Prognostic and Management of CMV Fetal Infection€¦ · •Meconial peritonitis •Hepatomegaly...
Transcript of Prognostic and Management of CMV Fetal Infection€¦ · •Meconial peritonitis •Hepatomegaly...
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
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2,500
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HIV
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SB
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DS
4000
Toxo
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FAS
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Annual N
um
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of D
am
aged B
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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
of fetal CMV infection
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
of fetal CMV infection
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
Am J Obstet Gynecol 2016
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
Presence of non-severe US symptoms
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
Presence of non-severe US symptoms
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’
Am J Obstet Gynecol 2016
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
Am J Obstet Gynecol 2016
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
Am J Obstet Gynecol 2016
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