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

2. Which infection?
CMV
Syphilis
Toxoplasmosis
HIV
Varicella zoster

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

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

5. 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

6. CMV – cytomegalovirus

7. 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 / 1000 Live Births

8. CMV- Primary Infection, Reactivation or Reinfection ?
CMV primary infection in pregnancy  % 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. 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

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

13. 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

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

15. 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

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

17. 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

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

20. 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

21. Treatment
Can we treat ?

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

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

24. 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

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

26. 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

27. valganciclovir Oral form Blood pharmacokinetics similar
No data on CNS comparisons

29. 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).

30. 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

32. 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 %
“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

33. Good website
cmvaction.org.uk

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

37. 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 %
Early latent syphilis 40%
Late latent disease 10%

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

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

40. 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

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

43. 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

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

48. 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

49. 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

50. 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

51. 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

52. Have they been treated?
Is the treatment adequate?

53. 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

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

55. 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

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

57. 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

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

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

60. 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

61. 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

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