Infectious Diseases in Children and Newer Vaccines Tapan Kr Ghosh
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Intrauterine Infection – Interpretation of Tests and Management Protocols1

M Indrashekhar Rao
 
INTRODUCTION
Maternal infections acquired shortly before conception or during gestation can adversely affect pregnancy outcome indirectly through nonspecific effects of maternal illness or directly through microbial invasion of fetus or neonate.
  1. Pathogens can be transmitted from mother to their fetus through hematogenous spread across placenta (e.g., CMV, Toxoplasma).
  2. Ascending infection from infected cervix (e.g., HSV).
  3. Intimate contact between a fetus and infected genital secretions during vaginal delivery (e.g., HSV, HIV).
  4. Maternal coinfection by other organisms may enhance the risk of fetal infection.
  5. Iatrogenic fetal infections can occur even after procedures such as fetal scalp monitoring or intrauterine transfusions.
 
Vertically Transmitted Infections
These can be considered into two major categories:
  1. Congenital infections—Consist of infections transmitted to fetus in utero.
  2. Perinatal infections—Consist of infections which are acquired in the intrapartum period or immediate postpartum period.
Intrauterine infection may lead to resorption of embryo, fetal demise resulting in spontaneous abortion or stillbirth, or delivery of an infected neonate. Infected neonates suffer from acute neonatal infections such as pneumonias, hepatitis (HSV), congenital malformation (CMV, rubella), IUGR, prematurity. The infected infant asymptomatic at birth may develop chronic infection later as in late infancy or early childhood, (e.g., HIV, CMV, hepatitis C) or in adulthood, (e.g., hepatitis B).
 
TORCH
The acronym—TORCH has long been used as a reminder that a number of pathogens can cause clinically similar illness in the neonate and shares clinical features e.g., microcephaly, hepatosplenomegaly, petechiae, etc.
The TORCH infection can also cause aymptomatic infection in the newborn and has risk of causing long-term sequelae e.g., Treponema pallidum, HIV, coxsackie. The diagnostic workup of infants includes both invasive and noninvasive procedures.
 
 
Invasive Investigations
These procedures are not absolutely free from hazards affecting the fetus including fetal loss.
2These include:
(1) Amniocentesis. (2) Cordocentesis. (3) Chorionic villus sampling. (4) Electron-microscopy.
 
Noninvasive Investigations
(1) Umbilical artery doppler resistance index.
(2) Culture. (3) Antenatal USG. (4) Maternal serology. (5) Neonatal serology.
 
Invasive Investigations
  1. Amniocentesis—Midtrimester amniocentesis performed between 15 and 17 weeks of gestation, by USG guided percutaneous abdominal needle. One ml of fluid per week of gestation is collected for bacterial, viral culture e.g.,
    • CMV, VZV, HIV.
    • Gram stain.
    • Quantitative assay of immunoglobulins.
    • Tissue innoculation and PCR.
  2. Cordocentesis—Fetal blood sampling by percutaneous puncture of umbilical cord done after 15 weeks of gestation using high resolution USG.
    • Detection of virus-specific IgM antibody.
    • Detection of viral DNA, e.g., Toxoplasma.
    • Visualization of viral particles by immune electron microscopy.
    • Viral culture, e.g., CMV assay.
    • PCR assay.
  3. Chorionic villus sampling — Excellent technique performed transcervically and transabdominally as early as 7 to 10 weeks of gestation. The proceedure is associated with IUGR and fetal death.
  4. Electron microscopy—Useful for detection of virus particles in fetus with negative pathogen-specific IgM and normal total IgM. Once the microscopy of the the virus particles has been identified a targetted search for the IgM or lgG-specific staining is possible
 
Noninvasive Investigations
  1. Umbilical artery doppler resistance index—This is measured sonographically, the index is typically elevated in fetus with intrauterine viral infections due to fetal hypoxemia and acidosis.
  2. Culture—Body fluids including CSF, urine, blood, skin can be cultured for detection of offending organism based on the predilection of an organism in different organ systems, e.g., urine culture—CMV, vesicular fluid culture —HSV.
  3. Antenatal ultrasound—The 3D USG display X, Y, Z planes and generates additional views and helps in visualizing diverse abnormalities associated with IU infection like fetal growth retardation, non-immune hydrops, oligohydramnios, microcephaly and cerebral calcifications.
  4. Serology—The specific IgM in serum is increased in acute infection. Recent advances helps in direct DNA analysis of fetoplacental unit to determine whether infection has occurred.
Now, let us view in detail the clinical diagnostic criteria, interpretation of laboratory tests and management protocols of various viral, protozoal, spirochetal and bacterial intrauterine infection.
 
Herpes Simplex Virus
There are two distinct type 1 and type 2 HSV is an important cause of neonatal disease. Intrapartum transmission is the most common mode of transmission and is associated with active shedding of the virus from cervix and vagina. In utero infection is rare. Diagnosis is by high degree of clinical suspicion. An infant presents with the disease as vesicles on the 6th to 9th day on the skin, eye and mucotanneous membranes. One-third of the affected children present with enecephalitis, one-third with disseminated infection with seizures, shock and DIC/hepatitis.
Diagnosis—IgM Serology is of little use as cannot be detected up to 3 weeks. Virus specific IgM can also be isolated from lesions of oro and nasopharynx. In encephalitis identification of 3viral DNA in CSF by PCR, increased CSF protein levels and pleocytosis are often seen.
Management—Acyclovir is used at 10–15mg/kg every 6 to 8 hours for 10 to 14 days. In CNS or disseminated disease, the drug is to be used for 21 days.
 
HIV
HIV is a cytopathic RNA virus which enters the host CD4 cell and destroys the host immune system. In utero and intrapartum transmission from the infected mothers accounts for most of the pediatric cases. Transmission can occur throughout gestation period and HIV has been isolated from cord blood and products of the conception as early as14 to 20 weeks of gestation.
Diagnosis—In the early neonatal period diagnosis is difficult when HIV-specific IgG antibody is passively transferred. The median age for clearance is 13 months.
Positive IgG in child less than 18 months indicate maternal infection but cannot confirm fetal infection.
Virus co-culture, p24 anitgen detection, HIV specific IgM/IgA all three have low sensitivity in the 1st week of life.
Early dignosis of HIV DNA is by PCR assay, positive predictative value in neonates having in 56 per cent and older infants 83 per cent.
Table 1.1 shows interpretation of PCR assay.
Table 1.1   Interpretation of PCR assay
Age
Result
Interpretation
At birth
30-50% +ve
Intrautrine infection
7 Days
–ve at birth but
+ve at 7 days
Intrapartum transmission
False positive PCR indicates contamination with maternal blood.
Child exposed to HIV should be tested at 1, 2, 4 months by viral culture and PCR, if negative at 4 months >95 per cent assurance that the infant is not infected.
Exposed infant is considered negative when: (a) No physical finding of infection. (b) Virologocal tests are negative. (c) Immunoloical tests – CD4 counts are normal. (d) >12 months of age and 2 or more HIV antibody tests are negative.
Management—Management of HIV is symptomatic optimization of nutrition, prophylaxis against opportunistic infections and prompt recognition of the symptoms and signs of HIV-related complications aiming improve longivity and quality of life. Treatment is being tried with the following retroviral therapies:
  1. Drugs inhibiting viral proteins such as reverse transcriptase like zidovudine. It is beneficial in children with symptomatic HIV especially with CNS manifestations.
  2. Immunotherapy—Interferon / monoclonal antibody.
 
Rubella
This human-specific RNA virus is a member of Toga-virus family causes mild self-limiting infection in adults but has a devastating effect on fetus. Infection can occur at anytime during the pregnancy but early gestation infection is very destructive. Congenital rubella syndrome (CRS) presents as cataract, IUGR, retinopathy, microcephaly, meningoencephalitis, congential heart disease, splenomegaly, thrombocytopenic purpura. With infection in the 1st 12 weeks rate of infection is 81 per cent. As the gestational age advances the rate drops, and again after 36 weeks and beyond increases up to 100 per cent.
Prenatal diagnosis—Isolating virus from amniotic fluid.
Identification of rubella specific IgM by percutaneous umbilical blood sampling. In these tests sensitivity specifity are limited.
Postnatal diagnosis—Definitive diagnosis by virus isolation in pharyngeal washing, CSF, conjunctiva and lens at autopsy.
Rubella virus RNA can be detected by PCR in clinical specimens.
4Detection of rubella-specific immunoglobulin (Ig) in cord blood.
In addition to the congenital defects, the persistent rubella specific IgG with no decline as expected from maternally acquired IgG the diagnosis of congenital rubella syndrome is made.
Management—Treatment is symptomatic.
Prevention—By rubella immunization of adolescent girls or by universal immunization.
 
Cytomegalovirus
Members of herpes virus family characterized by typical cytopathology of infected cells, cellular enlargement with internuclear and cytoplasmic inclusions. The rate of the intrauterine transmission from primary maternal infection is 30 to 40 per cent.
Approximately 18 per cent develop significant disease. In mother's with recurrent infection, fetus and the newborn are rarely infected. Risk of transmission in relation to gestational age is uncertain although infection during early gestation causes a higher risk of fetal disease.
Symptomatic CMV may presents as an acute fulminant infection with multisystem involvement with petechiae, purpura, hepatosplenomegaly, jaundice and pneumonia.
A second insidious presentation with microcephaly and IUGR, chorioretinitis and periventricular calcification present with mental retardation, hearing and motor abnormalities and visual disturbances.
Prenatal diagnosis—Amniocentesis and cordocentesis to detect CMV DNA by PCR.
Postnatal diagnosis—Infant presents with the characteristic symptoms. Isolation of virus from urine or saliva within 1 to 2 weeks results in definitive diagnosis, and after 2 weeks indicates that the disease may have been perinatally acquired.
Shell viral cultures are used for better isolation.
Also CMV DNA by PCR can be measured.
Management—There is highly effective antiviral therapy currently available, gancyclovir and hyperimmune CMV immunoglobulins can be used in older immunosuppressed patients. Termination of pregnancy can be advised.
 
Varicella Zoster Virus
Member of the herpes virus family. Incidence of congenital varicella syndrome following maternal infetcion in first trimester is 2 per cent.
Prenatal diagnosis—By sonographic abnormalities like hypoplastic extremities, clubfoot, flexed limbs hydrocephalas and microcephaly can be detected. VZV specific antibody in fetal blood is confusing.
VZV DNA detection by PCR in amniotic fluid is specific.
At birth—Virus isolation from vesicular fluid on culture. Demonstration of four-fold rise in VZV antibody titre by fluorescent antibody to membrane antigen.
Management—Infants with perinatal varicella acquired from maternal illness near the time of delivery are at risk of severe disease.
Acyclovir 30 mg/kg per day 3 lines a day for 7 days should be given. In disseminated disease higher dose may be appropriate.
VZ immunoglobulin may be of prophylactic value when given within 72 hours of exposure. The dose of newborns is 125 units IM.
 
Parvovirus
These are small unenveloped viruses, most infectious strain is B19 whose overall rate of transmission from an infected mother to fetus is one-third. Risk of fetal loss is 10 per cent. It has been firmly linked to fetal nonimmune hydrops by affecting the hematopoietic cell lines. If acute or recent parovirus B19 infection is confirmed 5in pregnant women by positive B19-specific IgM assay serial ultrasound should be done for fetal hydrops.
 
Prenatal Diagnosis
  1. Fetal blood and amniotic fluid for parovirus IgM specific antibody.
  2. PCR to detect B 19 DNA. Hundred per cent results when fetal blood is subjected to in situ hybridization.
 
Postnatal Diagnosis
  1. Serum IgM rises in 3 days and falls by 2 to 3 months.
  2. Serum IgG appears a few days after IgM disappears and lasts for years.
Management—Generally supportive. IV immunoglobulin is given in those with hematological disorders in limited number of patients. Intrauterine blood transfusion has been used in cases with fetal hydrops.
 
Hepatitis Viruses
 
Hepatitis C
Single-stranded RNA virus related to flavivirus family. There is high transmission rate in mothers with high viral loads. Coinfection with HIV increases transmission.
Diagnosis–HCV RNA PCR should be done.
Management–IV immunoglobulin shows no benefit. In chronic infections alpha interferon may be given.
 
Hepatitis B
Intrauterine transmission is rare. Detection is by HBsAg specific IgG in serum.
 
Spirochetes
 
Syphilis
Syphilis can be transmitted to the infant regardless of duration of maternal disease but more so in the 1st year of infection. Transmission occurs more commonly after 4th month of pregnancy. Liver is primary site of infection followed by secondary spread to skin, mucous membranes and bones.
Prenatal diagnosis—Amniocentesis and fetal blood sampling to detect spirochetes by:
  1. Dark field microscopy.
  2. Indirect immunoflourescent staining.
  3. Innoculation in rabbit.
  4. Detection of DNA by PCR
Diagnosis at birth—(a) Dark field examination of monocutaneous lesions. (b) If RPR and VDRL titers fourfold greater than maternal titers fetal infection is very likely. (c) IgM fluorescent antibody. (d) Congenital neurosyphilis difficult to diagnose. CSF mononuclear pleocytosis, increased protein, reactive CSF VDRL may indicate infection.
Management—Infection without CNS involvement–Aqueous crystalline penicillin G 1 to 1.5 lakh units/kg/IM/IV –10 to 14 days
For CNS infection—Treatment for 3 weeks.
Infants with low risk for congenital syphilis but close follow-up is doubtful – Benzathine penicillin G 50,000 units/kg/day IM single dose.
 
Protozoa
 
Toxoplasmosis
An intracellular protozoan with 30 to 40 per cent vertical transmission. The severity of fetal disease is inversely proportional to gestational age. Primary neurological disease presents with intracranial calcifications, chorioretinitis and convulsions. The generalised disease presents with hepatosplenomegaly, lymphadenopathy, jaundice and anemia.
Prenatal diagnosis—(a) Serial USG to detect hydrops, ventricular dialatation, cerebral or hepatic calcification and ascites. (b) Amniocentesis to isolate organisms by inoculation in mice or by tissue culture. (c) PCR analysis B1 6gene amplification of amniotic fluid has 97.4 per cent sensitivity.
Postnatal diagnosis—(a) Isolation of toxoplasma in infant blood peaks in 1st week. (b) Detection antigen/DNA by PCR in bodyfluids is diagnostic. (c) Levels of maternally-acquired IgG drops at the rate of 50 per cent per month. If not so, active fetal infection is suspected. (d) In children < 3 months transformation of lymphocytes on exposure to toxoplasma antigen is sensitive.
Management—Extended therapy for both symptomatic and subclinical congenital infection should be given with pyrimethamine and sulphadiazine or triple sulphonamides.
 
Malaria
It is an obligate intracellular protozoan of genus Plasmodium. Neonatal infection has been recorded with all species. The placenta has been involved in most women who acquire malaria during pregnancy. It is not clear whether transmission to infant is transplacental or from direct contact with placental blood during parturition. Most infants have onset of symptoms by 8th week of life with fever, anemia and splenomegaly. About one-third have jaundice.
Diagnosis—Maternal history of febrile illness can be elicited in most cases. The diagnosis of congenital malaria can be entertained in any infant who presents with fever, anemia, hepatosplenomegaly and born to mother who resided in an endemic area. The parasite can be identified in cord blood and peripheral blood by thick and thin smear.
Management—Chloroquine given as 10mg/kg as initial dose followed by 5mg/kg for 3 days. If no response IV quinine may be given
 
Bacteria
 
Listeria Monocytogenes
It is a nonsporulating beta-hemolytic short Grampositive organisms. Transplacental transmission is believed to be most significant mechanism for acquiring early onset disease although ingestion of aspirated amniotic fluid before delivery is possible. Infected neonates present with sepsis and pneumonia. They manifest with anorexia, lethargy, vomiting, respiratory distress, apnea, cyanosis and petechial rash.
Diagnosis—Prompted by maternal history of stillbirth and repeated abortions. Diagnosis is by culture of blood, urine and CSF. Gram staining shows Gram-variable organisms which look like diptheroids.
Management—Ampicillin 100 to 200 mg/kg/day and gentamicin 5mg/kg up to 14 to 21 days.
 
CONCLUSION
Diagnosis of intrauterine infections are mainly by a great deal of clinical suspicion and confirmation of infection based on the available laboratory diagnostic facilities, interpretation based on diagnostic criteria. Management protocols are aimed to reduce morbidity as multiorgan involvement has occurred. Emphasis is laid on prevention of intrauterine infection to ensure healthy fetus and healthy neonate without any hazards of such infection.