PUBLISHED VERSION

Objective: Small for gestational age (SGA) infants comprise up to 50% of all stillbirths and a minority are detected before birth. We aimed to develop and validate early pregnancy predictive models for SGA infants. Methods: 5628 participants from SCOPE, a prospective study of nulliparous pregnant women, were interviewed at 1561 weeks’ gestation. Fetal anthropometry, uterine and umbilical Doppler studies were performed at 2061 weeks’. The cohort was divided into training (n = 3735) and validation datasets (n = 1871). All-SGA (birthweight ,10th customised centile), Normotensive-SGA (SGA with normotensive mother) and Hypertensive-SGA (SGA with mother who developed hypertension) were the primary outcomes. Multivariable analysis was performed using stepwise logistic regression firstly using clinical variables and then with clinical and ultrasound variables. Receiver operator curves were constructed and areas under the curve (AUC) calculated. Results: 633 infants (11.3%) in the whole cohort were SGA; 465 (8.3%) Normotensive-SGA and 165 (3.0%) Hypertensive-SGA. In the training dataset risk factors for All-SGA at 1561 weeks’ included: family history of coronary heart disease, maternal birthweight ,3000 g and 3000 g to 3499 g compared with $3500 g, . 12 months to conceive, university student, cigarette smoking, proteinuria, daily vigorous exercise and diastolic blood pressure $80. Recreational walking $4 times weekly, rhesus negative blood group and increasing random glucose were protective. AUC for clinical risk factors was 0.63. Fetal abdominal or head circumference z scores ,10 centile and increasing uterine artery Doppler resistance at 2061 weeks’ were associated with increased risk. Addition of these parameters increased the AUC to 0.69. Clinical predictors of Normotensive and Hypertensive-SGA were sub-groups of All-SGA predictors and were quite different. The combined clinical and ultrasound AUC for Normotensive and Hypertensive-SGA were 0.69 and 0.82 respectively. Conclusion: Predictors for SGA of relevance to clinical practice were identified. The identity and predictive potential differed in normotensive women and those who developed hypertension. Citation: McCowan LME, Thompson JMD, Taylor RS, North RA, Poston L, et al. (2013) Clinical Prediction in Early Pregnancy of Infants Small for Gestational Age by Customised Birthweight Centiles: Findings from a Healthy Nulliparous Cohort. PLoS ONE 8(8): e70917. doi:10.1371/journal.pone. 0070917 Editor: Carmen J. Marsit, Dartmouth Medical School, United States of America Received April 2, 2013; Accepted June 24, 2013; Published August 5, 2013 Copyright: 2013 McCowan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the following funders: New Zealand: New Enterprise Research Fund, Foundation for Research Science and Technology (EM 04–05/03); Health Research Council (04/198); Evelyn Bond Fund, Auckland District Health Board Charitable Trust; Australia: Premier’s Science and Research Fund, South Australian Government; London: Guy’s and St Thomas’ Charity, United Kingdom, Tommy’s the Baby Charity; Manchester: UK Biotechnology and Biological Sciences Research Council, UK National Health Services NEAT Grant, University of Manchester Proof of Concept Funding, Tommy’s the Baby Charity, NIHR; Leeds: Cerebra, UK; and Cork, Ireland: Health Research Board, Ireland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The following do not have any conflicts of interest: LM, JMDT, RST, LP, JM, CR, GAD and NABS. The following declare potential competing interests: RN declares the following: a patent which to date has not been licensed to a company: Blumenstein M, North RA, McMaster MT, Black MA, Kasabov NK, Cooper GJS. Biomarkers for prediction of pre-eclampsia and/or cardiovascular disease. PCT number WO/2009/108073. RN has a research grant from Alere, USA, to King’s College London to investigate biomarkers for preeclampsia. RN had a consultancy with Pronota, Belgium, on biomarkers for preeclampsia through a grant from Pronota to King’s College London. PB and LK have minority share holdings in Metabolomic Diagnostics, a company with an interest in preeclampsia and SGA biomarkers, based on technology developed by PB and LK and licensed from University College Cork. JJW declares that he is the Senior Vice-President of the RCOG with a remit for Global Health. He is the Medical Director of APEC, a patient Charity for Pre-eclampsia in the UK. He is a medical adviser for Alere, a Biomarker Company and has been paid both to advise and speak on their behalf. None of the authors have support from any company for the submitted work. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: l.mccowan@auckland.ac. nz PLOS ONE | www.plosone. org 1 August 2013 | Volume 8 | Issue 8 | e70917