Neonatal sepsis

Neonatal sepsis is a systemic infection occurring in infants at less than 28 days of life and is an important cause of morbidity and mortality of newborns ¹. Sepsis is a life-threatening medical emergency that happens when your baby has an overwhelming immune response to a bacterial infection. The chemicals released into the baby’s blood to fight the infection trigger widespread inflammation. This leads to blood clots and leaky blood vessels. They cause poor blood flow, which deprives your baby’s organs of nutrients and oxygen. In severe cases, one or more organs (e.g., kidneys, lungs, brain, and heart) fail. In the worst cases, blood pressure drops and the heart weakens, leading to septic shock and death.

Neonatal sepsis is divided into 2 groups based on the time of presentation after birth: early-onset sepsis (day of life 0-3, sepsis in neonates at or before 72 hours of life) and late-onset sepsis (sepsis occurring at or after 72 hours of life, some experts use 7 days as the cutoff date) ². 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 ³ . Onset is most rapid in premature neonates.

Early-onset sepsis remains a common and serious problem for neonates, especially preterm infants. Group B streptococcus is the most common causative agent, while Escherichia coli is the most common cause of mortality ⁴. Current efforts toward maternal intrapartum antimicrobial prophylaxis have significantly reduced the rates of group B streptococcus disease but have been associated with increased rates of Gram-negative infections, especially among very-low-birth-weight infants.

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 ⁵. 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.

The diagnosis of neonatal sepsis is based on a combination of clinical presentation; the use of nonspecific markers, including C-reactive protein and procalcitonin (where available); blood cultures; and the use of molecular methods, including polymerase chain reaction (PCR). Cytokines, including interleukin 6 (IL-6), interleukin 8 (IL-8), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), and cell surface antigens, including soluble intercellular adhesion molecule (sICAM) and CD64, are also being increasingly examined for use as nonspecific screening measures for neonatal sepsis. Viruses, in particular enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis  ⁴. Empirical treatment should be based on local patterns of antimicrobial resistance but typically consists of the use of ampicillin and gentamicin, or ampicillin and cefotaxime if meningitis is suspected, until the etiologic agent has been identified. Current research is focused primarily on development of vaccines against group B streptococcus.

Early onset neonatal sepsis

Early-onset neonatal sepsis has been variably defined based on the age at onset, with bacteremia or bacterial meningitis occurring at less than 72 hour in infants hospitalized in the neonatal intensive care unit (NICU), versus less than 7 days in term infants ⁶. In preterm infants, early-onset neonatal sepsis is most consistently defined as occurring in the first 3 days of life and is caused by bacterial pathogens transmitted vertically from mother to infant before or during delivery ⁷.

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 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 ⁸:

• Group B Streptococcus
• Escherichia coli
• Coagulase-negative Staphylococcus
• Haemophilus influenzae
• Listeria monocytogenes

In a study involving 4696 women, prenatal cultures showed a group B streptococcus colonization rate of 24.5%, with a positive culture rate of 18.8% at the time of labor ⁹. 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 group B streptococcus disease ⁹.

Late onset neonatal sepsis

Late-onset sepsis occurs at 4-90 days of life and is acquired from the environment. Late-onset neonatal sepsis is sepsis occurring after 72 hour in neonatal intensive care unit infants and 7 days of life in term infants, has been variably defined as occurring up to the age of <90 or 120 days, and may be caused by vertically or horizontally acquired pathogens ¹⁰. Early-onset neonatal infections of viral or fungal etiology may also occur at less than 7 days of life and must be distinguished from bacterial sepsis ¹¹.

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

• Coagulase-negative Staphylococcus
• Staphylococcus aureus
• E coli
• Klebsiella
• Pseudomonas
• Enterobacter
• Candida
• Group B streptococcus
• 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 ¹². The infant’s skin, respiratory tract, conjunctivae, gastrointestinal tract, and umbilicus may become colonized via contact with the environment or caregivers.

Neonatal sepsis causes

Early-onset sepsis 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 become infected in utero or during delivery as they pass through the vaginal canal. Typical bacterial pathogens for early-onset sepsis include Group B streptococcus, Escherichia coli, coagulase-negative Staphylococcus, Haemophilus influenza, or Listeria monocytogenes. Other maternal factors that increase the risk of neonatal sepsis include chorioamnionitis, delivery before 37 weeks, and prolonged rupture of membranes greater than 18 hours ¹³.

Late-onset sepsis usually occurs via the transmission of pathogens from the environment after delivery, such as contact from healthcare workers or caregivers. Late-onset sepsis may also be caused by a late manifestation of vertically transmitted infection. Infants that require intravascular catheter insertion, or other invasive procedure that disrupts the mucosa, are at increased risk for developing late-onset sepsis. Preterm neonates are at higher risk for sepsis/infection than term neonates, as they tend to require more invasive procedures than term neonates. Coagulase-negative staphylococcal species, especially Staphylococcus epidermidis, is the leading cause, responsible for greater than 50% of late-onset sepsis cases in industrialized countries, although many bacterial and viral pathogens can be associated with late-onset sepsis ¹³.

The epidemiology of neonatal sepsis has been changing with time ¹⁴. The incidence of early-onset sepsis has decreased since the 1990s due to the introduction of universal screening of group B streptococcus in pregnant women and intrapartum antibiotic prophylaxis ¹⁵. However, rates of late-onset sepsis have remained relatively the same. Escherichia coli now accounts for more cases of early-onset sepsis compared to group B streptococcus ¹⁶. In the United States, the incidence of early-onset sepsis with positive blood cultures is estimated to be 0.77 to 1 per 1,000 live births ¹⁷. 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 concerning factors are present. Although approximately 7% to 13% of all neonates are worked up for sepsis, only 3% to 8% develop positive cultures ¹³. 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 group B streptococcus and late-onset sepsis, likely secondary to the higher rate of group B streptococcus carrier rates in African American females. Males have a higher risk of sepsis and meningitis, especially with gram-negative enteric bacilli ¹³.

Neonatal sepsis signs and symptoms

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. Physicians must, therefore, 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 ¹³. 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.

Infants with neonatal sepsis may have the following symptoms:

• Body temperature changes
• Breathing problems
• Diarrhea or decreased bowel movements
• Low blood sugar
• Reduced movements
• Reduced sucking
• Seizures
• Slow or fast heart rate
• Swollen belly area
• Vomiting
• Yellow skin and whites of the eyes (jaundice)

The signs and symptoms of sepsis can include a combination of any of the following:

• Fever or low temperature (newborns and infants may have low temperature)
• Fast heart rate
• Fast breathing
• Feeling cold/cold hands and feet
• Clammy and pale skin
• Confusion, dizziness or disorientation
• Shortness of breath
• Extreme pain or discomfort
• Nausea and vomiting

The physical exam may reveal nonspecific signs of sepsis.

Important Note: Many of these signs and symptoms alone are common in babies and children when they are sick. Most of the time, they do not have sepsis. However, when more than one of these signs and symptoms happen together, or when a baby or child just seems sicker than usual—you should seek medical help. If your baby or child’s skin is cold, pale, or has developed strange colors or markings; if your baby or child has become unresponsive or is struggling to breathe; or if your baby has dry diapers for more than 12 hours—you should take him or her to the emergency room without delay.

Neonatal sepsis complications

In addition to the increased mortality rate associated with neonatal sepsis, the morbidity rate is also high. Risk factors associated with increased morbidity include very low birth weight, cardiac dysfunction, acute renal failure, metabolic acidosis, increased bleeding, neutropenia, and bleeding. Very low birth weight infants have been found to have a higher risk of chronic lung disease, and extremely low birth weight infants are at a greater risk of neurodevelopmental risks, such as hearing and visual deficits, cerebral palsy, and impaired psychomotor and mental development ¹⁸. Administration of broad-spectrum antibiotics also predisposes to fungal infections, including invasive candidiasis and meningitis. However, preterm infants recovered from early-onset sepsis have not been shown to have increased risk for development of late-onset sepsis ¹⁹.

Neonatal sepsis diagnosis

Bacteremia may be present in a neonate with apparently normal clinical 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 1ml of blood as low-level bacteremia may not be detected with smaller aliquotes and is common in neonatal sepsis ²⁰. Cultures should also be drawn from the catheter site if one is in place. Urine cultures are usually not recommended for evaluation of early-onset sepsis but should be performed for evaluation of late-onset sepsis ²¹. Lumbar puncture with cerebrospinal fluid (CSF) analysis and culture should be evaluated in any infant with positive blood culture or when clinical or metabolic abnormalities strongly suggest bacterial sepsis, as meningeal signs may not be present on the physical exam. Lumbar puncture should be repeated if the patient fails to improve on antibiotic treatment, if symptoms worsen or if positive blood cultures result. 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 ¹³.

CSF analysis may reveal:

• Elevated protein level
• Elevated white blood cell
• 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 ²⁰. Neutropenia has better specificity than neutrophilia as a marker of neonatal sepsis ²². Elevated immature to total neutrophil 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 ²³. These counts may be falsely elevated, especially after birth. It is better to perform complete blood count 6 to 12 hours after birth as alteration in these neutrophil indices usually require an established inflammatory response ²⁴.

C-reactive protein (CRP) levels start rising within 6 to 8 hours during an infectious episode in neonates and peak at about 24 hours ²⁵. Persistently normal CRP levels provide strong evidence against bacterial sepsis and antimicrobial agents can be safely discontinued. Other inflammatory markers, including procalcitonin, haptoglobin, and cytokines can also be obtained to support the diagnosis or to monitor during treatment. Radiography of the chest may be performed to look for any pulmonary findings. CT or MRI of the head may be warranted if concerns for hydrocephalus, infarction, or abscess exist ².

Neonatal sepsis treatment

The treatment regimen for neonatal sepsis varies based on various risk factors and conditions. The typical antibiotics used are discussed below, but the duration of therapy can vary based on the underlying etiology, isolated organisms, the presence of any neonatal complications, or other risk factors. 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 the intial choice of antibiotics. Typical treatment regimens include intravenous (IV) broad-spectrum penicillin and aminoglycosides to cover for the most common pathogens in neonates: group B streptococcus, E. coli, and L. monocytogenes. The combination of ampicillin and gentamicin is the most commonly used antibiotic regimen ²⁰. With late-onset sepsis, 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 combination of vancomycin and an aminoglycoside ²⁶. A Third-generation cephalosporins should be given if Gram-negative meningitis is suspected ²⁷. It provides adequate penetration via blood brainbarrier and coverage for these pathogens. However, ceftriaxone should be avoided, as it can lead to hyperbilirubinemia. Increasing antibiotic resistance is a concern for neonatal sepsis and treatment should always be de-escalated as soon as possible ²⁸.

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 ¹³. Despite standard recommendations to discontinue antibiotics once cultures are negative, many clinicians will continue therapy for 10 to 14 days based on the organism, or 21 days if meningitis was suspected ²⁶. Increasing the duration of antibiotics may be necessary for some situations. However, it does contribute to the increasing incidence of antibiotic resistance and puts the neonate at increased risk of complications including necrotizing enterocolitis or death ²⁹.

The treatment for suspect early-onset sepsis with negative cultures is also variable. Cultures can be negative for a variety of 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, and an empiric 10-day treatment course is completed, as long as the neonate’s symptoms have improved ¹³.

Neonatal sepsis prognosis

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. 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 ³⁰. 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. Residual neurologic damage occurs in 15%-30% of neonates with septic meningitis.

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.

Mortality rates are inversely proportional with gestational age, such that preterm or younger neonates have higher mortality rates than do term neonates ³¹. E. coli has also found to be associated with a higher mortality rate when compared with group B streptococcus. As noted above, the introduction of group B streptococcus intrapartum antibiotic prophylaxis has decreased mortality rates caused by group B streptococcus. The treatment of clinically suspected neonates with negative cultures has also significantly decreased mortality rates.

Preterm infants with sepsis may gone to develop impaired neurodevelopment ³². 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 1.4-1.7), developmental delay (odds ratio 1.3-1.6), and vision impairment (odds ratio 1.3-2.2) as well as other neurodevelopmental disabilities than infants who did not have sepsis ³³. In addition others may have vision impairment. Those infants pretreated with aminoglycosides may also develop ototoxicity and nephrotoxicity.

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