Congenital Infection
Introduction
There are a number of organisms that can cause congenital neonatal illness - often with devestating long term consequences. Rubella embryopathy was the first documented neonatal congenital infection, being recognised in 1941 by an Australian Ophthalmologist - Sir Norman Grigg.
Congenital infection can occur during pregnancy or the peri-partum period. Primary infection in the mother, generally, results in greater risk of consequences to the developing fetus compared with 're-activation'. The timing of infection is important in regards to the severity of neonatal illness and in relation to the organism involved.
Toxoplasmosis
Summary
- Congenital Toxoplasmosis occurs in between 0.2 to 10 per thousand pregnancies
- Risk of fetal infection is lowest in early pregnancy but most fetuses infected early have severe consequences
- Specific therapy is available to treat congenital toxoplasmosis
Introduction
Toxoplasma gondii is a parasitic organism. The domestic cat is the primary host. Infection can be contracted by
- ingesting oocytes present in faecal material of infected hosts
- eating pseudocysts present in undercooked meat.
Most women have no symptoms. Although 15% of women report acute flu-like illness with lymphadenopathy.
Risk of fetal infection is lowest in early pregnancy but most fetuses infected early have severe consequences.
Risk of fetal infection Severe consequences of infection 1st trimester 10% 70% 3rd trimester 60% <1%
Clinical features
Infants congenitally infected with Toxoplasmosis can be
- completely asymptomatic
- unaffected at birth and manifest problems later
- severely affected in-utero and at birth
Infection usually affects the neurological and haemopoietic systems. The classical tetrad described by Sabin in 1942 includes
- hydrocephalus/microcephaly
- chorioretinitis
- convulsions (link)
- other evidence of CNS involvement (including calcification)
Haemopoietic manifestations include
- hydrops due to anaemia
- rash due to thrombocytopenia purpura
- blueberry muffin appearance (seen in 25% of generalised infection)
- lymphadenopathy
- hepatosplenomegaly
Neurological manifestations include
- convulsions
- hydrocephalus with bulging fontanelle
- microcephaly
- chorioretinitis can be present early or develop later
Generalised features include
- lethargy and malaise
- poor feeding
- vomiting
- diarrhoea
- temperature instability
- jaundice
Investigation
Antenatal diagnosis can be performed using fetal blood sent for
- PCR
- IgM assay
- culture
Postnatal investigations include
- specific IgM or IgA in cord or baby's blood
- FBE (anaemia/thrombocytopenia)
- liver function tests
- culture by inoculation of blood/placenta in mice
- cranial US (hydrocephalus and calcification)
- CT scan (more sensitive than ultrasound at identifying calcification)
- ophthalmological review
Management
Treatment consists of prolonged therapy for the first year of life with
- pyrimethamine (1mg/kg orally daily)
- sulphadiazine (50mg/kg orally, twice daily)
- folinic acid (1ml/kg, orally twice weekly) is added
Bone marrow suppression and hepatotoxicity can develop, and fortnightly blood tests are needed.
An alternative regime aimed at minimising toxicity may be used
- 4 x 21 day cycles of pyrimethamine, sulphadiazine and folinic acid
- spiramycin (50mg/kg, orally twice daily) used for 30 days in between
The addition of steroids in severe infection has been suggested, but no evidence exists for this practice.
Ongoing opthalmological and developmental follow up is mandatory.
Outcome
Infants symptomatic at birth have high incidence of long term difficulties
- chorioretinitis (over 90%)
- developmental delay (50%)
- seizures (40%)
- microcephaly (20%)
- deafness
- hydrocephalus
Outcome data for infants who are asymptomatic at birth is scant.
In 'asymptomatic' neonates, it appears that a significant number develop long-term sequelae if left untreated. Up to 92% develop long-term problems, usually due to ophthalmological disease. Chorioretinitis may not become evident for many years. Although prolonged therapy reduces the incidence of sequelae compared to untreated infants sequelae may still occur (over 80%).
Prevention
Prevention of Toxoplasmosis is aimed at preventing ingestion of infected material. Pregnant women should be warned to avoid foods/products that may be contaminated with the oocytes - including care with the family cat (there may be a role for advocating against acquiring a new cat in households with pregnant women).
Rubella
Introduction
Most people develop immunity (if not immunised) during childhood. In non-immunised populations, 10-20% of women of child bearing age are susceptible.
Re-infection occurs in around 2% of people but is generally subclinical. Cases of congenital infection have been described with maternal re-infection.
Rubella vaccination is effective in almost totally eliminating congenital rubella infection - provided coverage remains high.
Clinical features
Most congenital infection is the result of primary maternal infection. The mother may have had little, if any, symptoms of infection.
Onset of maternal infection Fetal Complications <12 weeks Congenital rubella syndrome (>90%) 12-18 weeks Sensorineural deafness (20%) >18 weeks Rare
Congenital rubella syndrome is a severe, disabling condition featuring
- eye disorders (cloudy cornea/cataracts, salt and pepper chorioretinitis, microphthalmia)
- sensorineural deafness
- cardiovascular (pulmonary stenosis and PDA)
- microcephaly
- growth restriction
- haemopoietic disorders
- hepatosplenomegaly
- lymphadenopathy
- thrombocytopenia
- anaemia
- extramedullary heamopoiesis (blueberry muffin skin appearance)
- long bones radiolucencies seen on Xray
- pneumonitis with associated respiratory signs
- renal tract abnromalities
Investigations
Diagnosis is usually demonstrated by evidence of maternal seroconversion or rising IgG titres. This occurs some 10 days after contact. IgM assay is useful where exact 'contact time' is not known. IgM persists for around 2 months after primary infection. Re-infection can be identified by seeing a four-fold or more rise in IgG titres.
Fetal diagnosis is possible from
- cord blood IgM
- rubella PCR of amniotic fluid
Postnatal diagnosis is by
- IgM
- isolation of rubella virus (possible form many sites including NPA, eye, throat, CSF, stool and urine for up to 12 months)
Other test include
- FBE
- renal function and electrolytes
- liver function tests
- cranial ultrasound (looking for discrete calcification)
- echocardiography (looking particularly for Pulmonary Stenosis and PDA)
- renal ultrasound
- LP (pleocytosis with elevated protein)
- CXR (indicated if the baby has respiratory symptoms)
- long Bone Xrays
- hearing assessment is mandatory, even in babies with no overt disease at birth.
Deafness may be progressive, and therefore serial hearing assessments over the 1st few years of life are essential.
Ophthalmological assessment is also essential and progressive retinal damage can be seen.
Endocrine problems can occur in the long term including diabetes mellitus and hypothyroidism .
Management
There is no specific treatment. Management is supportive and aimed at addressing specific problems present (developmental/sensory/endocrine/cardiac/etc ).
Prevention
Rubella immunisation is offered to all children in combination with measles and mumps vaccination at 1 year of age. This also reduces the 'viral pool' in the population and helps protect susceptible pregnant women. New arrivals into Australia also are a potential group of susceptible individuals.
All women should be screened at first antenatal clinic appointment, and if found to be rubella susceptible, offered immunisation in the post-partum period.
If rubella infection is confirmed in the pregnant woman, then appropriate counselling is essential to provide the woman with information regarding the likely effects on the unborn child and options for management.
Outcome
Children with congenital rubella syndrome are likely to have severe developmental issues.
Ongoing hearing and vision assessments are essential in babies whose mothers contracted rubella after 12 weeks gestation.
Rarely, a form of subacute sclerosing panencephalitis, with demonstration of raised rubella antibodies in CSF, has been documented.
Cytomegalovirus (CMV) infection
Introduction
CMV is a ubiquitous herpes virus that usually it causes only mild disease. It is commonly acquired in infancy and childhood through 'saliva sharing', particularly in less developed countries where over 90% are infected in childhood compared to around 60% in Western countries.
Clinical features
Overall, around 5 to 10 per 1000 babies are born with congenital CMV infection - with only 5-10% being symptomatic.
Congenital CMV can develop from maternal primary infection or re-activation, with primary infection more likely to result in sequelae. Risk for sequelae is highest after fetal infection during the first trimester.
Around 1% of non-immune women develop primary CMV in pregnancy, approximately 50% of their fetuses become infected.
In women with prior CMV infection, re-activation can occur in pregnancy with 5% of babies developing infection in-utero.
Perinatal and postnatal infection can occur through birth canal secretions and breast milk or blood. If affected the clinical syndrome is usually mild and self-limiting. Severe infection can result in transfusion-acquired disease. Use of CMV negative donor blood or deglycerolised frozen blood transfused through a leucocyte filter prevents this problem.
Symptomatic babies can be variously affected including
- growth restriction
- haemotological problems
- thrombocytopenia and purpura are common
- anaemia, neutropenia, lymphocytosis are occasional
- hepatosplenomegaly
- lymphandenopathy
- neurological problems
- poor tone and poor suck
- seizures
- microcephaly
- chorio-retinitis
- cerebral calcification (classically periventricular)
- deafness (can be a late manifestation and is the most common cause of sensori-neural hearing loss)
- pneumonitis
- colitis
- hepatitis
- dental defects
Investigations
A high index of suspicion is needed.
Investigation is warranted in
- babies whose mothers have developed primary infection in pregnancy or have 're-activated'
- growth restricted infants with low platelet count
Tests performed include
- IgM assayed from cord/baby blood ( tests have poor sensitivity)
- viral culture from urine (the test of choice)
- throat/saliva swab and NPA sent for PCR can give a more rapid answer.
Culture and PCR should be performed as soon as possible in the first 2 weeks of life as CMV detected after this time can indicate peri/post natal infection.
Management
Attention to 'general' measures include management of
- nutrition
- haemotological disturbances (low platelets)
- respiratory disease
Specific treatment with foscarnet of ganciclovir has not been shown to be associated with long-term benefits in congenital infection. There is a role for their use in life-threatening CMV infection (particularly post-natal disease in preterm babies) or in the setting of chorio-retinitis but this will not reverse damage that has already been done.
Long-term follow-up is essential with attention to
- management of neurological sequelae
- hearing testing, continued for the first 2 to 5 years of life, due to the risk of late-onset deafness
Prevention
Two groups require consideration
- hospitalised newborn infants
- prevention of transfusion acquired infection is achieved by use of leucocyte filters or CMV negative blood
- standard precautions and aseptic measures (particularly hand-washing, especially after nappy changing) is important to prevent nosocomial spread of infection
- potentially 'at-risk' pregnant women
After infection viral shedding can either persist for months or occur transiently and then recur intermittently. Testing for viral shedding will not guarantee a baby is not shedding virus at other times.
Seronegative staff members have a low risk (around 1-5%) of developing a primary infection.
Attention to prevention through use of standard precautions is important.
Likewise, it is difficult to advise parents of babies with documented CMV infection as to what to tell friends/family. Re-assurance and explanation about prevention of spread through scrupulous attention to hand washing after performing baby care are the most valuable tools.
Herpes Simplex Virus (HSV)
Introduction
HSV 1 and HSV 2 are uncommon, but important, causes of neonatal illness.
Neonatal infection is usually the result of HSV 2 as this is the main virus associated with genital infection.
The overall rate of genital HSV infection varies from country to country and many women (amd men) remain asymptomatic, with no history of infection despite shedding virus. HSV can remain latent for long periods, with shedding or re-activation occurring at any time.
There is a 1% chance of a women with a past history of genital HSV infection shedding virus at the time of delivery.
In cases of neonatal infection, most women do not give a history of active genital herpes at the time of delivery.
Babies born to mothers with a primary genital infection at the time of delivery have a 50% risk of developing infection, compared with <5% in cases of recurrent infection present at the time of delivery.
Clinical features
Neonatal HSV usually presents within 2 weeks of birth
Infection occurs in less than 5 per 100,000 deliveries (up to 10 times more in the USA).
- 90% are acquired during passage through the birth canal or through ascending infection
- 5% have 'congenital' HSV infection
- 5% have post-natally acquired infection
Usual clinical presentations are
- skin/eye/mouth (SEM) localised disease
- untreated, >70% will progress to disseminated disease
- 25% will have virus in CSF at initial presentation
- isolated vesicles or 'crops
- occassionally other skin reactions can be present, including zoster-like eruptions
- keratoconjuncitivitis with dendritic ulcers
- choriodoretinitis
- single of multiple oral vesicular lesions can be present
- disseminated disease
- poor prognosis, with over 70%mortality untreated
- non-specific presentation with
- lethargy
- poor feeding
- fever
- convulsion
- apnoea
- respiratory distress
- hepatomegaly
- jaundice
- DIC
- pneumonitis
- tends to occur day 4 to 7
- respiratory distress and can develop into haemorrhagic pneumonitis
- CXR shows diffuse pnuemonic change
- rare but dissemination is common if untreated
- meningo-encephalitis
- isolated or part of dissemnated disease
- presents with
- encephalopathy (mean 11 days of age)
- seizures are common and often intractable
- absent gag-reflex is a particular feature
- EEG shows characteristic temporal/parieto-temporal focus with periodic slow and fast waves.
- brain imaging (CT/MRI) shows disease particularly affecting the temporal areas. Later calcification and cerebral atrophy can develop.
Investigations
Neonatal HSV infection is uncommon and a high level of vigilance is needed, particularly since most affected newborns are born to mothers with no history of current genital HSV lesions.
The unwell baby should be examined for vesicles including oral.
Specimens from lesions, throat and eye swabs should be performed. The use of immunoflourescence can provide rapid evidence of infection. Viral culture can take 5 days to demonstrate typical cytopathic changes.
Lumbar puncture is mandatory, with CSF sent for PCR and culture. However, negative PCR testing on CSF does not completely rule out HSV infection, and the clinical picture of herpes encephalopathy is important in determining treatment.
EEG and brain imaging are useful adjuncts in cases where diagnosis of CNS infection is in doubt.
Serological studies are of little value early on as IgM may take 2 weeks to appear and IgG titres may not rise in babies and may reflect maternal antibody status.
Management
Specific early treatment is with
- Acyclovir 10mg/kg IV three times daily for a total of 14 to 21 days
- Vidarabine 15mg/kg 12 hourly, IV is also effective but is more cumbersome
Supportive care as always is vitally important with attention to general care.
Eye lesions require topical treatment (eg. Idoxuridine) and ophthalmological referral is essential.
Prognosis
Mortality and morbidity rates for disseminated and CNS disease are very high, even with early and aggressive treatment.
Even in the setting of localised SEM disease, 10% have long-term neurological sequelae.
Recurrent skin and eye eruptions can occur. Oral acyclovir has a role in this setting.
Prevention
Babies born to mothers with active genital herpes lesions, particulary primary infection, at the time of delivery are at high risk. LUSCS should be performed as soon as possible, particularly within 6 hours of ROM. Swabs from the baby's eyes and throat should be sent and if positive, the baby treated with acyclovir sysemtically. However, consideration to treatment even in the setting of CS should be given - especially if there delay in getting results occurs. Babies born vaginally in the face of active genital lesions should be treated systemically.
Nosocomial infection can occur and vigorous infection control measures should be instituted.
Relatives or staff with 'cold-sores' should be discouraged from handling newborn infants as there is a risk of infection.
Mothers with cold-sores present a low-risk to the infant as passive antibody protection of the baby should be present, but in this setting the wearing of masks/rigorous handwashing and topical cold-sore treatment should be advocated.
Syphilis
Introduction
Congenital syphilis is rare in Australia, disadvantaged groups are at higher risk.
Screening at the initial antenatal visit is part of routine obstetric care since women may have asymptomatic latent disease.
Untreated maternal syphilis can result in
- stillbirth/perinatal death
- premature delivery
- about half of survivors have long-term neurological sequelae.
Transmission rates are around 50% for primary, secondary or early latent syphilis. In established latent syphilis, vertical transmission occurs in around 10%.
Treponema pallidum infection remains treatable with penicillin.
Clinical features
The infected baby can
- be asymptomatic at birth
- have disseminated sepsis with
- reticulo-endothelial/haemotogical features
- generalised lymphadenopathy and hepatosplenomegaly seen in over 50%
- haemolytic anaemia/thrombocytopenia/pancytopenia can occur
- occassional leucocytosis
- jaundice (unconjugated/conjugated or mixed) is common
- mucosal features
- rhinitis (snuffles) develops at 1 week and worsens. Initially clear then progressively purulent and blood stained
- mucous 'patches' seen on palate and lips
- perioral and perianal condylomata
- ulceration of nasal mucosa can lead to 'saddle-nose deformity' in longer term
- cutaneous features
- maculo-papular eruption over buttocks and lower torso, palms and soles
- bullous eruptions (pemphigus syphiliticus) which mimic staphyloccal infection
- desquamation
- bone involvement
- osteo-chondritis, periostitis, osteitis is very common (>75% of cases). Usually asypmtomatic initially but can lead to deformity and pathological fracture
- neurosyphilis (rare at birth)
- meningitis
- eye involvement
- gluacoma
- chorioretinitis
- chancres
- uveitis
- myocarditis
- pneumonitis
- renal (nephrotic) involvement
- if untreated, late features include
- Hutchison's teeth and other dental deformity
- Sabre tibia
- keratitis and blindness
- nerve deafness
- saddle nose deformity
- frontal skull bossing
- scarring
- development impairment
- reticulo-endothelial/haemotogical features
Investigations
Pregnant women are screened with non-specific treponemal tests (RPR and VDRL titre). If positive, then a specific TPHA/FTA-Abs titre will be performed.
Serum IgM in newborn babies with congenital syphilis is positive in around 90%.
Diagnosis of congenital infection can be confirmed by demonstration of treponema pallidum on dark ground microscopy on specimens from lesions on skin, placenta or other tissues.
A fourfold rise in the baby's antibody titre over the first 3 months is considered diagnostic.
Other tests
- FBE
- liver function tests
- urinalysis for proteinuria
- X-rays of long bones
- lumbar puncture
- CSF abnormalities should be considered suggestive of CNS infection
- a positive CSF VDRL titre or treponema PCR is diagnostic of CNS involvement
Management
Babies born to mothers who have not been adequately treated should be considered as infected.
Infants with suspected or confirmed infection should be treated with penicillin for at least 10 days.
Benzyl penicillin, 30mg/kg per dose 12 hourly, IM or IV or
Procaine penicillin, 30mg/kg daily, IM
Infants with low antibody levels whose mother was treated appropriately and has evidence of falling RPR/VDRL titres, is unlikely to be at risk. Ongoing follow up will be needed and if follow up cannot be assured, the baby should be treated.
Follow up
Babies should be evaluated at 3-monthly intervals over the first year of life, with serological tests performed at each visit.. In cases of neurosyphilis, ongoing serum and CSF analysis should be undertaken 6-monthly for the first 5 years of life. Re-treatment is needed if titres do not fall, or clincial signs of disease persist or develop.
Prevention
Prevention relies upon adequate antenatal services and screening facilities.
Further reading
- Isaacs D, Moxon ER. "Handbook of Neonatal Infections - a practical guide". WB Saunders, London. 1999.
- Remington JS, Klein JO. "Infectious Diseases of the Fetus and Newborn Infant" 5Th Ed. WB Saunders, Philadelphia. 2000.
- Davies EG, Elliman DAC, et al. "Manual of Childhood Infections". WB Saunders, London, 1996.
- Jeffries DG, Hudson CN. "Viral infections in Obstetrics and Gynaecology". Arnold, London, 1999.
- Jones JL. Lopez A. Wilson M. Schulkin J. Gibbs R. Congenital toxoplasmosis: a review. Obstetrical & Gynecological Survey. 56(5):296-305, 2001 May
- Beazley DM. Egerman RS. Toxoplasmosis. Seminars in Perinatology. 22(4):332-8, 1998 Aug.
- Jacobs RF. Neonatal herpes simplex virus infections. Seminars in Perinatology. 22(1):64-71, 1998 Feb.
- Murph JR. Rubella and syphilis: continuing causes of congenital infection in the 1990s. Seminars in Pediatric Neurology. 1(1):26-35, 1994 Sep.
- Riley LE. Herpes simplex virus.Seminars in Perinatology. 22(4):284-92, 1998 Aug.
- Hollier LM. Cox SM. Syphilis. Seminars in Perinatology. 22(4):323-31, 1998 Aug
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