirmed the importance of a low BPP score, and
specifically the absence of fetal breathing, as a reliable test for amnionitis prior to
32 weeks' gestation (Sherer, 1997; Ghidini, 2000).
Before the fetus is viable, vaginal ultrasonography has been used to identify
women with a shortened cervical canal, which has been associated with a higher
risk of preterm delivery. Researchers are still investigating how a shortened cervical
canal and an ascending urogenital infection may interact to initiate premature labor,
premature rupture of the membranes, or both.

Other Tests

The common tests used to diagnose maternal chorioamnionitis are discussed


above. Tests still in investigational stages are not included in this review.

Procedures

Needle aspiration and analysis of amniotic fluid is the only invasive procedure used
to confirm diagnosis of acute chorioamnionitis (see Examination of amniotic fluid
and urogenital secretions). This procedure can be risky with intact fetal
membranes, because the fetal membranes can rupture during or after the
procedure. Bleeding or placental abruption can also be a consequence of the

procedure. Perform the procedure using ultrasonographic guidance to avoid fetal


injury. For these reasons, aspiration of amniotic fluid to diagnose maternal
chorioamnionitis has had limited application in obstetric practice.

Histologic Findings
Gross and microscopic examinations of the placenta, fetal membranes, and umbilical cord
for evidence of inflammation and infection are crucial to make a definitive diagnosis of
chorioamnionitis. Anatomic studies should be correlated with an aseptic culture obtained
from the fetal surface of the placenta. The microbiologic cultures should include an
attempt to isolate aerobic and anaerobic bacteria. When specific types of infections are
suspected, perform an appropriate corresponding examination of the placenta. Only in this
way can the pathologist help the bedside clinician delineate the cause of maternal
chorioamnionitis and neonatal sepsis. These studies are infrequently performed.
Clinicians are encouraged to ask pathologists for help in their search for infections causing
disease in the pregnant woman, fetus, and newborn.

TREATMENT
Section 6 of 10

Medical Care
This section addresses 2 topics. The first topic includes maternal interventions to treat
suspected chorioamnionitis and, in doing so, therapy that protects the fetus and newborn
from infection. The second topic includes the reasons, the diagnostic approach, and the
appropriate treatment in neonates born to mothers with suspected chorioamnionitis.
The observation that epidural anesthesia during labor may create findings suggestive of
maternal chorioamnionitis is discussed. A maternal fever that occurs when epidural
anesthesia is used during the intrapartum period has been interpreted as chorioamnionitis.
This may not be the case, and the neonate is needlessly treated after birth.
Another discussion addresses the problems of using ampicillin chemoprophylaxis to
prevent GBS disease in the neonate. Ampicillin-resistant E coli infections in the mother
and her infant are reported as an increasing problem. The use of penicillin as the
chemotherapeutic agent to prevent GBS infections of the newborn is encouraged.

Obstetric management influencing neonatal outcome

When acute chorioamnionitis is evident, delivery must be expedited. Upon


signs of serious fetal distress, delivery must be emergent. Withholding
maternal antibiotics to obtain postnatal cultures from the neonate is not

appropriate. This was once an accepted practice based on the assumption


that waiting to obtain cultures from the newborn would help to delineate the
cause of infection. The morbidity and mortality in the mother and newborn
may actually increase because of these delays. Studies suggest that
obtaining cultures from the mother and beginning antibiotics before delivery
improves the outcome for the neonate.
o The physician who cares for such neonates must then decide whether the
fetus was infected and whether pretreatment with antibiotics before birth
should be continued. The history, physical examination findings, and findings
of certain laboratory studies can assist the physician in deciding whether to
continue antibiotics started during the intrapartum period. Because antibiotic
chemoprophylaxis reduces the risk of GBS infection in neonates, the
physician must always consider beginning penicillin during the intrapartum
period when a mother has defined risk factors for GBS disease. The
physician for the infant must judge whether the chemoprophylaxis was
sufficient to prevent infection (especially in a healthy, full-term neonate) or
whether the infant must continue antibiotic therapy after birth. The 2006 Red
Book provides a paradigm for evaluation and treatment on pages 620-627.
o Determining the appropriate procedures in the setting of preterm labor,
prelabor, or premature rupture of membranes is more complex. The mother
who has preterm labor or premature rupture of membranes and no clinical
signs or symptoms of chorioamnionitis should receive prophylactic
antibiotics and corticosteroid therapy. The cutoff postconceptual age (eg, 34,
36, or 37 completed weeks' gestation) at which the physician should use
intrapartum antibiotics is unclear. However, such an approach enhances the
latent phase before labor begins and allows time for the corticosteroids to
have beneficial effects in the fetus. Certainly, patients with preterm labor or
premature rupture of membranes at 36 weeks' gestation or less should
receive prophylactic antibiotics. Mothers at term gestation with accepted risk
factors for GBS infection in their fetus should also receive
chemoprophylaxis.
o Some obstetricians have observed little effect of corticosteroids on lung
maturity after 32 weeks' gestation, while others have extended the use of
corticosteroids to 34 weeks' gestation. Studies have not clearly
demonstrated that the use of corticosteroids increases the risk of bacterial
infection in the fetus, but this issue remains controversial.
Maternal antibiotic prophylaxis to prevent infection (risks vs benefits to the fetus
and newborn)

The use of intrapartum penicillin or ampicillin is now a recognized therapy to


prevent fetal infection or early-onset neonatal infections associated with
urogenital colonization by GBS (Apgar, 2005).
In 1994, Amstey and Gibbs recommended that penicillin G rather than
ampicillin be administered to the mother for the prevention of early-onset
neonatal GBS disease. Their rationale was that penicillin G
chemoprophylaxis would not result in colonization of the urogenital tract with

ampicillin-resistant gram-negative bacteria. This assumption now seems


correct based on recent reports of neonatal deaths caused by ampicillinresistant E coli.
o Akin to the recommendations of Amstey and Gibbs, a recent report showed
an increased occurrence of infections caused by ampicillin-resistant E coli in
premature neonates (Alarcon, 2004; Gibbs, 2004). These mothers had
received ampicillin for chemoprophylaxis rather than penicillin, and these
authors again recommended use of intrapartum penicillin to prevent fetal or
early-onset neonatal infections with GBS.
Neonatal immunology and the risks created by maternal chorioamnionitis

Newborns are vulnerable to infection because of an immature or


underdeveloped immune system. Factors that render neonates susceptible
to bacterial infections include reduced numbers and/or function of
macrophages and dendritic cells in peripheral tissues (eg, lung); lower
numbers of neutrophils in the bone marrow storage pool; decreased
immunoglobulin G (IgG) and complement levels, especially in prematurely
born infants; an inability to respond to bacterial carbohydrate antigens; an
increased percentage of T cells bearing nave cell surfaces and
correspondingly underdeveloped functional behaviors related to foreign
antigens; and anatomic and biochemical immaturity of skin and mucosal
barriers (eg, lung, gut epithelia) as they relate to local host defenses.
o Emerging treatments, such as the use of intravenous immunoglobulins and
hematopoietic growth factors, may correct deficiencies of the neonatal
immune system. However, the mainstays of current neonatal intensive care
for bacterial sepsis in neonates continue to be prompt recognition of
bacterial infection, antimicrobial therapy, and supportive care.
Communication between obstetric and pediatric caregivers is essential to recognize
neonatal infection.

Recognition or suspicion of maternal chorioamnionitis is essential to


reducing neonatal morbidity and mortality caused by early-onset bacterial
infections in the neonate. Nurses and physicians who care for the mother
must communicate their concerns about maternal infection to the nurses and
physicians who care for the newborn after birth. Likewise, caregivers in the
nursery must be aware of a neonate's signs and symptoms in relationship to
the antepartum and intrapartum history.
Signs and symptoms in the mother that suggest chorioamnionitis and
increase the risk of fetal or neonatal infection are described in Physical.
Although numerous ways to approach the diagnosis and treatment of
neonatal sepsis exist, a hands-on assessment is the main key to recognition.
The experienced physician or nurse in the nursery may indicate to fellow
caregivers that the newborn has a septic appearance.

Surgical Care

Surgical interventions are required infrequently in early-onset bacterial infections of the


neonate. The conditions that may require intervention include epidural or brain abscess,
subcutaneous abscesses, infections localized to the pleural space, certain intra-abdominal
infections (especially if intestinal perforation is present), and bone or joint infections.

Consultations
Depending on the hospital setting and the status of the neonate, a family physician may
seek a pediatric consultation. Depending on the severity of infection and other neonatal
diseases and the hospital in which the newborn is located, the pediatrician may seek
consultation with a neonatologist, a pediatric infectious disease subspecialist, or both. If
organ system failure is present or impending organ system failure (eg, respiratory,
cardiovascular, renal) secondary to infection is a concern, the infant should be transferred
to an appropriate level 3 or level 4 neonatal intensive care unit (NICU). Transportation to a
level 3 or 4 NICU is clearly indicated for extremely premature infants requiring highfrequency oscillatory ventilation or near-term or term neonates nearing criteria for
extracorporeal membrane oxygenation (ECMO).

Diet
Seriously or critically ill newborns with early-onset bacterial infections require parenteral
fluids and nutrition until their condition improves. Infections involving the GI tract may need
a special approach to feeding when feedings are reinstituted.

MEDICATION
Section 7 of 10

Early delivery, supportive care, and antibiotic administration for the mother with
chorioamnionitis are discussed in Medical Care. The antibiotics used most often to treat
mothers with acute chorioamnionitis are also discussed briefly. The treatment of bacterial
vaginosis is also discussed above; however, antibiotic therapy for this condition is not
often successful (Boggess, 2005; Shennan, 2006).
Because of maternal chorioamnionitis, the treatment of the potentially septic neonate is
complex. An overview of the treatment for early-onset neonatal infection is summarized in
Medical Care.
Maternal antibiotics for chorioamnionitis
The standard drug treatment in the mother with chorioamnionitis includes clindamycin and

an aminoglycoside (usually gentamicin). Ampicillin may replace clindamycin or be used in


addition if the mother is not allergic to penicillin. In cases involving premature labor or
premature rupture of membranes, ampicillin is frequently administered as a
chemotherapeutic agent to prevent GBS colonization of the fetus. The use of penicillin
alone is suggested for GBS chemoprophylaxis during the intrapartum period. Using
penicillin rather than ampicillin may avoid colonization of the fetus with ampicillin-resistant
E coli. The rationale for ampicillin use when maternal chorioamnionitis is suspected is that
ampicillin would treat GBS, Haemophilus species, most enterococci strains, and Listeria
species. If a urinary tract infection is present, the appropriate antibiotic(s) should be used
to treat the specific bacterium isolated from the urine.
Clindamycin may treat S aureus and anaerobes. Gentamicin provides broad-spectrum
coverage against gram-negative bacteria. These antibiotics should be administered
intravenously. The aforementioned drugs are generally safe for mother and fetus. An
absolute contraindication in using these antibiotics is a known allergic reaction to them.
Renal function must always be considered when using antibiotics, especially
aminoglycosides.
Erythromycin is infrequently used in women allergic to penicillin. Its ability to enter
urogenital secretions has been questioned, especially in the treatment of Ureaplasma
urealyticum colonization in pregnant women. Of the GBS strains that are currently
isolated, 10-15% are resistant to either clindamycin or erythromycin. This suggests that
erythromycin or clindamycin used as chemoprophylaxis to prevent GBS infection in
neonates born to women with penicillin allergy may not always be successful.
Dosages of antibiotics to treat maternal chorioamnionitis are not provided, because this is
a pediatric review addressing maternal chorioamnionitis as it affects the newborn infant.
Supportive, immune, and antibiotic therapy of early-onset bacterial infection
An extensive discussion of the management of septic neonates is not possible in this
review. Critical points to ensure intact survival of the neonate are mentioned for
completeness. For example, ventilator management and surfactant replacement therapy
can be used to treat the neonate with congenital bacterial pneumonia, but a complete
discussion of the techniques involved in this therapy are covered in other articles.
Physicians and nurses attending the delivery of a newborn whose mother is suspected of
having chorioamnionitis should be ready to perform a full resuscitation, including
intubation, providing positive-pressure ventilation, and treatment of hypovolemia, shock,
and acidosis. Low Apgar scores may be another indicator of sepsis. After initial
stabilization of a neonate with potential infection in the delivery room, direct attention
toward the following variables that influence survival:

Warmth, monitoring of vital signs, and maintenance of fluid and electrolyte balance
Glucose homeostasis
Treatment of respiratory distress that may entail surfactant replacement (for

pneumonia, respiratory distress syndrome) and assisted ventilation


Correction of metabolic acidosis and hypovolemia and maintenance of optimal
myocardial performance with inotropic drugs (These factors are often intertwined
with respiratory problems.)
Assessment and treatment of coagulopathy, if present

The aforementioned elements of supportive care are essential to reducing morbidity and
mortality. When myocardial dysfunction, cardiovascular collapse, and severe pulmonary
hypertension are not reversible, ECMO may be a life-saving intervention. In critically ill
septic neonates, the importance of early referral for ECMO cannot be overstated.
Pulmonary hypertension can complicate the management of neonatal sepsis, and inhaled
nitric oxide may reverse this complication. The use of inhaled nitric oxide in a non-ECMO
facility may be problematic. This is particularly true if the septic neonate deteriorates and
must be transferred to an ECMO facility while on inhaled nitric oxide therapy. The referring
facility may not have the capability to provide inhaled nitric oxide during transport to the
ECMO facility. In this circumstance, the seriously ill infant may become critically ill with the
cessation of inhaled nitric oxide therapy during transport. Therefore, guidelines for referral
to an ECMO center should be established for each NICU based on the center's own
resources and ability to safely transport such infants.
Guidelines for immunotherapy in early-onset bacterial infections are not well established.
Treatments used currently or described previously include administration of granulocyte or
granulocyte-macrophage colony-stimulating factors (eg, filgrastim, sargramostim),
intravenous administration of IgG (particularly a high-titer IgG antibody against a specific
bacterial pathogen), and leukocyte transfusions for depletion of neutrophils in the bone
marrow storage pool.
Immunotherapy recommendations are beyond the scope of this review. A neonatologist,
pediatric infectious disease subspecialist, or both should be consulted if immunotherapy is
contemplated.
Antibiotic therapy for early-onset bacterial infection of the neonate usually includes the
administration of a penicillin (ampicillin is most often used for additional coverage against
Haemophilus species and listeriosis), and an aminoglycoside (usually gentamicin) is most
often used for ample gram-negative bacterial coverage. The newer cephalosporins should
be used as part of the antibiotic regimen if resistant E coli is suspected based on maternal
history, amniotic fluid cultures, and the clinical picture. Antibiotic administration in
newborns is based on birth weight criteria and gestational age at birth. Doses of antibiotics
change with increasing postnatal age and improving renal function.
Final decisions about antibiotics should be based on positive culture results from
appropriate anatomic sites. If renal dysfunction exists, antibiotic dosages should be
adjusted during the course of their administration. This is particularly true for
aminoglycoside administration in extremely premature newborns and in newborns with
urogenital anomalies.

Recommendations on the appropriate antibiotic dose can be found in neonatology


handbooks (ie, Neonatology: Management, Procedures, On-Call Problems, Diseases, and
Drugs or Manual of Neonatal Care) and textbooks. Specific textbooks about antibiotic use
in pediatric patients, including neonates (ie, Nelson's Pocketbook of Pediatric
Antimicrobial Therapy), have also been written. The 2006 Red Book also has
recommendations for antibiotic therapy for neonatal infections. For this review, the 2006
Neofax was used for selecting the dose per kilogram and interval between the
administration of doses for specific antibiotics.
Lastly, the physician must consider the duration of antibiotic therapy. This is particularly
true when deciding the duration of antibiotic treatment for well-appearing term neonates.
In the era of managed care, in which cost reductions are typical, discontinuing antibiotics
in healthy term neonates within 48 hours of initiating therapy is probably safe. With current
bacteriologic techniques, more than 90-95% of neonatal blood cultures become positive
within 48 hours of the time they are obtained. In conjunction with screening tests, such as
a negative CRP determination at 48 hours after birth, discontinuing antibiotic treatment
and discharging the well-appearing term neonate by 2 days after birth would be
appropriate.
In neonates with proven infection, the well-being of the infected newborn should guide the
duration of antibiotic therapy. The bacterium causing the infection and the site of the
infection also influence the duration of antibiotic therapy. For example, bacterial
pneumonia is often treated for 7-10 days with antibiotics. Bacteremia is often treated with
antibiotics for 10-14 days. Because of the potential for recurrence with shorter courses of
treatment, 10 days of antibiotics is often considered a minimum for GBS-associated
bacteremia.
CSF infections may require antibiotic therapy for 2-4 weeks based on the bacterium
responsible for the infection, findings on an analysis of CSF indicating the resolution of
infection, and the presence of complications associated with meningitis. For
uncomplicated GBS-related infections of the CSF, 2 weeks may be sufficient; other grampositive and all gram-negative bacteria require 3-4 weeks of antibiotic therapy (2006 Red
Book). Surgical interventions for localized CNS infections (eg, epidural, brain abscess) or
the presence of postinfectious hydrocephalus may indicate antibiotic therapy needs to be
significantly extended (>4 wk).
The following information reviews the antibiotics that are commonly used to treat earlyonset bacterial infections in the neonate. The antibiotics covered are not exhaustive. For
example, the use of clarithromycin to treat congenital pneumonia caused by Urealyticum
in extremely premature newborns and the use of vancomycin to treat catheter-related
nosocomial bacteremia are not reviewed. Issues related to these and other specific
bacterial infections of neonates require consultation with a neonatologist or pediatric
infectious diseases subspecialist.

Drug Category: Antibiotic agents


Empiric antimicrobial therapy must be comprehensive and should cover all likely
pathogens in the clinical setting. Antibiotic combinations are usually recommended for
serious gram-negative bacillary infections. This approach ensures coverage for a broad
range of organisms and polymicrobial infections. In addition, it prevents resistance from
bacterial subpopulations and provides additive or synergistic effects. Once organisms and
sensitivities are known, the use of antibiotic monotherapy is then recommended.
Drug Name

Ampicillin (Marcillin, Omnipen, Polycillin)

Description

A more broad-spectrum aminopenicillin used for many years as


either a definitive or a prophylactic therapy for early-onset bacterial
infection of neonates. May provide additional coverage against
Haemophilus species, many enterococci, other streptococci,
Listeria monocytogenes, and a limited number of susceptible
gram-negative enteric bacteria. Indicated for neonatal bacteremia
or meningitis due to GBS.

Pediatric Dose

Bacteremia: 50 mg/kg/dose IV/IM q12h


Meningitis or severe GBS infections: 100-200 mg/kg/dose IV q12h;
in early-onset infections before 44 wk of gestation, the dosing
interval for ampicillin is q12h; for GBS infections, some experts
recommend using penicillin G at doses of 200,000 U/kg/d for
bacteremia and 450,000 U/kg/d for meningitis
IV administration and dividing the daily dose into 2 injections 12 h
apart is the preferred route of drug delivery

Documented hypersensitivity; anaphylactic shock mediated by


Contraindications penicillin-related allergy (rare in neonates); bacterial resistance to
ampicillin (use other antibiotics)

Interactions

Admixture incompatibilities include amikacin, amiodarone,


erythromycin lactobionate, fat emulsion, fluconazole, gentamicin,
hydralazine, metoclopramide, midazolam, nicardipine, and
tobramycin; check for solution compatibility (ie, compatible with 5%
dextrose, 10% dextrose, normal saline) and terminal injection site
compatibility via Y-site administration (ie, compatible with dextrose
and amino acid solutions, fat emulsion; see Neofax, 2006)

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Rapid administration of high doses can cause seizures;


morbilliform or blotchy rash related to ampicillin infrequently
observed (must rule out cytomegalovirus infection as cause for this
type of rash); thrush or diaper dermatitis caused by a secondary
infection with Candida species is particularly common with
ampicillin-related use; diarrhea secondary to ampicillin occurs
occasionally because of its effects on the intestinal flora of

newborns (also consider antibiotic-related colitis as a cause of


diarrhea); drug fever, serum sickness, or reduced leukocyte or
platelet numbers (caused by bone marrow suppression or
idiopathic) are rare with ampicillin
Drug Name

Penicillin G (Pfizerpen) or benzylpenicillin

Description

Do not confuse with benzathine or procaine penicillin used only for


IM injections; it is the original antibiotic in the penicillin class.
Recommended for treatment of GBS infections. May provide
adequate coverage for Streptococcus pneumoniae when it is a
cause of early-onset bacterial infection in neonates (infrequent).
Other modified penicillins such as oxacillin or nafcillin
(antistaphylococcal), netilmicin (antipseudomonal and gramnegative enteric bacteria), and piperacillin (antipseudomonal) are
not typically used as first-line antibiotics for treatment of earlyonset neonatal infections. The aforementioned modified penicillins
are designed to treat infections caused by penicillin-resistant
bacteria that can express beta-lactamase. These modified
penicillins are usually reserved for the treatment of postnatally
acquired infections in hospitalized neonates. Methicillin-resistant
staphylococcal infections have emerged in pregnant women, and
reports of their neonates having early-onset infections
with these staphylococci are beginning to appear; such infections
would require treatment with vancomycin (see Neofax, 2006 or
other antibiotic handbooks for administration guidelines for
antibiotics).

Pediatric Dose

Bacteremia: 25,000-50,000 U/kg/dose IV infused over 15 min or


IM
Meningitis: 75,000-100,00 U/kg/dose IV infused over 30 min or IM;
before 44 wk of gestation, the dosing interval is q12h for earlyonset neonatal infections;
For GBS infections, some experts recommend using penicillin G at
doses of 200,000 U/kg/d IV divided q12h for bacteremia and
450,000 U/kg/d IV divided q12h for meningitis

Documented hypersensitivity; anaphylactic shock mediated by


Contraindications penicillin-related allergy (rare in neonates); bacterial resistance
(use other antibiotics)

Interactions

Incompatible as admixture with amikacin, aminophylline,


amphotericin B, gentamicin, hydralazine, metoclopramide,
netilmicin, and tobramycin; check for solution compatibility (ie,
compatible with 5% dextrose, 10% dextrose, normal saline) and
compatible at terminal injection via Y-site (ie, compatible with
dextrose and amino acid solutions, fat emulsion); see Neofax 2006
and other antibiotic handbooks for additional information

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Adverse effects include allergic rashes related to penicillin G (rare


in neonates); drug fever, serum sickness, or reduced leukocyte or
platelet numbers (caused by bone marrow suppression or
idiopathic) are rare with penicillin G

Drug Name

Cefotaxime (Claforan)

Description

A third-generation cephalosporin with enhanced potency against


many gram-negative bacteria. Generally considered inactive
against enterococci, Listeria, and most strains of pseudomonads
and bacteroides. Effective; some experts consider this antibiotic
the preferred therapy for neonatal meningitis caused by gramnegative bacteria if the bacterium is sensitive to it (in conjunction
with an aminoglycoside). This preference is based on more
effective CNS penetration of cefotaxime. Indicated when
aminoglycosides may be contraindicated (eg, significant renal
failure) or when aminoglycosides may have enhanced toxicity.

Pediatric Dose

50 mg/kg/dose IV q12h infused over 30 min or IM; before 44 wk of


gestation, the dosing interval is q12h;

Documented hypersensitivity (absolute contraindication but


extremely rare in neonates); bacterial resistance (use other
Contraindications antibiotics); presence or potential for severe renal dysfunction (eg,
extreme prematurity, severe birth asphyxia, known and severe
renal malformations)

Interactions

May increase the nephrotoxicity of aminoglycosides and loop


diuretics (eg, furosemide; compatible with 5% dextrose, 10%
dextrose, normal saline); terminal injection at Y-site
incompatibilities include aminophylline, fluconazole, sodium
bicarbonate, and vancomycin; see 2006 Neofax and other
antibiotic handbooks for terminal site incompatibilities (ie,
compatible via Y-site injection with dextrose and amino acid
solutions, fat emulsion)

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Third-generation cephalosporins may alter microbial flora on


mucosal surfaces (thus, oral infections and genital dermatitis with
Candida species must be identified and treated promptly); the
routine use of cefotaxime rather than an aminoglycoside in
evaluations to rule out neonatal sepsis or in prolonged treatment of
proven or unproven gram-negative bacterial infections may result
in the emergence of gram-negative bacterial flora in NICUs that
are resistant to multiple cephalosporins; pain may be more intense
after IM injection of cephalosporins; cephalosporins may cause
thrombophlebitis during IV administration; cefotaxime can cause
antibiotic-related pseudomembranous colitis (eg, infections caused
by Clostridium difficile); adjust dose in severe renal insufficiency

(high doses may cause CNS toxicity)


Drug Name

Gentamicin (Garamycin)

Description

Although available during the past 30 years, gentamicin is


considered one of the newer aminoglycoside antibiotics along with
amikacin, netilmicin, and tobramycin. Generally, gentamicin has
activity against Pseudomonas aeruginosa, whereas kanamycin
does not. First choice for prophylactic or definitive therapy of earlyonset bacterial infections in neonates because it has broad activity
against many gram-negative bacilli. Amikacin and tobramycin are
usually reserved to treat nosocomial infections caused by gramnegative bacteria that are resistant to gentamicin.
Aminoglycosides should not be used alone to treat infections
potentially caused by gram-positive bacteria. Thus, penicillin is
always included in the treatment of early-onset bacterial infections
in neonates. Furthermore, to prevent the emergence of highly
antibiotic-resistant gram-negative bacteria, nosocomial infections
in hospitalized neonates should never be treated with an
aminoglycoside alone. A second antibiotic should be administered
in addition to the aminoglycoside, and its mechanism of action that
causes microbial death should be different from that of the
aminoglycoside.
Elevated blood concentrations of aminoglycosides may cause
significant injury to the kidney, the eighth cranial nerve, or both.
Thus, peak and trough levels of aminoglycosides in neonatal sera
must be measured if their use is going to exceed an initial period
of prophylaxis (48 h after birth) to exclude sepsis.
Aminoglycosides demonstrate concentration-dependent killing of
bacteria, suggesting a potential benefit related to higher serum
concentrations that are achieved with less-frequent dosing (eg,
daily administration).

Pediatric Dose

Postmenstrual age < 29 weeks: 5 mg/kg IV q48h during the first 7


d of life
Postmenstrual age 30-34 weeks: 4.5 mg/kg IV q36h during the first
7 d of life
Postmenstrual age >35 weeks: 4 mg/kg IV q24h during the first 7 d
of life
IV administration is preferred because IM doses have variable
absorption, especially in extremely preterm infants; infuse
gentamicin IV over 30 min

Contraindications Documented hypersensitivity


Interactions

Antipseudomonal penicillins may decrease serum aminoglycoside


concentrations, especially if renal failure is present;
coadministration with other aminoglycosides, cephalosporins,
penicillins, and amphotericin B may increase nephrotoxicity;

aminoglycosides enhance effects of neuromuscular blocking


agents (eg, pancuronium, magnesium sulfate)and prolonged
respiratory depression may occur; coadministration with loop
diuretics may increase auditory toxicity of aminoglycosides;
possible irreversible hearing loss of varying degrees may occur
(regularly monitor blood levels of the aminoglycoside); compatible
with 5% dextrose, 10% dextrose, normal saline and terminal
injection Y-site compatibility with dextrose and amino acid
solutions and fat emulsion; see Neofax 2006 or other antibiotic
handbooks for compatibilities when injecting into other drug
solutions; incompatible with amphotericin B, ampicillin, cefepime,
furosemide, imipenem/cilastatin, heparin (>1 U/mL), indomethacin,
methicillin,mezlocillin,
nafcillin, oxacillin, penicillin G, propofol, and ticarcillin/clavulanate
Pregnancy

Precautions

Bacterial resistance mandates selection of another


aminoglycoside, cephalosporin, a beta-lactamaseresistant
penicillin, or a combination for therapyWith treatment after 48
hours, monitor a serum peak (obtain 30 min after a dose is given)
and a serum trough level (just prior to the next dose); with
prolonged therapy, determine what peak levels of gentamicin the
hospital laboratory considers therapeutic and what trough levels
are considered toxic; ask the pharmacist for recommendations in
changing the dose and/or the interval of gentamicin when peak
and/or trough levels of gentamicin are out of range; monitor
urinalysis and serum BUN and creatinine concentrations for signs
of nephrotoxicity (abnormalities in these test results are late signs
of aminoglycoside-related nephrotoxicity) based on increased
urinary concentrations of enzymes released from renal epithelial
cells; aminoglycoside-related toxicity occurs long before
abnormalities in the urinalysis or blood BUN/creatinine
concentration are
presentWell-appearing neonates who have negative bacterial
culture results and normal CRP levels in blood usually do not
require treatment with antibiotics 48 h after birth.

FOLLOW-UP
Section 8 of 10

Further Inpatient Care

Both the mother with suspected chorioamnionitis and her newborn with rule-out

sepsis require frequent assessments over the first 48 hours following birth. Mothers
with chorioamnionitis who appear well after a brief intravenous course of antibiotics
may be discharged on oral antibiotic therapy, but thorough outpatient follow-up care
is required. Usually, general and gynecologic health is normal after maternal
chorioamnionitis.
Term neonates undergoing an evaluation to exclude sepsis who consistently
appear well can probably go home with their mothers within 48 hours after birth.

Further Outpatient Care

Depending on the nature of the infection and other risk factors associated with the
hospitalization (eg, extreme prematurity, need for home oxygen), an outpatient
follow-up visit may be scheduled from 1 day to 2 weeks after discharge. Home
health care follow-up visits by a reliable and well-trained nursing service may also
be indicated.

In/Out Patient Meds

Outpatient antibiotics used to treat a term neonate with rule-out sepsis have not
been evaluated. Some managed care plans have discharged neonates with proven
infection who appear well after antibiotic therapy. These newborns complete a
course of intravenous antibiotics at home. The intravenous antibiotics are often
administered via a percutaneous venous line placed before hospital discharge. A
visiting nurse comes to the home to administer the antibiotics twice daily.
Depending on the type of infection found in the neonate, the duration of intravenous
therapy with antibiotics ranges from 7 days to 4 weeks.

Transfer

Infected neonates born at hospitals with level 1 (normal) or level 2 (special care)
nurseries may require transfer to a level 3 or 4 NICU. Transfer depends on the
circumstances of the neonatal infection, degree of prematurity, presence of
anomalies, and other disease states. Reasons for transfer of the neonate from a
level 1 or 2 nursery to a higher-level facility are outlined in Consultations. Transfer
requirements such as oxygen or assisted ventilation, mode of transportation (eg,
ambulance, helicopter, fixed wing aircraft), and health care personnel to transport
the patient are beyond the scope of this article.

Deterrence/Prevention

Maternal antibiotic prophylaxis, especially as it relates to GBS colonization in


pregnant women, is discussed above (see 2006 Red Book for recommendations on
intrapartum chemoprophylaxis for GBS colonization). In a 2006 review, Romero
proposed that control of intrauterine inflammation will improve neonatal outcome in
the future.

Complications

For the mother with chorioamnionitis, serious infectious complications include


endometritis, localized pelvic infections requiring drainage, and intra-abdominal
infections. Maternal chorioamnionitis or other secondary infectious complications
may cause thrombosis of pelvic vessels and the potential for pulmonary emboli.
Serious complications, including septic shock, pulmonary hypertension, respiratory
failure, and meningitis, occur in early-onset bacterial infections of the neonate. The
duration of hospitalization can be quite prolonged in an extremely premature infant
because of infectious complications such as maternal chorioamnionitis or
congenital pneumonia. Either condition increases the probability of chronic lung
disease in prematurely born and term babies.

Prognosis

The outcome of neonatal infections depends on the causative organism, nature of


infection, time of infection onset to administration of appropriate therapy, symptoms
at time of birth, and gestational age of the infant. Prematurity and birth defects are
cofactors that must be considered when a prognosis is offered to parents or
caregivers of an infected newborn. When each of these factors is considered, a
prognosis may be provided.
Outcome may not be evident during the neonatal period, and long-term follow-up
care is indicated in these infected neonates; thus, referring these infants to a
neonatal follow-up clinic after discharge is prudent. Provided that parental
permission is obtained, records of the neonatal course must be readily available to
physicians in the future.

Patient Education

Parents or other caregivers of infected neonates need specific instructions about


their subsequent care. This is particularly true for secondary complications
associated with these infections. For example, in patients with meningitis that has
caused postinfectious hydrocephalus requiring a ventriculoperitoneal shunt,
caregivers must be provided with specific instructions about shunt malfunctions or
infection. Similarly, caregivers of patients with long-term pulmonary complications
of congenital pneumonia may require specific education (eg, administration of
oxygen or bronchodilators at home). Parental education in neonatal resuscitation is
indicated in most cases.

MISCELLANEOUS
Section 9 of 10

Medical/Legal Pitfalls

In the United States, medicolegal actions are always a threat to health care
professionals. This is particularly true for obstetricians and neonatologists. If the
diagnosis and treatment of obvious sepsis or meningitis are missed in the neonate,
physicians, other health care professionals, and the hospital face significant
medicolegal risk.
The initial signs and symptoms of neonatal infections may be subtle or absent; they
may be followed by a rapid and fulminant course.
The potential for severe disability or death as a consequence of neonatal bacterial
infection has resulted in the treatment of 1 infected infant out of 20 infants who
received initial therapy but had no proven disease.
The evaluation to exclude sepsis is a classic example of the difficulty in
differentiating infants with infection from those who are not infected. Antibiotic
therapy for early-onset neonatal sepsis is a classic example of family practitioners
and pediatricians practicing defensive medicine.
The importance of chorioamnionitis takes on added medicolegal significance
because several carefully controlled studies demonstrate an association between
intrauterine infection and cerebral palsy in term infants (Shalak, 2002; Wu, 2003).
The relationship has also been demonstrated in the preterm infant (Grether, 2003;
Graham, 2004). The legal profession now sees an opportunity for litigation, and
attorneys are filing frivolous lawsuits that suggest earlier antibiotic therapy would
have mitigated cerebral palsy.
A 20-year review of factors associated with professional liability in a single NICU
has recently been published. This publication indicates the paucity of information
on this subject in the neonatology literature.

Special Concerns

Epidural anesthesia

Labor may be prolonged by epidural anesthesia, and mothers who receive


this type of anesthesia may become dehydrated and exhausted. These
women may develop an elevated temperature; in turn, their fetus may have
an increased heart rate associated with epidural anesthesia and maternal
fever. The presence of maternal fever and fetal tachycardia initiate an
investigation of the cause, and the obstetrician often administers antibiotics
thereafter.
Fever associated with epidural anesthesia in the absence of
chorioamnionitis can be confirmed based on placental histology and
microbiologic culture findings. Typically, newborns appear and act healthy
when epidural anesthesiarelated fever occurs in mothers and their babies.
The temperature rapidly returns to normal in babies without infection.
Controversy exists regarding conducting an evaluation for sepsis in
neonates with this history. Some pediatricians or family practitioners may

elect to perform an evaluation for sepsis and treat for 48-72 hours with
antibiotics pending the culture results. Controversy also exists regarding
performing a lumbar puncture as part of every evaluation for sepsis in a wellappearing term newborn who may be bacteremic. In cases involving a
mother who had epidural anesthesia and an elevated temperature during
labor, many pediatricians and neonatologists may not perform a lumbar
puncture as part of the evaluation for sepsis.
Summary: This article is an introduction to the topic of bacterial infections during
pregnancy and subsequent bacterial infections of the fetus and newborn. The
subject is expansive in scope, and readers are encouraged to seek more
information from other sources. Other articles of interest include Congenital
Pneumonia; Meningitis, Bacterial; and Neonatal Sepsis.

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Maternal Chorioamnionitis excerpt

Article Last Updated: Dec 20, 2006