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Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway diseases in females only

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Abstract

Observational as well as experimental studies support that prenatal challenges seemed to be associated with an increased risk for allergic airway diseases in the offspring. However, insights into biomarkers involved in mediating this risk are largely elusive. We here aimed to test the association between endogenous and exogenous factors documented in pregnant women, including psychosocial, endocrine, and life style parameters, and the risk for allergic airway diseases in the children later in life. We further pursued to functionally test identified factors in a mouse model of an allergic airway response. In a prospectively designed pregnancy cohort (n = 409 families), women were recruited between the 4th and 12th week of pregnancy. To investigate an association between exposures during pregnancy and the incidence of allergic airway disease in children between 3 and 5 years of age, multiple logistic regression analyses were applied. Further, in prenatally stressed adult offspring of BALB/c-mated BALB/c female mice, asthma was experimentally induced by ovalbumin (OVA) sensitization. In addition to the prenatal stress challenge, some pregnant females were treated with the progesterone derivative dihydrodydrogesterone (DHD). In humans, we observed that high levels of maternal progesterone in early human pregnancies were associated with a decreased risk for an allergic airway disease (asthma or allergic rhinitis) in daughters (adjusted OR 0.92; 95 % confidence interval [CI] 0.84 to 1.00) but not sons (aOR 1.02, 95 % CI 0.94-1.10). In mice, prenatal DHD supplementation of stress-challenged dams attenuated prenatal stress-induced airway hyperresponsiveness exclusively in female offspring. Reduced levels of maternal progesterone during pregnancy—which can result from high stress perception—increase the risk for allergic airway diseases in females but not in males.

Key messages

  • Lower maternal progesterone during pregnancy increases the risk for allergic airway disease only in female offspring.

  • Prenatal progesterone supplementation ameliorates airway hyperreactivity in prenatally stressed murine offspring.

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Study funding

Financial support to address the analyses and experiments presented herein were provided by the Allergy, Genes and Environment Network (AllerGen NCe) in Canada, the Excellence Initiative of the State of Hamburg in Germany, and the Association for Prevention and Information for Allergy and Asthma (Pina e.V.).

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Authors and Affiliations

  1. Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Isabel R. V. Hartwig, Katherina Ramisch & Petra C. Arck

  2. Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Christian A. Bruenahl

  3. Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany

    Thomas Keil

  4. Firestone Institute for Respiratory Health, St Joseph’s Healthcare, McMaster University, Hamilton, Canada

    Mark Inman

  5. Department of Pediatrics, Division Pneumology and Immunology, Charité University Medical Center, Berlin, Germany

    Maike Pincus

  6. Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20246, Hamburg, Germany

    Isabel R. V. Hartwig & Petra C. Arck

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  1. Isabel R. V. Hartwig
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  2. Christian A. Bruenahl
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  3. Katherina Ramisch
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  4. Thomas Keil
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  5. Mark Inman
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  6. Petra C. Arck
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  7. Maike Pincus
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Corresponding authors

Correspondence to Isabel R. V. Hartwig or Petra C. Arck.

Additional information

Isabel R V Hartwig and Christian A Bruenahl equally contributed to this work. Petra C Arck and Maike Pincus equally supervised this work.

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Hartwig, I.R.V., Bruenahl, C.A., Ramisch, K. et al. Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway diseases in females only. J Mol Med 92, 1093–1104 (2014). https://doi.org/10.1007/s00109-014-1167-9

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  • DOI: https://doi.org/10.1007/s00109-014-1167-9

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