Neonatal infection

Neonatal infection
26-week gestation, premature infant, weighing <990gm with ventilator
Classification and external resources
Specialty	Infectious disease, Pediatrics
ICD-10	P36 A50 P37 P35P23 Y95

Neonatal infections are infections of the neonate (newborn) during the neonatal period or first four weeks after birth.^[1] Neonatal infections may be contracted by transplacental transfer in utero, in the birth canal during delivery (perinatal), or by other means after birth.^[2] Some neonatal infections are apparent soon after delivery, while others may develop postpartum within the first week or month. Some infections acquired in the neonatal period do not become apparent until much later such as HIV, hepatitis B and malaria.

There is a higher risk of infection with preterm or low birth weight neonates. Respiratory tract infections contracted by preterm neonates may continue into childhood or possibly adulthood with long-term effects that limit one's ability to engage in normal physical activities, decreasing one's quality of life and increasing health care costs. In some instances, neonatal respiratory tract infections may increase one's susceptibility to future respiratory infections and inflammatory responses related to lung disease.^[3]

Antibiotics can be effective treatments for neonatal infections, especially when the pathogen is quickly identified. Instead of relying solely on culturing techniques, pathogen identification has improved substantially with advancing technology; however, neonate mortality has not kept pace and remains 20% to 50%.^[4] While preterm neonates are at a particularly high risk, full term and post-term infants can also develop infection. Neonatal infection may also be associated with premature rupture of membranes (breakage of the amniotic sac) which substantially increases the risk of neonatal sepsis by allowing passage for bacteria to enter the womb prior to the birth of the infant.^[5][6] Research to improve treatment of infections and prophylactic treatment of the mother to avoid infections of the infant is ongoing.

Causes

Neonatal infection can be distressing to the family and it initiates concentrated effort to treat it by clinicians. In industrialized countries, treatment for neonatal infections takes place in the neonatal intensive care unit. The causes and reasons for neonatal infection are many. The origin of infectious bacteria and some other pathogens is often the maternal gastrointestinal and genitourinary tract. Many of the maternal infections with these organisms are asymptomatic in the mother. Other maternal infections that may be transmitted to the infant in utero or during birth are bacterial and viral sexually transmitted infections.^[7] The infant's ability to resist infection is complicated by its immature immune system. The causative agents of neonatal infection are bacteria, viruses, and fungi. In addition, the immune system of the neonate may respond in ways that can create problems that complicate treatment, such as the release of inflammatory chemicals. Congenital defects of the immune system also affect the infants ability to fight off the infection.^[8]

Bacteria

Listeria monocytogenes

Group B streptococcus are typically identified as the cause of the majority of early-onset infections in the neonate.^[7] This pathogen is vertically transmitted (transmitted directly from the mother) to the infant.^[9] Enteric bacilli that originate from the digestive system of the mother have become as prevalent as the group B streptococcus pathogens and are currently as likely to cause infection. With the advances in preventing group B streptococcus infections, β-lactam-resistant Escherichia coli infections have increased in causing neonatal deaths in very low birthweight and premature infants.^[9] Infections with Staphylococcus aureus are also diagnosed, but not as frequently as group B streptococcus infections.^[5]

Listeria monocytogenes can also cause infection acquired from tainted food and present in the mother.^[4][10] The presence of this pathogen can sometimes be determined by the symptoms that appear as a gastrointestinal illness in the mother. The mother acquires infection from ingesting food that contains animal products such as hot dogs, unpasteurized milk, delicatessen meats, and cheese.

Neonatal infection can also occur in term and post-term infants.^[11] Infections that develop one month after the birth of the infant are more likely due to Gram-positive bacteria and coagulase positive staphylococci.^[12] Acquired maternal infection and subsequent inflammation from Ureaplasma urealyticum is accompanied by a strong immune response and is correlated with the need for prolonged mechanical ventilation.^[3][7]

Other bacterial pathogens include Streptococcus agalactiae, Streptococcus pyogenes, Viridans streptococci, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa.^[13]

Viruses

Sixty percent of mothers of preterm infants are infected with cytomegalovirus (CMV). Infection is asymptomatic in most instances but 9% to 12% of postnatally infected low birth weight, preterm infants have severe, sepsis-like infection. CMV infection duration can be long and result in pneumonitis in association with fibrosis. CMV infection in infants has an unexpected effect on the white blood cells of the immune system causing them to prematurely age. This leads to a reduced immune response similar to that found in the elderly.^[3]

Other viral infections such as respiratory syncytial virus (RSV), metapneumovirus (hMPV), rhinovirus, parainfluenza (PIV), and human coronavirus in the neonatal period are associated with recurrent wheezing in later childhood. RSV infections can be prolonged. Premature infants born at less than 32 weeks gestation have more days of cough and wheeze at 1 year of age than those uninfected with RSV.^[3]

Herpes simplex virus (HSV) can infect the infant during birth. Most women with HVS genital herpes develop asymptomatic infection during pregnancy. HVS inoculation from mother to fetus has a high likelihood of occurring. Mothers who are treated with antiviral prophylaxis are less prone to have an active, symptomatic case at the time of birth. Mothers who have received prophylactic antiviral medication have been shown to be less likely to require a cesarean section. At delivery, mothers treated with antiviral medication are less likely to have a viral shedding at the time of birth.^[14]

Human immunodeficiency virus type I (HIV) infection can occur during labor and delivery, in utero, mother-to-child transmission postnatally by way of breastfeeding.^[15]

Zika fever is caused by a virus that is acquired by the mother and then transmitted to the infant in utero. The CDC is concerned with the potential that this viral infection may cause microcephaly in newborns.^[16][17][18]

Fungi

In very low birth weight infants (VLBWI), systemic fungus infection is a hospital-acquired infection with serious consequences. The pathogens are usually Candida albicans and Candida parapsilosis. A small percentage of fungal infections are caused by Aspergillus, Zygomycetes, Malassezia, and Trichosporon.^[19][20] Infection is usually late-onset. Up to 9% of VLBWI with birth weights of <1,000 g develop these fungus infections leading to sepsis or meningitis. As many as one-third of these infants can die. Candidiasis is associated with retinopathy, prematurity and negative neurodevelopmental consequences. Candida can colonize the gastrointestinal tract of low birthweight infants (LBI). This gastrointestinal colonization is often a precursor to a more serious invasive infection. The risk of serious candida infection increases when multiple factors are present. These are: thrombocytopenia, the presence of candidal dermatitis, the use of systemic steroids, birth weights of <1,000 g, presence of a central catheter, postponing enteral feeding, vaginal delivery, and the amount of time broad-spectrum antibiotics were given.^[20]

Protozoans

Infants born with malaria can be infected with a variety of species; Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium falciparum. In most instances of congenital marlaria is caused by P. vivax and P. falciparum. Women living in areas where malaria is prevalent and common are repeatedly exposed to malaria. In response to maternal infection, mothers develop antimalarial antibodies. It is probable that the antibodies present in the mother offers protection for the baby. Bacterial infection can develop with malaria.^[19]

Infants that are infected by the protozoanToxoplasma gondii in utero can be born with chorioretinitis or ocular toxoplasmosis. Globally, it is the most common cause of infections of the back of the eye. (posterior segment). The most common sign is decreased vision in one eye. Other signs and symptoms may appear after the neonatal period and include: miscarriage, stillbirth, chorioretinitis development later in life, intracranial calcification hydrocephalus or central nervous system abnormalities.^[21]

Risk factors

Risk factors are those conditions which increase the likelihood that an infant will be born with or develop an infection.

Risk factors for neonatal infection within the first week

Factor	Notes	References
prematurity	birth before 40 weeks gestation	[8]
meconium aspiration	inspiration of stool in utero	[11]
Postpartum endometritis	inflammation of the uterus after the birth	[11]
low birth weight	< 40 weeks gestation	[8][12]
premature rupture of membranes	<12 hours	[5][8][12][22]
prolonged premature rupture of membranes	>12 hours	[5][22]
pre-term onset of labor	labor begins before 40 weeks gestation	[8][12]
chorioamnionitis	inflammation of the fetal membranes(amnion and chorion) due to a bacterial infection	[8]
vaginal discharge	abnormal discharge can be a result of an infection	[8]
tender uterus	discomfort when the uterus is examined	[23]
rupture of membranes	<12 hours	[5]
prolonged rupture of membranes	>12 hours)	[8][23]
in utero infection with pathogens	the period of infection allows for the logarithmic growth of pathogens	[7]
maternal urinary tract infection	bladder and/or kidney infection	[8]
prolonged labor		[23]
vaginal examinations during labor	risk increases with the number of vaginal examinations during labor	[8][23]
maternal colonization with group B streptococcus	the presence of this bacterium is usually asymptomatic	[5][8]
previous baby with early-onset GBS infection		[8][23]
gender	males are more susceptible;This risk declines after respiratory distress syndrome is treated	[12]
multiples	risk is increased for the firstborn	[12]
iron supplementation	iron is a growth factor for some bacteria	[12]
maternal intrapartum fever	> 38 °C	[8][22]
after insertion of intravenous line	may introduce pathogens into the circulation	[12]
immature immune system		[12]
invasive medical procedures	may introduce pathogens into the circulation	[12]
hypoxia	unexpected resuscitation after birth	[12][23]
low socioeconomic status		[12]
hypothermia	relatively low blood temperature	[12]
metabolic acidosis	a pH imbalance in the blood	[12]
obstetrical complications		[12]
prevalence of resistant bacteria in the neonatal intensive care unit	nosomial populations	[12]
maternal exposure to Toxoplasmosis gondii	a parasite present in cat litter and other animal excrement	[21]

Risk factors for late onset for neonatal infection >one week after birth

Factor	Notes	References
after insertion of an intravenous line	hypothermia
	poor feeding
	lethargy
	more likely to develop osteoarthritis
	soft tissue infection
	meningitits	[12]
	Mother resides in endemic malaria area	[19]

The risk for developing catheter-related infections is offset by the increased survival rate of premature infants that have early onset sepsis. Intravenous administration of prophylactic immunoglobin enhances immunity of the immature infant and is used for treatment.^[12]

Mechanism

Chorioamnionitis

Inflammation accompanies infection and is likely to complicate treatment and recovery. Inflammation is linked to reduced growth of the lungs of the premature baby.^[3]

Pathogenesis

The recent identification of the presence of microorganisms in maternal-infant body fluids that were previously thought to be sterile has provided one explanation for the presence of the inflammatory response in both the mother and infant. Sixty-one percent of pregnant women with chorioamnionitis, or inflammation of the amniotic fluid, were found to be infected by microorganisms. Often, more than one pathogen was present. In fifteen percent of pregnant women inflammation was still evident even though there was no evidence of pathogens. This may indicate that there are other causes. A high percentage, 51% to 62%, of pregnant women who had chorioamnionitis also had inflammation of the placenta.^[3]

Diagnosis

Diagnosis of infection is based upon the recovery of the pathogen or pathogens from the typically sterile sites in the mother or the baby. Unfortunately, as many half of pregnant women are asymptomatic with a gonorrhea infection and other sexually transmitted infections.^[24][25][26] Samples are obtained from urine, blood or cerebrospinal fluid. Diagnosis of infection can also be aided by the use of more nonspecific tests such as determining the total white blood cell count, cytokine levels and other blood tests and signs.^[12]

Signs of infection	Notes	References
abnormal complete blood count	looking for signs of infection in the blood: increased white cell count; presence of immature neutrophils	[5][23]
increased C-reactive protein	a chemical in the blood that shows that the baby's immune system is actively reacting to infection	[5][23][27]
accessory muscle use	using the intercostal muscles to assist in breathing	[23]
tachycardia	a heart rate that is faster than normal	[5]
bradycardia	a heart rate that is slower than normal	[5]
chest recession		[23]
respiratory distress	the baby has trouble breathing	[5][23]
nasal flaring	the baby's nostrils expand when it inhales	[23]
expiratory grunt	a sound of effort when the baby exhales	[23][28]
apnea	the baby stops breathing	[5][23]
rash		[23]
positive urine culture		[5]
positive cerebral spinal fluid		[5]
other positive cultures	from eyes, ear canal, umbilicus axilla anus	[5]
lethargy	the baby seems tired and has slow or no movements	[5][23]
hypotonia	the muscles seem flabby and weak	[5][23]
hypothermia		[5]
irritability	infant appears uncomfortable and and has difficulty being soothed	[5][23]
weak cry		[23]
pneumonia		[5]
poor perfusion	poor circulation	[5][23]
hypotension	low blood pressure	[23]
acidosis	pH imbalance in the blood	[5][23]
diarrhea	water-like, unformed stools	[23]
poor feeding		[5]
oxygen requirement		[5]
bulging fontanel	the soft spot on the head is bulging	[23]
seizures		[5][23]
fever		[5]
disseminated intravascular coagulation	widespread clotting of blood	[23]
renal failure	kidneys do not function	[23]
bacteremia	bacteria cultured from the blood of the newborn	[5]

Viral infection

Symptoms and the isolation the virus pathogen the upper respiratory tract is diagnostic. Virus identification is specific immunologic methods and PCR. The presence of the virus can be rapidly confirmed by the detection of the virus antigen. The methods and materials used for identifying the RSV virus has a specificity and sensitivity approaching 85% to 95%. Not all studies confirm this sensitivity. Antigen detection has comparatively lower sensitivity rates that approach 65% to 75%.^[29]

Protozoan infection

Congential malaria has its own set of signs:

Signs of congenital malaria infection	Notes	References
splenomegaly	enlarged speen
fever
anemia
jaundice
poor feeding
hepatomegaly	enlarged liver
failure to thrive
loose stools
irritability
hyperbilirubinemia
central nervous system infection
splenic rupture
renal failure
blackwater fever	infection with P. falciparum only	[19]

Neonatal sepsis

Neonatal sepsis of the newborn is an infection that has spread through the entire body. The inflammatory response to this systematic infection can be as serious as the infection itself.^[3] In infants that weigh under 1500 g, sepsis is the most common cause of death. Three to four percent of infants per 1000 births contract sepsis. The mortality rate from sepsis is near 25%.^[4] Infected sepsis in an infant can be identified by culturing the blood and spinal fluid and if suspected, intravenous antibiotics are usually started. Lumbar puncture is controversial because in some cases it has found not to be necessary while concurrently, without it estimates of missing up to one third of infants with meningitis is predicted.^[12]

Prevention

To reduce neonatal infection, routine screening of pregnant women for HIV, hepatitis B, syphilis, and rubella susceptibility is required in the UK.^[30]

Treatment with an vaginal antibiotic wash prior to birth does not prevent infection with group B streptococcus bacteria.^[5][31] Breast milk protects against necrotizing enterocolitis.^[8]

Because GBS bacteria can colonize the lower reproductive tract of 30% of women, typically pregnant women are tested for this pathogen from 35 to 37 weeks of pregnancy. Before delivery treatment of the mother with antibiotics reduces the rate of neonatal infection.^[5] Prevention of the infection of the baby is done by treating the mother with penicillin. Since the adoption of this prophylatic treatment, infant mortality from GBS infection has decreased by 80%.^[4] Mothers with symptomatic HSV and who are treated with antiviral prophylaxis are less prone to have an active, symptomatic case at the time of birth and it may be able to reduce the risk of passing on HSV during birth. Cesarean delivery reduces the risk of infection of the infant.^[14]

Treatment

Neonatal infection treatment is typically started before the diagnosis of the cause can be confirmed. Neonatal infection can be prophylactically treated with antibiotics.^[7] Maternal treatment with antibiotics is primarily used to protect against group B streptococcus.^[12]

Women with a history of HSV, can be treated with antiviral drugs to prevent symptomatic lesions and viral shedding that could infect the infant at birth. The antiviral medications used include acyclovir, penciclovir, valacyclovir, and famciclovir. Only very small amounts of the drug can be detected in the fetus. There are no increases in in drug-related abnormalities in the infant that could be attributed to acyclovir. Long-term effects of antiviral medications have not been evaluated for their effects after growth and development of the child occurs. Neutropenia can be a complication of acyclovir treatment of neonatal HSV infection, but is usually transient.^[14] Treatment with immunoglobulin therapy has not been proven to be effective.^[32]

Epidemiology

Up to 3.3 million newborns die each year and 23.4% of these die of neonatal infection. About half of the deaths caused by sepsis or pneumonia happen in the first week postpartum. In industrialized countries, prophylactic antibiotic treatment of the mothers identified with group B streptococcus, early identification of sepsis in the newborn, and administration of antibiotics to the newborn has reduced mortality.^[5] Neonatal herpes in North America is estimated to be from 5 – 80 per 100,000 live births. HSV has a lower prevalence in mothers outside the United States. In the United Kingdom the incidence is much lower and estimated to be 1.6 per 100,000 live births. Approximately 70% to 80% of infected infants are born to mothers with no reported history of HSV infection.^[14]

Regions with low neonatal mortality include Europe, the Western Pacific, and the Americas, which have sepsis rates that account for 9.1% to 15.3% of the total neonatal deaths worldwide. This is in contrast with the 22.5 to 27.2% percentage of total deaths in resource-poor countries such as Nigeria, the Democratic Republic of the Congo, India, Pakistan, and China.^[5]

In the UK, the proportions of pregnant women who are newly screened positive for hepatitis B, syphilis, and HIV have remained constant since 2010 at about 0.4%, 0.14% and 0.15%, respectively. Estimated prevalence levels among pregnant women for hepatitis B and HIV, including previous diagnoses, were higher at 0.67% and 0.27%. Pregnant women evaluated as susceptible to rubella due to low antibody levels have increased by over 60%, to about 7.2%. However, this increase is probably due to changes in testing methods and evaluation criteria.^[33]

In North America, prior to the 1950s, group A β-hemolytic streptococcus (GAS) was the most common pathogen associated with neonatal sepsis prior to the 1960s. In the past twenty years, the most common pathogen causing sepsis is coagulase-negative staphylococci that exist as biofilms associated with infected central venous or arterial catheters.^[7] Infections can be fatal and contribute to long-term morbidity and disability among the infants who survive into childhood.^[7] Neonatal sepsis effects 128 cases per 1000 live births. Meningitis can occur in the septic infant.^[12] Expectant mothers with HVS have a 75% chance of at least one flare-up during their pregnancy.^[14] In limited studies it was found that infants in Africa born to mothers with malaria have a 7% of acquiring congenital malaria.^[19]

Early-onset infections

Early onset sepsis can occur in the first week of life. It usually is apparent on the first day after birth. This type of infection is usually acquired before the birth of the infant. Premature rupture of membranes and other obstetrical complications can add to the risk of early-onset sepsis. If the amniotic membrane has been ruptured greater than 18 hours before delivery the infant may be at more risk for this complication. Prematurity, low birth weight, chorioamnionitis, maternal urinary tract infection and/or maternal fever are complications that increase the risk for early-onset sepsis. Early onset sepsis is indicated by serious respiratory symptoms. The infant usually suffers from pneumonia, hypothermia, or shock. The mortality rate is 30 to 50%.^[12]

Late onset infections

Infections that occur after the first week of life but before the age of 30 days are considered late onset infections. Obstetrical and maternal complications are not typically the cause of these late onset infections; they are usually acquired by the infant in the hospital neonatal intensive care unit. The widespread use of broad-spectrum antibiotics in the nursery intensive care unit can cause a higher prevalence of invasive antibiotic resistant bacteria.^[12] Meconium aspiration syndrome has a mortality rate just over 4%. This accounts for 2% for all neonatal deaths.^[11]

Research

The susceptibility to risk of infection and immune deficiencies are active areas of research. Studies regarding the role of viruses in neonatal infections are lacking. Research also continues into the role and protective effect of gut, skin and other human microbiomes and the colonization during the neonatal period.^[3][12] The comparison between resource rich countries and resource poor countries makes it somewhat difficult to compare the diagnosis success since industrialized regions are able to confirm the diagnosis and presence of pathogens in the clinical laboratory. Clinical testing may not be available in all settings and clinicians must rely on the signs of infection in the newborn. Research data from Africa and Southeast Asia is scarce.^[5]

The result of some research has been the identification of diagnostic tools and procedures that could identify mothers with group B streptococcus infection in resource-poor regions. These procedures would be easy and inexpensive to use. Those mothers who are identified as being infected could then be prophylactly treated prior to the birth of the baby.^[5]

Probiotic administration of Lactobacillus species has shown some success.^[13]

A GBS vaccine is currently being tested but not currently available. Vaccination is estimated to being able to prevent 4% of GBS infections for preterm births and 60–70% for neonatal GBS infections in the US. The projected benefits of maternal vaccination is the prevention of 899 cases of GBS disease and 35 deaths among infants. The cost savings in the prevention of GBS may be over 43 million dollars. Vaccination may be especially beneficial in low to middle income countries where screening and prophylactic treatment is not possible. Analysts project that GBS vaccination would prevent 30–54% of infant GBS cases. Screening, prophylactic antibiotics and vaccine would prevent 48% of infection.^[34]

See also

• Preterm birth

References

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15. Polin, Richard (2014). Fetal and neonatal secrets. Philadelphia: Elsevier Saunders. ISBN 978-0-323-09139-8; Access provided by the University of Pittsburgh.
16. Leonardo Aguiar. "Ministério da Saúde confirma relação entre vírus Zika e microcefalia". Portal da Saúde – Ministério da Saúde – http://www.saude.gov.br. External link in |work= (help)
17. Oliveira Melo, A. S.; Malinger, G.; Ximenes, R.; Szejnfeld, P. O.; Alves Sampaio, S.; Bispo de Filippis, A. M. (1 January 2016). "Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?". Ultrasound in Obstetrics & Gynecology. 47 (1): 6–7. doi:10.1002/uog.15831. ISSN 1469-0705.
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Further reading

• Jenster, Meike; Bonifacio, Sonia L.; Ruel, Theodore; Rogers, Elizabeth E.; Tam, Emily W.; Partridge, John Colin; Barkovich, A. James; Ferriero, Donna M.; Glass, Hannah C. (2014-07-01). "Maternal or neonatal infection: association with neonatal encephalopathy outcomes". Pediatric research. 76 (1): 93–99. doi:10.1038/pr.2014.47. ISSN 0031-3998. PMC 4062582. PMID 24713817.
• "National Guideline Clearinghouse | Antibiotics for early-onset neonatal infection. Antibiotics for the prevention and treatment of early-onset neonatal infection.". www.guideline.gov. Retrieved 2016-01-15.

External links

• "WHO | Newborn death and illness". www.who.int. Retrieved 2016-01-15.