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Impact of maternal fetal surgery for myelomeningocele on the progression of ventriculomegaly in utero
S68 SMFM Abstracts 31
NITRIC OXIDE/CYCLIC GUANOSINE 3,5 MONOPHOSPHATE RESPONSE TO CYCLOOXYGENASE (COX)-2 INHIBITION IN A RABBIT MODEL OF RU486-INDUCED PRETERM BIRTH DAVID GORENBERG1, KAY BEHARRY2, AAMIR AKMAL3, KENJI NISHIHARA3, JOSHUA WALTZMAN3, TAMEROU ASRAT3, 1University of California, Irvine, Obstetrics and Gynecology, Orange, CA 2University of California, Irvine, Pediatrics, Orange, CA 3Long Beach Memorial Medical Center, Obstetrics and Gynecology, Long Beach, CA OBJECTIVE: Nitric oxide (NO) may maintain uterine quiescence during pregnancy. The onset of labor is associated with an increase in cyclooxygenase (COX)-2 activity. We investigated whether COX-2 inhibition in a rabbit model of RU486-induced preterm pregnancy loss would influence the NO/cGMP signaling mechanisms in the uterus and cervix. STUDY DESIGN: 3 groups of pregnant rabbits (n = 8/group) were induced with a single 50-mg IM dose of RU486 at 22 days’ gestation. 60, 90, or 120 mg/ kg/day of celecoxib (Cel) or vehicle (Veh) was administered orally and daily until delivery. Gestational age-matched controls (n = 6/group) were induced with 100% ethanol IM and were administered equivalent oral doses of Cel or Veh. Serum levels of NO metabolites, NOx and cGMP, were determined prior to induction and following delivery. Uterine and cervical levels were determined at delivery. RESULTS: A prolongation of gestation was seen among rabbits induced with RU486 that received celecoxib vs vehicle (78.9 vs 57.4 hrs). Uterine NO levels were elevated in all ETOH groups compared to their age-matched RU486 groups (P < 0.05 to P < 0.0001). No differences in cervical NO levels were noted. In contrast, cervical cGMP levels were elevated in all ETOH groups compared to the RU486 groups (P < 0.05), with no change in uterine cGMP levels. Treatment with Cel induced greater serum NO production (mmol/L) with significance achieved in the Cel 120 group (368.3 ± 59.3) vs Veh (117.0 ± 22.3, P < 0.01). This response was abolished in the RU486-treated group receiving a similar dose of 120 mg/kg/day (53.2 ± 6.2, P < 0.0001). Cel treatment had no significant effect on serum cGMP levels. CONCLUSION: These data demonstrate an association between COX-2 and NO/cGMP signaling system. COX-2 inhibition appears to induce NO synthesis, which may further promote uterine quiescence. This effect is abolished with progesterone antagonism, suggesting an interaction between COX-2 and progesterone receptor.
December 2003 Am J Obstet Gynecol 33
IMPACT OF MATERNAL FETAL SURGERY FOR MYELOMENINGOCELE ON THE PROGRESSION OF VENTRICULOMEGALY IN UTERO AMY ADELBERG1, ANGELA BLOTZER2, GARY KOCH2, RACHAEL MOISE1, NANCY CHESCHEIR1, HONOR WOLFE3, 1University of North Carolina at Chapel Hill, Obstetrics/Gynecology, Chapel Hill, NC 2University of North Carolina, School of Public Health, Chapel Hill, NC 3University of North Carolina, Obstetrics/Gynecology, Chapel Hill, NC OBJECTIVE: Maternal-fetal surgery (MFS) for myelomeningocele (MMC) has been reported to decrease hindbrain herniation and the need for postnatal ventriculoperitoneal shunt. This study examines the impact of MFS on the progression of ventriculomegaly in utero. STUDY DESIGN: Medical records for all cases of fetal MMC diagnosed at UNC from 6/1988 to 4/2003, were reviewed. The relationship between the repeated measurements of the lateral ventricle with advancing gestational age (GA) and MFS was evaluated with generalized estimating equations for a multivariate linear regression model that included baseline ventricle measurement, GA, GA at baseline, level of spinal cord lesion, and gender, as well as linear and quadratic GA during follow-up for pre- or postnatal surgical repair. RESULTS: 52 of 79 prenatally diagnosed cases of MMC had records available. 13 (25%) had in utero and 39 (75%) had postnatal repair. Atrial size was larger for male fetuses, with no difference in rate of progression by gender. There was a nonsignificant trend toward larger ventricle measurements with a higher level of lesion. MFS did not transiently or permanently impact the progression of ventriculomegaly in utero. The overall rate of progression for both groups was 0.43 mm/week. CONCLUSION: After controlling for baseline degree of ventriculomegaly and level of spinal cord lesion, MFS does not appear to transiently or permanently impact the progression of ventriculomegaly in utero. Other CNS dynamics may explain the reported decrease in need for postnatal ventriculoperitoneal shunts following MFS.
Variable Gender (Female vs Male) Lesion (Lumbosacral vs Thoracic) Lesion (Sacral vs Thoracic) GA-Baseline Ventricle Measurement-Baseline Repair (Postnatal vs Prenatal) GA §Significant at the alpha = 0.05 level.
32
POLYMORPHISM IN INTRON 2 OF INTERLEUKIN 1 RECEPTOR ANTAGONIST GENE, ABNORMAL VAGINAL MICROFLORA IN MIDTRIMESTER AND PRETERM DELIVERY MEHMET R. GENC1, ANDREW ONDERDONK2, SANTOSH VARDHANA3, MARY L. DELANEY2, ERROL R. NORWITZ1, RUTH E. TUOMALA4, LILLY-ROSE PARASKEVAS3, STEVEN S. WITKIN3, 1Brigham and Women’s Hospital, Obstetrics & Gynecology, Boston, MA 2Harvard University, Laboratory Medicine and Pathology, Boston, MA 3Cornell University Medical College, Div. Immunology and Infectious Diseases; Obstetrics & Gynecology, New York, NY 4 Harvard University, Obstetrics and Gynecology, Boston, MA OBJECTIVE: This study investigated the association between the qualitative and quantitative vaginal microbiology, polymorphisms in intron 2 of interleukin 1 receptor antagonist gene (IL1RN), concentrations of interleukin receptor antagonist (IL-1ra) and interleukin-1b (IL-1b) in the cervicovaginal discharge, and the rate of preterm birth. STUDY DESIGN: Vaginal swabs and lavage samples were collected prospectively from 212 women at 18-22 weeks’ gestation. Demographic and pregnancy outcome data were recorded. Qualitative and quantitative microbiological methods were used to characterize the vaginal microflora. Polymerase chain reaction was used to determine IL1RN alleles. IL-1b and IL-1ra concentrations in lavage samples were measured by ELISA. RESULTS: In black women, carriage of IL1RN allele 2 (IL1RN*2) was associated with an abnormal vaginal ecology characterized by an elevated vaginal pH of 5.93 and microflora dominated by anaerobic gram-negative rods, mycoplasmas, and peptostreptococci and the lack of lactobacilli. Among white women, the mean vaginal pH was also higher in carriers of IL1RN*2 (4.93 vs 4.49, P = 0.005), but less so than in blacks and was not accompanied by an obviously altered microflora. In women colonized with anaerobic gram-negative rods and/or Gardnerella vaginalis, vaginal IL-1b concentrations were elevated in non-carriers (6.46 pg/mL), but not in carriers (3.07 pg/mL) of ILRN*2 (P = 0.01). The overall preterm delivery rate was 14% (30/212); fewer preterm deliveries occurred among maternal IL1RN*2 carriers as compared to noncarriers (6% vs 18%, P = 0.02). CONCLUSION: Maternal IL1RN*2 carriage is associated with an elevated vaginal pH, a decreased proinflammatory IL-1b response to lower genital tract microorganisms, and in black women, an abnormal composition of the vaginal flora.
34
Estimate
Standard Error
Type III P value
ÿ2.3135 ÿ3.2714 ÿ6.4743 ÿ0.3058 0.9051 0.1285 0.4254
0.9536 3.9747 4.0874 0.2095 0.1546 1.1169 0.1794
0.0271§ 0.1071 0.1071 0.1501 0.0053§ 0.9083 0.0090§
INCREASED LARGE-VESSEL CEREBRAL BLOOD FLOW IN SEVERE PREECLAMPSIA BY MAGNETIC RESONANCE (MR) EVALUATION GERDA ZEEMAN1, MUSTAPHA HATAB2, DIANE TWICKLER2, 1University of Texas Southwestern Medical School, Obstetrics and Gynecology, Dallas, TX 2 University of Texas Southwestern Medical School, Radiology, Dallas, TX OBJECTIVE: To compare third-trimester maternal cerebral blood flow (CBF) in normotensive healthy pregnant women and in severe preeclampsia (SPE) prior to treatment. STUDY DESIGN: Velocity-encoded phase-contrast MR imaging measures absolute blood flow velocity; this combined with high-resolution imaging, which enables vessel localization and cross-sectional area measurement, results in accurate flow measurement. Women with SPE were recruited to undergo MR imaging of the bilateral middle and posterior cerebral arteries prior to instituting therapy; similar acquisitions were performed on controls. All women were asked to return 6-8 weeks post partum for a non-pregnant study. Vessel diameter (mm) and CBF (vessel area3velocity, mL/min) were analyzed with Student t-test. A P value of < 0.05 was considered statistically significant. RESULTS: Nine normotensive women (mean EGA 37.2 wk) and 12 women with SPE (mean EGA 37.1 wk) participated. CBF was significantly higher in SPE in all 4 arteries studied. Velocity was significantly increased in all vessels, while there was no change in vessel area. There was no statistical difference in vessel area or CBF between the two groups in the non-pregnant state. CONCLUSION: Phase-contrast velocity encoded MR imaging revealed a significant increase in third-trimester maternal CBF in women with SPE when compared to normotensive pregnant controls. Cerebrovascular hemodynamics are altered in SPE; we hypothesize that increased cerebral blood flow in SPE could ultimately lead to eclampsia by means of hyperperfusion and loss of autoregulation.
CBF Contr. 3rd PIH 3rd P value Contr. 6 wk pp PIH 6 wk pp P value RMCA LMCA RPCA LPCA
117.4 118.9 46.5 42.0
154.0 147.0 58.1 61.7
0.001 0.005 0.012 0.008
145.5 150.4 56.2 55.4
158.7 153.4 63.3 64.0
0.15 0.81 0.25 0.25
NITRIC OXIDE/CYCLIC GUANOSINE 3,5 MONOPHOSPHATE RESPONSE TO CYCLOOXYGENASE (COX)-2 INHIBITION IN A RABBIT MODEL OF RU486-INDUCED PRETERM BIRTH DAVID GORENBERG1, KAY BEHARRY2, AAMIR AKMAL3, KENJI NISHIHARA3, JOSHUA WALTZMAN3, TAMEROU ASRAT3, 1University of California, Irvine, Obstetrics and Gynecology, Orange, CA 2University of California, Irvine, Pediatrics, Orange, CA 3Long Beach Memorial Medical Center, Obstetrics and Gynecology, Long Beach, CA OBJECTIVE: Nitric oxide (NO) may maintain uterine quiescence during pregnancy. The onset of labor is associated with an increase in cyclooxygenase (COX)-2 activity. We investigated whether COX-2 inhibition in a rabbit model of RU486-induced preterm pregnancy loss would influence the NO/cGMP signaling mechanisms in the uterus and cervix. STUDY DESIGN: 3 groups of pregnant rabbits (n = 8/group) were induced with a single 50-mg IM dose of RU486 at 22 days’ gestation. 60, 90, or 120 mg/ kg/day of celecoxib (Cel) or vehicle (Veh) was administered orally and daily until delivery. Gestational age-matched controls (n = 6/group) were induced with 100% ethanol IM and were administered equivalent oral doses of Cel or Veh. Serum levels of NO metabolites, NOx and cGMP, were determined prior to induction and following delivery. Uterine and cervical levels were determined at delivery. RESULTS: A prolongation of gestation was seen among rabbits induced with RU486 that received celecoxib vs vehicle (78.9 vs 57.4 hrs). Uterine NO levels were elevated in all ETOH groups compared to their age-matched RU486 groups (P < 0.05 to P < 0.0001). No differences in cervical NO levels were noted. In contrast, cervical cGMP levels were elevated in all ETOH groups compared to the RU486 groups (P < 0.05), with no change in uterine cGMP levels. Treatment with Cel induced greater serum NO production (mmol/L) with significance achieved in the Cel 120 group (368.3 ± 59.3) vs Veh (117.0 ± 22.3, P < 0.01). This response was abolished in the RU486-treated group receiving a similar dose of 120 mg/kg/day (53.2 ± 6.2, P < 0.0001). Cel treatment had no significant effect on serum cGMP levels. CONCLUSION: These data demonstrate an association between COX-2 and NO/cGMP signaling system. COX-2 inhibition appears to induce NO synthesis, which may further promote uterine quiescence. This effect is abolished with progesterone antagonism, suggesting an interaction between COX-2 and progesterone receptor.
December 2003 Am J Obstet Gynecol 33
IMPACT OF MATERNAL FETAL SURGERY FOR MYELOMENINGOCELE ON THE PROGRESSION OF VENTRICULOMEGALY IN UTERO AMY ADELBERG1, ANGELA BLOTZER2, GARY KOCH2, RACHAEL MOISE1, NANCY CHESCHEIR1, HONOR WOLFE3, 1University of North Carolina at Chapel Hill, Obstetrics/Gynecology, Chapel Hill, NC 2University of North Carolina, School of Public Health, Chapel Hill, NC 3University of North Carolina, Obstetrics/Gynecology, Chapel Hill, NC OBJECTIVE: Maternal-fetal surgery (MFS) for myelomeningocele (MMC) has been reported to decrease hindbrain herniation and the need for postnatal ventriculoperitoneal shunt. This study examines the impact of MFS on the progression of ventriculomegaly in utero. STUDY DESIGN: Medical records for all cases of fetal MMC diagnosed at UNC from 6/1988 to 4/2003, were reviewed. The relationship between the repeated measurements of the lateral ventricle with advancing gestational age (GA) and MFS was evaluated with generalized estimating equations for a multivariate linear regression model that included baseline ventricle measurement, GA, GA at baseline, level of spinal cord lesion, and gender, as well as linear and quadratic GA during follow-up for pre- or postnatal surgical repair. RESULTS: 52 of 79 prenatally diagnosed cases of MMC had records available. 13 (25%) had in utero and 39 (75%) had postnatal repair. Atrial size was larger for male fetuses, with no difference in rate of progression by gender. There was a nonsignificant trend toward larger ventricle measurements with a higher level of lesion. MFS did not transiently or permanently impact the progression of ventriculomegaly in utero. The overall rate of progression for both groups was 0.43 mm/week. CONCLUSION: After controlling for baseline degree of ventriculomegaly and level of spinal cord lesion, MFS does not appear to transiently or permanently impact the progression of ventriculomegaly in utero. Other CNS dynamics may explain the reported decrease in need for postnatal ventriculoperitoneal shunts following MFS.
Variable Gender (Female vs Male) Lesion (Lumbosacral vs Thoracic) Lesion (Sacral vs Thoracic) GA-Baseline Ventricle Measurement-Baseline Repair (Postnatal vs Prenatal) GA §Significant at the alpha = 0.05 level.
32
POLYMORPHISM IN INTRON 2 OF INTERLEUKIN 1 RECEPTOR ANTAGONIST GENE, ABNORMAL VAGINAL MICROFLORA IN MIDTRIMESTER AND PRETERM DELIVERY MEHMET R. GENC1, ANDREW ONDERDONK2, SANTOSH VARDHANA3, MARY L. DELANEY2, ERROL R. NORWITZ1, RUTH E. TUOMALA4, LILLY-ROSE PARASKEVAS3, STEVEN S. WITKIN3, 1Brigham and Women’s Hospital, Obstetrics & Gynecology, Boston, MA 2Harvard University, Laboratory Medicine and Pathology, Boston, MA 3Cornell University Medical College, Div. Immunology and Infectious Diseases; Obstetrics & Gynecology, New York, NY 4 Harvard University, Obstetrics and Gynecology, Boston, MA OBJECTIVE: This study investigated the association between the qualitative and quantitative vaginal microbiology, polymorphisms in intron 2 of interleukin 1 receptor antagonist gene (IL1RN), concentrations of interleukin receptor antagonist (IL-1ra) and interleukin-1b (IL-1b) in the cervicovaginal discharge, and the rate of preterm birth. STUDY DESIGN: Vaginal swabs and lavage samples were collected prospectively from 212 women at 18-22 weeks’ gestation. Demographic and pregnancy outcome data were recorded. Qualitative and quantitative microbiological methods were used to characterize the vaginal microflora. Polymerase chain reaction was used to determine IL1RN alleles. IL-1b and IL-1ra concentrations in lavage samples were measured by ELISA. RESULTS: In black women, carriage of IL1RN allele 2 (IL1RN*2) was associated with an abnormal vaginal ecology characterized by an elevated vaginal pH of 5.93 and microflora dominated by anaerobic gram-negative rods, mycoplasmas, and peptostreptococci and the lack of lactobacilli. Among white women, the mean vaginal pH was also higher in carriers of IL1RN*2 (4.93 vs 4.49, P = 0.005), but less so than in blacks and was not accompanied by an obviously altered microflora. In women colonized with anaerobic gram-negative rods and/or Gardnerella vaginalis, vaginal IL-1b concentrations were elevated in non-carriers (6.46 pg/mL), but not in carriers (3.07 pg/mL) of ILRN*2 (P = 0.01). The overall preterm delivery rate was 14% (30/212); fewer preterm deliveries occurred among maternal IL1RN*2 carriers as compared to noncarriers (6% vs 18%, P = 0.02). CONCLUSION: Maternal IL1RN*2 carriage is associated with an elevated vaginal pH, a decreased proinflammatory IL-1b response to lower genital tract microorganisms, and in black women, an abnormal composition of the vaginal flora.
34
Estimate
Standard Error
Type III P value
ÿ2.3135 ÿ3.2714 ÿ6.4743 ÿ0.3058 0.9051 0.1285 0.4254
0.9536 3.9747 4.0874 0.2095 0.1546 1.1169 0.1794
0.0271§ 0.1071 0.1071 0.1501 0.0053§ 0.9083 0.0090§
INCREASED LARGE-VESSEL CEREBRAL BLOOD FLOW IN SEVERE PREECLAMPSIA BY MAGNETIC RESONANCE (MR) EVALUATION GERDA ZEEMAN1, MUSTAPHA HATAB2, DIANE TWICKLER2, 1University of Texas Southwestern Medical School, Obstetrics and Gynecology, Dallas, TX 2 University of Texas Southwestern Medical School, Radiology, Dallas, TX OBJECTIVE: To compare third-trimester maternal cerebral blood flow (CBF) in normotensive healthy pregnant women and in severe preeclampsia (SPE) prior to treatment. STUDY DESIGN: Velocity-encoded phase-contrast MR imaging measures absolute blood flow velocity; this combined with high-resolution imaging, which enables vessel localization and cross-sectional area measurement, results in accurate flow measurement. Women with SPE were recruited to undergo MR imaging of the bilateral middle and posterior cerebral arteries prior to instituting therapy; similar acquisitions were performed on controls. All women were asked to return 6-8 weeks post partum for a non-pregnant study. Vessel diameter (mm) and CBF (vessel area3velocity, mL/min) were analyzed with Student t-test. A P value of < 0.05 was considered statistically significant. RESULTS: Nine normotensive women (mean EGA 37.2 wk) and 12 women with SPE (mean EGA 37.1 wk) participated. CBF was significantly higher in SPE in all 4 arteries studied. Velocity was significantly increased in all vessels, while there was no change in vessel area. There was no statistical difference in vessel area or CBF between the two groups in the non-pregnant state. CONCLUSION: Phase-contrast velocity encoded MR imaging revealed a significant increase in third-trimester maternal CBF in women with SPE when compared to normotensive pregnant controls. Cerebrovascular hemodynamics are altered in SPE; we hypothesize that increased cerebral blood flow in SPE could ultimately lead to eclampsia by means of hyperperfusion and loss of autoregulation.
CBF Contr. 3rd PIH 3rd P value Contr. 6 wk pp PIH 6 wk pp P value RMCA LMCA RPCA LPCA
117.4 118.9 46.5 42.0
154.0 147.0 58.1 61.7
0.001 0.005 0.012 0.008
145.5 150.4 56.2 55.4
158.7 153.4 63.3 64.0
0.15 0.81 0.25 0.25