Congenital Infections impact on newborns and infants Jennifer Evans November 15th 2016

Which infection? CMV Syphilis Toxoplasmosis HIV Varicella zoster

The impact Uncertainty Lack of clarity Around the diagnosis Around the prognosis Have I given something to my baby?

The impact Uncertainty Lack of clarity Around the diagnosis Around the prognosis Uncertainty can persist for years Have I given something to my baby?

Clear pathway of diagnostics & investigations Referral to a team who may not know all the answers but are in a position to “travel “ with the family

CMV – cytomegalovirus

CMV - commonest congenital viral infection in UK Herpesvirus  Primary infection  Latency Antenatal CMV sero-positivity 46% Caucasians 88% Asians 77% African / Caribbean Women at most risk of acquiring CMV adolescents mothers with children <2yrs day care workers Primary CMV in pregnancy 1-3% of sero-negative women Incidence of congenital CMV 0.5 - 3 / 1000 Live Births

CMV- Primary Infection, Reactivation or Reinfection ? CMV primary infection in pregnancy  30- 40% CMV transmission rate to fetus CMV re-activation / re-infection in pregnancy  1-3% CMV transmission rate to fetus If a women gets primary CMV in pregnancy 30-40% chance of trans – higher in later stages of pregnancy

10-15% of infected newborns are symptomatic at birth But of the 85% + who are asymptomatic at birth 13.5% develop sequelae - including sensorineural hearing loss

Diagnosis of CMV during pregnancy Maternal illness Most infections are asymptomatic Fetal ultrasound

Evidence of CMV infection in pregnancy - Is the baby infected? Key to the diagnosis Presence of CMV in the urine at less than three weeks of age Saliva PCR highly sensitive and specific

scenarios CMV diagnosed antenatally - test urine or saliva and then look for evidence of organ damage

Looking for end organ damage Confirm CMV PCR(urine/saliva) Brain – US +/- MRI Eyes – fundoscopy Hearing – diagnostic test Bone marrow – FBC Liver – LFTs Gut Lungs

Scenario 2 – unwell at birth Typical clinical features Petechiae Blueberry muffin rash IUGR Microcephaly Hepatosplenomegaly

Neonates- who should be screened for cCMV? Intracranial ventriculomegaly (without other explanation) Calcification on cranial USS (often periventricular) Congenital cataracts Failed neonatal hearing screen Petechiae or purpura in the newborn Hepatosplenomegaly Prolonged jaundice with transaminitis Unexplained thrombocytopenia Evidence of maternal primary CMV infection in pregnancy, usually diagnosed serologically with evidence of CMV IgG seroconversion and/or presence of CMV IgM Neonates- to consider Screening Prematurity IUGR London consensus guideline for cCMV – courtesy of Dr Hermione Lyall

scenarios CMV diagnosed antenatally - test urine or saliva and then look for evidence of organ damage Symptomatic baby Don’t knows? – asymptomatic babies

Importance of follow up Asymptomatic infected babies Audiology every 3-6 months up to 3 years then annually up to 6 years Ophthalmology annually to 5 years Neurodevelopmental assessment 6 & 12 months

Treatment Can we treat ?

Treatment Can we treat ? Yes we can but it is also complicated

ganciclovir Only one phase 3 randomised trial to assess outcome following ganciclovir treatment 100 babies 6 weeks v no treatment

ganciclovir Only one phase 3 randomised trial to assess outcome following ganciclovir treatment 100 babies 6 weeks v no treatment Prevented hearing deterioration at 6m and 1 year Reduced developmental delay but still developmentally behind

This data cannot be used to infer a benefit for newborns without CNS disease or asymptomatics.

Who to treat: Current best evidence suggests treatment should be limited to those with - Symptomatic CNS disease: microcephaly (if in combination with other signs), radiological abnormalities on MRI or CrUSS, a positive CMV csf PCR, chorioretinitis, or a sensorineural hearing loss Severe focal organ disease: hepatitis, bone marrow suppression – ie anaemia, neutropenia, thrombocytopenia, colitis or pneumonitis

valganciclovir Oral form Blood pharmacokinetics similar No data on CNS comparisons

Conclusion Treating symptomatic congenital CMV with valganciclovir for 6 months, versus 6 weeks did not improve hearing in the short term (at 6 months) but appeared to improve hearing and developmental outcomes modestly in the longer term (24 months).

Treat – risk vs benefit? brain, hearing, bone marrow “Symptomatic congenital CMV” brain, hearing, bone marrow Yes treat – 6 months oral valganciclovir Audiology F/U 3-6 monthly to 5-6 yrs “Asymptomatic congenital CMV” SNHL one ear only Risks Short term – FBC, LFTs, 2 & 4 weeks then monthly Long term - carcinogenicity? fertility? Which infants with congenital CMV benefit from antiviral therapy? ADC April 2014, online

CMV and Sensory Neural Hearing Loss (SNHL) CMV is the leading cause of non-genetic hearing loss in children up to 1/3 of SNHL is due to CMV SNHL incidence in infants with congenital CMV: “Symptomatic” at birth 30-40% “Asymptomatic” at birth 5-10% CMV SNHL  unilateral / bilateral, progressive in up to 50% delayed onset is common, even up to 5-6 years May not be detected by neonatal hearing screening

Good website cmvaction.org.uk

Since 1998 sharp increase in syphilis in heterosexual population Women most likely to become infected 16-34 years Antenatal screening programmes BUT In 2005 36 cases of congenital syphilis were identified

Transmission to the foetus Usually via the placenta Can occur during delivery if active lesions Risk of transmission decreases as maternal disease progresses Primary syphilis 70-100% Early latent syphilis 40% Late latent disease 10%

Untreated or inadequately treated women Premature birth Low birth weight Non immune hydrops Intrauterine death

Congenital syphilis Most asymptomatic at birth 2/3 develop symptoms by 3-8 weeks Almost all by 3 months Late disease >2 years

Early syphilis Persistent rhinitis - highly infectious Deep seated infection of umbilical cord Non tender generalised lymphadenopathy Hepatoplenomegaly Conjugated hyperbilirubinaemia Rash - vesiculobullous or maculopapular rash on palms & soles Erythema multiforme

CNS in early syphilis Acute syphilitic meningitis occurs rarely CSF changes are common - 80% Raised protein and positive VDRL on CSF

Bones Decalcification of subchondral bone Irregularity of cartilage Periosteal thickening Osteochondritis - pseudo paralysis Bone changes can be reversed with treatment but if not - classic permanenet deformities Saddle nose Palatal erosions Sabre tibia

Late congenital syphilis Over the age of 2 Often in puberty Bones teeth nervous system Deafness Notched incisors Interstitial keratitis Poor response to treatment

Antenatal testing VDRL / RPR non treponemal tests used in screening Tests are quantitative and correlate with disease activity and response to therapy Confirmatory test with treponemal tests FTA-ABS - remain active for life

No syphilis or incubating syphilis No syphilis - false positive Non treponemal test VDRL Treponemal test FTA-ABS mother infant Mother - No syphilis or incubating syphilis + No syphilis - false positive Recent or previous syphilis in mother possible infection in infant Mother successfully treated for syphilis before or early in pregnancy

No syphilis or incubating syphilis No syphilis - false positive Non treponemal test VDRL Treponemal test FTA-ABS mother infant Mother - No syphilis or incubating syphilis + No syphilis - false positive Recent or previous syphilis in mother possible infection in infant Mother successfully treated for syphilis before or early in pregnancy

No syphilis or incubating syphilis No syphilis - false positive Non treponemal test VDRL Treponemal test FTA-ABS mother infant Mother - No syphilis or incubating syphilis + No syphilis - false positive Recent or previous syphilis in mother possible infection in infant Mother successfully treated for syphilis before or early in pregnancy

Have they been treated? Is the treatment adequate?

What is adequate treatment in pregnancy? Single dose of 2.4MU penicillin G May be repeated one week later if titre very high or in 3rd trimester Or if do not see response Macrolides are not adequate

Follow up serological testing Need to see a four fold decrease in titres - VDRL tests become negative after 1-2 years FTA-Ab persist

Evaluation of the infant born to a positive mother Was there adequate treatment with corresponding fall in titres? If YES Paired sera at birth Follow baby in clinic to ensure loss of antibody

If inadequate treatment or doubtful treatment Examine placenta Paired titres on mother & baby IgM on the neonate

High risk for infection Infant is symptomatic Increased titre in mother Baby has 4 fold greater titre than the mother Mother treatment inadequate Treatment started <1 m before delivery

Clinical evaluation If in doubt start treatment while awaiting results Evaluation includes CSF - inc. VDRL LFTs / FBC / U&E Long bone Xrays Ophthalmic assessment

Treatment IV benzylpenicillin 30mg/kg/dose 12 hourly for 7 days Then 8hourly for a total of 10 days. Think about the siblings

Follow up 3 6 and 12 months of age Until non treponemal tests become negative At 6-12 months of age treated children with persisting or increasing titres should be re evaluated including CSF and retreated. A persisting +VDRL in the CSF is an indication for re treatment

Untreated babies Who were asymptomatic Whose mother was adequately treated Who had a 4 fold lower titre at birth These require no further follow up Any uncertainty VDRL at 3 and 6 months - if titre persisting full clinical evaluation

THANK YOU Focused today on CMV & syphilis HIV , toxoplasmosis Infections during pregnancy with implications for neonatal illness Varicella zoster Pertussis THANK YOU