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This study investigates the possible relationship between ultrasound estimated fetal weight (EFW) at third trimester and the risk of preterm birth following spontaneous preterm labor in otherwise uncomplicated pregnancies.We performed a nested case–control study including 281 cases of spontaneous preterm labor with preterm delivery in the third trimester and 3372 matched controls within a cohort of 6207 consecutive pregnant women. Pregnancies with fetal growth restriction (birth weight <10th centile of population-based normograms) or fetal anomalies were not included. EFW was calculated by using Hadlock′s formula and converted to fetal gender adjusted multiples of median (MoM) for each gestational age.EFW correlated with birth weight (r = 0.959, p < 0.0001) and was lower in preterm than in control fetuses (p < 0.0001). The odds ratios (95% confidence intervals) for preterm birth for fetuses below 0.9 MoM, 0.85 MoM, 0.80 MoM, and 0.75 MoM of EFW were, respectively, 4.6 (3.6–5.9), 5.7 (4.3–7.5), 8.5 (5.9–12.1), and 11.2 (6.8–18.3). The independent relationship between preterm birth and lower EFW was confirmed in multivariate analysis with adjustment for potential confounders, such as maternal age, parity, and fetal gender.In asymptomatic women between 28 and 36 weeks of gestation, an EFW lower than 0.90 MoM increases by 4.6 times the risk of spontaneous preterm birth, and the risk increases proportionally to the degree of weight reduction. © 2012 John Wiley & Sons, Ltd.