Published online before print December 18, 2003, doi: 10.1161/01.STR.0000107232.50242.1B
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(Stroke. 2004;35:e1.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
"Conception Origin" Versus "Fetal Origins" Hypothesis and Stroke
Department of Epidemiology and Biostatistics, University Medical Centre Nijmegen, Nijmegen, the Netherlands
To the Editor:
Barker and Lackland found high stroke mortality in areas of England and Wales characterized in the past by poor living standards, high neonatal mortality rates, and short stature in the adult population.1 They conclude that stroke may originate through maternal influences associated with poverty, which is in line with recent findings that rates of stroke in adulthood are higher among people who had low birth weight. The authors refer to the fetal origins hypothesis, which proposes that coronary heart disease and stroke and the disorders related to them—hypertension and type 2 diabetes—originate through responses to undernutrition during fetal life and infancy.
Given the many controversies related to this fetal origins hypothesis,2,3 we suggest a paradigm shift away from the unspecificity of what is called "fetal life and infancy." It is our intention to pinpoint ovopathy, ie, the conception origin hypothesis, as etiological pathway in "innate disease entities of complex origin."4–6
Mothers with low socioeconomic status are known to suffer from more menstrual disorders,7,8 low standards of nutrition, and abnormal body mass index.9 They also are more likely to be smokers or drug users10,11 and to employ less safe methods of contraception, resulting in more unplanned and unwanted pregnancies, particularly at the extremes of maternal reproductive age and during the postpartum restoration of the ovulatory pattern, ie, after very short interpregnancy intervals.12 These conditions are known to be related to the critical stages of oocyte maturation, to constrain the quality of the maturing oocyte at ovulation or at fertilization, and to result in pregnancy wastage, perinatal mortality, or morbidity in adulthood, ie, preovulatory overripeness ovopathy (PrOO) or delayed ovulation and postovulatory overripeness ovopathy (PoOO) or delayed fertilization. The teratological consequences of nonoptimal ovulation and fertilization are based on animal experiments and human observations.4–6
Concurrence of both oocyte maturation and liquefaction of the mucus plug is modulated by estrogens before the mid-cycle. At the core of the fertile window of the menstrual cycle, it facilitates equal access of Y- and X-bearing spermatocytes to optimally matured oocytes and guarantees full expression of the genetic potential of the gametes and good embryo quality in either sex and, in turn, optimal implantation and developmental survival up to adult age.13 In contrast, nonoptimal liquefaction, elicited by endogenous or exogenous disturbing factors, facilitates differential migration and preferential fertilization by Y-bearing spermatocytes, which are smaller than the X-bearing ones, particularly at the very beginning and the end of the fertile window.
Concurrence of nonoptimal oocyte maturation and nonoptimal mucus liquefaction during the receptive period entrains preferential fertilization of nonoptimally matured oocytes by Y-bearing spermatocytes, and thus, deficiencies in organogenesis and differentiation of the various tissues and organ systems. The pleiotropic nature of nonoptimally matured oocytes and the teratogenic consequences of it will depend on the degree of molecular, biochemical, and physiological processes in the oocyte, which encompass both nuclear and cytoplasm constituents. The intricate interplay between nonoptimal oocyte maturation and genes results in a complex pathogenesis of the resultant fetuses or individuals. This occurs incidentally in well-timed menstrual cycles, but more so in instances of distorted hormonal tuning, not only in deprived socioeconomic conditions but also at the extremes of maternal reproductive life, among endocrinologically unbalanced mothers, after very short pregnancy intervals, during the seasonal transitions of the "ovulatory" seasons, etc. A same broad spectrum of male-biased developmental anomalies—low birth weight and length, small stature at school age or adulthood, morbidity, and mortality—is present in all these circumstances.4–6
This "conception origin" hypothesis, thus, does explain not only the social patterning of stroke morbidity and mortality but also its strong male bias.13 In addition, the gradual decrease of conceptopathology in the 20th century, as a correlate of improving socioeconomic circumstances,14 elucidates both the decreasing trends in cerebral infarcts and coronary heart diseases established in retrospective analyses and their presumed common cause.15,16 Finally, the geographic latitude effect in incidence rate of stroke and other diseases (stomach cancer) in England and Wales17 and elsewhere may be a consequence of the stronger seasonal ovulatory pattern the further away from the Equator, just as in animals, and, in turn, stronger transitional stages between the ovulatory seasons and, thus, more poor quality oocytes, as argued elsewhere.18 This concept may be put to the test by demonstrating the same increase of stroke incidence rate—and of other "innate disease entities of complex origin"— in the other mentioned high-risk conception categories.
References
1. Barker JP, Lackland DT. Prenatal influences on stroke mortality in England and Wales. Stroke. 2003; 34: 1598–1603.
2. Williams S, Poulton R. Birth size, growth, and blood pressure between the ages of 7 and 26 years: failure to support the fetal origins hypothesis. Am J Epidemiol. 2002; 155: 849–852.
3. Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birth weight and subsequent blood pressure? Lancet. 2002; 360: 659–665.[CrossRef][Medline] [Order article via Infotrieve]
4. Jongbloet PH. The effects of preovulatory overripeness of human eggs on development. In: Blandau RJ, ed. Aging Gametes: Their Biology and Pathology. International Symposium on Aging Gametes, Seattle, Wash, 1973. Basel, Switzerland: Karger; 1975: 300–329.
5. Jongbloet PH. Prepregnancy care: background biological effects. In: Chamberlain G, Lumley J, eds. Prepregnancy Care: A Manual for Practice. New York, NY: J. Wiley & Sons LTD; 1986: 31–51.
6. Jongbloet PH. The ageing of gamete in relation to birth control failures and Down syndrome. Eur J Pediatr. 1985; 144: 343–347.[CrossRef][Medline] [Order article via Infotrieve]
7. Munster K, Schmidt L, Helm P. Length and variation in the menstrual cycle: a cross sectional study from a Danish county. Br J Obstet Gynaecol. 1992; 99: 422–429.[Medline] [Order article via Infotrieve]
8. Power C, Matthews S. Origins of health inequalities in a national population sample. Lancet. 1997; 350: 1584–1589.[CrossRef][Medline] [Order article via Infotrieve]
9. Sarlio-Lahteenkorva S, Lahelma E. The association of body mass index with social economic disadvantage in women and men. Int J Epidemiol. 1999; 28: 445–449.
10. Butler NR, Alberman ED. The effects of smoking in pregnancy. In: Perinatal Problems: The Second Report of the 1958 British Perinatal Mortality Survey. Edinburgh, UK: E&S Livingstone LTD; 1969: 72–84.
11. Pierrce JP, Fiore MC, Novotny TE, et al. Trends in cigarette smoking in the United States. JAMA. 1989; 61: 56–60.
12. Hellerstedt WL, Pirie PL, Lando HA, et al. Differences in preconceptional and prenatal behaviors in women with intended pregnancies. Am J Public Health. 1998; 88: 663–666.
13. Jongbloet PH. Overripeness ovopathy, sex ratio increase and sex ratio reversal: a challenging hypothesis for sex ratio modulation.Hum Reprod. 2003;19. In press.
14. Jongbloet PH, Zielhuis GA, Groenewoud HMM, Pasker-de Jong PCM. The secular trends in male: female ratio at birth in postwar industrialized countries. Env Health Perspect. 2001; 109: 749–752.
15. Lawlor DA, Davey Smith G, Leon DA, Sterne JAC, Ebrahim S. Secular trends in mortality by stroke subtype in the 20th century: a retrospective analysis Lancet. 2002; 360: 1818–1823.[CrossRef][Medline] [Order article via Infotrieve]
16. McCarron P, McCarron MO, Murray L, Kee F. Secular trends in stroke mortality and early life environment. Lancet. 2003; 361: 1059–1060.
17. Maheswaran R, Strachan DP, Dodgeon B, Best NG. A population-based case-control study for examining early influences on geographical variation in adult mortality in England and Wales using stomach cancer and stroke as examples. Int J Epidemiol. 2002; 31: 375–382.
18. Jongbloet PH. Is the Mediterranean diet relevant to myocardial infarction? Olive oil consumption versus geographical latitude. Int J Epidemiol. 2003; 32: 878–879.Letter.
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