S

Congenital Infections

The elephant in the room Fetal Medicine – Old and New

Dr JL van der Merwe

SASOG 2014

S Originally TORCH complex

S Toxoplasmosis

S Other [T. pallidum]

S Rubellavirus

S Cytomegalovirus (CMV)

S Herpes Simplex Virus (HSV)

S Now also perpetrators….

S Parvovirus B19

S Varicella-zoster virus

S Hep B

S Plasmodium

S HIV

S Mycobacterium tuberculosis

S Listeria Monocytogenes, Enterovisuses, Borrelia burgdorferi (Lyme Disease) …

Transmission Routes

Transmission Timing

Manifestation influenced by…

Mode of acquisition

Maternal immunity

Timing (gestation)

Effect of pathogen on organogenesis

Fetal genetics

Teratogens:

• Varicella, Rubella

• CMV, HSV

• Influenza

S

Patho

genesis

S D0 : Maternal Infection - Viraemia, Bacteraemia, Paracitaemia

S ?Clinical Symptomatology

S D1-7: Nonspecific (fever, chills headache myalgia)

S D5-21: Specific (rash, arthritis, pharyngitis, meningitis (up to 21d)

S D5-24: Transmission (1-3w)

S Fetal Infection from D1

S Fetal Affection - ultrasound features (weeks -months)

S Neonatal presentation

Patho

genesis

S D0 : Maternal Infection - Viraemia, Bacteraemia, Paracitaemia

S ?Clinical Symptomatology

S D1-7: Nonspecific (fever, chills headache myalgia)

S D5-21: Specific (rash, arthritis, pharyngitis, meningitis (up to 21d)

S D5-24: Transmission (1-3w)

S Fetal Infection from D1

S Fetal affection - Ultrasound features (weeks -months)

S Neonatal presentation

Patho

genesis

• Maternal Immunity • Virulence organism • Severity of disease • Gestational age

Patho

genesis

• Foreign graft – placenta immunological barrier

• Immature immunologic mechanism

• Persistence of organism

?

Patho

genesis

Placental damage

Patho

genesis

Progressive tissue

destruction • Toxoplasmosis • Syphilis • Rubella • CMV • HSV

Patho

genesis

Patho

genesis

Patho

genesis

Pretest Probability and detection

Neg Predictive Value

Pos Predictive Value

Prevalence

S Primary Prevention

Current antenatal screening

Test Purpose Action

HIV antibody To enable measures to be taken to reduce vertical transmission.

If positive, ARVs and screening OI.

Syphilis To detect active infection. If reactive, treat with penicillin

Urine culture Treatment of asymptomatic UTI If asymptomatic bacteriuria, treat and repeat culture

Hep B surface antigen To determine chronic carriers. If positive, administer hepatitis B Ig and vaccine to infant at birth

Rubella IgG To determine susceptibility If negative, MMR before conception / post-partum.

CMV

S Primary Prevention – detect seronegative women (IgG -)

S Avoid high risk (children under 6y, sharing utensils)

S Good hygiene

S Primary screening – not recommended

S No vaccine is available

S In seropositive women, ? distinguish between primary –non-primary infection or determine the timing

S No evidence - antiviral drug treatment of primary infection

S Although fetal infection detected, no way to predict outcome

Toxoplasmosis

S Primary Prevention – detect seronegative women (IgG -)

S Avoid high risk (undercooked / cured meat, soil-contaminated fruit / vegetables)

S Primary screening – not recommended

S Screen IgM and/or IgG avidity

S IgM false positive rate (10-13m post after infection)

S Serial IgG titres - lab reproducibility problems

S IgM + and IgG –; both positive two weeks later can be useful

S Although treatment decrease significant CNS affect

What to do?

Assess risk profile

Inform of risks of exposure

Educate on preventative measures

• Vaccinations

• Hand hygiene

• Food (deli meats, soft cheese, unwashed veg)

• Cat litter boxes

• Avoid contact with sick people, wild pets, toddlers

S Secondary Prevention

Presentation

Maternal Features Contact with known infection

History of suggestive infection

Diagnosis

Diagnosis

S Serology

S Prim infection = seroconversion

S Probable recent if IgM + WITH low IgG avidity

S Recurrent infection:

S Specific IgG + without IgM before pregnancy

S NOW significant increase IgG + titre

Diagnosis

S Avidity Test

S Abs avidity indicates -strength of multivalent Abs binding to multivalent antigen

S Low avidity <30% - suggests primary infection (<3 months)

S High avidity >70% - suggests infection of >4m ago

Prognosis

Number of cases

Severity of infection

Gestation

Transmission Toxo Transmission CMV Transmission Rubella

S Tertiary Prevention

Fetal Presentation

Maternal Features

Contact with known infection

History of suggestive infection

Ultrasound Abnormalities

Ventriculomegaly, Calcifications, echogenic bowels, Hepato- / Splenomegaly, Hydrops fetalis

Antenatal Ultrasound

Infection Main Features of Syndrome

Congenital toxoplasmosis Microcephaly, hydrocephalus, intracranial calcifications, ascites

Congenital syphilis Hepatosplenomegaly, ascites

Congenital rubella syndrome Cataracts, cardiac malformations (eg, patent ductus arteriosus, pulmonary artery hypoplasia), microcephaly, hepatosplenomegaly …

Congenital cytomegalovirus IUGR, microcephaly, hypotonia, intracranial calcifications

Congenital varicella syndrome Atrophy of extremities, microcephaly, cataracts, microphthalmia

Ultrasound Features

Ultrasound Features

Example Ventricular dilatation (A), hyperechogenicity of the ventricular wall (B).

Ultrasound Features

Ultrasound Features

Ultrasound Features

Diagnosis - Fetal

S US Features - Syndromes

S Amniocentesis (after 20w)

S Viral culture 100% specific (…false-negative)

S Viral DNA isolation – PCR both sensitive and specific

S Cordocentesis – FBS

S Detection of viral PCR, IgM, or viral culture

S Together with hematologic, immunologic, and enzymatic measurements

Prognosis

Sonographic abnormalities:

• Associated abnl / extent

• No guarantee of normal fetus/infant if absent

Fetal blood parameters:

• specific IgM, viral load, biochemical, haematological

Viral load in amniotic fluid

S

Specific Infections

Rubella

S Mother:

S Isolate virus from throat / blood

S Paired serological samples

S IgG +, IgM + (Recent infection /reinfection) - Repeat 2w

S IgG -, IgM – (Susceptibility) Repeat if < 3w since contact, < 7d since onset)

S IgG -, IgM + Possible recent infection

S IgG +, IgM – Past infection /immunisation

Rubella

S Congenital rubella syndrome

S Transient abnormalities:

S Permanent abnormalities: cataract, glaucoma, CVS, deafness, microcephaly, MR

S Late abnormalities:

05

101520253035404550

1-4 wks 5-8 wks 9-12 wks > 12 wks

Risk of fetal infection

S Fetal Risk

S T1 - 80-90% transmission

80% abnl (multiple organ damage, miscarraige)

S T2 – 25% abnl (±100% hearing impairment/ ±50% eye abnl)

S >16w - Fetal affectation rare

CMV

S High risk groups for primary CMV

S Day care workers (11% incidence per year)

S Parents with child in day care (incidence of 20 – 30 %/y)

S Cannot be eradiated!

(Reactivation and reinfection common)

S Serologic testing recommended for:

S History suggestive

S Exposure to known CMV

S Immunocompromised

S Abnormalities on routine antenatal ultrasound

CMV

S Prim infect. - 30-40% transm.

S Reinfection - 1-2% transm.

S T1: severe sequelae

(deafness and mental

retardation)

S 10 - 20% infected infants:

sensorineural hearing loss,

ocular damage, impairment of

cognitive / motor function

0

10

20

30

40

50

60

70

1sttrimester

3rdtrimester

Primary Maternal Infection

CongenitalInfections

Symptomsat birth

Severehandicaps

CMV Diagnosis

S Ultrasound [detect typical features, sensitivity 30 – 50 %

S Amniocentesis [for PCR + culture] 4-6w after infection S 45 % sensitive If < 20 weeks

S 80 – 100 % sensitive if > 20 weeks gestation. Specificity up to 100 %.

S Viral loads of >103 copies/mL =symptomatic fetal infection (sens 70%)

S Fetal blood sampling S CMV- IgM > 20 weeks 50 – 80 % sensitive

S Severe congenital CMV

S Consider TOP

S experimental protocols with IV ganciclovir / Valganciclovir

Parvovirus B19

S Childhood viral exanthem erythema infectiosum

(Fifth disease or "Slapped cheek disease")

S Transmision:

S Transplacental up to 30%

S Fetal loss about 9% (T2)

S Overall fetal loss rate 1/60

[<20w up to 17%]

0

2

4

6

8

10

12

14

16

1-12 wks 13-20 wks > 20 wks

Risk of Fetal Infection

Parvovirus B19

S Fetal Affectation

S Aplastic anaemia

S Direct cadriomyopathy

S NIHF (nonimmune hydrops fetalis)

S IUFD – 1-12w after infection

S FBS:

S Fetal serology can be false negative

S PCR (best)

S Fetus – 1-2w review for 3m

S signs of hydrops

S MCA PSV

Toxoplasmosis

S Protozoan, Toxoplasma gondii [intracellular patasite]

S Fetal

S T1 Miscarraige

S Chorioretinits (blindness), encephalitis (micro- ,hydrocephaly and calcifications), jaundice

0%

10%

20%

30%

40%

50%

60%

70%

T1 T2 T3

Transplacental Toxoplasma and Congenital Infection

Transmission

Severe symptoms

Toxoplasmosis

S Investigations

S Ultrasound (>20w) - IUGR, ventriculomegaly, intracranial calcifications, or ascites

S Amniocentesis (4w after maternal) PCR and / or culture

S If US and AF negative - still consider treatment

S Infected mothers

S Spiramycin (1.5 grams every 12 hours) to prevent fetal infection

S 60% reduction

S Infected fetus

S Pyrimethamine and sulfadiazine with folinic acid (Leukovorin)

S TOP

Varicella-Zoster Virus

S Primary infection - chickenpox

S Highly infectious

S 10% respiratory complications

S Herpes zoster ("shingles")

S Not cause congenital /neonatal varicella

S Transplacental passage of antibodies [mother] T2 and T3

S Fetal infection rate 25%

S 2% - 10% fetuses develop VZV embryopathy

S 6 - 12 weeks - limb abn

S 16 to 20 weeks - eye and brain

S Later less frequent & severe

Varicella-Zoster Virus Management

S Infected mothers:

S VZIG does not protect the fetus

S Antiviral agent - acyclovir 5-10mg/kg IVI 8hly x 7d

S Women exposed - VZIG 125 U/10kg IMI (max 625 U)

S Women infected last few days of gestation - born within 2-4 days after the onset

S 20% risk for neonatal varicella - develop progressive varicella

S Administration of VZIG most valuable

Herpes Simplex

S HSV persist in latent state, resurfacing at any time

S Mostly acquired during delivery

S Primary infection - 33 to 50% transmission

S Recurrent disease - 1 to 3% transmission

S Primary HSV infection:

S Miscarriage

S Disseminated – hepatitis,

encephalitis,death

S PTL

S Perinatal infection

S Manifests during 1st month

Herpes Simplex Effects

S 3 major categories seen

S localized skin, eye and mouth infection

S encephalitis with or without skin, eye, and mouth disease

S disseminated infection [irritability, seizures, respiratory distress, jaundice, bleeding diathesis, and shock]

S CNS infections – chorioretinits, meningitis, encephalitis, MR

Herpes Simplex Management

S Caesarean section if primary, first episode, or recurrent HSV lesions present in labour

S Infants - cultures of nose, mouth, urine, and stool [24 – 48h]

S If any maternal cultures are positive or if disease is apparent

S Diagnosed new-borns - isolated to prevent nosocomial transmission

S Treatment include acyclovir IV (20 mg/kg/dose) q8 hours for 14 to 21 days