Assisted Reproductive Technology and Major Structural Birth Defects in US
Background: With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects.
Methods: We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality.
Results: ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied.
Conclusions: These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

According to data from the 2002 National Survey of Family Growth, 11.9% of US women aged 15-44 years reported ever using any infertility services (Chandra et al., 2005). In the USA and worldwide, the use of assisted reproductive technology (ART) to treat infertility is increasing rapidly, with an estimated total of 200 000 babies born after use of ART worldwide in 2000 (Adamson et al., 2006). ART is defined as infertility treatments in which both oocytes and sperm are handled outside the body such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). In the USA in 2005, more than 134 000 ART procedures were performed and more than 52 000 infants were live-born as a result of these procedures, representing >1% of all US births (Wright et al., 2008). This proportion is expected to continue to rise and research on short- and long-term health effects has not kept pace with rapid advances in treatment technology. Two meta-analyses were published in 2005, one that addressed the association between ART and birth defects (Hansen et al., 2005), and the other more specifically addressed the association between ICSI and birth defects (Lie et al., 2005). These two reviews included most of the existing literature on this topic and found an increased risk for birth defects overall after the use of IVF, but no additional risk from ICSI when compared with IVF (Hansen et al., 2005; Lie et al., 2005). However, the studies in these reviews were limited by a number of methodological problems, including small numbers of affected infants, heterogeneous case groups, lack of appropriate control groups and potential confounding (Schieve et al., 2005).

In this study, we used data from an ongoing population-based, multicenter, case-control study of birth defects to examine possible associations between ART and major structural birth defects.