UOG Journal Club: September 2013

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. Moland 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. Methods: Literature search, study selection, data collection and quality assessment • 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-eclampsiain 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-eclampsiaand in which gestational age at ultrasound, Doppler ultrasound findings and the occurrence of pre-eclampsiahad been recorded • The corresponding authors of eligible studies were invited to participate in the project and share their original datasets

5. Methods: Data analysis • 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-eclampsiawas 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

6. Results MEDLINE and EMBASE search (1995-2009) resulted in 3199 citations 176 study reports deemed eligible (111 correspondingauthors) 107 authors were contacted 49 (46%) replied that they were interested in the project and willing to share data 22 authors did not share data despite an expressed intention to do so 3 of thesewere no longer available 2 had not been given institutional review board approval for data sharing 27 authors shared their datasets of 30 studies 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. Results: Selection of Doppler ultrasound predictors • 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

8. Results: Added value of Doppler ultrasound measurements to patient characteristics The discriminative ability of the models including both patient characteristics and Doppler parameters was significantly better than either in isolation The results for all models involving mean RI were similar to those involving mean PI

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

10. Results: Prediction of pre-eclampsia requiring delivery before 34 weeks The discriminative ability of the models predicting pre-eclampsiarequiring delivery before 34 weeks was significantly improved by adding Doppler parameters to models including only patient characteristics (BMI)

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

12. Discussion • In nulliparous women, the combination of Doppler ultrasound parameters and bilateral notching significantly improves the prediction of pre-eclampsiabased 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-eclamspiadeliver 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. 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 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

14. 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 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-eclampsiain high risk women identified in the second trimester?