UOG Journal Club: May 2014
Angiogenic Factors vs. Doppler Surveillance in the Prediction of
Adverse Outcome Among Late-Pre...
UOG Journal Club: May 2014
Angiogenic Factors vs. Doppler Surveillance in the Prediction of
Adverse Outcome Among Late-Pre...
Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse
Outcome Among Late-Pregnancy Small-for-Gestationa...
To investigate the value of angiogenic factors measured
in maternal plasma at the time of diagnosis in
comparison with Dop...
Inclusion Criteria
•Singleton gestations between 30– 40 weeks’ gestation receiving a third
trimester ultrasound exam betwe...
Data Collection
•Doppler studies: Umbilical artery, Middle cerebral artery,
Cerebroplacental ratio (CPR), Uterine artery
•...
Determination of Abnormal Thresholds
•34% of patients in the cohort had pathologic Doppler findings
• Umbilical artery pul...
Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome
among late-pregnancy small-for-gestationa...
Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome
among late-pregnancy small-for-gestationa...
Conclusions
• Angiogenic factors (PlGF and sFlt-1) measured at the time of SGA
diagnosis in the third trimester of pregnan...
• Prospective and complete data
collection on both Doppler
indices and serum biomarkers
• Evaluation of angiogenic
markers...
Discussion Points
Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome
among late-pregnancy sm...
UOG Journal Club: May 2014
Uterine Artery Doppler and sFlt-1/PlGF Ratio: Prognostic
Value in Early-Onset Pre-Eclampsia
P.I...
Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset
pre-eclampsia
Gomez-Arriaga et al., UOG 2014...
To evaluate the usefulness of the combination of the
mean uterine artery pulsatility index and the automated
measurement o...
Design: Prospective cohort of women with early-onset pre-eclampsia
(diagnosed prior to 34 weeks)
Inclusion Criteria
•Singl...
Outcomes
•Adverse maternal outcome
• Development of any pre-eclampsia-related complication that was
considered an indicati...
Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset
pre-eclampsia
Gomez-Arriaga et al., UOG 2014...
Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset
pre-eclampsia
Gomez-Arriaga et al., UOG 2014...
Conclusions
• Gestational age at diagnosis remains the single most predictive factor for
both adverse maternal and neonata...
• Prospective cohort study
• Evaluation of early-onset pre-
eclampsia only
• Strict clinical criteria
necessitating delive...
Discussion Points
Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset
pre-eclampsia
Gomez-Arriag...
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UOG Journal Club: Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age Fetuses and Uterine Artery Doppler and sFlt-1/PlGF Ratio: Prognostic Value in Early-Onset Pre-Eclampsia

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The Journal club for May features 2 papers. The first is a study on Angiogenic Factors vs. Doppler Surveillance in the Prediction of ddverse outcomes in late pregnancy SGA fetuses. The second studies the uterine artery Doppler and sFlt-1/PlGF ratio, discussing its value in diagnosis of early-onset pre-eclampsia.

Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age Fetuses
S.M. Lobmaier, F. Figueras, I, Mercade, M. Perello, A. Peguero, F. Crovetto, J.U. Ortiz, F. Crispi and E. Gratacos
Volume 43, Issue 5, Date: May 2014, pages 533-540

Uterine Artery Doppler and sFlt-1/PlGF Ratio: Prognostic Value in Early-Onset Pre-Eclampsia
P.I. Gomez-Arriaga, I. Herraiz, E.A. Lopez-Jiminez, D. Escribano, B. Denk and A. Galindo
Volume 43, Issue 5, Date: May 2014, pages 525-532

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UOG Journal Club: Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age Fetuses and Uterine Artery Doppler and sFlt-1/PlGF Ratio: Prognostic Value in Early-Onset Pre-Eclampsia

  1. 1. UOG Journal Club: May 2014 Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy SGA Fetuses S.M. Lobmaier, F. Figueras, I, Mercade, M. Perello, A. Peguero, F. Crovetto, J.U. Ortiz, F. Crispi and E. Gratacos Journal Club slides prepared by Dr. Katherine Goetzinger (UOG Editor for Trainees) Uterine Artery Doppler and sFlt-1/PlGF Ratio: Prognostic Value in Early-Onset Pre-Eclampsia P.I. Gomez-Arriaga, I. Herraiz, E.A. Lopez-Jiminez, D. Escribano, B. Denk and A. Galindo
  2. 2. UOG Journal Club: May 2014 Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age Fetuses S.M. Lobmaier, F. Figueras, I, Mercade, M. Perello, A. Peguero, F. Crovetto, J.U. Ortiz, F. Crispi and E. Gratacos Volume 43, Issue 5, Date: May 2014, pages 533-540
  3. 3. Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age Fetuses Lobmaier et al., UOG 2014 • Fetuses diagnosed as small for gestational age (SGA) late in pregnancy may experience adverse perinatal outcome even in the setting of normal umbilical artery Doppler studies • Doppler of vessels such as the middle cerebral artery and uterine artery may help in the clinical management of these pregnancies; however, these require specialized experience and equipment • Since uteroplacental insufficiency reflects a state of unbalanced angiogenesis, cases of late-onset fetal growth restriction may be detectable by measuring angiogenic biomarkers in maternal serum. These biomarkers have the potential to be used in predicting which SGA fetuses are at highest risk for adverse outcome
  4. 4. To investigate the value of angiogenic factors measured in maternal plasma at the time of diagnosis in comparison with Doppler ultrasound, in the risk stratification of adverse outcome among SGA fetuses Objective Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age Fetuses Lobmaier et al., UOG 2014
  5. 5. Inclusion Criteria •Singleton gestations between 30– 40 weeks’ gestation receiving a third trimester ultrasound exam between October 2010 and January 2012 •Estimated fetal weight <10th percentile for gestational age Exclusion Criteria •Fetal malformations •Diagnosis of preeclampsia at time of inclusion Methodology Prospective Cohort Study Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014
  6. 6. Data Collection •Doppler studies: Umbilical artery, Middle cerebral artery, Cerebroplacental ratio (CPR), Uterine artery • Followed up 2 weeks if normal and weekly if abnormal •Maternal serum collected within 2 weeks of SGA diagnosis • Placental growth factor (PlGF) • Soluble fms-like tyrosine-kinase 1 (sFlt-1) Adverse Perinatal Outcome •Intrapartum status giving cause for concern that required: • Emergency operative delivery (Cesarean section or vaginal operative delivery) OR the presence of neonatal metabolic acidosis (pH<7.15 and base excess>12mEq/L) Methodology Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014
  7. 7. Determination of Abnormal Thresholds •34% of patients in the cohort had pathologic Doppler findings • Umbilical artery pulsatility index (PI) >95th percentile • Middle cerebral artery PI <5th percentile • Uterine artery PI >95th percentile • CPR <5th percentile •Cut-off values for each angiogenic biomarker were identified which yielded the same proportion of abnormal cases (~34%) • PlGF <0.125 MoM • sFlt-1 >2.4 MoM • sFlt-1/PlGF ratio >16 MoM Analysis •Receiver operating characteristic (ROC) curves constructed using logistic regression analysis and the areas under the curve (AUC) compared using pairwise analysis Methodology Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014
  8. 8. Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014 Results: Incidence of Pre-Eclampsia and Adverse Perinatal Outcome Pre-Eclampsia (n=27) Adverse Perinatal Outcome (n=65)
  9. 9. Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014 Results: ROC Curve Comparison On pairwise comparison, no model was shown to be superior for the prediction of: Pre-Eclampsia (p=0.851) Or Adverse Perinatal Outomce (p=0.579)
  10. 10. Conclusions • Angiogenic factors (PlGF and sFlt-1) measured at the time of SGA diagnosis in the third trimester of pregnancy may be able to predict adverse perinatal outcome • Could play a future role in distinguishing constitutionally small growth from placenta-mediated fetal growth restriction • These angiogenic biomakers demonstrate a similar predictive value compared to Doppler indices for identification of complications associated with late-onset fetal growth restriction • These angiogenic factors could replace Doppler ultrasound evaluation for risk stratification of SGA fetuses in situations where Doppler studies are not feasible Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014
  11. 11. • Prospective and complete data collection on both Doppler indices and serum biomarkers • Evaluation of angiogenic markers in the third trimester of pregnancy at the time of SGA diagnosis • Standardized technique for measuring PlGF and sFlt-1 levels with adjustment for gestational age Strengths Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014 • Relatively small sample size • Lack of longitudinal measurements of PlGF and sFlt-1 levels • Provider subjectivity in determining when operative delivery was indicated • No correlation with placental pathology available • Variable timing of delivery Limitations
  12. 12. Discussion Points Angiogenic factors vs. Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for-gestational-age fetuses Lobmaier et al., UOG 2014 • What is the optimal method to distinguish constitutionally small growth from late-onset fetal growth restriction? • Which fetal vessels should be interrogated by Doppler stuides and at what screening interval? • Are there factors, other than gestational age, that affect the measurement of maternal serum angiogenic biomarkers? • If angiogenic biomarkers are used in clinical practice for the prediction of adverse pregnancy outcome, should their measurement be standardized and validated in a single laboratory? • What is the cost-effectiveness of measuring angiogenic biomarkers in the third trimester of pregnancy? • How would the finding of abnormal levels of maternal serum PlGF and/or sFlt-1 alter your clinical managment of pregnancy?
  13. 13. UOG Journal Club: May 2014 Uterine Artery Doppler and sFlt-1/PlGF Ratio: Prognostic Value in Early-Onset Pre-Eclampsia P.I. Gomez-Arriaga, I. Herraiz, E.A. Lopez-Jiminez, D. Escribano, B. Denk and A. Galindo Volume 43, Issue 5, Date: May 2014, pages 525-532
  14. 14. Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014 • Early-onset pre-eclampsia (requiring delivery <34 weeks) is associated with adverse maternal and fetal outcome • Determing which patients are suitable candidates for expectant management remains a challenge • Abnormal uterine artery Doppler studies have been shown to be predictive of adverse fetal outcome (with low specificity) • Abnormal ratios of PlGF to sFlt-1 has been correlated with disease severity; however, its prognostic potential for fetal complications remains unknown
  15. 15. To evaluate the usefulness of the combination of the mean uterine artery pulsatility index and the automated measurement of sFlt-1/PlGF ratio to predict severe maternal and neonatal complications and the expected time-to-delivery in pregnant women admitted with early- onset preeclampsia Objective Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014
  16. 16. Design: Prospective cohort of women with early-onset pre-eclampsia (diagnosed prior to 34 weeks) Inclusion Criteria •Singleton non-anomalous gestations who were determined to be candidates for expectant management Data Collection •Single evaluation of uterine artery Doppler PI and measurement of PlGF and sFlt-1 from maternal serum within 7 days of diagnosis •Patient management of pre-eclampsia was by Spanish guidelines with frequent maternal and fetal surveillance Methodology Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014
  17. 17. Outcomes •Adverse maternal outcome • Development of any pre-eclampsia-related complication that was considered an indication for expeditious delivery that was not present at the time of diagnosis •Adverse neonatal outcome • 5 minute Apgar score<7, umbilical artery pH<7.0, fetal or neonatal death or significant neonatal morbidity Analysis •Logistic regression analysis used to construct predictive models •Accuracy of models assessed using ROC curves •Time-to-delivery analysis •Survival analysis (Kaplan-Meier plots) Methodology Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014
  18. 18. Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014 Results Of 51 patients evaluated, there were 26 cases (51%) of adverse maternal outcome and 14 cases (27%) of adverse neonatal outcome Both uterine artery PI and sFlt-1/PlGF ratio were significantly higher in pregnancies with adverse neonatal outcome There was no difference in uterine artery PI or SFlt-1/PlGF ratio in pregnancies with adverse maternal outcome GA + Uterine Artery PI + sFlt-1/ PlGF ratio for prediction of adverse neonatal outcome AUC 0.89 Sens 64%; Spec 95% PPV 83%; NPV 88%
  19. 19. Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014 Uterine Artery PI sFlt-1/PlGF ratio ─ >3rd quartile -- ≤ 3rd quartile ─ >3rd quartile -- ≤ 3rd quartile
  20. 20. Conclusions • Gestational age at diagnosis remains the single most predictive factor for both adverse maternal and neonatal outcome in cases of early-onset pre- eclampsia •The addition of uterine artery Doppler and sFlt-1 and PlGF measurements may improve the prognostic accuracy of predicting adverse neonatal outcome •The sFlt/PlGF ratio may also aid in predicting which patients are candidates for pregnancy prolongation in the setting of early-onset pre- eclampsia •Further studies are warranted to validate these findings and determine whether implementation of these markers can impact pregnancy management Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014
  21. 21. • Prospective cohort study • Evaluation of early-onset pre- eclampsia only • Strict clinical criteria necessitating delivery • Use of quartiles to attempt to establish abnormal thresholds • Potential clinical application to pregnancy management and patient counseling Strengths Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014 • Small sample size • Lack of longitudinal measurements of PlGF and sFlt-1 levels • Composite outcomes of adverse maternal and neonatal outcomes • Maternal clinical characteristics and risk factors not included in prediction models Limitations
  22. 22. Discussion Points Uterine artery doppler and sFlt-1/PlGF Ratio: prognostic palue in early-onset pre-eclampsia Gomez-Arriaga et al., UOG 2014 • What tools currently exist to guide timing of delivery in cases of early- onset pre-eclampsia in order to maximize both maternal and neonatal outcome? • How could the addition of maternal clinical risk factors have affected the performance of the prediction models? • Should thresholds for abnormal uterine artery Doppler and/or angiogenic biomarkers be standardized or individualized? • What is the biologic plausability of the finding that uterine artery Doppler studies and sFlt/PlGF ratios were only predictive of adverse neonatal outcome in comparison to adverse maternal outcome? • Will the findings from this study alter your clinical practice in the management and counseling of patients with early-onset pre- eclampsia?

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