ORAL CONCURRENT SESSION B Hypertension Medical Complications Epidemiology Clinical Ob Thursday, February 8, 2001, 1:15 pm – 3:30 pm

ORAL C O N C U R R E N T S E S S I O N B Hypertension Medical Complications Epidemiology Clinical Ob Thursday, February 8, 2001 1:15 pm - 3:30 pm

Moderators:

James T. Christmas, MD James N. Martin, Jr., MD

Judges:

Michael A. Belfort, MD Donald R. Coustan, MD Gary D.V. Hankins, MD

Carson Abstract Numbers 18-26

$10 SMFM Abstracts 0018

ULTRASOUND MONITORING OF AMNIOTIC FLUID DEEPEST POOL IN PROLONGED PREGNANCY: AN A L ~ A T I V E T O ROUTINE INDUCTION OF LABOR C. O'Herlihy t , K. McQuillan2, IUniversity College Dublin, Obstetrics & Gynaeculogy, Dublin, Ireland; 2Department of Obstetrics, National Maternity Hospital and University College Dublin OBJECTIVE: Perinatal risk is increased at gestations of 42 weeks or more compared with term, and routine induction of labor has been proposed as a preventative obstetric strategy. Quantitation of amniotic fluid (AF) using ultrasound is an effective fetal surveillance method post-term. We report perinatal outcome using this technique as an adjuvant to modified expectant management. METHODS: Prospective evaluation of routine ultrasound measurement of deepest AF pool every 3 to 6 days in pregnancies of 42 weeks or more, during a 16-year period, combined with mandatory induction of labor when oligohydramnios was detected. Endpoints for analysis included stillbirth, neonatal death, and abnormal neonatal neurology. ~TS: During the 1984-1999 period, 11,471 women delivered at 42 weeks' gestation. There were 75 perinatal deaths; 37 with lethal malformations were excluded from analysis. Perinatal loss rate among 9868 (84%) women who had ultrasound AF quantitation was 2.3/1000, compared with 10.1/1000 among 1603 unscanned pregnancies. Antepartum stillbirth rate was 10-fold lower (0.7/1000 vs 7.0/I000) in the scanned pregnancies; only 3 antepartum stillbirths occurred (1/3289 pregnancies) after a normal (>30 ram) AF pool measurement. Labor was induced in 4290 (37%) prolonged pregnancies, and 39% of intrapartum and neonatal deaths followed induction. Abnormal neonatal neurology rates were comparable in scanned (4.1/1000) and unscanned (5.6/1000) prolonged pregnancies. CONCLUSIONS: Perinatal mortality was significandy lower in ultrasound AF-monitored, compared with unscanned, prolonged pregnancies, and the "false-negative" antepartum stillbirth risk after reassuring AF measurement was less than I in 3000. This simple ultrasound technique can serve as a safe alternative to routine induction at 42 weeks' gestation.

J a n u a r y 2001 AmJ Obstet Gynecol 0020

DOES PREGNANCY ALTER THE NORMAL DIASTOLIC PATI'ERNS DURING EXERCISE? Jean-Claude Veille l, Dalane Kitzman2; IWake Forest University, Obstetrics & Gynecology, Winston-Salem, NC; ~¢/ake Forest University, Cardiology, Winston-Salem, NC INTRODUCTION: Diastolic function (DF) evaluates ventricular filling properties noninvasively using pulsed Doppler ultrasound. Ventricular relaxation (VR) and DF are important determinants ofventricular performance. The effect of exercise on VR and DF have not been evaluated previously. METHODS: Ten healthy women were studied 4 times (first, second, third, and 6 weeks postpartum [NP]) at rest and after maximal exercise on a stationary bicycle (SB). The following variables were studied: total time velocity (TVI), heart rate (HR), peak early (E), atrial (A) filling velocity, E/A ratio, E deceleration time (DT), isovolumetric relaxation time (IVR). RESULTS: There were no significant differences between all 3 trimesters; thus for clarity, values were grouped and presented in the Table as pregnant. Results are presented as mean ± SD. CONCLUSIONS: (1)Exercise on a SB significantly increased TVI, HR, E and A peak velocities. (2) Exercise significantly decreased E/A ratio, DT, and IVR reflecting an increase in cardiac output and decreased LV compliance. (3) Pregnancy does not significandy alter the normal LV diastolic filling response to exercise. Diastolic function at rest and immediately after exercise HR (PEAK)

E (PEAK)

A

E/A RATIO

18.9 ± 2.9 65.7 ± 6.4

65.7 + 6.4 76.4 ± 12.1"

77.4 ± 8.1 87.9 ± 13.4

47.4 ± 10.8 57.4 ± 13.0

1.7 ± 0.4 1.6 ± 0.4

+2.1"

+32.3*

+26.7*

+46.8*

-0.54* -90.0* -29.2*

+2.7*

+30.0*

+32.1"

+38.9*

-0.34* -51.7" -27.3*

TVI Nonpregnant: rest Pregnant: rest Nonpregnant: exercise* Pregnant: exercise*

DT

IVR

249 ± 91 ± 66 7.5 205 + 86.1 ± 40 3.8

*Changes after exercise. tSignificant differences with P'Jalue <.01.

0019

THIRD-TRIMESTER UNEXPLAlNF~ INTRAI.FrER/NE FETAL DEATH IS ASSOCIATED wrrI-I INH]gRITED THROMBOPHILIA Many Ariel I, Ronit Elad 2, Yuval Yaron s, Eldor Amiram4, Joseph Lessing2, Michael KupermincS; lTel Aviv University, Dept. of Ob/Gyn, Tel Aviv; ~q'el Aviv University, Ob/Gyn, Tel Aviv; STel Aviv University, Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv; 4Tel Aviv University, Dept. of Hematology, Tel Aviv; ~£el Aviv University, DepL of Ob/Gyn, Tel Aviv OBJECTIVE: Hypercoagulability, leading to placental thrombosis, has been implicated in severe pregnancy complications and fetal loss. The majority of cases of intrauterine fetal death (IUFD) remain unexplained. The purpose of this study is to determine the risk of thrombophilias in women with unexplained IUFD, STUDY DESIGN: All women with IUFD >27 weeks' gestation, during a period of 3 years in our institution, were initially assessed. Cases with congenital anomalies, intrauterine infection, severe hypertensive disease, or diabetes mellitm were excluded. The remaining 39 women with unexplained IUFD (study group) were matched for age and ethnicity with 39 healthy women who had at least one normal pregnancy (control group). All women in both groups were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase (MTHFR), and for deficiencies of protein S, protein C, and antithrombin III. All were also tested and found to be negative for anticardlolipin antibodies. RESULTS- The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 41% in the study group compared with 16% in the control group (OR 3.8; 95% CI 1.16 to 13.03; P = .01). CONCLUSIONS: Third-trimester IUFD is significandy associated with thrombophilla~= These findings suggest that thrombophilia workup should be part of IUFD investigation and may have therapeutic and prognostic implications in future pregnancies.

0021

BLOOD VOLUME STRATD1ED BY ANGIOTENSINOGEN GENOTYPES IN NORMAL AND HYPERTENSIVE PREGNANCY Helayne Silver l, Terry Morgan, MD, PhD 2, Kenneth Ward3; IBrown University, Obstetrics-Gynecology, Providence, RI; 2Stanford University, Pathology, Stanford, CA; 3University of Utah, Obstetrics and Gynecology, Salt Lake City, UT OBJEC'flVE: To determine if blood volume is reduced in association with the homozygous T235 angiotensinogen genotype (Tr) in the hypertensive disorders of pregnancy and in normal third-trimester pregnancy. STUDY DESIGN: Angiotensinogen genotyping was performed on subjects from a prior study of total blood volume (TBV) in preeclampsia, gestational hypertension (GH), and normal pregnancy and additional control subjects from an ongoing longitudinal study of blood volume in primigravidas. Plasma volume was measured by Evans blue dye dilution and red cell volume using red cells labeled with a stable isotope of chromium. RE.$ULTS: In this cohort, as noted in other cohorts, a higher frequency of the TT genotype in found in the hypertensive disorders of pregnancy. TBV studies, normalized by body surface area ( m L / m 2) and stratified by angiotensinogen genotypes in normal, GH, and preeclamptic pregnancies are shown in the Table. TBV is decreased in normotensive gravidas with the TT in comparison to the MM (P = .04) and the TM genotype (P = ,02). Although there are no associations noted in the hypertensive groups between TBV and angiotensinogen genotype, when analysis is restricted to nulliparas, there is a Lrend toward decreased TBV in the preeclamptic subjects with the T'F in comparison to the MM genotype (P = .07). CONCLUSION: TBV is reduced in normal gravidas with the T r angiotensinogen genotype. Blood volume results

GENOTYPE MM TM TT

CONTROL ('N = 44) 2978 ± 522 (n = 18) 2918±641 (n =20) 2953 ± 726 (n = 6)

GESTATIONAL HYPERTENSION (N = lS)

PREECI,AMPSIA (N = 18)

2927 ± 824 (n = 3) 2991+211 ( n = 5 ) 3148 ± 336 (n = 5)

2579 ± 430 (n = 5) 2759±526 (n =7) 2536 ± 112 (n = 6)

SMFM Abstracts $11

V o l u m e 184, N u m b e r 1 AJn J O b s t e t G y n e c o l 0022

A POTENTIAL ROLE FOR HUMAN RECOMBINANT VASCULAR ENDOTHELIUM GROWTH FACTOR IN THE DEVELOPMENT OF VASCULAR DYSFUNCTION IN PREGNANCY Eimantas Svedas I, H e n r y Nisell ~, Khalid Islam 3, Yorgos Nikas 4. Karolina Kuhlickiene4; IKarolinska Institutet, Stockhohn; '-'Huddinge University Hospital, Obstetrics a n d Gynecology; 3Karolinska lnstitutet, Gene T h e r a p y C e n t r u m , Stockholm; 4 H u d d i n g e University Hospital, Obstetrics and Gynecolngy, Stockhohn. Sweden OBJECTIVE: Vascular e n d o t h e l i u m growth factor (VEGF) has been suggested to be invoh,ed in the pathogenesis of preeclampsia. Therefore we wanted to cvahmte whether prolonged incuhation with h u m a n recombinant VEGF may alter endothelium-dependent dilatation and basal tone in isolated resistallce arteries from normal pregnant women. STUDY DESIGN: S u b c u t a n e u s arteries (approximately 200 lain) were dissected from fat biopsies obtained at p l a n n e d cesarean section a n d then m o n n t e d on a pressure a r t e r i o g r a p h . After preconstriction with norepinephrine (1 ].tmol/L), concentration response curves to bradykinin (BK, 1 n m o l / L to 3 lamol/L) were compared before and after prolonged iutraluminal incubation (3 hours) with VEGF (0.5 or 1 n m o l / L ) or physiologic salt solution (PSS). During the incubation period at constant intraluminal pressure o f 60 mm Hg, internal diameter was continously recorded to evaluate changes in basal tone in the presence of VEGF or PSS alone. Finall); all arteries were fixed for scanning electron microscopy (SEM) to evaluate morphologic changes of the endothelial cells layer. RESULTS: BK-mediated relaxation was similarly impaired in arteries after incubation wkh either VEGF 0.5 nM (eg, dilatation at 1 tiM of BK: 279% ± 16% in PSS vs 156% ± 20% after VEGF; n = 10, P< .O1) or VEGF 1 nM (eg, dilatation at 1 I.tM 197% + 23% in PSS vs 92% ± 5% after VEGF; n=3, P< .Ol), respectively. In contrast, BK-mediated dilatation was unaffected after incubation with VEGF vehicle (n = 7). Basal tone was higher after 60 minutes incubation with VEGF in comparison to that developed in PSS (eg, 25% ± 4% with VEGF 0.5 n m o l / L vs 9% ± 4% in PSS, P < .05). SEM d e m o n s t r a t e d m o r p h o l o g i c changes of endothelial cell layer. CONCLUSIONS: Incubation with VEGF impaired BK-mediated endothelium-dependent dilatation a n d e n h a n c e d basal tone in arteries from a normal pregnant woman. This might indicate a potential role for VEGF in development of endothelial dysflmcdon seen in preeclampsia.

0024

GRAVES' DISEASE IN PREGNANCY--EVALUATION OF MANAGEMENT PROTOCOL WITH SELECTIVE USAGE OF UMBILICAL VEIN SAMPLING Z o h a r N a c h u m I, Yardena Rakover 2, Raed Salim I, E h u d Weiner -~, Eliezer Shalev4; I HaEmek Medical Center, Afula; ~HaEmek Medical Center, Pediatric Endocrine Unit, Afula; 3HaEmek Medical Center, O b & Gyn, Afula; 4HaEmek Medical Center, O b & Gyn, Afula, Haifa OBJECTIVE: To evaluate the impact on neonatal outcome of prospective protocol for m a n a g e m e n t of Graves' disease (GD) in p r e g n a n c y using umbilical vein sampling (UVS) in selected cases. STUDY DESIGN: All pregnancies of mothers with GD were m a n a g e d prospectively in the Izst 9 years by a protocol designed to control the metabolic state of both mother and fetus. Evaluadon included serial maternal level of thyroid-stimulating immunoglobulins (TSI) and funcdon tests, and ultrasound (US) examinations for fetal heart rate, anthropometric measurements, signs of cardiac failure, a n d the a p p e a r a n c e of goiter. UVS was r e c o m m e n d e d whenever TSI were abnormally high or fetal tachycardia, goiter, IUGR, or hydrops were present. UVS was not r e c o m m e n d e d when both TSI a n d US findings were normal. Fetal thyroid status served to modify treatment. RESULTS: A total of 19 pregnancies in 13 women who had 21 babies were treated. In 11 fetuses criteria were met a n d 7 mothers elected to undergo the procedure. Three underwent one LrVS a n d resulted in normal findings a n d babies. In 4 there were abnormal findings a n d repeat UVS was performed. In all 15 UVS p r o c e d u r e s no complications were recorded. In 2 fetal hypothyroidism was diagnosed a n d in 2, hyperthyroidism. In the hypothyroidic fetuses one improved with reduction of maternal PTU dose a n d the other also required intra-amnintic elthroxin, resulting in reversal of goiter. In the hyperthyroidic fetnses maternal PTU was increased, resulting in fetal euthyroidism a n d reversal of goiter in one. Only one of the 7 fetuses was born with transient byperthyroidism. In the 4 who did not elect UVS ultrasound findings remained normal up to term a n d newborns were normal. O n e of the newborns to the 10 mothers, in whom we did not r e c o m m e n d UVS, was b o r n with mild and transient hypothyroidism. All children, followed up 1 to 9 years, are normally developing. CONCLUSIONS: In pregnancies of women with GD tied protocol using UVS in selected cases is recommended.

0023

MATERNAL SYSTEMIC INFLAMMATION: A MECHANISM OF DISEASE IN PREECLAMPSIA Maria-Teresa Gervasi, MD t, T i n n a k o r n Chaiworapongsa, MD 2, Percy Pacora, MD ~, Nihal Naccasha, MD 4, Bo Hyun Yoon, MD 5, Eli Maymon, MD l, Roberto Romero, MDt; IPerinatology Research Branch, NICHD, Bethesda, MD, Detroit. MI; 2Perinatology Research Branch, NICHD, Detroit, MI; 3Perinatology Research Branch, Detroit, MI; 4Wayne State University/Hutzel Hospital, D e p a r t m e n t of Obstetrics a n d Gynecology, Detroit, MI; 5Seoul National University, Seoul, Korea; 6perinatology Research Branch, NICHD, Bethesda, MD, Detroit, MI OBJECTIVE: Preeclampsia has traditionally been considered a vascular disorder associated with defective placentafion a n d uteroplacental ischemia. Recently, the maternal syndrome of preeclampsia has been attributed to deportation of trophoblast into the maternal circulation which leads to a systemic intravascular inflammatory response and endothelial cell activation/dysfunction (AmJ Obstet Gynecol 1999). This novel hypothesis has cousiderable clinical and biological implications. This study was designed to determine if women with preeclampsia have evidence of systemic inflammation by exantining the in vivo state of activation of monocytes and neutrophils. STUDY DESIGN: A prospective cohort study was p e r f o r m e d including patients with severe preeclampsia (n = 29) and normal pregnancy in = 14). lntravascular inflammation ~vasstudied using flow cytometry. Peripheral venous blood was assayed for evidence of neutrophil and monocyte activation using monoclonal antibodies for selective cluster differentiation (CD) antigens. The panel of antibodies included: CD1 lb, CD14, CD49d, CD62L, CD64, CD66b, and HLA-DR. Analysis was conducted with a Mann-Whitney Utest. RESULTS: Preeclampsia was associated with a significant increase in the surface expression of CD 11b and CD64 in neutrophils (P < .0005 a n d P = .041, respectively) a n d monocytes (P< .0005 a n d P < .006, respectively); CD49d a n d HLA-DR in monocytes (P = .013 a n d P = .039, respectively); a n d CD66b in neutrophils (P = .01 ). The intensity of activation was significantly increased in CDI lb on neutrophils a n d monocytes (P = .003 a n d .02, respectively) a n d CD62L on neutrophils (P = .001). CONCLUSIONS: (1) Preeclampsia is associated with activation of the innate limb (neutrophils a n d monocytes) of the immunoresponse. (2) This evidence calls for a reexamination of the mechanism of disease traditionally invoked to explain the pathogenesis of this condition.

0025

ELEVATED PLASMA HOMOCYSTEINE IN EARLY PREGNANCY: A RISK FACTOR FOR THE DEVELOPMENT OF SEVERE PREECLAMPSIA Amanda Cotter l, Anne Molloy2,J. M. Scotts, Sean F. Daly4; tCoombe Women's Hospital, Dublin, Ireland; -'2"I'rinityCollege Dublin, Clinical Medicine, Dublin; ~Coombe W o m e n ' s Hospital/Trinity College, Dublin; 4Coombe Women's Hospital, Dublin, Ireland OBJECTIVE: Elevated plasma homocysteine (Hey) levels have b e e n implicated in the pathogenesis of placental vascular disease a n d several studies have d e m o n s t r a t e d elevated Hey levels in p r e e c l a m p d c patients in late p r e g n a n c y c o m p a r e d with normotensive pregnancies. T h e purpose o f o u r study was to determine if an elevated plasma homocysteine in early pregnancy predisposes patients to severe preeclampsia (PET). STUDY DESIGN: Booking bloods were obtained from patients attending for routine antenatal care d u r i n g the period 1986-1990 (before the introduction of periconceptual folic acid). Cases were asymptomadc women who subsequendy developed severe PET, defined according to ACOG criteria. Controls were women who remained normotensive a n d without proteinuria throughout pregnancy matched to cases by gestadonal age at booking a n d by date of sample collection. Homocysteine levels were m e a s u r e d using fluorescence polarization immunoassay. Data analysis was p e r f o r m e d using parametric methods. RESULTS: From a total patient base of 16,000 bloods, there were 56 cases of severe PET sampled at a mean gestation (±SD) of 15.3 ± 4.04 weeks a n d 112 controls at 14.0 ± 3.41 weeks (NS). The PET cases had a mean (:I:SD) Hey level of 9.8 ± 3.3 g m o l / L while controls had a mean Hey of 8.4:1:1.9 g r n o l / L ( P ~ .0001). With a plasma Hey >10 p.mol/L at 14 weeks' gestation, there is a significantly increased risk of developing severe PET (OR 2.84, 95% CI 1.37 to 5.88). CONCLUSION: Women who develop severe PET have elevated plasma Hcy levels in early p r e g n a n c y c o m p a r e d with w o m e n who r e m a i n n o r m o tensive throughout pregnancy. An elevated plasma Hey in early pregnancy can increase the risk of developing severe PET almost threefold.

$12 SMFM Abstracts 00~

DItt-Je~EN'rIAL.EXPRESSION OF THE CELL SURFACE RECEPTOR (CD95) FOR THE DEATH CEIJ. FACTOR FAS-LIGAND IN PREECLAMPSIA AND MATERNAL INFECTION Maria-Teresa Gervasi, MD I, Tinnakorn Chaiworapongsa, MD 1, Nihal Naccasha, MD 2, Susan Berman, MD s, Bo Hyun Yoon, MD 4, Eli Maymon, MI~, Robertu Romero, MDI; IPerinatulogy Research Branch, NICHD, Bethesda, MD, Detroit, MI; 2Wayne State University, Obstetrics and Gynecology, Detroit, M1; SWayne State University, ObsteUics/Gynecology, Detroit, MI; 4Seoul National University, Obstetric and Gynecology, Seoul, Korea; SPerinatulogy Research Branch, NICHD, Detroit, MI OBJECTIVE: Delayed neutrophil programmed cell death has been implicated in the pathogenesis of preeclampsia (PE) and sepsis. Activated neutrophils in maternal circulation are thought to induce endothelial cell activation/dysfunction in both PE and sepsis. However, the mechanisms responsible for delayed neutrophil apoptosis have not been determined. CD05 is the cell surface receptor for Fas-ligand, capable of inducing neutrophil apoptosis. We propose that changes in the expression of this receptor may account for delayed apoptosis in PE. This study was conducted to examine the behavior of this receptor in patients with normal pregnancy, PE, and systemic maternal infection. STUDY DESIGN: A cross-sectional study was constructed to include patients with normal pregnancy (n = 14), PE (n = 28), and maternal sepsis with positive blood cultures for bacteria (n = 8). CD95 neutrophil cell surface expression was determined using flow cytometry with specific monoclonal antibodies. Results were expressed as fluorescence intensity (mean channel brightness [MCB]). Statistical analysis was conducted by regression analysis and t test. RESULTS: (1) The mean MCB for CD95 neutrnphiis was significantly lower in PE than in normal pregnancy (mean 2.6 + 0.3 vs mean 2.8 + 0.3, respectively, P = .01). (2) In contrast, patients with sepsis had a higher mean MCB for CD95 than those with PE and normal pregnancy (mean 3.7 + 0.9 ~ 2.6 + 0.3 and 3.7 ± 0.9 vs 2.8 ± 0.3, P = .01 and .03, respectively). (3) MCB for CD95 decreased with advancing gestational age in normal pregnancy (r = -0.54, P= .04). CONCLUSIONS: Decreased expression of the cell surface receptor for the death factor, Fas-ligand, is observed in PE but not in sepsis. This may explain, at least in part, the delayed apoptosis observed in PE. Differential expression of CD95 in sepsis and PE suggests qualitative differences in the nature of neutrophil activation in these conditions.

,January 2001 Am J Obstet Gynecol