Frequency of Downʹs syndrome and neural-tube defects in the same family

Background There is evidence that some mothers of infants with Downʹs syndrome have abnormal metabolism of folate and methyl, as well as mutations in folate genes, which are features that are also seen in neural-tube defects (NTD). We therefore investigated whether Downʹs syndrome and NTD arise more often in the same family than would be expected from the incidence of each disorder considered separately. Methods We studied two series of families using information obtained from medical records about maternal age, pregnancy outcome, congenital malformations, and karyotype: the first, 493 families from Israel who were at high risk of NTD (445 with a history of NTD and 48 with isolated hydrocephalus); and the second, 516 families from the Ukraine at high risk of Downʹs syndrome. Findings In the families at risk of NTD, there were a total of 11 pregnancies affected by Downʹs syndrome in 1492 at-risk pregnancies (compared with 1•87 expected on the basis of maternal age), which was a significant increase (p<0•00001). In the families at risk of Downʹs syndrome, there were seven NTD pregnancies in 1847 at risk, compared with 1•37 expected (p<0•001). Interpretation In this study, we provide direct evidence of a link between Downʹs syndrome and NTD. Folate supplementation before conception has the potential to reduce the frequency of Downʹs syndrome.