Neonatal Sepsis - StatPearls - NCBI Bookshelf https://www.ncbi.nlm.nih.

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Neonatal Sepsis
Meenakshi Singh; Mahdi Alsaleem; Cory P. Gray.

Author Information
Last Update: March 3, 2021.

Continuing Education Activity

Neonatal sepsis refers to an infection involving bloodstream in newborn infants less than 28 days
old. It continues to remain a leading cause of morbidity and mortality among infants, especially in
middle and lower-income countries. It is divided into early-onset sepsis (EOS) or late-onset
sepsis (LOS) based on the age of presentation after birth with different experts using 72 hours or
7 days as the cutoff. This activity describes the treatment and evaluation of neonatal sepsis and
explains the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the etiology of early and late onset neonatal sepsis.

• Describe various clinical and laboratory findings associated with neonatal sepsis

• Review the various treatment and management options available for neonatal sepsis.

• Explain the importance of improving care coordination amongst interprofessional team

members to improve outcomes for neonates affected by sepsis.

Access free multiple choice questions on this topic.

Introduction
Neonatal sepsis refers to an infection involving the bloodstream in newborn infants less than 28
days old. It remains a leading cause of morbidity and mortality among neonates, especially in
middle and lower-income countries [1]. Neonatal sepsis is divided into two groups based on the
time of presentation after birth: early-onset sepsis (EOS) and late-onset sepsis (LOS). EOS refers
to sepsis in neonates at or before 72 hours of life ( some experts use seven days), and LOS is
defined as sepsis occurring at or after 72 hours of life [2].

Etiology
Early-onset sepsis(EOS) is generally caused by the transmission of pathogens from the female
genitourinary system to the newborn or the fetus. These pathogens can ascend the vagina, the
cervix, and the uterus, and can also infect the amniotic fluid. Neonates can also become infected
in utero or during delivery as they pass through the vaginal canal. Typical bacterial pathogens for
EOS include Group B streptococcus (GBS), Escherichia coli, coagulase-negative Staphylococcus,
Haemophilus influenza, and Listeria monocytogenes. Maternal factors that increase the risk of
neonatal sepsis include chorioamnionitis, GBS colonization, delivery before 37 weeks, and
prolonged rupture of membranes greater than 18 hours [3].

Late-onset sepsis (LOS) usually occurs via the transmission of pathogens from the surrounding
environment after delivery, such as contact from healthcare workers or caregivers. A percentage
ofLOS may also be caused by a late manifestation of vertically transmitted infection. Infants
requiring intravascular catheter insertion, or other invasive procedures that disrupt the mucosa,
are at increased risk for developing LOS.

Preterm neonates are at higher risk for sepsis/infection than term neonates. The increased
susceptibility for infections seen in preterm neonates is mainly due to :

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• Deficient immune system, mainly due to decreased IgG antibodies and incompetent
opsonization and complement activation

• Comprised innate immune system, caused primarily by the immature epithelial barrier

• The increased need for invasive devices ( vascular access, endotracheal tube, feeding tubes
and uriarny tract catheters) due to associated severe illnesses

Coagulase-negative staphylococcal species, especially Staphylococcus epidermis, is the leading

cause, responsible for greater than 50% of LOS cases in industrialized countries. However, many
other bacterial and viral pathogens can be associated with LOS [3].

Epidemiology
The epidemiology of neonatal sepsis has been changing with time [4]. The incidence of EOS has
decreased since the 1990s due to the introduction of universal screening of group B streptococcus
(GBS) in pregnant women and intrapartum antibiotic prophylaxis (IAP) [5]. However, rates of
LOS have remained relatively the same. Escherichia coli now accounts for more cases of
EOS [6]. In the United States, the incidence of EOS with positive blood cultures is estimated to
be 0.77 to 1 per 1,000 live births [7][8]. Due to the nonspecific neonatal presentation for sepsis
and the high risk of mortality and morbidity without treatment, many asymptomatic neonates
undergo a sepsis workup if risk factors are present and/or clinically indicated. Although
approximately 7% to 13% of all neonates are worked up for sepsis, only 3% to 8% have positive
cultures [3]. Maternal administration of antibiotics and the low blood volume obtained for blood
culture could explain the low rate of positive blood cultures. The incidence of sepsis is
significantly higher in premature infants, as well as those with very low birth weight (<1000
grams). African American infants have an increased risk of GBS and LOS, likely secondary to
the higher rate of GBS carrier rates in African American females. Males have a higher risk of
sepsis and meningitis, especially with gram-negative enteric bacilli [3].

Pathophysiology
The immature immune system is the major contributing factor for increased neonatal
susceptibility to sepsis. The immature function of polymorphonuclear neutrophils, macrophages,
and T lymphocytes makes these cells incapable of carrying out a complete inflammatory response
in neonates. Furthermore, neonates have a limited number of immunoglobulins at birth and
cannot generate a quantitative and/or qualitative adequate mounting response against infectious
agents. The insufficient time that premature has in the uterus decrease the transfer of immune
globulins to the fetus. This deficiency in immunoglobulins makes premature infants at much
higher risk for sepsis when compared to term infants [9].

History and Physical

Signs and symptoms of neonatal sepsis can range from nonspecific or vague symptoms to
hemodynamic collapse. Early symptoms may include irritability, lethargy, or poor feeding. Others
may quickly develop respiratory distress, fever, hypothermia or hypotension with poor perfusion
and shock. Sometimes the diagnosis may only be suspected on the basis of laboratory findings,
which may reveal hyperglycemia or hypoglycemia, acidosis, or hyperbilirubinemia. A high index
of suspicion is, therefore, necessary for timely diagnosis. Therefore, physicians must be aware of
any factors that may increase an infant’s risk of developing sepsis. Prematurity and very low
birth weights are also important risk factors to consider. Maternal factors that put neonates at risk
of early-onset sepsis include GBS status, the presence of chorioamnionitis, infant prematurity, or
prolonged rupture of membranes [3]. For late-onset infection, consider whether the patient has
indwelling foreign bodies such as a central venous catheter or endotracheal tube, is dependent on
parenteral nutrition, or receives proton-pump inhibitor or histamine-2 blocking therapy.

Evaluation

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Neonates with bacteremia can be asymptomatic and have a normal physical examination. Thus
laboratory testing plays an important role in diagnosis. In a neonate with suspected sepsis, blood
culture should be immediately drawn. It is recommended to draw at least 1 ml of blood as low-
level bacteremia may not be detected with smaller aliquotes [10]. Cultures should also be drawn
from the catheter site if one is in place. Urine cultures are usually not recommended for
evaluation of EOS but should be considered for evaluation of LOS [11]. Lumbar puncture with
cerebrospinal fluid (CSF) analysis and culture should be evaluated in any infant with positive
blood culture or if the neonate has a clinical presentation that suggests central nervous system
involvement. Lumbar puncture should be repeated within 48 hours of therapy to confirm sterility
of the CSF. New technology using polymerase chain reaction (PCR) is currently being studied as
a diagnostic tool to identify sepsis and the causative organism faster than blood cultures [12]

CSF analysis may reveal:

• Elevated protein level

• Elevated WBC

• Positive cultures

• Decreased glucose concentration

• Positive PCR

Complete blood count (CBC) with differential and C-reactive protein (CRP) are also important
lab tests to obtain and are often collected on a serial basis. These indices are poor at identifying
neonatal sepsis but are better used for ruling it out [10]. Neutropenia has better specificity than
neutrophilia as a marker of neonatal sepsis [13]. Elevated immature to total neutrophil (I/T)ratio
of more than 0.27 has a very high negative predictive accuracy (99%) but an inadequate positive
predictive value (25%) as it may be elevated in up to 50% of uninfected infants [14][15]. These
counts may be falsely elevated, especially after birth. It is better to perform CBC 6 to 12 hours to
avoid the normal physiological CBC parameters' changes seen immediately after delivery[16].

CRP levels start rising within 6 to 8 hours during an infectious episode in neonates and peak at
about 24 hours [17]. Persistently normal CRP levels provide strong evidence against bacterial
sepsis. This good correlation can be used to support the clinical judgment of stopping antibiotics
in an otherwise well-appearing neonate. Other inflammatory markers, including procalcitonin,
haptoglobin, and cytokines, can also be obtained to support the diagnosis or evaluate treatment
efficacy. Radiography of the chest may be performed to look for any pulmonary findings in a
neonate with respiratory symptoms or signs.

Treatment / Management
Empiric treatment with antibiotics should be started as soon as sepsis is clinically suspected, even
without confirmatory lab data. In general, antimicrobial resistance patterns of common bacteria in
the neonatal intensive care unit should guide antibiotics' initial choice. Typical treatment
regimens include intravenous (IV) ampicillin and aminoglycosides to cover for the most common
pathogens in EOS (GBS, E. coli, and L. monocytogenes) [10]. With LOS, nosocomial coverage
should be provided for the hospital-acquired pathogens such as coagulase-
negative Staphylococcus, S. aureus, and Pseudomonas species. It is recommended to start these
patients on a combination of vancomycin and an aminoglycoside [18]. Aminoglycosides have
poor CNS penetration; for that reason, a third-generation cephalosporin should be considered if
CNS infection is suspected [19]. However, ceftriaxone should be avoided, as it can lead to
hyperbilirubinemia and the serious precipitation of calcium-ceftriaxone crystals. Increasing
antibiotic resistance is a concern for neonatal sepsis. Antibiotics stewardship teams play an
essential role in preventing the unjustified prolonged use of antibiotics [20].

Differential Diagnosis

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Given the nonspecific signs of neonatal sepsis, several differentials must be considered, including
but not limited to:

• Infection due to other agents ( virus, fungal or parasite)

• Congenital heart disease

• Neonatal encephalopathy

• Metabolic disease

• Prematurity and associated complications ( respiratory distress syndrome, intraventricular

hemorrhage, apnea of prematurity, and others)

• Hypo or hyperthyroidism

• Transient tachypnea of the newborn

• Meconium aspiration

• Hypoglycemia

Treatment Planning
The treatment regimen for neonatal sepsis varies based on various risk factors and conditions.
The typical antibiotics used are discussed above. The duration of therapy can vary based on the
isolated organisms, type of the infection, the presence of any neonatal complications. Neonates
with positive blood cultures typically respond to treatment within 24 to 48 hours, and repeat
cultures and studies are usually negative by 72 hours [3]. Persistent positive blood cultures should
alert the clinicians to a seeding focus that should be managed ( central venous access, cardiac
vegetations, abscess or osteomyelitis). Many providers would continue intervenous therapy for 7
to 14 days based on the organism, or longer if meningitis was suspected [18]. Increasing the
duration of antibiotics may be necessary for some situations. Increasing the incidence of
antibiotic resistance necrotizing enterocolitis or death are two crucial principles that should
motivate the clinicians to tailor the antimicrobial therapy if clinically indicated[21].

The treatment for suspect EOS with negative cultures is also variable. Cultures can be negative
for various reasons, including maternal antibiotic use, initiation of antibiotics prior to obtaining
cultures, or false-negative tests. Determining adequate antibiotic therapy without any positive
cultures can make the determining duration of therapy difficult. Most neonates with highly
suspected clinical sepsis with negative culture will receive 7-10 days of antimicrobial
therapy [3].

Prognosis
Mortality rates are inversely proportional to gestational age, such that preterm or younger
neonates have higher mortality rates than do term neonates [22]. E. coli has also been found to be
associated with a higher mortality rate when compared with GBS. As noted above, the
introduction of GBS intrapartum antibiotic prophylaxis has decreased mortality rates caused by
GBS. The treatment of clinically suspected neonates with negative cultures has also significantly
decreased mortality rates.Preterm infants with sepsis may develop impaired neurodevelopment.
Also, others may have vision impairment. Those infants pretreated with aminoglycosides may
also develop ototoxicity and nephrotoxicity.

Complications
Neonatal sepsis remains a significant contributor to morbidity and mortality in neonates.
Prematurity and delayed treatment are commonly associated with adverse outcomes. VLBW
infants have been found to have a higher risk of chronic lung disease, and extremely low birth
weight (ELBW) infants are at a greater risk of neurodevelopmental risks, such as hearing and

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visual deficits, cerebral palsy, and impaired psychomotor and mental development [23]. On the
other hand, the unnecessary overuse of antibiotics can increase the chances of severe candidiasis
and multi-drug resistant organisms.

Consultations
Pediatricians or neonatologists can adequately manage neonatal sepsis. However, the following
subspecialties and ancillary services can provide essential support in complicated cases:

• Pediatric surgery: to manage associated surgical complications ( gastrointestinal

perforation, abscess, necrotizing fasciitis, omphalitis, and others)

• Pediatric infectious disease specialist if the infant is not responding to antibiotics, or if

there is concern regarding adequate antimicrobial coverage

• Pediatric pharmacists can provide meaningful input and recommendations about

monitoring trough levels to avoid toxic antibiotic levels

Deterrence and Patient Education

Educating the neonate's family about the disease process and keeping them updated throughout
the treatment process is an integral part of management. Neonatal sepsis is often an unexpected
and scary situation for parents and caregivers. Doctors should be mindful of this and ensure that
parents be informed of all of the tests that must be performed, the importance of each test, and the
results. Any changes in antibiotics or the treatment plan must be communicated to the
parents.Upon hospital discharge, caregivers of all infants, including healthy newborns, should be
educated to watch for signs of illness or sepsis. These may include fever, jaundice, increased
lethargy, a decline in feeding habits, difficulty or increased breathing, and cyanosis of the
fingertips and toes. Caregivers should be informed to call their doctors if their neonate
experiences any of these symptoms, as they could indicate LOS.

Enhancing Healthcare Team Outcomes

Neonatal sepsis is a significant cause of morbidity and mortality in neonates. Attempts to prevent
sepsis's development or progression have been a driving factor for many quality improvement
projects in newborn nurseries and NICUs.Managing such infants is complex and requires
multidisciplinary care approach ( Clinicians, nurses, pharmacies, lactation consultant, and social
worker) supported by medical decisions made during family-based care rounds. Obstetric
physicians are important in ensuring that GBS screening and all other prenatal screening for
infections are performed and adequately treated before and during delivery. Nursery nurses are
also important in preventing and managing neonatal sepsis as they can pick up and detect early
signs of sepsis. In-hospital pediatricians are essential in managing the evolving treatment of
neonatal sepsis and making adjustments as necessary. They are also important in reaching out to
the proper consultants, such as pediatric surgeons and pharmacists. Despite optimal treatment,
neonatal sepsis continues to have high mortality rates and poor outcomes. While the mortality
rates have started to decline, the recovery for most infants is prolonged, and there is a risk for
neurodevelopmental disabilities.

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

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