Correspondence
Major Birth Defects after Assisted Reproduction
N Engl J Med 2002; 347:1449-1451October 31, 2002
- Article
To the Editor:
We agree with Hansen et al. (March 7 issue)1 that many studies of birth defects after in vitro fertilization suffer from methodologic problems, but we believe that their study has similar limitations. The authors compared the outcomes of roughly 1000 children conceived with in vitro fertilization with those of control infants born to mothers who were significantly younger than the women who conceived with in vitro fertilization, were more likely to be parous, and were more ethnically diverse. In addition, they made no attempt to control for a history of infertility or the age of the father — factors that have previously been reported to be prognostic of adverse outcomes of pregnancy.2,3
Each year, the Society for Assisted Reproductive Technology collects data on the outcomes of in vitro fertilization from its members, whose clinics perform more than 90 percent of all such procedures in the United States. Among 134,985 children conceived as a result of assisted reproductive technology between 1996 and 2000, 2597 infants (1.9 percent) were reported to have a major birth defect. This rate is similar to the incidence of major abnormalities reported in general populations in both Europe and North America.4,5 Although we acknowledge that infertility treatment is not without risks, we believe that our data should be reassuring to both practitioners who perform in vitro fertilization procedures and their patients.
5 ReferencesMichael P. Steinkampf, M.D.
Jamie Grifo, M.D., Ph.D.
Society for Assisted Reproductive Technology, Birmingham, AL 35216-28091
Hansen M ,Kurinczuk JJ ,Bower C ,Webb S . The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725-730
Full Text | Web of Science | Medline2
Draper ES ,Kurinczuk JJ ,Abrams KR ,Clarke M . Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999;353:1746-1749
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McIntosh GC ,Olshan AF ,Baird PA . Paternal age and the risk of birth defects in offspring. Epidemiology 1995;6:282-288
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Calzolari E ,Cavazzuti GB ,Cocchi G , et al. Congenital malformations in 100,000 consecutive births in Emilia Romagna region, northern Italy: comparison with the EUROCAT data. Eur J Epidemiol 1987;3:423-430
CrossRef | Web of Science | Medline5
Van Regemorter N ,Dodion J ,Druart C , et al. Congenital malformations in 10,000 consecutive births in a university hospital: need for genetic counseling and prenatal diagnosis. J Pediatr 1984;104:386-390
CrossRef | Web of Science | Medline
To the Editor:
Classification of neonatal abnormalities is often problematic in reports on the condition of children conceived with in vitro fertilization or intracytoplasmic sperm injection. Hansen et al. put hypoplastic left heart syndrome and tetralogy of Fallot in the same category as tricuspid aortic valve and ventricular septal defect, although the latter two are minor or equivocal defects that do not usually require surgical correction. The authors do not report which specific defects occurred in which group (in vitro fertilization vs. intracytoplasmic sperm injection vs. control), nor do they report which couples had profound male-factor infertility necessitating the use of intracytoplasmic sperm injection. Since gonadal failure in men has been linked to a higher incidence of abnormalities of the sex chromosomes in offspring conceived with intracytoplasmic sperm injection,1 observed defects in children conceived with assisted reproductive technology could derive from intrinsic paternal factors, rather than from the procedures used.
Moreover, Hansen et al. do not consider the potential effect of the experience of the clinician with in vitro fertilization or intracytoplasmic sperm injection. Data from clinical pregnancies or delivery rates per embryo transferred might give some indication of this effect, but these data were not reported. As others have observed,2 putative causal relations between assisted reproduction and reproductive outcomes may be affected by the standards according to which procedures are performed. In the context of different findings from other large studies,3,4 the data of Hansen et al. appear to suggest only that infants conceived with intracytoplasmic sperm injection or in vitro fertilization at the three Australian clinics they studied may have a different risk of some birth defects than do infants who are conceived naturally.
4 ReferencesE. Scott Sills, M.D.
Atlanta Medical Center, Atlanta, GA 30312-1212Gianpiero D. Palermo, M.D.
Weill Medical College of Cornell University, New York, NY 10021-4872
gdpalerm@med.cornell. edu 1
Levron J ,Aviram-Goldring A ,Madgar I ,Raviv G ,Barkai G ,Dor J . Sperm chromosome abnormalities in men with severe male factor infertility who are undergoing in vitro fertilization with intracytoplasmic sperm injection. Fertil Steril 2001;76:479-484
CrossRef | Web of Science | Medline2
Tucker M ,Graham J ,Han T ,Stillman R ,Levy M . Conventional insemination versus intracytoplasmic sperm injection. Lancet 2001;358:1645-1646
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Palermo GD ,Colombero LT ,Schattman GL ,Davis OK ,Rosenwaks Z . Evolution of pregnancies and initial follow-up of newborns delivered after intracytoplasmic sperm injection. JAMA 1996;276:1893-1897
CrossRef | Web of Science | Medline4
Bonduelle M ,Wilikens A ,Buysse A , et al. Prospective follow-up of 877 children born after intracytoplasmic sperm injection (ICSI), with ejaculated epididymal and testicular spermatozoa and after replacement of cryopreserved embryos obtained after ICSI. Hum Reprod 1996;11:Suppl 4:131-155
Web of Science | Medline
To the Editor:
The results reported by Hansen et al. are somewhat at variance with other published data, including those from a large Belgian series1 and a Danish national study,2 both of which included larger numbers of children conceived with intracytoplasmic sperm injection. Possible reasons for the discrepancies include the use by Hansen et al. of criteria derived from the International Classification of Diseases, 9th Revision, 3 which do not allow one to draw distinctions easily between major and minor birth defects, and the investigators' attempt to avoid observational bias by using one pediatrician to determine whether the observed congenital anomalies were more likely to occur in a population of infants conceived with intracytoplasmic sperm injection. No evidence is given to support the validity of this method, but the results depend fundamentally on its use.
3 ReferencesAlastair G. Sutcliffe, M.D.
Royal Free and University College Medical School, London NW3 2PF, United Kingdom
icsi@rfc.ucl. ac. uk Maryse Bonduelle, M.D.
Free University, B-1090 Brussels, BelgiumBrent W. Taylor, F.R.C.P., Ph.D.
Royal Free and University College Medical School, London NW3 2PF, United Kingdom1
Bonduelle M ,Liebaers I ,Deketelaere V , et al. Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999). Hum Reprod 2002;17:671-694
CrossRef | Web of Science | Medline2
Loft A ,Petersen K ,Erb K , et al. A Danish national cohort of 730 infants born after intracytoplasmic sperm injection (ICSI) 1994-1997. Hum Reprod 1999;14:2143-2148
CrossRef | Web of Science | Medline3
Sutcliffe AG ,Taylor B ,Saunders K , et al. Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study. Lancet 2001;357:2080-2084
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. Steinkampf and Grifo question our failure to adjust for paternal age, ethnic group, and type of infertility. Questions are also raised about the size of our study. However, our study was powered to be large enough to demonstrate statistically significant results with adjustment for maternal age, parity, the sex of the infant, and correlations between siblings. Although the Aboriginal population has a higher rate of birth defects, this population was underrepresented in the groups that used assisted reproductive technology and cannot therefore account for the excess risk. Stratification according to type of infertility, although potentially informative, would inevitably have led to small, underpowered analyses that would have been susceptible to misinterpretation.1 We did adjust for maternal age; maternal and paternal ages are highly correlated, and it is therefore unlikely that any residual effects of paternal age could account for our findings.
Drs. Steinkampf and Grifo suggest that data from the Society for Assisted Reproductive Technology and population-based data from other parts of the world are more reassuring than our results, and Drs. Sills and Palermo express reservations about the classifications of birth defects we used. We used registry data and so were not reliant, as the Society for Assisted Reproductive Technology is, on practitioners' reports of birth defects that are present at delivery.2 We agree that the classification of major birth defects is problematic and that there is no consensus on this matter.3 However, we had the advantage that our data on birth defects for all three groups of infants were identified through the same reporting mechanism, which extends beyond birth, and were classified according to the same system, thus ensuring comparability among groups.4
Drs. Sills and Palermo argue that excess defects in infants conceived with intracytoplasmic sperm injection may be due to paternal factors rather than to the technology itself and that the performance standards in Western Australia may explain our findings. We agree that it is impossible to disentangle the intrinsic conditions underlying the need for intracytoplasmic sperm injection from risks associated with the technology itself. There are no data, however, to substantiate the latter concern. Western Australian clinics use protocols that are similar to those used by others, and their success rates mirror those found elsewhere, including the United States.2,5
Dr. Sutcliffe and colleagues question our decision to have a single independent pediatrician who was blinded to the mode of conception assess which defects might have been diagnosed earlier because of closer surveillance during the first year of life. This secondary analysis was intended specifically to minimize the possibility of differential diagnostic vigilance among groups and confirmed the results of our primary analyses, which did not depend “fundamentally” on it.
5 ReferencesJennifer J. Kurinczuk, M.D.
University of Leicester, Leicester LE1 6TP, United Kingdom
jjk6@le.ac. uk Michèle Hansen, M.P.H.
Carol Bower, M.B., B.S., Ph.D.
University of Western Australia, Perth 6009, Australia1
Gurrin LC ,Kurinczuk JJ ,Burton PR . Bayesian statistics in medical research: an intuitive alternative to conventional data analysis. J Eval Clin Pract 2000;6:193-204
CrossRef | Web of Science | Medline2
Society for Assisted Reproductive Technology, American Society for Reproductive Medicine
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Mitchell AA . Intracytoplasmic sperm injection: offering hope for a term pregnancy and a healthy child? BMJ 1997;315:1245-1246
CrossRef | Web of Science | Medline4
Kurinczuk JJ ,Bower C . Birth defects in infants conceived by intracytoplasmic sperm injection: an alternative interpretation. BMJ 1997;315:1260-1266
CrossRef | Web of Science | Medline5
Western Australian Reproductive Technology Council. Annual report, 1 July 1999–30 June 2000. Perth, Western Australia: Health Department of Western Australia, 2000.
- Citing Articles (6)
Citing Articles
1
Queenie V. Neri, Takumi Takeuchi, Gianpiero D. Palermo. (2008) An Update of Assisted Reproductive Technologies Results in the United States. Annals of the New York Academy of Sciences 1127:1, 41-48
CrossRef2
Gianpiero D Palermo, Queenie V Neri, Takumi Takeuchi, Jane Squires, Fred Moy, Zev Rosenwaks. (2008) Genetic and epigenetic characteristics of ICSI children. Reproductive BioMedicine Online 17:6, 820-833
CrossRef3
Pedro N Barri, Jose M Vendrell, Francisca Martinez, Buenaventura Coroleu, Begoña Arán, Anna Veiga. (2005) Influence of spermatogenic profile and meiotic abnormalities on reproductive outcome of infertile patients. Reproductive BioMedicine Online 10:6, 735-739
CrossRef4
(2003) Current Awareness: Pharmacoepidemiology and Drug Safety. Pharmacoepidemiology and Drug Safety 12:3, 253-268
CrossRef5
(2003) Current Awareness in prenatal diagnosis. Prenatal Diagnosis 23:2, 179-185
CrossRef6
GD Palermo, T Takeuchi, QV Neri, Y Katagiri, LL Veeck, Z Rosenwaks. (2003) Application of intracytoplasmic sperm injection in assisted reproductive technologies. Reproductive BioMedicine Online 6:4, 456-463
CrossRef
