Newborn screening is the process of testing newborn babies for treatable genetic, endocrinologic, metabolic and hematologic diseases.^[1][2] Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using blood samples on filter paper obtained by pricking a newborn baby’s heel on the second day of life to get a few drops of blood. ^[3] Congenital hypothyroidism was the second disease widely added in the 1970s.^[4] The development of tandem mass spectrometry screening by Edwin Naylor and others in the early 1990s led to a large expansion of potentially detectable congenital metabolic diseases that affect blood levels of organic acids.^[5] Additional tests have been added to many screening programs over the last two decades. Newborn screening has been adopted by most countries around the world, though the lists of screened diseases vary widely.

Disease qualification

Common considerations in determining whether to screen for disorders:

1. A disease that can be missed clinically at birth
2. A high enough frequency in the population
3. A delay in diagnosis will induce irreversible damages to the baby
4. A simple and reasonably reliable test exists
5. A treatment or intervention that makes a difference if the disease is detected early

[edit] Newborn Screening Program in the Philippines

The following tests are mandated in the R.A. 9288 or Newborn Screening program of 2004.Newborn screening is available in practicing health institutions (hospitals, lying-ins, Rural Health Units and Health Centers) with cooperation with DOH. If babies are delivered at home, babies may be brought to the nearest institution offering newborn screening. A negative screen mean that the result of the test is normal and the baby is not suffering from any of the disorders being screened. In case of a positive screen, the NBS nurse coordinator will immediately inform the coordinator of the institution where the sample was collected for recall of patients for confirmatory testing. Babies with positive results should be referred at once to the nearest hospital or specialist for confirmatory test and further management. Should there be no specialist in the area, the NBS secretariat office will assist its attending physician. Disorders Screened:

 

Heel Prick Method for the newborn screening

• CH (Congenital hypothyroidism) – is a condition of thyroid hormone deficiency present at birth. Approximately 1 in 4000 newborn infants has a severe deficiency of thyroid function, while even more have mild or partial degrees. If untreated for several months after birth, severe congenital hypothyroidism can lead to growth failure and permanent mental retardation. Treatment consists of a daily dose of thyroid hormone (thyroxine) by mouth. Because the treatment is simple, effective, and inexpensive, nearly all of the developed world practices newborn screening to detect and treat congenital hypothyroidism in the first weeks of life.
• CAH (Congenital adrenal hyperplasia) – refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis). Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. Approximately 95% of cases of CAH are due to 21-hydroxylase deficiency.
• GAL (Galactosemia) – is a rare genetic metabolic disorder which affects an individual’s ability to properly metabolize the sugar galactose. Lactose in food (such as dairy products) is broken down by the body into glucose and galactose. In individuals with galactosemia, the enzymes needed for further metabolism of galactose are severely diminished or missing entirely, leading to toxic levels of galactose to build up in the blood, resulting in hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, and brain damage. Without treatment, mortality in infants with galactosemia is about 75%.
• PKU (Phenylketonuria) – is an autosomal recessive genetic disorder characterized by a deficiency in the enzyme phenylalanine hydroxylase (PAH). This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine. PAH is found on chromosome number 12.Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures. However, PKU is one of the few genetic diseases that can be controlled by diet. A diet low in phenylalanine and high in tyrosine can be a very effective treatment. There is no cure. Damage done is irreversible so early detection is crucial.
• G6PD Deficiency – is an X-linked recessive hereditary disease characterized by abnormally low levels of the glucose-6-phosphate dehydrogenase enzyme (abbreviated G6PD or G6PDH). It is a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism.
• Newborn screening results are available within three weeks after the NBS Lab receives and tests the samples sent by the institutions. Results are released by NBS Lab to the institutions and are released to your attending birth attendants or physicians.Parents may seek the results from the institutions where samples are collected. Christian Nieto,EACSN

[edit] Newborn screening in the United States

The following tests are mandated (required to be performed on every newborn born in the state) in most of the United States. According to the U.S. Centers for Disease Control, approximately 3,000 babies with severe disorders are identified in the United States each year using newborn screening programs at current testing rates. States vary, and not all tests are required in every state, and a few states mandate more than this. The first test to be universally mandated across the U.S. was the Guthrie test for phenylketonuria (PKU), and in many areas and hospitals, the newborn blood test is often erroneously referred to as a “PKU test”, even though all states now universally test for congenital hypothyroidism, galactosemia, and increasing numbers of other diseases as well.

• Endocrine disorders: Congenital adrenal hyperplasia (CAH), Congenital hypothyroidism
• Blood cell disorders: sickle-cell disease (SS)
• Inborn errors of carbohydrate metabolism: Galactosemia
• Inborn errors of amino acid metabolism: Phenylketonuria (PKU), Maple syrup urine disease (MSUD), Homocystinuria
• Inborn errors of organic acid metabolism: Biotinidase deficiency

For a recent state-by-state list, see U.S. National Newborn Screening and Genetics Resource Center. According to this resource, the only tests mandated in every state are the following:

• CH – Congenital hypothyroidism
• H-HPE – Benign hyperphenylalaninemia
• PKU — Phenylketonuria/hyperphenylalaninemia
• HEAR – Hearing
• GALT – Transferase deficient galactosemia

[edit] Usual procedures and responses to positive results

 

Heel blood on a filter paper card for the newborn screening

In nearly all of the United States, the newborn screening program is a division of the state health department. State law mandates collecting a sample by pricking the heel of a newborn baby to get enough blood (typically, two to three drops) to fill a few circles on filter paper labeled with names of infant, parent, hospital, and primary physician. It is usually specified that the sample be obtained on the second or third day of life, after protein-containing feedings (i.e., breast milk or formula) have started, and the postnatal TSH surge subsided. Every hospital in the state as well as independent midwives supervising home deliveries are required to collect the papers and mail each batch each day to the central laboratory.

The state health department agency in charge of screening will either run a laboratory or contract with a laboratory to run the mandated screening tests on the filter paper samples. The goal is to report the results within a short period of time. If screens are normal, a paper report is sent to the submitting hospital and parents rarely hear about it.

If an abnormality occurs, employees of the agency, usually nurses, begin to try to reach the physician, hospital, and/or nursery by telephone. They are persistent until they can arrange an evaluation of the infant by an appropriate specialist physician (depending on the disease). The specialist will attempt to confirm the diagnosis by repeating the tests by a different method or laboratory, or by performing other corroboratory tests. Depending on the likelihood of the diagnosis and the risk of delay, the specialist will initiate treatment and provide information to the family. Performance of the program is reviewed regularly and strenuous efforts are made to maintain a system that catches every infant with these diagnoses. Guidelines for newborn screening and follow up have been published by the American Academy of Pediatrics.^[6]

[edit] Expanded screening and controversies

With the development of tandem mass spectrometry in the early 1990s, the number of detectable diseases quickly grew, especially in the categories of fatty acid oxidation disorders and organic acidoses. Screening tests for the disorders listed below (and an increasing number of others) are now available, though not universally mandated. There is considerable variability from state to state, and sometimes from hospital to hospital within a state, on disease that are screened. To make matters more confusing, some hospitals routinely obtain supplemental screening (most of the tests below) on all infants even if not mandated by the state or requested by parents. In recent years in the United States, expanded newborn screening with tandem mass spectrometry has become a profitable commercial venture.

Newborn screening tests have become a subject of political controversy in the last decade. Two California babies, Zachary Wyvill and Zachary Black, were both born with Glutaric acidemia type I. Wyvill’s birth hospital only tested for the four diseases mandated by state law, while Black was born at a hospital that was participating in an expanded testing pilot program. Black’s disease was treated with diet and vitamins; Wyvill’s disease went undetected for over six months, and during that time the damage from the enzyme deficiency became irreversible. Birth-defects lobbyists pushing for broader and more universal standards for newborn testing cite this as an example of how much of an impact testing can have.

Instituting MS/MS screening often requires a sizable up front expenditure. When states choose to run their own programs the initial costs for equipment, training and new staff can be significant. To avoid at least a portion of the up front costs, some states such as Mississippi have chosen to contract with private labs for expanded screening. Others have chosen to form Regional Partnerships sharing both costs and resources. But for many states, screening is an integrated part of the department of health which can not or will not be easily replaced. Thus the initial expenditures can be difficult for states with tight budgets to justify. Screening fees have also increased in recent years as healthcare costs rise and more states add MS/MS screening to their programs. (See Report of Summation of Fees Charged for Newborn Screening, 2001–2005) Dollars spent for these programs may reduce resources available to other potentially lifesaving programs. It has been recommended that one disorder, Short Chain Acyl-coenzyme A Dehydrogenase Deficiency, or SCAD, be eliminated from screening programs, due to a “spurious association between SCAD and symptoms. ^[7] However, recent studies suggest that expanded screening is cost effective (see ACMG report page 94-95 and articles published in Pediatrics ^[8]‘^[9]. Advocates are quick to point out studies such as these when trying to convince state legislatures to mandate expanded screening.

Expanded newborn screening is also opposed by among some health care providers who are concerned that effective follow-up and treatment may not be available, that false positive screening tests may cause harm, and issues of informed consent^[10].

[edit] Conditions and disorders

The following list includes most of the disorders detected by the expanded or supplemental newborn screening by mass spectrometry. This expanded screening is not yet universally mandated by most states, but may be privated purchased by parents or hospitals at a cost of approximately US$80. Perhaps one in 5,000 infants will be positive for one of the metabolic tests below (excluding the congenital infections).

The 29 marked with a “@” were recommended as “core panel” by the 2005 report of the American College of Medical Genetics (ACMG). The incidences reported below are from their report, pages 143-307, though the rates may vary in different populations. (WARNING: The file is a very large PDF.)

[edit] Blood cell disorders

• Glucose-6-phosphate dehydrogenase deficiency (G6PD)
• Sickle cell anemia (Hb SS) > 1 in 5,000; among African-Americans 1 in 400
• Sickle-cell disease (Hb S/C) > 1 in 25,000
• Hb S/Beta-Thalassemia (Hb S/Th) > 1 in 50,000

[edit] Inborn errors of amino acid metabolism

• Tyrosinemia I (TYR I) < 1 in 100,000
• Tyrosinemia II
• Argininemia
• Argininosuccinic aciduria (ASA) < 1 in 100,000
• Citrullinemia (CIT) < 1 in 100,000
• Phenylketonuria (PKU) > 1 in 25,000
• Maple syrup urine disease (MSUD) < 1 in 100,000
• Homocystinuria (HCY) < 1 in 100,000

[edit] Inborn errors of organic acid metabolism

• Glutaric acidemia type I (GA I) > 1 in 75,000
• Glutaric acidemia type II
• HHH syndrome (Hyperammonemia, hyperornithinemia, homocitrullinuria syndrome)
• Hydroxymethylglutaryl lyase deficiency (HMG) < 1 in 100,000
• Isovaleric acidemia (IVA) < 1 in 100,000
• Isobutyryl-CoA dehydrogenase deficiency
• 2-Methylbutyryl-CoA dehydrogenase deficiency
• 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC) > 1 in 75,000
• Beta-methyl crotonyl carboxylase deficiency
• 3-Methylglutaconyl-CoA hydratase deficiency
• Methylmalonyl-CoA mutase deficiency (MUT) > 1 in 75,000
• Methylmalonic aciduria, cblA and cblB forms (MMA, Cbl A,B) < 1 in 100,000
• Beta-ketothiolase deficiency (BKT) < 1 in 100,000
• Propionic acidemia (PROP) > 1 in 75,000
• Adenosylcobalamin synthesis defects
• Multiple-CoA carboxylase deficiency (MCD) < 1 in 100,000

[edit] Inborn errors of fatty acid metabolism

• Carnitine palmityl transferase deficiency type 2 (CPT)
• Long-chain acyl-CoA dehydrogenase deficiency (LCAD)
• Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) > 1 in 75,000
• Short-chain acyl-CoA dehydrogenase deficiency (SCAD)
• Short-chain hydroxy Acyl-CoA dehydrogenase deficiency (SCHAD)
• Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) > 1 in 25,000
• Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) > 1 in 75,000
• Carnitine/acylcarnitine Translocase Deficiency (Translocase)
• Multiple acyl-CoA dehydrogenase deficiency (MADD)
• Trifunctional protein deficiency (TFP) < 1 in 100,000
• Carnitine uptake defect (CUD) < 1 in 100,000

[edit] Congenital infections

• Congenital toxoplasmosis
• HIV

[edit] Miscellaneous multisystem diseases

• Cystic fibrosis (CF) > 1 in 5,000
• Maternal vitamin B12 deficiency
• Congenital hypothyroidism (CH) > 1 in 5,000
• Biotinidase deficiency (BIOT) > 1 in 75,000
• Congenital adrenal hyperplasia (CAH) > 1 in 25,000
• Classical galactosemia (GALT) > 1 in 50,000

[edit] Newborn screening by other methods than blood testing

• Congenital deafness (HEAR) > 1 in 5,000

[edit] Newborn screening programs worldwide

Newborn screening has also been adopted by most countries in Europe and around the world, though the lists of screened diseases vary widely.

Should I wake my baby for feedings?

For the first few weeks of life, I usually recommend that Mom wake the baby to breastfeed at least every two to three hours, measured from the start of one feeding to the start of the next, during the day and evening hours. It’s okay to let the baby take one longer stretch of sleep at night if she is able to do that.

Read more: http://parenting.ivillage.com/baby/bbreastfeed/0,,8n69dpmw,00.html#ixzz0VXIFcGKN

Background

Neonatal sepsis may be categorized as early or late onset. Eighty-five percent of newborns with early-onset infection present within 24 hours, 5% present at 24-48 hours, and a smaller percentage of patients present within 48-72 hours. Onset is most rapid in premature neonates. Early onset sepsis syndrome is associated with acquisition of microorganisms from the mother. Transplacental infection or an ascending infection from the cervix may be caused by organisms that colonize in the mother’s genitourinary tract, with acquisition of the microbe by passage through a colonized birth canal at delivery. The microorganisms most commonly associated with early-onset infection include group B Streptococcus (GBS), Escherichia coli , coagulase-negative Staphylococcus, Haemophilus influenzae , and Listeria monocytogenes .¹

Trends in the epidemiology of early onset sepsis show a decreasing incidence of GBS sepsis.² This article primarily focuses on bacterial infection and sepsis. Please see relevant eMedicine chapters for discussion of congenital infection, fungal infection, and viral infection of the newborn.

Late-onset sepsis syndrome occurs at 4-90 days of life and is acquired from the caregiving environment. Organisms that have been implicated in causing late-onset sepsis syndrome include coagulase-negative staphylococci, Staphylococcus aureus , E coli, Klebsiella, Pseudomonas, Enterobacter, Candida, GBS, Serratia, Acinetobacter, and anaerobes. Trends in late-onset sepsis show an increase in coagulase-negative Streptococcal sepsis; most of these isolates are susceptible to first-generation cephalosporins.² The infant’s skin, respiratory tract, conjunctivae, GI tract, and umbilicus may become colonized from the environment, leading to the possibility of late-onset sepsis from invasive microorganisms. Vectors for such colonization may include vascular or urinary catheters, other indwelling lines, or contact from caregivers with bacterial colonization.

Pneumonia is more common in early onset sepsis, whereas meningitis and bacteremia are more common in late-onset sepsis. Premature and ill infants have an increased susceptibility to sepsis and subtle nonspecific initial presentations; therefore, they require much vigilance so that sepsis can be effectively identified and treated.

Pathophysiology

The infectious agents associated with neonatal sepsis have changed over the past 50 years. S aureus and E coli were the most common bacterial infectious hazards for neonates during the 1950s in the United States. Over the ensuing decades, GBS replaced S aureus as the most common gram-positive organism that caused early-onset sepsis. During the 1990s, GBS and E coli continued to be associated with neonatal infection; however, coagulase-negative Staphylococcus epidermidis is now more frequently observed. Additional organisms, such as 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 syndrome can also be caused by infection with adenovirus, enterovirus, or coxsackievirus. Additionally, sexually transmitted diseases (eg, gonorrhea, syphilis, herpes simplex virus [HSV], cytomegalovirus [CMV], hepatitis, human immunodeficiency virus [HIV], rubella, toxoplasmosis, Trichomonas vaginalis, Candida species) have all been implicated in neonatal infection.

Bacterial organisms with increased antibiotic resistance have also emerged and have further complicated the management of neonatal sepsis. The colonization patterns in nurseries and personnel are reflected in the organisms currently associated with nosocomial infection. In neonatal ICUs (NICUs), infants with lower birth weight and infants who are less mature have an increased susceptibility to these organisms.

Staphylococcus 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 and intraventricular shunts. 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.

Biofilms are formed on indwelling catheters by the aggregation of organisms that have multiplied with 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 the host defense, as well as antibiotic action, making coagulase-negative staphylococcal septicemia more difficult to treat. The toxins formed by this organism have also been associated with necrotizing enterocolitis.

In addition to being a cause of neonatal sepsis, the ubiquitous nature of coagulase-negative Staphylococcus as part of the normal skin flora makes it a frequent contaminant of blood and cerebrospinal fluid (CSF) cultures; therefore, a culture growing coagulase-negative Staphylococcus may represent a contaminated sample rather than true coagulase-negative staphylococcal septicemia. The clinical setting, colony counts, and presence of polymorphonuclear (PMN) cells on gram stain of the submitted specimen often help to differentiate true infection and positive culture from a false-positive or contaminated specimen.

In addition to the specific microbial factors mentioned above, numerous host factors predispose the newborn infant to sepsis. These factors are especially prominent in the premature infant and involve all levels of host defense, including cellular immunity, humoral immunity, and barrier function.

Cellular immunity

The neonatal neutrophil or polymorphonuclear (PMN) cell, which is vital for effective killing of bacteria, is 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. Also, neonatal PMNs are less deformable; therefore, they are less able to move through the extracellular matrix of tissues to reach the site of inflammation and infection. The limited ability of neonatal PMNs for phagocytosis and killing of bacteria is further impaired when the infant is clinically ill. Lastly, neutrophil reserves are easily depleted because of the diminished response of the bone marrow, especially in the premature infant.

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 bacteriocidal 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.

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 when activated and do not effectively produce the cytokines that assist with B-cell stimulation and differentiation and granulocyte/monocyte proliferation. A delay occurs in the formation of antigen specific memory function following primary infection, and the cytotoxic function of neonatal T cells is 50-100% as effective as 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 upon primary stimulation than do adult NK cells. This combination of findings may contribute to the severity of HSV infections in the neonatal period.

Humoral immunity

The fetus has some preformed immunoglobulin present, 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.

The neonate is also capable of synthesizing immunoglobulin M (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, thereby stimulating increased IgM production. Immunoglobulin G (IgG) and immunoglobulin E (IgE) may be synthesized in utero. Most of the IgG is acquired from the mother during late gestation. The neonate may receive immunoglobulin A (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 widely varies among individual neonates. Although some infants have had complement levels comparable with those in adults, deficiencies appear to be greater in the alternative pathway than in the classic pathway. The terminal cytotoxic components of the complement cascade that leads to killing of organisms, especially gram-negative bacteria, are deficient. This deficiency is more marked in preterm infants. Mature complement activity is not reached until infants are aged 6-10 months. Neonatal sera have reduced opsonic efficiency against GBS, E coli, and S 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 mucus membranes are broken down easily in the premature infant. Neonates who are ill and/or premature are additionally at risk because of the invasive procedures that breach their physical barriers to infection. Because of the interdependence of the immune response, these individual deficiencies of the various components of immune activity in the neonate conspire to create a hazardous situation for the neonate exposed to infectious threats.

Frequency

United States

The incidence of culture-proven sepsis is approximately 2 per 1000 live births. Of the 7-13% of neonates who are evaluated for neonatal sepsis, only 3-8% have culture-proven sepsis. The early signs of sepsis in the newborn are nonspecific; therefore, many newborns undergo diagnostic studies and the initiation of treatment before the presence of sepsis has been proven. Additionally, because the American Academy of Pediatrics (AAP),³ American Academy of Obstetrics and Gynecology (AAOG), and Centers for Disease Control and Prevention (CDC)⁴ all have recommended sepsis screening and/or treatment for various risk factors related to GBS diseases, many asymptomatic neonates now undergo evaluation. Because the mortality rate of untreated sepsis can be as high as 50%, most clinicians believe that the hazard of untreated sepsis is too great to wait for confirmation based on positive culture results; therefore, most clinicians initiate treatment while awaiting culture results.

Mortality/Morbidity

The mortality rate in neonatal sepsis may be as high as 50% for infants who are not treated. Infection is a major cause of fatality during the first month of life, contributing to 13-15% of all neonatal deaths. Neonatal meningitis, a serious morbidity of neonatal sepsis, occurs in 2-4 cases per 10,000 live births and significantly contributes to the mortality rate in neonatal sepsis; it is responsible for 4% of all neonatal deaths. In the preterm infant, inflammatory mediators associated with neonatal sepsis may contribute to brain injury and poor neurodevelopmental outcomes.

Race

Black infants have an increased incidence of GBS disease and late-onset sepsis. This is observed even after controlling for risk factors of low birth weight and decreased maternal age.

Sex

The incidence of bacterial sepsis and meningitis, especially for gram-negative enteric bacilli, is higher in males than in females.

Age

Premature infants have an increased incidence of sepsis. The incidence of sepsis is significantly higher in infants with very low birth weight (<1000 g), at 26 per 1000 live births, than in infants with a birth weight of 1000-2000 g, at 8-9 per 1000 live births. The risk for death or meningitis from sepsis is higher in infants with low birth weight than in full-term neonates.

Clinical

History

The most common risk factors associated with early onset neonatal sepsis include maternal group B Streptococcus (GBS) colonization (especially if untreated during labor), premature rupture of membranes (PROM), preterm rupture of membranes, prolonged rupture of membranes, prematurity, maternal urinary tract infection, and chorioamnionitis.

Other factors associated with or predisposing to early onset neonatal sepsis include low Apgar score (<6 at 1 or 5 min), maternal fever greater than 38°C, maternal urinary tract infection, poor prenatal care, poor maternal nutrition, low socioeconomic status, recurrent abortion, maternal substance abuse, low birth weight, difficult delivery, birth asphyxia, meconium staining, and congenital anomalies.⁵ Risk factors implicated in neonatal sepsis reflect the stress and illness of the fetus at delivery, as well as the hazardous uterine environment surrounding the fetus before delivery.

Late onset sepsis is associated with the following risk factors: prematurity, central venous catheterization (duration of >10 d), nasal cannula or continuous positive airway pressure (CPAP) use, H2 blocker/proton pump inhibitor use, and gastrointestinal tract pathology.

An awareness of the many risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing mortality and morbidity.

• Maternal GBS status
  • The most common etiology of neonatal bacterial sepsis is GBS. Nine serotypes exist, and each is related to the polysaccharide capsule of the organism. Types I, II, and III are commonly associated with neonatal GBS infection. The type III strain has been shown to be most highly associated with CNS involvement in early-onset infection, whereas types I and V have been associated with early-onset disease without CNS involvement.
  • The GBS organism colonizes the maternal GI tract and birth canal. Approximately 30% of women have asymptomatic GBS colonization during pregnancy. GBS is responsible for approximately 50,000 maternal infections per year in women, but only 2 neonates per 1000 live births are infected. Women with heavy GBS colonization and culture results that are chronically positive for GBS have the highest risk of perinatal transmission. Also, heavy colonization at 23-26 weeks of gestation is associated with prematurity and low birth weight. Colonization at delivery is associated with neonatal infection. Intrapartal chemoprophylaxis of women with positive culture results for GBS has been shown to decrease the transmission of the organism to the neonate during delivery.
• PROM may occur in response to an untreated urinary tract infection or birth canal and is also associated with previous preterm delivery, uterine bleeding in pregnancy, and heavy cigarette smoking during pregnancy.
  • Rupture of membranes without other complications for more than 24 hours prior to delivery is associated with a 1% increase in the incidence of neonatal sepsis; however, when chorioamnionitis accompanies the rupture of membranes, the incidence of neonatal infection is quadrupled.
  • A recent multicenter study demonstrated that clinical chorioamnionitis and maternal colonization with GBS are the most important predictors of subsequent neonatal infection following PROM.⁶
  • When membranes have ruptured prematurely before 37 weeks’ gestation, a longer latent period precedes vaginal delivery, increasing the likelihood that the infant will be infected. The relationship between duration of membrane rupture and neonatal infection is inversely related to gestational age. Therefore, the more premature an infant, the longer the delay between rupture of membranes and delivery, and the higher the likelihood of neonatal sepsis.
  • A study by Seaward et al found that more than 6 vaginal digital examinations, which may occur as part of the evaluation for PROM, were associated with neonatal infection even when considered separately from the presence of chorioamnionitis.⁶
• Prematurity: The relationship between preterm PROM and neonatal sepsis has already been described; however, other associations between prematurity and neonatal sepsis increase the risk for premature infants.
  • Preterm infants are more likely to require invasive procedures, such as umbilical catheterization and intubation.
  • Prematurity is associated with infection from cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis B, toxoplasmosis, Mycobacterium tuberculosis, Campylobacter fetus, and Listeria species.
  • Intrauterine growth retardation and low birth weight are also observed in CMV and toxoplasmosis infections.
  • Premature infants have less immunologic ability to resist and combat infection.  This leads to infection with common organisms such as coagulase-negative staphylococci an organism usually not associated with severe sepsis.
• Chorioamnionitis: The relationship between chorioamnionitis and other risk variables is strong. Suspect chorioamnionitis in the presence of fetal tachycardia, uterine tenderness, purulent amniotic fluid, elevated maternal WBC count, and unexplained maternal temperature above 100.4°F (38°C).

Physical

The clinical signs of neonatal sepsis are nonspecific and are associated with characteristics of the causative organism and the body’s response to the invasion. These nonspecific clinical signs of early sepsis syndrome are also associated with other neonatal diseases, such as respiratory distress syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery. Given the nonspecific nature of these signs, providing treatment for suspected neonatal sepsis while excluding other disease processes is prudent.

• Congenital pneumonia and intrauterine infection: Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. This may not be caused by the action of the microorganisms themselves but may be caused by aspiration of amniotic fluid containing maternal leukocytes and cellular debris. Tachypnea, irregular respirations, moderate retracting, apnea, cyanosis, and grunting may be observed. Neonates with intrauterine pneumonia may also be critically ill at birth and require high levels of ventilatory support. The chest radiograph may depict bilateral consolidation or pleural effusions.
• Congenital pneumonia and intrapartum infection: Neonates who are infected during the birth process may acquire pneumonia through aspiration of the microorganisms during the delivery process. The aspiration may lead to infection with pulmonary changes, infiltration, and destruction of bronchopulmonary tissue. This damage is partly due to the granulocytes’ release of prostaglandins and leukotrienes. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure with an RDS-like presentation. Vascular congestion, hemorrhage, and necrosis may occur.
  • Klebsiella species and S aureus are especially likely to generate severe lung damage, producing microabscesses and empyema.
  • Early onset GBS pneumonia has a particularly fulminant course, with significant mortality in the first 48 hours of life.
  • Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue. Coughing, grunting, costal and sternal retractions, nasal flaring, tachypnea and/or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed.
  • Radiographic evaluation may demonstrate segmental or lobar atelectasis or a diffuse reticulogranular pattern, much like what is observed in RDS.
  • Pleural effusions may be observed in advanced disease.
• Postnatal infection: Postnatally acquired pneumonia may occur at any age. Because these infectious agents exist in the environment, the likely cause depends heavily on the infant’s recent environment. If the infant has remained hospitalized in an NICU environment, especially with endotracheal intubation and mechanical ventilation, the organisms may include Staphylococcus or Pseudomonas species. Additionally, these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Therefore, the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and the local antibiotic-resistance patterns.
• Cardiac signs: In overwhelming sepsis, an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia may occur. These cardiopulmonary disturbances may be due to the activity of granulocyte-derived biochemical mediators, such as hydroxyl radicals and thromboxane B2, an arachidonic acid metabolite. These biochemical agents have vasoconstrictive actions that result in pulmonary hypertension when released in pulmonary tissue. A toxin derived from the polysaccharide capsule of type III Streptococcus has also been shown to cause pulmonary hypertension. The early phase of pulmonary hypertension is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. The infant manifests overt shock with pallor, poor capillary perfusion, and edema. These late signs of shock are indicative of severe compromise and are highly associated with mortality.
• Metabolic signs: Hypoglycemia, hyperglycemia, metabolic acidosis, and jaundice all are metabolic signs that commonly accompany neonatal sepsis syndrome. The infant has an increased glucose requirement because of sepsis. The infant may also have impaired nutrition from a diminished energy intake. Hypoglycemia accompanied by hypotension may be secondary to an inadequate response from the adrenal gland and may be associated with a low cortisol level. Metabolic acidosis is due to a conversion to anaerobic metabolism with the production of lactic acid. When infants are hypothermic or they are not kept in a neutral thermal environment, efforts to regulate body temperature can cause metabolic acidosis. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction.
• Neurologic signs: Meningitis is the common manifestation of infection of the CNS. It is primarily associated with GBS (36%), E coli (31%), and Listeria species (5-10%) infections, although other organisms such as S pneumoniae, S aureus, Staphylococcus epidermis, H influenzae, and species of Pseudomonas, Klebsiella, Serratia, Enterobacter, and Proteus may cause meningitis. Acute and chronic histologic features are associated with specific organisms.
  • Ventriculitis
    • Ventriculitis is the initiating event, with inflammation of the ventricular surface. Exudative material usually appears at the choroid plexus and is external to the plexus. Then, ependymitis occurs with disruption of the ventricular lining and projections of glial tufts into the ventricular lumen. Glial bridges may develop by these tufts and cause obstruction, particularly at the aqueduct of Sylvius.
    • The lateral ventricles may become multiloculated, which is similar to forming abscesses. Multiloculated ventricles can isolate organisms in an area, making treatment more difficult.
    • Meningitis is likely to arise at the choroid plexus and extend via the ventricles through aqueducts 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, it complicates effective treatment because achieving adequate antibiotic levels in the cerebral ventricles is difficult.
    • When present, ventricular obstruction causes additional problems.
  • Arachnoiditis: This is the next phase and is the hallmark of meningitis. The arachnoid is infiltrated with inflammatory cells that produce an exudate that is thick over the base of the brain and more uniform over the rest of the brain. Early in the infection, the exudate is primarily polymorphonuclear (PMN) cells, bacteria, and macrophages. Exudate is prominent around the blood vessels and extends 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 of cranial roots 3-8 occurs. After this period, the exudate decreases. Thick strands of collagen form, and arachnoid fibrosis occurs, which is responsible for obstruction. Hydrocephalus results. Early onset GBS meningitis is characterized by much less arachnoiditis than late-onset GBS meningitis.
  • Vasculitis: This extends the inflammation of the arachnoid and ventricles to the blood vessels surrounding the brain. Occlusion of the arteries rarely occurs; however, venous involvement is more severe. Phlebitis may be accompanied with thrombosis and complete 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.
  • Cerebral edema: This may occur during the acute state of meningitis. The edema may be severe enough to greatly diminish the ventricular lumen. The cause is unknown, but it is likely 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: This is a prominent and serious feature of neonatal meningitis. It occurs 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.
  • Laboratory findings
    • Meningitis due to early onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneural signs. Neurologic signs may include stupor and irritability. Overt signs of meningitis occur in only 30% of cases. Even culture-proven meningitis may not demonstrate white cell changes in the CSF. Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80-90%). Impairment of consciousness (ie, stupor with or without irritability), coma, seizures, bulging anterior fontanel, extensor rigidity, focal cerebral signs, cranial nerve signs, and nuchal rigidity occur. In the neonate, many of these physical examination findings are subtle or nonapparent.
    • The CSF findings in infectious neonatal meningitis are an elevated WBC count (predominately PMNs), an elevated protein level, a decreased CSF glucose concentration, and positive culture results. The decrease in CSF glucose concentration does not necessarily reflect serum hypoglycemia. Glucose concentration abnormalities are more severe in late-onset disease and with gram-negative organisms. The CSF WBC count is within the reference range in 29% of GBS meningitis infections; in gram-negative meningitis, it is within the reference range in only 4%. Reference range CSF protein and glucose concentrations are found in about 50% of patients with GBS meningitis; however, in gram-negative infections, reference range CSF protein and glucose concentrations are found in only 15-20%.
    • Temperature instability is observed with neonatal sepsis and meningitis, either in response to pyrogens secreted by the bacterial organisms or from sympathetic nervous system instability. The neonate is most likely to be hypothermic. The infant may also have decreased tone, lethargy, and poor feeding. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs.
• Hematologic signs
  • The platelet count in the healthy newborn is rarely less than 100,000/µL in the first 10 days of life. Thrombocytopenia with counts less than 100,000 may occur in neonatal sepsis in response to the cellular products of the microorganisms. These cellular products cause platelet clumping and adherence leading to platelet destruction. Thrombocytopenia may be a presenting sign and can last as long as 3 weeks; 10-60% of infants with sepsis have thrombocytopenia. Because of the appearance of newly formed platelets, mean platelet volume (MPV) and platelet distribution width (PDW) are shown to be significantly higher in neonatal sepsis after 3 days. Because of the myriad of causes of thrombocytopenia and its late appearance in neonatal sepsis, the presence of thrombocytopenia does not aid the diagnosis of neonatal sepsis.
  • Although WBC counts and ratios are more sensitive for determining sepsis than platelet counts, they remain very nonspecific and have low positive predictive value. Normal WBC counts may be initially observed in as many as 50% of cases of culture-proven sepsis. Infants who are not infected may also demonstrate abnormal WBC counts related to the stress of delivery or several other factors. A differential may be of use in diagnosing sepsis. Total neutrophil count (PMNs and immature forms) is slightly more sensitive in determining sepsis than total leukocyte count (percent lymphocyte + monocyte/PMNs + bands). Abnormal neutrophil counts, taken at the time of symptom onset, are only observed in two thirds of infants; therefore, the neutrophil count does not provide adequate confirmation of sepsis. Neutropenia is observed in sepsis, maternal hypertension, severe perinatal asphyxia, and periventricular or intraventricular hemorrhage.
  • Neutrophil ratios have been more useful in diagnosing or excluding neonatal sepsis; the immature-to-total (I/T) ratio is the most sensitive. All immature neutrophil forms are counted, and the maximum acceptable ratio for excluding sepsis during the first 24 hours is 0.16. In most healthy, nonseptic newborns, the ratio falls to 0.12 within 60 hours of life. The sensitivity of the I/T ratio has ranged from 60-90%, and elevations may be observed with other physiological events, limiting the positive predictive value of these ratios; therefore, when diagnosing sepsis, the elevated I/T ratio should be used in combination with other signs.
  • Disseminated intravascular coagulation (DIC) can occur in infected infants. Predicting which infants will be affected at the onset of sepsis is difficult. Affected infants show abnormalities in prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen and D-dimer levels and may need blood products, including fresh frozen plasma (FFP) and cryoprecipitate, to replace coagulation factors consumed in association with DIC. If infants show signs consistent with impaired coagulation, including gastric blood, bleeding from intravenous or laboratory puncture sites, or other bleeding, evaluating coagulation by checking these values is important.
• GI signs: The intestinal tract can be colonized by organisms in utero or at delivery by swallowing infected amniotic fluid. The immunologic defenses of the intestinal 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 because antibody response and cytokine formation is immature until approximately 46 weeks. Necrotizing enterocolitis (NEC) has been associated with the presence of a number of species of bacteria in the immature intestine, and bacterial overgrowth of these organisms in the neonatal lumen is a component of the multifactorial pathophysiology of NEC.