UOG Journal Club: September 2013 Value of adding second-trimester uterine artery Doppler to patient characteristics in identification of nulliparous women at increased risk for pre-eclampsia: an individual patient data meta-analysis C. E. Kleinrouweler, P. M. M. Bossuyt, B. Thilaganathan, K. C. Vollebregt, J. Arenas Ramírez, A. Ohkuchi, K. L. Deurloo, M. Macleod, A. E. Diab, H. Wolf, J. A. M. van der Post, B. W. J. Mol and E. Pajkrt Volume 42, Issue 3, Date: September 2013, pages 257–267 Link to the free-access article: onlinelibrary.wiley.com/doi/10.1002/uog.12435/abstract

1. UOG Journal Club: September 2013
Value of adding second-trimester uterine artery Doppler to patient
characteristics in identification of nulliparous women at increased risk for
pre-eclampsia: an individual patient data meta-analysis
C. E. Kleinrouweler, P. M. M. Bossuyt, B. Thilaganathan, K. C. Vollebregt,
J. Arenas Ramírez, A. Ohkuchi, K. L. Deurloo, M. Macleod, A. E. Diab, H. Wolf,
J. A. M. van der Post, B. W. J. Mol and E. Pajkrt
Volume 42, Issue 3, Date: September 2013, pages 257–267
Journal Club slides prepared by Dr Aly Youssef
(UOG Editor for Trainees)

2. • Accurate prediction of pre-eclampsia (PE) in early pregnancy
would allow for timely allocation of monitoring resources, with
the prospect of improving maternal and perinatal outcomes
• Doppler ultrasound can be used to assess blood flow velocity in
the maternal uterine arteries and thus potentially identify
pregnancies at increased risk for pre-eclampsia
• There is uncertainty about the prognostic accuracy of Doppler
ultrasound findings, when combined with more readily available
patient characteristics such as blood pressure and weight

3. Value of adding second-trimester uterine artery Doppler to patient
characteristics in identification of nulliparous women at increased risk for pre-
eclampsia: an individual patient data meta-analysis
Kleinrouweler et al., UOG 2013
The aim of the present individual patient data (IPD) meta-analysis was
to investigate the added value of uterine artery Doppler (UtAD)
measurements in the identification of nulliparous women at risk for
pre-eclampsia, based on analyses of individual patient data from
previously published studies

4. • The IPD-POPULAR project relies on a systematic search of the literature,
invitations to share data and a comparison of multivariable prediction
models for pre-eclampsia in these data
• A MEDLINE and EMBASE search was conducted between 1995-2009 to
identify eligible studies
• Studies were eligible if UtAD was performed at any gestational age, at
any level of risk for pre-eclampsia and in which gestational age at
ultrasound, Doppler ultrasound findings and the occurrence of pre-
eclampsia had been recorded
• The corresponding authors of eligible studies were invited to participate
in the project and share their original datasets
Methods: Literature search, study selection, data collection
and quality assessment

5. • The analysis performed in the present study was restricted to nulliparous
women who had had a 2nd trimester UtAD
• The relationship between each patient characteristic or Doppler
ultrasound parameter and pre-eclampsia was evaluated by univariable
logistic regression analysis
• Identification of the best predictive patient characteristic or combination of
patient characteristics, and the best predictive Doppler parameter, or
combination of Doppler parameters, was performed
• Models consisting only patient characteristics, Doppler parameters only,
and a model containing both patient characteristics and Doppler
ultrasound findings were compared
• Model discrimination was assessed by calculating the area under the
curve (AUC) in a receiver–operating characteristics (ROC) plot
Methods: Data analysis

6. Results
MEDLINE and EMBASE search (1995-2009) resulted in
3199 citations
22 authors did not share data despite
an expressed intention to do so
3 of these were no longer available
2 had not been given institutional
review board approval for data sharing
176 study reports deemed eligible
(111 corresponding authors)
27 authors shared their datasets of
30 studies
107 authors were contacted
49 (46%)
replied that they were interested in the project and willing to share
data
Eight studies (including 6708 unselected nulliparous women, of whom
302 (4.5%) developed PE) used in analysis as these had data on
nulliparous women with 2nd trimester UtAD

7. • Mean PI performed better than lower and higher PI (although this
was not statistically significant)
• Mean RI performed significantly better than lower RI but not
significantly better than higher RI
• The addition of bilateral notching to models with mean PI alone or
mean RI alone significantly improved model fit
• The predictive models using mean PI either alone or in
combination with bilateral notching performed slightly better than
the models with using mean RI, though not significantly
Results: Selection of Doppler ultrasound predictors

8. The discriminative ability of the models including both patient characteristics and Doppler
parameters was significantly better than either in isolation
Results: Added value of Doppler ultrasound measurements to patient characteristics
Systolic BP
Mean PI and bilateral
notching
Systolic BP + mean PI +
bilateral notching
AUC (95% CI) 0.64 (0.45–0.84) 0.75 (0.55–0.95) 0.85 (0.67–1.00)
BMI
mean PI and bilateral
notching
BMI + mean PI +
bilateral notching
AUC (95% CI) 0.64 (0.59–0.69) 0.67 (0.61–0.73) 0.73 (0.68–0.79)
BMI + systolic BP
mean PI and bilateral
notching
BMI + systolic BP + mean
PI + bilateral notching
AUC (95% CI) 0.65 (0.45–0.84) 0.75 (0.56–0.95) 0.85 (0.67–1.00)
The results for all models involving mean RI were similar to those involving mean PI

9. The model with BMI, mean RI and bilateral
notching showed good calibration.
Women in the two deciles with highest
calculated probabilities of pre-eclampsia can
be easily distinguished from women with
lower probabilities
Results: Added value of Doppler ultrasound measurements to patient characteristics

10. The discriminative ability of the models predicting pre-eclampsia requiring delivery
before 34 weeks was significantly improved by adding Doppler parameters to models
including only patient characteristics (BMI)
Results: Prediction of pre-eclampsia requiring delivery before 34 weeks
BMI
BMI + mean RI and
bilateral notching
P value
AUC (95% CI) 0.66 (0.57–0.76) 0.92 (0.87–0.98) <0.001
BMI
BMI + mean PI and
bilateral notching
P value
AUC (95% CI) 0.62 (0.48–0.75) 0.95 (0.92–0.98) <0.001

11. Women ranked in the highest centiles of predicted probabilities from both models
delivered earlier than women with lower probabilities of pre-eclampsia
Results: Time to delivery, Survival curves
BMI +
mean UtA RI +
bilateral notching
Systolic BP +
mean UtA PI +
bilateral
notching
Survival curves showing time to delivery in women grouped by percentiles (p) of predicted
risk for pre-eclampsia in two predictive models; ––––, ≤p75; ------, >p75–p80; ───,>p80–
p85; ------, >p85–p90; ─── , >p90–p95; ------,>p95

12. Discussion
• In nulliparous women, the combination of Doppler ultrasound
parameters and bilateral notching significantly improves the
prediction of pre-eclampsia based on the patient characteristics BMI
and systolic blood pressure
• Women at higher risk of pre-eclampsia (>10–15%) can be well
differentiated from women with lower risks
• Women with the highest calculated risk of pre-eclamspia deliver
earlier than women at lower risk
• The methodology of IPD meta-analysis has several advantages over
conventional meta-analysis, including the ability to use all available
data from a study, including unpublished data, superior quality
checks and better interpretation of the results

13. Limitations
• As all studies included were primarily designed to investigate
uterine artery Doppler, the number and type of patient
characteristics differed between studies. This led to the
investigation of only a limited number of patient
characteristics
Future perspectives
• The results of the present meta-analysis should be externally
validated in another large dataset
• Further research investigating the effectiveness of a screen-
and-treat strategy in the second trimester is needed

14. Discussion points
• How can the results of this meta-analysis be applied in clinical practice?
• In the light of the present meta-analysis, should all women be offered
second-trimester uterine artery Doppler?
• How should nulliparous low-risk women with abnormal second-trimester
uterine artery Doppler be counselled and managed?
• Is there an effective intervention to reduce the risk of pre-eclampsia in
high risk women identified in the second trimester?
Value of adding second-trimester uterine artery Doppler to patient
characteristics in identification of nulliparous women at increased risk for pre-
eclampsia: an individual patient data meta-analysis
Kleinrouweler et al., UOG 2013