Objectives: To correlate placental thickness during pregnancy and histopathological results with placental Zika virus (ZIKV) infection.Methods: During the ZIKV epidemic in French Guiana, trans-placental contamination was defined either by a positive RT-PCR or identification of specific IgM in at least one placental, fetal or neonatal sample. Placentas were classified as non-exposed (from non-infected pregnant woman), exposed (from ZIKV-infected pregnant women without trans-placental contamination) or infected (from ZIKV-infected pregnant women with proven trans-placental contamination). Placentas were assessed by monthly prenatal ultrasound, measuring placental thickness and umbilical artery Doppler, and anatomopathologic examination after birth or IUFD. Placental thickness during pregnancy and anatomopathologic findings were correlated to the ZIKV-status of the placenta.Results: Among 291 fetuses/placentas from proven infected mothers, trans-placental infection was confirmed in 76 cases, of which 16 resulted in Congenital Zika Syndrome (CZS) and 11 in fetal loss. The 215 remaining placentas without evidence of ZIKV infection represented the exposed group. A total of 334 placentas from ZIKV-negative pregnant women represented the non-exposed group. Placentomegaly (thickness>40 mm) was observed more frequently in infected placentas (39.5%) compared to exposed placentas (17.2%) or controls (7.2%), even when considering gestational age at diagnosis and co-morbidities (adjusted Hazard Ratio aHR 2.02 95%CI 1.22-3.36 and aHR 3.23 95%CI 1.86-5.61, respectively), and appeared earlier in infected placentas. Placentomegaly was observed even more frequently in case of CZS (62.5%) or fetal loss (45.5%) compared to asymptomatic congenital infection (30.6%) (aHR 5.43 95%CI 2.17-13.56 and aHR 4.95 95%CI 1.65-14.83, respectively). Umbilical artery Doppler anomaly was observed more frequently in case of trans-placental infection resulting in fetal loss (30.0% vs 6.1%; adjusted Relative Risk aRR 4.83 95%CI 1.09-20.64). Infected placentas also exhibited a higher risk of any pathological anomalies than exposed placentas (aRR 2.60 1.40-4.83).Conclusions: Early placentomegaly may represent the first sign of trans-placental contamination and should lead to an enhanced follow-up of these pregnancies.