Prognostic and Management of CMV Fetal Infection › ...CMV-Fetal-Infection-Pr... · Heart...

Prognostic and Management of CMV

Fetal Infection

Enrico David, 2014, « The Assumption of Wee »

Screening Programmes Antenatal Advice

8,000

7,500

7,000

6,500

6,000

5,500

5,000

4,500

4,000

3,500

3,000

2,500

2,000

1,500

1,000

500

0

HIV

200CRS

10

SB

3000

DS

4000

Toxo

1000

FAS

5000

Annual N

um

ber

of D

am

aged B

abie

s

CMV

7670

Neither

Cannon M. BMC Pub Hlth, 5, 70, 2005. Dollard, S. RMV, 17, 355-362, 2007. Wang, C. Clin Inf Dis, 52, e11-e13, 2011.

Comparison with other conditions

Courtesy of P. Griffiths

Rationale

• Need for improvement of

Positive and Negative

Predictive Value

• Early reassurance

• Early access to TOP

• Opportunity for treatment

Prediction of neonatal outcome in

congenital cytomegalovirus infection

at the time of prenatal diagnosis

L. Frederic, The source of life, 1890 Philadelphia museum of Art

Prognosis based upon

clinical neonatal evaluation

This sets the goal of prenatal management by extrapolating neonatal

symptoms to prenatal evaluation

5-10% Severe 5-10% Moderate 90% Asymptomatic

•IUGR

•Microcephaly

•Ventriculomegaly

•Seizures

•Spasticity

• Meconial peritonitis

•Hepatomegaly

•Splenomegaly

•Hepatitis

•Thrombocytopenia

•No clinical sign

Neonatal

Death

30%

Sequelae Neurosensory Neurosensory

Hearing loss Hearing loss

30% 60% 5-15%

Modified from Fowler et al N Eng J Med 1992

Placentitis

Oligohydramnios

Polyhydramnios

Ileus

Meconial peritonitis /Ascites

Liver & Spleen enlargement

Ubiquitous Calcifications

Pericardial / Pleural Effusion

Dilated Myocarditis

Heart Calcifications

Hydrops

Growth Restriction / Small for GA

Extra-cerebral ultrasound features

of fetal CMV infection

Presented in the theoretical chronological order of their development

Django Hernandez, 2008

Ultrasound to my mother history-we got twins!

Decrease the gain and switch off the harmonics to compre the echogenicity of the bowel to that of the

bones (Grade 3 : > ou = bone)

260 cases of echogenic bowel, (0.4%)

13 cases (5%) of trisomy 21,

1 case (0.4%) of trisomy 18,

2 cases (0.8%) of trisomy 13,

1 case (0.4%) of chromosomal mosaicism,

5 documented cases (1.9%) of CMV infection, 6 documented cases (2.3 %) of CF,

1 case (0.4%) of both documented CF

and chromosomal mosaicism.

43 cases had associated anomalies,

Hyperechogenic bowel

Obstet Gynecol. 2011

Obstet Gynecol 1985

Toshiyuki Hata,and Russell L. Deter, J Clin Ultrasound 1992, 20:155-174

Liver and Spleen Measurement and Biometry

Right liver lobe in a sagittal plane

Longest dimeter of the

spleen In an axial plane

Extra-cerebral ultrasound features


Cou

rte

sy o

f P

r. R

. C

ha

ou

i

Odds ratio 95% CI

Death 1.2 0.2-9.0

Abnormal neuroimaging 7.8 2.2-28.1

Suspected SNHLb 87.6 11.8-633.4

Suspected SNHL and deathc 40.6 7.1-231.1

Congenital CMV: Adjusteda Odds Ratios of Outcomes

a.Adjusted for maternal age and race, antenatal steroids, gestational age and small for gestational age, b.N=148

(excludingdeaths and hearing screen results unknown) c. N=188 (excluding screening results unknown)

Pediatrics 2014;133:e609–e615

Prevalence of hypotrophy in 131 infected neonates (N=131)

in relation with neurological assessment

NORMAL

Neurological examination

CT scan

42 / 114 (37%)

ABNORMAL

Neurological examination

Or CT scan

8 / 17 (51%)Boppana et al 1997, Pass et al 1980, Noyola et al 2001

The Unclear prognostic value of Growth restriction

in fetal CMV Infection

4594 Very Lo w Birthweight infants (1993 – 2008) : 18 positive for

CMV (0.39% (95% CI, 0.25%–0.62% )) V. 180 CMV negative controls

Jean Dubuffet, Childbirth,1944, MOMA

Study

Guerra B, Am J Obs Gyne, 2008

jacquemard , BJOG, 2007

Liesnard Obstet Gynecol, 2000

Lipitz, Ultrasound Obs Gyne , 2010

Picone, Prenat Diag, 2008

Asymptomatic

6

10

3

4

4

Total

14

20

9

7

13

0.2 0.4 0.6 0.8

Proportion

0.43

0.43

0.50

0.33

0.57

0.31

95%-CI

[0.31; 0.56]

[0.18; 0.71]

[0.27; 0.73]

[0.07; 0.70]

[0.18; 0.90]

[0.09; 0.61]

100%

W(random)

23.0%

33.5%

13.4%

11.5%

18.6%

2763

Am J Obstet Gynecol 2016

Prognosis of fetal infection

with non-cerebral features on ultrasound

Prognosis of fetal infection

by ultrasound throughout pregnancy

Odd ratio to be found symptomatic at

birth or at Termination of Pregnancy :

– 4.4 if for extra-cerebral

ultrasound anomalies

– 40.6 for cerebral

ultrasound anomalies

E. Munch, Le cri, 1893, National Gallery, Oslo

Benoist G et al , 2008, British J Obstet Gynaecol, 115: 823-9

Benoist G Ultrasound Obstet Gynecol. 2008 Dec;32(7):900–5

Picone O, Prenat Diagn. 2008 Aug;28(8):753–8.

Lipitz S, Ultrasound Obstet Gynecol. 2013 May;41(5):508–14.

Farkas N, Prenat Diagn. 2011 Apr;31(4):360–6.

Prognostic value of prenatal imaging

• PPV of isolated extra-cerebral US

features at any time during the

pregnancy for being symptomatic at

birth is ∼55%

• NPV of normal imaging (US + MRI)*

throughout the pregnancy is ∼90%

Benoist G et al , 2008, British J Obstet Gynaecol, 115: 823-9

Benoist G Ultrasound Obstet Gynecol. 2008 Dec;32(7):900–5

Picone O, Prenat Diagn. 2008 Aug;28(8):753–8.

Lipitz S, Ultrasound Obstet Gynecol. 2013 May;41(5):508–14.

Farkas N, Prenat Diagn. 2011 Apr;31(4):360–6.

S. Dali: l'Enfant géopolitique observant la naissance

de l'homme nouveau, 1943

Salvador Dali Museum

* Cumulative performance of US and MRI up to 3rd T

Cerebral ultrasound features


Presented in order of increasing severity

• Ventriculomegaly (A)

• Parenchymal calcifications (B)

• Sub-ependymal Cysts (C)

• Calcifications of the lenticulostriate

• vessels (D)

• Intraventricular septation (E)

• Periventricular Hyperechogenicity (F,G)

• Periventricular Cysts (G

• Cystic Periventricular leukomalacia (I)

• Abnormal Gyration / Lisencephaly (J/30 w)

• Enlarged pericerebral spaces (J,K,L)

• Polymicrogyria (K)

• Microencephaly (L)

• Microcephaly (M)

A B C

D E F

G H I

J K LM


Sensitivity

(%)

Specificity

(%) PPV (%) NPV (%)

US+ 63.6 94.4 77.8 89.5

MRI+ 51 100 81 67

US+ and MRI+ 54.5 100 100 87.8

US +and/or

MRI+72.7 88.9 66.7 91.4

Sensitivity

(%)

Specificity

(%)PPV (%) NPV (%)

MRI- US- 89.2 80 94.3 80

Prediction of a good outcome

Targetted ultrasound v. MRI to depict brain lesions

in infected fetuses

Benoist UOG 2008

Fetal Prognosis

Brain Imaging = Fetal US + Fetal MRI

Quantitative/Objective Assessment

of T2 Hyper Signal Intensity

• Single-shot fast spin echo (SSFSE) T2-weighted sequence

(TE=90 ms, TR=1298 ms) slice thickness of 3 or 4 mm

• Region of interest in the areas of higher intensity or in the temporal

region if there were no HSI

• SI ratio= SI Temporal / SI Basal Ganglia

Deloison et al 2013

Infections with an impact

on the fetal brain directly or indirectly

Malformative Sequence / Cascade f (Gestational Age - ?)

Abno

rmal N

euro

nal M

igra

tion

Schizencephaly

Microencephaly /

Microcephaly

Hydrocephalus

Polymicrogyria

Pachygyria

Lissencephaly

Encephalomalacia

Inflammatory

Response

Pro

infla

mm

ato

ry c

yto

kin

es +

lack o

f m

odula

ting p

rote

ins

Apoptosis

Viral lesion

Necrosis

Periventricular

Leukomalacia

Gliosis

Hypoxia

Vasculitis

Hemorrhage

First & Early Second Trimester (<

18 w)

• Loss of neurons and glia

Lissencephaly with a thin cortex,

cerebellar hypoplasia, and

ventriculomegaly

• Delayed myelination and

periventricular calcification

Late Second Trimester (18–24 W)

Migrational abnormalities such as

polymicrogyria,

Third Trimester (after 26 Weeks)

Delayed myelination, dysmyelination,

and white matter disease

Gyration tends to be normal

Impact on the fetal brain

with gestational age at fetal infection

Malformative Sequence / Cascade f (Gestational Age - ?)

* TOP because of severe brain features at follow-up

**3 with deafness, 2 with profound UHL, 1 with severe UHL, 1 with mild UHL, 4 with thrombocytopenia or IUGR or both

***2 with profound BHL, 2 with profound UHL, 1 with severe UHL and monoparesia of 1 arm, 1 with severe UHL, 2 with mild UHL, 1 with vestibulopathy without HL

****2 with mild UHL

Prognosis of Fetal CMV Infection

at 23 (22-28) weeks’

L. Bourgeois, Femme 2005

Logistic regression

OR IC95% p. value

CMV DNA in fetal blood

(for each 1 log of IU/ml increase)

N=54

5.77 2.02-16.53 0.001

Thrombocytopenia

(for each 10 000/mm3 decrease)

N=49

0.74 0.60-0.89 0.002

Presence of non-severe US symptoms

N=63

18.29 4.29-78.04 <0.001

Abnormal fetal blood results

N=50

40.44 4.64-352.72 0.001

Adjusted CMV DNA in amniotic fluid (for each 1 log of IU/ml

increase)

N=48

2.31 1.15-4.64 0.018


Adjusted CMV DNA in amniotic fluid (for each 1 log of IU/ml

increase)

N=48

10.45

2.35

1.96-55.63

1.09-5.08

0.006

0.03

Abnormal fetal blood results


N=50

17.76

5.36

1.92-164.02

1.01-28.53

0.011

0.049

. Complete laboratory data were not available for all cases. Some amniocenteses were done in another centre and therefore the amniotic fluid

sample was not tested in Necker laboratory. Some women declined having cordocentesis.

US= ultrasound

Abnormal fetal blood results = platelets count ≤ 114,000/ mm3 and/or CMV DNA load ≥ 4.93 log10 IU/ml.

Prognostic factors of a symptomatic

status at birth or at Termination

In 63 fetuses presenting with no US features or non-severe US features at the time of prenatal diagnosis at 23 (IQ: 22-28) weeks’


Interval from seroconversion to amniocentesis (weeks)

Prognostic value of amniotic fluid viral load

Symptomatic

V.

Asymptomatic

Scatter plot. Empty dots are cases asymptomatic at birth; full dots are cases symptomatic at birth or at TOP (TOP: termination of pregnancy)

CMV DNA loads in fetal blood

and as fetal platelets counts

in relation to the asymptomatic or symptomatic status at birth or at

termination of pregnancy


Specificity

Sensitiv

ity

0.0 0.2 0.4 0.6 0.8 1.0

0.0

0.2

0.4

0.6

0.8

1.0

ROC curves . The small hatched line shows the CMV DNA loads in fetal blood. The bold line shows the

fetal platelets counts and the large hatched line shows the CMV DNA loads in amniotic fluid.

Area Under the Curve for CMV DNA load in amniotic fluid

and fetal blood and of fetal platelet count

for a symptomatic status at birth or at TOP


Viral Load and Platelet Count in fetal bloodin the prognostic evaluation of an infected fetus

Platelet Count < 114 000 / mm3NO YES

Viral Load in fetal blood

> 4.93 log10 / ml

NO YES

Symptomatic

3.2 %N=32

Symptomatic

57.1 %N=7

Symptomatic

62.5 %N=16

(Algorithm based on recursive partitioning model) Am J Obstet Gynecol 2016

• Ganciclovir / valganciglovir is a validated option for

symptomatic CMV infection involving the CNS

• Stabilization or improvement of hearing but severe

neonatal cerebral lesions are irreversible

• Prenatal antiviral treatment given to infected fetuses to

avoid constitution of irreversible cerebral lesions:

– First trial using valacyclovir to treat infected fetuses

Antiviral treatment for infected fetuses?

Why Valacyclovir ?

• Although in vitro, – ValACV is not the most efficient drug against CMV

– High IC50 values (10-67 µM) / GCV (2.5-5.5 µM) (Tyms et al, AAC 1981)

• In the clinical setting: high valACV dosage (2gx4/day) has proved efficient to prevent CMV disease in transplanted patients (Lowance et al,N Engl J Med 1999).

• ValACV has the best safety profile among anti CMV drugs

• No cell transformation, no increase risk of neoplasia in vitro / GCV extremely genotoxic

• Reassuring safety data : no association with an increase risk of birth defects in thousand of women exposed in pregnancy (Stone et al, 2004; Pasternak, JAMA, 2010)

• Good tolerance

CYMEVAL 2 (NCT01651585)

• Phase II multicenter study, open labelled, with only one arm: all included women were treated with ValACV 8 g/day up to delivery

• In order to minimize the sample size : we used the optimal two-stage Simon’ design

• Sample size ( α = 5%, Power 80%)

• P0 = the non acceptable proportion of asymptomatic infants < 60%• P1= acceptable proportion of asymptomatic infants ≥ 80%

– Number of cases• First step: 11 cases• If at least 7 / asymptomatic, continue up to 43 cases

Inclusion criteria

Fetal infection (positive CMV PCR in amniotic fluid) AND one or more of the following

1. extra-cerebral anomalies • Intrauterine growth restriction (IUGR) • Abnormal amniotic fluid volume • Ascites and/or pleural effusion• Skin edema• Hydrops• Placentomegaly > 40 mm • Hyperechogenic bowel • Hepatomegaly > 40 mm• Splenomegaly > 30 mm• Liver calcifications

3. mild cerebral anomalies• Moderate isolated ventriculomegaly (<15 mm) • Isolated cerebral calcifications• Isolated intraventricular adhesion• Calcifications of lenticulate vessels

4.biological anomalies• Fetal viremia > 3000 copies/ml • Fetal platelets < 100 000/mm3

Non inclusion criteria

1. Contraindication to valacyclovir

1. Or absence of any fetal ultrasound anomalies

or a fetal viremia < 3000 copies/ml or fetal

platelets > 100 000/mm3

2. Or presence of severe cerebral anomalies:

• Ventriculomegaly ≥ 15mm

• Periventricular hyperechogenicity

• Cysts

• Hydrocephalus

• Microcephaly (HC<*3SD)

• Megacysterna magna >10 mm

• Vermian hypoplasia

• Porencephaly

• Lissencephaly

• Abnormal corpus callosum

End point = Asymptomatic at birth

• No IUGR < 10° percentile (Mamelle curves)

• Normal clinical examination– No hydrops

– No petechia or purpura

– No hepato-splenomegaly

– No microcephaly (> - 3SD)

– No hypotonia

– No suckling difficulties

– No lethargy

– No seizures

• Normal biological parameters– Platelets > 100 000/mm3

– Hemoglobin level > 11g/dl

– ALAT < 80 UI /l

– Conjugated bilirubin <20 and < 10% of total bilirubin

• No severe cerebral imaging anomalie(s) (ultrasound and/or CT) – No intracranial calcifications

– No periventricular hyperechogenicity

– No severe ventriculomegaly (>15 mm)

• Normal eye examination

• Normal audiology

The trial was successful: ValACV given to the mother was successful

at obtaining more than 30 asymptomatic neonates

Study

Random effect model

Valaciclovir effect *

Guerra B, Am J Obs Gyne, 2008

jacquemard , BJOG, 2007

Liesnard Obstet Gynecol, 2000

Lipitz, Ultrasound Obs Gyne , 2010

Picone, Prenat Diag, 2008

Success

6

10

3

4

4

Total

14

20

9

7

13

0.2 0.4 0.6 0.8

Proportion

0.43

0.82

0.43

0.50

0.33

0.57

0.31

95%-CI

[0.31; 0.56]

[0.67; 0.88]

[0.18; 0.71]

[0.27; 0.73]

[0.07; 0.70]

[0.18; 0.90]

[0.09; 0.61]

100%

--

W(random)

23.0%

33.5%

13.4%

11.5%

18.6%

* Unbiased estimation of the binomial probability in a multisage design

34

27

43

63

Prognostic and Management of CMV Fetal Infection › ...CMV-Fetal-Infection-Pr... · Heart...

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