Prof. Dr. K. MEER MUSTAFA HUSSAIN, MD (PED.) DCH, Ph.D. *
(Neonatology), H.O.D. Division of Neonatology
Institute of Child Health & Hospital for Children, Egmore, Chennai - 600008. *
Perinatal infections are among the important conditions that adversely affect the human fetus and the newborn. The majority of these infections are viral. In viral infections, the diagnosis and treatment is difficult and therefore a preventive approach is most essential.
The organisms causing intrauterine infections can be classified as:
Viral: Rubella, CMV, HSV, HIV, VZV, Parvovirus, Hepatitis, Coxsackie
Protozoal: Toxoplasma, Malaria
Spirochaetal: Treponema pallidum
Bacterial: Listeria monocytogenes, GBS
The mode of infection can be hematogenous across placenta, ascending infection from infected cervix or due to contact between fetus and infected genitalia during parturition.
USEFULNESS OF SEROLOGY
- Detection of specific IgM antibody in neonatal blood sample, cord blood (or) amniotic fluid - is diagnostic.
- Maternal serum - Negative of specific IgG - useful to exclude particular infections.
- High IgM levels in first few weeks establishing acute infection of CMV & Rubella infections.
- Determination of four fold titer rise in antibody level in paired samples (2-4 weeks apart) - Highest diagnostic value.
- Nucleic acid tests are very useful for early diagnosis of Toxo, HIV, CMV, & parvovirus.
1. Rubella: [German Measles]
Infection can occur at any time during pregnancy but early gestational infection is very destructive. Congenital rubella syndrome presents as cataract, IUGR, retinopathy, microcephaly, meningoencephalitis, congenital heart disease, splenomegaly, thrombocytopenic purpura. With maternal infection in first 12 weeks, the rate of fetal infection is 81%. As the gestational age advances, the infection rate drops. Risk for congenital defects is low, if fetal infection occurs beyond 20 weeks.
It is mainly done by isolating virus from amniotic fluid and by identification of rubella-specific IgM by percutaneous umbilical blood sampling. These tests have limited sensitivity and specificity.
Definitive diagnosis is by virus isolation in pharyngeal washings, CSF, conjunctiva and lens at autopsy. Rubella virus RNA can be detected by PCR in clinical specimens. Detection of rubella-specific IgM in neonatal or cord blood is also confirmatory.
Table 1. Interpretation of ELISA for rubella-specific antibodies
Rubella IgM/IgG: Negative < 0.9 U / ml
Equivocal: 0.91 - 1.1 U / ml
Positive: > 1.1 U / ml
There is no specific therapy for maternal or congenital rubella infection. If primary maternal infection occurs during first trimester of pregnancy, termination is advised. Initially, the infant may need general supportive care. Longterm care requires a multidisciplinary approach consisting of occupational and physical therapy, close neurologic and audiologic monitoring and surgical interventions as needed for cardiac malformations and cataracts.
The rate of intrauterine transmission from primary maternal infection is 30-40%. Approximately 18% develop significant disease. In mothers with recurrent infection, the fetus and newborn rarely show clinical symptoms. Risk of transmission in relation to gestational age is uncertain although infection during early gestation carries a higher risk of fetal disease. Symptomatic CMV presents either as an acute fulminant infection with multisystem involvement like petechiae, purpura, hepatosplenomegaly and jaundice. A second insidious presentation is with microcephaly, IUGR, chorioretinitis, periventricular calcifications, mental retardation, hearing deficits, motor abnormalities, visual disturbances, etc.
Amniocentesis and cordocentesis to detect CMV DNA by PCR.
Infant presents with characteristic symptoms. Isolation of virus or demonstration of CMV DNA by PCR from urine or saliva at birth or within 1-2 weeks indicates definitive diagnosis. When detected after 2 weeks, it might have been perinatally acquired. Cell viral cultures are used for better isolation. The determination of CMV antibody titres has got limited use. (Table 2).
Table 2. Interpretation of CMV antibody titres:
CMV IgG / IgM antibodies
Negative : < 0.91 U / ml
Equivocal : 0.91 - 1.1 U / ml
Positive :> 1.1 U / ml
Management of CMV
- I.V. Ganciclovir, Valganciclovir x 6 weeks
- Side-effects: Neutropenia - Thromobcytopenia
- Hyper-immune CMV Immunoglobulin also tried
3. Herpes simplex virus
Intrapartum transmission is the most common mode of transmission and is associated with active shedding from cervix and vagina. Intrauterine infection is rare. Diagnosis is by high degree of clinical suspicion. An infant presents with the disease as vesicles on 6th-9th day over skin, eye and mucocutaneous membranes. One third of affected children present with encephalitis and another one third with disseminated infection with seizures, shock and DIC / hepatitis.
Virus isolation from lesions of or and nasopharynx.
In encephalitis identification of viral DNA in CSF by PCR, increased CSF protein levels and pleocytosis.
HSV - Management
Dose: 45-60 mg/kg/day Std. Dose is 30 mg/kg/day
10-15 mg/kg/day x 8th hour x 14 days
10-15 mg/kg x tds x 21 days
4. Human Immunodeficiency Virus
In-utero and intrapartum transmission from infected mother accounts for 90% of pediatric cases. Transmission can occur throughout gestation and HIV has been isolated from cord blood and products of conception as early as 14-20 weeks of gestation.
Positive IgG in a child less than 18 months indicates maternal infection but cannot diagnose fetal infection.
Virus co-culture, p24 antigen detection, HIV-specific IgM have low sensitivity in 1st week of life.
Early diagnosis of HIV DNA is by PCR assay, positive predictive value in neonates is 56% and older infants is 83%.
False positive PCR: 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 there is a> 95% assurance that infant is not infected.
Exposed infant is considered negative if there are:
- no physical finding of infection
- virological tests are -ve
- immunological tests - CD4 counts are normal
- >12 months of age and two or more HIV antibody tests are negative
The major part of the management of HIV infection is antiretroviral therapy. This should be offered to all symptomatic patients regardless of CD4+ cell count. But the goal of antiretroviral therapy is to suppress the HIV viral load to non-detectable and to maintain or reconstitute CD4+ cell numbers to greater than 25%. Generally, these agents are of three classes:
- Nucleoside or nucleotide analogue Reverse Transcriptase Inhibitors (NRTIs: e.g., zidovudine / AZT).
- Non-nucleoside analogue Reverse Transcriptase Inhibitors (NNRTIs: e.g., nevirapine). They are generally more potent than the NRTIs, but resistance can develop rapidly if the viral load is not controlled.
- Protease Inhibitors (PIs) prevent processing of viral proteins. These agents are quite potent.
5. Varicella zoster virus
Congenital varicella syndrome following maternal infection in first trimester is 2%.
By sonographic abnormalities like hypoplastic extremities, clubfoot, flexed limbs, ventriculomegaly, porencephalic cyst, polyhydramnios, ascites, hydrops and calcification of lungs and myocardium.
VZV specific IgM in fetal blood is non-specific
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 membranes antigen.
Therapy with acyclovir is generally recommended. Acyclovir is used for the treatment of neonatal varicella.
There is no established immunotherapy for the treatment of V-Z virus infections, but varicella-zoster immune globulin (VZIG) may be of prophylactic value. When administered within 72 hours of exposure, VZIG is effective in preventing or attenuating V-Z virus infection. The dose for newborns is 125 units intramuscularly.
Overall rate of transmission from an infected mother to fetus is 33%. Risk of fetal loss is 10%. It has been firmly linked to non-immune fetal hydrops by affecting the hematopoietic cell lines. If acute or recent parvovirus B19 infection is confirmed in pregnant woman by positive B19 specific IgM assay, serial ultrasonogram should be done for fetal hydrops or meconium peritonitis.
Fetal blood and amniotic fluid for parvovirus IgM specific antibody.
PCR to detect B 19 DNA. 100% results when fetal blood is subjected to in situ hybridization.
Postnatal diagnosis :
Serum IgM rises in 3 days and falls by 2-3 months. Serum IgG appears a few days after IgM disappears and lasts for years.
7. Hepatitis Viruses
- Hepatitis C:
There is high transmission rate in mothers with high viral loads. Co-infection with HIV increases transmission.
- Hepatitis B:
Intrauterine transmission is rare. Detection is by HBsAg-specific IgG in serum.
Management at Birth
The following precautions should be taken if the mother is HBsAg positive: Avoid contact of maternal blood and amniotic fluid with skin or mucus membranes; gentle resuscitation and suction of the baby to avoid nasopharyngeal trauma; and thorough cleaning and bath after initial stabilization. These babies should receive HBIG 0.5 ml at birth (efficacy declines markedly if delayed beyond 2 days) along with the first dose of HB vaccine. Breast-feeding should continue.
Syphilis can be transmitted to the infant regardless of duration of maternal disease but more so in the first year of infection. Transmission occurs more commonly after fourth month of pregnancy. Liver is the primary site of infection followed by secondary spread to skin, mucous membranes and bones.
Treatment for infants with proven or highly probable disease should consist of either:
- Aqueous crystalline penicillin G 100,000 to 150,000 units/kg/day IV, divided every 12 hours during the first 7 days and every 8 hours thereafter for a total of 10 to 14 days or;
- Procaine penicillin G 50,000 units/kg per dose IM daily in a single dose for 10 days.
An intracellular protozoan with 30-40% vertical transmission. Rate increase with gestational age at which acute infection occurs and appears to correlate well with increasing placental blood flow and is 90% at term. The severity of fetal disease is inversely proportional to gestational age. Primary neurological disease presents with intracranial calcifications, chorioretinitis and convulsions. The generalized disease presents with hepatosplenomegaly, lymphadenopathy jaundice and anemia.
Serial USG to detect hydrops, ventricular dilatation, cerebral or hepatic calcification and ascites in the antenatal period.
Amniocentesis to isolate organisms by inoculation in mice or by tissue culture.
PCR analysis-B1 gene amplification of amniotic fluid has 97.4% sensitivity.
IgM titres and Sabin-Feldman Dye Test are extremely useful.
Management Program for Perinatal Infections of Toxoplasma:
- Pyrimethamine 1 mg/kg daily for 2-6 months
1 mg/kg on alternatew days x 1 year
- Sulphadiazine 100 mg/kg X BD X Daily X 1 Year
- Folinic acid 10 mg 3 times / week for pyrimethamine toxicity
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