Cost-effectiveness of acyclovir prophylaxis for pregnant women with a history of genital HSV
1
169 INFLAMMATORY-MEDIATED MODEL OF CEREBRAL PALSY WITH DEVELOPMENTAL SEQUELAE SARAH POGGI 1 , JANE PARK 2 , LAURA TOSO 2 , HAIM EINAT 3 , ROBIN ROBERSON 2 , VERONICA DUNLAP 2 , JADE WOODARD 2 , DANIEL ABEBE 2 , CATHERINE SPONG 2 , 1 Georgetown University, Obstetrics and Gynecology, Washington, District of Columbia, 2 UPDN, NICHD, NIH, Bethesda, Maryland, 3 LMP, NIMH, NIH, Bethesda, Maryland OBJECTIVE: Cerebral palsy (CP) is a neurologic disorder characterized by lifelong impairments in motor function. There is increasing clinical evidence that CP may result from inflammatory and infection-mediated white matter damage. Animal models for CP have predominately used prenatal ischemia to reproduce the characteristic histological finding of periventricular leukomalacia (PVL) without phenotype evaluation. Our objective was to develop an inflammatory mediated animal model for CP based on chronic lipopolysaccharide (LPS) endotoxin exposure with a recognizable phenotype in exposed offspring. STUDY DESIGN: On gestational days 15, 17, and 19 (w20-28 wks human gestation), pregnant Fischer 344 rats were intracervically injected with 0.15 mg/ kg LPS or saline. Neonatal behavior tests for motor and cognitive developmen- tal milestones were performed on postnatal days 1-21 (LPS N = 25; control N = 26). 6 adults per group were tested at 8 weeks on open field for motor activity. Statistical analysis included Mann-Whitney U and ANOVA. RESULTS: LPS-exposed offspring were significantly delayed achieving motor developmental milestones: negative geotaxis (ability of rat to right itself on an inclined plane), with LPS achieving this milestone one day later than controls (day 7.5 G 1.8 vs. 6.8 G 1.8, P ! .001) and cliff aversion (ability to avoid falling by stepping backwards) with LPS achieving this on day 16.8 G 2.7 vs. day 13.0 G 2.3 (control) (P = ! .01). There was no difference between the two groups for weight, righting, rooting, forelimb grasp, audio startle, air righting,eye opening, and activity. There was a trend towards decreased median speed in LPS-exposed adultsin open field assessment (10.1 vs. 7.5 cm/s, P = .08). CONCLUSION: Using an animal model for CP that mimics a chronic intrauterine inflammation, we have demonstrated a phenotype that is relevant to the human CP manifestations. This model may allow improved understanding of pathogenesis as well as allow for testing of preventative therapies. 170 EXPERIMENTAL GENITAL MYCOPLASMOSIS DOES NOT INCREASE IL-1b, COX-1 OR COX-2 EXPRESSION IN FETAL BRAINS MORGAN PELTIER 1 , BRANDON BARNEY 1 , MARY BROWN 2 , 1 University of Utah, Obstetrics and Gynecology, Salt Lake City, Utah, 2 University of Florida, Department of Pathobiology, Gainesville, Florida OBJECTIVE: Intrauterine infection is one of the many suspected causes of cerebral palsy.The majority of intrauterine infections are associated with the genital mycoplasmas, Ureaplasma urealyticum and Mycoplasma hominis. Pre- vious studies by our group have shown that experimental genital mycoplasmosis in a well-defined rat model increases the production of proinflammatory cytokines in fetal brains. In other animal models where neural injury is induced by fetal ischemia, there is increased production of COX-2 and prostaglandins. How intrautuerine infection may alter cyclooxygenase levels in the fetal brain in vivo has not been widely studied. It is possible that IL-1b, a proinflammatory cytokine that can upregulate COX-2 is increased during intrauterine infection which could lead to altered production of prostaglandins. Therefore, we tested the hypothesis that experimental genital mycoplasmosis would alter mRNA levels of IL-1b, COX-1 and COX-2 in fetal brains. STUDY DESIGN: On gestational day (gd) 14, Sprague-Dawley rats were anesthetized and 10 7 CFU M pulmonis or an equivalent volume of sterile broth was injected into the heart. Rats were allowed to recover and were later necropsied at gd 18 or gd 21. Total RNA was purified from snap frozen tissues and mRNA for IL-1b, COX-1, COX-2 and 18S rRNA was determined by real- time RT-PCR using 2 ug total RNA and commercially available reagents. Data were analyzed by analysis of covariance using 18S rRNA expression as a covariate. RESULTS: Messenger RNA levels for IL-1b, COX-1 and COX-2 in fetal brains were similar between control animals and those infected with M pulmonis for rats necropsied at gd 18 and gd 21. CONCLUSION: Experimental genital mycoplasmosis does not alter the pro- duction of IL-1b, COX-1 and COX-2 production in fetal brains. This suggests that the pathophysiology of brain inflammation may differ between intrauterine ischemia and intrauterine infection. 171 COST-EFFECTIVENESS OF ACYCLOVIR PROPHYLAXIS FOR PREGNANT WOMEN WITH A HISTORY OF GENITAL HSV SARAH LITTLE 1 , AARON B. CAUGHEY 1 , 1 University of California, San Francisco, Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California OBJECTIVE: Previous literature has shown acyclovir to be cost-effective as prophylaxis for women with symptomatic HSV recurrence during pregnancy. We extend this analysis by adding quality-adjusted life year measurements and expanding the population to women with a history of HSV but without recurrence in pregnancy. STUDY DESIGN: A decision tree was designed to compare acyclovir pro- phylaxis to no treatment. Baseline assumptions include a prevalence of 5% for known genital HSV history among 4 million deliveries per year, prevalence of lesions at time of delivery of 1.1% for HSV-2 and 0.37% for HSV-1, and asymptomatic shedding at time of delivery of 0.55% for HSV-2 and 0.18% for HSV-1. We assumed acyclovir prophylaxis to be 75% effective at reducing lesion occurrence and 91% effective at reducing asymptomatic shedding. Sensitivity analysis included univariate and Monte Carlo simulations. RESULTS: 22,286 women need to be treated to prevent one neonatal death, 8,985 to prevent one affected child, and 177 to prevent one cesarean section. The Table shows the potential outcomes both with and without acyclovir for the 200,000 births next year to women with a known history of genital HSV. Acyclovir is the dominant strategy, as it is on average both cheaper ($12,055 vs. $12,102) and more effective (56.711 QALYs vs. 56.707). In univariate sensitivity analysis this dominance was robust to all reasonable probabilities and QALY estimates and with treatment costs up to 188% of our baseline estimate of $55. Monte Carlo simulation showed acyclovir to be cost-effective in 100% of 200,000 trials and cost-saving over 99% of the time. CONCLUSION: Acyclovir prophylaxis for pregnant women with a history of genital HSV is cost-effective over a wide range of assumptions. This conclusion is most sensitive to the price of acyclovir therapy. Outcomes for 200,000 pregnant women with a known history of HSV No acyclovir Acyclovir Cesarean sections 50,304.48 49,176.12 Neonatal deaths 9.1648 0.1906 Severely neurologically impaired children 7.45 0.1588 172 DURATION OF MEMBRANE RUPTURE AND VERTICAL TRANSMISSION OF HIV: DOES THE FOUR HOUR RULE STILL APPLY? AMANDA COTTER 1 , M. LUNTHITA DUTHELY 1 , VICTOR GONZALEZ-QUINTERO 1 , MARY J. O. SULLIVAN 1 , 1 University of Miami, Dept Ob/Gyn, Miami, Florida OBJECTIVE: Membrane rupture for more than four hours is a recognized risk factor for perinatal transmission of HIV. However the critical time of membrane rupture in women with a low viral load and/or receiving combination antiretroviral therapy (ARV) is unknown. Our objective was to investigate if more than four hours of membrane rupture remains a significant risk factor for perinatal transmission in the era of combination ARV. STUDY DESIGN: Using prospectively gathered data from a perinatal database, women diagnosed HIV positive prior to or during pregnancy with care at our prenatal clinic from 1990-2002, whose infants HIV status had been confirmed were identified. RESULTS: The cohort comprised 1071 mother-infant pairs. The perinatal transmission rate with ruptured membranes less than four hours was 6.7% and 12.3% when more than four hours (excluding elective cesarean delivery). The risk of perinatal transmission was significant for membrane rupture 4-8 hours (OR1.96, 1.1-3.6) and 9 hours or more (OR1.95, 1.2-3.3). After adjusting for possible confounders, duration of membrane rupture was no longer a significant risk factor for vertical transmission. Maternal factors independently associated with perinatal transmission were monotherapy (OR 6.3, 2.4-16.6), no therapy (OR 17.4, 6.7-45.5) and viral load greater than 1000 copies/ml (OR 9.9, 1.2-84.5). CONCLUSION: Duration of membrane rupture for more than four hours is not a significant risk factor for perinatal transmission of HIV in women with a viral load less than 1000 copies/ml or who receive combination ARV during pregnancy. S56 SMFM Abstracts
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Transcript of Cost-effectiveness of acyclovir prophylaxis for pregnant women with a history of genital HSV
169 INFLAMMATORY-MEDIATED MODEL OF CEREBRAL PALSY WITH DEVELOPMENTALSEQUELAE SARAH POGGI1, JANE PARK2, LAURA TOSO2, HAIM EINAT3,ROBIN ROBERSON2, VERONICA DUNLAP2, JADE WOODARD2, DANIEL ABEBE2,CATHERINE SPONG2, 1Georgetown University, Obstetrics and Gynecology,Washington, District of Columbia, 2UPDN, NICHD, NIH, Bethesda,Maryland, 3LMP, NIMH, NIH, Bethesda, Maryland
OBJECTIVE: Cerebral palsy (CP) is a neurologic disorder characterized bylifelong impairments in motor function. There is increasing clinical evidence thatCP may result from inflammatory and infection-mediated white matter damage.Animal models for CP have predominately used prenatal ischemia to reproducethe characteristic histological finding of periventricular leukomalacia (PVL)without phenotype evaluation. Our objective was to develop an inflammatorymediated animal model for CP based on chronic lipopolysaccharide (LPS)endotoxin exposure with a recognizable phenotype in exposed offspring.
STUDY DESIGN: On gestational days 15, 17, and 19 (w20-28 wks humangestation), pregnant Fischer 344 rats were intracervically injected with 0.15 mg/kg LPS or saline. Neonatal behavior tests for motor and cognitive developmen-tal milestones were performed on postnatal days 1-21 (LPS N = 25; controlN = 26). 6 adults per group were tested at 8 weeks on open field for motoractivity. Statistical analysis included Mann-Whitney U and ANOVA.
RESULTS: LPS-exposed offspring were significantly delayed achieving motordevelopmental milestones: negative geotaxis (ability of rat to right itself on aninclined plane), with LPS achieving this milestone one day later than controls(day 7.5 G 1.8 vs. 6.8 G 1.8, P ! .001) and cliff aversion (ability to avoid fallingby stepping backwards) with LPS achieving this on day 16.8 G 2.7 vs. day 13.0G 2.3 (control) (P = ! .01). There was no difference between the two groupsfor weight, righting, rooting, forelimb grasp, audio startle, air righting,eyeopening, and activity. There was a trend towards decreased median speed inLPS-exposed adultsin open field assessment (10.1 vs. 7.5 cm/s, P= .08).
CONCLUSION: Using an animal model for CP that mimics a chronicintrauterine inflammation, we have demonstrated a phenotype that is relevantto the human CP manifestations. This model may allow improved understandingof pathogenesis as well as allow for testing of preventative therapies.
170 EXPERIMENTAL GENITAL MYCOPLASMOSIS DOES NOT INCREASE IL-1b, COX-1 ORCOX-2 EXPRESSION IN FETAL BRAINS MORGAN PELTIER1, BRANDON BARNEY1,MARY BROWN2, 1University of Utah, Obstetrics and Gynecology, Salt LakeCity, Utah, 2University of Florida, Department of Pathobiology, Gainesville,Florida
OBJECTIVE: Intrauterine infection is one of the many suspected causes ofcerebral palsy.The majority of intrauterine infections are associated with thegenital mycoplasmas, Ureaplasma urealyticum and Mycoplasma hominis. Pre-vious studies by our group have shown that experimental genital mycoplasmosisin a well-defined rat model increases the production of proinflammatorycytokines in fetal brains. In other animal models where neural injury is inducedby fetal ischemia, there is increased production of COX-2 and prostaglandins.How intrautuerine infection may alter cyclooxygenase levels in the fetal brainin vivo has not been widely studied. It is possible that IL-1b, a proinflammatorycytokine that can upregulate COX-2 is increased during intrauterine infectionwhich could lead to altered production of prostaglandins. Therefore, we testedthe hypothesis that experimental genital mycoplasmosis would alter mRNAlevels of IL-1b, COX-1 and COX-2 in fetal brains.
STUDY DESIGN: On gestational day (gd) 14, Sprague-Dawley rats wereanesthetized and 107 CFU M pulmonis or an equivalent volume of sterile brothwas injected into the heart. Rats were allowed to recover and were laternecropsied at gd 18 or gd 21. Total RNA was purified from snap frozen tissuesand mRNA for IL-1b, COX-1, COX-2 and 18S rRNA was determined by real-time RT-PCR using 2 ug total RNA and commercially available reagents. Datawere analyzed by analysis of covariance using 18S rRNA expression asa covariate.
RESULTS: Messenger RNA levels for IL-1b, COX-1 and COX-2 in fetalbrains were similar between control animals and those infected with M pulmonisfor rats necropsied at gd 18 and gd 21.
CONCLUSION: Experimental genital mycoplasmosis does not alter the pro-duction of IL-1b, COX-1 and COX-2 production in fetal brains. This suggeststhat the pathophysiology of brain inflammation may differ between intrauterineischemia and intrauterine infection.
S56 SMFM Abstracts
171 COST-EFFECTIVENESS OF ACYCLOVIR PROPHYLAXIS FOR PREGNANT WOMEN WITHA HISTORY OF GENITAL HSV SARAH LITTLE1, AARON B. CAUGHEY1, 1University ofCalifornia, San Francisco, Obstetrics, Gynecology and Reproductive Sciences,San Francisco, California
OBJECTIVE: Previous literature has shown acyclovir to be cost-effective asprophylaxis for women with symptomatic HSV recurrence during pregnancy.We extend this analysis by adding quality-adjusted life year measurements andexpanding the population to women with a history of HSV but withoutrecurrence in pregnancy.
STUDY DESIGN: A decision tree was designed to compare acyclovir pro-phylaxis to no treatment. Baseline assumptions include a prevalence of 5% forknown genital HSV history among 4 million deliveries per year, prevalence oflesions at time of delivery of 1.1% for HSV-2 and 0.37% for HSV-1, andasymptomatic shedding at time of delivery of 0.55% for HSV-2 and 0.18% forHSV-1. We assumed acyclovir prophylaxis to be 75% effective at reducing lesionoccurrence and 91% effective at reducing asymptomatic shedding. Sensitivityanalysis included univariate and Monte Carlo simulations.
RESULTS: 22,286 women need to be treated to prevent one neonatal death,8,985 to prevent one affected child, and 177 to prevent one cesarean section. TheTable shows the potential outcomes both with and without acyclovir for the200,000 births next year to women with a known history of genital HSV.Acyclovir is the dominant strategy, as it is on average both cheaper ($12,055 vs.$12,102) and more effective (56.711 QALYs vs. 56.707). In univariate sensitivityanalysis this dominance was robust to all reasonable probabilities and QALYestimates and with treatment costs up to 188% of our baseline estimate of $55.Monte Carlo simulation showed acyclovir to be cost-effective in 100% of200,000 trials and cost-saving over 99% of the time.
CONCLUSION: Acyclovir prophylaxis for pregnant women with a history ofgenital HSV is cost-effective over a wide range of assumptions. This conclusion ismost sensitive to the price of acyclovir therapy.
Outcomes for 200,000 pregnant women with a known history of HSV
No acyclovir Acyclovir
Cesarean sections 50,304.48 49,176.12Neonatal deaths 9.1648 0.1906Severely neurologically impaired children 7.45 0.1588
172 DURATION OF MEMBRANE RUPTURE AND VERTICAL TRANSMISSION OF HIV: DOESTHE FOUR HOUR RULE STILL APPLY? AMANDA COTTER1, M. LUNTHITA DUTHELY1,VICTOR GONZALEZ-QUINTERO1, MARY J. O. SULLIVAN1, 1University of Miami, DeptOb/Gyn, Miami, Florida
OBJECTIVE: Membrane rupture for more than four hours is a recognized riskfactor for perinatal transmission of HIV. However the critical time of membranerupture in women with a low viral load and/or receiving combinationantiretroviral therapy (ARV) is unknown. Our objective was to investigate ifmore than four hours of membrane rupture remains a significant risk factor forperinatal transmission in the era of combination ARV.
STUDY DESIGN: Using prospectively gathered data from a perinatal database,women diagnosed HIV positive prior to or during pregnancy with care at ourprenatal clinic from 1990-2002, whose infants HIV status had been confirmedwere identified.
RESULTS: The cohort comprised 1071 mother-infant pairs. The perinataltransmission rate with ruptured membranes less than four hours was 6.7% and12.3% when more than four hours (excluding elective cesarean delivery). Therisk of perinatal transmission was significant for membrane rupture 4-8 hours(OR1.96, 1.1-3.6) and 9 hours or more (OR1.95, 1.2-3.3). After adjusting forpossible confounders, duration of membrane rupture was no longer a significantrisk factor for vertical transmission. Maternal factors independently associatedwith perinatal transmission were monotherapy (OR 6.3, 2.4-16.6), no therapy(OR 17.4, 6.7-45.5) and viral load greater than 1000 copies/ml (OR 9.9, 1.2-84.5).
CONCLUSION: Duration of membrane rupture for more than four hours isnot a significant risk factor for perinatal transmission of HIV in women witha viral load less than 1000 copies/ml or who receive combination ARV duringpregnancy.
