UOG Journal Club: Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome...

UOG Journal Club: May 2014Angiogenic 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

UOG Journal Club: May 2014

Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome Among Late-Pregnancy Small-for-Gestational-Age

FetusesS.M. Lobmaier, F. Figueras, I, Mercade, M. Perello, A. Peguero, F.

Crovetto, J.U. Ortiz, F. Crispi and E. GratacosVolume 43, Issue 5, Date: May 2014, pages 533-540

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

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


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


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



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





Results: Incidence of Pre-Eclampsia and Adverse Perinatal Outcome

Pre-Eclampsia (n=27) Adverse Perinatal Outcome (n=65)



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)

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



• 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



• 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

Discussion Points



• 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?

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

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

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



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



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





ResultsOf 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 0.89Sens 64%; Spec 95%PPV 83%; NPV 88%



Uterine Artery PI sFlt-1/PlGF ratio

─ >3rd quartile-- ≤ 3rd quartile

─ >3rd quartile-- ≤ 3rd quartile

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



• 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



• 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

Discussion Points



• 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?

UOG Journal Club: Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome...

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Transcript of UOG Journal Club: Angiogenic Factors vs. Doppler Surveillance in the Prediction of Adverse Outcome...