In vitro fertilization is associated with an increase in major birth defectsMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCESIn vitro fertilization is associated with an increase inmajor birth defectsChristine K. Olson, M.D., M.P.H.,aKim M. Keppler-Noreuil, M.D.,bPaul A. Romitti, Ph.D.,cWilliam T. Budelier,cGinny Ryan, M.D.,aAmy E. T. Sparks, Ph.D.,aand Bradley J. Van Voorhis, M.D.aaDivision of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa;bIowa State Birth Defects Registry; andcCollege of Public Health, University of Iowa, Iowa City, IowaObjective: To determine the risk of major birth defects in cohorts of children conceived through IVF or throughIUI as compared with naturally conceived children.Design: Retrospective cohort study.Setting: Academic medical center.Patient(s): Children conceived by IVF or IUI at the University of Iowa from 1989 through 2002, compared witha matched cohort of naturally conceived children.Intervention(s): None.Main Outcome Measure(s): Outcome data were obtained from Iowa state birth and fetal death certificates andfrom the Iowa Birth Defects Registry.Result(s): Ninety of 1,462 IVF-conceived children (6.2%) and 17 of 343 IUI-conceived children (5.0%) had amajor birth defect, compared with 369 of 8,422 naturally conceived children (4.4%). The adjusted odds ratio ofa major birth defect in all IVF-conceived children was 1.30 (95% confidence interval [CI] 1.00–1.67) and 1.11(95% CI 0.67–1.84) for IUI-conceived children. The birth defect rate was increased after IVF when the analysiswas limited to term singletons. Cardiovascular and musculoskeletal defects and known birth defect syndromeswere increased after IVF. Among IVF-conceived children, there was no difference in birth defect rates afterintracytoplasmic sperm injection (ICSI) or after transfer of cryopreserved embryos.Conclusion(s): Infants conceived through IVF have a slightly higher rate of major birth defects. More birthdefects are noted among children born to infertile couples treated with IUI, although this difference is notstatistically significant. Larger studies of infants conceived by infertile couples after all types of infertilitytreatment are needed to definitively determine whether the increased risk of birth defects is secondary to problemsinherent in the infertile couple and/or factors associated with some aspect of the treatment. (Fertil Steril威 2005;84:1308–15. ©2005 by American Society for Reproductive Medicine.)Key Words: IVF, infertility, intrauterine insemination, ovulation induction, birth defects, congenital anomalyThe association between IVF and an increased risk of birthdefects is controversial. Early studies suggesting that IVFwas safe with respect to birth defects are difficult to interpretowing to small size, lack of appropriate controls, and incon-sistent methods for detecting birth defects in the treated andcontrol groups (1–5). Several more recent matched cohortstudies have demonstrated an increased risk of birth defectsin general (6) or cardiovascular birth defects in particular (7)associated with IVF, whereas others have not found anincreased risk (8, 9). Two recent studies comparing IVF birthdefect rates with national registry data have found increasedrates of birth defects in children conceived with IVF, but thedifference lost significance when the data were controlled formaternal age, parity, and plurality (10, 11).Clarifying the possible association between IVF and birthdefects is critical because almost 1% of children in theUnited States are now conceived by IVF. Of equal impor-tance is identifying the mechanism behind this possibleassociation. Some have speculated that epigenetic errors,such as defects in DNA methylation and imprinting, mightbe caused by the embryo culture that follows IVF. Thishypothesis is supported by recent reports of the associationbetween IVF and Beckwith-Wiedemann syndrome (12–14),retinoblastoma (15), and Angelman Syndrome (16, 17), con-ditions caused by defects in genomic imprinting. Other pos-sible mechanisms of the purported association between IVFand birth defects could include the effects of controlledovarian hyperstimulation and ovulation induction, in vitrosperm preparation, or an inherent defect in the infertilecouple perhaps leading to both the infertility and the birthdefect in the resulting child. We sought to determine therisks of birth defects in children conceived after infertilitytreatment as compared with the risk of defects in a cohort ofnaturally conceived children born in Iowa. Our study has thebenefit of including infants conceived both by IVF withembryo culture and by IUI in which no embryo culture ormanipulation occurred. Comparing birth defect rates in theseReceived September 16, 2004; revised and accepted March 3, 2005.Reprint requests: Bradley J. Van Voorhis, M.D., University of Iowa Hos-pitals and Clinics, Department of Obstetrics and Gynecology, 200Hawkins Drive, Iowa City, IA 52242 (FAX: 319-353-6659; E-mail: [email protected]).1308Fertility and Sterility姞 Vol. 84, No. 5, November 2005 0015-0282/05/$30.00Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2005.03.086two groups of children with birth defect rates in a cohort ofnaturally conceived children helps to elucidate whether birthdefects result from IVF and embryo culture, from otherinfertility treatments, or from a factor outside of infertilitytreatment protocols. Importantly, we have a statewide birthdefects registry in which all birth defects are reported in auniform and unbiased manner.MATERIALS AND METHODSThe study population included the total cohort of IVF andIUI births (live births and stillbirths delivered at ⱖ20 weeks’gestational age) conceived at the University of Iowa from1989 through 2002, excluding children born to couples liv-ing outside Iowa and children whose birth certificate did notlist Iowa as their state of residence. These children wereexcluded because we could not be sure that we had accuratebirth defect data for them.For the purpose of this analysis, IVF is defined as anytreatment that included retrieval of oocytes and fertilizationof those oocytes in vitro (either by intracytoplasmic sperminjection [ICSI] or by culturing oocytes and spermatozoatogether) followed by some period of embryo culture. Thus,IVF conceptions include babies born after zygote intrafallopiantransfer (ZIFT, culture