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Periconceptional smoking and male:female ratio of newborns
- Fabio Parazzini (1 November 2006)
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Dose-response fallacy in the male:female ratio of newborns
- Piet H. Jongbloet, Nel Roeleveld (1 November 2006)
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Fabio Parazzini, researcher Clinica Mangiagalli Fondazione Mangiagalli Policlinico Regina Elena Università di Milano
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Dear Editor, I wish to thank Piet H Jongbloet and Nel Roeleveld for their kind attention to our work. They have raised several interesting and speculative considerations regarding the effect of smoking on male:female ratio of newborns. As they conclude, an inverted dose response gradient may happen among heavy smokers. However, I think that, in first hypothesis, we have to look for a dose response relationship and only on the basis of large studies conducted in different populations calendar periods we have to accept the idea of an inverted dose reponse gradient. Thus, our data do not clearly support a relation between smoking and male:female ratio at birth. Conflict of Interest:None declared |
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Piet H. Jongbloet, PhD Radboud University Nijmegen Medical Centre,P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, Nel Roeleveld
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Parazzini et al. found no clear relationship between the number of cigarettes smoked per day during the periconceptional period and the male: female ratio of newborns and concluded that smoking wa not associated with.1 This key point conclusion seems unwarranted because of the possibility of an inverted dose-response gradient, as is often the case in weak associations.2 Sex ratio reversal in female direction due to preterm loss of male fetuses leads to a dose-response fallacy,3 which appears to be the rule according to the ovopathy concept.4 The general trend in Parazzini’s study was that the sex ratio increased among low dose smoking parents (1-19 cigarettes/day), but decreased among heavier smokers (>20 cigarettes/day), comparable with the results of studies in Japan and Denmark.5,6 In case of non-smoking fathers, the decreasing trend was stronger for smoking mothers (1.23 to 1.05) than the decrease for smoking fathers in case of non-smoking mothers (1.24 to 1.13). When both parents smoked, the ratio initially increased and then decreased both among mothers (1.22 to 1.00) and among fathers (1.22 to 0.90), as well as among couples (1.22 to 1.09). In the latter situation when both parents parents smoked >20 cigarettes/day, however, the cumulative effect would have predicted the lowest ratio. Nevertheless, low dose exposure to smoking appears to result in an increase of the male:female ratio at birth, and high dose exposure in a ‘dose-response inversion’. Similar increases in male direction followed by sex reversal in female direction have been documented in other conditions which are characterized by reproductive hormonal dysregulation, e.g. advanced maternal age, exposure to undernutrition, stress, war, or toxicants, such as dioxine.4,7 These conditions are characterized by menstrual cycle disturbances, inherent non-optimal maturation of the oocyte, and delayed fertilisation. It has been shown in animals and humans that nicotine inhibits the hormonally driven fine tuning of oocyte maturation, ovulation, and fertilization. Active and passive smoking in women has been associated with dysmenorrhoea, prolonged time-to-pregnancy, low oestradiol in serum, and a broad continuum of poor-quality follicles, diploid oocytes and triploid zygotes, reproductive wastage, and infant mortality.8 In smoking men, similar disturbances have been noticed in male reproductive functions, which may result in delayed fertilisation. In optimal reproductive conditions, cervical liquefaction concurs with oocyte maturation during the follicle formation at the core of the fertile window within the menstrual cycle. This facilitates equal access and fertilisation of optimally matured oocytes by either X- or Y-bearing sperm and guarantees approximately equalized 100:100 sex ratios, full expression of the genetic potential of the gametes, good embryo quality, and inherent optimal condition of the progeny. In non-optimal or high-risk conditions, in which hormonal imbalances are elicited by endogenous and exogenous disturbing factors, male-biased pathological progeny is more prevalent. Poor implantation and development results in ‘vanishing male fetuses’ and male-biased pregnancy loss, which turns the ratio into a female-biased or inverted dose-response gradient, particularly in extreme conditions.4 This may happen among heavy smokers. There are no conflicts of interest References 1 Parazzini F., Chatenoud L, Maffioletti C, Chiaffarino F, Casserta D. Periconceptional smoking and male:female ratio of newborns by Parazzini et al. Eur J Public Health 2005;15:613-4. 2 Khoury MJ, James LM, Flanders WD, Erickson JD. Interpretation of the recurring weak associations obtained from epidemiologic studies of suspected human teratogens. Teratology 1992;46:69-77. 3 Selevan SG, Lemasters GK: The dose-response fallacy in human reproductive studies of toxic exposures. J Occup Med 1987;29:451-455. 4 Jongbloet PH: Over-ripeness ovopathy–A challenging hypothesis for sex ratio modulation. Hum Reprod 2004;19:769-774 and 1036-1038. 5 Fukuda M, Fukuda K, Shimizu T, Andersen CY, Byskov AG. Parental periconceptional smoking and male: female ratio of newborn infants. Lancet 2002;359:1407-8. 6 Obel C, Henriksen TB, Hedegaard M, Bech BH, Wisborg K, Olsen J. Periconceptional smoking and the male to female ratio in the offspring—re- assessment of a recently proposed hypothesis. Int J Epidemiol 2003;32:470- 1. 7 Jongbloet PH, Roeleveld N, Groenewoud HMM: Where the boys aren’t: dioxine and the sex ratio. Environ Health Persp 2002;110:1-3. 8. Kleinman JC, Pierre MB, Madans JH, Land GH, Schramm WF. The effects of maternal smoking on fetal and infant mortality. Am J Epidemiol 1988;127:274-82. Conflict of Interest:None declared |
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