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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. 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?