Correspondence
Nitrous Oxide and Fertility
N Engl J Med 1993; 328:284-285January 28, 1993
- Article
To the Editor:
The study by Rowland et al. (Oct. 1 issue)1 clearly demonstrated reduced fertility among female dental assistants exposed to high levels of unscavenged nitrous oxide. The authors also reported, but did not comment on, a higher rate of spontaneous abortion (50 percent) in 10 pregnant women exposed to high levels of unscavenged nitrous oxide, as compared with an 8 percent rate of fetal loss in 315 pregnant women with no exposure to nitrous oxide or exposure to a lower level. This difference is significant (P = 0.001 by Fisher's exact test) and suggests that nitrous oxide may reduce fertility by increasing fetal loss, as has been reported in other studies2.
2 ReferencesRonald H. Gray, M.D., M.Sc.
Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 212051
Rowland AS ,Baird DD ,Weinberg CR ,Shore DL ,Shy CM ,Wilcox AJ . Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993-997
Full Text | Web of Science | Medline2
Office of Technology Assessment. Reproductive health hazards in the workplace. Washington, D.C.: Government Printing Office, 1985:53-82.
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Gray that our data suggest that exposure to high levels of nitrous oxide increases the risk of spontaneous abortion. We chose not to comment on the incidence of spontaneous abortion in the 418 women in our study because there were only 30 spontaneous abortions. However, pregnancy data on the 4856 women who returned our mailed screening questionnaire also suggest an increased risk of spontaneous abortion. Preliminary analysis indicates that women exposed to unscavenged nitrous oxide for five or more hours per week had a threefold increase in the risk of spontaneous abortion (relative risk, 3.1; 95 percent confidence interval, 1.5 to 6.2; P<0.002) after adjustment for age, smoking status, and exposure to ethylene oxide1.
Does this imply, as Dr. Gray asserts, that nitrous oxide increases the length of time to conception by increasing unrecognized fetal loss? It is certainly a possible mechanism. However, data in animals suggest that nitrous oxide may block the secretion of gonadotropin-releasing hormone by the hypothalamus and disrupt ovulation, thus acting before a conceptus is formed2. Our data do not allow us to distinguish between these alternatives.
2 ReferencesAndrew S. Rowland, Ph.D.
Donna Day Baird, Ph.D.
Clarice R. Weinberg, Ph.D.
National Institute of Environmental Health Sciences, Research Triangle Park, NC 277091
Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide associated with spontaneous abortion in female dental assistants. abstract. Am J Epidemiol (in press).
2
Kugel G ,Letelier C ,Zive MA ,King JC . Nitrous oxide and infertility. Anesth Prog 1990;37:176-180
Medline
Author/Editor Response
At the conclusion of her editorial (Oct. 1 issue)1 on the toxic effects of nitrous oxide on reproduction in women, Baird suggested that fertility in men may be impaired by occupational exposure to nitrous oxide. There is already some evidence to support this contention.
Epidemiologic studies of anesthesiologists and dentists in the 1960s reported that the unexposed wives of men who were occupationally exposed to waste anesthetic gases (nitrous oxide and the more potent halogenated anesthetics) had an increased incidence of spontaneous abortion. The single epidemiologic study that specifically examined reproductive outcome in men exposed only to nitrous oxide found a dose-related increase in the incidence of spontaneous abortion in their wives2.
Although nitrous oxide was once considered innocuous, evidence began to be gathered in the early 1950s that it had potentially serious side effects. Subsequently, it was demonstrated that nitrous oxide inactivates the vitamin B12-dependent enzyme methionine synthase, an enzyme involved in normal cell division and DNA production. Although its specific role is unknown, normal vitamin B12 activity appears to be essential for both male and female fertility. For example, exogenous vitamin B12 improves sperm motility and enhances artificial insemination in animals3. Lower-than-normal levels of vitamin B12 are seen in the semen of men with a high percentage of morphologically abnormal sperm. It has even been suggested that all patients with unexplained sterility be screened for a vitamin B12 deficiency4.
The mechanism for the undesirable reproductive outcomes in men and women occupationally exposed to nitrous oxide may be the depression of some essential vitamin B12-dependent process in the germ cell, mature spermatozoa, or oocyte by nitrous oxide. Testicular methionine synthase activity is depressed by higher, clinically relevant concentrations of nitrous oxide5. Can prolonged exposure to trace levels of nitrous oxide in operating rooms and dental offices have a similar effect?
5 ReferencesJay B. Brodsky, M.D.
Stanford University School of Medicine, Stanford, CA 943051
Baird PA . Occupational exposure to nitrous oxide -- not a laughing matter. N Engl J Med 1992;327:1026-1027
Full Text | Web of Science | Medline2
Cohen EN ,Gift HC ,Brown BW , et al. Occupational disease in dentistry and chronic exposure to trace anesthetic gases. J Am Dent Assoc 1980;101:21-31
Web of Science | Medline3
Watson AA . Seminal vitamin B12 and sterility. Lancet 1962;2:644-644
CrossRef | Web of Science | Medline4
Blair JH ,Stearns HE ,Simpson GM . Vitamin B12 and fertility. Lancet 1968;1:49-50
CrossRef | Web of Science | Medline5
Brodsky JB ,Baden JM ,Serra M ,Kundomal Y . Nitrous oxide inactivates methionine synthetase activity in rat testis. Anesthesiology 1984;61:66-68
Web of Science | Medline
Author/Editor Response
Dr. Baird replies:
To the Editor: Dr. Brodsky reinforces and elaborates on the points in my editorial about the risk that exposure to nitrous oxide may pose to male fertility. In fact, he cites the same paper that I did regarding previous epidemiologic studies of this issue1. Such surveys as the study by Cohen et al. have potential sources of error,2 but theirs nevertheless remains the largest such study of outcomes in a very large sample of male dentists, their wives, and female dental assistants.
The paper by Rowland et al.3 on the effects of exposure to nitrous oxide on the fertility of female dental assistants does not speculate on the mechanism of the effect, but it is inviting to hypothesize that the reduced fertility is related to the effect of nitrous oxide on a process involving vitamin B12 activity, as Dr. Brodsky suggests. The points I wish to emphasize, however, are not only the relevance of nitrous oxide to male fertility in this specific case, but also the fact that too many studies examining the effect of exposures on reproduction do not pay sufficient attention to possible effects on male infertility, concentrating only on female infertility or birth defects as outcomes. I suggest that this blind spot has hampered our understanding of male infertility in the past and will continue to do so in the future if we do not reexamine our approach to the investigation of this problem.
3 ReferencesPatricia A. Baird, M.D.
University of British Columbia, Vancouver, BC V6T 1Z3, Canada1
Cohen EN ,Gift HC ,Brown BW , et al. Occupational disease in dentistry and chronic exposure to trace anesthetic gases. J Am Dent Assoc 1980;101:21-31
Web of Science | Medline2
Tannenbaum TN ,Goldberg RJ . Exposure to anesthetic gases and reproductive outcome: a review of the epidemiologic literature. J Occup Med 1985;27:659-668
Medline3
Rowland AS ,Baird DD ,Weinberg CR ,Shore DL ,Shy CM ,Wilcox AJ . Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993-997
Full Text | Web of Science | Medline
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