Older wombs linked to complications in pregnant mice

Deciding to start a family later in life could be about more than just the age of your eggs. A new study in mice suggests the age of a mother’s womb may also have a part to play. This work, led by Dr Myriam Hemberger at the Babraham Institute and the Centre for Trophoblast Research in Cambridge, UK, is one of the first to look at the effects of age on womb health and it is expected to lead to new research into human pregnancies.

The risks of complications during pregnancy all increase with age. A woman in her late 30s is twice as likely as a younger woman to have a stillbirth, she is also 20% more prone to giving birth prematurely and more likely to experience conditions such as pre-eclampsia. Many of these effects have been linked to the deteriorating quality of ageing egg cells. Yet, this new research, published in Nature Communications, reveals that older wombs also have more trouble adapting to pregnancy.

By examining first pregnancies in aged mice, the team showed that, for mice as for humans, the risk of complications increases with age. Closer examination revealed that the wombs of older mothers are less able to support the growth of a placenta, meaning the developing young have poor blood supply, which slows their growth and can cause birth defects.

The co-first authors were Ms Laura Woods and Dr Vicente Perez-Garcia. Speaking about the findings, Ms Woods said: “We wanted to enhance our understanding of the increased risks of pregnancy in older mothers. When we compared mice who have their first litter in middle age to their younger counterparts, we found that the lining of the uterus does not respond as well to pregnancy hormones and this delays placenta formation. By identifying the key pathways affected by age in mice we have a better idea of what to look for in humans.”

Understanding the potential risks of pregnancy with age is an increasingly important issue. In the UK, more and more women are starting families later and in 2015, 53% of UK births were to women aged 30 or over. A 2016 report by the Human Fertilisation and Embryology Authority showed that freezing eggs for later use is also growing in popularity. In 2001, just 29 women opted for the treatment, rising to 816 by 2014.

Lead author, Dr Hemberger, Group Leader in Epigenetics at the Babraham Institute, said: “Overall, our study highlights the importance of the ageing uterine environment as a cause of reproductive decline in female mice. This is one of the first times that the considerable impact of age on pregnancy has been studied in detail beyond the effects of egg fitness. More research will be needed to establish if and how our results translate to humans.”

The shorter lifespan of mice means that they are useful for studying the effects of age on pregnancy but these results cannot always be directly applied to human pregnancies. These new results will help to guide long-term studies in humans but it is not yet clear what the implications of these findings will mean for family planning and human healthcare. It is clear that other factors besides egg quality may need to be considered when planning a family.

As a member of the Royal College of Obstetricians and Gynaecologists, Ashley Moffett, Professor of Reproductive Immunology at the University of Cambridge and expert on placenta formation, said: “We know that the so-called Great Obstetrical Syndromes, in particular pre-eclampsia are more common in older women but it’s still not clear why. Although more work is needed to demonstrate this effect in humans, this study could help advance research into these important questions”.

Notes to Editors:

Publication Reference
Woods L, Perez-Garcia V, Kieckbusch J, Wang X, DeMayo F, Colucci F, Hemberger M, (2017) 'Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat Comms 8. http://dx.doi.org/10.1038/s41467-017-00308-x

Research Funding
This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC; Strategic Programme Grant BB/J004499/1), the Centre for Trophoblast Research, University of Cambridge, UK and a Medical Research Council (MRC) DTP studentship.

Image Credit
Credit: Ms Laura Woods
This is a fluorescent microscopy image of the womb of an elderly mouse. The areas in green show cells which respond to pregnancy hormones. As a mouse ages, the womb becomes less sensitive to hormones, as shown by the uneven, patchy areas of green. This is reflected in the developmental problems we see in the offspring from these older mothers.

Affiliated Authors (in author order):
Laura Woods, Epigenetics Programme, Babraham Institute
Vicente Perez-Garcia, Epigenetics Programme, Babraham Institute
Myriam Hemberger, Group Leader, Epigenetics Programme, Babraham Institute

Animal Statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.

The use of animals in this study was performed in full compliance with UK Home Office regulations and with approval of the animal welfare committee (AWERB) at The Babraham Institute, and with the relevant project and personal licences. The study used the wild type C57BL/6 strain of mice housed at the Babraham Institute. Pregnancy was studied in mice between the ages of 8 and 12 weeks or 40 and 58 weeks. Embryo and placenta development were assessed around 11.5 days into pregnancy.

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About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.