- Email: [email protected]
529: Cervical cerclage, progesterone supplementation, and spontaneous preterm birth
Poster Session III
Doppler Assess, Fetus, Prematurity, U/S, Med-Surg-Diseases
STUDY DESIGN: We compared outcomes between two large cohorts of twin pregnancies who delivered in New York City from 2003-2012. One cohort (n⫽532) was managed by a single maternal-fetal medicine practice and delivered at one large academic medical center. This cohort underwent routine CL screening every 2-3 weeks starting at 16 weeks and fFN screening every 2-3 weeks beginning at 22 weeks. The second cohort (n⫽456) were all twin pregnancies delivered at a second large academic center. The second cohort did not undergo routine CL and fFN screening and only had these tests done as clinically indicated. Outcomes measured include cerclage placement, PTB, spontaneous PTB (SPTB), and antenatal corticosteroid (ACS) exposure. RESULTS: Rates of cerclage placement, PTB, and SPTB were similar between the two groups (Table). However, routine screening using CL and fFN was associated with improved rates of ACS exposure in women who delivered ⬍34 weeks and 34-36 6/7 weeks, without an increased ACS exposure in women who delivered at term. CONCLUSION: In twin pregnancies, routine CL and fFN screening does not reduce the risk of PTB or SPTB. However, the routine use of these tests significantly improves ACS exposure for women who deliver preterm without significantly increasing ACS exposure to women who deliver at term.
528 Leukotriene receptor antagonist as a novel tocolytic in an in vitro model of human uterine contractility for preventing preterm labor Stéphanie Corriveau1, Simon Blouin1, Éric Rousseau2, JeanCharles Pasquier1 1 Université de Sherbrooke, Obstetrics and gynecology, Sherbrooke, QC, Canada, 2Université de Sherbrooke, Physiology and Biophysic, Sherbrooke, QC, Canada
OBJECTIVE: The presence of an inflammatory process is a risk factor for prematurity. Among tocolysis, indomethacin (COX inhibitor) remains efficient but leads to major secondary effects. In a previous study, we explored the inhibition of an alternative arachidonic metabolic pathway: the lipoxygenases (LOX) which inhibit leukotriene production and had potency similar to indomethacin. This study analyzed the ability of montelukast, a leukotriene receptor antagonist, to produce a potent tocolytic effect alone or in combination with nifedipine, a Ca2⫹ channel blocker currently used in clinic. STUDY DESIGN: Uterine biopsies were performed, from consenting women undergoing elective C-sections at term (N⫽20). Isometric tension measurements were performed on human myometrial strips (n⫽120) to establish concentration-response curves and to quantify Ca2⫹ sensitivity to montelukast on -escin permeabilized tissues. Contractile activities were quantified by calculating the area under the curve (AUC). Myometrial fractions were analyzed by immunoblotting and mRNA was extracted to quantify LOX gene expression levels. RESULTS: The immunodetection analysis as well as the gene expression levels indicate the presence of LOX enzymes in myometrium. An increase in AUC was quantified following the addition of LTD4, an end-product of the LOX pathway (p⫽0.02). Hence, the addition of montelukast produced a significant tocolytic effect by decreasing the frequency and the AUC (IC50⫽1M). Addition of 1M montelukast also results in a reduced Ca2⫹ sensitivity as compared to the control
S226
www.AJOG.org
(EC50 of 589 and 295nM, respectively). An additive effect is also observed with the combined use of nifedipine (p⫽0.01). CONCLUSION: We demonstrated the potency of montelukast as a tocolytic in a human uterine model. The results obtained with montelukast in combination with nifedipine could represent a therapeutic approach to reduce inflammation associated with prematurity while facilitating the inhibition of preterm labor.
529 Cervical cerclage, progesterone supplementation, and spontaneous preterm birth Tracy Manuck1, Manijeh Kamyar1, M. Sean Esplin2, Robert Silver1, T. Flint Porter2, Michael Varner1 1
University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, Intermountain Healthcare, Maternal-Fetal Medicine, Murray, UT
2
OBJECTIVE: Women with a prior spontaneous preterm birth (SPTB) and/or prior or current cervical insufficiency may be candidates for both supplementation with 17-alpha hydroxyprogesterone caproate (17P) and cervical cerclage placement. However, the relationship between the simultaneous use of these interventions and SPTB is uncertain. We sought to examine pregnancy outcomes among women with cerclage with and without 17P. STUDY DESIGN: Retrospective cohort of women with singleton pregnancies from 2 tertiary-care centers 2009-2012. Women undergoing cervical cerclage placement for any indication ⬍26 weeks were included. Women who also received 17P prophylaxis (cerclage⫹17P group) were compared to those who did not receive 17P (cerclageonly group). Data were analyzed with Chi-square, Student’s t-test, and logistic regression. RESULTS: 87 women were included; 39 (44.8%) received 17P. Women in the cerclage⫹17P group did not differ from those in the cerclageonly group with regards to earliest prior SPTB (23.3 vs. 23.2, p⫽0.96) or number of prior PTB (median⫽1 for both groups). Other characteristics and outcomes also were similar among groups (Table). Survival analysis revealed no differences in delivery gestational age based on 17P (Figure). In regression analyses controlling for potential confounders, 17P use was not associated with pregnancy prolongation. CONCLUSION: Among women with a cervical cerclage, the addition of 17P does not appear to prolong pregnancy, and overall rates of prematurity are high. Larger studies should confirm this finding and further investigate additional preventative strategies for women with cervical insufficiency.
Data are n (%) unless otherwise indicated
American Journal of Obstetrics & Gynecology Supplement to JANUARY 2013
www.AJOG.org
Doppler Assess, Fetus, Prematurity, U/S, Med-Surg-Diseases
Poster Session III
STUDY DESIGN: The Nationwide Inpatient Sampla (NIS) data from
Antenatal characteristics and pregnancy outcomes among women with cerclage, stratified by 17P supplementation
530 Next generation sequencing identifies the IL-12 receptor beta gene as a potential mediator in the response to 17-alpha-hydroxyprogesterone caproate for the prevention of recurrent prematurity Tracy Manuck1, Scott Watkins2, Sean Esplin3, Marc Jackson3, Lynn Jorde2, Michael Varner1 1
University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, University of Utah, Human Genetics, Salt Lake City, UT, 3Intermountain Healthcare, Maternal Fetal Medicine, Salt Lake City, UT 2
OBJECTIVE: 17-alpha-hydroxyprogesterone caproate (17P) reduces recurrent preterm birth (PTB) in some, but not all, women. We hypothesized that genetic polymorphisms affect variable response to 17P. STUDY DESIGN: Women with a history of ⱖ1 spontaneous singleton PTB ⬍34 wks who received weekly 17P were recruited prospectively from a prematurity prevention clinic from 2008-2010. Women were classified as a 17P responder or non-responder based on the difference in delivery gestational age (GA) between their 17P treated and untreated pregnancy/pregnancies. Whole exome sequencing was performed using Illumina® HiSeq2000 next generation technology. Each individual was sequenced for ⬃180,000 protein-coding exons. Genomes were compared between responders and non-responders using the Variant Annotation, Analysis & Search Tool (VAAST), a probabilistic search tool for identifying disease causing variants in personal genome sequences. Genome-wide significance was set at p⬍2.4x10-6. RESULTS: 24 women (19 responders, 5 non-responders), all Caucasian, were included. Responder and non-responder groups did not differ with regards to median number of pregnancies (3 vs. 4, p⫽0.67), history of cervical insufficiency (26% vs. 20%, p⫽0.77), or history of PPROM (32% vs. 40%, p⫽0.72). The GA of each woman’s earliest PTB also did not differ (27.9 vs. 29.7 wks, p⫽0.35), but responders achieved ⫹9.1 wks longer with 17P, vs. ⫹1.5 wks for nonresponders (p⬍0.001). All samples met genotype quality filters. The average genome-wide coverage depth was 47.3 (range 20.1-64.6). We assumed recessive inheritance and locus heterogeneity. VAAST identified IL12RB1 (Interleukin-12 receptor beta) as associated with nonresponse to 17P (p⫽3.03 ⫻ 10⫺8). CONCLUSION: Response to 17P for the prevention of recurrent PTB may be genetically mediated. These results should be confirmed in a larger cohort and may lead to the development of a ‘17P response panel.’
531 Epidemic of opioids use during pregnancy and the risk of preterm birth in the United States Valerie Whiteman1, Hamisu Salihu2, Jason Salemi2, Mulubrhan Mogos2 1 University of South Florida Morsani College of Medicine, OB/GYN Division of Maternal Fetal Medicine, Tampa, FL, 2University of South Florida College of Public Health, Epidemiology and Biostatistics, Tampa, FL
OBJECTIVE: To demonstrate the national increase in threatened preterm labor and preterm delivery in patients with opioid use during pregnancy.
1998-2009 was utilized in this retrospective cohort study. We investigated the association between opioid use during pregnancy and threatened preterm labor (TPTL) and preterm birth(PTB). To account for the complex sampling design in the NIS data, we used the SURVEYMEANS and SURVEYLOGISTIC procedures in SAS 9.2 to generate the estimates. We used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) codes to identify discharges with TPRL(ICD9-CM - 644.0x) and PTB (ICD9-CM - 644.2x). RESULTS: During the study period there were a total of 55,781,965 pregnancy related discharges. There were 1,246,430 discharges for TPRL, 3,644,534 discharges for PTB and 4,889,853 discharges for TPTL and/or PTB. The prevalence of opioid use during pregnancy among these women in 1998 was 25.04 per 10,000 pregnancy related discharges. By 2009 this increased to 40.22/10,000 representing a 61.1% increase in opioid use during the study period. After controlling for age, race and household income; discharges with the diagnosis of opioid use demonstrated an increased risk of TPTL: Adjusted Odds Ratio[AOR]⫽1.35 and 95% confidence interval [CI]:1.23-1.49; PTB: AOR⫽1.98, CI 1.84-2.13; and combined TPTL/PTB AOR⫽1.86, CI: 1.84-2.13. This risk remains significant even after controlling for alcohol and tobacco use: TPTL AOR⫽1.33,CI:1.21-1.46; PTB AOR⫽1.76: CI 1.64-1.89 and combined TPLT/PTB AOR⫽1.69;CI: 1.58-1.80. CONCLUSION: Opioid use in pregnancy is associated with a significant risk for threatened preterm labor and preterm delivery, even after considering social factors, tobacco and alcohol use. Efforts to reduce this potentially avoidable risk of prematurity warrant serious consideration.
Adjusted estimates for the association between opioid during pregnancy and threatening preterm labor, preterm birth or either of the diagnoses in the United States, 1998-2009
*Estimate statistically significant at a p-value of 0.05.
532 Short cervix and activity restriction William Grobman1 1 Maternal-Fetal Medicine Units Network, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD
OBJECTIVE: To evaluate determinants of and outcomes associated with activity restriction among women with a short cervix. STUDY DESIGN: Secondary analysis of a randomized trial of 17-alpha hydroxyprogesterone caproate (17OHP) for prevention of preterm birth (PTB) ⬍ 37 weeks among women with singleton gestations and cervices ⬍ 30 mm by mid-trimester transvaginal ultrasound. Women were asked weekly whether they had been placed on pelvic, work, or non-work rest. “Any activity restriction” was defined as being placed on any type of rest. Factors associated with any activity restriction were determined. The association between PTB and activity restriction was estimated by both univariable and multivariable analyses. RESULTS: Of the 657 women in the trial, 646 (98%) responded to questions regarding activity restriction. 252 (39.0%) were placed on any activity restriction at a median of 23.9 weeks (IQ range 22.6 - 27.9 weeks). Women placed on activity restriction had an older mean age (23.1 vs. 21.6 years, p ⬍ .001), had a shorter mean cervical length (21.8 vs. 25.2 mm, p ⬍ .001), were more likely to have funneling (29% vs.
Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology
S227
Doppler Assess, Fetus, Prematurity, U/S, Med-Surg-Diseases
STUDY DESIGN: We compared outcomes between two large cohorts of twin pregnancies who delivered in New York City from 2003-2012. One cohort (n⫽532) was managed by a single maternal-fetal medicine practice and delivered at one large academic medical center. This cohort underwent routine CL screening every 2-3 weeks starting at 16 weeks and fFN screening every 2-3 weeks beginning at 22 weeks. The second cohort (n⫽456) were all twin pregnancies delivered at a second large academic center. The second cohort did not undergo routine CL and fFN screening and only had these tests done as clinically indicated. Outcomes measured include cerclage placement, PTB, spontaneous PTB (SPTB), and antenatal corticosteroid (ACS) exposure. RESULTS: Rates of cerclage placement, PTB, and SPTB were similar between the two groups (Table). However, routine screening using CL and fFN was associated with improved rates of ACS exposure in women who delivered ⬍34 weeks and 34-36 6/7 weeks, without an increased ACS exposure in women who delivered at term. CONCLUSION: In twin pregnancies, routine CL and fFN screening does not reduce the risk of PTB or SPTB. However, the routine use of these tests significantly improves ACS exposure for women who deliver preterm without significantly increasing ACS exposure to women who deliver at term.
528 Leukotriene receptor antagonist as a novel tocolytic in an in vitro model of human uterine contractility for preventing preterm labor Stéphanie Corriveau1, Simon Blouin1, Éric Rousseau2, JeanCharles Pasquier1 1 Université de Sherbrooke, Obstetrics and gynecology, Sherbrooke, QC, Canada, 2Université de Sherbrooke, Physiology and Biophysic, Sherbrooke, QC, Canada
OBJECTIVE: The presence of an inflammatory process is a risk factor for prematurity. Among tocolysis, indomethacin (COX inhibitor) remains efficient but leads to major secondary effects. In a previous study, we explored the inhibition of an alternative arachidonic metabolic pathway: the lipoxygenases (LOX) which inhibit leukotriene production and had potency similar to indomethacin. This study analyzed the ability of montelukast, a leukotriene receptor antagonist, to produce a potent tocolytic effect alone or in combination with nifedipine, a Ca2⫹ channel blocker currently used in clinic. STUDY DESIGN: Uterine biopsies were performed, from consenting women undergoing elective C-sections at term (N⫽20). Isometric tension measurements were performed on human myometrial strips (n⫽120) to establish concentration-response curves and to quantify Ca2⫹ sensitivity to montelukast on -escin permeabilized tissues. Contractile activities were quantified by calculating the area under the curve (AUC). Myometrial fractions were analyzed by immunoblotting and mRNA was extracted to quantify LOX gene expression levels. RESULTS: The immunodetection analysis as well as the gene expression levels indicate the presence of LOX enzymes in myometrium. An increase in AUC was quantified following the addition of LTD4, an end-product of the LOX pathway (p⫽0.02). Hence, the addition of montelukast produced a significant tocolytic effect by decreasing the frequency and the AUC (IC50⫽1M). Addition of 1M montelukast also results in a reduced Ca2⫹ sensitivity as compared to the control
S226
www.AJOG.org
(EC50 of 589 and 295nM, respectively). An additive effect is also observed with the combined use of nifedipine (p⫽0.01). CONCLUSION: We demonstrated the potency of montelukast as a tocolytic in a human uterine model. The results obtained with montelukast in combination with nifedipine could represent a therapeutic approach to reduce inflammation associated with prematurity while facilitating the inhibition of preterm labor.
529 Cervical cerclage, progesterone supplementation, and spontaneous preterm birth Tracy Manuck1, Manijeh Kamyar1, M. Sean Esplin2, Robert Silver1, T. Flint Porter2, Michael Varner1 1
University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, Intermountain Healthcare, Maternal-Fetal Medicine, Murray, UT
2
OBJECTIVE: Women with a prior spontaneous preterm birth (SPTB) and/or prior or current cervical insufficiency may be candidates for both supplementation with 17-alpha hydroxyprogesterone caproate (17P) and cervical cerclage placement. However, the relationship between the simultaneous use of these interventions and SPTB is uncertain. We sought to examine pregnancy outcomes among women with cerclage with and without 17P. STUDY DESIGN: Retrospective cohort of women with singleton pregnancies from 2 tertiary-care centers 2009-2012. Women undergoing cervical cerclage placement for any indication ⬍26 weeks were included. Women who also received 17P prophylaxis (cerclage⫹17P group) were compared to those who did not receive 17P (cerclageonly group). Data were analyzed with Chi-square, Student’s t-test, and logistic regression. RESULTS: 87 women were included; 39 (44.8%) received 17P. Women in the cerclage⫹17P group did not differ from those in the cerclageonly group with regards to earliest prior SPTB (23.3 vs. 23.2, p⫽0.96) or number of prior PTB (median⫽1 for both groups). Other characteristics and outcomes also were similar among groups (Table). Survival analysis revealed no differences in delivery gestational age based on 17P (Figure). In regression analyses controlling for potential confounders, 17P use was not associated with pregnancy prolongation. CONCLUSION: Among women with a cervical cerclage, the addition of 17P does not appear to prolong pregnancy, and overall rates of prematurity are high. Larger studies should confirm this finding and further investigate additional preventative strategies for women with cervical insufficiency.
Data are n (%) unless otherwise indicated
American Journal of Obstetrics & Gynecology Supplement to JANUARY 2013
www.AJOG.org
Doppler Assess, Fetus, Prematurity, U/S, Med-Surg-Diseases
Poster Session III
STUDY DESIGN: The Nationwide Inpatient Sampla (NIS) data from
Antenatal characteristics and pregnancy outcomes among women with cerclage, stratified by 17P supplementation
530 Next generation sequencing identifies the IL-12 receptor beta gene as a potential mediator in the response to 17-alpha-hydroxyprogesterone caproate for the prevention of recurrent prematurity Tracy Manuck1, Scott Watkins2, Sean Esplin3, Marc Jackson3, Lynn Jorde2, Michael Varner1 1
University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, University of Utah, Human Genetics, Salt Lake City, UT, 3Intermountain Healthcare, Maternal Fetal Medicine, Salt Lake City, UT 2
OBJECTIVE: 17-alpha-hydroxyprogesterone caproate (17P) reduces recurrent preterm birth (PTB) in some, but not all, women. We hypothesized that genetic polymorphisms affect variable response to 17P. STUDY DESIGN: Women with a history of ⱖ1 spontaneous singleton PTB ⬍34 wks who received weekly 17P were recruited prospectively from a prematurity prevention clinic from 2008-2010. Women were classified as a 17P responder or non-responder based on the difference in delivery gestational age (GA) between their 17P treated and untreated pregnancy/pregnancies. Whole exome sequencing was performed using Illumina® HiSeq2000 next generation technology. Each individual was sequenced for ⬃180,000 protein-coding exons. Genomes were compared between responders and non-responders using the Variant Annotation, Analysis & Search Tool (VAAST), a probabilistic search tool for identifying disease causing variants in personal genome sequences. Genome-wide significance was set at p⬍2.4x10-6. RESULTS: 24 women (19 responders, 5 non-responders), all Caucasian, were included. Responder and non-responder groups did not differ with regards to median number of pregnancies (3 vs. 4, p⫽0.67), history of cervical insufficiency (26% vs. 20%, p⫽0.77), or history of PPROM (32% vs. 40%, p⫽0.72). The GA of each woman’s earliest PTB also did not differ (27.9 vs. 29.7 wks, p⫽0.35), but responders achieved ⫹9.1 wks longer with 17P, vs. ⫹1.5 wks for nonresponders (p⬍0.001). All samples met genotype quality filters. The average genome-wide coverage depth was 47.3 (range 20.1-64.6). We assumed recessive inheritance and locus heterogeneity. VAAST identified IL12RB1 (Interleukin-12 receptor beta) as associated with nonresponse to 17P (p⫽3.03 ⫻ 10⫺8). CONCLUSION: Response to 17P for the prevention of recurrent PTB may be genetically mediated. These results should be confirmed in a larger cohort and may lead to the development of a ‘17P response panel.’
531 Epidemic of opioids use during pregnancy and the risk of preterm birth in the United States Valerie Whiteman1, Hamisu Salihu2, Jason Salemi2, Mulubrhan Mogos2 1 University of South Florida Morsani College of Medicine, OB/GYN Division of Maternal Fetal Medicine, Tampa, FL, 2University of South Florida College of Public Health, Epidemiology and Biostatistics, Tampa, FL
OBJECTIVE: To demonstrate the national increase in threatened preterm labor and preterm delivery in patients with opioid use during pregnancy.
1998-2009 was utilized in this retrospective cohort study. We investigated the association between opioid use during pregnancy and threatened preterm labor (TPTL) and preterm birth(PTB). To account for the complex sampling design in the NIS data, we used the SURVEYMEANS and SURVEYLOGISTIC procedures in SAS 9.2 to generate the estimates. We used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) codes to identify discharges with TPRL(ICD9-CM - 644.0x) and PTB (ICD9-CM - 644.2x). RESULTS: During the study period there were a total of 55,781,965 pregnancy related discharges. There were 1,246,430 discharges for TPRL, 3,644,534 discharges for PTB and 4,889,853 discharges for TPTL and/or PTB. The prevalence of opioid use during pregnancy among these women in 1998 was 25.04 per 10,000 pregnancy related discharges. By 2009 this increased to 40.22/10,000 representing a 61.1% increase in opioid use during the study period. After controlling for age, race and household income; discharges with the diagnosis of opioid use demonstrated an increased risk of TPTL: Adjusted Odds Ratio[AOR]⫽1.35 and 95% confidence interval [CI]:1.23-1.49; PTB: AOR⫽1.98, CI 1.84-2.13; and combined TPTL/PTB AOR⫽1.86, CI: 1.84-2.13. This risk remains significant even after controlling for alcohol and tobacco use: TPTL AOR⫽1.33,CI:1.21-1.46; PTB AOR⫽1.76: CI 1.64-1.89 and combined TPLT/PTB AOR⫽1.69;CI: 1.58-1.80. CONCLUSION: Opioid use in pregnancy is associated with a significant risk for threatened preterm labor and preterm delivery, even after considering social factors, tobacco and alcohol use. Efforts to reduce this potentially avoidable risk of prematurity warrant serious consideration.
Adjusted estimates for the association between opioid during pregnancy and threatening preterm labor, preterm birth or either of the diagnoses in the United States, 1998-2009
*Estimate statistically significant at a p-value of 0.05.
532 Short cervix and activity restriction William Grobman1 1 Maternal-Fetal Medicine Units Network, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD
OBJECTIVE: To evaluate determinants of and outcomes associated with activity restriction among women with a short cervix. STUDY DESIGN: Secondary analysis of a randomized trial of 17-alpha hydroxyprogesterone caproate (17OHP) for prevention of preterm birth (PTB) ⬍ 37 weeks among women with singleton gestations and cervices ⬍ 30 mm by mid-trimester transvaginal ultrasound. Women were asked weekly whether they had been placed on pelvic, work, or non-work rest. “Any activity restriction” was defined as being placed on any type of rest. Factors associated with any activity restriction were determined. The association between PTB and activity restriction was estimated by both univariable and multivariable analyses. RESULTS: Of the 657 women in the trial, 646 (98%) responded to questions regarding activity restriction. 252 (39.0%) were placed on any activity restriction at a median of 23.9 weeks (IQ range 22.6 - 27.9 weeks). Women placed on activity restriction had an older mean age (23.1 vs. 21.6 years, p ⬍ .001), had a shorter mean cervical length (21.8 vs. 25.2 mm, p ⬍ .001), were more likely to have funneling (29% vs.
Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology
S227