May 30, 2019

expert reaction to study on stress in early pregnancy and sperm count in male offspring

Research published in Human Reproduction demonstrates that maternal stressful life events in early gestation were negatively associated with total sperm count in offspring.

Dr Jane Stewart, Chair of the British Fertility Society said:

“There is accruing evidence of the effects of intrauterine life on adult health. This association of stressful events and male reproductive function may be a further piece of evidence.

“That said, the study does not confirm a causative relationship. As the authors quite correctly point out there are several potential confounding factors. These include how each of the mothers may have responded to stressors.”

Prof Allan Pacey, Professor of Andrology, University of Sheffield, said:

“This is a very elegant and well conducted study which fits the theory that one of the most critical phases for determining sperm quality in the adult male is before he is even born. However, we should be cautious about the interpretation of this data as the authors have only described an association and not “cause and effect”. Moreover, from my reading of the paper, whilst pre-natal exposure to severe life events seems to reduce sperm concentration in adult men it has not been shown that it increases their risk of infertility (although the two are obviously linked).”

Dr Rod Mitchell, Consultant Paediatric Endocrinologist & Group Leader, MRC Centre for Reproductive Health, University of Edinburgh, said:

“There is evidence that sperm counts are declining in Western men. This well conducted study contributes to a growing body of evidence to suggest that environmental or lifestyle factors are contributing to the decline in sperm counts. However, the specific factors that contribute to this decline are still not clear.

“The sensitive period for male reproductive development described in rodent studies is believed to be equivalent to ~8-14 weeks gestation in humans. Therefore, the association seen in this study appears to coincide with this critical period of development.

“Testosterone production in the human testis during this period of fetal life, critical for male reproductive development, may be impacted by many factors. For example, we have shown experimentally that pharmaceutical (e.g. paracetamol) exposure can reduce testosterone production in the human fetal testis.

“The researchers rightly emphasise that they are describing an association and that this does not necessarily imply causation. Other factors that tend to occur alongside stress (e.g. pharmaceutical use and smoking) could be alternative explanations for this association. Therefore, whether the impacts on sperm count in sons are a direct result of maternal stress or other associated exposures during pregnancy cannot be concluded.

“The impact of stressful events on the mother and fetus will depend on the nature of the event(s), the biological effect (e.g. rise in ‘stress hormones’) and the resilience of the mother. The present study was not designed to measure these factors, which are important for determining causation.

“Although there are significant reductions in number of sperm in the ejaculate, the average sperm count remains in the normal range even for those exposed to multiple stressful life events. This indicates that should stress be a proved to directly contribute to a decline in sperm count, additional factors would still likely be required to impair fertility.

‘Whilst it cannot be concluded from this study that stress during pregnancy is directly responsible for the effects on future reproductive function in sons, avoiding and managing stress during pregnancy remains important for the general health of mother and baby.”

Prof Richard Sharpe, Honorary Professor, MRC Centre for Reproductive Health, University of Edinburgh, said:

“The present publication from this study is the first to provide convincing human data to show that stress in early (1st trimester), but not late (3rd trimester), pregnancy is associated with lowered sperm count and lower blood testosterone in males resulting from such pregnancies. Such studies can never prove cause and effect, but there are biologically plausible explanations, centering around suppression of testosterone production by the fetal testis, that would support the view that too much stress in early pregnancy might be detrimental to optimal male reproductive development. However, even if this is true, the present study suggests that the effects (eg on sperm count) are small, and on their own would be unlikely to result in infertility. Nevertheless, the most important take-home message from this study is that current thinking about the critical importance of early pregnancy for normal male reproductive development appears spot on and encourages the view that far more support (eg. emotional, psychological, practical, financial) for pregnant women in the first 3 months of pregnancy is likely to have beneficial effects on later reproductive health of the baby if it’s a boy (the same may also be true for girls).

“There is growing concern that reproductive health in men is deteriorating, one example of which is that sperm counts appear to have fallen over the past 60+ years. The most favoured hypothesis to explain such adverse changes is that they stem from suboptimal development of the male reproductive system (which occurs between ~8-14 weeks of pregnancy during the 1st trimester). Circumstantial evidence from human clinical studies support this hypothesis and there is strong direct evidence to support this from animal experimental studies.

“However, proving that adverse events in early human pregnancy might affect reproductive health (eg sperm count) in adult men is a Herculean task, as such studies have to relate events (and collect data) that are separated by 20 or more years. To add to the difficulty, we have no means of monitoring what is happening within the developing reproductive system of the male fetus during the first trimester of pregnancy (when the fetus is tiny). To investigate this in a scientifically meaningful way requires great ingenuity, tremendous patience, lots of funding and huge dedication by the human subjects and their attendant doctors. Professor Roger Hart and the Raine study in Western Australia have done just this and, over the past 5 years have been publishing the outcomes of their unique studies.

 “The Raine study (https://www.rainestudy.org.au/) , from which the present data come, is a prospective study that collected data from over 2800 pregnant women and then followed up their sons and daughters  after birth through into young adulthood. It is designed for purpose and is the best there is – indeed it is unique in many respects – it has been running for 27 years!”

* ‘The association between in utero exposure to stressful life events during pregnancy and male reproductive function in a cohort of 20-year-old offspring: The Raine Study”, by Bräuner et al. was published in Human Reproduction at 00:05 UK time on Thursday 30^th May.

Declared interests

Prof Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility and Trustee of the Progress Educational Trust (all unpaid).  Also, recent work for the World Health Organisation, British Broadcasting Corporation, Purple Orchid Pharma (paid consultancy with all monies going to University of Sheffield).  Co-applicant on a research grant from the Medical Research Council (ref: MR/M010473/1).”

Dr Rod Mitchell: “I have no conflicts of interest to declare.”

Prof Richard Sharpe: “No conflicts to declare.”

None others received.