Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models

doi:10.1186/s12916-017-0827-3

. 2017 Mar 30;15(1):68.

doi: 10.1186/s12916-017-0827-3.

Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models

Shakila Thangaratinam^{1

2}, John Allotey^{3

4}, Nadine Marlin⁵, Julie Dodds^{1

2}, Fiona Cheong-See^{1

2}, Peter von Dadelszen⁶, Wessel Ganzevoort⁷, Joost Akkermans⁸, Sally Kerry⁵, Ben W Mol^{9

10}, Karl G M Moons¹¹, Richard D Riley¹², Khalid S Khan^{1

2}; PREP Collaborative Network

Collaborators, Affiliations

Collaborators

PREP Collaborative Network:
Raajkumar Sundararajah, Avideah Nejad, Rehan Khan, Celia Burrell, Manish Gupta, Vincent Oon, Rezan Kadir, Zeudi Ramsey-Marcelle, Louise Page, Baskaran Thilaganathan, Bill Martin, Shagaf Haj Bakour, Hassan Morsi, David Churchill, Fidelma O'Mahony, Karen Powell, Jayasree Srinivasan, Michele Mohajer, Siobhan Quenby, Lakshmi Thirumalaikumar, Justin Konje, Jim Thornton, George Bugg, Shonag Mackenzie, Aarti Ullal, Marie Smith, Rita Arya, Simon Cunnigham, James Walker, Nigel Simpson, Joanne Page, Claire Oxby, Karen Watkins, Derek Tuffnell, S Bober, A Wijesiriwardana, Helene Brandon, Saif El-Badawy, Sara Brigham, Lanre Shorinola, Aethele Khunda, Shaku Kalla, Mohammed M Abdullah Agha, Stephen Poku, Ayo Olawo, Johnson Amu, Philip Banfield, Franz Majoko, Julia Alcide, Jyothi Rajeswary, Marwan Salloum, Alexandra Rees, Odiri Oteri, Sunday Ikhena, Janet Creswell, Feroza Dawood, Umber Agarwal

Affiliations

¹ Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK.
³ Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. j.allotey@qmul.ac.uk.
⁴ Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK. j.allotey@qmul.ac.uk.
⁵ Pragmatic Clinical Trials Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK.
⁶ Institute of Cardiovascular and Cell Sciences, St George's, University of London, London, UK.
⁷ Departments of Obstetrics and Gynecology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
⁸ Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands.
⁹ The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
¹⁰ The South Australian Health and Medical Research Institute, Adelaide, Australia.
¹¹ Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹² Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, UK.

PMID: 28356148
PMCID: PMC5372261
DOI: 10.1186/s12916-017-0827-3

Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models

Shakila Thangaratinam et al. BMC Med. 2017.

. 2017 Mar 30;15(1):68.

doi: 10.1186/s12916-017-0827-3.

Authors

Collaborators

PREP Collaborative Network:
Raajkumar Sundararajah, Avideah Nejad, Rehan Khan, Celia Burrell, Manish Gupta, Vincent Oon, Rezan Kadir, Zeudi Ramsey-Marcelle, Louise Page, Baskaran Thilaganathan, Bill Martin, Shagaf Haj Bakour, Hassan Morsi, David Churchill, Fidelma O'Mahony, Karen Powell, Jayasree Srinivasan, Michele Mohajer, Siobhan Quenby, Lakshmi Thirumalaikumar, Justin Konje, Jim Thornton, George Bugg, Shonag Mackenzie, Aarti Ullal, Marie Smith, Rita Arya, Simon Cunnigham, James Walker, Nigel Simpson, Joanne Page, Claire Oxby, Karen Watkins, Derek Tuffnell, S Bober, A Wijesiriwardana, Helene Brandon, Saif El-Badawy, Sara Brigham, Lanre Shorinola, Aethele Khunda, Shaku Kalla, Mohammed M Abdullah Agha, Stephen Poku, Ayo Olawo, Johnson Amu, Philip Banfield, Franz Majoko, Julia Alcide, Jyothi Rajeswary, Marwan Salloum, Alexandra Rees, Odiri Oteri, Sunday Ikhena, Janet Creswell, Feroza Dawood, Umber Agarwal

Affiliations

¹ Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK.
³ Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. j.allotey@qmul.ac.uk.
⁴ Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK. j.allotey@qmul.ac.uk.
⁵ Pragmatic Clinical Trials Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK.
⁶ Institute of Cardiovascular and Cell Sciences, St George's, University of London, London, UK.
⁷ Departments of Obstetrics and Gynecology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
⁸ Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands.
⁹ The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
¹⁰ The South Australian Health and Medical Research Institute, Adelaide, Australia.
¹¹ Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹² Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, UK.

PMID: 28356148
PMCID: PMC5372261
DOI: 10.1186/s12916-017-0827-3

Abstract

Background: Unexpected clinical deterioration before 34 weeks gestation is an undesired course in early-onset pre-eclampsia. To safely prolong preterm gestation, accurate and timely prediction of complications is required.

Method: Women with confirmed early onset pre-eclampsia were recruited from 53 maternity units in the UK to a large prospective cohort study (PREP-946) for development of prognostic models for the overall risk of experiencing a complication using logistic regression (PREP-L), and for predicting the time to adverse maternal outcome using a survival model (PREP-S). External validation of the models were carried out in a multinational cohort (PIERS-634) and another cohort from the Netherlands (PETRA-216). Main outcome measures were C-statistics to summarise discrimination of the models and calibration plots and calibration slopes.

Results: A total of 169 mothers (18%) in the PREP dataset had adverse outcomes by 48 hours, and 633 (67%) by discharge. The C-statistics of the models for predicting complications by 48 hours and by discharge were 0.84 (95% CI, 0.81-0.87; PREP-S) and 0.82 (0.80-0.84; PREP-L), respectively. The PREP-S model included maternal age, gestation, medical history, systolic blood pressure, deep tendon reflexes, urine protein creatinine ratio, platelets, serum alanine amino transaminase, urea, creatinine, oxygen saturation and treatment with antihypertensives or magnesium sulfate. The PREP-L model included the above except deep tendon reflexes, serum alanine amino transaminase and creatinine. On validation in the external PIERS dataset, the reduced PREP-S model showed reasonable calibration (slope 0.80) and discrimination (C-statistic 0.75) for predicting adverse outcome by 48 hours. Reduced PREP-L model showed excellent calibration (slope: 0.93 PIERS, 0.90 PETRA) and discrimination (0.81 PIERS, 0.75 PETRA) for predicting risk by discharge in the two external datasets.

Conclusions: PREP models can be used to obtain predictions of adverse maternal outcome risk, including early preterm delivery, by 48 hours (PREP-S) and by discharge (PREP-L), in women with early onset pre-eclampsia in the context of current care. They have a potential role in triaging high-risk mothers who may need transfer to tertiary units for intensive maternal and neonatal care.

Trial registration: ISRCTN40384046 , retrospectively registered.

Keywords: Complications; Early-onset; Maternal; Pre-eclampsia; Prognostic models.

PubMed Disclaimer

Figures

**Fig. 1**
Flow of women recruited in the PREP study for development of prediction model(s) for adverse maternal outcomes

**Fig. 2**
Apparent performance and calibration in the external cohorts of the PREP models for predicting adverse maternal outcomes in early onset pre-eclampsia

See this image and copyright information in PMC

Cited by

Thresholds for Ambulatory Blood Pressure Monitoring Based on Maternal and Neonatal Outcomes in Late Pregnancy in a Southern Chinese Population.
Lv LJ, Ji WJ, Wu LL, Miao J, Wen JY, Lei Q, Duan DM, Chen H, Hirst JE, Henry A, Zhou X, Niu JM. Lv LJ, et al. J Am Heart Assoc. 2019 Jul 16;8(14):e012027. doi: 10.1161/JAHA.119.012027. Epub 2019 Jul 3. J Am Heart Assoc. 2019. PMID: 31267796 Free PMC article.
Maternal medicine in the COVID era.
Relph S, Thangaratinam S. Relph S, et al. Best Pract Res Clin Obstet Gynaecol. 2021 Jun;73:113-124. doi: 10.1016/j.bpobgyn.2021.03.003. Epub 2021 Mar 18. Best Pract Res Clin Obstet Gynaecol. 2021. PMID: 33839044 Free PMC article. Review.
Consecutive prediction of adverse maternal outcomes of preeclampsia, using the PIERS-ML and fullPIERS models: A multicountry prospective observational study.
Yang G, Montgomery-Csobán T, Ganzevoort W, Gordijn SJ, Kavanagh K, Murray P, Magee LA, Groen H, von Dadelszen P. Yang G, et al. PLoS Med. 2025 Feb 4;22(2):e1004509. doi: 10.1371/journal.pmed.1004509. eCollection 2025 Feb. PLoS Med. 2025. PMID: 39903757 Free PMC article.
Angiogenic Biomarkers: Are They Good Tools to Predict Perinatal Outcomes in Hypertensive Disorders of Pregnancy? A Retrospective Cohort Study.
Bednarek-Jędrzejek M, Maksym K, Feduniw S, Simeonova Krstevska S, Samardziski I, Góra T, Ciebiera M, Zahorowska A, Pruś K, Dzidek S, Jasiak-Jóźwik H, Drzycimska M, Kwiatkowska E, Torbé A, Kwiatkowski S. Bednarek-Jędrzejek M, et al. Diagnostics (Basel). 2025 Mar 21;15(7):799. doi: 10.3390/diagnostics15070799. Diagnostics (Basel). 2025. PMID: 40218149 Free PMC article.
Prediction of Adverse Outcomes in De Novo Hypertensive Disorders of Pregnancy: Development and Validation of Maternal and Neonatal Prognostic Models.
Chen J, Ji Y, Su T, Jin M, Yuan Z, Peng Y, Zhou S, Bao H, Luo S, Wang H, Liu J, Han N, Wang HJ. Chen J, et al. Healthcare (Basel). 2022 Nov 18;10(11):2307. doi: 10.3390/healthcare10112307. Healthcare (Basel). 2022. PMID: 36421631 Free PMC article.

See all "Cited by" articles

References

1. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97(4):533–8. - PubMed
1. von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143–8. doi: 10.1081/PRG-120021060. - DOI - PubMed
1. von Dadelszen P, Menzies JM, Payne B, Magee LA, PIERS (Pre-eclampsia Integrated Estimate of RiSk) Study Group Predicting adverse outcomes in women with severe pre-eclampsia. Semin Perinatol. 2009;33(3):152–7. doi: 10.1053/j.semperi.2009.02.009. - DOI - PubMed
1. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton-Pipkin F, Cote AM, Douglas MJ, Gruslin A, Hutcheon JA, Joseph KS, Kyle PM, Lee T, Loughna P, Menzies JM, Merialdi M, Millman AL, Moore MP, Moutquin JM, Ouellet AB, Smith GN, Walker JJ, Walley KR, Walters BN, Widmer M, Lee SK, Russell JA, Magee LA, PIERS Study Group Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. 2011;377(9761):219–27. doi: 10.1016/S0140-6736(10)61351-7. - DOI - PubMed
1. Murphy DJ, Stirrat GM. Mortality and morbidity associated with early-onset preeclampsia. Hypertens Pregnancy. 2000;19(2):221–31. doi: 10.1081/PRG-100100138. - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

09/22/163/DH_/Department of Health/United Kingdom

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

[1] MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97(4):533–8. - PubMed

[2] MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97(4):533–8. - PubMed

[3] von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143–8. doi: 10.1081/PRG-120021060. - DOI - PubMed

[4] von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143–8. doi: 10.1081/PRG-120021060. - DOI - PubMed

[5] von Dadelszen P, Menzies JM, Payne B, Magee LA, PIERS (Pre-eclampsia Integrated Estimate of RiSk) Study Group Predicting adverse outcomes in women with severe pre-eclampsia. Semin Perinatol. 2009;33(3):152–7. doi: 10.1053/j.semperi.2009.02.009. - DOI - PubMed

[6] von Dadelszen P, Menzies JM, Payne B, Magee LA, PIERS (Pre-eclampsia Integrated Estimate of RiSk) Study Group Predicting adverse outcomes in women with severe pre-eclampsia. Semin Perinatol. 2009;33(3):152–7. doi: 10.1053/j.semperi.2009.02.009. - DOI - PubMed

[7] von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton-Pipkin F, Cote AM, Douglas MJ, Gruslin A, Hutcheon JA, Joseph KS, Kyle PM, Lee T, Loughna P, Menzies JM, Merialdi M, Millman AL, Moore MP, Moutquin JM, Ouellet AB, Smith GN, Walker JJ, Walley KR, Walters BN, Widmer M, Lee SK, Russell JA, Magee LA, PIERS Study Group Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. 2011;377(9761):219–27. doi: 10.1016/S0140-6736(10)61351-7. - DOI - PubMed

[8] von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton-Pipkin F, Cote AM, Douglas MJ, Gruslin A, Hutcheon JA, Joseph KS, Kyle PM, Lee T, Loughna P, Menzies JM, Merialdi M, Millman AL, Moore MP, Moutquin JM, Ouellet AB, Smith GN, Walker JJ, Walley KR, Walters BN, Widmer M, Lee SK, Russell JA, Magee LA, PIERS Study Group Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. 2011;377(9761):219–27. doi: 10.1016/S0140-6736(10)61351-7. - DOI - PubMed

[9] Murphy DJ, Stirrat GM. Mortality and morbidity associated with early-onset preeclampsia. Hypertens Pregnancy. 2000;19(2):221–31. doi: 10.1081/PRG-100100138. - DOI - PubMed

[10] Murphy DJ, Stirrat GM. Mortality and morbidity associated with early-onset preeclampsia. Hypertens Pregnancy. 2000;19(2):221–31. doi: 10.1081/PRG-100100138. - DOI - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models

Collaborators

Affiliations

Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models

Authors

Collaborators

Affiliations

Abstract

Figures

Similar articles

Cited by

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous

Abstract

Figures

Similar articles

Cited by

References

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous