Clinical Review

2013 Update on fertility

OBG Manag. 2013 February;25(2):39-46

References

1. Infertility FAQs. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/reproductivehealth/infertility. Updated April 19 2012. Accessed January 20, 2013.

2. Pfeifer S, Fritz M, Goldberg J, et al. the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400-1406.

3. Hull MG, North K, Taylor H, Farrow A, Ford WC. Delayed conception and active and passive smoking: The Avon Longitudinal Study of Pregnancy and Childhood Study Team. Fertil Steril. 2000;74(4):725-733.

4. Cooper GS, Baird DD, Hulka BS, Weinberg CR, Savitz DA, Hughes CL, Jr. Follicle-stimulating hormone concentrations in relation to active and passive smoking. Obstet Gynecol. 1995;85(3):407-411.

5. Storgaard L, Bonde JP, Ernst E, et al. Does smoking during pregnancy affect sons’ sperm counts? Epidemiology. 2003;14(3):278-286.

6. Yang Q, Sherman SL, Hassold TJ, et al. Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case-control study. Genet Med. 1999;1(3):80-88.

7. Zenzes MT, Wang P, Casper RF. Cigarette smoking may affect meiotic maturation of human oocytes. Hum Reprod. 1995;10(12):3213-3217.

8. Klonoff-Cohen H, Natarajan L, Marrs R, Yee B. Effects of female and male smoking on success rates of IVF and gamete intra-Fallopian transfer. Hum Reprod. 2001;16(7):1382-1390.

9. Hughes EG, Lamont DA, Beecroft ML, Wilson DM, Brennan BG, Rice SC. Randomized trial of a “stage of change” oriented smoking cessation intervention in infertile and pregnant women. Fertil Steril. 2000;74(3):498-503.

10. 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(12):437-443.

11. 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(10):725-730.

12. 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(2):328-338.

13. Schieve LA, Rasmussen SA, Reefhuis J. Risk of birth defects among children conceived with assisted reproductive technology: providing an epidemiologic context to the data. Fertil Steril. 2005;84(5):1320-1324.

14. Lie RT, Lyngstadaas A, Ørstavik KH, Bakketeig LS, Jacobsen G, Tanbo T. Birth defects in children conceived by ICSI compared with children conceived by other IVF-methods; a meta-analysis. Int J Epidemiol. 2005;34(3):696-701.

15. Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility infertility treatment, and congenital malformations: Danish national birth cohort. BMJ. 2006;333(7570):679.-

16. Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA. National Birth Defects Prevention Study. Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod. 2009;24(2):360-366.

17. El-Chaar D, Yang Q, Gao J, et al. Risk of birth defects increased in pregnancies conceived by assisted human reproduction. Fertil Steril. 2009;92(5):1557-1561.

18. Källén B, Finnström O, Nygren KG, Olausson PO. In vitro fertilization (IVF) in Sweden: infant outcome after different IVF fertilization methods. Fertil Steril. 2005;84(3):611-617.

19. Bonduelle M, Wennerholm U, Loft A, et al. A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception. Hum Reprod. 2005;20(2):413-419.

20. Kurinczuk JJ. Safety issues in assisted reproduction technology: from theory to reality — just what are the data telling us about ICSI offspring health and future fertility and should we be concerned? Hum Reprod. 2003;18(5):925-931.

21. Pinborg A, Loft A, Aaris Henningsen AK, Rasmussen S, Andersen AN. Infant outcome of 957 singletons born after frozen embryo replacement: the Danish National Cohort Study 1995-2006. Fertil Steril. 2010;94(4):1320-1327.

22. Halliday JL, Ukoumunne OC, Baker HW, et al. Increased risk of blastogenesis birth defects, arising in the first 4 weeks of pregnancy, after assisted reproductive technologies. Hum Reprod. 2010;25(1):59-65.

23. Wennerholm U, Söderström-Anttila V, Bergh C, et al. Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data. Hum Reprod. 2009;24(9):2158-2172.

24. Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population based study. Lancet. 2002;359(9305):461-465.

25. Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803-1813.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

WHAT THIS EVIDENCE MEANS FOR PRACTICE

Although the vast majority of births resulting from assisted reproduction were free of birth defects, treatment with ART was associated with an increased risk of birth defects, compared with spontaneous conception. After adjustment for potential confounders, including maternal age, the risk persisted for conceptions associated with ICSI but not IVF.

While the exact mechanisms responsible for this increased risk remain unknown, the finding of an increased risk of birth defects among women with infertility who conceived without ART indicates that inherent patient factors, rather than assisted reproductive technologies alone, contribute to the risk. These findings can help to guide couples considering assisted reproduction for the treatment of infertility.