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212 Relationship between amniotic IL-18 and preterm delivery in patients with preterm labor and preterm prelabor rupture of the membranes
SMFM Abstracts S139
Volume 185, Number 6 A m J Obstet Gynecol 209
HISTAMINE EFFECTS DIFFER IN PHASICALY AND TONICALY CONTRACTED PREGNANT HUMAN UTERINE TISSUE EGLE BYTAUTIENE ], YURI VEDERNIKOV 1, GEORGE 8AADE ], ROBERTO ROMERO 2, ROBERT GARFIELD]; ]University of Texas Medical Branch, Obstetrics a n d Gynecology, Galveston, TX; 2NICHD, Perinatology Research Branch, Betbesda, MD OBJECTIVE: O u r objective was to compare the effects of histamine on spontaneously a n d i n d u c e d tonic contractile activity of uterine strips fi'om p r e g n a n t women. STUDY DESIGN: Longitudinal uterine strips (10 m m x 3 lnln) obtained t?om the lower uterine segment in term n o n l a b o r i n g patients u n d e r g o i n g cesarean section were h u n g in o r g a n chambers filled with Krebs" solution, b u b b l e d with 5% CO2 in air for isometric tension recording. Contractionresponse relation (CRR) to histamine (10-8 - 10-4 M) were o b t a i n e d in spontaneously contracting strips or in strips tonically contracted with a protein kinase C activator (-)-indolactam V (IND V) in the absence or presence of S (+)chlorpheniramine maleate (10-5 M; H1 receptor antagonist), or cimetidine (10-5 M; H2 r e c e p t o r antagonist). After each c o n c e n t r a t i o n , c h a n g e s in integral activity for 10 min were expressed as % of the reference contraction to 60 mM KCI in the spontaneously active strips a n d changes in tension were expressed as % of baseline in tlae IND V contracted strips. One-way ANOVA was used for statistical analysis (significance: P < .05). RESULTS: Histamine increased s p o n t a n e o u s uterine contractility in a c o n c e n t r a t i o n d e p e n d e n t m a n n e r . H I r e c e p t o r antagonist significantly r e d u c e d uterine contractile responses to histanfine, while H2 r e c e p t o r antagonist trended to increase responses to histamine. Histamine h a d no effect in tonically contracted strips incubated with H1 receptor antagonist. However, in the absence of any r e c e p t o r antagonist or after H2 r e c e p t o r blockade, histamine induced relaxation of the tonic uterine contraction. CONCLUSION: Histamine increases spontaneous uterine contractility, but inhibits tonic uterine contractions. Botll effects are mediated t h r o u g h H1 receptors. Differences in contractile status a n d receptor-type p r e d o m i n a n c e could determine the response to histamine-mediated type [ hypersensitivity reaction in the gravid uterus, a process that has significant similarities with preterm labor.
211
MONOCYTE CHEMOTACTIC PROTEIN-1 IS INCREASED IN THE AMNIOTIC FLUID OF PATIENTS WITH PRETERM DELIVERY IN THE PRESENCE OR ABSENCE OF INTRA-AMNIOTIC INFECTION MICHAEL ESPLIN t, TINNAKORN CHAIWORAPONGSA'-', YEON MEE KIM 2, SAM EDWIN 2, EL1 ADASHI 1, ROBERTO ROMERO2; 1University of Utah, Obstetrics a n d Gynecology, SLC, UT: 2Perinatology Research Branch, Detroit, MI OBJECTIVE: Inflammation a n d itS mediators have been implicated in the mechanisms of term a n d preterm parturition. Monocyte chemotactic protein-1 (MCP-1) is a c h e m o k i n e capable of recruiting a n d activating m o n o c y t e s / m a c r o p b a g e s . MCP-1 is expressed by uterine tissues (decidua a n d myometrium) and, thus, may participate in the control of parturition. This study was undertaken to determine if MCP-1 concentrations change in the amniotic fluid (AF) of patientS with preterm labor a n d preterm PROM in the presence or absence of microbial invasion of the amniotic cavity (MIAC). STUDY DESIGN: A cross-sectional study was designed to determine MCP1 concentrations in AF of patients with preterm labor a n d preterm PROM. The study included patients in the following groups: (1) Preterm labor (PTL) without MIAC who delivered at term (n = 36); (2) PTL who delivered preterm (<37 weeks) without MIAC (n = 52); (3) PTL with MIAC (n = 26); (4) Preterm PROM without MIAC (n = 36); a n d (5) Preterm PROM with MIAC (n = 26). MCP-1 levels were determined with a specific a n d sensitive imlnunoassay. Nonparametric statistics were used for analysis. RESULTS: (1) MCP-I was detected in all AF samples; (2) PatientS with MIAC (with intact or ruptured membranes) h a d significantly higher median AF MCP-1 concentrations than those without MIAC (P< .001 a n d P < .003); (3) Patients with PTL who delivered preterm without MIAC h a d higher median AF MCP-1 concentrations than those with PTL who delivered at term (P < .001); (4) Histologic c h o r i o a m n i o n i t i s was associated with increased AF MCP-1 concentrations (P = .04); (5) T h e r e was a strong relationship between AF concentrations of MCP-1 a n d the interval to delivery (P < .01). CONCLUSION: Microbial invasion of the amniotic cavity (with intact or n~ptured membranes) a n d preterm labor leading to preterm delive1~¢ in the absence of intraamniotic infection are associated with increased AF concentrations of MCP-1.
210
THE EFFECT OF CGMP-SPECIFIC PHOSPHOD1ESTERASE INHIBITORS O N OXYTOCIN-INDUCED M Y O M E T ~ CONTRACTIONS JAE SUNG C H O ] , REGENT LAPORTE 2, JUAN ALVAREZ 3, KEE-HAK LIM4; 1yonsei University, Obstetrics a n d Gynecolgy, Seoul; 2Beth Israel Deaconess Medical Center, Boston, MA; 3Beth Israel Deaconess Medical Center, Obstetrics a n d Gynecology, Boston, MA; 4Betb Israel Deaconess Medical Center, Obstetrics, Gynecology a n d Reproductive Biology, Boston, MA OBJECTIVE: To examine the effectiveness of cGMP-specific p h o s p h o diesterase inhibitors (PDEi's) in suppressing oxytocin-induced rat a n d h u m a n myometrial contractions. STUDY DESIGN: We e x a m i n e d the effect of cGMP-specific PDEi's, zaprinast, and a type V PDEi (UK 363664) on oxytocin-induced contractions in term a n d preterm myometrium from rat a n d human. Alter oxytocin stimulation, various concentrations of zaprinast a n d UK 363664 were used. IBMX, a pan-PDEi, was used as a control. The contractile activity was c o m p u t e r digitized a n d normalized tor tissue cross-section area. The area u n d e r curve (AUC) was compared a n d statistically analyzed. RESULTS," In term rat m y o m e t r i u m (n = 3), IBMX suppressed the contractions by 60% at 1×10-5 raM. Zarinast and UK 363664 showed minimal suppression. In preterm rat myometrium (n ~ 4), IBMX suppressed 60% of contractions. Both zaprinast a n d UK 363664 showed 45% to 55% reduction in contractions at l x l 0 - 5 m M (P < .05). In term h u m a n myometrium (n = 4), 1BMX supressed the contractions by 45%. Zaprinast a n d UK 363664 h a d minimal suppressive effect. In preterm h u m a n myometrimn (n = 3), IBMX reduced the contractions by approximately 45% a n d UK 363664, by 60 to 70% at lx10-5 nM (P < .05). Zaprinast demonstrated 40% reduction in the area u n d e r the cmwe, but this was not statistically significant ( P - .15). CONCLUSION: O u r data show that IBMX, a pan-PDEi, is highly effective in suppressing contractions in term and preterm myometrium fi-om r a t a n d h u m a n , cGMP-specific PDEi's did n o t suppress contractions in term myometrium. However, cGMP-specific PDEi's partially suppressed contractions in preterm myometrimn from rat a n d human. This observation supportS the idea that cGMP may play a role in myometrial relaxation during early gestation. This study was supported by grants from OB/GYN Foundation at Beth Isreal Deaconess Medical Center a n d Pfizer Limited. UK363664 was provided by Pfizer Limited.
212
RELATIONSHIP BETWEEN AMNIOTIC I b l 8 AND PRETERM DELIVERY IN PATIENTS WITH PRETERM LABOR AND PRETERM PRELABOR RUPTURE OF THE MEMBRANES B. JACOBSSON 1, R.-M. H O L S T 2, H. BOKSTROM 2, B. ANDERSCH 1, I. MATTSBY-BALTZER 3, U.-B. WENNERHOLM l, H. HAGBERGI; 1perinatal Center, O b / G y n , Goteborg, 2Perinatal Center, O b / G y n , 3perinatal Center, Microbiology, Goteborg OBJECTIVE: Interleukin (IL)-18 is a proinflaminatory cytokine believed to be critically involved in the host defence against infection. There is a lack of information on the possible role of IL-18 in preterm labor (PTL)/ preterm p r e l a b o r r u p t u r e of the m e m b r a n e s (pPROM), even t h o u g h one p i o n e e r study ] has d e m o n s t r a t e d its presence in amniotic fluid a n d a significant association between IL-18 and microbial invasion of the amniotic fluid. STUDY DESIGN: A cohort of 66 patientS with PTL a n d 55 with pPROM (<34 gestational weeks) were included. Amniotic fluid was obtained (within 12 h) in 59 patientS with PTL (42% delivered <34 weeks) a n d 47 with pPROM (72% delivered <34 weeks). Analyses were p e r f o r m e d for IL-6, IL-8 a n d IL-18 using ELISA a n d the levels were related to time of delivery. RESULTS: IL-18 (as well as IL-6 a n d IL-8) were significantly higher in PTL cases delivered _<7 c o m p a r e d to >7 days (Table). O n the contrary, patients in the pPROM g r o u p with IL-18 _>1000 p g / m L h a d longer latency to delivery (median: 37 days; range: 1-117) than those with IL-18 <1000 p g / m L (median: 4 days; range: 0-55). CONCLUSION: In a g r e e m e n t with previous studies, IL-6 a n d IL-8 predicted preterm birth. In PTL cases, high IL-18 was significantly associated with prm'npt delivery, whereas IL-18 levels in pPROM correlated to longer latency to delivery. Table
IL-6 IL-8 IL-18
DELIVERY -<7 DAYS
DELIVERY >7 DAYS
P VALUE
6684 (150-4166650) 3900 (150-18932673) 1010 (150-8330)
315 (150-23097) 150 (150-8894) 570 (150-6890)
<.0001 <.0001 <.05
1. Pacora et al. AJOG 183:1138~13.
Volume 185, Number 6 A m J Obstet Gynecol 209
HISTAMINE EFFECTS DIFFER IN PHASICALY AND TONICALY CONTRACTED PREGNANT HUMAN UTERINE TISSUE EGLE BYTAUTIENE ], YURI VEDERNIKOV 1, GEORGE 8AADE ], ROBERTO ROMERO 2, ROBERT GARFIELD]; ]University of Texas Medical Branch, Obstetrics a n d Gynecology, Galveston, TX; 2NICHD, Perinatology Research Branch, Betbesda, MD OBJECTIVE: O u r objective was to compare the effects of histamine on spontaneously a n d i n d u c e d tonic contractile activity of uterine strips fi'om p r e g n a n t women. STUDY DESIGN: Longitudinal uterine strips (10 m m x 3 lnln) obtained t?om the lower uterine segment in term n o n l a b o r i n g patients u n d e r g o i n g cesarean section were h u n g in o r g a n chambers filled with Krebs" solution, b u b b l e d with 5% CO2 in air for isometric tension recording. Contractionresponse relation (CRR) to histamine (10-8 - 10-4 M) were o b t a i n e d in spontaneously contracting strips or in strips tonically contracted with a protein kinase C activator (-)-indolactam V (IND V) in the absence or presence of S (+)chlorpheniramine maleate (10-5 M; H1 receptor antagonist), or cimetidine (10-5 M; H2 r e c e p t o r antagonist). After each c o n c e n t r a t i o n , c h a n g e s in integral activity for 10 min were expressed as % of the reference contraction to 60 mM KCI in the spontaneously active strips a n d changes in tension were expressed as % of baseline in tlae IND V contracted strips. One-way ANOVA was used for statistical analysis (significance: P < .05). RESULTS: Histamine increased s p o n t a n e o u s uterine contractility in a c o n c e n t r a t i o n d e p e n d e n t m a n n e r . H I r e c e p t o r antagonist significantly r e d u c e d uterine contractile responses to histanfine, while H2 r e c e p t o r antagonist trended to increase responses to histamine. Histamine h a d no effect in tonically contracted strips incubated with H1 receptor antagonist. However, in the absence of any r e c e p t o r antagonist or after H2 r e c e p t o r blockade, histamine induced relaxation of the tonic uterine contraction. CONCLUSION: Histamine increases spontaneous uterine contractility, but inhibits tonic uterine contractions. Botll effects are mediated t h r o u g h H1 receptors. Differences in contractile status a n d receptor-type p r e d o m i n a n c e could determine the response to histamine-mediated type [ hypersensitivity reaction in the gravid uterus, a process that has significant similarities with preterm labor.
211
MONOCYTE CHEMOTACTIC PROTEIN-1 IS INCREASED IN THE AMNIOTIC FLUID OF PATIENTS WITH PRETERM DELIVERY IN THE PRESENCE OR ABSENCE OF INTRA-AMNIOTIC INFECTION MICHAEL ESPLIN t, TINNAKORN CHAIWORAPONGSA'-', YEON MEE KIM 2, SAM EDWIN 2, EL1 ADASHI 1, ROBERTO ROMERO2; 1University of Utah, Obstetrics a n d Gynecology, SLC, UT: 2Perinatology Research Branch, Detroit, MI OBJECTIVE: Inflammation a n d itS mediators have been implicated in the mechanisms of term a n d preterm parturition. Monocyte chemotactic protein-1 (MCP-1) is a c h e m o k i n e capable of recruiting a n d activating m o n o c y t e s / m a c r o p b a g e s . MCP-1 is expressed by uterine tissues (decidua a n d myometrium) and, thus, may participate in the control of parturition. This study was undertaken to determine if MCP-1 concentrations change in the amniotic fluid (AF) of patientS with preterm labor a n d preterm PROM in the presence or absence of microbial invasion of the amniotic cavity (MIAC). STUDY DESIGN: A cross-sectional study was designed to determine MCP1 concentrations in AF of patients with preterm labor a n d preterm PROM. The study included patients in the following groups: (1) Preterm labor (PTL) without MIAC who delivered at term (n = 36); (2) PTL who delivered preterm (<37 weeks) without MIAC (n = 52); (3) PTL with MIAC (n = 26); (4) Preterm PROM without MIAC (n = 36); a n d (5) Preterm PROM with MIAC (n = 26). MCP-1 levels were determined with a specific a n d sensitive imlnunoassay. Nonparametric statistics were used for analysis. RESULTS: (1) MCP-I was detected in all AF samples; (2) PatientS with MIAC (with intact or ruptured membranes) h a d significantly higher median AF MCP-1 concentrations than those without MIAC (P< .001 a n d P < .003); (3) Patients with PTL who delivered preterm without MIAC h a d higher median AF MCP-1 concentrations than those with PTL who delivered at term (P < .001); (4) Histologic c h o r i o a m n i o n i t i s was associated with increased AF MCP-1 concentrations (P = .04); (5) T h e r e was a strong relationship between AF concentrations of MCP-1 a n d the interval to delivery (P < .01). CONCLUSION: Microbial invasion of the amniotic cavity (with intact or n~ptured membranes) a n d preterm labor leading to preterm delive1~¢ in the absence of intraamniotic infection are associated with increased AF concentrations of MCP-1.
210
THE EFFECT OF CGMP-SPECIFIC PHOSPHOD1ESTERASE INHIBITORS O N OXYTOCIN-INDUCED M Y O M E T ~ CONTRACTIONS JAE SUNG C H O ] , REGENT LAPORTE 2, JUAN ALVAREZ 3, KEE-HAK LIM4; 1yonsei University, Obstetrics a n d Gynecolgy, Seoul; 2Beth Israel Deaconess Medical Center, Boston, MA; 3Beth Israel Deaconess Medical Center, Obstetrics a n d Gynecology, Boston, MA; 4Betb Israel Deaconess Medical Center, Obstetrics, Gynecology a n d Reproductive Biology, Boston, MA OBJECTIVE: To examine the effectiveness of cGMP-specific p h o s p h o diesterase inhibitors (PDEi's) in suppressing oxytocin-induced rat a n d h u m a n myometrial contractions. STUDY DESIGN: We e x a m i n e d the effect of cGMP-specific PDEi's, zaprinast, and a type V PDEi (UK 363664) on oxytocin-induced contractions in term a n d preterm myometrium from rat a n d human. Alter oxytocin stimulation, various concentrations of zaprinast a n d UK 363664 were used. IBMX, a pan-PDEi, was used as a control. The contractile activity was c o m p u t e r digitized a n d normalized tor tissue cross-section area. The area u n d e r curve (AUC) was compared a n d statistically analyzed. RESULTS," In term rat m y o m e t r i u m (n = 3), IBMX suppressed the contractions by 60% at 1×10-5 raM. Zarinast and UK 363664 showed minimal suppression. In preterm rat myometrium (n ~ 4), IBMX suppressed 60% of contractions. Both zaprinast a n d UK 363664 showed 45% to 55% reduction in contractions at l x l 0 - 5 m M (P < .05). In term h u m a n myometrium (n = 4), 1BMX supressed the contractions by 45%. Zaprinast a n d UK 363664 h a d minimal suppressive effect. In preterm h u m a n myometrimn (n = 3), IBMX reduced the contractions by approximately 45% a n d UK 363664, by 60 to 70% at lx10-5 nM (P < .05). Zaprinast demonstrated 40% reduction in the area u n d e r the cmwe, but this was not statistically significant ( P - .15). CONCLUSION: O u r data show that IBMX, a pan-PDEi, is highly effective in suppressing contractions in term and preterm myometrium fi-om r a t a n d h u m a n , cGMP-specific PDEi's did n o t suppress contractions in term myometrium. However, cGMP-specific PDEi's partially suppressed contractions in preterm myometrimn from rat a n d human. This observation supportS the idea that cGMP may play a role in myometrial relaxation during early gestation. This study was supported by grants from OB/GYN Foundation at Beth Isreal Deaconess Medical Center a n d Pfizer Limited. UK363664 was provided by Pfizer Limited.
212
RELATIONSHIP BETWEEN AMNIOTIC I b l 8 AND PRETERM DELIVERY IN PATIENTS WITH PRETERM LABOR AND PRETERM PRELABOR RUPTURE OF THE MEMBRANES B. JACOBSSON 1, R.-M. H O L S T 2, H. BOKSTROM 2, B. ANDERSCH 1, I. MATTSBY-BALTZER 3, U.-B. WENNERHOLM l, H. HAGBERGI; 1perinatal Center, O b / G y n , Goteborg, 2Perinatal Center, O b / G y n , 3perinatal Center, Microbiology, Goteborg OBJECTIVE: Interleukin (IL)-18 is a proinflaminatory cytokine believed to be critically involved in the host defence against infection. There is a lack of information on the possible role of IL-18 in preterm labor (PTL)/ preterm p r e l a b o r r u p t u r e of the m e m b r a n e s (pPROM), even t h o u g h one p i o n e e r study ] has d e m o n s t r a t e d its presence in amniotic fluid a n d a significant association between IL-18 and microbial invasion of the amniotic fluid. STUDY DESIGN: A cohort of 66 patientS with PTL a n d 55 with pPROM (<34 gestational weeks) were included. Amniotic fluid was obtained (within 12 h) in 59 patientS with PTL (42% delivered <34 weeks) a n d 47 with pPROM (72% delivered <34 weeks). Analyses were p e r f o r m e d for IL-6, IL-8 a n d IL-18 using ELISA a n d the levels were related to time of delivery. RESULTS: IL-18 (as well as IL-6 a n d IL-8) were significantly higher in PTL cases delivered _<7 c o m p a r e d to >7 days (Table). O n the contrary, patients in the pPROM g r o u p with IL-18 _>1000 p g / m L h a d longer latency to delivery (median: 37 days; range: 1-117) than those with IL-18 <1000 p g / m L (median: 4 days; range: 0-55). CONCLUSION: In a g r e e m e n t with previous studies, IL-6 a n d IL-8 predicted preterm birth. In PTL cases, high IL-18 was significantly associated with prm'npt delivery, whereas IL-18 levels in pPROM correlated to longer latency to delivery. Table
IL-6 IL-8 IL-18
DELIVERY -<7 DAYS
DELIVERY >7 DAYS
P VALUE
6684 (150-4166650) 3900 (150-18932673) 1010 (150-8330)
315 (150-23097) 150 (150-8894) 570 (150-6890)
<.0001 <.0001 <.05
1. Pacora et al. AJOG 183:1138~13.