title: Maternal stress before and during pregnancy and subsequent infertility in daughters: a nationwide population-based cohort study.
abstract: OBJECTIVE
  Is maternal stress following the death of a close relative before or during pregnancy associated with the risk of infertility in daughters?
  
  
  CONCLUSIONS
  Compared with unexposed women, women whose mothers had experienced bereavement stress during, or in the year before, pregnancy had a similar risk of infertility overall, but those exposed to maternal bereavement during the first trimester had a higher risk of infertility.
  
  
  BACKGROUND
  Animal studies have shown that prenatal maternal stress results in reduced offspring fertility. In humans, there is evidence that girls who have been prenatally exposed to stress have a more masculine behaviour and a slight delay in having their first child.
  
  
  METHODS
  This population-based cohort study, included 660 099 females born in Denmark between 1 January 1973 and 31 December 1993 to mothers of Danish origin and with at least one living relative in the exposure window, and followed the women through 31 December 2011.
  
  
  METHODS
  Overall, 13 334 women (2.0%) were considered prenatally exposed to stress because their mother had lost a spouse/partner, a child, a parent, or a sibling during pregnancy or in the year before conception. Infertility was defined as any record of infertility treatment or diagnosis of female infertility. We considered the date of onset as the date of the first appearance of any such record. The association between exposure and outcome was examined using hazard ratios (HR) with 95% confidence intervals (CI).
  
  
  RESULTS
  Based on our definition, 40 052 (6.5%) women were infertile in the follow-up period (median age at the end of follow-up: 26.7 years, maximum age: 39 years). Overall, prenatal exposure to maternal stress was not associated with risk of infertility (adjusted HR = 1.04 [CI: 0.95-1.14]). However, women prenatally exposed during the first trimester had a higher estimated risk (adjusted HR = 1.40 [CI: 1.05-1.86]). These findings were consistent in subgroups defined by the relationship of the mother to the deceased and in several sensitivity analyses, including a sibling-matched analysis, and in analyses restricted to women who were married or cohabitating with a man, or to women born at term.
  
  
  CONCLUSIONS
  We did not have a direct measure of stress, but bereavement due to death of a close relative is likely to be very stressful. We based the timing of exposure on the date of the death of the family member, although the stress may well have started earlier. Infertility was also defined indirectly, and many women in the cohort were too young at the end of the follow-up to have been diagnosed. However, misclassification of the outcome was most likely non-differential, and the similar results from all sensitivity analyses suggest that it is unlikely that the effect observed in first trimester exposure would be due to chance.
  
  
  CONCLUSIONS
  Prenatal exposure to maternal stress in the first trimester may affect the later fecundity of daughters.
  
  
  BACKGROUND
  This study was supported by a grant from the European Research Council (ERC-2010-StG-260242-PROGEURO) to the ProgEuro project (http://progeuro.au.dk). O.P.-R. is partly supported by a fellowship from Aarhus University and a travel grant from Oticon Fonden. The authors report no conflict of interests.
authors.affiliation: Section of Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada opr@ph.au.dk.
authors.forename: O
authors.initials: O
authors.lastname: Plana-Ripoll
authors.affiliation: Section of Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: The Fertility Clinic, Department of Obstetrics and Gynecology, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: U S
authors.initials: US
authors.lastname: Kesmodel
authors.affiliation: Section of Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Olsen
authors.affiliation: Section of Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Parner
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada Department of Obstetrics and Gynecology, McGill University, Montreal, Canada.
authors.forename: O
authors.initials: O
authors.lastname: Basso
mesh_terms: D000328:Adult; D001601:Bereavement; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000209:etiology*; D009035:Mothers; D009679:Nuclear Family; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011297:Prenatal Exposure Delayed Effects; D016016:Proportional Hazards Models; D012307:Risk Factors; D013315:Stress, Psychological / Q000150:complications*
keywords: bereavement; infertility; infertility treatment; pregnancy; stress