Nephrotic syndrome in pregnancy
Volume 164 Number 2
idiopathic forms of the nephrotic syndrome, or a secondary type associated with a systemic disease such as systemic lupus erythematosus, diabetes mellitus, or preeclampsia. The history in this patient provided the key to the diagnosis. Because she was seen in early pregnancy without hypertension made preeclampsia unlikely, and there were no findings to suggest either diabetes or systemic lupus erythematosus. She had a clear history of steroid-responsive nephrotic syndrome beginning in childhood, typical of minimal-change nephropathy. Her history of explosive onset of severe nephrotic syndrome is also characteristic of this disorder. Acute renal failure is not typically associated with minimal-change nephropathy; however, this complication has been well described, particularly in adults with this disease. Although the diagnosis of this disease can be established with certainty only by renal biopsy, it was believed that the presentation was so typical of this disease that a
therapeutic trial of corticosteroids was the safest approach. Rapid response to treatment with complete resolution of nephrotic syndrome and renal failure supported the diagnosis. If there had been no response to therapy, then a renal biopsy to exclude other disorders would have been appropriate. This patient who was seen with renal failure in early pregnancy illustrates the importance of a systematic approach to this problem. By making a presumptive diagnosis of nephrotic syndrome as a result of minimalchange disease on the basis of her clinical presentation, therapy with prednisone led to an uneventful pregnancy with successful delivery.
REFERENCES 1. Studd JWW, Blainey JD. Pregnancy and the nephrotic syndrome. Br Med J elin Res 1969; 1:276-80. 2. Krane NK. Acute renal failure in pregnancy. Arch Intern Med 1988;148:2347-57.
Pharmacokinetics of acyclovir in the term human pregnancy and neonate Lisa M. Frenkel, MD,. Zane A. Brown, MD,b YvonneJ. Bryson, MD,. Lawrence Corey, MD; Jashvant D. Unadkat, PhD,d Paul A. Hensleigh, MD, PhD,. Ann M. Arvin, MD,' Charles G. Prober, MD,' and James D. Connor, MDg Los Angeles, Stanford, and San Diego, California, and Seattle, Washington Concern about neonatal herpes often leads to cesarean delivery of infants in women with a history of genital herpes. The antiviral drug acyclovir has been used effectively to suppress genital herpes simplex virus recurrences in nonpregnant adults. Its administration to pregnant women with recurrent genital herpes may reduce herpes simplex virus recurrences and thus may decrease the cesarean section rate among this population. To study the pharmacokinetics, safety, and patient tolerance of suppressive oral acyclovir, either 200 mg (n = 7) or 400 mg (n = 8) was administered orally every 8 hours to pregnant women with a history of recurrent herpes simplex virus, from 38 weeks' gestation until delivery. The mean ± SO plasma levels for the 200 and 400 mg groups, respectively, were: first dose peak, 1.7 ± 0.6 and 2.3 ± 1.0 /Lmol/L; steady-state trough, 0.7 ± 0.3 and 0.8 ± 0.6 /Lmol/L; steady-state peak, 1.9 ± 1.0 and 3.3 ± 1.0 /Lmol/L. In late gestation maternal acyclovir pharmacokinetics were similar to those of nonpregnant adults from other studies. Acyclovir was concentrated in the amniotic fluid; however, there was no accumUlation in the fetus (mean maternal/infant plasma ratio at delivery was 1.3). Acyclovir was well tolerated, and no toxicity was seen in the mothers or infants. The administration of acyclovir, 400 mg every 8 hours, appears appropriate for use in an efficacy and safety study regarding ,suppression of herpes simplex virus recurrences during the last weeks of pregnancy. (AM J OSSTET GYNECOL 1991 ;164:569-76.)
Key words: Genital herpes in pregnancy, acyclovir pharmacokinetics From the Division of Infectious Diseases, Department of Pediatrics, University of California at Los Angele Center for Health Sciences: the Departments of Obstetrics and Gynecology,' Medical Virology,' and Pharmaceutics," University of Washington at Seattle, the Department of Obstetrics and Gynecology' and the Division of Infectious Diseases, Department of Pediatrics,! Stanford University, and the Division of Infectious Diseases, Department of Pediatrics, University of California at San Diego. g
Received for publication March 27, 1990; revised August 3, 1990; accepted August 31, 1990. Reprint requests: Lisa M. Frenkel, MD, Assistant Professor of Pediatrics in Residence, UCLA Center for Health Sciences, 10833 LeConte Avenue, Room 22-442 MDCC, Los Angeles, CA 900241752.
611/25065
569
570
Frenkel et al.
February 1991 Am J Obstet Gynecol
Table I. Demographic characteristics of mother and newborn Acyclovir 200 mg t.i.d. Patient No.1
Age Weight No. of days of acyclovir No. of recurrences, this pregnancy Labor and delivery complications Delivery route Apgar score (I and 5 min) Sex Weight (gm) Newborn complications Normal at 6 mo
Patient No.7
29 65
30 82
38 72
29 62
30 70
29 84
36 89
10
7
6
11
15
10
16
10
2
5
8
3
3
Yes* Vag.
9/9
M 3263 No Yes
Not Vag.
9/9
F 3575 No Yes
Yes:j: Vag.
9/9
F 3234 Yestt Yes
No Vag. 9110 M 3405 No Yes
No Vag.
8/8
M 3459 No Yes
Yes§ CIS
8/9
M 3902 No Yes
Yesll
CIS
8/9 F 3602 No Yes
The demographic characteristics of the mothers and infants include a mean maternal age of 31.7 years and mean weight of 74 kg. Several minor complications occurred during labor and delivery. *Retained placenta with postpartum bleeding. t Meconium staining of amniotic fluid. :j: Approximately 10% abruptio placentae. § Cephalopelvic disproportion. II Failure of labor to progress. ~Umbilical cord prolapse. #HSV. ** Breech presentation. tt Delayed closure of ductus arteriosus.
Although neonatal herpes simplex virus (HSV) infections are not routinely reported to public health officials, studies from the state of Washington showed an increase in the incidence of neonatal herpes from 2.6 per 100,000 in 1969 to 11.9 per 100,000 in 1981 1 and to 15.4 per 100,000 from 1982 to 1985.2 This increase probably occurred as the result of an increased prevalence of genital HSV infection in the population of childbearing age, as suggested by a nationwide 7.5-fold increase in private physician consultations for genital herpes from 1966 to 1981' and a similar increase in the incidence of genital herpes found in Rochester, Minnesota from 1965 to 1979'A cesarean section rate in excess of 50% has been reported for patients entering pregnancy with a history of symptomatic recurrent genital herpes, and is attributed in part to reactivation of HSV within 1 week of the onset of labor.' A substantial proportion (25%) of these cesarean sections has been assessed to be unnecessary6 and to represent unwarranted risks, morbidity, and cost. In addition to the number of unnecessary cesarean deliveries, it is also disconcerting that cesarean section, even when performed before rupture of membranes, may not prevent transmission of HSV from the maternal birth canal to the infant. 7 Acyclovir (Zovirax; Burroughs Wellcome, Research
Triangle Park, N.C.), an antiviral agent, is activated selectively in HSV-infected cells and has been found to be safe and effective in the treatment of HSV infections, as well' as in suppression of HSV recurrences in nonpregnant adults. B. l5 Acyclovir, taken orally in late pregnancy to supress reactivation of HSV, could reduce the high rate of cesarean section and the risk of HSV transmission to the infants of women with recurrent HSV infection. The appropriate dose and safety of acyclovir for use in human pregnancy have not been established. We studied the pharmacokinetics and safety of oral acyclovir in a group of pregnant women with recurrent genital HSV. Study deSign and methods
Subjects were enrolled into this study at three medical centers: UCLA Medical Center in Los Angeles, the University of Washington in Seattle, and Stanford U niversity Medical Center in Stanford, Calif. The protocol was approved by each institution's human subjects protection committee. After giving informed consent, subjects were given a screening interview and a physical examination. Only subjects with previous culturedocumented genital HSV type 2 infection and a history of active recurrent genital lesions antedating and during pregnancy were included. Women with high-risk
Acyclovir pharmacokinetics in the human pregnancy
Volume 164 l\umber 2
571
Acyclovir 400 mg t.i.d. Patient No.1
Patient No.2
Patient No.4
Patient No.5
Patient No.6
Patient No.7
Patient No.8
33 69
30 81
27 65
37 60
28 88
32 65
37 76
39 84
29
3
6
22
14
15
8
11
4
2
3
3
4
5
Yes§ CIS
No
C/S#
8/9
9/9
F
M
4404 No
Yes
Patient No.3
3432 No
Yes
No Vag.
Yes~
CIS
No Vag.
8/9
9/9
F
8/9
M
M
3253 No
Yes
4146 No
Yes
pregnancies or active genital herpes lesions at the time of enrollment were excluded. Normal test results for complete blood count and differential cell count, serum creatinine, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, bilirubin, and urinalysis were required for enrollment. Acyclovir was administered to 14 healthy women, beginning at 38 weeks' gestation until delivery, during 15 pregnancies. The first seven enrollees were given acyclovir at the dose recommended in the package insert for initiation of suppressive therapy (200 mg orally, every 8 hours). Because acyclovir is erratically absorbed and because 200 mg acyclovir is not universally effective in suppressing clinical genital herpes, a subsequent group of eight subjects was studied at a dose of 400 mg administered every 8 hours. After the first dose of acyclovir, plasma of the patients was obtained to determine the peak value. Subjects were seen biweekly during the study period for cervical and vulvar HSV cultures and steady-state peak and trough acyclovir levels. In early labor the vulva and cervix were inspected and cultured for HSV. At delivery, maternal and cord blood were collected for determination of acyclovir concentrations, hematologic results, and blood chemistry values. In selected cases amniotic fluid, gastric aspirates of the infant, colostrum, and placental tissue were obtained for determination of acyclovir levels. The nasopharynx and rectum of the infants were cultured for HSV at birth and between 48 and 72 hours of life. If a fetal monitor was used, the site was also cultured. Maternal and infant blood samples were obtained in heparinized tubes at 1.5, 3, 6, 9, 12, 24, and 48 hours post partum for acyclovir determination of plasma levels. Acyclovir concentrations were determined by radioimmunoassay,16 in the laboratory of James Connor, MD, at the University of California, San Diego. In addition to routine
3720 No
Yes
No
C/S**
No Vag.
8/9
8/9
M
F
3600 No
Yes
3540 No
Yes
Yes§ CIS
9/9 F
4090 No
Yes
postpartum care, the well-being of the mothers and children at 6 months post partum was determined by physical examination and by telephone interviews with the patients or with their health care providers. Results
Clinical and laboratory parameters of mothers and newborns (Table I). The mothers enrolled in our study were from 27 to 39 (mean, 31.7) years old, mostly (13/14) white, gravida 1 to 4 (mean, 2.1), para 0 to 1 (mean, 0.2), and had had recognized genital herpes for 1 to 10 years (mean, 4.4). During the pregnancies studied, these women had one to 10 (mean, 3.7) HSV recurrences. The acyclovir courses ranged between 3 and 29 (mean, 13.7) days' duration. Acyclovir was well tolerated by the mothers; there were no complaints of nausea, vomiting, headache, or other symptoms, and in all cases the complete blood count with differential cell count, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, and urinalysis (including no crystaluria) were normal on days 1, 6, and 11 or the last day of therapy). At birth, all infants appeared normal and were given Apgar scores 2!:8. The cord blood and newborn complete blood count with differential cell count, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, and urinalysis values were normal. Except for a delay in the closure of the ductus arteriosus of one infant, there were no postnatal complications, and at 6 months of age all infants were reportedly normal. Viral cultures and recurrences of genital HSV. No symptomatic HSV recurrences or asymptomatic viral shedding was noted in14 of the 15 pregnancies monitored during the study period. One woman (patient 2, who was taking 400 mg of acyclovir) entered the study
572
Frenkel et al.
February 1991 Am J Obstet Gyneco1
Table II. Peripartum acyclovir levels Acyclovir 200 mg t.i.d. Patient No.1
No. of days of acyclovir Maternal plasma at delivery (/LmoI!L) Cord plasma (/LmoI!L) Maternal! cord plasma Amniotic fluid (/LmoI!L) Gastric aspirate (/LmoI!L) Placenta (/LmoI!L) Breast milk (/LmoI!L)
Patient No.7
11
7
6
1.09
1.70
0.65
0.76
0.80
3.51
1.09
1.08 1. 90
1.23 1.38
0.59 1.l0
0.46 1.60
0.67 1.19
2.23 1.57
1.02 1.07
3.42
1.87
6.06
4.00 6.19
4.37 1.34
5.31 1.08
10
1.31
15
10
16
Peripartum acyclovir levels for all subjects are shown (l /Lmol! L = 0.225 /Lg1 ml). Maternal acyclovir levels at time of birth were greater than those of infants (except for subject 6 of the 400 mg group), even though amniotic fluid levels were concentrated by a factor of 3 to 6. Breast milk samples were collected 4(a), 3(b), and 5(c) days after last acyclovir dose.
with a recently healed perianal HSV lesion. Culture on day 1 was negative for HSV. On the day after initiation of acyclovir (day 2), after two doses, HSV antigen was detected by an enzyme-linked immunosorbent assay on a specimen obtained from the site of the healed lesion. Labor began the next day, and the infant was delivered by cesarean section before rupture of membranes. Subsequently, a culture obtained on day 2 from the healed lesion site became positive for HSV. All cultures from this infant were negative for HSV, as were all the cultures from the other infants. Acyclovir pharmacokinetics. Plasma acyclovir concentrations obtained after the first doses are shown in Fig. 1, A. The peak acyclovir plasma levels occurred between 1V2 and 3 hours after the dose was administered. The mean ± SD acyclovir plasma levels at 1V2 hours for the 200 and 400 mg dose groups were 1.7 ± 0.6 and 2.3 ± 1.0 fLmol!L, respectively. One subject in the 200 mg dose group appeared to absorb acyclovir unusually well. In this patient acyclovir levels were evaluated by a statistical technique that tests extreme observations in a sample. 17 Her 1.5-hour value rose above the 95th percentile of the sampling distribution and therefore was excluded from the data analysis. The mean acyclovir plasma levels for the 200 and 400 mg doses, respectively, were 1.4 ± 1.3 and 2.4 ± 0.9, at 3 hours after the dose and 0.5 ± 0.1 and 1.0 ± 0.5 fLmol!L at 6 hours after the dose. Plasma acyclovir trough and peak concentrations obtained on days 6 and 11 were similar and are shown in a combined fashion in Fig. 1, B. The mean and SD plasma trough values of acyclovir in the 200 and 400 mg dose groups were 0.7 ± 0.3 and 0.8 ± 0.6 fLmol!L, respectively. One subject in the 400 mg group
took the drug three times daily instead of every 8 hours. This was reflected in high trough levels, which were determined 3 and 4 hours aftrer the previous dose. These values were excluded from the mean and SD calculation. During steady state, the 400 mg dose group's mean peak level (3.3 ± 1.0 fLmol!L) was increased, as compared with the first-dose mean peak level (2.3 ± 1.1 fLmoIlL), whereas the suggestion of acyclovir accumulation was not seen during steady state in the 200 mg dose group with a steady-state mean acyclovir peak of 1.9 ± 1.0 fLmol!L and a mean firstdose peak of 1.7 ± 0.6 fLmol!L. The peridelivery acyclovir levels are shown in Table II. The cord plasma acyclovir levels were less than the maternal acyclovir plasma levels that were obtained at the same time in all but one maternal-infant pair. In this latter case the mother's plasma acyclovir level of 0.7 fLmol!L was low and was not significantly different from her infant's level of 0.8 fLmol!L. The mean ratio of the maternal! cord acyclovir plasma levels was 1.3 ± 0.3. Acyclovir concentrations in the amniotic fluid (1.87 to 15.5 fLmoIlL, n = 6) were found to be three to six times higher than the corresponding cord plasma levels. Not surprisingly, gastric aspirates from the newborns (n = 3) had acyclovir levels similar to those of the amniotic fluid. At 3 to 5 days after the last dose of acyclovir was administered, low concentrations of the drug (n = 2) were detectable in breast milk. Also urine of the newborns that was collected between 12 hours and 3 days after the last dose of acyclovir had acyclovir levels between 7 and 140 fLmollL (data not shown). The maternal plasma acyclovir levels obtained immediately before to 2 days after the last dose of acyclovir are shown in Fig. 2, together with the newborn
Acyclovir pharmacokinetics in the human pregnancy
Volume 164 Number 2
573
Acyclovir 400 mg t.i.d. Patient No.1
29
3.36
Patient No.2
3
0.84
Patient No.3
6
2.82 4.20
0.21" 0.22'
Patient No.4
22
Patient No.5
14
Patient No.6
15
Patient No.7
8
Patient No.8
11
4.10
0.50
0.67
1.70
2.20
2.90 1.41
0.00
0.81 0.83
1.50 1.13
1.90 1.16
11.4
00
15.5
0.09 b
levels obtained from birth to 2 days after the last maternal dose of acyclovir. The values are plotted from the time since the last dose of acyclovir, not in relation to the time of parturition. The mean maternal (solid line) and newborn (dashed line) acyclovir plasma values are shown. The mean maternal acyclovir plasma level is higher than that obtained from the newborn shortly after the last dose of acyclovir. However, the maternal mean acyclovir level dropped more rapidly that that of the newborn, although maternal and infant levels were similarly low by 16 to 48 hours after the last dose of acyclovir.
Comment This study shows that acyclovir, taken orally at doses of 600 to 1200 mg/day for 3 to 29 days, was well tolerated by women late in pregnancy and did not accumulate or cause adverse effects in their newborn infants. Pharmacokinetic values of acyclovir in the pregnant women studied were similar to values of nonpregnant adults, although these comparisons are made among a limited number of subjects. First-dose oral acyclovir peak values are not published for the 200 mg oral dose in nonpregnant humans; however, M.R. Blum, PhD, of Burroughs Wellcome, provided computer-simulated values for our dosage regimens from data compiled from trials conducted among nonpregnant subjects. The Burroughs Wellcome computer-projected plasma peak for a healthy adult who ingests 200 mg of acyclovir is 1.7 /-LmoIlL, which is identical to our mean value of 1.7 ± 0.6 /-LmollL. A first-dose mean acyclovir plasma peak in nonpregnant, healthy subjects who took 400 mg for a study of acyclovir suppression of recurrent genital herpes l5 was similar to that of our pregnant women and to the Burroughs Wellcome computed value (2.3 ± 0.4 vs 2.3 ± l.0 vs 2.6, respectively). The pregnant women's steady-
state acyclovir levels for the dose of 200 mg every 8 hours compared favorably with levels of nonpregnant adults l5 and with the Burroughs Wellcome computergenerated values (mean plasma trough levels of 0.7 ± 0.3 vs 0.7 ± 0.1 vs 0.4 /-LmollL and peak levels of l.9 ± l.0 vs 2.0 ± 0.2 vs 2.0 /-LmoIlL, respectively). No steady-state acyclovir values for 400 mg taken every 8 hours by nonpregnant humans have been published; however, our pregnant women's values were similar to the Burroughs Wellcome computed values with mean plasma trough values of 0.8 ± 0.6 versus 0.6 /-LmollL and peak values of 3.3 ± 1.0 versus 3.0 /-LmoIlL, respectively. The large standard deviations observed were not unexpected because acyclovir has a low bioavailability and is variably absorbed. IS The increased blood volume of pregnant women and hence the theoretical volume of distribution of acyclovir, coupled with an increased cardiac output and concomitant renal blood flow in late gestation, suggest that acyclovir levels may be less in pregnancy than in the nonpregnant state. Surprisingly, this was not observed among our population. Acyclovir is excreted by glomerular filtration and tubular secretion. 18 The excretion of acyclovir by the pregnant women studied appeared normal and was demonstrated both by trough values similar to those of nonpregnant humans with normal renal function l5 and by the similarity in the day 6 and day II trough acyclovir values. Acyclovir was concentrated in the amniotic fluid, presumably by excretion of acyclovir in the fetal urine. Approximately 85% to 95% of acyclovir is excreted unchanged in the urine. 19 The high levels of acyclovir in the amniotic fluid may provide a pharmacologic barrier for ascending or transamniotic membrane HSV infection. No accumulation of acyclovir was observed in the fetuses of the pregnant women studied. This is
574
Frenkel et al.
February 1991 Am J Obstet Gynecol
3.0
1.5
6.0
4.5
7.5
Hours Post Dose 0 0
4.0 .....
0
0 ~
3.0
::l...
(f)
Q)
2.0
B
•
0*
0* 0
>
" " "
Q)
---.J
> u
Volume 164 Number 2
idiopathic forms of the nephrotic syndrome, or a secondary type associated with a systemic disease such as systemic lupus erythematosus, diabetes mellitus, or preeclampsia. The history in this patient provided the key to the diagnosis. Because she was seen in early pregnancy without hypertension made preeclampsia unlikely, and there were no findings to suggest either diabetes or systemic lupus erythematosus. She had a clear history of steroid-responsive nephrotic syndrome beginning in childhood, typical of minimal-change nephropathy. Her history of explosive onset of severe nephrotic syndrome is also characteristic of this disorder. Acute renal failure is not typically associated with minimal-change nephropathy; however, this complication has been well described, particularly in adults with this disease. Although the diagnosis of this disease can be established with certainty only by renal biopsy, it was believed that the presentation was so typical of this disease that a
therapeutic trial of corticosteroids was the safest approach. Rapid response to treatment with complete resolution of nephrotic syndrome and renal failure supported the diagnosis. If there had been no response to therapy, then a renal biopsy to exclude other disorders would have been appropriate. This patient who was seen with renal failure in early pregnancy illustrates the importance of a systematic approach to this problem. By making a presumptive diagnosis of nephrotic syndrome as a result of minimalchange disease on the basis of her clinical presentation, therapy with prednisone led to an uneventful pregnancy with successful delivery.
REFERENCES 1. Studd JWW, Blainey JD. Pregnancy and the nephrotic syndrome. Br Med J elin Res 1969; 1:276-80. 2. Krane NK. Acute renal failure in pregnancy. Arch Intern Med 1988;148:2347-57.
Pharmacokinetics of acyclovir in the term human pregnancy and neonate Lisa M. Frenkel, MD,. Zane A. Brown, MD,b YvonneJ. Bryson, MD,. Lawrence Corey, MD; Jashvant D. Unadkat, PhD,d Paul A. Hensleigh, MD, PhD,. Ann M. Arvin, MD,' Charles G. Prober, MD,' and James D. Connor, MDg Los Angeles, Stanford, and San Diego, California, and Seattle, Washington Concern about neonatal herpes often leads to cesarean delivery of infants in women with a history of genital herpes. The antiviral drug acyclovir has been used effectively to suppress genital herpes simplex virus recurrences in nonpregnant adults. Its administration to pregnant women with recurrent genital herpes may reduce herpes simplex virus recurrences and thus may decrease the cesarean section rate among this population. To study the pharmacokinetics, safety, and patient tolerance of suppressive oral acyclovir, either 200 mg (n = 7) or 400 mg (n = 8) was administered orally every 8 hours to pregnant women with a history of recurrent herpes simplex virus, from 38 weeks' gestation until delivery. The mean ± SO plasma levels for the 200 and 400 mg groups, respectively, were: first dose peak, 1.7 ± 0.6 and 2.3 ± 1.0 /Lmol/L; steady-state trough, 0.7 ± 0.3 and 0.8 ± 0.6 /Lmol/L; steady-state peak, 1.9 ± 1.0 and 3.3 ± 1.0 /Lmol/L. In late gestation maternal acyclovir pharmacokinetics were similar to those of nonpregnant adults from other studies. Acyclovir was concentrated in the amniotic fluid; however, there was no accumUlation in the fetus (mean maternal/infant plasma ratio at delivery was 1.3). Acyclovir was well tolerated, and no toxicity was seen in the mothers or infants. The administration of acyclovir, 400 mg every 8 hours, appears appropriate for use in an efficacy and safety study regarding ,suppression of herpes simplex virus recurrences during the last weeks of pregnancy. (AM J OSSTET GYNECOL 1991 ;164:569-76.)
Key words: Genital herpes in pregnancy, acyclovir pharmacokinetics From the Division of Infectious Diseases, Department of Pediatrics, University of California at Los Angele Center for Health Sciences: the Departments of Obstetrics and Gynecology,' Medical Virology,' and Pharmaceutics," University of Washington at Seattle, the Department of Obstetrics and Gynecology' and the Division of Infectious Diseases, Department of Pediatrics,! Stanford University, and the Division of Infectious Diseases, Department of Pediatrics, University of California at San Diego. g
Received for publication March 27, 1990; revised August 3, 1990; accepted August 31, 1990. Reprint requests: Lisa M. Frenkel, MD, Assistant Professor of Pediatrics in Residence, UCLA Center for Health Sciences, 10833 LeConte Avenue, Room 22-442 MDCC, Los Angeles, CA 900241752.
611/25065
569
570
Frenkel et al.
February 1991 Am J Obstet Gynecol
Table I. Demographic characteristics of mother and newborn Acyclovir 200 mg t.i.d. Patient No.1
Age Weight No. of days of acyclovir No. of recurrences, this pregnancy Labor and delivery complications Delivery route Apgar score (I and 5 min) Sex Weight (gm) Newborn complications Normal at 6 mo
Patient No.7
29 65
30 82
38 72
29 62
30 70
29 84
36 89
10
7
6
11
15
10
16
10
2
5
8
3
3
Yes* Vag.
9/9
M 3263 No Yes
Not Vag.
9/9
F 3575 No Yes
Yes:j: Vag.
9/9
F 3234 Yestt Yes
No Vag. 9110 M 3405 No Yes
No Vag.
8/8
M 3459 No Yes
Yes§ CIS
8/9
M 3902 No Yes
Yesll
CIS
8/9 F 3602 No Yes
The demographic characteristics of the mothers and infants include a mean maternal age of 31.7 years and mean weight of 74 kg. Several minor complications occurred during labor and delivery. *Retained placenta with postpartum bleeding. t Meconium staining of amniotic fluid. :j: Approximately 10% abruptio placentae. § Cephalopelvic disproportion. II Failure of labor to progress. ~Umbilical cord prolapse. #HSV. ** Breech presentation. tt Delayed closure of ductus arteriosus.
Although neonatal herpes simplex virus (HSV) infections are not routinely reported to public health officials, studies from the state of Washington showed an increase in the incidence of neonatal herpes from 2.6 per 100,000 in 1969 to 11.9 per 100,000 in 1981 1 and to 15.4 per 100,000 from 1982 to 1985.2 This increase probably occurred as the result of an increased prevalence of genital HSV infection in the population of childbearing age, as suggested by a nationwide 7.5-fold increase in private physician consultations for genital herpes from 1966 to 1981' and a similar increase in the incidence of genital herpes found in Rochester, Minnesota from 1965 to 1979'A cesarean section rate in excess of 50% has been reported for patients entering pregnancy with a history of symptomatic recurrent genital herpes, and is attributed in part to reactivation of HSV within 1 week of the onset of labor.' A substantial proportion (25%) of these cesarean sections has been assessed to be unnecessary6 and to represent unwarranted risks, morbidity, and cost. In addition to the number of unnecessary cesarean deliveries, it is also disconcerting that cesarean section, even when performed before rupture of membranes, may not prevent transmission of HSV from the maternal birth canal to the infant. 7 Acyclovir (Zovirax; Burroughs Wellcome, Research
Triangle Park, N.C.), an antiviral agent, is activated selectively in HSV-infected cells and has been found to be safe and effective in the treatment of HSV infections, as well' as in suppression of HSV recurrences in nonpregnant adults. B. l5 Acyclovir, taken orally in late pregnancy to supress reactivation of HSV, could reduce the high rate of cesarean section and the risk of HSV transmission to the infants of women with recurrent HSV infection. The appropriate dose and safety of acyclovir for use in human pregnancy have not been established. We studied the pharmacokinetics and safety of oral acyclovir in a group of pregnant women with recurrent genital HSV. Study deSign and methods
Subjects were enrolled into this study at three medical centers: UCLA Medical Center in Los Angeles, the University of Washington in Seattle, and Stanford U niversity Medical Center in Stanford, Calif. The protocol was approved by each institution's human subjects protection committee. After giving informed consent, subjects were given a screening interview and a physical examination. Only subjects with previous culturedocumented genital HSV type 2 infection and a history of active recurrent genital lesions antedating and during pregnancy were included. Women with high-risk
Acyclovir pharmacokinetics in the human pregnancy
Volume 164 l\umber 2
571
Acyclovir 400 mg t.i.d. Patient No.1
Patient No.2
Patient No.4
Patient No.5
Patient No.6
Patient No.7
Patient No.8
33 69
30 81
27 65
37 60
28 88
32 65
37 76
39 84
29
3
6
22
14
15
8
11
4
2
3
3
4
5
Yes§ CIS
No
C/S#
8/9
9/9
F
M
4404 No
Yes
Patient No.3
3432 No
Yes
No Vag.
Yes~
CIS
No Vag.
8/9
9/9
F
8/9
M
M
3253 No
Yes
4146 No
Yes
pregnancies or active genital herpes lesions at the time of enrollment were excluded. Normal test results for complete blood count and differential cell count, serum creatinine, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, bilirubin, and urinalysis were required for enrollment. Acyclovir was administered to 14 healthy women, beginning at 38 weeks' gestation until delivery, during 15 pregnancies. The first seven enrollees were given acyclovir at the dose recommended in the package insert for initiation of suppressive therapy (200 mg orally, every 8 hours). Because acyclovir is erratically absorbed and because 200 mg acyclovir is not universally effective in suppressing clinical genital herpes, a subsequent group of eight subjects was studied at a dose of 400 mg administered every 8 hours. After the first dose of acyclovir, plasma of the patients was obtained to determine the peak value. Subjects were seen biweekly during the study period for cervical and vulvar HSV cultures and steady-state peak and trough acyclovir levels. In early labor the vulva and cervix were inspected and cultured for HSV. At delivery, maternal and cord blood were collected for determination of acyclovir concentrations, hematologic results, and blood chemistry values. In selected cases amniotic fluid, gastric aspirates of the infant, colostrum, and placental tissue were obtained for determination of acyclovir levels. The nasopharynx and rectum of the infants were cultured for HSV at birth and between 48 and 72 hours of life. If a fetal monitor was used, the site was also cultured. Maternal and infant blood samples were obtained in heparinized tubes at 1.5, 3, 6, 9, 12, 24, and 48 hours post partum for acyclovir determination of plasma levels. Acyclovir concentrations were determined by radioimmunoassay,16 in the laboratory of James Connor, MD, at the University of California, San Diego. In addition to routine
3720 No
Yes
No
C/S**
No Vag.
8/9
8/9
M
F
3600 No
Yes
3540 No
Yes
Yes§ CIS
9/9 F
4090 No
Yes
postpartum care, the well-being of the mothers and children at 6 months post partum was determined by physical examination and by telephone interviews with the patients or with their health care providers. Results
Clinical and laboratory parameters of mothers and newborns (Table I). The mothers enrolled in our study were from 27 to 39 (mean, 31.7) years old, mostly (13/14) white, gravida 1 to 4 (mean, 2.1), para 0 to 1 (mean, 0.2), and had had recognized genital herpes for 1 to 10 years (mean, 4.4). During the pregnancies studied, these women had one to 10 (mean, 3.7) HSV recurrences. The acyclovir courses ranged between 3 and 29 (mean, 13.7) days' duration. Acyclovir was well tolerated by the mothers; there were no complaints of nausea, vomiting, headache, or other symptoms, and in all cases the complete blood count with differential cell count, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, and urinalysis (including no crystaluria) were normal on days 1, 6, and 11 or the last day of therapy). At birth, all infants appeared normal and were given Apgar scores 2!:8. The cord blood and newborn complete blood count with differential cell count, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, and urinalysis values were normal. Except for a delay in the closure of the ductus arteriosus of one infant, there were no postnatal complications, and at 6 months of age all infants were reportedly normal. Viral cultures and recurrences of genital HSV. No symptomatic HSV recurrences or asymptomatic viral shedding was noted in14 of the 15 pregnancies monitored during the study period. One woman (patient 2, who was taking 400 mg of acyclovir) entered the study
572
Frenkel et al.
February 1991 Am J Obstet Gyneco1
Table II. Peripartum acyclovir levels Acyclovir 200 mg t.i.d. Patient No.1
No. of days of acyclovir Maternal plasma at delivery (/LmoI!L) Cord plasma (/LmoI!L) Maternal! cord plasma Amniotic fluid (/LmoI!L) Gastric aspirate (/LmoI!L) Placenta (/LmoI!L) Breast milk (/LmoI!L)
Patient No.7
11
7
6
1.09
1.70
0.65
0.76
0.80
3.51
1.09
1.08 1. 90
1.23 1.38
0.59 1.l0
0.46 1.60
0.67 1.19
2.23 1.57
1.02 1.07
3.42
1.87
6.06
4.00 6.19
4.37 1.34
5.31 1.08
10
1.31
15
10
16
Peripartum acyclovir levels for all subjects are shown (l /Lmol! L = 0.225 /Lg1 ml). Maternal acyclovir levels at time of birth were greater than those of infants (except for subject 6 of the 400 mg group), even though amniotic fluid levels were concentrated by a factor of 3 to 6. Breast milk samples were collected 4(a), 3(b), and 5(c) days after last acyclovir dose.
with a recently healed perianal HSV lesion. Culture on day 1 was negative for HSV. On the day after initiation of acyclovir (day 2), after two doses, HSV antigen was detected by an enzyme-linked immunosorbent assay on a specimen obtained from the site of the healed lesion. Labor began the next day, and the infant was delivered by cesarean section before rupture of membranes. Subsequently, a culture obtained on day 2 from the healed lesion site became positive for HSV. All cultures from this infant were negative for HSV, as were all the cultures from the other infants. Acyclovir pharmacokinetics. Plasma acyclovir concentrations obtained after the first doses are shown in Fig. 1, A. The peak acyclovir plasma levels occurred between 1V2 and 3 hours after the dose was administered. The mean ± SD acyclovir plasma levels at 1V2 hours for the 200 and 400 mg dose groups were 1.7 ± 0.6 and 2.3 ± 1.0 fLmol!L, respectively. One subject in the 200 mg dose group appeared to absorb acyclovir unusually well. In this patient acyclovir levels were evaluated by a statistical technique that tests extreme observations in a sample. 17 Her 1.5-hour value rose above the 95th percentile of the sampling distribution and therefore was excluded from the data analysis. The mean acyclovir plasma levels for the 200 and 400 mg doses, respectively, were 1.4 ± 1.3 and 2.4 ± 0.9, at 3 hours after the dose and 0.5 ± 0.1 and 1.0 ± 0.5 fLmol!L at 6 hours after the dose. Plasma acyclovir trough and peak concentrations obtained on days 6 and 11 were similar and are shown in a combined fashion in Fig. 1, B. The mean and SD plasma trough values of acyclovir in the 200 and 400 mg dose groups were 0.7 ± 0.3 and 0.8 ± 0.6 fLmol!L, respectively. One subject in the 400 mg group
took the drug three times daily instead of every 8 hours. This was reflected in high trough levels, which were determined 3 and 4 hours aftrer the previous dose. These values were excluded from the mean and SD calculation. During steady state, the 400 mg dose group's mean peak level (3.3 ± 1.0 fLmol!L) was increased, as compared with the first-dose mean peak level (2.3 ± 1.1 fLmoIlL), whereas the suggestion of acyclovir accumulation was not seen during steady state in the 200 mg dose group with a steady-state mean acyclovir peak of 1.9 ± 1.0 fLmol!L and a mean firstdose peak of 1.7 ± 0.6 fLmol!L. The peridelivery acyclovir levels are shown in Table II. The cord plasma acyclovir levels were less than the maternal acyclovir plasma levels that were obtained at the same time in all but one maternal-infant pair. In this latter case the mother's plasma acyclovir level of 0.7 fLmol!L was low and was not significantly different from her infant's level of 0.8 fLmol!L. The mean ratio of the maternal! cord acyclovir plasma levels was 1.3 ± 0.3. Acyclovir concentrations in the amniotic fluid (1.87 to 15.5 fLmoIlL, n = 6) were found to be three to six times higher than the corresponding cord plasma levels. Not surprisingly, gastric aspirates from the newborns (n = 3) had acyclovir levels similar to those of the amniotic fluid. At 3 to 5 days after the last dose of acyclovir was administered, low concentrations of the drug (n = 2) were detectable in breast milk. Also urine of the newborns that was collected between 12 hours and 3 days after the last dose of acyclovir had acyclovir levels between 7 and 140 fLmollL (data not shown). The maternal plasma acyclovir levels obtained immediately before to 2 days after the last dose of acyclovir are shown in Fig. 2, together with the newborn
Acyclovir pharmacokinetics in the human pregnancy
Volume 164 Number 2
573
Acyclovir 400 mg t.i.d. Patient No.1
29
3.36
Patient No.2
3
0.84
Patient No.3
6
2.82 4.20
0.21" 0.22'
Patient No.4
22
Patient No.5
14
Patient No.6
15
Patient No.7
8
Patient No.8
11
4.10
0.50
0.67
1.70
2.20
2.90 1.41
0.00
0.81 0.83
1.50 1.13
1.90 1.16
11.4
00
15.5
0.09 b
levels obtained from birth to 2 days after the last maternal dose of acyclovir. The values are plotted from the time since the last dose of acyclovir, not in relation to the time of parturition. The mean maternal (solid line) and newborn (dashed line) acyclovir plasma values are shown. The mean maternal acyclovir plasma level is higher than that obtained from the newborn shortly after the last dose of acyclovir. However, the maternal mean acyclovir level dropped more rapidly that that of the newborn, although maternal and infant levels were similarly low by 16 to 48 hours after the last dose of acyclovir.
Comment This study shows that acyclovir, taken orally at doses of 600 to 1200 mg/day for 3 to 29 days, was well tolerated by women late in pregnancy and did not accumulate or cause adverse effects in their newborn infants. Pharmacokinetic values of acyclovir in the pregnant women studied were similar to values of nonpregnant adults, although these comparisons are made among a limited number of subjects. First-dose oral acyclovir peak values are not published for the 200 mg oral dose in nonpregnant humans; however, M.R. Blum, PhD, of Burroughs Wellcome, provided computer-simulated values for our dosage regimens from data compiled from trials conducted among nonpregnant subjects. The Burroughs Wellcome computer-projected plasma peak for a healthy adult who ingests 200 mg of acyclovir is 1.7 /-LmoIlL, which is identical to our mean value of 1.7 ± 0.6 /-LmollL. A first-dose mean acyclovir plasma peak in nonpregnant, healthy subjects who took 400 mg for a study of acyclovir suppression of recurrent genital herpes l5 was similar to that of our pregnant women and to the Burroughs Wellcome computed value (2.3 ± 0.4 vs 2.3 ± l.0 vs 2.6, respectively). The pregnant women's steady-
state acyclovir levels for the dose of 200 mg every 8 hours compared favorably with levels of nonpregnant adults l5 and with the Burroughs Wellcome computergenerated values (mean plasma trough levels of 0.7 ± 0.3 vs 0.7 ± 0.1 vs 0.4 /-LmollL and peak levels of l.9 ± l.0 vs 2.0 ± 0.2 vs 2.0 /-LmoIlL, respectively). No steady-state acyclovir values for 400 mg taken every 8 hours by nonpregnant humans have been published; however, our pregnant women's values were similar to the Burroughs Wellcome computed values with mean plasma trough values of 0.8 ± 0.6 versus 0.6 /-LmollL and peak values of 3.3 ± 1.0 versus 3.0 /-LmoIlL, respectively. The large standard deviations observed were not unexpected because acyclovir has a low bioavailability and is variably absorbed. IS The increased blood volume of pregnant women and hence the theoretical volume of distribution of acyclovir, coupled with an increased cardiac output and concomitant renal blood flow in late gestation, suggest that acyclovir levels may be less in pregnancy than in the nonpregnant state. Surprisingly, this was not observed among our population. Acyclovir is excreted by glomerular filtration and tubular secretion. 18 The excretion of acyclovir by the pregnant women studied appeared normal and was demonstrated both by trough values similar to those of nonpregnant humans with normal renal function l5 and by the similarity in the day 6 and day II trough acyclovir values. Acyclovir was concentrated in the amniotic fluid, presumably by excretion of acyclovir in the fetal urine. Approximately 85% to 95% of acyclovir is excreted unchanged in the urine. 19 The high levels of acyclovir in the amniotic fluid may provide a pharmacologic barrier for ascending or transamniotic membrane HSV infection. No accumulation of acyclovir was observed in the fetuses of the pregnant women studied. This is
574
Frenkel et al.
February 1991 Am J Obstet Gynecol
3.0
1.5
6.0
4.5
7.5
Hours Post Dose 0 0
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