- Email: [email protected]
337: Transplacental administration of rosiglitazone attenuates hyperoxic lung injury in a preterm rabbit model
Poster Session II initial presentation of threatened preterm birth.The frequency of HCA and funisitis were determined according to the causes; PTL, PROM, or IIOC. RESULTS: 1) A total of 278 women were included in the study (111 cases of PTL, 148 cases of PROM, and 19 cases of IIOC) and the frequency of HCA and funisitis were 51% (141/278) and 16%(45/ 278), respectively; 2) The frequency of HCA and funisitis were not different between cases with PTL and those with PROM; 3) However, the frequency of HCA and funisitis in IIOC were higher than that in PTL or PROM. The different frequency of funisitis between PTL and IIOC remained significant after adjustment. CONCLUSION: The frequency of funisitis in IIOC was higher than in PTL. This finding could be interpreted by two different points of views: 1) the dilated cervical os (the absence of cervix as a barrier) may be more critical in the development of ascending infection from vagina rather than uterine contraction, or 2) there may be fundamental difference in the pathogenesis between CI and PTL.
The frequency of HCA and funisitis according to the etiology of PTB
P(a), between PTL and PROM; P(b), between PROM and IIOC; P(c), between PTL and IIOC; P(d), among three groups
334 Identification of 22q11 microdeletions by noninvasive prenatal testing (NIPT) e the clinical experience
Juan-Sebastian Saldivar1, Thomas Monroe1, Theresa Boomer1, Jenna Wardrop1, Julie Jesiolowski1, Nilesh Dharajiya1 1
Sequenom Laboratories, San Diego, CA
OBJECTIVE: NIPT for fetal aneuploidies has become routine practice
in pregnancy management. It’s accuracy and no associated risk for pregnancy loss has resulted in widespread adoption of the test. A whole genome approach enables detecting subchromosomal events. A novel algorithm using low coverage sequencing data to identify fetal microdeletion events with data output akin to microarray has been developed by Sequenom Laboratories. STUDY DESIGN: Maternal blood samples submitted to Sequenom Laboratories were subjected to DNA extraction and library preparation followed by whole genome massively parallel sequencing as described by Jensen et al. Sequencing data was analyzed using an algorithm to detect subchromosomal events such as 22q11 microdeletions. RESULTS: The MaterniT21TM PLUS test identified 20 cases with a 22q11 deletion (0.5 - 3.15 Mb). Eleven cases were confirmed by subsequent invasive testing. Five other cases had clinical findings of complex heart defects or Tetralogy of Fallot consistent with the NIPT result. Confirmatory testing in these cases was either declined or pending. In four additional cases, no clinical signs were identified and outcomes were pending. No confirmed false positives have been identified. One of the confirmed cases was a twin gestation where one twin was positive for the 22q deletion. Additionally, carrier status was established in the mother who has a history of developmental delay and phonation abnormality suggestive of a laryngeotracheal anomaly which might be seen in 22q deletion syndrome. CONCLUSION: Noninvasive testing has rapidly become a part of the standard of care for aneuploidy testing since launching in 2011. We have demonstrated continued expansion of the capabilities of this technology by effectively detecting 22q11 microdeletions. This abstract provides clinical evidence and support to broaden the scope of non-invasive testing to detect subchromosomal deletion/duplication events and the potential to derive fetal karyotypes in the future.
335 Withdrawn
ajog.org 336 Mid-trimester sonographic fetal thymus measurements do not predict preterm birth Justin Brandt1, Jamie Bastek1, Eileen Wang1, Stephanie Purisch1, Nadav Schwartz1 1 Maternal and Child Health Research Program, University of Pennsylvania Perelman School of Medicine, Dept of OBGYN, Philadelphia, PA
OBJECTIVE: Emerging evidence suggests that fetal thymus involution may occur as a non-specific response to in utero stress and inflammation (DiNaro, AJOG, 2006). We therefore sought to determine if antenatal assessment of the fetal thymus during the mid-trimester anatomy scan could identify pregnancies at increased risk for preterm birth. STUDY DESIGN: Transabdominal fetal thymus measurements and transvaginal cervical length measurements were prospectively obtained in singleton pregnancies from 18-23 6/7 weeks gestation from 05/01-10/01/2013. The transverse thymus diameter (TRAN), the anterior-posterior thymus diameter (AP), and the thymic-thoracic ratio (TT) were measured. The primary outcome was defined as a PTD<37 weeks (PTD37). Secondary outcomes included spontaneous PTB<37 weeks (sPTD37) and PTD<34 weeks (PTD34). Assuming a prevalence of 12%, we estimated that 517 patients would be needed to be powered to see a sensitivity of 80% for the prediction of PTD37. The study sonographers demonstrated good reproducibility of all measurements prior to starting the study with ICC for each measurement >0.8. RESULTS: Complete OB data and thymus measurements were available for 520 patients. The prevalence of PTB37 was 12.3% (n¼64). Among those who had a term vs preterm delivery, there was no difference in median GA at which ultrasounds were performed (20.5 vs 20.6 weeks, p¼0.9). There were no differences in TRAN, AP, and TT between the groups (TABLE). There were no significant differences when these analyses were repeated after excluding patients with a prior preterm birth. Additionally, there were no significant differences between thymus measurements and sPTD37 (TRAN: p¼0.88, AP: p¼0.21, and TT: p¼0.38) or PTD34 (TRAN: p¼0.72, AP: p¼0.06, and TT: p¼0.3). CONCLUSION: In this powered, negative study, sonographic assessment of the mid-trimester fetal thymus did not identify patients at risk for PTB37. Routine thymus measurements during the anatomy scan is not clinically useful for preterm birth prevention.
Mid-trimester thymus measurements and the prediction of preterm birth
Data are median (IQR) and meanSTD. P-values determined by Wilcoxon rank-sum (non-parametric continuous data) and T-Test (parametric continuous data).
337 Transplacental administration of rosiglitazone attenuates hyperoxic lung injury in a preterm rabbit model
Jute Richter1, Jan Deprest1, Taro Nagatomo2, Julio Jimenez1, Jeroen Vanoirbeek3, Jaan Toelen2
1 University Hospitals Leuven, OB/GYN, Leuven, Belgium, 2University Hospitals Leuven, Pediatrics, Leuven, Belgium, 3KU Leuven, Department of Public Health, Leuven, Belgium
OBJECTIVE: Continuous improvements in perinatal care have allowed the survival of ever more premature infants. The establishment of respiration with an extremely immature yet still developing lung ultimately results in chronic lung injury with significant mortality and morbidity. Lipids are cytoprotective against hyperoxic lung injury. Rosiglitazone is a potent inhibitor of peroxisome proliferator-
S178 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2015
Poster Session II
ajog.org activated receptor g (PPARg), affecting lipid trafficking in lipofibroblasts and is effective in a rodent model for hyperoxic lung injury. Herein we explore the effect of prenatal administration of rosiglitazone to prevent hyperoxia induced lung injury by prenatal administration of rosiglitazone in a preterm rabbit model (Richter et al, Am J Physiol Lung Cell Mol Physiol. 2014). STUDY DESIGN: Time mated pregnant rabbits were injected with saline (sal) or rosiglitazone (rosi; 3mg/kg) 48 and 24 hours prior to preterm delivery at 28 days (term¼31 d). The pups were held in normoxia (21% O2) or hyperoxia (>95% O2) at 32 C, with twice daily feeding and antibiotic administration. Their lungs were examined at three different sacrifice time points (1 hour, 24 hours and 7 days), using lung function (Flexivent ventilation), morphometry and immunohistochemistry for VEGF, Flk-1, SP-B. RESULTS: Rosiglitazone administration resulted in a significant increased expression of VEGF, Flk-1 and SP-B immediately after delivery. At day 7 there was a sustained increase in SP-B and a more mature lung parenchymal architecture in rosiglitazone exposed pups (Fig 1). Functionally this coincided with a significant decrease in tissue damping (resistance; Fig 2). CONCLUSION: In a preterm rabbit model prenatal maternal administration of rosiglitazone attenuates neonatal hyperoxic lung injury and results in a more mature pulmonary parenchyma.
STUDY DESIGN: Time mated pregnant rabbits were used. Omeprazole was administered (1) directly to the fetus (24 or 28 hrs prior to preterm delivery day 28 out of 31), (2) to the dam (8, 24 or 48 hrs before delivery) and (3) neonatal to the pups in different doses (2 low; 10 - medium or 20 - high mg/kg), controls were injected with the same volume of saline. Pups were housed in normoxia (21%) or hyperoxia (>95%) for 5 days. Outcome parameters were induction of CYP1A1 measured by real-time polymerase chain reaction (RTPCR) immediately after delivery, at day 3 and day 5, as well as lung function, morphometry and immunohistochemistry assessed at day 5 of life. RESULTS: Only daily neonatal injections demonstrated a dosedependent increase in CYP1A1 (Fig1). Lung function tests showed a significant improvement in tissue damping, tissue elasticity, total lung capacity, static compliance and elastance (Fig2). Morphometry revealed a more complex distal airway architecture for the highest dose omeprazole. Surfactant protein B, vascular endothelial growth factor and its receptor were significantly increased after treatment with omeprazole. CONCLUSION: Neonatal daily administration of omeprazole induces CYP1A1 in a dose-dependent matter and attenuate hyperoxic lung injury in preterm rabbits.
Figure 1: CYP1A1 induction.
Fig 1: Forced oscillation primewave-8 measurement for Airway Resistance (Rn), Tissue Damping (G) and Tissue Elasticity (H). Bars are mean SEM
Figure 2: Lung function tests in neonatal pups at 3 resp. 5 days of life. Fig 2: Morphometric analysis of the linear intercept (Lm), mean terminal bronchiolar density (MTBD) and mean wall transection length (Lmw).
339 Predictors of preterm birth: a comparison of cervical length, fetal fibronectin and fetal adrenal gland enlargement Kataneh Salari1, Marjorie Treadwell1, Katherine Thompson1 1
University of Michigan, Obstetrics and Gynecology, Cupertino, CA
OBJECTIVE: To test whether fetal adrenal gland enlargement (FAG
338 Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury
Jute Richter1, Julio Jimenez1, Taro Nagatomo1, Jeroen Vanoirbeek2, Jan Deprest1, Jaan Toelen1
1 KU Leuven, Department of Development and Regeneration, Leuven, Belgium, 2KU Leuven, Department of Public Health and Primary Care, Leuven, Belgium
OBJECTIVE: The administration of supplemental oxygen to treat
ventilatory insufficiency can result in the formation of reactive oxygen species and subsequent tissue damage. Cytochrome P4501A1 (CYP1A1) can modulate hyperoxic lung injury by a currently unknown mechanism. Our objective was to evaluate the effect of administration of omeprazole on the induction of CYP1A1 and its influence on hyperoxic lung injury in a preterm rabbit model (Richter et al, Am J Physiol Lung Cell Mol Physiol. 2014).
ratio) on 2-dimensional ultrasound is an independent predictor of preterm birth (PTB) and whether it performs superior to transvaginal cervical length or fetal fibronectin in identifying women at risk for PTB within 7 days. STUDY DESIGN: Pregnant women between 21 and 34 weeks’ gestation who presented with signs of preterm labor, preterm premature rupture of membranes or cervical shortening were recruited. Twodimensional ultrasound was used to perform transvaginal cervical length (TVCL) and fetal adrenal gland measurements within 24 hours of evaluation. Patients were then followed prospectively until delivery. RESULTS: A total of 76 patients were recruited, of whom 10 (13.2%) delivered within 7 days of evaluation. Multivariate logistic regression revealed that the FAG ratio was an independent predictor of PTB (OR 4.2; P ¼ 0.04). Fetal adrenal gland enlargement > 57.8% was
Supplement to JANUARY 2015 American Journal of Obstetrics & Gynecology
S179
The frequency of HCA and funisitis according to the etiology of PTB
P(a), between PTL and PROM; P(b), between PROM and IIOC; P(c), between PTL and IIOC; P(d), among three groups
334 Identification of 22q11 microdeletions by noninvasive prenatal testing (NIPT) e the clinical experience
Juan-Sebastian Saldivar1, Thomas Monroe1, Theresa Boomer1, Jenna Wardrop1, Julie Jesiolowski1, Nilesh Dharajiya1 1
Sequenom Laboratories, San Diego, CA
OBJECTIVE: NIPT for fetal aneuploidies has become routine practice
in pregnancy management. It’s accuracy and no associated risk for pregnancy loss has resulted in widespread adoption of the test. A whole genome approach enables detecting subchromosomal events. A novel algorithm using low coverage sequencing data to identify fetal microdeletion events with data output akin to microarray has been developed by Sequenom Laboratories. STUDY DESIGN: Maternal blood samples submitted to Sequenom Laboratories were subjected to DNA extraction and library preparation followed by whole genome massively parallel sequencing as described by Jensen et al. Sequencing data was analyzed using an algorithm to detect subchromosomal events such as 22q11 microdeletions. RESULTS: The MaterniT21TM PLUS test identified 20 cases with a 22q11 deletion (0.5 - 3.15 Mb). Eleven cases were confirmed by subsequent invasive testing. Five other cases had clinical findings of complex heart defects or Tetralogy of Fallot consistent with the NIPT result. Confirmatory testing in these cases was either declined or pending. In four additional cases, no clinical signs were identified and outcomes were pending. No confirmed false positives have been identified. One of the confirmed cases was a twin gestation where one twin was positive for the 22q deletion. Additionally, carrier status was established in the mother who has a history of developmental delay and phonation abnormality suggestive of a laryngeotracheal anomaly which might be seen in 22q deletion syndrome. CONCLUSION: Noninvasive testing has rapidly become a part of the standard of care for aneuploidy testing since launching in 2011. We have demonstrated continued expansion of the capabilities of this technology by effectively detecting 22q11 microdeletions. This abstract provides clinical evidence and support to broaden the scope of non-invasive testing to detect subchromosomal deletion/duplication events and the potential to derive fetal karyotypes in the future.
335 Withdrawn
ajog.org 336 Mid-trimester sonographic fetal thymus measurements do not predict preterm birth Justin Brandt1, Jamie Bastek1, Eileen Wang1, Stephanie Purisch1, Nadav Schwartz1 1 Maternal and Child Health Research Program, University of Pennsylvania Perelman School of Medicine, Dept of OBGYN, Philadelphia, PA
OBJECTIVE: Emerging evidence suggests that fetal thymus involution may occur as a non-specific response to in utero stress and inflammation (DiNaro, AJOG, 2006). We therefore sought to determine if antenatal assessment of the fetal thymus during the mid-trimester anatomy scan could identify pregnancies at increased risk for preterm birth. STUDY DESIGN: Transabdominal fetal thymus measurements and transvaginal cervical length measurements were prospectively obtained in singleton pregnancies from 18-23 6/7 weeks gestation from 05/01-10/01/2013. The transverse thymus diameter (TRAN), the anterior-posterior thymus diameter (AP), and the thymic-thoracic ratio (TT) were measured. The primary outcome was defined as a PTD<37 weeks (PTD37). Secondary outcomes included spontaneous PTB<37 weeks (sPTD37) and PTD<34 weeks (PTD34). Assuming a prevalence of 12%, we estimated that 517 patients would be needed to be powered to see a sensitivity of 80% for the prediction of PTD37. The study sonographers demonstrated good reproducibility of all measurements prior to starting the study with ICC for each measurement >0.8. RESULTS: Complete OB data and thymus measurements were available for 520 patients. The prevalence of PTB37 was 12.3% (n¼64). Among those who had a term vs preterm delivery, there was no difference in median GA at which ultrasounds were performed (20.5 vs 20.6 weeks, p¼0.9). There were no differences in TRAN, AP, and TT between the groups (TABLE). There were no significant differences when these analyses were repeated after excluding patients with a prior preterm birth. Additionally, there were no significant differences between thymus measurements and sPTD37 (TRAN: p¼0.88, AP: p¼0.21, and TT: p¼0.38) or PTD34 (TRAN: p¼0.72, AP: p¼0.06, and TT: p¼0.3). CONCLUSION: In this powered, negative study, sonographic assessment of the mid-trimester fetal thymus did not identify patients at risk for PTB37. Routine thymus measurements during the anatomy scan is not clinically useful for preterm birth prevention.
Mid-trimester thymus measurements and the prediction of preterm birth
Data are median (IQR) and meanSTD. P-values determined by Wilcoxon rank-sum (non-parametric continuous data) and T-Test (parametric continuous data).
337 Transplacental administration of rosiglitazone attenuates hyperoxic lung injury in a preterm rabbit model
Jute Richter1, Jan Deprest1, Taro Nagatomo2, Julio Jimenez1, Jeroen Vanoirbeek3, Jaan Toelen2
1 University Hospitals Leuven, OB/GYN, Leuven, Belgium, 2University Hospitals Leuven, Pediatrics, Leuven, Belgium, 3KU Leuven, Department of Public Health, Leuven, Belgium
OBJECTIVE: Continuous improvements in perinatal care have allowed the survival of ever more premature infants. The establishment of respiration with an extremely immature yet still developing lung ultimately results in chronic lung injury with significant mortality and morbidity. Lipids are cytoprotective against hyperoxic lung injury. Rosiglitazone is a potent inhibitor of peroxisome proliferator-
S178 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2015
Poster Session II
ajog.org activated receptor g (PPARg), affecting lipid trafficking in lipofibroblasts and is effective in a rodent model for hyperoxic lung injury. Herein we explore the effect of prenatal administration of rosiglitazone to prevent hyperoxia induced lung injury by prenatal administration of rosiglitazone in a preterm rabbit model (Richter et al, Am J Physiol Lung Cell Mol Physiol. 2014). STUDY DESIGN: Time mated pregnant rabbits were injected with saline (sal) or rosiglitazone (rosi; 3mg/kg) 48 and 24 hours prior to preterm delivery at 28 days (term¼31 d). The pups were held in normoxia (21% O2) or hyperoxia (>95% O2) at 32 C, with twice daily feeding and antibiotic administration. Their lungs were examined at three different sacrifice time points (1 hour, 24 hours and 7 days), using lung function (Flexivent ventilation), morphometry and immunohistochemistry for VEGF, Flk-1, SP-B. RESULTS: Rosiglitazone administration resulted in a significant increased expression of VEGF, Flk-1 and SP-B immediately after delivery. At day 7 there was a sustained increase in SP-B and a more mature lung parenchymal architecture in rosiglitazone exposed pups (Fig 1). Functionally this coincided with a significant decrease in tissue damping (resistance; Fig 2). CONCLUSION: In a preterm rabbit model prenatal maternal administration of rosiglitazone attenuates neonatal hyperoxic lung injury and results in a more mature pulmonary parenchyma.
STUDY DESIGN: Time mated pregnant rabbits were used. Omeprazole was administered (1) directly to the fetus (24 or 28 hrs prior to preterm delivery day 28 out of 31), (2) to the dam (8, 24 or 48 hrs before delivery) and (3) neonatal to the pups in different doses (2 low; 10 - medium or 20 - high mg/kg), controls were injected with the same volume of saline. Pups were housed in normoxia (21%) or hyperoxia (>95%) for 5 days. Outcome parameters were induction of CYP1A1 measured by real-time polymerase chain reaction (RTPCR) immediately after delivery, at day 3 and day 5, as well as lung function, morphometry and immunohistochemistry assessed at day 5 of life. RESULTS: Only daily neonatal injections demonstrated a dosedependent increase in CYP1A1 (Fig1). Lung function tests showed a significant improvement in tissue damping, tissue elasticity, total lung capacity, static compliance and elastance (Fig2). Morphometry revealed a more complex distal airway architecture for the highest dose omeprazole. Surfactant protein B, vascular endothelial growth factor and its receptor were significantly increased after treatment with omeprazole. CONCLUSION: Neonatal daily administration of omeprazole induces CYP1A1 in a dose-dependent matter and attenuate hyperoxic lung injury in preterm rabbits.
Figure 1: CYP1A1 induction.
Fig 1: Forced oscillation primewave-8 measurement for Airway Resistance (Rn), Tissue Damping (G) and Tissue Elasticity (H). Bars are mean SEM
Figure 2: Lung function tests in neonatal pups at 3 resp. 5 days of life. Fig 2: Morphometric analysis of the linear intercept (Lm), mean terminal bronchiolar density (MTBD) and mean wall transection length (Lmw).
339 Predictors of preterm birth: a comparison of cervical length, fetal fibronectin and fetal adrenal gland enlargement Kataneh Salari1, Marjorie Treadwell1, Katherine Thompson1 1
University of Michigan, Obstetrics and Gynecology, Cupertino, CA
OBJECTIVE: To test whether fetal adrenal gland enlargement (FAG
338 Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury
Jute Richter1, Julio Jimenez1, Taro Nagatomo1, Jeroen Vanoirbeek2, Jan Deprest1, Jaan Toelen1
1 KU Leuven, Department of Development and Regeneration, Leuven, Belgium, 2KU Leuven, Department of Public Health and Primary Care, Leuven, Belgium
OBJECTIVE: The administration of supplemental oxygen to treat
ventilatory insufficiency can result in the formation of reactive oxygen species and subsequent tissue damage. Cytochrome P4501A1 (CYP1A1) can modulate hyperoxic lung injury by a currently unknown mechanism. Our objective was to evaluate the effect of administration of omeprazole on the induction of CYP1A1 and its influence on hyperoxic lung injury in a preterm rabbit model (Richter et al, Am J Physiol Lung Cell Mol Physiol. 2014).
ratio) on 2-dimensional ultrasound is an independent predictor of preterm birth (PTB) and whether it performs superior to transvaginal cervical length or fetal fibronectin in identifying women at risk for PTB within 7 days. STUDY DESIGN: Pregnant women between 21 and 34 weeks’ gestation who presented with signs of preterm labor, preterm premature rupture of membranes or cervical shortening were recruited. Twodimensional ultrasound was used to perform transvaginal cervical length (TVCL) and fetal adrenal gland measurements within 24 hours of evaluation. Patients were then followed prospectively until delivery. RESULTS: A total of 76 patients were recruited, of whom 10 (13.2%) delivered within 7 days of evaluation. Multivariate logistic regression revealed that the FAG ratio was an independent predictor of PTB (OR 4.2; P ¼ 0.04). Fetal adrenal gland enlargement > 57.8% was
Supplement to JANUARY 2015 American Journal of Obstetrics & Gynecology
S179