Voluson e8 equipment

From November 2010 until December 2012 women received weekly transvaginal 3D ultrasound scans from enrolment up to the 13th week of pregnancy. From December 2012 onwards, the number of ultrasound scans was reduced to three scans at the 7th, 9th and 11th weeks of gestation, as this was sufficient to accurately model growth. Ultrasound scans were performed with a 6-12 MHz transvaginal probe using GE Voluson E8 equipment and 4D View™ software (General Electric Medical Systems, Zipf, Austria). Subsequently, images were transferred to the Barco I-Space (a Cave Automatic Virtual Environment-like virtual reality system). The V-Scope volume rendering application creates an interactive hologram, allowing real depth perception. Using a tracing application, the CRL was measured three times per embryo, and the mean of these measurements was used for analysis (Verwoerd-Dikkeboom et al., 2008) . Besides allowing depth perception, V-Scope also offers the possibility of measuring the embryonic volume (semi-) automatically, using grayscale differences. The embryonic volume measurements were performed once, as previously described (Rousian et al., 2010) , and all measurements were performed by trained research staff.

Participants received three standardized three-dimensional ultrasound scans at 7, 9 and 11 weeks of gestation carried out by seven medical doctors, who were trained in carrying out first-trimester ultrasound scans, with a 6-12 MHz transvaginal probe using the GE Voluson E8 equipment and 4D View software (General Electric Medical Systems, Zipf, Austria). These three-dimensional ultrasound scans were stored as Cartesian volumes and visualized using the Barco I-Space virtual reality system at the Department of Bioinformatics of the Erasmus MC, University Medical Center Rotterdam, the Netherlands. The V-Scope software used in the Barco I-Space, allows efficient measurements of the embryo to be obtained by creating an interactive three-dimensional hologram of the ultrasound scan (Koning et al., 2009; Rousian et al., 2010) . CRL measurements were repeated three times, and the average of these measurements was used. Embryonic volume measurements were carried out once using a semi-automatic method based on gray-scale differences. The accuracy and reliability of the embryonic volume measurements were studied previously and were proven to be outstanding (interobserver variability: intraclass correlation coefficient = 0.999, 95% CI 0.997 to 0.999; intraobserver variability: intraclass correlation coefficient = 0.999, 95% CI 0.998, 0.999) (Rousian et al., 2010) .