Neonatal Herpes

1
Neonatal Herpes

• David W Kimberlin, MD
• Department of Pediatrics, Division of Clinical
  Virology, The University of Alabama at
  Birmingham, Alabama, USA

2
Neonatal HSV disease

• Incidence and manifestations
• Risk factors for neonatal HSV infection
• Management
• Sequelae
• Prevention

3
Neonatal HSV disease

• Incidence and manifestations
• Risk of neonatal HSV infection
• Management
• Sequelae
• Prevention

4
Incidence of neonatal HSV infection
5
Neonatal HSV acquisition

• Route of Infection
• In utero 5
• Intrapartum/peripartum 85
• Postpartum 10

6
Intrauterine HSV infection

• Clinical Characteristics Cases () n71
• Prematurity 42 (59)
• Small for gestational age 17 (24)
• Spectrum of disease
• Cutaneous lesions/scarring alone 5 (
  7)
• Ocular CNS lesions 4 ( 6)
• Cutaneous ocular lesions 10 (14)
• Cutaneous CNS lesions 24 (34)
• Cutaneous ocular CNS lesions 28
  (39)

Baldwin S, Whitley RJ. Teratology 198939110
7
Intrapartum and postpartum HSV infection

• Disseminated disease 25
• Disseminated intravascular coagulation
• Pneumonia
• Hepatitis
• CNS involvement (60 to 75)
• Encephalitis (CNS disease) 30
• Seizures
• Lethargy
• Irritability
• Poor feeding
• Temperature instability
• Skin, eyes, and/or mouth (SEM disease) 45

8
Signs and symptoms prior to study enrolment

• SEM CNS Disseminated
• Skin Vesicles
• Percentage of Patients 83 63
  58
• Duration of symptoms 3.8 ? 0.5 6.1 ? 1.0
  3.7 ? 0.6
• Lethargy
• Percentage of Patients 19 49
  47
• Duration of symptoms 3.3 ? 0.7 4.6 ? 0.7
  3.4 ? 0.7
• Fever
• Percentage of Patients 17 44
  56
• Duration of symptoms 4.6 ? 1.5 3.1 ? 0.4
  4.6 ? 0.6
• Seizure
• Percentage of Patients 2 57
  22
• Duration of symptoms 7.0 2.9 ? 0.5
  2.5 ? 0.7

Days ? SE
Kimberlin D. et al. Pediatrics 2001108223229
9
Temporal changes in neonatal herpes
Kimberlin D. et al. Pediatrics 2001108223229
10
Neonatal HSV disease

• Incidence and manifestations
• Risk factors for neonatal HSV infection
• Management
• Sequelae
• Prevention

11
Factors that influence HSV transmission

• Type of maternal infection
• Transplacental antibody
• Fetal scalp monitor
• Duration of rupture of membranes
• Mode of delivery

12
Risk of HSV transmission - type of maternal
infection
Women delivered (without clinical evidence of HSV
at delivery) (n58 288)
Adapted from Brown Z et al. JAMA 2003289203209
Virus cultured within 48 h (n39 949) (69)
Subclinical HSV shedding (n128, 0.3)
HSV serology available (n121, 95)
13
Risk of HSV transmission - type of maternal
infection
Women delivered (n58 288)
Adapted from Brown Z et al. JAMA 2003289203209
Cultured within 48 h (n39 949, 69)
Subclinical HSV shedding (n128, 0.3)
HSV serology available (n121, 95)
First episode genital HSV (n23) (19)
1º HSV-1 (n3) (13)
1º HSV-2 (n4) (17)
Infant with HSV (n3)
Infant with HSV (n1)
57
14
Risk of HSV transmission - type of maternal
infection
Women delivered (n58 288)
Adapted from Brown Z et al. JAMA
2003289203209
Cultured within 48 h (n39 949, 69)
Subclinical HSV shedding (n128, 0.3)
HSV serology available (n121, 95)
First episode genital HSV (n23) (19)
1º HSV-1 (n3) (13)
Non-1º HSV-1 (n1) (4)
Non-1º HSV-2 (n15) (65)
1º HSV-2 (n4) (17)
Infant with HSV (n3)
Infant with HSV (n1)
Infant with HSV (n4)
Infant with HSV (n0)
57
25
15
Risk of HSV transmission - type of maternal
infection
Women delivered (n58 288)
Adapted from Brown Z et al. JAMA
2003289203209
Cultured within 48 h (n39 949, 69)
Subclinical HSV shedding (n128, 0.3)
HSV serology available (n121, 95)
First episode genital HSV (n23) (19)
Recurrent genital HSV (n98) (81)
1º HSV-1 (n3) (13)
Non-1º HSV-1 (n1) (4)
Non-1º HSV-2 (n15) (65)
1º HSV-2 (n4) (17)
HSV-1 (n8) (8)
HSV-2 (n90) (92)
Infant with HSV (n3)
Infant with HSV (n1)
Infant with HSV (n4)
Infant with HSV (n2)
Infant with HSV (n0)
Infant with HSV (n0)
57
25
2
16
Risk of HSV transmission - protective effect of
antibody
Prober CG et al. N Engl J Med 1987316240244
17
Risk of transmission - fetal scalp monitor
Clinical or subclinical shedding at delivery
(n202)
Invasive monitors (n79)
No invasive monitors (n123)
Neonatal HSV (n8) (10)
Neonatal HSV (n2) (2)
Adapted from Brown Z et al, JAMA
2003289203209
P0.02
18
Risk of transmission duration of rupture of
membranes (ROM)

• Type of Delivery No.
  infected/ No. of cases
• Vaginal 9/18 (50)
• Caesarean Section
• ROM 6 h 4/4 (100)
• Intact membranes or ROM 4 h 0/4 (0)

Nahmias A. Am J Obstet Gynecol 1971110825834
19
Neonatal HSV disease

• Incidence and manifestations
• Risk of neonatal HSV infection
• Management
• Sequelae
• Prevention

20
Morbidity and mortality among 229 infantswith
neonatal HSV infection, 19741998
Disseminated
CNS
SEM
Kimberlin D. Rev Med Virol 200111157163
21
Mortality among infants with disseminated HSV
disease
Aciclovir doses
(n18)
Proportion Surviving
(n7)
(n34)
historical cohort
Kimberlin D et al. Pediatrics 2001108230238
22
Mortality among infants with HSV CNS disease
(n35)
(n5)
(n23)
Proportion Surviving
historical cohort
Kimberlin D et al. Pediatrics 2001108230238
23
Development of abnormal laboratory values on
intravenous aciclovir therapy
Kimberlin D et al., Pediatrics 2001108230238
24
PCR results from neonatal CSF

• Disease classification
• SEM CNS Disseminated
• PCR result (n29) (n34) (n14)
• Positive 7 (24) 26 (76) 13 (93)
• Negative 22 (76) 8 (24) 1 (7)

Kimberlin D et al., J Infect Dis
199617411621167
25
Neonatal HSV disease

• Incidence and manifestations
• Risk of neonatal HSV infection
• Management
• Sequelae
• Prevention

26
Neonatal morbidity among survivors with known
outcomes after 12 months
n28
n13
n5
n18
n46
n2
Percentage
SEM disease
CNS disease
Disseminated disease
ACV intravenous aciclovir therapy
Kimberlin D et al., Pediatrics 2001108230238
27
Prognostic factorsdisseminated disease
Whitley R et al. N Engl J Med 1991324450454
Kimberlin D et al. Pediatrics 2001108223229
SD with aciclovir 30 mg/kg/day only P0.076
28
Prognostic factorsCNS disease

• Relative risk
• Dominant factors Mortality Morbidity
• Decreased level of consciousness 6.1
  NS
• Prematurity 5.0 NS
• Seizures 8.0 29

P0.0637
Whitley R et al. N Engl J Med 1991324450454
Kimberlin D et al, Pediatrics 2001108223229
29
Prognostic factorsSEM disease
Whitley R et al. N Engl J Med 1991324450454
30
PCR resultspost-therapy CSF specimens

• PCR negative PCR positive
• Outcome n11 () n19 ()
• Normal 6 (54) 1 (5) Plt0.001
• Mild 0 (0) 0 (0)
• Moderate 1 (9) 3 (16)
• Severe 2 (18) 10 (53)
• Dead 0 (0) 5 (26)
• Unknown 2 (18) 0 (0)

Kimberlin D et al. J Infect Dis 199617411621167
31
Cutaneous recurrences of HSV during suppressive
oral aciclovir therapy
Kimberlin D et al. Pediatr Infect Dis J
199615247254
32
Abnormal laboratory values during suppressive
oral aciclovir therapy

• Dosage (300mg/m2/dose)
• TID BID Total
• Abnormal laboratory value n21 n5
  n26
• Absolute neutrophil count
• lt500/mm3 3 (14) 1 (20) 4 (15)
• 5001000/mm3 6 (29) 2 (40) 8 (31)

Kimberlin D et al. Pediatr Infect Dis J
199615247254
33
Neonatal HSV disease

• Incidence and manifestations
• Risk of neonatal HSV infection
• Management
• Sequelae
• Prevention

34
Special challenges of neonatal HSV disease
prevention

• History not generally available
• 6080 of infected infants are born to mothers
  with
• NO maternal history of genital HSV
• History not particularly helpful
• Women with known history of genital HSV are at
• LESSER risk compared with women acquiring HSV
  during pregnancy

35
Prevention of neonatal HSV by Caesarean section

• Type of delivery No.
  infected/No. of cases
• Vaginal 9/18 (50)
• Caesarean section
• ROM 6 h 4/4 (100)
• Intact membranes or ROM 4 h 0/4 (0)
• ROM rupture of membranes

Nahmias AJ et al. Am J Obstet Gynecol
1971110825834
36
Prevention of neonatal HSV by Caesarean section
Clinical or subclinical shedding at delivery
(n202)
Serology available (n177)
First episode genital HSV (n26)
Recurrent genital HSV (n151)
Lesions (n53)
No lesions (n98)
Lesions (n3)
No lesions (n23)
Caesarean (n41)
Vaginal (n12)
Caesarean (n18)
Vaginal (n80)
Caesarean (n3)
Vaginal (n0)
Caesarean (n6)
Vaginal (n17)
Adapted from Brown Z. JAMA 2003289203209
Neonatal HSV (n2)
Neonatal HSV (n1)
Neonatal HSV (n7)
P 0.047 1/85 (1) vs.
9/117 (8)
37
Aciclovir in pregnancy registry 1 June 1984 31
July 1998
Outcomes with birth
800
defects
19
700
82
Induced abortions
600
76
Spontaneous fetal losses
500
7
400
Number
Live births
0
2
300
562
2
1
200
0
269
100
185
0
First
Second
Third
Earliest trimester of exposure
Total patients 1207
Reiff-Eldridge R et al. Am J Obstet Gynecol
2000182159163
38
Clinical evidence of HSV at delivery
P0.002
P0.046
NS
NS
NS
P0.0003
Scott LL et al. Obstet Gynecol 1996876973 Smith
JR et al. Br J Obstet Gynaecol
1998105255260 Scott LL et al. Infect Dis
Obstet Gynecol 2002107177 Stray-Pedersen B.
Lancet 1990336756 Watts DH et al. Am J Obstet
Gynecol 2003188836843 Braig S et al. Eur J
Obstet Gynecol Reprod Biol 2001965558
39
Caesarean section due to HSV at delivery
Plt0.001
P0.002
NS
NS
NS
P0.0003
Scott LL et al. Obstet Gynecol 1996876973 Smit
h JR et al. Br J Obstet Gynaecol
1998105255260 Scott LL et al. Infect Dis
Obstet Gynecol 2002107177 Stray-Pedersen B.
Lancet 1990336756 Watts DH et al. Am J Obstet
Gynecol 2003188836843 Braig S et al. Eur J
Obstet Gynecol Reprod Biol 2001965558
40
Asymptomatic viral shedding during therapy or at
delivery
NS
NS
NS
NS
NS
P0.013
Scott LL et al. Obstet Gynecol 1996876973 Smith
JR et al. Br J Obstet Gynaecol
1998105255260 Scott LL et al. Infect Dis
Obstet Gynecol 2002107177 Stray-Pedersen B.
Lancet 1990336756 Watts DH et al. Am J Obstet
Gynecol 2003188836843 Braig S et al. Eur J
Obstet Gynecol Reprod Biol 2001965558
41
Neonatal HSV disease
NS
NS
NS
NS
NS
NS
Scott LL et al. Obstet Gynecol 1996876973 Smith
JR et al. Br J Obstet Gynaecol
1998105255260 Scott LL et al. Infect Dis
Obstet Gynecol 2002107177 Stray-Pedersen B.
Lancet 1990336756 Watts DH et al. Am J Obstet
Gynecol 2003188836843 Braig S et al. Eur J
Obstet Gynecol Reprod Biol 2001965558
42
Aciclovir concentrations following infantile and
maternal suppression
Mean (? SD) Aciclovir Concentration (?g/mL)
Kimberlin D et al. Pediatr Infect Dis J
199615247254 Kimberlin D et al. Am J
Obstet Gynecol 1998179846851
43
Abnormal laboratory values during suppressive
oral aciclovir therapy
Kimberlin D et al. Pediatr Infect Dis J
199615247254
44
Summary

• Neonatal HSV is a rare but life-threatening
  disease
• Treatment has improved mortality more than
  morbidity
• Prevention strategies must focus on women with
  primary infection
• Antiviral suppression in the gravid woman may
  reduce Caesarean sections, but is of unproven
  safety to the fetus
• Potential risks should be assessed