Dehydrosteroid measurements in maternal urine or serum for the prenatal diagnosis of Smith–Lemli–Opitz syndrome (SLOS)

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Abstract
In a large multi‐center trial involving prenatal screening for Smith–Lemli–Opitz syndrome (SLOS), we evaluated maternal urine and serum steroid analysis as a non‐invasive diagnostic alternative to amniotic fluid sterol analysis. Candidate steroid ratios included: 7‐dehydropregnanetriol/pregnanetriol (7‐PT/PT), 8‐dehydropregnanetriol/PT (8‐PT/PT), the sum of these two (7 + 8‐PT/PT), and dehydroestriol/estriol (DHE3/E3). Results are presented from 19 SLOS pregnancies, and 732 reference pregnancies that were screen positive for SLOS but negative on testing in amniotic fluid. Steroid ratios are expressed as multiples of the 75th centile (MoS), rather than multiples of the median, as most reference measurements were undetectable. All four urine ratios were available in 12 SLOS pregnancies; the median 7‐PT/PT MoS was 94, with no overlap between affected and reference pregnancies in the second trimester. The separation between these groups increased by 27% per week. The other three ratios performed similarly in urine, with (7 + 8)‐PT/PT ratios being marginally superior, due to fewer high reference outliers. All four steroid ratios in urine were diagnostic for SLOS between 14 and 22 weeks' gestation. In six SLOS pregnancies in which all serum analytes were measured, the median 7‐PT/PT MoS was 71, and there was slight overlap in the second trimester. The separation increased by 28% per week. Steroid ratios in serum were less definitive than in urine but might be useful in certain circumstances, at 14 weeks gestation or later. Urine testing performance prior to 14 weeks gestation appears promising, but reference data are sparse.