Neonatal Herpes

1
Neonatal Herpes

• David W. Kimberlin, M.D.

2
Neonatal HSV Disease

• Incidence and manifestations
• Risk of 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

• Country Population Rate of neonatal HSV
• USA Seattle, WA 1 in 3,200
• USA Birmingham, AL 1 in 2,700
• UK National voluntary reporting 1 in 60-70,000
• Netherlands National 1 in 35,000
• Norway National (CNS only) 1 in 25,000
• Sweden Stockholm 1 in 15,000
• Japan National 1 in 14-20,000

5
Neonatal HSV Acquisition

• Route of Infection
• in utero 5
• Intrapartum 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)

Teratology 1989391-10
7
Intrapartum and PostpartumHSV Infection

• Disseminated disease 25
• DIC
• 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 SymptomsPrior to Study Enrollment

• 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 et al., Pediatrics 2001108223-229
9
Changes in Characteristicsby Extent of Disease

• SEM CNS Disseminated
• 1981-88 1989-97 1981-88 1989-97
  1981-88 1989-97
• Characteristic
• Premature 41 20
  27 36 28 41 
• Enrollment Age 11.2 ? 0.9 12.0 ? 2.2 15.2 ?
  1.3 19.7 ? 1.6 10.3 ? 1.1 11.4 ? 0.8
• (days ? SE)
•  
• Time between 5.9 ? 0.7 5.7 ? 1.3 6.6
  ? 0.8 7.4 ? 1.3 5.3 ? 0.7 5.6 ? 0.7
• earliest HSV and
• enrollment
• (days ? SE)
•  

Kimberlin et al., Pediatrics 2001108223-229
10
Neonatal HSV Disease

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

11
Factors That Influence Transmission

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

12
Risk of TransmissionAsymptomatic Shedding During
Labor
Women delivered (n58,288)
Adapted from JAMA 2003289203-209
Cultured within 48 hrs (n39,949) (69)
Subclinical shedding (n128) (0.3)
Serologies 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
13
Protective Effect of Antibody

• NAb Titer Exposed but Uninfected
  Infected
• (CB or 2 wks) (n 33) (n 29)
• lt 15 0 ( 0) 12 (41) P lt
  0.00001
• 15 to 120 7 (21) 15 (52)
• gt 120 26 (79) 2 ( 7) P lt
  0.0002

N Engl J Med 1987316240-4
14
Prevention of Neonatal HSVby Cesarean Section
Delivery

• Type of Delivery
  infected/ cases
• Vaginal 9/18 ( 50)
• Cesarean Section
• ROM 6 hrs 4/ 4 (100)
• Intact membranes or ROM 4 hrs 0/ 4 ( 0)

Am J Obstet Gynecol 1971110825-34
15
Neonatal HSV Disease

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

16
Morbidity and Mortality Among 229 Infantswith
Neonatal HSV Infection, 1974-1998
Disseminated
CNS
SEM
Kimberlin, Rev Med Virol 200111157-163
17
Mortality Among Infantswith Disseminated Disease
historical cohort
Kimberlin et al., Pediatrics 2001108230-238
18
Mortality Among Infantswith CNS Disease
historical cohort
Kimberlin et al., Pediatrics 2001108230-238
19
Development of Abnormal Laboratory Values On
Therapy

• CNS or SEM HSV Disease (n38)
• Laboratory Parameter 45 mg/kg/d 60 mg/kg/d
  Total
• ANC
• 500-1,000/mm3 1/4 (25) 5/29 (17) 6/33
  (18)
• lt 500/mm3 0/4 ( 0) 1/29 ( 3) 1/33 (
  3)
• 1 CNS
• 3 CNS, 2 SEM

Kimberlin et al., Pediatrics 2001108230-238
20
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 et al., J Infect Dis 19961741162-7
21
Neonatal HSV Disease

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

22
Neonatal Morbidity Among Survivors With Known
Outcomes After 12 Months
n46
n2
n28
n13
n5
n18
SEM Disease
CNS Disease
Disseminated Disease
Kimberlin et al., Pediatrics 2001108230-238
23
Prognostic FactorsDisseminated Disease

• Mortality
• AST gt 10X ULN (SD only) P0.0006
• Lethargy P0.0194
• Morbidity
• Seizures P0.076

Kimberlin et al., Pediatrics 2001108223-229
24
Prognostic FactorsCNS Disease

• Mortality
• Prematurity P0.0493
• Seizures P0.0637
• Morbidity
• Seizures P0.0001

Kimberlin et al., Pediatrics 2001108223-229
25
PCR ResultsPost-therapy CSF Specimens

• PCR Negative PCR Positive
• Outcome (n 11) (n 19)
• Normal 6 (54) 1 ( 5) P lt 0.001
• 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 et al., J Infect Dis 19961741162-7
26
Cutaneous Recurrences of HSV During Suppressive
Acyclovir Therapy

• 300mg/m2/dose
• Number of TID BID
• Skin Recurrences n16 n2
• 0 13 (81) 0 ( 0)
• 1 1 ( 6) 1 (50)
• 2 1 ( 6) 1 (50)
• ³ 3 0 ( 0) 0 ( 0)
• Unknown 1 ( 6) 0 ( 0)

Kimberlin et al., Pediatr Infect Dis J
199615247-54
27
Abnormal Laboratory Values During Suppressive
Oral Acyclovir Therapy

• Dosage (300mg/m2/dose)
• TID BID Total
• Abnormal Laboratory Value n21 n5 n26
• Absolute Neutrophil Count
• lt 500 / mm3 3 (14) 1 (20) 4 (15)
• 500-1000 / mm3 6 (29) 2 (40) 8 (31)

Kimberlin et al., Pediatr Infect Dis J
199615247-54
28
Neonatal HSV Disease

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

29
Special Challenges ofNeonatal HSV Disease
Prevention

• History not generally available
• 60-80 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

30
Prevention of Neonatal HSVby Cesarean Section
Delivery

• Type of Delivery
  infected/ cases
• Vaginal 9/18 ( 50)
• Cesarean Section
• ROM 6 hrs 4/ 4 (100)
• Intact membranes or ROM 4 hrs 0/ 4 ( 0)

Am J Obstet Gynecol 1971110825-34
31
Acyclovir in Pregnancy RegistryJune 1, 1984
July 31, 1998
Outcomes with birth
800
defects
19
700
82
Induced abortions
600
76
Spontaneous fetal losses
500
7
Number
400
Live births
0
2
300
562
2
1
200
269
100
185
0
First
Second
Third
Earliest trimester of exposure
Total patients 1207
Am J Obstet Gynecol 2000182159-63
32
Clinical Evidenceof HSV at Delivery
P0.002
NS
NS
P0.0003
9/25
6/32
Percentage
15/121
3/46
2/31
0/21
0/46
0/167
Obstet Gynecol 19968769-73
Br J Obstet Gynaecol
1998105275-280 Lancet
1990336756
Eur J Obstet Gynecol Reprod Biol
20019655-58
33
Cesarean SectionDue to HSV at Delivery
P0.002
NS
Plt0.001
P0.0003
9/25
8/32
9/46
Percentage
4/31
15/121
0/21
0/46
0/167
Obstet Gynecol 19968769-73
Br J Obstet Gynaecol
1998105275-280 Lancet
1990336756
Eur J Obstet Gynecol Reprod Biol
20019655-58
34
Asymptomatic Viral Shedding During Therapy or At
Delivery
NS
NS
NS
P0.013
Percentage
2/31
4/121
1/46
0/25
0/21
0/32
0/46
0/167
Obstet Gynecol 19968769-73
Br J Obstet Gynaecol
1998105275-280 Lancet
1990336756
Eur J Obstet Gynecol Reprod Biol
20019655-58
35
Neonatal HSV Disease
NS
NS
NS
NS
Percentage
0/21
0/25
0/31
0/32
0/46
0/46
0/167
0/167
Obstet Gynecol 19968769-73
Br J Obstet Gynaecol
1998105275-280 Lancet
1990336756
Eur J Obstet Gynecol Reprod Biol
20019655-58
36
Acyclovir Concentrations Following Infantile and
Maternal Suppression
Kimberlin et al., Pediatr Infect Dis J
199615247-254 Kimberlin et al., Am J
Obstet Gynecol 1998179846-51
37
Abnormal Laboratory Values During Suppressive
Oral Acyclovir Therapy

• Dosage (300mg/m2/dose)
• TID BID Total
• Abnormal Laboratory Value n21 n5 n26
• Absolute Neutrophil Count
• lt 500 / mm3 3 (14) 1 (20) 4 (15)
• 500-1000 / mm3 6 (29) 2 (40) 8 (31)

Kimberlin et al., Pediatr Infect Dis J
199615247-54
38
Summary

• Neonatal HSV is a rare but life-threatening
  disease
• Treatment has improved mortality to greater
  extent than morbidity
• Prevention strategies must focus on women with
  primary infection
• Antiviral suppression in the gravid woman is of
  unproven safety to the fetus