Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes

Acyclovir Suppression to Prevent Cesarean Delivery After First-Episode Genital Herpes L. LAURIE SCOTT, MD, PABLO /. SANCHEZ, MD, GREGORY L. JACKSON, MD, FIKER ZERAY, RN, AND GEORGE D. WENDEL, fr, MD Objective: To determine if suppressive acyclovir therapy given to term gravidas experiencing a first episode of genital herpes simplex virus (HSV) infection during pregnancy decreases the need for cesarean delivery for that indication. Methods: Forty-six pregnant women with first episodes of genital herpes during pregnancy were randomly assigned to receive oral acyclovir 400 mg or placebo, three times per day, from 36 weeks’ gestation until delivery as part of a prospective, double-blind trial. Herpes simplex virus cultures were obtained when patients presented for delivery. Vaginal delivery was permitted if no clinical recurrence was present; otherwise, a cesarean was performed. Neonatal HSV cultures were obtained and infants were followed-up clinically. Results: None of the 21 patients treated with acyclovir and nine of 25 (36%) treated with placebo had clinical evidence of recurrent genital herpes at delivery (odds ratio [OR] 0.04, 95% confidence interval [CII 0.002-0.745; P = .002). No woman treated with acyclovir had a cesarean for herpes, compared with nine of 25 (36%) of those treated with placebo (OR 0.04, CI 0.002-0.745; P = .002). No patient in either treatment group experienced asymptomatic genital viral shedding at delivery. No neonate had evidence of herpes infection or adverse effects from acyclovir. Conclusion: Suppressive acyclovir therapy reduced the need for cesarean for recurrent herpes in women whose first clinical episode of genital HSV occurred during pregnancy. Suppressive acyclovir treatment did not increase asymptomatic viral shedding and was not harmful to the term fetus. (Obstet Gpecol 1996;87:69-7.3)

infection, it is currently recommended’z2 that pregnant women with visible genital herpes lesions or prodromal symptoms at labor be delivered by cesarean. Gravidas without visible lesions or prodromal symptoms should be allowed to continue in labor because they have a low risk of neonatal HSV transmission.‘,’ Using these guidelines, it is estimated that one poor neonatal outcome from HSV infection is averted (at a cost of $2.5 million) for every 1580 cesareans performed for maternal clinical HSV recurrences.” Suppressive acyclovir therapy decreases the frequency of symptomatic recurrences of genital herpes in nonpregnant adults,3 but the safety and efficacy of such long-term therapy in pregnancy is unknown. A typical oral suppressive dose in the nonpregnant adult is 200 mg, three times per day.i However, pharmacokinetic studies in the term gravida have shown that 400 mg given orally three times per day may be necessary to achieve similar therapeutic serum levels.h The purpose of this study was to determine if acyclovir suppressive therapy, administered from 36 weeks’ gestation, would decrease the frequency of symptomatic genital herpes recurrences at delivery in women whose first clinical episode of genital herpes occurred during the pregnancy, and thereby decrease the number of cesareans for this indication.

Matevials and Methods It is estimated that 5’; of the general population has a known history of genital herpes.’ This creates a large population of women who are known to be at risk for transmitting herpes simplex virus (HSV) to their infants during delivery if they have a peripartum recurrence. To avoid intrapartum HSV exposure and neonatal

Eligible subjects included any gravida ical episode of genital herpes occurred

whose during

first clinthe index

Financial Disclosure Burroughs Wellcome Company, a manufacturer of acyclovir, provided the drug and paid for the cultures in this study. In addition, Drs. Scott and Wendel have received compensation from Burroughs Wellcome Company as consultants and lecturers.

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pregnancy. All women denied having been diagnosed with herpes, or having had similar lesions, before becoming pregnant. The diagnosis was confirmed by a positive viral culture for HSV. Women with primary infection, those with first genital nonprimary episodes, and those with a first clinical episode of recurrent disease were eligible.7 Serology was not performed to distinguish between these groups of patients. Exclusion criteria for enrollment included a serum creatinine greater than 1.5 mg/dL, immunosuppressive diseases (eg, human immunodeficiency virus infection), a known requirement for cesarean delivery (eg, previous cesarean with a classical uterine incision), enrollment in another study protocol, a gestational age greater than 36 weeks on identification, delivery before 36 weeks‘ gestation, or previous acyclovir intolerance. Patients who were ineligible or who declined enrollment were also followed prospectively; these women comprised an additional cohort that was compared with the placebo-treated group to ascertain whether significant selection bias had occurred. Subjects were excluded from statistical evaluation of efficacy for voluntary withdrawal, noncompliance with the study protocol, loss of follow-up for delivery, or delivery within 1 week of beginning treatment. A patient was considered to be noncompliant if she had not taken any study medication for 7 or more days before delivery. Informed consent was obtained from eligible patients by 36 completed weeks‘ gestation. At 36 weeks’ estimated gestation, a schedule generated from a randomnumber table was consulted and the women were assigned to receive either oral acyclovir 400 mg or an identical-appearing placebo, three times per day until delivery. The acyclovir and placebo were dispensed in coded bottles, and the patients and their physicians were blinded to the assigned study regimen. An individual not involved with patient care maintained the randomization list and assigned the study drug group. The women were evaluated every week after 36 weeks’ gestation and were questioned at each visit about genital lesions, prodromal symptoms, compliance, and side effects from the treatment. An examination for genital HSV lesions was performed at each visit. Herpes simplex virus cultures were obtained only if the patient described prodromal symptoms or if a lesion was identified. The collection, handling, and culture technique has been described previously.8 On presentation for delivery, the patients were examined for genital lesions and questioned regarding prodromal symptoms. Herpes simplex virus cultures of the usual lesion site and cervix were obtained to detect asymptomatic viral shedding. Any visible genital or cervical lesions were also cultured for HSV. Obstetric house staff or nurse practitioners who had been in-

70

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17rld Cesi7rcnii

strutted in proper viral culture collection technique collected the samples from patients on admission to the labor and delivery unit. Study medications were not continued intrapartum. Patients were delivered by cesarean if prodromal symptoms or lesions suspicious for genital herpes were present, regardless of the length of time the amniotic membranes had been ruptured. They were allowed to labor if there were no prodromal symptoms and lesions. The route of delivery and indication for cesarean were recorded. The pediatricians were informed of the mother’s participation in the study, and a physical examination was performed on the infant’s admission to the newborn nursery. Neonatal HSV cultures were taken from the conjunctiva, oropharynx, and rectum 24-72 hours after delivery. The infants were observed for clinical evidence of acyclovir toxicity (abnormal renal, liver, or central nervous system function) and HSV infection. Prophylactic acyclovir therapy was not administered unless the infant was thought to have been exposed to an active herpes lesion. Mothers were instructed to contact the investigators for any problems in the first month after discharge, and the infants’ medical records were reviewed at least 1 month after delivery. Statistical analysis included the two-tailed Fisher exact test to evaluate differences between the acyclovir and placebo treatment groups. The Breslow-Day test for the homogeneity of odds ratios (OR) was used to examine the homogeneity of the placebo-treated patients and the nonparticipating control patients to help identify possible selection bias. Hypothesizing a symptomatic genital herpes recurrence rate at delivery of 130/c,” a 50% decrease in recurrences at delivery in the treated group, and an 80% power, a sample size of 326 patients in each group (acyclovir and placebo) was projected. Chi-square analysis, the Student t test, and the Mann-Whitney U test were used to compare maternal and neonatal characteristics between the two study groups. P < .05 was considered statistically significant. Odds ratios and confidence intervals (CI) were calculated using the Epi Info software package, version 5 (Centers for Disease Control and Prevention, Atlanta, GA) and SAS software (Statistical Analysis System, Cary, NC). Interim analysis of results was performed after completion of every 25 mother-infant pairs. To guide decisions regarding continued enrollment, the triangular test of sequential hypotheses’0 was used after statistical significance with the Fisher exact test had been reached, to determine the point at which a significant P value was unlikely to revert back to a nonsignificant value. This statistical test is designed to allow early termination of a clinical trial before the projected sample size is reached by demonstrating that one treatment arm (pla-

Obstetrics

~5 Gynecology

cebo or study drug) is clearly superior to the other.“’ An achieved power of greater than 8OYc,was also used as a guide for enrollment termination. The Food and Drug Administration granted an Investigational Drug Number for this protocol, and the investigational review boards of the University of Texas Southwestern Medical Center, Parkland Memorial Hospital, and St. Paul Medical Center granted approval for the study.

Results Between February 1, 1992, and June 13, 1994, 1OY women were diagnosed with first-episode genital herpes during their pregnancies. Forty-nine (45%) were either ineligible or declined to participate (Table 1). Ten women (six in the acyclovir group and four in the placebo group) began but did not complete the study protocol. These women were excluded from statistical evaluation for efficacy of the therapeutic regimen,“,‘2 but they were included in an intent-to-treat analysis. Two withdrew because of fetal concerns, one delivered less than 72 hours after beginning treatment, six were noncompliant with the study protocol and had not taken the study drug for at least 7 days before delivery, and one was lost to follow-up. Four others who completed the study protocol were later determined to have been diagnosed with genital herpes before pregnancy. These four were excluded from all statistical evaluation because they did not meet the eligibility criteria. Forty-six subjects completed the study protocol and were eligible for evaluation of efficacy. The mean gestational age at diagnosis of the first herpes outbreak was 18.2 weeks in the acyclovir group and 21.0 weeks in the placebo group. The mean total number of herpes outbreaks (including the initial outbreak) during the pregnancies was 1.5 in the acyclovir-treated patients and 1.8 in the placebo-treated patients. Other maternal characteristics are provided in Table 2. There was no difference between the acyclovir and placebo treatment groups in ethnic distribution, maternal age, parity, gestational age at first genital herpes diagnosis, or number of outbreaks during pregnancy.

Table

1. lieawns

for

Nonparticipation ,I

Declined Identification after 36 tveeks’ grstatlon Enrolled but lost to tallow-up before randomization Preterm delivery Spontaneous abortion Human immunodeticwncy vuu> infection Total

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Table

2. Maternal

and

Neonatal

Acyclovir-treated (n = 21) Ethnicity* (‘7 1 Black. White Hispanic Maternal agt,’ (y) Parity* Gestational age at diagnosis (wk) Outbreaks during pregnancy’ 01) Gestational age at delivery’ (cvk) Birth weight’ (g) S-min Apgar score’ C‘ord aH * Data art’ a Dab are * Data are ’ Data are test used.

presented presented presented presented

Characteristics Placebo-treated (n = 2.5)

P .41

67 5 29 20.3 0 18.2

62 16 32 22.8 1 21 .o

.13 .22 .31

1.5

1.8

.28

39.6

39.6

1.00

3422 9 7.23

3331 9 7.26

.46 1.00 .I8

as % of n; ,$ analysis used. as the mean of the sample; Student t test used. as the median of the sample; Student t test used. as the median of the sample; Mann-Whitney U

Of the women who completed the study protocol, 21 received acyclovir and 25 received placebo. None of the acyclovir-treated patients had recurrent genital herpes at delivery, whereas nine placebo-treated patients (36%) had recurrent genital herpes at delivery; all nine had cesareans. There were significant differences in the frequency of symptomatic recurrent herpes at delivery and cesareans for HSV between the acyclovir-treated and placebo-treated groups (OR 0.04, 95% CI 0.0020.745; P = .002). The triangular test of sequential hypotheses demonstrated that these differences were likely to remain significant, even with a larger number of patients (P = .002). After statistical significance was achieved with the triangular test of sequential hypotheses, a two-tailed power analysis incorporating our results demonstrated a power of 90%; further enrollment in the study protocol was discontinued at that point. Overall, four (none for herpes, four for other indications) of 21 (19%) of the acyclovir-treated patients had cesarean deliveries, compared with ten (nine for herpes, one for another indication) of 25 (40%) of the placebo-treated patients (OR 0.35, CI 0.07-1.59; P = .22). in the absence oi clinical lesions, there were no patients in either treatment group whose viral cultures at delivery were positive. One of nine placebo-treated patients had virus recovered from a clinical lesion present at delivery. Nine subjects with known outcomes who did not complete the study protocol were excluded from the efficacy analysis. Three had clinical genital herpes recurrences at delivery, although none had a positive viral culture; two had been assigned to acyclovir and

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one to placebo. These three patients were noncompliant with prenatal care and had not taken their study medication for 7 or more days before delivery. When all patients with known outcomes were included in the intent-to-treat analysis, the acyclovir-treated patients still had significantly fewer genital HSV recurrences at delivery: two of 26 (8%) in the acyclovir arm and ten of 29 (34%) in the placebo arm (OR 0.16, CI 0.02-0.90; P = .016). One patient was lost to follow-up and her outcome is unknown. In an effort to determine whether selection bias had occurred, the placebo group and the nonparticipating cohort were evaluated with the Breslow-Day test. This analysis demonstrated homogeneity across the groups (data not shown), indicating that no significant selection bias had occurred. The mean gestational age at delivery for both the acyclovir and placebo groups was 39.6 weeks. The mean (-’ standard deviation) birth weight for the acyclovir and placebo groups was 3422 2 382 and 3331 2 435 g, respectively. All but one infant (in the acyclovir group) had 5-minute Apgar scores greater than 7 (Table 2). Two infants received prophylactic antiviral therapy until their HSV cultures returned negative. One infant was delivered by cesarean from a placebo-treated mother with a herpes lesion; a fetal scalp electrode had been inadvertently placed on admission for labor. The other infant was born in the placebo arm to a mother who had been noncompliant with treatment; she had a vaginal delivery with an active lesion present. No infant in either the acyclovir or placebo group had clinical or virologic evidence of HSV infection, including the two infants treated prophylactically with acyclovir. No infant experienced any clinically apparent neurologic, hepatic, or renal complications or other adverse effects attributable to acyclovir during the neonatal period.

Discussion In an effort to prevent intrapartum herpes virus transmission, obstetricians generally resort to cesarean delivery when a patient presents for delivery with recurrent genital HSV lesions or prodromal symptoms. Under current guidelines, a vaginal delivery is appropriate in the absence of these findings.‘,’ Daily acyclovir therapy suppresses recurrent genital HSV outbreaks in the nonpregnant adult,’ and this treatment has been suggested as a means to prevent herpes reactivation at delivery. However, several questions regarding the use of suppressive acyclovir in pregnancy have been posed: Is acyclovir effective in preventing genital HSV recurrences in the term pregnant woman? Does acyclovir suppress clinical recurrences by changing clinically evident outbreaks into asymptomatic HSV shedding

episodes? What effect does the suppressive therapy have on the near-term fetus?‘” Our study demonstrated that pregnant women whose first clinical episode of genital herpes occurred during the index pregnancy benefited from suppressive doses of acyclovir given from 36 weeks’ gestation until delivery. They had both fewer recurrences of genital HSV lesions at delivery as well as fewer cesareans for HSV than did those given placebo. These findings are consistent with the preliminary results reported in a letter by Stray-Pedersen (Acyclovir in late pregnancy to prevent neonatal herpes simplex. Lancet 1990;336:756). A theoretic concern has been whether symptomatic recurrences would be converted to asymptomatic shedding episodes by suppressive treatment, thus potentially increasing an infant’s perinatal exposure to HSV through a vaginal delivery. The reported incidence of asymptomatic HSV shedding at any given time in pregnant women with genital herpes is approximately 1-2Li(,‘“m’h In our study, suppressive acyclovir therapy significantly decreased the need for cesareans for recurrent HSV lesions without concomitantly increasing the frequency of asymptomatic viral shedding. However, the number of patients in this study is too small to exclude a significant difference in asymptomatic HSV shedding between the acyclovir- and placebo-treated groups. Further investigation regarding the impact of acyclovir suppression on asymptomatic viral shedding in the term gravida is warranted. On short-term follow-up, there were no apparent adverse effects on any of the neonates who had prenatal exposure to acyclovir, 1200 mg/day, at term. Limited data from the Acyclovir in Pregnancy Registry do not suggest adverse outcomes attributable to acyclovir in over 600 prenatal exposures, regardless of gestational age. ” Additional anecdotal evidence of acyclovir’s safety is provided indirectly through reported pediatric clinical experience. Both term and preterm infants treated daily with intravenous acyclovir tolerate the drug well.‘XJ’y Furthermore, the fetal serum levels in gravidas taking 1200 mg/day of acyclovir have been reported to be much lower than the acyclovir levels achieved during neonatal parenteral treatment.6~‘8~‘9 However, because of the small number of mother-infant pairs in this study, we cannot yet conclude that prenatal suppressive acyclovir therapy is completely safe for the fetus. Further evaluation of short- and long-term neonatal outcomes is necessary. Specifically, this should include the evaluation of the impact of maternal acyclovir suppression on the fetal and neonatal kidney. There are several limitations to our study. First, we did not discriminate between primary, first-episode nonprimary, and first-clinical-episode recurrent genital infections. Although the risk of clinical recurrences at

Obstetrics

& Gynecology

term may be higher after a primary infection during a pregnancy, we did not have type-specific serology available. Prospective randomization of the patients should have resulted in similar numbers of women with each type of infection in each treatment group. Second, we did not differentiate between HSV-1 and HSV-2 genital infections. Previous studies7r2” have indicated that HSV-1 genital infections have a lower frequency of recurrence than HSV-2 genital infections (one per year and four per year, respectively); however, genital herpes is predominantly due to HSV-2. Prospective randomization of the patients should have resulted in similar numbers of women with each virus type in the two treatment groups. Thirty-eight percent of the identified patients at risk for recurrent herpes were not eligible and 7% chose not to participate in our study. This high level (45%) of nonparticipation is another limitation. However, most (73%) of the ineligible patients were lost to follow-up or did not present to the investigators’ clinic early enough in pregnancy to begin the study. Statistical analysis showed that the placebo-treated patients and the nonparticipating patients were similar, confirming that no selection bias was present. Our findings demonstrate that, in our cohort, acyclovir suppressive therapy given from 36 weeks’ gestation until delivery prevented recurrent genital HSV at delivery and decreased the need for cesarean for recurrent genital herpes in women who experienced their first episode of genital herpes earlier during the pregnancy. Although the small sample size does not provide sufficient statistical power to draw conclusions regarding the impact of acyclovir suppression on asymptomatic viral shedding or fetal outcome, we did not detect any changes in the rate of asymptomatic HSV shedding at delivery or any short-term, adverse neonatal effects.

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term

neonates.

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rates in genital herpes Ann Int Med 1994;121:

to:

MD

Obstetrics and Gynecology

of Texas

University 5323 Harry Dallas, TX

and

Southwestern Hines Boulevard 75235-9032

Medical

Center

l’erinatal no. 122.

and

CG. Cesarean

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