Caught by ingesting oocysts from cat faeces (in soil or water) or infected meat (but cats are vector). Mother to child transmission occurs only in primary infection, which is usually asymptomatic. About a third of newly infected mothers will transmit infection, but very dependent on gestational age at time of seroconversion; risk rises by 12% per week of gestational age. Only 4% of those congenitally infected will be symptomatic.
Introduction in the UK of prenatal or neonatal screening for congenital toxoplasmosis would not be justified by the currently available evidence. 1 in 10 000 children is congenitally infected but only five in a million have severe neurological disease in infancy and some 20 or 30 per million develop brain or eye lesions by the age of 3 years... Acquired toxoplasmosis is a bigger problem than congenital (meat and meat products and, in some countries, water supply). (Journal of Medical Screening 2002;9:135)
Untreated congenital toxoplasmosis with generalized or neurologic abnormalities at presentation almost always develop mental retardation, seizures, and spasticity. For untreated, initially asymptomatic infants studies have found that although the mean IQ was in the average range it was significantly lower (93 versus 110); furthermore, sequelae were common - at a mean age of 8.5 years, uni/bilateral blindness (65%), sensorineural hearing loss (26%), seizures (17%), severe mental retardation (13%), and hydrocephalus or microcephaly (13%).
Early treatment is very effective. A prospective study (n=36) using pyrimethamine and sulfadiazine for 1 year beginning in the first months of life in symptomatic patients had excellent outcomes with nearly 80% having a normal IQ. Seizures, deafness and motor problems resolved in most cases. Poor prognostic factors were hydrocephalus at birth, or high CSF protein (>1g/dl), or hydrocephalus unresponsive to shunting fared less well. Other risk factors for poor outcome include diabetes insipidus, apnoea and bradycardia. Microcephaly does not always mean a poor outcome, esp if hydrocephalus does not complicate it.
In pregnancy, IgM is not necessarily diagnostic of recent infection (can persist in adults). If IgG only, probably old infection unless third trimester, so use reference lab if in doubt - do battery of tests incl dye test, IgA, agglutination. Serology not reliable in HIV. Amnio PCR only 80% sensitive and varies with gestation. Monthly antenatal USS can assess ventricular dilatation, calcification, hepatosplenomegaly. Chorioretinitis in pregnancy thought to be reactivation so not a risk to fetus.
In newborn, IgM, IgA or Sabin Feldman Dye test > 300 IU suggests infection. Avoid using cord blood in case of contamination from maternal blood. If unsure, do PCR and culture from blood, urine, CSF. Characteristic findings (in symptomatic?) are:
Chorioretinitis usually present if clinical disease, seen in 40% if subclinical. Rare in acquired disease (ie lymphadenopathy), only 1.5%.
Other initial manifestations include jaundice (64%); hepatomegaly (50%); splenomegaly (56%); abnormal tone (58%); microphthalmia (22%); CSF pleiocytosis (56%); and abnormal CSF protein (59%).
Trial ongoing in Chicago. Regimen (Feigin & Cherry) - First 6 months: pyrimethamine - 15mg/m2 or 1 mg/kg daily else alternate days if difficult to divide tablet). Sulfadiazine - 85mg/kg in 2 divided doses, with folinic acid 5mg every 3 days, IM in young infants, 10mg if bone marrow toxicity, more frequent in young infants. Next 6 months alternate pyri/sulfa with spiramycin 100mg/kg in 2 divided doses monthly. If active chorioretinitis, high CSF protein, jaundice add steroids (pred 1.5mg/kg in 2 divided doses!) until inflammation subsiding, then taper. FBC 2x/week.
Remington + Klein regimen - pyri 2mg/ml, 2mg/kg for 2 days loading then 1mg/kg/d, 3x/wk in second 6/12, sulfa 100mg/ml, 100mg/kg in 2 divided doses, crush 10mg folinic, add to formula M/W/F, pred 1mg/kg in 2 divided doses. Fansidar 1.25mg/kg used in Europe - prob less effective levels, risk of serious adverse reactions, but convenient 2wkly dosing...
Spiramycin is good for infected mums as long as baby is not thought to be infected, where pyrimethamine/sulphadiazine are required. Prenatal treatment using spiramycin or pyrimethamine with sulfadoxine or sulfadiazine from time of diagnosis until 1 year of age has been tried. No RCTs. Metanalysis (n-1745 mothers) showed that early (within 3 weeks of seroconversion) was slightly more effective than later treatment, but that the risk was very dependent on gestation at time of seroconversion. Clinical manifestations in infected children were just as frequent whether prenatally treated or not. But difficult data and very dependent on gestational age at seroconversion. Lancet Volume 369, Issue 9556 , 13 January 2007-19 January 2007, Pages 115-122
Differential diagnosis: CMV, Human LCMV (lymphocytic choriomeningitis virus, found in rodents esp hamsters) infection.
Clin Perinatol 2005;32:705-26. Pediatrics, January 1, 1995, 95:11-20
Commonest congenital infection in developed world - 0.3% of births. Assoc with STIs, breast feeding and childcare. About 40% of pregnant women seronegative. Primary maternal CMV transmits in 40%, of which 10% symptomatic. Symptomatic babies have 30% mortality, and 90% morbidity. Even asymptomatic babies have 5-15% long term sequlae esp deafness. Virus is found in all body fluids so spread by close contact. Survives in fomites for several hours, but no apparent increase in risk in health care environments cf nurseries. Transmission usually occurs during primary infection, but possible in maternal reactivation (but disease is less aggressive) - an important issue if a vaccine is ever considered. Gestation at time of infection not very important (cf toxo, rubella, etc!).
CMV positive mothers nearly all secrete CMV DNA in breast milk, even if other body fluids are negative! Main cause of postnatally acquired CMV - usually asymptomatic in term babies but can be severe in preterms. See Prevention, below.
Causes anaemia, thrombocytopaenia, petechiae, hepatosplenomegaly, pneumonitis. Can cause a sepsis-like syndrome. Also chorioretinitis, enteritis (even NEC type picture), conjugated jaundice, and/or aseptic meningitis. Later, abnormal teeth, deafness (about 12% of all cases, can be progressive but sometimes improves, major economic impact), cerebral palsy. CNS involvement can lead to abnormal tone and (rarely) seizures. Whether postnatal infection can also cause late effects is uncertain.(Pediatr 2003;143:16-25, PMID 12915819 )
CT to look for intracranial calcifications (more sensitive than USS), opthalmology. Urine/blood PCR, culture of urine and surface swabs. IgG will usually be maternal, as usual; IgM is only 70% sensitive and sometimes gives false positives (in adults, can persist or reappear during reactivation). The presence of low/moderate avidity anti-CMV antibody indicates primary infection, and persists for about 20 weeks.
USS is vaguely prognostic: (n=57) at least 1 sequela developed in all neonates with symptoms who had abnormal US results, whereas none of the neonates with symptoms who had normal US results had long-term sequelae. Unusual to get asymptomatic babies with abnormal scans. In the population without symptoms, sensorineural hearing loss developed in 3 of 37 (8.1%) neonates with normal US results, so NPV isn't great. (J Pediatrics Volume 150, Issue 2 , February 2007, Pages 157-161)
Guthrie PCR testing has been looked at, but sensitivity only about 70% cf urine.
Ganciclovir gives mixed results, many studies have been uncontrolled and small. Not curative: appears that viruria always returns. Drug is carcinogenic, mutagenic, causes infertility, needs central line, 6/52 course, causes neutropenia in 63% so line infection is a big problem. For sepsis-like syndrome, treatment with Ganciclovir is worthwhile until oral valganciclovir can be tolerated. For less severe infections, the risk:benefit balance of treatment is less clear. Kimberlin RCT (n=100) chose patients with:
Patients received 12mg/kg/d of Ganciclovir for 6 weeks. At 1 year, just 26% of untreated controls had normal hearing in their best ear. 50% of the ganciclovir group had improved hearing or maintained normal hearing cf 26% of controls (not significant). 21% of the ganciclovir group had deterioration cf 68% of controls (p=0.002). Interim results at 6 months were similar. These figures are for hearing in the best ear.
In conclusion, in a fairly small study, ganciclovir appears to help prevent hearing deterioration for at least a year, and may also help recovery of hearing impairment. The number needed to treat (NNT) is 1.91 to prevent 1 case of hearing deterioration at 6/12, and 3.66 at 1 year. There are, however, some problems with Kimberlin's trial.
Valganciclovir is a prodrug of ganciclovir. It is an oral preparation. Pharmacokinetic studies have found that a dose of 16mg/kg produces a similar AUC12 (area under the concentration-time curve over a 12 hour period) to that obtained with ganciclovir. Neutropenia was still seen but was less common, perhaps because of the dosing strategy and drug level monitoring.
It is an attractive alternative to ganciclovir but there is currently no evidence to show any long term benefit. A current UK placebo controlled study aims to compare 6 weeks and 6 months of valganciclovir (16mg/kg). A randomized comparison with ganciclovir has not been attempted, perhaps due to fears of a high drop out rate.
Given the limited evidence and the complex nature of the interventions, a full discussion should be had with the parents and a treatment plan drawn up with their explicit consent.
Issues to consider are:
Postnatal infection is known to occur, ie initial screening of the baby is negative, but blood PCR turns positive after 10 days, or urine after 3 weeks of age. Breast feeding is the most likely mechanism, given that blood products for transfusions are generally CMV negative or leucodepleted. CMV can be found in the breast milk of most seropositive mothers, even though it does not appear in maternal urine/blood, so it appears to be local reactivation in the breast! There also appear to be factors in the milk that inhibit CMV (hence virolactia is not the same as DNAlactia!).
The rate of postnatal infection varies widely between studies (6-55%), as does the rate of symptomatic infection (0-75%). (Hamprecht K, J Clin Virol 2008;41:198–205.) The mean age at seroconversion is 77 days; appears to be related to maternal IgG level, and whether virus can actually be cultured from milk or not.(PIDJ 2004 PMID 15361725) In term babies postnatal infection is rarely symptomatic, but in preterm babies a spectrum of disease is seen, with some developing a sepsis syndrome, others just transient neutropenia, thrombocytopenia, and cholestasis. The severity appears to relate to gestation and birth weight (inversely related, with the highest risk in birthweights below 1000g and gestation below 30 weeks).(Maschmann J, Clin Infect Dis 2001;33:1998–2003). Evidence to date does not support any long term sequelae of postnatal infection, in term or preterm babies. Luck S, Arch Dis Child 2009;94:F58-F64 PMID 18838466 Freeze-thawing and pasteurization are quite effective at eliminating CMV from breast milk (Holder pasteurization, ie for 30 min at 62.5°C, is probably more effective) and the UK association for milk banking (UKAMB) recommends a sequence of alternate freezing and pasteurization - but immunological qualities of breast milk are affected, and cases of severe infection have still been described.(Hamprecht K, J Clin Virol 2008;41:198–205.)
Whether the breastmilk of all seropositive mothers should be treated before being given to preterm babies is unclear. Austria and France currently support pasteurization. If risk factors for symptomatic infection could be identified, then a selective policy might be the best way forward.
Prevention in utero has been tried. IVIG should theoretically work if sufficient seropositives in donating population but a RCT of its use preventively did not show significant benefit. CMV hyperimmune globulin has been given to Italian women with CMV in amnio, only 1 of 31 had an infant with symptomatic CMV at birth, as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Appears to be safe, and also to prevent disease in women with primary infection. Not strictly an RCT, and surprisingly high rate of CMV disease in primary infection. N Engl J Med. 2005 Sep 29;353(13):1350-62
See Euro Cong CMV initiative, who have a register of cases and are looking at whether viral load will help predict which babies do badly.
Aggressive and nasty, particularly with primary maternal infections.
Improved neurodevelopmental outcomes with 2 yrs High-Dose Oral Acyclovir Therapy in congenital HSV infection (CNS or dissem)? - not controlled!
Hepatitis B can be acquired in utero or at birth from the mother. There is also a risk of postnatal transmission - as many as 40% of infants who escape infection during the intrapartum period become infected during the first 18 months of life. This does not, however, appear to be due to breastfeeding, which is not contra-indicated even prior to immunisation. Nonetheless, care should be taken to avoid cracked, bleeding nipples...
Low risk of transmission if anti-E positive, HBeAg negative - give active hepatitis vaccine alone. Add HBIG (immunoglobulin) for high risk viz absent (or unknown) HBe markers, or acute hepatitis B in pregnancy - very effective (see Green book).
Failure of hep B vaccine to protect babies is linked to presence of HbsAg in blood at birth, ie intrauterine infection - all cases in 1 study became chronic carriers, although overall rate of mother-child transmission is only 2%. Similarly, HBV DNA levels must be high, which is usually associated with HbeAg.
Low risk mums may still give fulminant disease in neonates! Risk 1 in 750. Due to mutant virus not exhibiting HbeAg.
Perinatally acquired HBV followed up for 10 years remain asymptomatic but only 30% convert to anti HBe, and very few clear HBsAg (cf horizontal transmission). Hepatic transaminases alone are not a reliable marker of liver pathology, and mild to moderate hepatitis on biopsy is common. They should therefore receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease.
Arch Fet 2004; 89
SIGN guideline from 2005.
Vertical transmission does not seem to occur if mum is PCR negative. Where it has occurred, it may be that mum was actually intermittently positive, or an insensitive assay was used.
HCV PCR positive, HIV-negative mothers transmit at a rate of 2.4-8%, depending on how congenital infection is defined... Risk increases with:
So obstetric management does not appear to be affected. Similarly, although RNA can be detected in breast milk, breast feeding is probably safe. Hard to be sure - titres very low, and most babies who become infected are PCR positive early on anyway so difficult to show that breast feeding makes any difference. Very low risk of intrafamilial spread eg adopted children cf HBV.
Diagnosing infection is complicated! Maternal antibody will persist, as usual, for 12 months or more, so not diagnostic. PCR for RNA shows whether there is circulating virus; but again, this does not necessarily mean infection, as early positives can clear spontaneously. Liver function tests are often deranged in both infected and non-infected, so not reliable either! So:
Journal of Infectious Diseases. 192(11):1880-9, 2005 [16267758]; Acta Paediatrica. 94(4):444-50, 2005 [16092459]
If infected during the first trimester (risk extends to 20th week), a fetus has a 1% chance of developing widespread scarring, hypoplastic limbs, cataracts and brain lesions. Affected infants have a poor neurodevelopmental outlook. If chickenpox is contracted by the mother in the week prior to delivery, the infant is at risk of developing severe disseminated disease after birth. See Maternal for more details on in utero exposure.
In US primary, secondary and cong syphilis all surged in the 90s, now focal outbreaks in urban, drug using population. In N Africa, 3% of pregnancies, up to 7% in Carribean. 1 million pregnancies affected worldwide, of which 50% will end in abortion or still birth, and the other 50% will be congenital cases (unlike TORCH).
Clinically, 2/3 affected neonates asymptomatic at birth. Otherwise:
VDRL from CSF not 100% sensitive so if congenital disease suspected, treat for neuro.
Years later:
The risk of transmission is very high, particularly for untreated primary (ie a chancre) or secondary (ie multiple lesions, lymphadenopathy) disease. The risk falls to 40% for early latent syphilis (ie test positive but asymptomatic, with infection likely to have occurred in the previous 12 months on the basis of previous tests, symptoms or exposure). A category exists of latent syphilis of unknown duration, which only applies to patients aged 13-35yrs with nontreponemal titre of 32 or more.
Treating syphilis in pregnancy - for early acquired disease (primary, secondary or latent of <1yr) benzathine penicillin 50 000U/kg, with second dose a week later if in third trimester [BNF] but exclude neuro. For late latent syphilis >1yr duration give 3 doses at weekly intervals. For neuro disease benzylpen 50 000U/kg qds for 10-14/7 followed by 3 doses benzathine penicillin as above. If HIV positive also, then there tends to be more CNS disease, treatment failure, and treatment reactions (fever, myalgia, preterm labour - give steroids).
Adequate antenatal treatment = adequate benzathinepenicillin dose (2.4M Units IM) once weekly x3 - erythromycin is not reliable), 30 days before birth, proven 4x drop in nontreponemal serology.
Syphilis tests are either nontreponemal or treponemal.
In newborns, direct microscopy and fluorescent antibody tests can be done from mucous patch, else from placenta (beware non pallidum treponemes in normal flora esp mouth). PCR can be done from lesions too. VDRL more than 2x dilutions richer than mum's is suggestive. IgM can be negative early esp infection occurring late in pregnancy, not always recommended. False positive VDRL may occur due to transplacental antibodies if high maternal levels.
Where disease is likely, or maternal treatment has been inadequate, further testing is required:
For screening adults, 1 step strip test available, and one off oral treatment (Azithro, 1.8g). Antibodies give only partial protection.
For congenital syphilis treat with benzylpen 100-150 000 U/kg/d in bd or tds doses for 10-14/7.
There is concern about CSF levels with procaine or benzathine penicillin, although sometimes these are used for asymptomatic babies with nontreponemal tests less than 4x mum's, which might occur with inadequate treatment. In this situation, any abnormal finding on evaluation requires full 10/7 course.
If late diagnosis (>4/52), give high dose viz 200-300 000 U/kg/d qds for 10-14/7. If CNS disease is excluded, this could be converted to benzathine penicillin.
Monitor to show fall in VDRL at 3-6 months.
(Rana Chakraborty, St George's)
Intracellular Gram positive organism, resistant to cold and salt hence survival in foodstuffs esp meat products (eg hotdogs, unless steaming hot, deli meats), cheeses esp soft (incl blue veined, but excl mozzarella), raw and cooked poultry, ice cream, raw vegetables, raw and smoked fish (unless in shelf stable form). Recently melons and hummus implicated in US listeriosis.
Infection in pregnancy often undiagnosed. May cause preterm labour or intrauterine death. Infection at birth may be severe, with classic fine papular rash, widespread microabscesses and granulomas, and bacteria visible on gram stain of the meconium. Or infection may be late in onset eg 1-2 weeks, with encephalitis, endocarditis, osteomyelitis etc.
Meningitis - low counts cf other causes. Needs only 10 days treatment!
Treat with high dose ampicillin. Gentamicin is synergistic but does not penetrate intracellular compartment (or CSF). For allergic, TMP-SMX is best alternative! Cephalosporins are useless! Treat for 3-4 weeks, longer if brain or heart involvement.
Preterm Mec staining of the amniotic fluid (MSAF) was observed in 4.3% of infants below 33/40. No maternal or infant listeriosis was identified in any of the 1000 cases. MSAF was associated with prolonged rupture of the membranes and severe (grade 3/4) intraventricular haemorrhage (OR 2), not sepsis or mortality. (Simpsons, Arch Dis Child Fet 2004)
Possible causes - alpha thalassaemia, fetomaternal haemorrhage, Congenital Heart Disease, SVT, cong nephrosis/hepatitis, renal vein thrombosis, TORCH/syphilis, umbilical vein thrombosis, neuroblastoma, placental chorioangioma
Truly congenital cf other cerebral AVMs. Midline, between corpus callosum and cerebellum. visible antenatally from 26/40 - usually neonatal heart failure (ascites, tachycardia, ectopics) else seizures, hydrocephalus. Microcatheter approach with coils & glue. Hydrocephalus is not obstructive - raised venous pressure reduces CSF absorption - so resolves.
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