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Fetal sex and very preterm birth

      To the Editors: In their report on the Epistage study, a prospective study of all very preterm births between 22 and 32 weeks in 9 French countries in 1997, Zeitlin et al
      • Zeitlin J.
      • Ancel P.-Y.
      • Larroque B.
      • Kaminski M.
      • the Epipage Group
      Fetal sex and indicated very preterm birth: results of the EPIPAGE study.
      wonder about the very low sex ratio when associated with hypertension, in contrast to the very high one, when not: 79.1 males versus 131.8 for 100 females, respectively. This contrast was independent on either live or stillbirth, and on either spontaneous or ‘indicated’ birth. The authors look at the hypothesized explanations for male infants having greater risk than females of being born preterm. The lack of greater male risk for ‘indicated’ preterm births would support explanations that are based on a labor-inducing mechanism, whatever that might be.
      The French results are very analogous to the ones found in a population-based study in Norway by measuring the sex ratio starting from very preterm up to term gestation.
      • Vatten L.J.
      • Skjærven R.
      Offspring sex and pregnancy outcome by length of gestation.
      An extremely high sex ratio was found in fetuses born after very short duration (16-19 weeks): 248:100. This ratio fell very steeply to 130:100 around the 20th week, remained almost at this level among premature births up to the 36th week, and stabilized at term around equity: 100:100. In contrast, in the case of preeclampsia, this ratio collapsed in the very preterm births and became even ‘inverted’ at 25 to 29 weeks: 67:100; longer duration of gestation again led to increasing ratios. These shifts were still more pronounced when preeclamptic gestation was associated with perinatal mortality. According to the Norwegian authors, this would ‘reflect that male embryos are subject to stronger intrauterine selection forces than females.’ Actually, both the French and Norwegian researchers suggest an active selection mechanism in the male sex in gestational hypertension and/or preeclampsia.
      In a commentary,
      • Jongbloet P.H.
      Offspring sex ratio at population level versus early and late onset preeclamsia.
      we have forwarded that an active selection mechanism in pathologic pregnancies is not necessary. Instead, an initial dose-response effect caused by high-risk conceptions would entrain both excessive male-biased embryos and subsequent loss of developmentally spoiled male embryos and fetuses. Placental dysfunction, very early fetal loss, preterm delivery, stillbirth, developmental defects are all in line with this over-ripeness ovopathy concept.
      • Jongbloet P.H.
      Over-ripeness ovopathy—a challenging hypothesis for sex ratio modulation.
      Nonoptimally matured oocytes, inherent bad implantation, and particularly the possibility of a ‘dose-related fallacy’ point to a common origin for different pregnancy complications, among others, gestational hypertension and/or preeclampsia. This concept explains many puzzles around their association with aneuploid pregnancies, young and advanced maternal age, short and prolonged interpregnancy intervals, seasonality, prepregnancy body mass index, the so-called protective effect of smoking, etc.
      • Jongbloet P.H.
      Offspring sex ratio at population level versus early and late onset preeclamsia.
      • Jongbloet P.H.
      Over-ripeness ovopathy—a challenging hypothesis for sex ratio modulation.

      References

        • Zeitlin J.
        • Ancel P.-Y.
        • Larroque B.
        • Kaminski M.
        • the Epipage Group
        Fetal sex and indicated very preterm birth: results of the EPIPAGE study.
        Am J Obstet Gynecol. 2004; 190: 1322-1325
        • Vatten L.J.
        • Skjærven R.
        Offspring sex and pregnancy outcome by length of gestation.
        Early Hum Dev. 2004; 76: 47-54
        • Jongbloet P.H.
        Offspring sex ratio at population level versus early and late onset preeclamsia.
        Early Hum Dev. 2004; 76: 159-163
        • Jongbloet P.H.
        Over-ripeness ovopathy—a challenging hypothesis for sex ratio modulation.
        Hum Reprod. 2004; 19: 769-774