BMJ  2006;333:665-666 (30 September), doi:10.1136/bmj.38982.702581.BE

Editorial

Congenital anomalies after treatment for infertility

Partly related to the cause of infertility

More than 10 000 children are born each year in the United Kingdom through in vitro fertilisation. Studies have shown an increased risk of adverse outcome in singleton infants conceived by the assisted reproductive technologies of in vitro fertilisation and intracytoplasmic sperm injection. These infants are at increased risk of intrauterine growth retardation, low birth weight, premature delivery, and perinatal mortality compared with infants born to fertile couples.¹ A twofold increase in the risk of major congenital malformations has also been reported,^2-4 and there is some evidence of a specific increased risk of imprinting disorders such as Beckwith-Wiedemann and Angelman's syndromes.^{5 6} The source of the increased overall risk of anomalies could be the infertility treatment, either from the in vitro procedure or the drugs used to stimulate ovulation, or intrinsic factors associated with infertility itself. Various data have suggested that infertility, especially female infertility, is likely to be the most important factor.^7-9

In this week's BMJ the relationship between infertility, infertility treatment, and the risk of congenital abnormality is addressed by a large scale, prospective cohort study by Zhu and colleagues.¹⁰ They found that women who took a prolonged time (> 12 months) to conceive but who did not receive infertility treatment had a small but significantly increased risk of having infants with congenital abnormalities. Furthermore, the authors show that when these women are compared with women who did receive infertility treatment, many of the apparent associations between assisted reproductive technologies and congenital abnormality are lost. However, they show that the association between infertility treatment and genital tract anomaly persists, even when rates are compared with women who took a long time to conceive.

The authors did not have information about infertility treatment among women who reported a time to pregnancy of less than six months. Although most of the women in this group are unlikely to have had such treatment, it is plausible that some couples with known causes of infertility (such as azoospermia due to failed vasectomy reversal or known severe endometriosis) may have conceived with infertility treatment within six months of starting their attempts to have a baby. Any misclassification due to this issue would tend to under-estimate the strength of association between infertility and anomalies, but the effect is likely to be small.

What are the implications of these results? To reproductive specialists, it is useful to know that infertility treatment may not be causally associated with the risk of adverse outcome in singleton infants conceived by assisted reproductive technologies. More likely, the causative factors for these outcomes are unrelated to the treatment, with the possible exception of malformations of the genital tract. Clearly, counselling about the spectrum of possible fetal adverse outcomes should form an integral part of the care of couples seeking fertility treatment. A balanced view should be offered, allowing couples to weigh up the small but significantly increased risk of complications against the benefit of parenthood that may not be otherwise achievable.

It may be helpful to emphasise the absolute risks. Zhu et al report an overall increased risk of congenital abnormalities in the region of 1-2% compared with women conceiving within 12 months. This is unlikely to be a major disincentive for most couples deciding on infertility treatment. The Human Fertilisation and Embryology Authority's website (www.hfea.gov.uk) and guide to infertility are important sources of accurate and up to date information about infertility treatment for UK patients. Future editions of these could reflect the new information provided by this study. A further valuable role for the authority may be to allow the use of its database of cycles of licensed fertility treatment for further research studies.

An increased risk of congenital malformations provides another reason for recommending that any pregnancy in subfertile couples, whether achieved naturally or through infertility treatment, is carefully monitored by a fetal medicine specialist, with detailed antenatal imaging. Given the possible link between infertility treatment and anomalies, counselling of affected couples in relation to future pregnancies may be more complex and require detailed input from clinical geneticists.

Finally, what are the possible genetic causes of sub-fertility in a parent that are associated with congenital anomalies in a baby? Constitutional chromosomal rearrangements, including reciprocal and robertsonian translocations, and inversions are all well known causes of reduced fertility, miscarriages, and a whole spectrum of birth defects in offspring who inherit a chromosomal imbalance.¹¹ In the presence of a normal karyotype, the possibility of a subtelomeric rearrangement or interstitial chromosomal deletions and duplications must also be considered.¹² Another possibility is gonadal mosaicism in a parent for these chromosomal alterations,¹³ or other currently unknown monogenic defects. Future research should focus on establishing the mechanisms of these associations and, hence, provide improved risk assessment and counselling.

Department of Medical Genetics, Addenbrooke's Hospital, Cambridge CB2 2QQ

Department of Reproductive Medicine, Addenbrooke's Hospital

Department of Obstetrics and Gynaecology, Cambridge University, Rosie Hospital, Cambridge CB2 2SW
(gcss2{at}cam.ac.uk)

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Research p 679

References

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2. 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: 725-30.[Abstract/Free Full Text]
3. Rimm AA, Katayama AC, Diaz M, Katayama KP. A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children. J Assist Reprod Genet 2004;21: 437-43.[CrossRef][ISI][Medline]
4. Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects—a systematic review. Hum Reprod 2005;20: 328-38.[Abstract/Free Full Text]
5. Maher ER, Afnan M, Barratt CL. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum Reprod 2003;18: 2508-11.[Abstract/Free Full Text]
6. Cox GF, Burger J, Lip V, Mau UA, Sperling K, Wu BL, et al. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 2002;71: 162-4.[CrossRef][ISI][Medline]
7. Williams MA, Goldman MB, Mittendorf R, Monson RR. Subfertility and the risk of low birth weight. Fertil Steril 1991;56: 668-71.[ISI][Medline]
8. Westergaard HB, Johansen AMT, Erb K, Andersen AN. Danish National In-Vitro Fertilization Registry 1994 and 1995: a controlled study of births, malformations and cytogenetic findings. Hum Reprod 1999;14: 1896-902.[Abstract/Free Full Text]
9. Lambert RD. Safety issues in assisted reproductive technology: aetiology of health problems in singleton ART babies. Hum Reprod 2003;18: 1987-91.[Abstract/Free Full Text]
10. Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006; doi: 10.1136/bmj.38919.495718.AE.[Abstract/Free Full Text]
11. Shah K, Sivapalan G, Gibbons N, Tempest H, Griffin DK. The genetic basis of infertility. Reprod 2003;126: 13-25.
12. Sismani C, Armour JA, Flint J, Girgalli C, Regan R, Patsalis PC. Eur J Hum Genet 2001;9: 527-32.[CrossRef][ISI][Medline]
13. Jones TM, Amarose AP, Lebowitz M. Testicular chromosomal mosaicism and infertility. J Clin Endocrinol Metab 1976;42: 888-93.[Abstract]

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