The Future of Prenatal Diagnosis: Rapid Testing or Full Karyotype? An Audit of Chromosome Abnormalities and Pregnancy Outcomes for Women Referred for Down???s Syndrome Testing

Abstract

At present, women at increased risk of fetal Down syndrome because of advanced maternal age, an abnormal screening test result, or a previous affected child are offered genetic amniocentesis with full fetal karyotype analysis. The advent of reliable and efficient rapid molecular techniques for identifying numeric chromosome abnormalities raises the question of whether a full fetal karyotype analysis is necessary when samples are analyzed solely because the risk of Down syndrome is increased. Without complete karyotyping, there is a risk that chromosomal abnormalities not demonstrated by rapid trisomy testing will go undiagnosed. However, some of these fetuses would have a malformation evident on ultrasound scanning, and a complete karyotype analysis would be offered. At the same time, some abnormal genotypes will have no significant phenotypic sequelae visible by ultrasound, some may be inherited and not associated with phenotypic abnormalities, and others will be of uncertain significance, raising parental anxiety and possibly resulting in unnecessary pregnancy terminations. This retrospective review included 32,674 pregnant women living in or near London who had invasive prenatal diagnosis from 1996 to 2002. More than three fourths of samples (24,891) were from women referred chiefly for Down syndrome testing. Among these samples were 118 sex chromosome abnormalities and 153 autosomal abnormalities not found by rapid testing (0.62%). Fifty-five of the 118 pregnancies with fetal sex chromosome abnormalities delivered at term; in 44 the outcome was unknown and 19 miscarried or were terminated. Among the 153 pregnancies with fetal autosomal abnormalities, the prognosis was classified as good for 98, uncertain for 37, and poor for 18. The 98 cases with a good prognosis included 46 live-born infants, 3 pregnancy terminations, one case each of intrauterine death and miscarriage, and 47 whose outcome was unknown. Of 37 cases with an uncertain prognosis, 20 resulted in a live-born infant, 5 were terminations, and in 12, the outcome was not ascertained. Among 18 cases with a poor prognosis were a single live-born infant, 2 miscarriages, 11 terminations, and 4 with unknown outcomes. In a separate analysis of phenotypically abnormal children under age 5 brought in for evaluation from 1995 to 1997, there were 90 nonnumeric chromosome abnormalities of which 78 were unbalanced and 12 were balanced chromosome rearrangements. Considering that there were approximately 46,430 live births per year in the referral region over the study period, the investigators estimated that the proportion of living children with unbalanced chromosome abnormalities causing concern in the first 5 years of life was 0.06%. The risk of having an infant with a nonnumeric unbalanced chromosomal abnormality was no higher in women at increased risk of a Down syndrome pregnancy than in those lacking such risk. The investigators concluded that if prenatal karyotyping was replaced by molecular trisomy testing for women at risk of a Down syndrome birth, substantial financial savings would result, and the results would be available rapidly and would not be ambiguous. In addition, anxiety will be lessened, and possibly unneeded terminations of pregnancy would be avoided.