New screening basics for the generalist

TABLE 2).

Integrated versus contingency screening. “Integrated” screening combines information from the first trimester (nuchal lucency and serum screen) with serum screening in the second trimester. This approach yields the lowest screen-positive rate (2.6%) and a high detection rate (90%), but has an important shortcoming: The results are not disclosed until the second trimester.

“Contingency” screening is emerging as an alternative: High first-trimester risks are relayed to the patient, while women with low screen values are excused from further testing. Patients with intermediate risk proceed to second-trimester serum screening.

Disadvantages of this approach include the need to coordinate the various steps and adequately inform the patient of them.

Added value of first-trimester nuchal lucency screening. Increased nuchal translucency alone is an important screen for structural abnormalities and adverse pregnancy outcomes. If a karyotypically normal fetus has an increased first-trimester nuchal lucency, the possibility of a structural anomaly on second-trimester ultrasound increases 2-to 10-fold. Absolute risk rises with increasing nuchal lucency.

Since an average of 10% to 15% of the identified anomalies are cardiac defects, fetal echocardiogram and a comprehensive fetal survey are appropriate in the second trimester.

TABLE 2

Detecting Down syndrome: Which test is best?

REFERENCE

1. Wapner R, Thom E, Simpsoon JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med. 2003;349:1405-1413.

Are children conceived with ART at increased risk?

Children born as a result of ART may face a higher risk of inherited disorders and congenital malformations, but it is unclear whether the risks are due to their parents’ infertility or to ART.

For this reason, it may be wise to refer ART patients for additional genetic counseling and fetal structural surveillance by ultrasound.

Schieve and colleagues attempted to clarify the risks by reviewing the theoretical and empiric literature. Two studies provide the bulk of evidence. In Western Australia, the background risk of birth defects doubled in infants conceived with ART: 9% risk in both intracytoplasmic sperm injection and IVF patients, compared with 4% with spontaneous conception.¹ This study is notable because ART programs are more highly regulated in Australia and similar methods were used to ascertain congenital anomalies in both groups.

A comparable study² in Sweden also noted an increased risk, but attributed it to the underlying cause of the parents’ infertility rather than to ART itself. The reason: The increased risk disappeared when the authors adjusted for the period of “involuntary childlessness.” However, they provided very little detail on how involuntary childlessness was defined and “whether and how strongly this measure is correlated with infertility severity in Sweden.”²

Imprinting disorders among ART offspring. Schieve et al also explored imprinting disorders, since diseases such as Beckwith-Wiedemann syndrome are attributed to them. Imprinting is an epigenetic phenomenon in which the allele of only 1 parent is active at a particular gene locus. The inactive—or imprinted—allele is rendered nonfunctional, often through methylation. Gametogenesis and preimplantation are times of increased imprinting. Identified imprinted genes include those that control embryonic growth and differentiation.

Analyses of Beckwith-Wiedemann syndrome registries in the United States, France, and the UK^3-5 revealed a 3- to 6-fold increase in ART conception among infants with the syndrome. Case reports of other rare imprinted disorders such as Angelman syndrome and retinoblastoma are also beginning to appear.

Direct treatment effect not established. According to Schieve et al and others, evidence of an increased risk of defects following ART does not indicate whether a direct treatment effect is present. Future studies that address methodological flaws are sure to be time-consuming; they also will require large sample sizes and consistent ascertainment and ART treatment.

Dr. Wilkins-Haug reports no relevant financial relationships.