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Reproductive technologies and the risk of birth defects.
N Engl J Med. 2012 May 10; 366(19):1803-13
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16 May 2012
New Finding
DOI: 10.3410/f.715347815.790852897
This is the most comprehensive study done thus far on the risk for birth defects among infertility patients conceiving spontaneously or with the use of different assisted reproductive technologies. This is also the first to show an increased risk for birth defects for pregnancies achieved with the use...Continue reading
This is the most comprehensive study done thus far on the risk for birth defects among infertility patients conceiving spontaneously or with the use of different assisted reproductive technologies. This is also the first to show an increased risk for birth defects for pregnancies achieved with the use of intracytoplasmic sperm injection (ICSI) after adjusting for patient characteristics.
This study is a population-wide cohort study that looked at the risk for major birth defects in pregnancies of infertility patients. The authors used several registries that included congenital abnormalities diagnosed at birth or with pregnancy terminations, and follow up occurred to the fifth birthday. They also examined several treatment modalities ranging from clomiphene citrate used with no monitoring through intrauterine insemination and in vitro fertilization (IVF) with or without ICSI. The study included a large database of 308,974 births and meticulous methodology. The authors also included a group of infertility patients that had a spontaneous pregnancy while waiting for treatment or following assisted conception in order to control the contribution of the patient characteristics to the risk for birth defects. The study showed an increased risk for birth defects with IVF and ICSI, although after adjusting for patient characteristics, only the increased odds ratio for ICSI remained significant (1.55). Interestingly, no increase in risk for birth defects was recorded with frozen embryo transfers. The highest odds ratio for birth defects was recorded for the use of clomiphene citrate without monitoring (3.19).
The study collected data on pregnancies achieved through 1986 to 2002. ICSI was introduced to clinical practice at the beginning of the 1990s. During the 10 years of ICSI use included in this study, many technical and practice changes took place. Initially, ICSI was used strictly for severe male factor infertility but, over the years, the indications have become more liberal. Currently, most IVF cycles include ICSI. It is possible that the higher risk for birth defects with ICSI reflects the poor quality of sperm involved in these pregnancies. It would be interesting to find whether liberalization of the indications for ICSI reduced the risk for birth defects associated with this procedure.
This study is a population-wide cohort study that looked at the risk for major birth defects in pregnancies of infertility patients. The authors used several registries that included congenital abnormalities diagnosed at birth or with pregnancy terminations, and follow up occurred to the fifth birthday. They also examined several treatment modalities ranging from clomiphene citrate used with no monitoring through intrauterine insemination and in vitro fertilization (IVF) with or without ICSI. The study included a large database of 308,974 births and meticulous methodology. The authors also included a group of infertility patients that had a spontaneous pregnancy while waiting for treatment or following assisted conception in order to control the contribution of the patient characteristics to the risk for birth defects. The study showed an increased risk for birth defects with IVF and ICSI, although after adjusting for patient characteristics, only the increased odds ratio for ICSI remained significant (1.55). Interestingly, no increase in risk for birth defects was recorded with frozen embryo transfers. The highest odds ratio for birth defects was recorded for the use of clomiphene citrate without monitoring (3.19).
The study collected data on pregnancies achieved through 1986 to 2002. ICSI was introduced to clinical practice at the beginning of the 1990s. During the 10 years of ICSI use included in this study, many technical and practice changes took place. Initially, ICSI was used strictly for severe male factor infertility but, over the years, the indications have become more liberal. Currently, most IVF cycles include ICSI. It is possible that the higher risk for birth defects with ICSI reflects the poor quality of sperm involved in these pregnancies. It would be interesting to find whether liberalization of the indications for ICSI reduced the risk for birth defects associated with this procedure.
Disclosures
None declared
Add Comment
Casper R and Bentov Y: F1000Prime Recommendation of [Davies MJ et al., N Engl J Med 2012, 366(19):1803-13]. In F1000Prime, 16 May 2012; DOI: 10.3410/f.715347815.790852897. F1000Prime.com/715347815#eval790852897
29 May 2012
Controversial
DOI: 10.3410/f.715347815.791552896
The long-term clinical ramifications of treatment with assisted reproductive technologies, specifically surrounding the incidence of birth defects, have long been debated. This study, with excellent numbers (6100 births from assisted reproductive technologies out of 308,000 births), followed children...Continue reading
The long-term clinical ramifications of treatment with assisted reproductive technologies, specifically surrounding the incidence of birth defects, have long been debated. This study, with excellent numbers (6100 births from assisted reproductive technologies out of 308,000 births), followed children for a long time (5 years after birth) and increased the validity of the data with the use of data from multivariate analyses and adjustment; the association of in vitro fertilisation (IVF) and risk of birth defects was not significant but there was an increased risk of birth defects associated with intracytoplasmic sperm injection (ICSI). Frozen embryos did not show significant differences in birth defects when compared to fresh embryos. Overall, regardless of the fertility treatment, there was an increased odds ratio of 1.47 in birth defects with assisted conception when compared to pregnancies not involving assistance.
Disclosures
None declared
Lin P: F1000Prime Recommendation of [Davies MJ et al., N Engl J Med 2012, 366(19):1803-13]. In F1000Prime, 29 May 2012; DOI: 10.3410/f.715347815.791552896. F1000Prime.com/715347815#eval791552896
30 May 2012
Controversial, Good for Teaching
DOI: 10.3410/f.715347815.791102852
Although the risk of birth defects in children conceived after assisted reproductive technology (ART) has been the subject of many studies before, this article uses an exceptionally large cohort of Australian children born either spontaneously or after ART. The authors clearly demonstrate an increased...Continue reading
Although the risk of birth defects in children conceived after assisted reproductive technology (ART) has been the subject of many studies before, this article uses an exceptionally large cohort of Australian children born either spontaneously or after ART. The authors clearly demonstrate an increased risk for birth defects among children born after ART although the absolute numbers are still low. It remains to be seen if the described association is due to the underlying subfertility, maternal/paternal factors or the techniques applied.
The described risk of birth defects in children, albeit low, should be included in the counselling given to patients undergoing ART.
The described risk of birth defects in children, albeit low, should be included in the counselling given to patients undergoing ART.
Disclosures
None declared
Repping S: F1000Prime Recommendation of [Davies MJ et al., N Engl J Med 2012, 366(19):1803-13]. In F1000Prime, 30 May 2012; DOI: 10.3410/f.715347815.791102852. F1000Prime.com/715347815#eval791102852
28 Sep 2012
Sarah Berga
F1000 Diabetes & Endocrinology
Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
F1000 Diabetes & Endocrinology
Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
Jennifer Fay Kawwass
F1000 Diabetes & Endocrinology
Emory University School of Medicine, Atlanta, GA, USA.
F1000 Diabetes & Endocrinology
Emory University School of Medicine, Atlanta, GA, USA.
Controversial, Good for Teaching
DOI: 10.3410/f.715347815.793461341
This population-wide cohort study, using Australian national data registries for birth defects diagnosed by age 5 and for infant births resulting from use of assisted reproductive technology (ART), attempts to clarify a long-standing question: are infants conceived using ART at increased risk of birth...Continue reading
This population-wide cohort study, using Australian national data registries for birth defects diagnosed by age 5 and for infant births resulting from use of assisted reproductive technology (ART), attempts to clarify a long-standing question: are infants conceived using ART at increased risk of birth defects as compared to their spontaneously conceived counterparts? The study includes 308,794 live births (6163 of which were the result of ART) between January 1986 and December 2002. Adjusted odds ratios (AORs) for the presence of any birth defect, including cerebral palsy, are calculated for infants conceived via ART as compared to those conceived spontaneously from a couple with a previous history of ART, those conceived from an infertile couple but without the use of ART, those conceived from a couple without a history of infertility. The ORs were adjusted for known confounders, namely parity, fetal sex, year of birth, maternal race, maternal smoking, maternal medical conditions during gestation, maternal socioeconomic status and maternal and paternal occupation. The unadjusted OR for a birth defect was significantly increased (OR 1.26, 95% confidence interval [CI] 1.07 to 1.48) for couples undergoing IVF as compared to spontaneously conceived infants.
However, the OR was no longer significant (AOR 1.07, 95% CI 0.90 to 1.26) after adjusting for parental factors. For IVF with the use of intracytoplasmic sperm injection (ICSI), both the unadjusted OR and AOR were increased in the ART groups, OR 1.77 and AOR 1.57 (95% CI 1.47 to 2.12 and 1.30 to 1.90), respectively.
The study strengths include the large number of study subjects, the completeness of the data set, the ability to control for known confounders and the predetermined decision to separate analysis for singleton and multiple pregnancies. The study is limited by its dependence on registry accuracy, the broad and subjective nature of defining a birth defect and the lack of information on paternal age. Overall, these findings are reassuring; they suggest that patient characteristics rather than the ART treatment itself may yield the slightly increased odds of having an infant with a birth defect. Even for the ICSI group, an underlying paternal characteristic that warranted the use of ICSI is as likely a determinant of having a child with a defect as is the ICSI procedure itself.
However, the OR was no longer significant (AOR 1.07, 95% CI 0.90 to 1.26) after adjusting for parental factors. For IVF with the use of intracytoplasmic sperm injection (ICSI), both the unadjusted OR and AOR were increased in the ART groups, OR 1.77 and AOR 1.57 (95% CI 1.47 to 2.12 and 1.30 to 1.90), respectively.
The study strengths include the large number of study subjects, the completeness of the data set, the ability to control for known confounders and the predetermined decision to separate analysis for singleton and multiple pregnancies. The study is limited by its dependence on registry accuracy, the broad and subjective nature of defining a birth defect and the lack of information on paternal age. Overall, these findings are reassuring; they suggest that patient characteristics rather than the ART treatment itself may yield the slightly increased odds of having an infant with a birth defect. Even for the ICSI group, an underlying paternal characteristic that warranted the use of ICSI is as likely a determinant of having a child with a defect as is the ICSI procedure itself.
Disclosures
None declared
Berga S and Kawwass J: F1000Prime Recommendation of [Davies MJ et al., N Engl J Med 2012, 366(19):1803-13]. In F1000Prime, 28 Sep 2012; DOI: 10.3410/f.715347815.793461341. F1000Prime.com/715347815#eval793461341
F1000Prime Recommendations, Dissents and Comments for [Davies MJ et al., N Engl J Med 2012, 366(19):1803-13]. In F1000Prime, 20 Jun 2013; F1000Prime.com/715347815
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Background The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain. Methods We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child's fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility. Results Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07 (95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects. Conclusions The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.).
PMID: 22559061
