Background The acquisition of genital herpes during pregnancyhas been associated with spontaneous abortion, prematurity,and congenital and neonatal herpes. The frequency of seroconversion,maternal symptoms of the disease, and the timing of its greatesteffect on the outcome of pregnancy have not been systematicallystudied.
Methods We studied 7046 pregnant women whom serologic testsshowed to be at risk for herpes simplex virus (HSV) infection.Serum samples obtained at the first prenatal visit, at approximately16 and 24 weeks, and during labor were tested for antibodiesto HSV types 1 and 2 (HSV-1 and HSV-2) by the Western blot assay,and the results were correlated with the occurrence of antenatalgenital infections.
Results Ninety-four of the women became seropositive for HSV;34 of the 94 women (36 percent) had symptoms consistent withherpes infection. Women who were initially seronegative forboth HSV-1 and HSV-2 had an estimated chance of seroconversionfor either virus of 3.7 percent; those who were initially seropositiveonly for HSV-1 had an estimated chance of HSV-2 seroconversionof 1.7 percent; and those who were initially HSV-2–seropositivehad an estimated chance of zero for acquiring HSV-1 infection.Among the 60 of the 94 pregnancies for which the time of acquisitionof HSV infection was known, 30 percent of the infections occurredin the first trimester, 30 percent in the second, and 40 percentin the third. HSV seroconversion completed by the time of laborwas not associated with an increase in neonatal morbidity orwith any cases of congenital herpes infection. However, amongthe infants born to nine women who acquired genital HSV infectionshortly before labor, neonatal HSV infection occurred in fourinfants, of whom one died.
Conclusions Two percent or more of susceptible women acquireHSV infection during pregnancy. Acquisition of infection withseroconversion completed before labor does not appear to affectthe outcome of pregnancy, but infection acquired near the timeof labor is associated with neonatal herpes and perinatal morbidity.
The prevalence of genital infection with herpes simplex virus(HSV) and its most serious complication, neonatal herpes, hasincreased during the past two decades.1,2,3,4,5,6 Neonatal HSVinfection most commonly results from contact between the newbornand either HSV type 1 (HSV-1) or HSV type 2 (HSV-2) that ispresent in the birth canal of an asymptomatic mother duringlabor and delivery.7,8,9 The consequences of neonatal infectionwith HSV are frequently catastrophic; death of the infectedneonate or severe neurodevelopmental disability is common.10HSV can be asymptomatically present in the genital tract atthe time of labor as a consequence of the reactivation of diseaseor the acquisition of genital herpes during pregnancy.8,9,11
Previous studies have suggested that genital HSV infection acquiredduring pregnancy is associated with preterm labor, intrauterinegrowth retardation, and spontaneous abortion.7,12,13 However,there have been few prospective studies of the frequency andconsequences of genital HSV infection acquired at differenttimes during pregnancy. Therefore, we used serologic and virologicmethods to study the acquisition of HSV infection among pregnantwomen.
Methods
Subjects, Setting, and Procedures
We obtained serum samples at the first prenatal visit and atthe time of labor to test for the presence of antibodies againstHSV-1 and HSV-2 in 8538 women receiving prenatal care at UniversityHospital in Seattle between January 1989 and December 1993 andat Madigan Army Hospital in Tacoma between August 1990 and December1993. In addition, serum samples obtained for routine prenataltests at 14 to 18 weeks and at 24 to 28 weeks of gestation weresaved and tested when indicated to define more precisely thetime of seroconversion. When the women entered the labor room,swabs for culture of HSV were obtained from the external genitaliaand cervix.8 Isolation and typing of HSV were performed as previouslydescribed.14 Infants born to women from whom HSV was isolatedduring labor were enrolled in ongoing studies.7
Antibodies to HSV-1 and HSV-2 were detected by Western blotassays.15,16,17,18,19 All serum samples from an individual womanwere analyzed simultaneously. For all women whose initial serumsample was positive for HSV-1 but in whom antibodies to HSV-2later developed, seroconversion was confirmed by absorption-blotassay.19 The medical records of all women who became seropositivefor HSV-1 or HSV-2 were reviewed for symptoms of genital HSVduring pregnancy.
Consent was obtained for the appropriate portions of the studyprotocol, including the review of medical records and the follow-upof infants, according to the guidelines of the human-subjectsreview board of the University of Washington.
Definitions
Seroconversion was defined as the appearance of antibodies toHSV in the serum sample obtained at the time of labor that werenot present at the initial prenatal visit.20,21,22,23 This changeindicates that HSV was acquired long enough before deliveryto permit the development of antibodies to HSV, a process thatusually requires four to six weeks. Primary HSV infection wasconsidered to have occurred when there were no detectable antibodiesto HSV in the first prenatal serum sample but antibodies toeither HSV-1 or HSV-2 were found in the sample obtained at thetime of labor. A non-primary first episode was defined as thepresence of antibodies to HSV-1 in the initial prenatal serumsample, with antibodies to both HSV-1 and HSV-2 in the sampleobtained at the time of labor. No woman who had antibodies toHSV-2 in the initial prenatal serum sample had antibodies toboth HSV-2 and HSV-1 in the sample obtained at the time of delivery.
Among women with symptomatic disease, the date of acquisitionof genital HSV infection was defined as the date of the firstreported genital lesions. Among those with subclinical disease,the date of infection was defined as the midpoint between thetime of the negative test for the particular HSV antibody andthe time of the first positive antibody test. Infection wasconsidered subclinical if a review of the woman's obstetricalrecords did not indicate any evidence of vulvovaginitis duringpregnancy. The first trimester was defined as the period fromconception to 12 completed weeks of gestation, the second trimesteras that from the beginning of week 13 through week 28, and thethird trimester as that from the beginning of week 29 to theonset of labor. Premature labor was defined as labor occurringbefore 259 days, or 37 weeks, from the first day of the woman'slast menstrual period.24
Statistical Analysis
The frequency of seroconversion was calculated as the ratioof the number of women who had HSV seroconversion to the numberat risk for seroconversion. Because the mean interval betweenthe first prenatal visit and the onset of labor was less thanthe length of a normal pregnancy, the frequency of seroconversionwas adjusted for a 40-week gestation period on the assumptionthat the rate of seroconversion was uniform throughout pregnancy.This method may result in the underestimation of the true frequencyof seroconversion because the interval between conception andthe first prenatal visit may be a period of normal or increasedsexual activity that then declines as pregnancy progresses.25
Categorical variables were compared between groups by meansof the chi-square or Fisher's exact test. Rates of seroconversionwere compared by permutation tests.26 Standard errors for theserates were estimated with bootstrap resampling.27 Two-groupcomparisons of distributions of continuous variables were performedby Mann–Whitney tests. All statistical tests were two-sided.Odds ratios for seroconversion, with 95 percent confidence intervals,were estimated from the results of logistic-regression analyses.Odds ratios indicating the influence of demographic variableson the rate of seroconversion were estimated by multivariateanalysis. Odds ratios for behavioral variables came from univariateanalyses, because missing data greatly reduced the number ofwomen who could be included in a multivariate analysis incorporatingthese variables.
Results
Characteristics of the Study Population
Of the 17,125 women who delivered babies at the two study hospitals,15,434 (90 percent) had serologic testing for HSV at the timeof labor. Serum samples obtained during labor were not availablefrom 1691 women (10 percent) because of oversight on the partof physicians, lost specimens, or the women's refusal to allowblood sampling. Serum samples from the first prenatal visitwere available for 8538 of the 15,434 women (55 percent). Serumsamples were not obtained at the first prenatal visit for 6896women because the women were referred to the study centers within30 days of delivery (26 percent of those with missing prenatalsamples), no prenatal care was received (7 percent), or prenatalcare was received elsewhere (22 percent). In addition, 16 percentof women had already had their initial prenatal visit when webegan the study and were thus ineligible for enrollment. Theremaining 29 percent of the women with missing prenatal sampleseither registered for care late in pregnancy, declined to haveblood drawn, or did not have the serologic tests because ofthe physician's oversight.
The demographic characteristics and HSV serologic status ofthe 8538 women from whom serum samples were obtained both atthe first prenatal visit and at the time of labor were similarto those of the 6896 women for whom results of serologic testingfor HSV were available only at the time of labor.
Frequency of Antenatal Seroconversion
At entry, 2033 of the 8538 women (24 percent) were HSV-negative;4074 (48 percent) were seropositive for HSV-1; 939 (11 percent)were seropositive for HSV-2; and 1492 (17 percent) were seropositivefor both HSV-1 and HSV-2. Of the 7046 women (83 percent) inwhom serologic tests showed susceptibility to HSV infectionduring pregnancy, 94 (1.3 percent) became seropositive for HSV-1or HSV-2; 64 (68 percent) acquired antibodies to HSV-2, and30 (32 percent) acquired antibodies to HSV-1 before the onsetof labor (Table 1). The median interval between the first prenatalHSV test and the HSV test at the time of labor was 196 days(range, 26 to 280) for the entire study group and 202 days (range,26 to 257) for the 94 women in whom seroconversion occurred.
Table 1. Frequency of Antenatal HSV Seroconversion among 7046 Initially HSV-Susceptible Women.
The estimated rate of seroconversion during pregnancy, adjustedfor a 40-week gestation, was 2.1 percent. The adjusted rateof seroconversion among the initially HSV-seronegative womenwas 3.7 percent; among those who were initially HSV-1–seropositive,1.7 percent became HSV-2–seropositive. Although the ratesof HSV-2 seroconversion among initially HSV-seronegative womenwere similar to those among HSV-1–seropositive women (1.4percent vs. 1.7 percent), the rate of HSV-1 seroconversion amongthose who were HSV-seronegative was significantly higher thanthat among those who were HSV-2–seropositive (2.3 percentvs. 0, P = 0.001), suggesting that prior HSV-2 infection preventedthe acquisition of HSV-1 (Table 1).
Frequency of Subclinical and Clinical HSV Infection
Among the 94 women who became HSV-seropositive during the prenatalperiod, 60 (64 percent) had subclinical infections (Table 2).The frequency of subclinical seroconversion was similar amongthose who acquired HSV-1 (22 of 30 [73 percent]) and those whoacquired HSV-2 (38 of 64 [59 percent]). All 26 women with clinicalsymptoms of HSV-2 infection and 6 of 8 with symptomatic HSV-1infection had genital lesions. Overall, 32 of the 34 women whohad seroconversion and symptomatic infection had genital infections;4 received antiviral therapy.
Table 2. Frequency of Symptoms and Trimester of Infection among Women with HSV Seroconversion during Pregnancy.
Time of Acquisition of HSV
Of the 34 women with symptomatic infection, 7 (21 percent) acquiredHSV in the first trimester, 15 (44 percent) in the second, and12 (35 percent) in the third. Of the 60 women with subclinicalHSV, 11 (18 percent) were infected in the first trimester, 3(5 percent) in the second, and 12 (20 percent) in the third(Table 2). In three women, infection was known only to haveoccurred in the first or second trimester. In 22 women, infectionoccurred in the second or third trimester. In nine women, interimserum samples were not available to permit us to identify thetrimester of HSV infection. Thus, of the 60 women in whom thetrimester of infection was known, 18 (30 percent) acquired HSVinfection in the first trimester, 18 (30 percent) in the second,and 24 (40 percent) in the third.
Demographic, Behavioral, and Obstetrical Characteristics of the Women with Seroconversion
We compared the demographic, behavioral, and obstetrical characteristicsof the 94 women who had HSV seroconversion with those of 6009women who did not have seroconversion (Table 3). In addition,the 49 initially HSV-seronegative women who became seropositivefor HSV-1 or HSV-2 and 45 HSV-1–seropositive women whobecame seropositive for HSV-2 were compared with HSV-seronegativewomen who remained HSV-seronegative and HSV-1–seropositivewomen who did not acquire HSV-2. Younger age, not being married,and the occurrence of other sexually transmitted diseases wereassociated with seroconversion.
Table 3. Demographic and Behavioral Characteristics of Women Who Had HSV Seroconversion and Women with Similar Serologic Profiles Who Did Not Have Seroconversion.
Overall, 25 of the 94 women who became seropositive for HSVduring pregnancy (27 percent) underwent a cesarean section (6because of the presence of active genital lesions), as comparedwith 17 percent of the women who did not have seroconversion(P = 0.02). Among the 32 women who acquired symptomatic genitalHSV during pregnancy, 10 (31 percent) delivered their infantsby cesarean section; 6 of these women had active, recurrentgenital lesions at the time of delivery. Among the 60 womenwho acquired subclinical HSV infection, 15 (25 percent) deliveredby cesarean section. The frequency with which fetal-scalp electrodesand intrauterine pressure catheters were used during labor anddelivery was similar among the 94 women who had seroconversion(56 percent and 52 percent, respectively) and the 6009 womenwho did not (62 percent and 50 percent).
Effects of Seroconversion to HSV Positivity on Neonates
There were no significant differences in the frequency of complicationsbetween the 94 infants born to mothers who had HSV seroconversionand the infants of the 6009 women who did not seroconvert (Table 4).There were no cases of herpes among the neonates of the94 women who seroconverted. On the basis of a binomial probabilitycalculation, we are 95 percent confident that the chance thata woman who becomes seropositive during pregnancy will infecther newborn with HSV is less than 3.2 percent. Of the 94 womenwith seroconversion, cultures for HSV were performed at thetime of labor in 71. Of these, five (7 percent) were positive.
Table 4. Outcome of Pregnancy among Women Who Had Seroconversion as Compared with Women with Similar Serologic Profiles Who Did Not Have Seroconversion.
Relation of Neonatal Herpes to Initial Episodes of Genital HSV at the Time of Labor
Nine women acquired a genital HSV infection near the onset oflabor, five of whom had lesions at the time of labor (Table 5).Since they had not completed HSV seroconversion by the timeof labor, they were excluded from the main study cohort. Duringlabor, all had either no detectable antibodies to HSV or antibodiesthat were different from the HSV type isolated from the genitalia.Serologic and virologic evidence indicated that seven of thesenine women had a non-primary first episode of HSV-2 infectionand the other two had a primary genital HSV-1 infection.
Table 5. Characteristics of HSV Infection Acquired near the Time of Labor and Neonatal Outcome.
Neonatal HSV infection developed in four of the nine infantsborn to these women — both of the infants born to motherswho had primary genital HSV-1 and two of the seven born to motherswith non-primary first episodes of infection (Table 5). Thefrequency of neonatal HSV infection was significantly higheramong the infants of women with first episodes of HSV near thetime of labor (4 of 9) than among those born to women who acquiredtheir infection earlier and had seroconversion before the onsetof labor (0 of 94, P<0.001).
Discussion
We estimate that HSV was acquired by 2 percent or more of susceptiblewomen during pregnancy. Among the infants of 94 women who becameseropositive for HSV before labor, there were no cases of neonatalherpes or any increase in pregnancy-related morbidity. However,among the infants born to nine women who acquired HSV infectionat or near the time of labor, neonatal HSV developed in four,of whom one died and one had long-term neurologic sequelae.
The absence of definable morbidity in association with HSV seroconversionbefore the onset of labor is comforting and yet surprising.Previous studies have demonstrated an association between firstepisodes of genital HSV infection and preterm labor, intrauterinegrowth retardation, and spontaneous abortion.7,12,13 These observationshave all come from studies based on cultures and serologic testsperformed at the time of labor. We studied seroconversion prospectivelyduring pregnancy in a large, well-defined cohort, comparingpregnancy outcomes among women with and without seroconversion.Although our study involved more than 8000 women and 94 casesof HSV seroconversion, the frequency of complications of pregnancywas low both among women who had seroconversion and among thosewho did not. Thus, it is possible that HSV may have some effecton pregnancy that could be demonstrated only by larger cohortstudies.
Of 60 women for whom we could identify the trimester when HSVwas acquired, 30 percent became infected in the first trimester,30 percent in the second, and 40 percent in the third —suggesting that the risk of acquisition is relatively uniformduring pregnancy. However, since the frequency of coitus ishigher in early pregnancy and declines thereafter, the actualrisk of HSV seroconversion may decline as the pregnancy advances.25
Among the eight women in whom seroconversion to HSV-1–positivitywas accompanied by clinical symptoms, six had genital lesionsand two had only oropharyngeal lesions. Several studies havedemonstrated an increase in the prevalence of genital HSV-1in recent years, especially among patients with recently acquiredHSV infection.1,2,6,19,20 Perhaps this increase results froma perception among young couples that oral–genital sexis "safe."
The two cases of neonatal HSV-1 infection underscore the importanceof recognizing that neonatal herpes can result from infectionwith either viral subtype and that the prevention of genitalHSV-1 infection in the third trimester is important in termsof the health of the neonate. Lastly, although 7 percent ofthe infants born to mothers who became HSV-seropositive beforethe onset of labor but had subclinical viral shedding at thetime of labor were exposed to HSV during delivery, none acquiredHSV infection. In contrast, four of the nine infants born tomothers who lacked type-specific antibodies to the homologousvirus acquired HSV infections. This finding underscores thepotential role of type-specific antibodies in protecting againstHSV transmission.
The absence of discernible perinatal morbidity among the babiesborn to women in whom seroconversion occurred during pregnancysuggests that routine antiviral chemotherapy may not be necessaryfor women who acquire HSV well before the onset of labor. Selectedwomen who are highly symptomatic or in whom there is evidenceof disseminated infection may require antiviral chemotherapy.Cases such as these were extremely uncommon in our study population.
Our study also suggests that efforts to reduce the high morbidityassociated with neonatal HSV infection should be concentratedon preventing the maternal acquisition of HSV infection in thelatter part of pregnancy. Serologic testing for HSV in the latterhalf of pregnancy could identify women who are susceptible toHSV infection, so that serologic testing of their partners andappropriate counseling as to the risk of acquiring genital herpescould be undertaken. Such counseling should promote awarenessof the risk of acquiring genital HSV-1 infection from oral–genitalcontact among those who are seronegative for both HSV-1 andHSV-2. Abstinence from intercourse or the use of condoms duringthe last trimester could also be recommended when the womanis at risk for acquiring HSV-1 or HSV-2.
Supported by a grant (AI-30731) from the National Instituteof Allergy and Infectious Diseases.
Source Information
From the Departments of Obstetrics and Gynecology (Z.A.B., D.H.W., S.B.), Laboratory Medicine (S.S., R.L.A., L.C.), Statistics (J.Z.), and Medicine (L.C.), University of Washington, Seattle; and the Department of Obstetrics and Gynecology, Madigan Army Medical Center, Tacoma, Wash. (J.K., A.M., M.H.). The opinions expressed in this article are solely those of the authors and do not necessarily reflect those of the Department of the Army or the Department of Defense.
Address reprint requests to Dr. Brown at Box 356460, University of Washington, Seattle, WA 98195-6460.
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