Prenatal Diagnosis

Parental Age

A long-recognized increase in aneuploidy as women become older is a cornerstone of prenatal diagnosis. For women who are 35 years of age at delivery, the chance of having a newborn with Down syndrome (trisomy 21) is approximately 1 in 308 pregnancies. Because trisomy 21 is associated with increased risk of miscarriage and stillbirth, for a 35-year-old woman the chance that Down syndrome will be diagnosed is actually higher at amniocentesis (1 in 258) or CVS (1 in 175). Although maternal age was the first screening criterion for Down syndrome, it performs poorly when assessed at a population level. Approximately 15% of women have children at age 35 years or older (screen-positive rate), and the likelihood in this subgroup of women that a pregnancy will be complicated by Down syndrome (positive predictive value) is only 1% to 3%. Furthermore, the detection rate is only approximately 20%; less than one fourth of Down syndrome infants are born to women in this older maternal age subcategory. When evaluated by these screening parameters, the utility of maternal age greater than 35 years alone as an indication for an invasive prenatal diagnostic test has been challenged. Genetic conditions associated with the father’s age are more difficult to delineate but include an increased risk of dominant mutations as exemplified by achondroplasia.

Reproductive History

Assessment of the couple’s reproductive history may also signal an increased genetic risk for the pregnancy. A history of repeat miscarriages (two or more) is associated with an increased risk of parental balanced translocation (6.8%). Other reproductive outcomes, such as a previous malformed stillbirth along with a single miscarriage, are also associated with an increased risk of a parental balanced translocation (5.4%). A history of three or more consecutive first-trimester abortions carries a 9.6% risk of a parental balanced translocation. Similarly, repeated failure of in vitro fertilization cycles (for more than 10 cycles) attributable to poor implantation is associated with an increased risk of a parental balanced translocation of 2.5%. By comparison, the overall rate of balanced translocations in newborns is 0.2%. A balanced translocation increases the person’s risk that offspring may inherit an unbalanced complement of chromosomes, with associated implications for mental and physical delays.

In addition to previous pregnancies, a diagnosis of infertility warrants closer examination of the identified etiologic disorder and the possible recommendation for prenatal diagnostic testing. Balanced translocations and sex chromosome aneuploidy occur in 14.3% and 6.5% of men with absent and low sperm counts, respectively. In addition, with male factor infertility related to obstructive azoospermia, congenital bilateral absence of the vas deferens (CBAVD) is a common diagnosis. Of men with CBAVD, almost two thirds carry at least one mutation in the gene responsible for classic cystic fibrosis (CF) (i.e., the CF transmembrane receptor gene [CFTR] ). Almost half (54.5%) of the men are double heterozygotes, possessing two mutations for classic CF, although most often the second mutation is a variant specifically associated with infertility and not classic CF. Because men with CBAVD can father children through assisted reproduction using intracytoplasmic sperm injection, carrier screening of the female partner is critical in view of the relatively high carrier frequency—1 in 25 in the white population. Couples in which both members carry a CFTR mutation face a 25% risk of having a child with CF; this finding emphasizes the importance of delineating the specifics of male factor infertility.

Female factor infertility also may have an underlying genetic etiology with subsequent risk to the offspring. In particular, poor ovarian reserve and oligomenorrhea or amenorrhea may reflect a premutation of fragile X. Classically, 3% of cases of sporadic premature ovarian failure and 13% of cases of familial premature ovarian failure are associated with a premutation of fragile X. Of significance for female factor infertility, earlier menopause in women with a premutation of fragile X heightens the possibility that these women will seek infertility evaluation and treatment with a diagnosis of poor ovarian reserve. In view of an overall frequency of fragile X premutations in the general population of approximately 1 in 200 women, infertility centers offer screening for fragile X to women. For fragile X premutation carriers, the implications for the offspring reflect the degree of expansion of the fragile X site (as discussed next under family history screening).