The risk of birth defects associated with assisted reproductive technology treatments was significantly increased compared with spontaneously conceived births in a large Australian observational study, but after adjustment for parental factors, the increased risk associated with in vitro fertilization was no longer significant.
The risk of birth defects associated with intracytoplasmic sperm injection (ICSI), however, remained significantly elevated, even after adjustment for maternal age and other risk factors, reported Michael Davies, Ph.D., from the Robinson Institute and School of Pediatrics and Reproductive Health, at the University of Adelaide (Australia), and his associates.
Dr. Michael J. Davies
"Although we cannot rule out the possibility that other patient factors contribute to or explain the observed associations, our findings can help provide guidance in counseling patients who are considering treatment for infertility," they added in reporting the study, which was published online May 5 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1008095). The publication coincided with Dr. Davies’ presentation of the results at the World Congress on Building Consensus in Gynecology, Infertility, and Perinatology in Barcelona.
Using different databases in South Australia, the investigators compared the risks of birth defects, including cerebral palsy, diagnosed before age 5 years, among 308,974 births in South Australia, from a census of births resulting from assisted reproductive technology (ART) treatment, a registry of births and pregnancy terminations, and birth defect registries. Of the total number of births, 6,163 resulted from ART.
As in previous studies, they found an association between ART and an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy, although they pointed out that there were no birth defects for the "large majority" of births resulting from assisted conception.
Overall, there were 513 birth defects among pregnancies resulting from assisted conception (8.3%), compared with 17,546 birth defects among those that did not involve assisted conception (5.8%) – with an unadjusted odds ratio of 1.47. After adjustment for maternal age, maternal conditions during pregnancy, and other potential confounders, the odds ratio was 1.28.
The odds ratio for birth defects associated with IVF was 1.26 in unadjusted analysis, but was only 1.07 in multivariate analysis and no longer statistically significant.
The unadjusted odds ratio for birth defects associated with ICSI was 1.77, and after adjustment for other confounding factors, the risk was 1.57, which remained significant. The authors said that it was "biologically plausible" that the effects of treatment with ICSI explain the increased risk of birth defects, but added that differences in male infertility factors that lead to the use of ICSI "may also underlie the association."
The birth defect risk was also significantly increased among women with a history of infertility but no treatment with ART, which was also found in a Danish registry study, and "implicates patient factors in this increased risk," they said.
Among the study’s other findings are the increased risk of birth defects associated with the home use of clomiphene citrate, which has also been found in previous case control studies. But the authors said that this finding should be interpreted cautiously, because of the small number of women who received this treatment, and that they could not rule out "residual confounding or chance" as an explanation.
In a statement issued by the University of Adelaide, Dr. Davies said that this group was small and the result needed to be confirmed with more research. But he added that the finding raises concerns because clomiphene citrate is widely available at a low cost, and "may easily be used contrary to manufacturers’ very specific instructions to avoid use if pregnant, as it may cause fetal malformations."
He and his associates also found a significant increase in the birth defect risk associated with fresh-embryo cycles of IVF or ICSI, but no increased risk associated with frozen-embryo cycles of either method. This finding could possibly be explained by the possibility that cryopreservation reduces the likelihood that "developmentally compromised embryos will survive the thawing process and the temporal separation of the developing embryo from exposure to hormonal stimulation drugs used early" in ART treatment, the researchers said in the study.
In a statement issued by the American Society for Reproductive Medicine (ASRM), the society’s president, Dr. Linda Giudice, said that the study "confirms what has been known for quite some time: Patients who need medical assistance to conceive have a somewhat higher risk of having children with birth defects than parents able to conceive on their own.
"Patients considering medically assisted conception have been, and should continue to be, counseled on those risks prior to undergoing any treatment," said Dr. Giudice, distinguished professor and chair of reproductive endocrinology and infertility, and the Robert B. Jaffe, M.D. Endowed Professor in the Reproductive Sciences at the University of California, San Francisco.