In 1858, Sir Jonathan Hutchinson described the triad of signs of congenital syphilis: notched incisors, interstitial keratitis and eighth nerve deafness. Current understanding of congenital infection, however, is attributed to Gregg, an Australian opthalmologist, who, in 1941, described the association of infection due to rubella in early pregnancy with cataracts and lesions of the heart in the neonate. We now recognize that the signs of infection presenting in the newborn may result from transplacental infection acquired in utero, infection from organisms in the maternal genital tract occurring at the time of delivery, or post-natal infection from human sources or contaminated materials or equipment. As many as 2% of fetuses are infected in utero and up to 10% of infants are infected during delivery or in the first few months of life. Infection acquired in utero may result in resorption of the embryo, abortion, stillbirth, malformation, intrauterine growth retardation, prematurity and the untoward sequelae of chronic postnatal infection. Infection acquired during the birth process or soon after birth may result in severe systemic disease that leads to death or persistent postnatal infection. The immediate as well as the long term effects of these infections are a major problem throughout the world.
This article reviews the historical. perspectives of infections presenting in the newborn infant, including the current status of diagnosis and management. For more information about the specific infections, the reader is referred to recent texts.[1,2]
INFECTIOUS DISEASES OF THE FETUS
The majority of infections in the pregnant woman involve the upper respiratory and gastrointestinal tracts and either resolve spontaneously without therapy or are readily treated with antimicrobial agents. Such infections usually remain localized and have no effect on the developing fetus. However, the infecting organism may invade the blood stream and progress to infection of the fetus. Transplacental spread following maternal infection and invasion of the blood stream is the usual route by which the fetus becomes infected. Although the pregnant woman is exposed to all the infections prevalent in the community, only a few organisms have been consistently associated with infection of the fetus: rubella, cytomegalovirus (CMV), herpes simplex virus, and Toxoplasma gondii. In the past, syphilis was a major cause of congenital disease. At the turn of the century, fetal pathology and fetal syphilis were considered almost synonymous terms.[3] Today, malaria is an important cause of congenital infection in many tropical areas. In recent years, chickenpox[4] and coxsackieviruses B3 and B45 have been identified as causes of congenital defects: chickenpox infection early in pregnancy resulted in a small number of cases with a unique syndrome of limb deformities, cicatricial skin lesions, cortical atrophy and ocular abnormalities; coxsackievirus infection was associated with congenital heart disease. Although bacteremia due to the pneumococcus or the meningococcus may affect the fetus by causing significant alterations of maternal metabolism and respiration, these organisms do not cross the placenta and do not invade fetal tissue.
The Past. Rubella was differentiated from measles and scarlet fever by German scientists in the eighteenth century and epidemics of rubella were described in Europe and the United States during the nineteenth century. Gregg's report of association of lesions in the newborn with infection acquired during delivery[6] stimulated investigators to isolate and identify the virus. In 1962, independently and almost simultaneously, rubella virus was isolated by Weller and Neva at Harvard[7] and Parkman, Buescher and Artenstein at the Walter Reed Armed Forces Institute of Pathology.[8] By 1969, a live virus vaccine was produced by continuous passage in tissue culture resulting in attenuation of the virus without loss of immunogenicity. Thus, within seven years, investigators progressed from isolation of the virus to a means of prevention of the disease.
The history of cytomegalovirus infection begins at the turn of the century when several reports appeared about inclusion bearing cells in the kidneys, lungs, liver and parotid gland of stillborn infants and infants dying between two months and two years of age.[9,10] Goodpasture and Talbot suggested that these inclusions were similar to those described by Tyzzer in 1906 in cutaneous lesions of varicella and suggested that the "cytomegaly" could be the result of a similar agent.[11] The term "salivary gland virus disease" was used by Farber and Wolbach[12] because of the propensity of this agent to produce nuclear inclusions in the cells of the salivary gland duct epithelium. Similar to the discovery of rubella virus, isolation o£ cytomegalovirus was achieved in the early 1950's independently in the unassociated laboratories of Smith,[13] Rowe,[14] and Weller.[15] The term "salivary gland virus" was soon discarded as the systemic nature of the virus was appreciated and "cytomegalovirus" (CMV) was adopted.
Herpetic disease was described by the Roman physician, Herodotus.[16] Genital herpes infection was described in the seventeenth century by the French physician, Astruc.[17] The first report of neonatal herpes simplex infection is attributed to Hass, who, in 1935, reported the histopathology of a fatal case.[18] Herpes virus has recently been divided into types 1 and 2: Type 1 infects primarily non-genital sites, whereas type 2 infects genital sites.[19] The majority of cases of neonatal herpes infections are caused by type 2.
In 1908, Nicole and Manceaux observed a parasite in tissues of the North African rodent, the gondi.[20] The name chosen for this organism was Toxoplasma (from the Greek toxon, arc) gondii. In 1923, a Czech opthalmologist, Janku, described the first case of toxoplasmosis recognized in humans in an 11 month old child with congenital hydrocephalus and microophthalmos who had parasitic cysts in the reina.[21] In the late 1930's, cases of apparent congenital infection were identified and Wolf, Cowen and colleagues performed studies which established Toxoplasma as a cause of congenital infection.[22] In 1948, Sabin and Feldman reported the dye test which provided a means for serologic identification of infection and information about the immune response.[23] In 1969, the definitive host of T. gondii was found to be the cat.
The Present. The highest incidence of congenital infection is that due to CMV: one per 100 live born infants. Congenital infection due to herpes simplex is much less frequent: one clinically detected case per 7500 deliveries. The incidence of congenital toxoplasmosis is approximately one per thousand live born infants in the United States but is higher in European studies (3 per 1000 in Paris and 6 to 7 per 1000 in Vienna). Although the number of cases of congenital rubella has been substantially reduced since introduction of the live virus vaccine, many cases of congenital infection are still reported each year.[1]
Clinical signs: The consequences of transplacental fetal infection include: prematurity (CMV, herpes simplex virus and T. gondii); intrauterine growth retardation and low birth weight (CMV and rubella); developmental anomalies (CMV and rubella) and congenital disease; and persistent postnatal infection (CMV, rubella, T. gondii and herpes simplex virus). Each infection may present with hepatosplenomegaly, jaundice, pneumonitis, petechiae and purpuric rashes, or meningoencephalitis. But each is also identified by signs that have special diagnostic significance: rubella: congenital heart lesions, bone lesions, glaucoma, and cataracts; CMV: microcephaly and periventricular intracranial calcifications; T. gondii: hydrocephaly and diffuse intracranial calcifications; and herpes simplex virus infection: vesicular skin lesions.
Most infants with congenital herpes simplex infection have signs of disease at birth. In contrast, approximately 90% of infants with congenital infection due to CMV or 7'. gondii are without apparent signs. Recent reports indicate that many of these infants do have sequelae of congenital infection and that signs develop or are detected later in childhood. Hanshaw followed children with congenital CMV infection who were asymptomatic at birth; by the fifth year of life the majority had some neurologic abnormality including mental retardation and sensorineural hearing loss.[24] A recent report by Wilson, et al. about children with congenital infection due to T. gondii who were without signs of disease at birth is equally disturbing. Twenty-four children were observed: the mean age of the children at last examination was 8.5 years. All but two of the children had developed chorioretinitis -- six children had unilateral, and five children had bilateral, blindness. Three children developed severe, permanent neurologic sequelae after they presented with eye signs.[25] Thus, we can no longer assume that children with congenital infection who appear normal at birth have escaped without sequelae.
Therapy: Specific treatment is available only for T. gondii. Drugs of value include pyrimethamine in combination with sulfadiazine and spiramycin (not available in the United States). The efficacy of these agents has been demonstrated in vitro and in experimental studies in animals, but there are no reports of controlled trials in humans. Nevertheless, most experts believe treatment is important for the child with overt disease to prevent further tissue invasion and destruction by the proliferative form of the parasite. The data of Wilson, et al[25] suggest that children should receive therapy when the diagnosis is established, whether or not signs of the disease are present.
Prevention: The live virus rubella vaccine is the only available mode of specific prevention of a congenital infection. The vaccine was initially developed by multiple passage in green monkey kidney cells and further passage in duck embryo, rabbit kidney or dog kidney cells. The product distributed in the United States today is a live virus vaccine attenuated by multiple passage in human diploid cells. More than 80 million doses of live attenuated rubella virus vaccine were distributed in the United States in 1977. The initial recommendation of public health groups was based on the concept of developing a high level of herd immunity among children who are the major source of transmission for the virus. Thus, the thrust of vaccine programs was to immunize infants at about one year of age. The vaccine has proved to be safe and highly effective. Outbreaks of disease have not occurred in the United States since; 1964. However, there has been a shift in the age specific attack rate for the natural infection. The highest rates of infection today occur in teenagers and young adults. In 1977, 70% of the cases occurred in those 15 years of age and older. Of persons in these age groups, 10% to 20% are susceptible, rates which are comparable to those present prior to introduction of the vaccine. Since the goal of the vaccine program is eradication of congenital infection, the program must be considered short of its goal until women in the child bearing years have high rates of protection. The shift in age specific attack rate suggests that congenital infection will continue to occur until widespread immunization has taken place in these age groups. Current programs for use of rubella vaccine encourage physicians to test females in the child bearing years for susceptibility and immunize those who are unprotected.
INFECTIONS ACQUIRED BY THE NEWBORN INFANT DURING BIRTH
The developing fetus is protected from the microbial flora of the maternal genital tract. Initial colonization of the newborn and of the placenta usually occurs after rupture of the maternal membranes. If delivery is delayed after the membranes rupture, the vaginal microflora may ascend and in some cases will produce inflammation of the fetal membranes, umbilical cord and placenta. Fetal infection may also result from aspiration of infected amniotic fluid. The variety of microorganisms that may be present in the maternal birth canal include: bacteria -- gram-positive cocci (groups A,B, and D streptococci), gram-negative enteric bacilli (Escherichia coli, Klebsiella and Enterobacter sp., Proteus sp., and Pseudomonas sp.); and anaerobic bacteria (Bacteroides sp. and Clostridiunt sp.); viruses -- CMV, hepatitis B virus and herpes simplex viruses; fungi -- Candida albicans; chlamydia -- C. trachomatis; mycoplasma -- M. hominis and Ureaplasma urealyticum; and Protozoa -- Trichomonas vaginalis. Bacterial infection is of most concern because of the continuing high mortality and morbidity.
The Past. Microbiology: The changing pattern of bacterial organisms responsible for neonatal sepsis is reflected in a series of reports by pediatricians at the Yale-New Haven Hospital covering the period 1933 to 1978 (Table 1).[26-28] Prior to the development of the sulfonamides, grain-positive cocci caused most cases of neonatal sepsis. With the introduction of antimicrobial agents, gram negative bacilli--particularly E. coli -- became the predominant cause of serious infections in the newborn infant. Staphylococcus aureus was a major concern in the years 1950 to 1963, but subsequently diminished in importance.
Prior to the introduction of antimicrobial agents, almost all infants with neonatal sepsis died. The mortality rate remained high, 67% during the period 1944 to 1957, years which included introduction of penicillin, streptomycin and the broad spectrum drugs, tetracyclines and chloramphenicol. The introduction of semi-synthetic penicillins and the aminoglycosides, such as kanamycin, had some effect but the mortality rate remained high, 45% for the years 1958 to 1965.
Antimicrobial agents: The clinical pharmacology of antimicrobial agents administered to the newborn infant is unique and cannot be extrapolated from data on absorption, excretion and toxicity in the adult. Although this concept is now well accepted, the special characteristic of pharmacology of drugs in the neonate was not appreciated at the beginning of the antibiotic era. Treatment schedules for neonates were usually adopted from those developed in older children and adults. The result was a series of mishaps that had not been noted with drug use in the other age groups. High levels of unconjugated chloramphenicol occurred in neonates when a dosage schedule derived from older children was used. The result was cardiovascular collapse and death (the gray baby syndrome).[29,30] Immaturity of the hepatic glucuronyl transferase system and diminished glomerular and tubular function in the newborn infant resulted in high serum concentration of free and conjugated chloramphenicol. The cardiovascular effects are believed to be a result of the high levels of the unconjugated drug. A significant increase in kernicterus occurred in premature infants who received sulfisoxazole.[31] The sulfonamide displaced bilirubin from albumin binding sites resulting in kernicterus at lower than expected levels of serum total bilirubin. Deafness resulted from excessive blood levels of dihidrostreptomycin[32] and kanamycin.[33] By 1960 the lessons were clear and new drugs were introduced for use in neonates only after carefully designed trials had been conducted in newborn infants of different gestational and post-natal ages.
The Present. Incidence of sepsis and meningitis: The incidence of neonatal sepsis (defined as clinical sepsis accompanied by bacteremia with a known pathogen during the first month of life) varies between one and 5.2 cases per 1000 live births. The incidence of meningitis is usually a fraction (approximately one-third) of the infants with sepsis. Infections of the urinary tract occur in approximately one per cent of live born infants. There has been little apparent change in the overall incidence of systemic infections in newborn infants in the past 40 years, although rates of disease differ among institutions and countries and there are changing patterns of causative organisms. The current mortality rate of neonatal sepsis varies between 10 and 30% and is approximately twice as high if meningitis ensues.
Microbiology: The most recent report from Yale 28 documents the current importance of group B streptococci and Escherichia coli in neonatal sepsis. The Yale experience is similar to those in other centers in the United States and Western Europe. The increasing incidence of group D streptococci and a small but surprising increase in bacteremia due to Haemophilus influenzae are also documented in the Yale report.
Use of antimicrobial agents: The choice of antimicrobial agents for treatment of bacterial infections is based on knowledge of the organisms responsible for neonatal sepsis and the patterns of their antimicrobial susceptibility. Group B Streptococcus and Escherichia coli are currently the bacterial pathogens most often responsible for sepsis and meningitis. Thus, initial therapy must include a penicillin for treatment of gram-positive organisms and an aminoglycoside for infections that are caused by gram-negative enteric bacteria. The choice of antibiotics is reevaluated when results of cultures and susceptibility tests are available.
The special problem of neonatal meningitis: Since the pathogens responsible for neonatal meningitis are the same as those that cause neonatal sepsis, initial therapy is the same. The mortality rate of neonatal meningitis remains high, approximately 30%, and gram-negative bacilli have been isolated from cerebrospinal fluid (CSF) even when bactericidal titers of the antimicrobial agents were present. Although the basis for the persistence of' organisms in CSF is unknown, it appears that the levels of antimicrobial activity in CSF is inadequate to sterilize the fluid. The persistence of organisms in CSF and the continued high mortality rate from neonatal meningitis have encouraged investigators to consider other modes of administration of antimicrobial agents, so that higher levels of drug can be achieved at the site of infection. A four year collaborative study of neonatal meningitis caused by gram-negative bacilli was conducted to determine the efficacy of parenteral gentamicin therapy alone, compared with parenteral plus intrathecal gentamicin.[34] The mortality rate was approximately 30%; no significant improvement was apparent in the group receiving the addition of intrathecal drug. A second collaborative study investigated the value of intraventricular therapy for neonatal meningitis: infants were randomly assigned to receive gentamicin by the parenteral route only or in combination with intraventricular gentamicin. Infants in the group receiving intraventricular gentamicin had a higher mortality rate than did infants receiving systemic therapy only.[35] Thus, the optimal therapy at present for neonatal meningitis caused by gram-negative enteric bacilli remains uncertain. Use of chloramphenicol or one of the new and more active cephalosporins (cefoperazone, cefotaxime or moxalactam) may be of value.
INFECTIONS OF THE NEWBORN INFANT ACQUIRED IN THE FIRST MONTH OF LIFE
The nursery is a small community of highly susceptible patients cared for by many adults. After arrival in the nursery, the newborn may become infected by various pathways involving either human carriers or contaminated materials and equipment. Human sources include personnel, mothers and other infants. Contaminated equipment or materials such as contaminated solutions used in nebulization equipment, room humidifiers or bath solutions have been implicated in common source nursery outbreaks.
After discharge from the nursery, the newborn is challenged by the microbial flora of members of the household. The infant is highly susceptible to infections agents that colonize in other members of the household and may be a source of infection for the newborn. Likewise, the infant with congenital rubella may shed virus for many months and be a source of infection for the family. Staphylococcal disease may occur in family members, because the infant or mother introduces a virulent strain into the household.
The Past. Outbreaks of respiratory and gastrointestinal illness, most of' which were caused by non-bacterial agents, were not infrequent in nurseries. Epidemics of staphylococcal disease in newborn nurseries were described in the nineteenth century and noted again in the late 1920's. Epidemic disease due to virulent strains of S. aureus were note throughout the world in a 15 year period beginning in 1950. The staphylococcus began to diminish in importance about 1963; the reasons for the decrease in infection and disease were not apparent but appear to be due to colonization in nurseries with strains of S. aureus that were less virulent than strains present in the previous decade.
The Present. An increasing number of low birth weight and premature infants are surviving in our nurseries because of the increased sophistication of life support mechanisms. These infants are immunologically immature and highly susceptible to invasive bacterial disease. In addition, many of the techniques that are used to stabilize respiration and metabolism, such as percutaneous and umbilical catheters and endotracheal tubes, are invasive and breach the usual defense mechanisms. Infection remains a leading cause of death in neonatal intensive care nurseries.
Group B Streptococcus and Escherichia coli are the leading causes of infection for late-onset disease (whose first signs appear after 5 days of age). Other organisms present in the nursery may infect the neonate, including Pseudomonas sp. and Klebsiella-Enterobacter sp. and, uncommonly, S. aureus. Initial therapy must be directed to the organisms known to be prevalent in the nursery. The extensive use of' antibiotics may result in alterations in the antibiotic susceptibility of bacteria and necessitate changes in considerations of initial therapy. The hospital laboratory must regularly monitor isolates of pathogenic bacteria to assist the physician in the choice of the most appropriate initial therapy.
The reasons for the changing pattern of bacteria responsible for neonatal sepsis are for the most part unknown. Undoubtedly, introduction of the various antibiotics over four decades was important, but equally important are the many changes in management of' the newborn infant, including introduction of the intensive care nursery with resulting increased survival of' immature infants. We are still uncertain about the basis for the diminished importance of S. aureus in recent years or the reason for the current prevalence of group B streptococcal infection.
The Future. Current investigations suggest new methods for more effective treatment and prevention of infections in the newborn infant. A brief discussion of selected studies indicates the scope and promise of these investigations.
Plotkin and colleagues at the Wistar Institute in Philadelphia are studying use of a live CMV vaccine prepared by multiple passage in human diploid cell cultures. The uncertainties about the immunology of CMV infection and the latency of the virus in infected individuals raise many important questions about the value of such a vaccine. These questions are discussed in a review by Osborn.[36] Anti-viral chemotherapeutic agents are available and are being studied in many centers. The most promising agent is acyclovir which inhibits the replication of herpes simplex viruses and has been demonstrated to be effective in infections in selected adults. These agents would be expected to be of limited value in treating in utero infections but may be important in therapy of infections acquired during delivery. Collaborative studies are in progress to determine the efficacy of anti-viral drugs for infections in the neonate due to CMV and herpes simplex virus.
Despite appropriate antimicrobial and optimal supportive therapy, mortality resulting from bacterial sepsis remains high. With the hope of improving survival and decreasing the severity of sequelae in survivors, investigators have turned their attention to studies of adjunctive modes of treatment which address themselves to demonstrate deficits in the host defenses of the infected neonate. These investigational therapies include transfusions of polymorphonuclear leukocytes, exchange transfusion and use of gamma globulin (both standard and modified hyper-immune serum globulin preparations). Results of preliminary studies[37-39] are promising and will stimulate large scale trials.
The fulminant nature of some cases of bacterial sepsis in the newborn limits the impact of any mode of therapy. The demonstration of group B streptococcal sepsis which occurred in infants born to mothers lacking protective antibodies led to current investigations of specific vaccines. A vaccine prepared from purified capsular polysaccharide from type III group B Streptococcus (which is responsible for more than 60% of invasive neonatal group B streptococcal disease) has been shown to be immunogenic in adult volunteers.[40] Additionally, cross reactivity between type III group B Streptococcus and type 14 Streptococcus pneumoniae (which is contained in the current 14 type pneumococcal vaccine) has been demonstrated and may provide a mode of active immunization."
|
Organism |
1933-43[25] |
1944-57[25] |
1958-65[26] |
1966-78[27] |
|
Beta-hemolytic streptococcus |
18 |
11 |
8 |
86 a |
|
- Group A |
16 |
5 |
0 |
0 |
|
- Group B |
2 |
4 |
1 |
76 |
|
- Group D |
0 |
1 |
7 |
9 b |
|
- Group F |
0 |
1 |
0 |
0 |
|
Staphylococcus aureus |
4 |
8 |
2 |
12 |
|
Streptococcus pneumoniae |
5 |
3 |
2 |
2 |
|
Haemophilus sp. |
0 |
0 |
1 |
9 c |
|
Escherichia coli |
11 |
23 |
33 |
76 |
|
Klebsiella-Enterobacter sp. |
0 |
0 |
8 |
28 |
|
Pseudomonas aeruginosa |
0 |
13 |
11 |
5 |
|
Proteus sp. |
0 |
0 |
0 |
4 |
|
Mixed |
3 |
1 |
0 |
11 |
|
Other |
3 |
3 |
8 |
6 |
|
Total |
44 |
62 |
73 |
239 |
a. One case ungroupable.
b 6 cases enterococcus, 3 cases Streptococcus bovis
c 1 type b, 1 type d, 2 type f, 4 non-typeable, 1 H.
parainfluenzae
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32. Robinson G. C., Cambon K. G.: Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy. New Eng. J. Med. 271:949, 1964.
33. Yow M. D., Tengg N. E., Bangs J., et al.: The ototoxic effects of kanamycin sulfate in infants and children. J. Pediatr. 60:230, 1962.
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37. Laurenti F. R., Isacchi G., et al.: Polymorphonuclear leukocyte transfusion for the treatment of sepsis in the newborn infant. J. Pediatr. 98:118, 1981.
38. Vain N. E., Mazlumian J. R., Swarner O. W., et al.: Role of exchange transfusion in the treatment of severe septicemia. Pediatrics. 66:693, 1980.
39. Santos J. I., Shigeoka A. O., Hill H. R.: Protective efficacy of a modified immune serum globulin in experimental group B streptococcal infection. Submitted for publication.
40. Baker C. J.: Summary of the workshop on perinatal infections due to group B streptococcus. J. Infect. Dis. 136:137, 1977.
41. Fischer G. W., Lowell G. H., Crumrine M. H., et al.: Immunoprecipitation and opsonic cross-reaction between type 14 pneumococcus and group-B Streptococcus type III. Lancet. 1:75, 1979.