Congenital Infections in Neonates

Some infections are more serious in pregnancy than in the non-pregnant state because of the potential for vertical transmission.
Infection can pass vertically from mother to fetus/neonate in several ways:

• Across the placenta - these include Toxoplasma gondii, Treponema pallidum, Rubella, CMV, Listeria monocytogenes, Falciparum.
• Ascending maternal infection and chorioamnionitis causing fetal infection, usually subsequent to prolonged rupture of membranes(PROM).
• Perinatal infection - acquired during birth via the haematogenous or genital route. These include HIV, HZV, HBV and Chlamydia trachomatis
• Postnatal infection via breastfeeding

Traditionally congenital infections were known as the TORCH infections, referring to toxoplasmosis, others (such as syphilis), rubella, CMV and herpes/hepatitis - this acronym is now obsolete as our awareness grows of other pathogens such as HIV.

Pre-pregnancy or routine antenatal screening determining presence or susceptibility to some of these infections can enable appropriate management to prevent adverse fetal or perinatal outcomes.

Routine antenatal screening tests in UK completed prior to 16 weeks gestation ¹

Surveillance indicates that rates of maternal infection are variable across the country with high concentrations in particular geographic areas. In 2002, amongst women booking for antenatal care in London, 1 in 100 were HBsAg positive, 1 in 200 were HIV (and most not diagnosed prior to antenatal screening),1 in 250 positive for syphilis and 1 in 30 susceptible to rubella.²

Currently there are no tests recommended nationally for antenatal screening of CMV, Toxoplasma, Parvovirus or Group B streptococcus.

Congenital rubella syndrome (CRS) is now rare in developed countries with rubella vaccination programmes (although poor uptake of MMR may jeopardize this progress) with most cases imported from areas where it remains endemic.

Risk of CRS is maximal in early pregnancy; 90% infants affected before 11 weeks gestation, 24% at 15-16 weeks. Syndrome does not usually occur with infections after 1st trimester.

Commonest manifestation is intrauterine growth retardation (IUGR); other common effects are cataracts often associated with microphthalmia, myocarditis with structural cardiac defects such as patent ductus arteriosus or pulmonary artery stenosis, sensorineural deafness, mental retardation, thrombocytopenia and purpura. Miscarriage or stillbirth may occur.

Diagnosis - PCR and rubella-specific IgG and IgM salivary tests can supplement serial blood antibody tests. Rubella is difficult to differentiate clinically from other rash causing infections such as measles and parvovirus B19. Detection of rubella IgG on antenatal screening in unvaccinated women recently arriving from areas of endemic rubella may indicate infection acquired early in pregnancy rather than immunity - seek a history of rash in early gestation in those who have recently immigrated.⁴ IgM disappears within 4-6 weeks of a primary infection.

Prevention - Vaccination programmes to prevent rubella-susceptibility. Routine antenatal screening detects those requiring puerperal vaccination.

An estimated 2.4 million HIV-infected women deliver children every year worldwide. In USA and Europe, transmission rates are 15-20% and 25-30% in rest of world. Infection occurs during delivery or breastfeeding.

Management of HIV in pregnancy: transmission can be reduced with zidovudine and nevirapine at delivery and for the neonate.⁶ Better efficacy can be achieved with the addition of single-dose nevirapine to short course zidovudine regimens.⁷ In industrialized countries, combination antiretroviral therapy is already standard in efforts to reduce vertical transmission. Other strategies include the use of elective Caesarean section and avoidance of breastfeeding.

Commonest congenital infection in developed world, 1-4% women acquire primary CMV infection in pregnancy which may be asymptomatic or produce symptoms similar to infectious mononucleosis. There is no effective prevention or treatment for congenital infection.

Primary infection during pregnancy will result in about 40% fetal infection rate. Reactivation of maternal infection during pregnancy will also cause fetal infection in about 1% but usually a much milder variant. Fetal damage is most likely early in pregnancy.

Most congenitally infected infants are apparently normal at birth but long-term sequelae occur in about 10-15%. Symptomatic diseases is characterised by mental impairment, growth retardation, microcephaly, thrombocytopenia and hepatitis. Also, 5-15% risk of impaired hearing in asymptomatic infants.

If primary maternal CMV infection is suspected, serology, liver function tests and a blood film are usually sufficient to confirm the diagnosis. If recent CMV infection is likely, especially in the first trimester, amniocentesis can be used to determine if the fetus is infected. Unfortunately proof of fetal infection does not indicate extent of morbidity - and so stage of pregnancy, viral load in the amniotic fluid, evidence of fetal abnormality or growth retardation are used to assess risk in those considering termination of pregnancy.

Infection occurs in 1/2000 pregnancies - with a 10-15% risk of fetal infection. The majority of fetal infection is transient and asymptomatic. 2-3% of infants of women with chickenpox in the first half of pregnancy do develop varicella syndrome (skin scarring, ipsilateral limb hypoplasia, visceral, neurological and eye lesions).

Neonatal zoster can occur if mother infected 5 days before to 2 days after delivery. Associated with up to 30% neonatal mortality and babies of mothers developing perinatal chickenpox should receive varicella-zoster immune globulin (VZIG) IM.

Varicella zoster vaccine is not currently recommended for susceptible women of child-bearing age or routine use in children in the UK.

The most important mode of transmission of Hepatitis B globally is vertical from mother to child. Significantly, congenital infection is less likely to be cleared (indicated by the persistence of HBsAg) and individuals are more likely to chronic infection compared to adults contracting the infection. Less than1% pregnant women are HBsAg positive in West compared to approximately 25% in parts of Africa and Asia.

In HBsAg positive/HBeAg negative mother risk is 5-20% of transmission and in HBsAg/HBeAg positive women it is 70-90%. Transmission rates can be significantly reduced by active immunisation with hepatitis B vaccine combined with passive immunisation using hepatitis B immunoglobulin within 12 hours of birth.

If HCV detectable by PCR in mother, vertical transmission occurs in approximately 6% cases. Risk increases to 23% if women are also HIV positive. Infected infants becomes viremic and at risk of chronic hepatitis. Interferon may be used postpartum. Elective caesarean section, formula feeding and use of immune globulin do not reduce vertical transmission.

Found in 12-26% of pregnant women, especially in the urine. Infection associated with pre-term delivery and ascending infection may produce fetal infection after rupture of membranes.

Neonatal sepsis with associated mortality of 6% occurring in 0.5-3.7/1000 live births. Can be prevented with intrapartum penicillin in high-risk cases. Currently there is no consensus regarding preventative strategies - some centres treat on the basis of risk alone (previous history of intrapartum fever, preterm labour, PROM>18hours), others treat on the combination of screening (third trimester vaginal and anal swabs) and risk factors.

Pregnant women are particularly susceptible to listeriosis - it can cause fetal death or chronic intrauterine, congenital or perinatal infection. Infection is via infected foods (salads contaminated with animal faeces, undercooked meats, unpasteurised milk, soft cheeses and pates.

Maternal disease manifests as bacteraemia with fever, sore throat, headaches and chills and sometimes mild diarrhoea. Investigate these symptoms associated in pregnant woman with a recent dietary history and blood cultures.

Transplacental infection of the fetus is more usual than ascending infection. Early infection in pregnancy usually results in miscarriage, thereafter, still birth (20%) and prematurity are more typical. In live infants, presents as granulomatosis infantiseptica (baby and placenta covered in miliary granulomata) or pneumonia without granulomata. May also be meningitis. Infant mortality is over 30%.

Diagnosis is from blood and CSF culture, meconium and placental examination. Treatment is with ampicillin with aminoglycoside.

0.02% pregnant women infected with syphilis in UK but screening even with low incidence remains cost-effective. Endemic in many other parts of the world (Africa, South East Asia and ex-USSR).¹¹

Transplacental transmission occurs in 90% of untreated women, with highest risk early in the disease. At birth, manifests as neonatal rhinitis, osteitis, skin bullae. Hutchinson's triad (abnormal teeth, interstitial keratitis and sensorineural deafness) arise later in untreated children.

Usually detected by antenatal screening using a non-treponemal test (eg VDRL) but note risk of false-positive results (due to concomitant infection or autoimmune disease) and confirmation with a specific treponemal test (eg FTA-ABS) is required. Treatment is with IM benzylpenicillin.

Affects 5-7% of pregnant women usually asymptomatic. Main symptom in neonate is conjunctivitis (occurs in 50% exposed infants) and more rarely a pneumonia at about 4-6 weeks old.¹²

Usually asymptomatic in pregnancy. Gonococcal cervicitis is associated with chorioamnionitis and increased risk of premature labour. 40% of untreated maternal cases cause ophthalmia neonatorum - presenting with purulent discharge, lid swelling, corneal hazing within 4 days of birth.

Like CMV, toxoplasmosis is usually asymptomatic or has mild, non-specific symptoms and primary infection during pregnancy can cause serious fetal effects. Unlike CMV, toxoplasmosis acquired during pregnancy can be treated, reducing the fetal adverse effects.

Toxoplasmosis is acquired by eating raw or undercooked meat, contaminated salad or ingesting soil contaminated with toxoplasma oocysts which are excreted in the faeces of infected cats.¹³ Pregnant women should be advised to avoid these exposures (wear gloves when gardening, avoid handling cat litter). Direct contact with cats is rarely a source of infection - most acquire infection as kittens and excrete oocysts for a short amount of time.

1/3 infants become infected if mother becomes infected during pregnancy, especially in later pregnancy (but severity of disease decreases).
Many different forms of presentation:

• Systemic disease of neonate - rash, jaundice, thrombocytopenic purpura, hepatosplenomegaly, pneumonia, progressive uveitis.
• Neurological disease - hydrocephalus, microcephaly, microphthalmia, retinochoroiditis, cerebral calcification.
• Mild disease - isolated retinochoroiditis or mild cerebral calcification and no sign of cerebral injury.
• Sub-clinical - occurs in 70% of infected babies.
• Relapsing - retinochoroiditis with flare-ups can occur at any age.

About 75% pregnant women are susceptible but seroconversion during pregnancy is uncommon.. Diagnosis is difficult: serological tests have poor sensitivity, false positive toxoplasma IgM is not uncommon and low levels of IgM persist for many years following primary infection. Confirmation of fetal infection is best done with amniotic fluid PCR.

Established congenital toxoplasmosis is treated with pyrimethamine,sulfadiazine and folic acid from second trimester until a year old.

Malaria tends to be more severe in pregnant women with higher risk of complications such as cerebral malaria, pulmonary oedema and renal failure. Severe anaemia associated with malaria may also cause spontaneous miscarriage, stillbirth and IUGR.

Congenital malaria occurs in about 1% of infected pregnancies. Neonates develop fever, respiratory distress, pallor, anaemia, hepatomegaly, jaundice and diarrhoea.

Antimalarial chemoprophylaxis during pregnancy appears to have an acceptable risk-benefit ratio in areas of high risk - reducing severe antenatal anaemia, increasing birthweight and decreasing perinatal deaths in low parity women.¹⁴ Insecticide-treated bednets used during pregnancy are also beneficial.¹⁵