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252: Placental telomere length in preterm fetal growth restriction due to placental insufficiency
Poster Session I
ajog.org
251 The systematic error in the estimation of fetal weight and the underestimation of fetal growth restriction (FGR): a population-level analytic model Justin R. Lappen, Stephen A. Myers MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
OBJECTIVE: Antenatal diagnosis of FGR remains poor with the ma-
jority of cases remaining undiagnosed. While several factors contribute to the underdiagnosis of FGR, the systematic error in ultrasound EFW is generally not considered. The objective of this study was to characterize and quantify the impact of the systematic error in EFW on the underdiagnosis of FGR. STUDY DESIGN: Previous analysis has demonstrated that with a modified Hadlock model, 80% of fetuses have a birth weight within 10% of EFW and 50% are within 5% of EFW (Lee 2009). An analytic model was generated using published data from the NICHD Fetal Growth Studies. The model applied the systematic error across centiles at 30-40 weeks gestation to calculate the EFW centile representing the point at which the error in estimation results in an EFW <10th. Quantification of the underdiagnosis of FGR was performed. We assumed a proportional, bidirectional error in EFW that does not vary by gestational age. Given the clinical significance of underdiagnosing FGR, this analysis focused on the 1-sided error resulting in an underestimation of fetal weight. RESULTS: Using the above parameters, 25% of all fetuses with an EFW at the 20th percentile have an EFW <10th. 25% of fetuses with an EFW at the 15th and 12th percentiles have an EFW <8th and <6th respectively. With 80% of fetuses within 10% of EFW, 10% of all fetuses with an EFW at the 30th percentile have an EFW <10th. 10% of fetuses with an EFW at the 25th and 15st percentile have an EFW <9th and <5th respectively (Figure 1). This effect is continuous across EFW centiles, with a clinically meaningful increase in FGR underestimation beginning at an EFW in the 20-25th percentile (Figure 2). CONCLUSION: The systematic error in the estimation of fetal weight is a significant factor contributing to the underestimation of fetuses predicted to have FGR, resulting in increased likelihood of missed diagnoses as percentile EFW decreases. The error in EFW should be incorporated into current screening and surveillance recommendations for the detection and management of FGR. Independent of the centile at which the morbidity related to FGR begins, whether the 10th, 5th or 3rd percentile, this analysis suggests the need to modify to the current paradigm for identifying and responding to fetuses estimated to be at risk.
252 Placental telomere length in preterm fetal growth restriction due to placental insufficiency Kiesha N. Benn1, Christine Abreu1, Jeanne D. Rolle2, Ye Sun2, Chia-ling Kuo1, M. Melinda Sanders1, Naveed Hussain1, Winston A. Campbell1 1
UConn Health Center, Farmington, CT, 2UConn School of Medicine, Farmington, CT
OBJECTIVE: Previous studies report shortened placental telomere length (TL) in growth restriction of term infants. Short telomere
S156 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2017
Poster Session I
ajog.org lengths may not be a late occurrence, but starts early in fetuses with fetal growth restriction (FGR). We evaluated if preterm fetuses with FGR due to placental insufficiency (PI) have shortened telomere lengths vs gestational age matched controls. STUDY DESIGN: We performed a retrospective matched (1:2) casecontrol study of preterm (24.0 - 36.6 weeks) fetuses with FGR due to PI vs appropriately grown preterm controls. Cases: FGR by ultrasound estimated fetal weight (EFW) or fetal abdominal circumference (AC) <10%ile & PI by abnormal umbilical artery Doppler velocimetry or placental histology features of PI. Controls: at risk for FGR but normal EFW or AC and no histologic features of PI. Exclusions: twins, stillbirths, fetal anomalies, illegal substance or tobacco use or fetal viral infections. TL was measured and expressed as a T/S ratio using a quantitative polymerase chain reaction (QPCR) technique. T is the relative quantity of amplified telomere repeats and S is a known single copy gene in the genome. Placental tissue was obtained from formalin fixed paraffin embedded (FFPE) biopsies at the base of the placental-site umbilical cord insertion (PUCI). RESULTS: We identified 38 cases, 68 controls. There was no difference in mean gestational age at the time of delivery for cases and controls, 30.39 3.51 vs 30.47 3.54 (P¼0.8829). Cases vs controls were more likely complicated by hypertensive disease (66% vs 29%, p0.0002), delivered by cesarean birth (84% vs 55%, p0.0032) and lower birth weight (1090.92 489.26 vs 1707.42 734.4, p0.00001). We performed a mean comparison between cases and controls with and without adjustment for potential confounders (gender, hypertensive disease, antenatal steroids, and maternal age). The confounders were not significant. Neonatal deaths were similar in both controls (1%) vs cases (3%). The mean and standard deviations of the T/S ratios were 0.56 0.34 vs 1.04 0.51(p<0.0001) for cases and controls. The mean T/S ratio was 46.1% less in the cases compared to controls. CONCLUSION: Our findings demonstrate that the telomere lengths of cases with preterm FGR are significantly shorter than, gestational age matched, normally grown preterm controls.
253 NICHD racial/ethnic standards for fetal growth - do they predict small for gestational age fetuses and short-term neonatal outcomes better than Hadlock’s chart? Rachel G. Sinkey1, Linda ODIBO1, Methodius G. Tuuli2, Anthony O. Odibo1 1
University of South Florida, Tampa, FL, 2Washington University School of Medicine in St. Louis, St. Louis, MO
OBJECTIVE: To compare the diagnostic accuracy and short-term neonatal outcomes when fetuses are classified by NICHD racial / ethnic standards as compared to Hadlock. STUDY DESIGN: A prospective study was performed recruiting patients with singleton gestations referred for a fetal growth ultrasound between 26 - 36 weeks. Fetal growth was recorded using both NICHD and Hadlock standards; FGR was defined at the 5th and 10th estimated weight (EFW) percentiles. Postnatal growth was defined using Alexander curves; SGA was defined as less than 10th% birthweight. The primary outcome was the sensitivity and specificity of the growth curve to diagnose an SGA neonate. Secondary outcomes included neonatal intensive care unit (NICU) admissions, cord pH less than 7.2, and 5 minute Apgar less than 7. Statistical analyses were performed using Chi-squared and student’s t-test. RESULTS: A total of 678 delivered patients were available for analysis. Median (IQR) age at study entry was 29 (24, 33). Self-reported race demographics included 5% Asian, 38% African American, 10% Hispanic, 46% Caucasian, and 1% multiracial. Median (IQR) prepregnancy BMI was 26.6 (22.2, 33.6). Median (IQR) gestational ages at recruitment and delivery were 32.1 (29.2, 34.1) and 39.0 (37.2, 39.4) weeks, respectively. When FGR was defined at less than 5th%, NICHD appeared to be more sensitive to detect FGR fetuses with subsequent Supplement to JANUARY 2017 American Journal of Obstetrics & Gynecology
S157
ajog.org
251 The systematic error in the estimation of fetal weight and the underestimation of fetal growth restriction (FGR): a population-level analytic model Justin R. Lappen, Stephen A. Myers MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH
OBJECTIVE: Antenatal diagnosis of FGR remains poor with the ma-
jority of cases remaining undiagnosed. While several factors contribute to the underdiagnosis of FGR, the systematic error in ultrasound EFW is generally not considered. The objective of this study was to characterize and quantify the impact of the systematic error in EFW on the underdiagnosis of FGR. STUDY DESIGN: Previous analysis has demonstrated that with a modified Hadlock model, 80% of fetuses have a birth weight within 10% of EFW and 50% are within 5% of EFW (Lee 2009). An analytic model was generated using published data from the NICHD Fetal Growth Studies. The model applied the systematic error across centiles at 30-40 weeks gestation to calculate the EFW centile representing the point at which the error in estimation results in an EFW <10th. Quantification of the underdiagnosis of FGR was performed. We assumed a proportional, bidirectional error in EFW that does not vary by gestational age. Given the clinical significance of underdiagnosing FGR, this analysis focused on the 1-sided error resulting in an underestimation of fetal weight. RESULTS: Using the above parameters, 25% of all fetuses with an EFW at the 20th percentile have an EFW <10th. 25% of fetuses with an EFW at the 15th and 12th percentiles have an EFW <8th and <6th respectively. With 80% of fetuses within 10% of EFW, 10% of all fetuses with an EFW at the 30th percentile have an EFW <10th. 10% of fetuses with an EFW at the 25th and 15st percentile have an EFW <9th and <5th respectively (Figure 1). This effect is continuous across EFW centiles, with a clinically meaningful increase in FGR underestimation beginning at an EFW in the 20-25th percentile (Figure 2). CONCLUSION: The systematic error in the estimation of fetal weight is a significant factor contributing to the underestimation of fetuses predicted to have FGR, resulting in increased likelihood of missed diagnoses as percentile EFW decreases. The error in EFW should be incorporated into current screening and surveillance recommendations for the detection and management of FGR. Independent of the centile at which the morbidity related to FGR begins, whether the 10th, 5th or 3rd percentile, this analysis suggests the need to modify to the current paradigm for identifying and responding to fetuses estimated to be at risk.
252 Placental telomere length in preterm fetal growth restriction due to placental insufficiency Kiesha N. Benn1, Christine Abreu1, Jeanne D. Rolle2, Ye Sun2, Chia-ling Kuo1, M. Melinda Sanders1, Naveed Hussain1, Winston A. Campbell1 1
UConn Health Center, Farmington, CT, 2UConn School of Medicine, Farmington, CT
OBJECTIVE: Previous studies report shortened placental telomere length (TL) in growth restriction of term infants. Short telomere
S156 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2017
Poster Session I
ajog.org lengths may not be a late occurrence, but starts early in fetuses with fetal growth restriction (FGR). We evaluated if preterm fetuses with FGR due to placental insufficiency (PI) have shortened telomere lengths vs gestational age matched controls. STUDY DESIGN: We performed a retrospective matched (1:2) casecontrol study of preterm (24.0 - 36.6 weeks) fetuses with FGR due to PI vs appropriately grown preterm controls. Cases: FGR by ultrasound estimated fetal weight (EFW) or fetal abdominal circumference (AC) <10%ile & PI by abnormal umbilical artery Doppler velocimetry or placental histology features of PI. Controls: at risk for FGR but normal EFW or AC and no histologic features of PI. Exclusions: twins, stillbirths, fetal anomalies, illegal substance or tobacco use or fetal viral infections. TL was measured and expressed as a T/S ratio using a quantitative polymerase chain reaction (QPCR) technique. T is the relative quantity of amplified telomere repeats and S is a known single copy gene in the genome. Placental tissue was obtained from formalin fixed paraffin embedded (FFPE) biopsies at the base of the placental-site umbilical cord insertion (PUCI). RESULTS: We identified 38 cases, 68 controls. There was no difference in mean gestational age at the time of delivery for cases and controls, 30.39 3.51 vs 30.47 3.54 (P¼0.8829). Cases vs controls were more likely complicated by hypertensive disease (66% vs 29%, p0.0002), delivered by cesarean birth (84% vs 55%, p0.0032) and lower birth weight (1090.92 489.26 vs 1707.42 734.4, p0.00001). We performed a mean comparison between cases and controls with and without adjustment for potential confounders (gender, hypertensive disease, antenatal steroids, and maternal age). The confounders were not significant. Neonatal deaths were similar in both controls (1%) vs cases (3%). The mean and standard deviations of the T/S ratios were 0.56 0.34 vs 1.04 0.51(p<0.0001) for cases and controls. The mean T/S ratio was 46.1% less in the cases compared to controls. CONCLUSION: Our findings demonstrate that the telomere lengths of cases with preterm FGR are significantly shorter than, gestational age matched, normally grown preterm controls.
253 NICHD racial/ethnic standards for fetal growth - do they predict small for gestational age fetuses and short-term neonatal outcomes better than Hadlock’s chart? Rachel G. Sinkey1, Linda ODIBO1, Methodius G. Tuuli2, Anthony O. Odibo1 1
University of South Florida, Tampa, FL, 2Washington University School of Medicine in St. Louis, St. Louis, MO
OBJECTIVE: To compare the diagnostic accuracy and short-term neonatal outcomes when fetuses are classified by NICHD racial / ethnic standards as compared to Hadlock. STUDY DESIGN: A prospective study was performed recruiting patients with singleton gestations referred for a fetal growth ultrasound between 26 - 36 weeks. Fetal growth was recorded using both NICHD and Hadlock standards; FGR was defined at the 5th and 10th estimated weight (EFW) percentiles. Postnatal growth was defined using Alexander curves; SGA was defined as less than 10th% birthweight. The primary outcome was the sensitivity and specificity of the growth curve to diagnose an SGA neonate. Secondary outcomes included neonatal intensive care unit (NICU) admissions, cord pH less than 7.2, and 5 minute Apgar less than 7. Statistical analyses were performed using Chi-squared and student’s t-test. RESULTS: A total of 678 delivered patients were available for analysis. Median (IQR) age at study entry was 29 (24, 33). Self-reported race demographics included 5% Asian, 38% African American, 10% Hispanic, 46% Caucasian, and 1% multiracial. Median (IQR) prepregnancy BMI was 26.6 (22.2, 33.6). Median (IQR) gestational ages at recruitment and delivery were 32.1 (29.2, 34.1) and 39.0 (37.2, 39.4) weeks, respectively. When FGR was defined at less than 5th%, NICHD appeared to be more sensitive to detect FGR fetuses with subsequent Supplement to JANUARY 2017 American Journal of Obstetrics & Gynecology
S157