Neonatal Sepsis

Updated: Jun 13, 2019
  • Author: Nathan S Gollehon, MD, FAAP; Chief Editor: Muhammad Aslam, MD  more...
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Neonatal sepsis may be categorized as early onset (day of life 0-3) or late onset (day of life 4 or later). Of newborns with early-onset sepsis, 85% present within 24 hours (median age of onset 6 hours), 5% present at 24-48 hours, and a smaller percentage present within 48-72 hours. Onset is most rapid in premature neonates.

Early-onset sepsis is associated with acquisition of microorganisms from the mother. Infection can occur via hematogenous, transplacental spread from an infected mother or, more commonly, via ascending infection from the cervix. Organisms that colonize the mother’s genitourinary (GU) tract may be acquired by the neonate as it passes through the colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include the following [1] :

Trends in the epidemiology of early-onset sepsis show a decreasing incidence of GBS disease following the widespread adoption of prenatal screening and treatment protocols. [2, 3, 4]

In a study involving 4696 women, prenatal cultures showed a GBS colonization rate of 24.5%, with a positive culture rate of 18.8% at the time of labor. [5] As many as 10% of prenatally culture-negative women were found to have positive cultures at the time of labor. In the study, intrapartum antibiotic prophylaxis occurred appropriately in 93.3% of cases, with 0.36 of 1000 infants developing early-onset GBS disease. [5]

Late-onset sepsis occurs at 4-90 days of life and is acquired from the environment. Organisms that have been implicated in late-onset sepsis include the following:

  • Coagulase-negative Staphylococcus

  • E coli

  • Klebsiella

  • Enterobacter

  • Candida

  • GBS

  • Serratia

  • Acinetobacter

  • Anaerobes

  • Many additional less-common organisms

Trends in late-onset sepsis show an increase in coagulase-negative streptococcal sepsis, with most isolates showing susceptibility to first-generation cephalosporins. [2] The infant’s skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized via contact with the environment or caregivers.

Pneumonia is more common in early-onset sepsis, whereas meningitis and bacteremia are more common in late-onset sepsis. Early-onset sepsis is 10 to 20 times more likely to occur in premature, very low birthweight infants. [6] Premature infants often have nonspecific, subtle symptoms; considerable vigilance is therefore required in these patients so that sepsis can be identified and treated in a timely manner.

For patient education information, see Sepsis.



The infectious agents associated with neonatal sepsis have changed since the mid-20th century. During the 1950s, S aureus and E coli were the most common bacterial pathogens among neonates in the United States. Over the ensuing decades, Group B Streptococcus (GBS) replaced S aureus as the most common gram-positive organism causing early-onset sepsis.

Currently, GBS and E coli continue to be the most commonly identified microorganisms associated with neonatal infection. Additional organisms, such as coagulase-negative Staphylococcus epidermidis, L monocytogenes, Chlamydia pneumoniae, H influenzae, Enterobacter aerogenes, and species of Bacteroides and Clostridium have also been identified in neonatal sepsis.

Meningoencephalitis and neonatal sepsis can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases (eg, gonorrheasyphilis, herpes simplex virus [HSV] infection, cytomegalovirus [CMV] infection, hepatitis, human immunodeficiency virus [HIV] infection, rubellatoxoplasmosis, trichomoniasis, and candidiasis) have all been implicated in neonatal infection.

Bacterial organisms with increased antibiotic resistance have emerged and have further complicated the management of neonatal sepsis. [7] The colonization patterns in nurseries and personnel are reflected in the organisms currently associated with nosocomial infection. In neonatal intensive care units (NICUs), infants with lower birth weight and younger gestational ages have an increased susceptibility to these organisms.

S epidermidis, a coagulase-negative Staphylococcus, is increasingly seen as a cause of nosocomial or late-onset sepsis, especially in the premature infant, in whom it is considered the leading cause of late-onset infections. Its prevalence is likely related to several intrinsic properties of the organism that allow it to readily adhere to the plastic mediums found in intravascular catheters commonly required for the care of these infants.

The bacterial capsule polysaccharide adheres well to the plastic polymers of the catheters. Also, proteins found in the organism (AtlE and SSP-1) enhance attachment to the surface of the catheter. The adherence creates a capsule between microbe and catheter, preventing C3 deposition and phagocytosis. [8, 9]

Biofilms are formed on indwelling catheters by the aggregation of organisms that have multiplied under the protection provided by the adherence to the catheter. Slimes are produced at the site from the extracellular material formed by the organism, which provides a barrier to host defense as well as to antibiotic action, making coagulase-negative staphylococcal bloodstream infection (BSI) more difficult to treat. The toxins formed by S epidermidis have also been associated with necrotizing enterocolitis.

In addition to being a cause of neonatal sepsis, coagulase-negative Staphylococcus is ubiquitous as part of the normal skin flora. Consequently, it is a frequent contaminant of blood and cerebrospinal fluid (CSF) cultures. When a culture grows this organism, the clinical presentation, colony counts, and the presence of polymorphonuclear neutrophils (PMNs) on Gram staining of the submitted specimen often help differentiate true infection from contaminated culture specimens.

In addition to the specific microbial factors mentioned above, numerous host factors predispose the newborn to sepsis. [10] These factors are especially prominent in the premature infant and involve all levels of host defense, including cellular immunity, humoral immunity, and barrier function. Immature immune defenses and environmental and maternal factors contribute to the risk for neonatal sepsis, morbidity, and mortality, particularly in preterm and/or very low birthweight (VLBW) infants. [10, 11]  There may also be a genetic association. [10]

Cellular immunity

PMNs are vital for effective killing of bacteria. However, neonatal PMNs are deficient in chemotaxis and killing capacity. Decreased adherence to the endothelial lining of blood vessels reduces their ability to marginate and leave the intravascular space to migrate into the tissues. Once in the tissues, they may fail to degranulate in response to chemotactic factors.

Furthermore, neonatal PMNs are less deformable and thus are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. The limited capacity of neonatal PMNs for phagocytosis and killing of bacteria is further impaired when the infant is clinically ill. Finally, neutrophil reserves are easily depleted because of the diminished response of the bone marrow, especially in the premature infant. [12]

Neonatal monocyte concentrations are at adult levels; however, macrophage chemotaxis is impaired and continues to exhibit decreased function into early childhood. The absolute numbers of macrophages are decreased in the lungs and are likely decreased in the liver and spleen as well. The chemotactic and bactericidal activity and the antigen presentation by these cells are also not fully competent at birth. Cytokine production by macrophages is decreased, which may be associated with a corresponding decrease in T-cell production. [13]

Although T cells are found in early gestation in fetal circulation and increase in number from birth to about age 6 months, these cells represent an immature population. These naive cells do not proliferate as readily as adult T cells do when activated, and they do not effectively produce the cytokines that assist with B-cell stimulation and differentiation and granulocyte/monocyte proliferation.

Formation of antigen-specific memory function after primary infection is delayed, and the cytotoxic function of neonatal T cells is 50%-100% as effective as that of adult T cells. At birth, neonates are deficient in memory T cells. As the neonate is exposed to antigenic stimuli, the number of these memory T cells increases.

Natural killer (NK) cells are found in small numbers in the peripheral blood of neonates. These cells are also functionally immature in that they produce far lower levels of interferon gamma (IFN-γ) upon primary stimulation than adult NK cells do. This combination of findings may contribute to the severity of HSV infections in the neonatal period.

Humoral immunity

The fetus has some preformed immunoglobulin (Ig), which is primarily acquired through nonspecific placental transfer from the mother. Most of this transfer occurs in late gestation, such that lower levels are found with increasing prematurity. The neonate’s ability to generate immunoglobulin in response to antigenic stimulation is intact; however, the magnitude of the response is initially decreased, rapidly rising with increasing postnatal age. [14]

The neonate is also capable of synthesizing IgM in utero at 10 weeks’ gestation; however, IgM levels are generally low at birth, unless the infant was exposed to an infectious agent during the pregnancy, which would have stimulated increased IgM production. [15]

IgG and IgE also may be synthesized in utero. Most IgG is acquired from the mother during late gestation. The neonate may receive IgA from breastfeeding but does not secrete IgA until 2-5 weeks after birth. Response to bacterial polysaccharide antigen is diminished and remains so during the first 2 years of life.

Complement protein production can be detected as early as 6 weeks’ gestation; however, the concentration of the various components of the complement system varies widely from one neonate to another. Although some infants have had complement levels comparable to those in adults, deficiencies appear to be greater in the alternative pathway than in the classic pathway. [16]

The terminal cytotoxic components of the complement cascade that lead to the killing of organisms, especially gram-negative bacteria, are deficient. This deficiency is more marked in preterm infants. Mature complement activity is not attained until infants reach 6-10 months of life. Neonatal sera have reduced opsonic efficiency against GBS, E coli, and Streptococcus pneumoniae because of decreased levels of fibronectin, a serum protein that assists with neutrophil adherence and has opsonic properties.

Barrier function

The physical and chemical barriers to infection in the human body are present in the newborn but are functionally deficient. Skin and mucous membranes are broken down easily in the premature infant. Neonates who are ill, premature, or both are at additional risk because of the invasive procedures that breach their physical barriers to infection.

Because of the interdependence of the immune response, the individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation when the neonate is exposed to infectious threats.

Gastrointestinal involvement in sepsis

The intestines are colonized by organisms in utero or at delivery through swallowing of, and exposure to, amniotic fluid and genitourinary tract secretions. The immunologic defenses of the gastrointestinal tract are not mature, especially in the preterm infant. Lymphocytes proliferate in the intestines in response to mitogen stimulation; however, this proliferation is not fully effective in responding to a microorganism, as antibody response and cytokine formation are immature until approximately 46 weeks' gestation.

Necrotizing enterocolitis has been associated with the presence of a number of species of bacteria in the immature intestine. Overgrowth of these organisms in the neonatal lumen can be a component of the multifactorial pathophysiology of necrotizing enterocolitis.



Ventriculitis is the initiating event in meningitis, with inflammation of the ventricular surface. Exudative material usually appears at the choroid plexus and is external to the plexus. Ependymitis then occurs, with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. Glial bridges may develop near these tufts and cause obstruction, particularly at the aqueduct of Sylvius.

The lateral ventricles may become loculated, a process that is similar to the formation of abscesses. Multiloculated ventricles can lead to the development of localized pockets of infection, making treatment more difficult.

Meningitis is likely to arise at the choroid plexus and extend via the ventricles through aqueducts and into the subarachnoid space to affect the cerebral and cerebellar surfaces. The high glycogen content in the neonatal choroid plexus provides an excellent medium for the bacteria. When meningitis develops from ventriculitis, effective treatment is complicated because adequate antibiotic levels in the cerebral ventricles are difficult to achieve, particularly if ventricular obstruction is present.


Arachnoiditis is the next phase of the process and is the hallmark of meningitis. The arachnoid is infiltrated by inflammatory cells producing an exudate that is typically thick over the base of the brain and more uniform over the rest of the brain. Early in the infection, the exudate primarily contains PMNs, bacteria, and macrophages. It is prominent around the blood vessels and can extend into the brain parenchyma.

In the second and third weeks of infection, the proportion of PMNs decreases; the dominant cells are histiocytes, macrophages, and some lymphocytes and plasma cells. Exudate infiltration can occur in cranial roots 3-8.

After this period, the exudate decreases. Thick strands of collagen form along with arachnoid fibrosis, ultimately leading to obstruction of CSF flow. Hydrocephalus results. Early-onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis.


Vasculitis extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Occlusion of the arteries rarely occurs; however, venous involvement can be severe. Phlebitis may be accompanied by thrombosis and complete vessel occlusion. Multiple fibrin thrombi are especially associated with hemorrhagic infarction. This vascular involvement is apparent within the first days of meningitis and becomes more prominent during the second and third weeks of infection.

Cerebral edema

Cerebral edema may occur during the acute state of meningitis and may be severe enough to diminish the ventricular lumen substantially. The cause is unknown but is likely to be related to vasculitis and the increased permeability of blood vessels. It may also be related to cytotoxins of microbial origin. Herniation of edematous supratentorial structures does not generally occur in neonates, because of the cranium’s distensibility.


Infarction is a prominent and serious feature of advanced neonatal meningitis, occurring in 30% of infants who die. Lesions occur because of multiple venous occlusions, which are frequently hemorrhagic. The loci of infarcts are most often in the cerebral cortex and underlying white matter but may also be subependymal within the deep white matter. Neuronal loss occurs, especially in the cerebral cortex, and periventricular leukomalacia may subsequently appear in areas of neuronal cell death. [17]



Early-onset neonatal sepsis

The microorganisms most commonly associated with early-onset neonatal sepsis include the following [1] :

Risk factors implicated in neonatal sepsis reflect the level stress and illness experienced by the fetus at delivery, as well as the hazardous uterine environment surrounding the fetus before delivery. The most common risk factors associated with early-onset neonatal sepsis include, but are not limited to, the following:

  • Maternal GBS colonization (particularly in the setting of inadequate prophylactic treatment)

  • Premature rupture of membranes (PROM)

  • Preterm rupture of membranes

  • Prolonged rupture of membranes

  • Premature birth

  • Maternal urinary tract infection (UTI)

  • Maternal fever greater than 38ºC (100.4ºF)

Other factors that are associated with or predispose to early-onset sepsis include the following [18, 19] :

  • Low Apgar score (< 6 at 1 or 5 minutes)

  • Poor prenatal care

  • Poor maternal nutrition

  • Low socioeconomic status

  • Black mother

  • History of recurrent abortion

  • Maternal substance abuse

  • Low birth weight

  • Difficult delivery

  • Birth asphyxia

  • Meconium staining

  • Congenital anomalies

Late-onset neonatal sepsis

Organisms that have been implicated in causing late-onset neonatal sepsis include the following:

  • Coagulase-negative staphylococci

  • E coli

  • Klebsiella

  • Enterobacter

  • Candida

  • GBS

  • Serratia

  • Acinetobacter

  • Anaerobes

  • Many additional less-common organisms

Late-onset sepsis is associated with the following risk factors [20] :

  • Prematurity

  • Central venous catheterization (duration >10 days)

  • Urinary catheterization

  • Chronic mechanical ventilation

  • Failure to advance enteral feeding

  • nasal cannula or continuous positive airway pressure (CPAP)

  • Use of H2 -receptor blocker or proton pump inhibitor (PPI)

  • Gastointestinal tract pathology


The principal pathogens in neonatal meningitis are GBS (36% of cases), E coli (31%), and Listeria species (5%-10%). Other organisms that may cause meningitis include the following:

  • S pneumoniae

  • S aureus

  • S epidermidis

  • H influenzae

  • Pseudomonas species

  • Klebsiella species

  • Serratia species

  • Enterobacter species

  • Proteus species



The incidence of culture-proven early-onset sepsis in the United States is approximately 0.3-2 per 1000 live births. Of the 7%-13% of neonates who are evaluated for neonatal sepsis, only 3%-8% of those screened will have culture-proven sepsis. This disparity arises from the cautious approach to management of neonatal sepsis. [21]

Because early signs of sepsis in the newborn are nonspecific, diagnostic studies are often ordered and treatment initiated in neonates before the presence of sepsis has been proven. Moreover, because the American Academy of Pediatrics (AAP), [22, 23] the American College of Obstetricians and Gynecologists (ACOG), [24]  and the Centers for Disease Control and Prevention (CDC) [25] all have recommended sepsis screening or treatment for various risk factors related to Group B Streptococcus (GBS) infections, many asymptomatic neonates now undergo evaluation and are exposed to antibiotics.

Mortality from untreated sepsis can be as high as 50%, leading many clinicians to err on the side of treating asymptomatic infants based on historical and maternal risk factors alone. This approach has been questioned in the past several years as more evidence emerges on the deleterious impact of unnecessary antibiotic exposure, including interference with the establishment of breast feeding, alternations in gut microbiome, increases in the incidence of childhood obesity, and development of antimicrobial resistance, amongst others. [26]  

The implementation of a prenatal screening and treatment protocol for GBS has resulted in a dramatic decrease in the incidence of GBS sepsis. This has changed the epidemiology of early-onset sepsis (see the image below).

Neonatal sepsis. Incidence of early-onset and late Neonatal sepsis. Incidence of early-onset and late-onset invasive group B Streptococcus (GBS) disease. Graph from Verani JR, McGee L, Schrag SJ, for the Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010 Nov 19. 59 (RR-10):1-36. Online at:

Age-, race-, and sex-related demographics

Premature infants have an increased incidence of sepsis, with a significantly higher occurrence in infants with a birth weight lower than 1500 g (11-22.7 per 1000 live births) than in infants born at 37 weeks or later (0.3-0.98 per 1000 live births). The risk of death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates.

Black infants have an increased incidence of GBS disease and late-onset sepsis. This is observed even after other risk factors such as low birth weight and younger maternal age have been controlled for. This finding may be in part due to higher carriage rates of GBS among black women, but this factor does not explain all of the variation. [19]

In all races, the incidence of bacterial sepsis and meningitis, especially with gram-negative enteric bacilli, is higher in males than in females.



With early diagnosis and treatment of neonatal sepsis, most term infants will not experience associated long-term health problems. However, if early signs or risk factors are missed, mortality increases. Residual neurologic damage occurs in 15%-30% of neonates with septic meningitis.

Mortality from neonatal sepsis may be as high as 50% for infants who are not treated. Infection is a major cause of mortality during the first month of life, contributing to 13%-15% of all neonatal deaths. Low birth weight and gram-negative infection are associated with worse outcomes. [27] Neonatal meningitis occurs in 2-4 cases per 10,000 live births and contributes significantly to mortality from neonatal sepsis; it is responsible for 4% of all neonatal deaths.

In preterm infants who have had sepsis, impaired neurodevelopment is a concern. [28] Proinflammatory molecules may negatively affect brain development in this patient population. In a large study of 6093 premature infants who weighed less than 1000 g at birth, preterm infants with sepsis who did not have meningitis had higher rates of cerebral palsy (odds ratio [OR] 1.4-1.7), developmental delay (OR 1.3-1.6), and vision impairment (OR 1.3-2.2) as well as other neurodevelopmental disabilities than infants who did not have sepsis. [29, 30]

Infants with meningitis may acquire hydrocephalus or periventricular leukomalacia. They may also have complications associated with the use of aminoglycosides, such as hearing loss or nephrotoxicity.