Prenatal screening for Down syndrome in pregnancies at risk for α‐thalassemia

I read with interest the recent article by Tongprasert et al. (2011), which evaluated the ability of maternal serum-free β-human chorionic gonadotrophin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A) and alpha fetoprotein (AFP) levels in the screening of fetuses with hemoglobin (Hb) Bart’s disease among pregnancies at risk during 18–22 weeks. The authors found that AFP concentrations were significantly higher in women with fetal Hb Bart’s disease than those with unaffected fetuses, whereas the concentrations of free β-hCG and PAPP-A were not significantly different between the two groups. They suggested second-trimester AFP as a useful screening test for fetal Hb Bart’s disease among pregnancies at risk. However, in our experience in prenatal screening for thalassemia, this approach might not be an attractive option. As a screening test for fetal Hb Bart’s disease, mid-second trimester is too late. Investigation for firsttrimester biomarkers in maternal blood would be more desirable. The authors used the Down screening markers to screen for Hb Bart’s disease. However, they had not mentioned the Down screening program in pregnancies at risk for Hb Bart’s disease. Are these pregnancies screened for Down syndrome? How is the screening test done? During the past 5 years, totally we had 745 pregnant women at risk for fetal Hb Bart’s disease, who were referred to our center for prenatal diagnosis before 20 weeks of gestation. We took a selective Down screening algorithm for these pregnancies after informed consent. For pregnancies with less than 14 weeks’ gestation, if the mother chose an immediate invasive test for thalassemia, no Down screening test was given, and chorionic villus sampling (CVS) was directly performed in the mother. The CVS samples were sent for genotyping by PCR-based assays and for karyotyping by quantitative fluorescent polymerase chain reaction (QF-PCR) which was also used to detect maternal contamination at the same time. QF-PCR allows detection, usually within 48 h, of aneuploidies of chromosomes 21, 18, 13, X and Y. If the mother chose serial ultrasonography to detect signs of fetal anemia (cardiomegaly and/or placentomegaly), the combined first-trimester screen test was given to the mother. Fetal nuchal translucency was measured, and blood was taken at the same day from the mother for serum PAPP-A and free β-hCG determination. The invasive test was only followed in those cases with abnormal ultrasound findings or positive screening results. For pregnancies beyond 14 weeks’ gestation, the mother was first subjected to an ultrasound scan; if signs of fetal anemia were found, the invasive test would be performed for confirmation. If the scan was normal, a triple serum screen test (β-hCG, AFP and uE3) was given to the mother at 15–20 weeks. In recent years, sonography has been in use for prenatal detection of Hb Bart’s disease at our Center, and has become a dominant method in prenatal diagnosis of α-thalassemia (Li et al., 2007; Liao et al., 2007). Among the 745 at-risk women, 403 were referred before 14 weeks; of these, 136 (33.7%) received direct invasive testing, and 267 (66.3%) received serial ultrasonography and the combined first-trimester screen test. Ten CVS procedures were performed because of a positive Down screening result, and 1 pregnancy with trisomy 21 fetus was diagnosed and terminated. Out of the 342 at-risk women who were referred beyond 14 weeks, 84 (24.6%) received an invasive test for confirmation of Hb Bart’s disease because of an abnormal ultrasound scan, and 258 (75.4%) had a normal scan by ultrasound and received a triple serum screen test; among these, 15 amniocenteses were conducted because of a positive Down screening result, and 1 pregnancy with 45, X fetus was diagnosed and terminated. Thalassemia is a monogenic disease. Couples with the α-thalassemia trait carry a 25% chance of having a fetus with homozygous α-thalassemia major. If all pregnancies at risk for α-thalassemia receive a prenatal Down screening test, there would be in one out of four that the screening test is performed in an affected pregnancy with no benefit for the couple. On the other hand, it would be unacceptable to the couples to give birth to a child with a chromosomal abnormality after having undergone a prenatal diagnosis of thalassemia. We therefore implemented the above-mentioned selective Down screening algorithm in these women, which offered the chance to pick up a trisomy 21 fetus in mother who had declined an invasive test, and, meanwhile, resulted in a reduction in the costs of karyotyping in mothers who had received an invasive test, especially in those with an affected fetus of Hb Bart’s disease.