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:

1. Across the placenta - infections include Toxoplasma gondii, Treponema pallidum, Listeria monocytogenes, Plasmodium falciparum (malaria), rubella and cytomegalovirus (CMV).
2. Ascending maternal infection and chorioamnionitis causing fetal infection, usually subsequent to prolonged rupture of membranes (PROM).
3. Perinatal infection acquired during birth via the haematogenous or genital route. These include human immunodeficiency virus (HIV), herpes zoster virus (HZV), hepatitis B virus (HBV) and Chlamydia trachomatis.
4. Postnatal infection transmitted via breastfeeding.

Pre-pregnancy or routine antenatal screening can determine the presence or susceptibility to some of these infections, enabling appropriate management to prevent adverse fetal or perinatal outcomes. Always try to consider the possibility of congenital infection when reviewing an unwell pregnant woman.

See Congenital Rubella Syndrome article.

• Congenital rubella syndrome (CRS) is now rare in developed countries with rubella vaccination programmes (although poor uptake of MMR vaccine may jeopardise 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. The syndrome does not usually occur with infections following the first trimester.
• Its 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.
• Rubella is difficult to differentiate clinically from other rash-causing infections such as measles and parvovirus BE19.
• Diagnosis is based on PCR and antibody tests. Rubella-specific IgG and IgM salivary tests can supplement serial blood antibody tests.
• The 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, so seek a history of rash in early gestation in those who have recently immigrated.² IgM disappears within 4-6 weeks of a primary infection.
• Vaccination programmes aim to prevent rubella-susceptibility. Routine antenatal screening detects those requiring puerperal vaccination. The rubella vaccine is a live attenuated vaccine, so should not be used in pregnancy although there is little evidence of harm where it has been given within 30 days of pregnancy or where a woman has not been aware of her pregnancy.³

See Congenital HIV article.

• An estimated 2.4 million HIV-infected women deliver children every year worldwide. Infection occurs during delivery or breastfeeding.
• Transmission can be reduced with the use of short courses of antiretroviral drugs. A combination of zidovudine and lamivudine given to mothers in the antenatal, intrapartum and postpartum periods and to babies for a week after delivery, or a single dose of nevirapine given to mothers in labour and babies immediately after birth may be most effective.⁵
• In industrialised countries, combination antiretroviral therapy is already standard in efforts to reduce vertical transmission, and transmission rates are between 1-2%.
• Other strategies include the use of elective Caesarean section⁶ and avoidance of breastfeeding where possible.⁷

• CMV is the commonest congenital infection in the developed world: 1-4% of 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 a 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 disease is characterised by mental impairment, growth retardation, microcephaly, thrombocytopenia and hepatitis. Also, there is a 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. 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.
• Treatment with antivirals may be appropriate for neonates with neurological involvement.¹⁰
• Until vaccines are available, hygiene measures, e.g. handwashing, are the most important prevention methods available.

• Infection occurs in 1/2,000 pregnancies with a 10-15% risk of fetal infection. The majority of fetal infection is transient and asymptomatic. A minority - 2-3% of infants of women with chickenpox in the first half of pregnancy - does 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. It is associated with up to 30% neonatal mortality. Babies of mothers developing perinatal chickenpox should receive varicella-zoster immune globulin (VZIG).
• Varicella zoster vaccine is not currently recommended for susceptible women of child-bearing age or routine use in children in the UK, although it is used widely elsewhere in the world, for example America and Australia.¹¹

• 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% of pregnant women in the UK is HBsAg positive compared to approximately 25% in parts of Africa and Asia.
• In an HBsAg positive/HBeAg negative mother, the risk of transmission is 5-20% compared to 70-90% in an HBsAg/HBeAg positive woman.
• 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.

• Vertical transmission in hepatitis C virus (HCV) RNA-negative pregnant women is approximately 1-3% versus approximately 4-6% in HCV RNA-positive women. Risk increases to 23% if women are also HIV-positive.
• Infected infants become viraemic and at risk of chronic hepatitis. Interferon may be used postpartum.
• Elective Caesarean section, formula feeding and use of immune globulin do not appear to reduce vertical transmission in women who are HIV-negative.
• The use of a scalp electrode and duration of membrane rupture beyond 6 hours may increase risk of transmission.

• Group B streptococci are found in 12-26% of pregnant women, especially in the urine. Infection has been associated with pre-term delivery and ascending infection following rupture of membranes may result in fetal infection.
• Neonatal sepsis with associated mortality of 6% occurs in 0.5-3.7/1,000 live births. It 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, pre-term labour, PROM >18 hours), others treat on the combination of screening (third trimester vaginal and anal swabs) and risk factors.
• Universal screening of all pregnant women, rather than a targeted high risk approach, may be more effective but even where this occurs, neonatal sepsis still occurs at a level of about 0.5/1000 live births.¹⁴

• Pregnant women are particularly susceptible to listeriosis. It can cause fetal death or chronic intrauterine, congenital or perinatal infection.
• Infection is via the ingestion of infected foods (for example, 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 in pregnant women 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; later infections may result in stillbirth or prematurity. In live infants, listeriosis presents as granulomatosis infantiseptica (baby and placenta covered in miliary granulomata) or pneumonia without granulomata. Meningitis may also occur. 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 are infected with syphilis in the UK but screening, even with such low incidence, remains cost-effective. Syphilis remains endemic in many other parts of the world (Africa, South East Asia and ex-USSR).¹⁵
• Transplacental transmission occurs in 90% of untreated women, with highest risk early in the disease. At birth, infection manifests as neonatal rhinitis, osteitis, skin bullae. Hutchinson's triad (abnormal teeth, interstitial keratitis and sensorineural deafness) arise later in untreated children.
• Maternal infection is usually detected by antenatal screening using a non-treponemal test (e.g. VDRL) but note there is a risk of false-positive results (due to concomitant infection or autoimmune disease) and confirmation with a specific treponemal test (e.g. FTA-ABS) is required.
• Treatment is with parenteral benzylpenicillin.

• Chlamydia affects 5-7% of pregnant women and is usually asymptomatic.
• The main symptom of neonatal infection is conjunctivitis (occurs in 50% exposed infants) and, more rarely, a pneumonia at about 4-6 weeks old.¹⁶

• Gonorrhoea is 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.¹⁷ 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.
• There is very little good evidence that prenatal education about the risks of CMV reduces the risk of congenital infection.¹⁸
• A third of infants become infected if their mother becomes infected during pregnancy, especially in later pregnancy (but the severity of disease decreases).
• There are many different presentations:
  • Systemic neonatal disease - 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 the 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 intrauterine growth restriction (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.¹⁹ Insecticide-treated bednets used during pregnancy are also beneficial.²⁰

Travel outside the UK can increase the risk of other potential congenital infections (e.g. leishmaniasis, Japanese encephalitis, typhoid fever, leptospirosis, dengue fever) besides malaria and a pregnant woman considering foreign travel should be advised accordingly.²¹

Routine antenatal screening tests in the UK completed prior to 16 weeks' gestation ²²

Surveillance indicates that rates of maternal infection are variable across the country with high concentrations in particular geographic areas. Based on data from women receiving antenatal care in London between 2000-2007, prevalence of HIV infection was 3/1,000 women, of hepatitis B was 11/1,000, of syphilis was 4/1,000 and of rubella susceptibility was 39/1,000.²³ Uptake of screening amongst this group of pregnant women was between 95-97%.

Currently there are no tests recommended nationally for antenatal screening of CMV, toxoplasma, parvovirus or group B streptococci.

Do not forget that acute maternal infection may occur after screening - in resource-rich settings such as the UK and America, a significant proportion of perinatal transmission of HIV occurs due to infection acquired during pregnancy.²⁴