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.

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach²:

Ask about smoking at every opportunity
Advise all smokers to stop
Assist willingness to stop
Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

WHAT THIS EVIDENCE MEANS FOR PRACTICE

The detrimental effects of smoking on reproductive health are substantial. Nonsmokers with excessive exposure to tobacco smoke have adverse reproductive effects that may be as great as those observed in smokers.

Studies suggest that much of the reduced fecundity observed in smokers may be reversed within 1 year of smoking cessation.² Clinicians who care for smokers with infertility have a tremendous opportunity to facilitate smoking cessation in their patients and their partners. Smoking-cessation intervention should be a key component of effective treatment of infertility.

The safety of assisted reproductive technologies

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

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.