INTRAUTERINE & PERINATAL INFECTIONSDr Maria Kahar BadorLecturerDepartment of Medical Microbiology

MBChb.BaO(UK), MSc Med Micro (Lond) Dip LSHTM (Lond)

OUTLINEA. DefinitionB. PathophysiologyC. Aetiological agentsD. General clinical featuresE. Specific agents -

1. Clinical Features2. Diagnosis3. Treatment4. Prevention

A. Definition

Neonatal inf – appearing within first 4wks of birth

____________l____________

Congenital Postnatal

___________________________

Intrauterine Perinatal

l(Transplacental) (Ascending At delivery)

B. Pathophysiology Foetus protected by: Maternal immunity (e.g. passive transfer of IgG) Foetal membranes

Foetus at risk: Immature immune system Organogenesis (depends on gestational age) High microbe load

C.Aetiological agents-

Congenital Infections TORCH

T oxoplasmosis O thers- Varicella, B19, Listeria,Syphilis ,Gonorrhoea,R ubellaC ytomegalovirusH erpes,Hepatitis B ,C, HIV

Perinatal infections

1. Sexually-transmitted– Neisseria gonorrhoeae– Chlamydia trachomatis– Human papillomavirus– Herpes simplex virus– HIV (also blood-borne)– Hepatitis B & C* (also blood-borne)(* not sexually-transmitted)

2. “Normal” maternal flora– Group B streptococcus (Strep. agalactiae)– Enterobacteria, e.g. E. coli

D. General Clinical Features

Common to TORCH infections * low birthweight * preterm delivery * anaemia, thrombocytopaenia * hepatitis with jaundice and hepatosplenomegaly * seizures * microcephaly * mental handicap * encephalitis * failure to thrive

E. Specific agents Toxoplasma gondii

Organism: Protozoa ,order Eucoccidia CAT: – definitive host for repro transmitted by oocysts in the faeces HUMANS: – acquired by ingestion of contaminated cysts or meat, lamb and pork (in)direct contact with cat faeces (sporocyst ) transfer within organ transplant Pathology: – Trophozoite obligate intracellular parasite reticuloendothelial cells mainly multiplies binary fission, cell disruption and death

Clinical features Gen : wide range– Most asymptomatic.– mild, self-limiting, non-specific IM syndrome– Disseminated organ damage brain, eyes, muscles, liver, and lungs– immunocompromised –severe , AIDS -focal neurological defect space-occupying lesion Cong 10% – severe damage at or shortly after birth– neurological damage– cerebral calcification, – hydrocephalus – chorioretinitis. 80 - 90%– months or years– bilateral visual loss due to chorioretinitis ,post uveitis – hepatosplenomegaly

Epidemiology of Congenital Toxoplasmosis

pregnant mothers primary infection 1 - 6 per 1000 in the UK fetal damage risk if infect earlier vertical transmission risk less 33 % symptomatic disease 1 in 10,000 increased HIV infection countries where raw meat is eaten

Diagnosis - may be difficult Maternal IgM, seroconversion IgG Cord IgM/ IgA PCR/ culture of amniotic fluid

Prevention Antenatal screening in some countries Treat infected mother & baby with spiramycin or pyrimethamine-sulphadiazine

Herpesviruses Enveloped double stranded DNA viruses. Three subfamilies:– Alphaherpesviruses - HSV-1, HSV-2, VZV– Betaherpesviruses - CMV, HHV-6, HHV-7– Gammaherpesviruses - EBV, HHV-8 Features-– Latent or persistent infection following primary infection– Reactivation during immunosurpression– more serious in immunocompromised patients.

o Varicella Zoster Virus Herpesviruses subfamily alphaherpesvirus ds DNA enveloped virus Genome size Serotype 1 antigenictype only some cross reaction with HSVGen clinical features Primary infection

varicella (chickenpox) Secondary

Herpes zoster (shingles) Pregnancy

Congenital herpes Neonatal herpes

Transmission Respiratory droplets, vesicles contact Incubation period 14-21 days

Infectious period from 4 days before the appearance of the rash until all lesions have scabbed over (approximately one week).

Pregnancy 3 per 1000 women ( UK ) Immune-

90% women have antibodies to varicella zoster virus also protected if secondary occurs

Nonimmune potentially dangerous disease fetal &maternal morbidity high five times more likely to be fatal than in non-pregnant women 14% develop pulmonary involvement esp smoking

Fetal outcome Most healthy

In utero breach -Congenital Perinatal-Neonatal

Congenital / fetal varicella syndrome Rare when infection occurs early Risk 0.5% if 2-12 weeks preg + 1.4% if 12-28 weeks 0% if from 28 weeks on 0.91% overall risk first 20 weeks Clin features skin loss/scarring CNS impairment (e.g. hypotonia) limb hypoplasia /paresis LBW microcephaly, ophthalmological abnormalities.

Neonatal Late stages of pregnancy

cross the placenta Immunity

sufficient – if rash in mother occurs >1 week before delivery

Insufficient– if mother ill 5 days before until 48 hrs after delivery

Clin features vary from a mild disease to a fatal disseminated infection.

Prevention &TreatmentFor susceptible mother:

Live attenuated vaccine (before pregnancy) VZ immunoglobulin (after exposure) infection control precautions

For newborn VZ immunoglobulin if mother gets c-pox last 7 days of pregnancy or the first 14 days after delivery. infection control precautions

Treatment If acute acyclovir

Laboratory Diagnosis Rarely required for primary characteristic clin features Virus Isolation

2-3 weeks for a results.

Serology IgG past infection and immunity IgM recent primary infection.

Direct detection EM vesicle fluids cannot distinguish HSV and VZV. IF on skin scrappings can distinguish PCR

Parvovirus B19Properties

naked icosahedral ss DNA Antigenically distinct from the viruses found in faeces, RA-1 and other parvoviruses

Epidemiology& Pathogenesis B19 present throughout the year Outbreaks in temperate climates outbreaks more in the spring and summer around primary schools 40% of pupils may be infected. Commonest amongst 4 - 10 yr olds. By adulthood 60% population seropositive.

Transmission Respiratory spread usual route Bloodborne occur

Clinical features Pregnancy not associated with increased risk of fetal malformation BUT fetal loss– majority of pregnancies proceed to term with delivery of normal infants – infection in first trimester 5 - 10% fetal loss.– Infection in second trimester 12.5%. Hydrops fetalis – seen in newborn with second and third trimester infection– Maternal infection occurs 2 to 12 weeks prior to diagnosis– Severe anaemia leads to heart failure, effusions, diffuse oedema– <20 weeks gestationClinical features Erythema infectiosum Chronic haemolytic anaemias Aplastic crisis Immunocompromised persistent infection in patients

Diagnosis Differential diagnosis all diseases of maculopapular rash eg. rubella, enteroviruses, arboviruses, streptococcal infection, allergy. Virus Detection detection of the virus in fetal blood samples or autopsy material direct or immune EM. RIA or DNA-DNA hybridization, PCR Antibody Detection ELISA or RIA. "antibody capture" detection of either (i) B19-specific IgM or (ii) a rising titre of B19 specific IgG. B19 specific IgM may be detected in such tests up to 3 months after the onset of symptoms. B19 IgG lasts longer but this antibody is not detectable lifelong following infection. patients with no detectable IgG may have experienced previous B19 infection

Treatment During pregnancy Supportive only pregnancy should be allowed to proceed with monitoring. At delivery examination of the cord blood for B19 IgM. Child followed up for delayed sequelae Immunocompromised persistent B19 infection only specific treatment administration of HNIG

Prevention Infection control HNIG

Treatment erythema infectiosum

rarely necessary,syptomatic chronic haemolytic anaemias transfusion of erythocytes until a satisfactory Hb level Prevention Inf control

Listeria monocytogenes GPR, β-haemolytic Mother infected by: contact with animals, soil eating contaminated food or unpasteurised milk/ soft cheese Mother mild, flu-like illness Bacteraemia may cause: abortion premature labour neonatal sepsis/ meningitis Treatment: ampicillin +/- gentamicin

RubellaProperties

Non-arthropod-borne togavirus Genus Rubivirus only member Enveloped virus, 60nm in diameter, nucleocapsid 33nm symmetry icosahedral but virus particle has a pleomorphic appearance.

Genome ssRNA +ve 40S RNA consists of 3 structural proteins; E1 E2 membrane bound glycoproteins, and C capsid protein E1 has 6 distinct antigenic determinants; 4 associated with haemagglutination, and 2 with neutralization serotype ONE

Growth in a wide range of cell lines. It I– nduces a CPE only in continuous cell lines such as RK13 (rabbit kidney) and VeroRubellaEpidemiology Worldwide

Before immunisation Outbreaks tend to occur Spring and Summer. uncommon in preschool children but outbreaks Infection involving school children and young adults were common. 50% of 10 year olds have rubella antibodies. 80% of women of childbearing age immune Problem uptakeRubellaPathogenesis Incubation period 13 to 20 days Transmission by respiratory route. Reinfection Natural infection high level of protection from reinfection. can occur which is generally asymptomatic.

Reinfection in pregnancy minimal risk to the fetus

Congenital infection virus enters fetus during maternal viraemic phase through the placenta. rapid death of some cells and persistent viral infection in others damage to all germ layers Chromosomal aberrations reduced cell division Virus high if the mother infected during first trimester. Immune sytem immature virus persists throughout the gestation– can be isolated from most organs,secretions.The mechanism of virus persistence defects in cell-mediated immunity

RubellaPathogenesis First trimester risk of major malformations 10% to 54% risk greatest first 8 weeks of pregnancy (Hanshaw et al 1985) critical phase of organogenesis. Cardiac and eye defects are more likely

13 and 16 weeks Deafness usually sole manifestation 16 to 20 weeks of gestation retinopathy and hearing defects

RubellaClinical Features Rash viraemia occurs & virus disseminates throughout the body. In children rash onset abrupt. In adults prodromal phase for a day or two rash develops. Typically maculopapular rash first appears on face spreads to the trunk and limbs. < 3 days. immunopathological mechanism Lymphadenopathy a week before rash and 2 weeks after the rash has goneRubellaClinical Features Joint involvement is the commonest complication and occurs in up to 60% of adult females. The fingers, wrists knees and ankles are most frequently affected. The arthralgia lasts usually 3-4 days. Arthralgia is rare in males and prepubertal females. An Encephalitis develops in 1 / 10000 but the prognosis is good. Trombocytopenic purpura may present as purpuric rash, epitaxis, haematuria and GI bleeding. In 25% the infection is subclinical.. RubellaClinical Features Congenital rubella syndrome (CRS)

Transient;- IUGR, thrombocytopenic purpura, hepatoslenomegaly and haemolytic anaemia. first few weeks of life not permanent . Transient bone lesions in 20% 25% have a meningoencephalitis +-leave neurological sequelae. Jaundice common

Developmental;-

Sensorineural deafness, mental retardation, insulin-dependent diabetes. – IDDM common manifestation of CRS ( up to 20%). Delayed onset adolescence or adulthood. Autoimmune mechanisms may be involved.

may take months before become apparent but persists permanently. Between 3 - 12 months late onset disease". – some infants develop a rubbelliform rash, persistent diarrhoea and pneumonitis referred to as high mortality. Permanent;- Heart defects (patent ductus, VSD, pulmonary valve stenosis), eye defects (retinopathy, cataract, microopthalmia, glaucoma, severe myopia), CNS defects (microcephaly, psychomotor retardation).  

RubellaClinical Features Congenital rubella syndrome (CRS)RubellaLab diagnosis Difficult clinically Serology Main diagnosis of rubella infection.SRH, ELISA A recent rubella infection can be diagnosed by 1) detection of rubella-specific IgM, (2) rising titres of antibody in HAI and ELISA tests (3) seroconversion History Essential accurate information relating date and time of exposure, onset of illness. A history of previous rubella vaccination +previous results of rubella screening tests. Pregnant women –blood collectec asap

Virus isolation Less used now from nasopharyngeal secretions ( and occasionally from faeces and urine ) 7 days before and up to 7 days after rash. RubellaDiagnosis congenitally acquired rubella Presence of rubella IgM in cord blood serum samples taken infancy

Detection of rubella antibodies at a time when maternal antibodies should have disappeared (approx.6 months of age)

Isolation of rubella virus from infected infants in the first few months of life

Prenatal diagnosis Amniotic fluid fetoscopy IgM

RubellaTreatment and Prevention Treatment Supportive , counselling in pregnancy

Prevention Vaccination Passive immunisation HNIG does not prevent infection in non-immune contacts may reduce the likelihood of clinical symptoms may reduce the level of maternal viraemia and risk to fetus. Antenatal screening Infection control

CytomegalovirusProperties

Herpesviruses subfamily betaherpesvirus ds DNA enveloped virusCytomegalovirusEpidemiology Incidence Developed countries – higher standard of hygiene, – 40% of adolescents are infected – 70% of the population is infected Developing countries– 90% of people infected

Transmission Very succesful Vertical and horizontal Blood and products In utero, peri &postnatal Perinatal 10 times more common

2 - 10% of infants are infected by the age of 6 months worldwide 1-2% live births are infected; up to 10% of these have symptoms

40% foetal infection if maternal primary infectionCytomegalovirusPathogenesis Life long Reactivation – Periodically– immunocompromised esp– infectious virions appear in the urine and the saliva– Rare leading to vertical transmission 0.15 - 1%.

Perinatal infection – mainly through infected genital secretions or breast milk.

Postnatal infection – mainly occurs through saliva. – Sexual transmission may occur as well as through – blood and blood products and transplanted organ.CytomegalovirusClinical 10 - 20% are symptomatic at birth

80 - 90% are asymptomatic at birth but later exhibit: mental handicap visual impairment progressive hearing loss delayed psychomotor retardation intrauterine infection less likely to be suspected

Congenital infection – cytomegalic inclusion disease Perinatal infection usually asymptomatic Postnatal infection – usually asymptomatic. minority ifectious mononucleosis

Immunocompromised AIDS & transplant recipients and AIDS severe CMV disease pneumonitis, retinitis, colitis, and encephalopathy. Reactivation or reinfection usually asymptomatic except in immunocompromised patientsCytomegalovirus Cytomegalic Inclusion Disease CNS abnormalities microcephaly, mental retardation, spasticity, epilepsy, periventricular calcification. Eye - choroidoretinitis and optic atrophy Ear – sensorineural deafness Liver - hepatosplenomegaly and jaundice Lung – pneumonitis Heart – myocarditis Blood Thrombocytopenic purpura, Haemolytic anaemia Late sequelae in individuals asymptomatic at birth hearing defects and reduced intelligence. Cytomegalovirus Laboratory Diagnosis Virus Isolation gold standard but up to 4 weeks rapid culture methods eg DEAFF test 24-48 hours. Baby- from urine 1-3 weeks

Direct detection Histology CMV inclusion antibodies /presence of CMV antigens. Low sensitivity pp65 CMV antigenaemia test in immunocompromised patients. PCR for CMV-DNA , interpretation probs Baby-urine 1-3 weeks Serology – Mum IgG antibody past infection. IgM antibody indicative of primary infection Also reactivation in immuno compromised patients – Baby Blood IgM in first 3 weeks of life

Cytomegalovirus Treatment &Prevention Treatment Supportive only unless immunocompromised– ganciclovir, forscarnet, and cidofovir. Congenital infections– Unless primary not usually possible to detect– counselling Peri and post natal - Not nec Prevention no reliable CMV vaccine available. best by reducing exposure to toddler's urine blood for donation to infants should be from CMV-negative donors.

Exposure of foetus to infection: outcomesWhat do we do to prevent foetal and neonatal infection? Vaccinate all potential mothers – Tetanus– Rubella– Hepatitis B– VZV (in USA, Japan

Antenatal screening of pregnant mothers– HIV– Hepatitis B surface antigen– Syphilis– Rubella (not done in Malaysia)– Toxoplasma (selected countries only, e.g. France)– Group B streptococcus (selected countries only, e.g. USA)

What do we do to prevent foetal and neonatal infection? In some infections in pregnant mothers, there are interventions to reduce risk of foetal/neonatal infection:

Maternal infection Maternal intervention Neonatal prophylactic intervention

HIV Antiretroviral drugs, caesarean, no breast-feeding

Antiretroviral drugs

Hepatitis B Screening Hep status in high risk groups IVDU , endemic

Active immunisation +/- immunoglobulin

VZV Immunoglobulin (if early pregnancy)

Immunoglobulin (if near delivery)

HSV-1 & 2 Caesarean Aciclovir

Syphilis Penicillin Penicillin

Toxoplasma Anti-Toxoplasma drugs Anti-Toxoplasma drugs

Group B strep Penicillin Observe +/- penicillin

Thank you !