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340 A role of non-aldosterone mineralocorticods in preeclampsia?
$174 SMFM Abstracts 337
DOES MAGNESIUM SULFATE EFFECTIVELY REDUCE BLOOD PRESSURE IN AN ANIMAL MODEL OF PREECLAMPSIA? CYNTHIA STANDLEYl, DEBORAH STERN l, lMidwestern University, Physiology, Glendale, AZ OBJECTIVE: Using N-nitro-arginine methyl ester (L-NAME), an irreversible inhibitor of constitutive nitric oxide syntbase, a preeelampsia-like condition can be induced in p r e g n a n t rats. This condition is characterized by increased maternal blood pressure, loss of vascular refractoriness to pressor stimuli, reduced litter size a n d decreased p u p weight. O u r objective was to test the utility of magnesium sulfate to block the development of hypertension in this rat model. STUDY DESIGN: 30 Female Sprague Dawley rats (150-175g) were i m p r e g n a t e d with male breeder rats. O n day 17 of pregnancy, female rats were anesthetized with a c o m b i n a t i o n of ketamine a n d xylazine a n d osmotic minipumps were inserted subcutaneously. The pumps were loaded to continuously deliver either vehicle (saline, control g r o u p ) , (L-NAME) alone or in combination with magnesimn sulfate. There were 10 animals per group. Prior to the insertion of the m i n i p u m p s , b l o o d pressure a n d h e a r t rate were measured with a pneumatic tail-cuff device, a n d a Mood sample was obtained. Blood pressure m e a s u r e m e n t s were d o n e again o n days 18, 20, a n d 21 of pregnancy a n d at 2 days postpartum. Blood was also obtained on day 21 and postpartum day 2 to assess electrolyte levels. Pups were weighed a n d measured to detect whether intrauterine growth retardation occurred. RESULTS: Overall, pregnancy led to a lowering of blood pressure values c o m p a r e d to baseline n o n p r e g n a n t values. W h e n rats were i m p l a n t e d o n gestational day 17 with the minipumps, those receiving L-NAME developed hypertension within 24 hours of implantation. Magnesium sulfate given along with the L-NAME appeared to blunt the development of the hypertension in p r e g n a n t rats. In rats receiving saline, b l o o d pressure r e m a i n e d the same during the course of treatment. CONCLUSION: The L-NAME treated p r e g n a n t rat offers a u n i q u e opportunity to further explore the mechanism of magnesium as an antihypertensive a n d therapeutic agent in preeclampsia-eelampsia.
December 2001 Am J Obstet Gynecol 339
PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PROFILE IN PREGNANT WOMEN WITH PYELONEPHRITIS TINNAKORN CHAIWORAPONGSA1, SAM EDWIN l, JU C H E O L KIM 1, YEON MEE KIM 1, GIANCARLO CONOSCENTI 1, BO HYUN YOON 2, ROBERTO ROMERO3; lperinatology Research Branch, NICHD, Detroit, MI; 2Seoul National University, Seoul; 5Perinatology Research Branch, N I C H D / N I H , Detroit, M1 OBJECTIVE: Pyelonephritis is associated with g r e a t e r risk of complications in pregnancy than in the non-pregnant state. Previous studies have d o c u m e n t e d the presence of intravascular systemic i n f l a m m a t i o n in patients with acute systemic infections. The present study was conducted to determine the pattern of maternal plasma concentrations of pro-inflanamatory and anti-inflammatory cytokines. STUDY DESIGN: A prospective cross-sectional study was p e r f o r m e d to c o m p a r e plasma c o n c e n t r a t i o n s of 8 different cytokines between n o r m a l p r e g n a n t women (n = 21) a n d p r e g n a n t women with pyelonephritis (n = 21). Cases a n d controls were m a t c h e d tor gestational age. Cytokines assayed included interleukin-l~ (IL-I~), IL-2, ILL[, IL-6, IL-8, IL-10, interferon-'/(IFN3') a n d t u m o r necrosis factorCt (TNFcQ. A highly efficient i n m m n o a s s a y method was used for this study. RESULTS: Patients with pyelonephritis h a d a significant increase in the plasma concentrations of IFN-3', TNFct, IL-6, IL-8 a n d IL-10, but not IL-I[~, IL-2 a n d I L 4 (Table). CONCLUSION: Pyelonephritis d u r i n g p r e g n a n c y is associated with a significant increase in the plasma concentration of IFN-./. This profile is quite different from the one observed in other complications of pregnancy, such as preeclampsia a n d small for gestational age. Table
IL-6 Normal 100.4 pregnancy (n = 21) Pregnancy 317.9 with acute infection (n = 21) Pvalue .04
IL-8
IL-10
IFN-y
TNFcz
IL-113
IL-2
IL-4
3.2
3.6
3.2
3.2
3.2
3.2
3.2
9.2
15
29.6
25.3
3.2
7.7
70.5
.02
.001
.00l
.001
NS
NS
NS
Value expressed as median (pg/ml).
338
PREECLAMPSIA IS CHARACTERIZED BY A SHIFF IN THE T CELL POPULATION CONSISTENT WITH PRIOR ANTIGENIC EXPOSURE TINNAKORN CFIAIWORAPONGSAt , MARIA-TERESA GERVASI t , JERR1E REFUERZO 2, J U C H E O L KIM 1, GIANCARLO CONOSCENTI 1, SEAN BLACKWELL 9, ROBERTO ROMEROt; !Periuatology Research Branch, Detroit, MI; 2Wayne State University School of Medicine, Obstetrics a n d Gynecology, Detroit, MI OBJECTIVE: The maternal syndrome of preeclampsia has recently been attributed to a systemic intravascular inflamnmtory response a n d endothelial cell activation a n d dysfunction (AJOG 1999;180:499; Placenta 2000;21:597). The stimulus responsible for intravascular inflammation in preeclarnpsia has not b e e n determined. T h e purpose of this study was to determine whether antigenic exposure h a d o c c u r r e d in patients with preeclampsia. This was accomplished by examining the expression of CD45 isoforms on the surface of CD4+ T lymphocytes. Naive T cells express CD45RA on their surface, whereas m e m o r y T cells express CD45RO. An increase in the CD45RO+ cells is indicative of prior antigenic exposure. STUDY DESIGN: A prospective study was c o n d u c t e d in patients with preeclampsia (n = 50) a n d normal pregnancy (n = 75). The percentage of CD45RA a n d CD45RO on CD4+ T lymphocytes was determined in peripheral b l o o d using m o n o c o l o n a l antibodies a n d flow cytometry. Results were reported as a percentage of CD4+ lymphocytes. Non-parametric statistics were used for analysis. RESULTS: 1) Patients with preeclampsia h a d a h i g h e r p e r c e n t a g e of CD45RO+ CD4+ T lynaphocytes than normal p r e g n a n t women (preeclampsia: median 52.4, range 32.9-80.0 vs. normal pregnant: median 48.5, range 19.186.8, P = .03); 2) A significantly lower p e r c e n t a g e of CD45RA+ CD4+ lyrnphocytes was f o u n d in patients with preeclampsia than in normal p r e g n a n t w o m e n (preeclampsia: median 35.1, r a n g e 15.5-62.3 vs. n o r m a l p r e g n a n t : m e d i a n 39.9, r a n g e 11.2-67.3, P = .03); a n d 3) T h e r e was no significant difference in the p e r c e n t a g e of cells with dual expression (CD45RA+/ CD45RO+) between the study groups. CONCLUSION: Preeclampsia is associated with a n increase in the percentage of lymphocytes that express the isoform CD45RO (memory T cells) and decrease in the naive T cell population (CD45RA). Therefore, patients with preeclampsia have evidence of prior antigenic exposure, the nature of which remains to be established.
340
A ROLE OF NON-ALDOSTERONE MINERALOCORTICODS IN PREECLAMPSIA? BASTIENNE WELLENSIECK 1, BERNHARD DICK'-', MARK BAUMANN t , BRIGITTE M. F ~ ' Y 'z, FELIXJ. FREY2, HENNING SCHNEIDER Â, MARKUS G. MOHAUPT2; 1University of Berne, Obstetrics a n d Gynecology, Berne, Berne; 2University of Berne, Nephrology/Hypertension, Berne, Berne OBJECTIVE: The physiological state of p r e g n a n c y is characterized by generalized vasodilatation a n d low blood pressure in spite of elevated sernm a n d urinary concentrations of aldosterone. In contrast, in preeclampsia low aldosterone levels are present. However, an i n a d e q u a t e activation of mineralocortieoid mechanisms has b e e n postulated before. Therefore, we hypothesized an elevated presence of non-aldosterone mineralocorticoids in preeclampsia. STUDY DESIGN: We collected 24-h urine samples from age-matched nonp r e g n a n t control women who did not take any steroid medication (n = 4), from normal women (n = 13), as well as p r e g n a n t women who clearly fulfilled the criteria of preeclampsia (n = 14). Normal p r e g n a n t a n d preeclampsia women were matched for age a n d gestation. Steroid profiling was p e r f o r m e d by gas c h r o m a t o g r a p h y - m a s s s p e c t r o m e t r y after extraction, hydrolysis, derivatisation a n d purification of the urine. Each sample was measured twice with an individually designed p r o g r a m to detect progesterone metabolites. RESULTS: T h e results of o u r u r i n a r y m e a s u r e m e n t s of deoxyeorticosterone (DOC), 18-OH-corticosterone (THA), a n d the respective ratios with reference to tetrahydroaldosterone (THALDO) are presented in the Table. CONCLUSION: These data indicate a potential role of non-aldosterone precursor mineralocorticods in the pathogenesis of preeclampsia. Whether a defect in the aldosterone synthase enzyme m i g h t be p r e s e n t which is i n a p p a r e n t in the n o n - p r e g n a n t state with its m u c h lower progesterone load needs further clarification. Table DOC (MUG/D)
No pregnancy 7.50 _+2.69 Regular pregnancy 2.20 ± 1.71§ Preeclampsia 49.29 _+11.65
THA (MUG/D)
95 + 16§ 471 + 81§* 992 + 225
DOC/ THALDO
THA/ THALDO
0.338 + 0.187"* 3.55 _+ 1.49§ 0.020 _+0.014 2.77_+ 1.09~ 0.855 ± 0.155"* 24.02 + 5.43
§P< .05 vs. preeclampsia, *P< .03 vs. no pregnancy, **P< .01 vs. regular pregnancy.
DOES MAGNESIUM SULFATE EFFECTIVELY REDUCE BLOOD PRESSURE IN AN ANIMAL MODEL OF PREECLAMPSIA? CYNTHIA STANDLEYl, DEBORAH STERN l, lMidwestern University, Physiology, Glendale, AZ OBJECTIVE: Using N-nitro-arginine methyl ester (L-NAME), an irreversible inhibitor of constitutive nitric oxide syntbase, a preeelampsia-like condition can be induced in p r e g n a n t rats. This condition is characterized by increased maternal blood pressure, loss of vascular refractoriness to pressor stimuli, reduced litter size a n d decreased p u p weight. O u r objective was to test the utility of magnesium sulfate to block the development of hypertension in this rat model. STUDY DESIGN: 30 Female Sprague Dawley rats (150-175g) were i m p r e g n a t e d with male breeder rats. O n day 17 of pregnancy, female rats were anesthetized with a c o m b i n a t i o n of ketamine a n d xylazine a n d osmotic minipumps were inserted subcutaneously. The pumps were loaded to continuously deliver either vehicle (saline, control g r o u p ) , (L-NAME) alone or in combination with magnesimn sulfate. There were 10 animals per group. Prior to the insertion of the m i n i p u m p s , b l o o d pressure a n d h e a r t rate were measured with a pneumatic tail-cuff device, a n d a Mood sample was obtained. Blood pressure m e a s u r e m e n t s were d o n e again o n days 18, 20, a n d 21 of pregnancy a n d at 2 days postpartum. Blood was also obtained on day 21 and postpartum day 2 to assess electrolyte levels. Pups were weighed a n d measured to detect whether intrauterine growth retardation occurred. RESULTS: Overall, pregnancy led to a lowering of blood pressure values c o m p a r e d to baseline n o n p r e g n a n t values. W h e n rats were i m p l a n t e d o n gestational day 17 with the minipumps, those receiving L-NAME developed hypertension within 24 hours of implantation. Magnesium sulfate given along with the L-NAME appeared to blunt the development of the hypertension in p r e g n a n t rats. In rats receiving saline, b l o o d pressure r e m a i n e d the same during the course of treatment. CONCLUSION: The L-NAME treated p r e g n a n t rat offers a u n i q u e opportunity to further explore the mechanism of magnesium as an antihypertensive a n d therapeutic agent in preeclampsia-eelampsia.
December 2001 Am J Obstet Gynecol 339
PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PROFILE IN PREGNANT WOMEN WITH PYELONEPHRITIS TINNAKORN CHAIWORAPONGSA1, SAM EDWIN l, JU C H E O L KIM 1, YEON MEE KIM 1, GIANCARLO CONOSCENTI 1, BO HYUN YOON 2, ROBERTO ROMERO3; lperinatology Research Branch, NICHD, Detroit, MI; 2Seoul National University, Seoul; 5Perinatology Research Branch, N I C H D / N I H , Detroit, M1 OBJECTIVE: Pyelonephritis is associated with g r e a t e r risk of complications in pregnancy than in the non-pregnant state. Previous studies have d o c u m e n t e d the presence of intravascular systemic i n f l a m m a t i o n in patients with acute systemic infections. The present study was conducted to determine the pattern of maternal plasma concentrations of pro-inflanamatory and anti-inflammatory cytokines. STUDY DESIGN: A prospective cross-sectional study was p e r f o r m e d to c o m p a r e plasma c o n c e n t r a t i o n s of 8 different cytokines between n o r m a l p r e g n a n t women (n = 21) a n d p r e g n a n t women with pyelonephritis (n = 21). Cases a n d controls were m a t c h e d tor gestational age. Cytokines assayed included interleukin-l~ (IL-I~), IL-2, ILL[, IL-6, IL-8, IL-10, interferon-'/(IFN3') a n d t u m o r necrosis factorCt (TNFcQ. A highly efficient i n m m n o a s s a y method was used for this study. RESULTS: Patients with pyelonephritis h a d a significant increase in the plasma concentrations of IFN-3', TNFct, IL-6, IL-8 a n d IL-10, but not IL-I[~, IL-2 a n d I L 4 (Table). CONCLUSION: Pyelonephritis d u r i n g p r e g n a n c y is associated with a significant increase in the plasma concentration of IFN-./. This profile is quite different from the one observed in other complications of pregnancy, such as preeclampsia a n d small for gestational age. Table
IL-6 Normal 100.4 pregnancy (n = 21) Pregnancy 317.9 with acute infection (n = 21) Pvalue .04
IL-8
IL-10
IFN-y
TNFcz
IL-113
IL-2
IL-4
3.2
3.6
3.2
3.2
3.2
3.2
3.2
9.2
15
29.6
25.3
3.2
7.7
70.5
.02
.001
.00l
.001
NS
NS
NS
Value expressed as median (pg/ml).
338
PREECLAMPSIA IS CHARACTERIZED BY A SHIFF IN THE T CELL POPULATION CONSISTENT WITH PRIOR ANTIGENIC EXPOSURE TINNAKORN CFIAIWORAPONGSAt , MARIA-TERESA GERVASI t , JERR1E REFUERZO 2, J U C H E O L KIM 1, GIANCARLO CONOSCENTI 1, SEAN BLACKWELL 9, ROBERTO ROMEROt; !Periuatology Research Branch, Detroit, MI; 2Wayne State University School of Medicine, Obstetrics a n d Gynecology, Detroit, MI OBJECTIVE: The maternal syndrome of preeclampsia has recently been attributed to a systemic intravascular inflamnmtory response a n d endothelial cell activation a n d dysfunction (AJOG 1999;180:499; Placenta 2000;21:597). The stimulus responsible for intravascular inflammation in preeclarnpsia has not b e e n determined. T h e purpose of this study was to determine whether antigenic exposure h a d o c c u r r e d in patients with preeclampsia. This was accomplished by examining the expression of CD45 isoforms on the surface of CD4+ T lymphocytes. Naive T cells express CD45RA on their surface, whereas m e m o r y T cells express CD45RO. An increase in the CD45RO+ cells is indicative of prior antigenic exposure. STUDY DESIGN: A prospective study was c o n d u c t e d in patients with preeclampsia (n = 50) a n d normal pregnancy (n = 75). The percentage of CD45RA a n d CD45RO on CD4+ T lymphocytes was determined in peripheral b l o o d using m o n o c o l o n a l antibodies a n d flow cytometry. Results were reported as a percentage of CD4+ lymphocytes. Non-parametric statistics were used for analysis. RESULTS: 1) Patients with preeclampsia h a d a h i g h e r p e r c e n t a g e of CD45RO+ CD4+ T lynaphocytes than normal p r e g n a n t women (preeclampsia: median 52.4, range 32.9-80.0 vs. normal pregnant: median 48.5, range 19.186.8, P = .03); 2) A significantly lower p e r c e n t a g e of CD45RA+ CD4+ lyrnphocytes was f o u n d in patients with preeclampsia than in normal p r e g n a n t w o m e n (preeclampsia: median 35.1, r a n g e 15.5-62.3 vs. n o r m a l p r e g n a n t : m e d i a n 39.9, r a n g e 11.2-67.3, P = .03); a n d 3) T h e r e was no significant difference in the p e r c e n t a g e of cells with dual expression (CD45RA+/ CD45RO+) between the study groups. CONCLUSION: Preeclampsia is associated with a n increase in the percentage of lymphocytes that express the isoform CD45RO (memory T cells) and decrease in the naive T cell population (CD45RA). Therefore, patients with preeclampsia have evidence of prior antigenic exposure, the nature of which remains to be established.
340
A ROLE OF NON-ALDOSTERONE MINERALOCORTICODS IN PREECLAMPSIA? BASTIENNE WELLENSIECK 1, BERNHARD DICK'-', MARK BAUMANN t , BRIGITTE M. F ~ ' Y 'z, FELIXJ. FREY2, HENNING SCHNEIDER Â, MARKUS G. MOHAUPT2; 1University of Berne, Obstetrics a n d Gynecology, Berne, Berne; 2University of Berne, Nephrology/Hypertension, Berne, Berne OBJECTIVE: The physiological state of p r e g n a n c y is characterized by generalized vasodilatation a n d low blood pressure in spite of elevated sernm a n d urinary concentrations of aldosterone. In contrast, in preeclampsia low aldosterone levels are present. However, an i n a d e q u a t e activation of mineralocortieoid mechanisms has b e e n postulated before. Therefore, we hypothesized an elevated presence of non-aldosterone mineralocorticoids in preeclampsia. STUDY DESIGN: We collected 24-h urine samples from age-matched nonp r e g n a n t control women who did not take any steroid medication (n = 4), from normal women (n = 13), as well as p r e g n a n t women who clearly fulfilled the criteria of preeclampsia (n = 14). Normal p r e g n a n t a n d preeclampsia women were matched for age a n d gestation. Steroid profiling was p e r f o r m e d by gas c h r o m a t o g r a p h y - m a s s s p e c t r o m e t r y after extraction, hydrolysis, derivatisation a n d purification of the urine. Each sample was measured twice with an individually designed p r o g r a m to detect progesterone metabolites. RESULTS: T h e results of o u r u r i n a r y m e a s u r e m e n t s of deoxyeorticosterone (DOC), 18-OH-corticosterone (THA), a n d the respective ratios with reference to tetrahydroaldosterone (THALDO) are presented in the Table. CONCLUSION: These data indicate a potential role of non-aldosterone precursor mineralocorticods in the pathogenesis of preeclampsia. Whether a defect in the aldosterone synthase enzyme m i g h t be p r e s e n t which is i n a p p a r e n t in the n o n - p r e g n a n t state with its m u c h lower progesterone load needs further clarification. Table DOC (MUG/D)
No pregnancy 7.50 _+2.69 Regular pregnancy 2.20 ± 1.71§ Preeclampsia 49.29 _+11.65
THA (MUG/D)
95 + 16§ 471 + 81§* 992 + 225
DOC/ THALDO
THA/ THALDO
0.338 + 0.187"* 3.55 _+ 1.49§ 0.020 _+0.014 2.77_+ 1.09~ 0.855 ± 0.155"* 24.02 + 5.43
§P< .05 vs. preeclampsia, *P< .03 vs. no pregnancy, **P< .01 vs. regular pregnancy.