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This was a randomized controlled trial from March 2001 to November 2004, involving one university teaching hospital and one regional hospital. The local ethics committee of each hospital approved the research protocol. Enrolled pregnant women were randomized into either the control group (10 to 14 + 6-week nuchal scan followed by routine 16–23-week scan) or the study group (10 to 14 + 6-week nuchal scan and detailed 12 to 14 + 6-week scan followed by routine 16–23-week scan). The exclusion criteria were: multiple pregnancy, molar pregnancy, ectopic pregnancy, late booking (over 15 weeks' gestation) and fetus at risk of homozygous α0-thalassemia12. During the study, integrated screening for fetal Down syndrome using first-trimester nuchal translucency thickness (NT) measurement, second-trimester biochemical markers (alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG)) and maternal age was offered to pregnant women of all ages.
Calculation of sample size
We assumed a detection rate for major fetal abnormalities of 50% in the control group, based on the detection rates of 35% in the RADIUS study3 and 61.4% in the Eurofetus study1. Assuming a detection rate of 75% for fetal abnormalities in the study group, the study would have a power of 80% to estimate a 25% difference in detection rate between the two groups, if 8800 subjects (4400 in each study arm) were recruited13.
Randomization was performed at prenatal booking, before ultrasound examination. After written consent was obtained, each woman was randomized using sealed numbered envelopes. A data collection book was used for recording the woman's information and a data collection sheet was used for recording ultrasound examination findings.
Transabdominal sonography was performed first, using an Acuson 128 XP10 or a Sequoia (Siemens Acuson Medical Systems, Mountain View, CA, USA) ultrasound machine, equipped with a C5–7-MHz curvilinear transducer. If necessary, transvaginal sonography using a C5–10-MHz curvilinear transducer was employed. Gestational age was ascertained by measurement of the fetal crown–rump length before 13 weeks of gestation, and biparietal diameter and head circumference between 13 and 14 + 6 weeks.
Eight experienced operators performed the 10 to 14 + 6-week ultrasound examinations. NT was measured adhering to the standard outlined by The Fetal Medicine Foundation14. We used our published nomograms to define increased NT15. Women allocated to the study group had an additional detailed fetal morphology scan between 12 and 14 + 6 weeks, consisting of a standard anatomical survey as in the second-trimester anomaly scan16, 17 (women enrolling into the study group before 12 weeks of gestation were given a later appointment for the detailed first-trimester anomaly scan, while those enrolling at or after 12 weeks of gestation underwent a combined nuchal and detailed first-trimester anomaly scan). Cardiac anatomy was evaluated by examining the four chambers and the aortic and pulmonary outflow tracts. Thirty minutes were allocated for each examination, which had to be performed within this time frame even if all target organs could not be well visualized because of an unfavorable fetal or uterine position. If the anatomical survey was normal, the woman underwent a routine 16–23-week ultrasound examination. Women allocated to the control group had a dating and nuchal scan between 10 and 14 + 6 weeks, followed by a routine 16–23-week ultrasound examination.
Increased NT in itself was not considered an abnormality, unless there was an associated structural abnormality. However, a cystic hygroma was regarded as an abnormality requiring further assessment and possibly invasive tests18, 19. Choroid plexus cyst and pyelectasis were recorded, but were not considered as abnormalities or markers of chromosomal abnormalities.
If abnormalities were suspected at the first-trimester or routine 16–23-week scan, one of two obstetricians (C.P.L. or M.T.) experienced in prenatal diagnosis also examined the woman to confirm the abnormalities. After confirmation, appropriate counseling and management were provided. Neonatal examination was performed by obstetricians and pediatricians. The following conditions were excluded because they were unlikely to be detected before birth: clicking hip, inguinal hernia, undescended testes, hydrocele, phimosis, isolated skin lesions and functional cardiac murmurs. Pregnancy outcome was obtained from the hospital records or by contacting the patients directly.
The SPSS for Windows 12.0 software package (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Primary outcome measures were compared between groups and detection rates with 95% confidence limits were calculated. The differences in proportions were analyzed using Fisher's exact test or the chi-square test. The differences in continuous data were calculated using Student's t-test. A two-sided value of P < 0.05 was considered statistically significant.