LAUSR

In vitro fertilization (IVF) is now responsible for achieving 1– 2% of US pregnancies and subsequent births (www.cdc.gov/art). A number of factors have led to the steady increase in IVF, including increasing rates of infertility and delayed onset of reproduction, especially for women [1]. In the early 2000s, reports of children born with imprinting disorders following IVF appeared in the literature. At first, these included Angelman (AS) and Beckwith-Wiedemann syndromes (BWS, [2–7]), but later Russell-Silver syndrome [8] as well. These reports were first anecdotal, followed by larger retrospective registry studies [9–14]. From the above, there clearly are increased risks for imprinting syndromes following IVF/ICSI. The estimates of increased risk vary significantly but range from 0-fold to about 13-fold. However, molecular details in the above studies are mostly lacking. In addition, there are no results from prenatal series and fewer studies on the increased risk for AS following IVF. To assess the increased risk of these disorders, we report on a consecutive series of 949 IVF pregnancies tested for imprinting disorders, AS and BWS (no case of BWS was detected), the only indication for testing.We have found one molecularly confirmed case of Angelman syndrome caused by an imprinting defect. The expected probability of this event in the general population is approximately 1/200,000 (prevalence of Angelman syndrome ~1/10,000–20,000, using a conservative high figure of 1/10,000, with only 2–5% being due to primary imprinting disorders, using a high figure of 5% to reach this overall risk), and the probability of detecting such an event in our small series is < .0001 (chi-square (www.medcalc.org/ calc/comparison_of_proportions.php)). We believe this observation provides substantial support to the assertion that IVF significantly increases the risk of fetal imprinting disorders, from this report specifically, AS.