Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of Serologic Status and Cesarean Delivery on Transmission Rates of Herpes Simplex Virus From Mother to Infant. JAMA. 2003;289(2):203-209. doi:10.1001/jama.289.2.203
Author Affiliations: Departments of Obstetrics and Gynecology (Dr Brown), Laboratory Medicine (Drs Wald, Morrow, and Corey and Ms Selke), Medicine, Statistics (Dr Zeh), and Epidemiology (Dr Wald), University of Washington, and the Program in Infectious Diseases, Fred Hutchinson Cancer Research Center (Drs Wald and Corey), Seattle.
Context Neonatal herpes most commonly results from fetal exposure to infected
maternal genital secretions at the time of delivery. The risk of transmission
from mother to infant as it relates to maternal herpes simplex virus (HSV)
serologic status and exposure to HSV in the maternal genital tract at the
time of labor has not been quantified. Furthermore, no data exist on whether
cesarean delivery, the standard of care for women with genital herpes lesions
at the time of delivery, reduces HSV transmission.
Objective To determine the effects of viral shedding, maternal HSV serologic status,
and delivery route on the risk of transmission of HSV from mother to infant.
Design Prospective cohort of pregnant women enrolled between January 1982 and
Settings A university medical center, a US Army medical center, and 5 community
hospitals in Washington State.
Patients A total of 58 362 pregnant women, of whom 40 023 had HSV cultures
obtained from the cervix and external genitalia and 31 663 had serum
samples tested for HSV.
Main Outcome Measure Rates of neonatal HSV infection.
Results Among the 202 women from whom HSV was isolated at the time of labor,
10 (5%) had neonates with HSV infection (odds ratio [OR], 346; 95% confidence
interval [CI], 125-956 for neonatal herpes when HSV was isolated vs not isolated).
Cesarean delivery significantly reduced the HSV transmission rate among women
from whom HSV was isolated (1 [1.2%] of 85 cesarean vs 9 [7.7%] of 117 vaginal;
OR, 0.14; 95% CI, 0.02-1.08; P = .047). Other risk
factors for neonatal HSV included first-episode infection (OR, 33.1; 95% CI,
6.5-168), HSV isolation from the cervix (OR, 32.6; 95% CI, 4.1-260), HSV-1
vs HSV-2 isolation at the time of labor (OR, 16.5; 95% CI, 4.1-65), invasive
monitoring (OR, 6.8; 95% CI, 1.4-32), delivery before 38 weeks (OR, 4.4; 95%
CI, 1.2-16), and maternal age less than 21 years (OR, 4.1; 95% CI, 1.1-15).
Neonatal HSV infection rates per 100 000 live births were 54 (95% CI,
19.8-118) among HSV-seronegative women, 26 (95% CI, 9.3-56) among women who
were HSV-1–seropositive only, and 22 (95% CI, 4.4-64) among all HSV-2–seropositive
Conclusion Neonatal HSV infection rates can be reduced by preventing maternal acquisition
of genital HSV-1 and HSV-2 infection near term. It can also be reduced by
cesarean delivery and limiting the use of invasive monitors among women shedding
HSV at the time of labor.
The prevalence of genital and neonatal herpes in the United States continues
to rise.1 About 1.6 million new herpes simplex
virus (HSV) 2 infections are acquired yearly and more than 2% of women seroconvert
to HSV-2 during pregnancy.2,3 Although
previous studies suggest that neonatal HSV infection is often a consequence
of HSV acquisition in late pregnancy,3- 10 the
risk of transmission of HSV-1 or HSV-2 from mother to infant as it relates
to maternal HSV serologic status and exposure to HSV in the maternal genital
tract at the time of labor has not been quantified. Furthermore, cesarean
delivery has been the standard of care for more than 3 decades for women with
genital herpes lesions at the time of delivery, but no data exist on whether
this procedure reduces HSV transmission, and some obstetrical authorities
have discussed abandoning this practice.11- 16
To evaluate the risk factors for the transmission of HSV from mother
to infant, women in labor had a genital viral culture obtained and serum samples
saved for retrospective analysis of HSV-1 and HSV-2 serologic status.
This study was carried out at University of Washington Medical Center,
Seattle, between January 1982 and December 1999, at 5 community hospitals
in Seattle between January 1984 and October 1990, and at Madigan Army Medical
Center, Tacoma, Wash, between August 1990 and September 1997. Viral cultures
were obtained from women in labor by swabbing the vulva, perineal, and perianal
areas. A separate swab was used to obtain a sample from the upper vagina and
cervix.3,8 If genital lesions
were identified on examination during delivery and the peripartum period,
cultures were obtained from the lesion and placed in a separate vial of transport
media.17 Only women who had cultures obtained
within 48 hours of delivery were included in the analysis. Prophylactic acyclovir
therapy was not used during pregnancy, at delivery, or during the immediate
postpartum period for any of the exposed infants.11,12,18 Maternal
HSV serologic status was determined from samples collected at delivery or
at obstetrical antepartum testing. Culture results were reported to the attending
physician, as were the results of HSV serologic tests after the test became
available for clinical use. Written informed consent was obtained for the
portions of the study protocol not included in routine clinical care according
to the University of Washington Institutional Review Board.
Routine demographic and delivery data were collected on deliveries at
all hospitals from 1989-1999 and at the University of Washington during the
entire 18-year study period. Delivery room charts were reviewed for history
and signs of genital herpes, duration of membrane rupture, and route of delivery
in women from whom HSV was isolated at delivery and in women whose infants
developed neonatal herpes.
Herpes simplex virus cultures and HSV DNA detection by polymerase chain
reaction were performed as previously described.19,20 Serum
samples obtained at the time of labor were stored and tested for antibodies
to HSV-1 and HSV-2 by Western blot assay following delivery.21
The serologic and virologic classification of HSV status at delivery
was defined as previously published.3,8,22 Women
with primary-episode genital herpes were defined as having HSV-1 or HSV-2
isolated from genital secretions without having concurrent HSV antibodies.
A nonprimary first-episode infection was defined as HSV-2 isolated from genital
secretions of a woman with only HSV-1 antibodies, or HSV-1 isolated from a
woman with only HSV-2 antibodies. Reactivation HSV-1 or HSV-2 was present
when the virus isolated from genital secretions was the same type as antibodies
present in the serum at the time of labor. Symptomatic shedding was defined
as the isolation of HSV when genital lesions were noted on entering the labor
suite, and subclinical shedding as isolation of HSV in the absence of genital
Relative risks were assessed by computing odds ratios (ORs) with 95%
confidence intervals (CIs). P values were obtained
using 2-sided χ2 or Fisher exact tests, with P<.05 considered statistically significant. Adjusted ORs were obtained
from bivariate logistic regression. In examining risk factors for neonatal
herpes, we adjusted for only 1 confounder at a time because of the small number
of infected neonates and the correlation among the risk factors. We estimated
rates of neonatal infection as a function of maternal serologic status at
the 2 hospitals (University of Washington and Madigan) at which routine serologic
testing for HSV was performed. These were derived with the assumption that
the infants of women with known serologic status were a random sample of all
infants delivered, stratified by hospital and time. Because serologic status
was known for most women, the estimated denominators of the rates were very
precisely determined, with coefficients of variation of 1%. Standard errors
for neonatal infection rates by maternal serologic status were derived by
the delta method, taking into account the uncertainty associated with the
small number of cases as well as the estimated serologies. As the SEs derived
by the delta method differed from SEs based on known denominators only in
the fifth significant digit, CIs were based on exact CIs for binomial proportions.
Statistical analyses were carried out using SPSS, version 8.0 (SPSS Inc, Chicago,
Ill), and S-PLUS, version 3.1 (Insightful Corp, Seattle, Wash). The same study
team carried out the study, including data management and analysis, for the
During the study period there were 58 362 live births in the study
hospitals; 18 cases of neonatal HSV were identified among these live births,
for a rate of 1 case of neonatal herpes per 3200 live births. Among the 18
cases, 8 neonates acquired HSV-1 and 10 acquired HSV-2 infection. Of the 10
infants with neonatal HSV-2 infection, 7 were born to mothers with primary
or nonprimary first-episode HSV-2 and 3 to mothers with reactivation HSV-2
infection. Of the 8 infants with neonatal HSV-1 infection, 4 were born to
mothers with primary HSV-1 and 4 to mothers with reactivation HSV-1.
Herpes simplex virus cultures were obtained within 48 hours of delivery
in 40 023 (69%) of the 58 362 women. Herpes simplex virus was isolated
from 202 women (0.5%). Serum samples for HSV antibody status were obtained
from 31 663, including 177 (88%) of the 202 women with positive cultures
(Figure 1). Of these 177 women,
26 had a first-episode genital HSV infection at delivery (3 with primary HSV-1,
6 with primary HSV-2, 1 with nonprimary HSV-1, and 16 with nonprimary HSV-2)
and 151 women had reactivation of previously acquired genital HSV (11 with
HSV-1, 140 with HSV-2).
Isolation of HSV at delivery from mothers was a major risk factor for
neonatal herpes (OR, 346; 95% CI, 125-956;
Neonatal transmission occurred in 10 (5%) of the 202
women from whom HSV was isolated. All 3 women shedding HSV-1 due to a primary
HSV-1 infection infected their infants, as did 1 (17%) of 6 women with primary
HSV-2 infection, 4 (25%) of 16 women with nonprimary first-episode HSV-2 infection,
and 2 (18%) of 11 women with reactivation HSV-1 (Figure 1). None of the 140 women with viral shedding due to reactivation
HSV-2 infected their infants.
We analyzed the effect of delivery route and presence of genital lesions
at delivery on neonatal transmission. Of the 202 women who had HSV isolated
from genital secretions, 117 (58%) were delivered vaginally and 85 (42%) underwent
cesarean delivery (Table 2). Lesions
presumed to be caused by genital herpes were the indication for cesarean delivery
in 60 (71%) of the cesarean deliveries. Neonatal HSV infection occurred in
1 (1.2%) of 85 cesarean deliveries vs 9 (7.7%) of 117 vaginal deliveries (OR,
0.14; 95% CI, 0.02-1.08; P = .047; Table 1). One woman with subclinical nonprimary first-episode HSV-2
infection transmitted HSV-2 to her infant after undergoing a cesarean delivery
because of failure to progress 19 hours after rupture of membranes. The protective
effect of cesarean delivery appeared to be similar after adjustment for stage
of infection (OR, 0.14; 95% CI, 0.02-1.26) or for HSV type (OR, 0.17; 95%
CI, 0.02-1.46), although no longer statistically significant.
Genital lesions at delivery were also associated with decreased risk
of neonatal herpes among women with HSV isolation. Sixty women had genital
lesions and underwent cesarean delivery; an additional 14 women had evidence
of genital lesions on retrospective review of the case record. These women
were delivered vaginally because their genital lesions were not noted until
it was too late to proceed with a cesarean delivery, or immediately following
delivery. None of these 74 women infected their infants in comparison with
10 of 128 women who were shedding virus without lesions (P = .01; Table 1 and Table 2).
Among 202 women who shed HSV at delivery, 102 had a history of genital
herpes and 100 did not. Of the 10 infected infants, 4 were born to mothers
with a history and the other 6 to women without a history of genital herpes.
Women without a history of genital herpes were more likely to shed HSV subclinically
than women with such a history (87 vs 41; P<.001).
However, women with a history of genital herpes were more likely to have cesarean
deliveries (OR, 5.7; 95% CI, 3.1-11), although this risk was attenuated by
adjustment for lesions at delivery (adjusted OR, 2.3; 95% CI, 1.1-4.9).
Among women from whom HSV was isolated, the lack of maternal antibodies
to the viral type shed was associated with a marked increase in the risk of
transmission to the infant (OR, 33.1; 95% CI, 6.5-168; P<.001; Table 1). The
increased transmission risk of newly acquired compared with reactivation disease
remained statistically significant after adjustment for viral type (OR, 59.3;
95% CI, 6.7-525) and was true both for HSV-2 (P<.001)
and HSV-1 infection (P = .08). In contrast with the
protection offered by homologous antibody, heterologous antibody did not protect
against HSV transmission (OR, 2.6; 95% CI, 0.5-15) for primary vs nonprimary
The rate of transmission of HSV from mother to infant was higher when
HSV-1 was isolated at delivery (5 [31.3%] of 16) compared with HSV-2 (5 [2.7%]
of 186) (OR, 16.5; 95% CI, 4.1-65), and the risk remained signficantly elevated
after adjustment for newly acquired infection (OR, 34.8; 95% CI, 3.6-335).
The risk of transmission was also elevated when HSV was isolated from the
cervix vs from the vulva only (OR, 32.6; 95% CI, 4.1-260) and remained statistically
significant after adjustment for newly acquired infection. Invasive monitoring,
such as fetal scalp electrodes, was noted in 79 (39%) of the 202 women with
HSV isolation at delivery and was also a significant risk factor for transmission
of HSV (OR, 6.8; 95% CI, 1.4-32). Other risk factors for neonatal HSV were
younger maternal age and premature delivery (Table 1), although the adjusted OR for these suggested confounding
with newly acquired infection.
Cultures were not obtained from 2 of the 18 women who transmitted HSV
and negative viral cultures were reported in 6. The viral isolates from the
infants and the maternal serum samples were available in all 8 cases. One
woman had primary HSV-1, 1 had primary HSV-2, 1 had nonprimary HSV-2, 2 had
reactivation HSV-1, and 3 had reactivation HSV-2. We were able to retrieve
the specimen obtained for viral isolation at delivery for 2 of the 6 negative
cultures. Herpes simplex virus 2 DNA was detected in both.
To evaluate the relationship between maternal HSV serologic status and
transmission, we limited our analyses to the 48 390 deliveries at the
2 hospitals where HSV serologic testing was routinely performed. Fifteen of
the 18 cases of neonatal herpes were from these hospitals. Among the 31 645
serum samples corresponding to these deliveries, 23% of women were HSV seronegative,
49% had only HSV-1 antibodies, 11% had only HSV-2 antibodies, and 17% had
both HSV-1 and HSV-2 antibodies. Table 3 shows the estimated rates of neonatal HSV infection computed from
these data. The highest (1 in 1900) occurred among women who had no HSV antibodies,
whereas the lowest (1 in 8000) was among women who were seropositive for HSV-1
and HSV-2. The small number of observed cases limits the power to detect statistically
significant differences among the rates.
Several novel observations about neonatal HSV infection emerged from
our analyses. First, while women with all HSV serologic classifications are
at risk of transmitting HSV to their infants, the highest risk for transmitting
infection to the infant was among HSV seronegative women. This high rate reflects
the high efficiency of HSV transmission from seronegative women who acquire
primary HSV-1 and HSV-2 and whose infants lack type-specific transplacental
antibodies. Second, women with previous HSV-2 infection are at a reduced risk
for transmitting HSV-2 to their infants and at essentially no risk of transmitting
HSV-1. This reflects the relatively inefficient transmission of HSV-2 in the
face of type-specific transplacental antibodies and the seemingly protective
effect of genital HSV-2 infection on the acquisition of genital HSV-1 infection.
Third, the transmission rate of HSV is highly influenced by management of
women in labor, including recognition of lesions, protection offered by cesarean
delivery, and maintenance of fetal skin integrity during labor.
Perhaps the most clinically important observation from our study was
the finding that cesarean delivery protects against neonatal transmission
of HSV. This is the first demonstration of this effect, despite that it has
been standard obstetric practice in the United States for 30 years.5,11,12 Our data, from a cohort
study that spans nearly 2 decades of management by various physicians at major
service and teaching institutions, provide the first evaluation of this procedure
for reducing neonatal HSV. Neonatal herpes occurred less frequently among
women with genital lesions than among those experiencing subclinical shedding
because women with genital lesions were more likely to undergo cesarean delivery.
Ideally, management practices such as cesarean delivery for genital herpes
should be defined by randomized trials. No such trial has been undertaken
in the past, and such an attempt is likely to encounter considerable ethical
difficulties. Although case series of neonatal HSV show that cesarean delivery
is not fully protective,24,25 our
data indicate that it is a rational intervention and should not be abandoned.
Another novel finding was the high efficiency of transmission of HSV-1
from mother to infant, both from primary infection and reactivation of genital
HSV-1, among women with genital shedding of HSV. The mechanism of this is
unclear but may help explain the increasing frequency of neonatal HSV-1 infection.26- 28
Development of a strategy to reduce this disease burden seems imperative.
While antiviral therapy for neonatal herpes is now available, the morbidity
is still high and few inroads in improving time to diagnosis have been made
in the last 2 decades.25,29,30 As
such, preventing transmission to the neonate by reducing acquisition of infection
in late pregnancy in the mother and altering obstetric management may be the
approach most likely to reduce neonatal HSV. Serologic assays that detect
antibodies to HSV-1– and HSV-2–specific glycoprotein G1 and G2
are now commercially available31 and can be
used to identify pregnant women who are seronegative for HSV-1, HSV-2, or
both and to identify partners who present a potential risk of transmitting
infection. These women can be counseled about the importance of avoiding unprotected
oral-genital contact or unprotected sex in the last trimester.
Serologic screening for HSV-2 will result in identifying a large number
of pregnant women with subclinical HSV-2 infections who are at risk of reactivating
HSV-2 at delivery.17,32- 35 Our
data indicate that the risk of HSV transmission is low among HSV-2–seropositive
women, and routine cesarean delivery is certainly not indicated. Management
strategies for HSV-2–seropositive women are complex and need systematic
evaluation.36- 38 Potential
strategies include suppression of reactivation with antiviral therapy, examination
for genital lesions and use of cesarean delivery, and identification of those
shedding virus at delivery and intervention in the delivery room, such as
cesarean delivery or prophylaxis of the exposed infant with antivirals. Small
studies suggest that genital lesions at term may be prevented by long-term
daily antiviral therapy in the last month of pregnancy, and such an approach
is approved by the American College of Obstetricians and Gynecologists, but
some experts still have concerns about the safety of this approach.11,39,40 The occurrence of
false-negative cultures decreases enthusiasm for relying on viral culture
alone. DNA amplification techniques offer obvious advantages and have been
considered for intrapartum diagnosis of group B streptococcal infections.41 But the technological issues in conducting and reporting
these assays quickly and accurately enough to influence obstetrical management
are not trivial. Antiviral, behavioral, and, of course, vaccine approaches
to reduce transmission from mother to infant need evaluation in large multi-institutional
trials to determine the most effective and economical strategies.