A recent paper in the European Journal of Epidemiology reported that recurrent miscarriage and stillbirths are associated with the occurrence of dementia, but there was insufficient evidence to establish such a connection between infertility and dementia [1].
Sex-specific differences in dementia risk
Dementia affects women more frequently than men. The authors of this paper discuss data from 2019 that shows that dementia was estimated to be responsible for one million deaths among women. In the case of men, the estimate is about half the number, at 600,000 deaths. Women also lose more years of life to dementia-related disability than men (17.7 million vs 10.6 million). Females’ long lifespans cannot explain these discrepancies fully [2, 3].
The authors believe that sex-specific dementia risk factors require investigation since well-known risk factors, such as lower education, smoking, diabetes, hypertension, depression, and pre-existing stroke, do not explain the higher magnitude of this problem among women [4].
Some studies have already addressed this issue and investigated a number of female-specific possible risk factors, suggesting that later age at menarche (first period), being nulliparous (a female who has never given birth), and premature and early menopause are dementia risk factors [5, 6]. However, as the authors point out, there has not been enough investigation into infertility and pregnancy loss (i.e., miscarriage and stillbirth) and their link to dementia.
Pregnancy loss and dementia association
For the analysis, the authors used data from 291,055 women with a median age of 55.0. Study participants were followed up for a median of 13.0 years. After the follow-up time, 3334 (1.2%) of these women developed dementia. The median age of developing the disease was 75.0. In the studied cohort, 17.9% had experienced infertility, 25.4% had experienced miscarriage, and 3.2% had experienced stillbirth.
According to the analyzed data, “there was insufficient evidence to establish an association between infertility and dementia.” However, the analysis indicated that recurrent miscarriage (three or more) leads to a “modestly higher risk of dementia” when compared to women who didn’t experience a miscarriage, and women who experienced recurrent (two or more) stillbirths also had a 1.64-fold increased dementia risk when compared to women who didn’t experience it. This effect size (1.64) is similar in size to the effect size of conditions such as obesity (1.6), hypertension (1.6), and diabetes (1.5) [4], which makes it an important risk factor.
Scarce research on the topic
The authors of current papers reviewed previous research on this topic, noting there were not many studies that addressed the relationship between stillbirths, miscarriages, infertility, and dementia risk.
In fact, the association between infertility and dementia was addressed by only one cohort study. The authors of that study observed a lower risk of dementia among women with secondary infertility [7]. One of the differences between that study and this one is that in this study, a much higher fraction of women was considered infertile (17.9% as opposed to 2.4% in the previous study). The difference stems from a different way of identifying infertile women, as that previous study didn’t include women who didn’t seek medical help for infertility, and this study had much broader inclusion criteria.
Regarding the link between recurrent miscarriages and dementia, the authors point to three previous studies that investigated it. They “found no evidence on the association between miscarriage (single or recurrent) and dementia” [7-9]. That is contradictory to this study, which reported a modest association between recurrent miscarriages, defined as three or more miscarriages, and dementia. The authors point to the lack of consensus regarding the definition of recurrent miscarriages, which makes a difference in the data analysis. The previous studies only distinguished between zero, one, or more than two miscarriages. They didn’t have a separate category for three or more miscarriages, as this study did (and where the association was observed).
Only two previous studies investigated the link between recurrent stillbirths and dementia, with inconsistent results. One reported the association, while the second didn’t [8, 9]. The authors point out that both studies have serious limitations, such as a short follow-up period to a median age of 49 and inadequate control for confounding factors. Those limitations were addressed in this study, which reported increased dementia risk for women with recurrent stillbirths.
Possible molecular mechanisms
Based on other observational studies, the authors hypothesized about possible underlying molecular processes. One of them is the role of oestrogen and progesterone, two hormones that play crucial roles in many female reproduction-related processes. They are also essential regulators of neuroplasticity [10]. The researchers note that “women with pregnancy loss may have inadequate levels of oestrogen or progesterone.” Such deficiencies can be the reason for declining neuroplasticity and dementia development.
They also note the possible impact on dementia development caused by molecular changes that result from stroke, diabetes, and depression, conditions more common among women who experience pregnancy loss [11-13]. However, studies are necessary to confirm those hypotheses.
Limitations of the study
As with every study, this one had some limitations, including data acquisition: the questionnaires might have introduced recall bias. Also, due to the nature of the data, the researchers were unable to distinguish whether infertility was due to her body or that of her male partner. They also didn’t have data regarding some factors that might influence the results, such as smoking, alcohol intake, BMI, hormonal or blood biomarkers, and missing dementia cases (as they might have been unidentified at the time). Additionally, the authors didn’t investigate different subtypes of dementia. The results have limited generalizability since the women included in the study were mostly Caucasian.
Literature
[1] Liang, C., Dobson, A. J., Chung, H. F., van der Schouw, Y. T., Sandin, S., Weiderpass, E., & Mishra, G. D. (2024). Association of infertility and recurrent pregnancy loss with the risk of dementia. European journal of epidemiology, 10.1007/s10654-024-01135-3. Advance online publication
[2] World Health Organization. Global health estimates: leading cause of death, cause specific mortality, 2000–2019.
[3] World Health Organization. Global health estimates: leading causes of DALYs disease burden, 2000–2019.
[4] Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen-Mansfield, J., Cooper, C., Costafreda, S. G., Dias, A., Fox, N., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A., Orgeta, V., … Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet (London, England), 396(10248), 413–446.
[5] Gilsanz, P., Lee, C., Corrada, M. M., Kawas, C. H., Quesenberry, C. P., Jr, & Whitmer, R. A. (2019). Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology, 92(17), e2005–e2014.
[6] Fu, C., Hao, W., Ma, Y., Shrestha, N., Virani, S. S., Mishra, S. R., & Zhu, D. (2023). Number of Live Births, Age at the Time of Having a Child, Span of Births and Risk of Dementia: A Population-Based Cohort Study of 253,611 U.K. Women. Journal of women’s health (2002), 32(6), 680–692.
[7] Andolf, E., Bladh, M., Möller, L., & Sydsjö, G. (2020). Prior placental bed disorders and later dementia: a retrospective Swedish register-based cohort study. BJOG : an international journal of obstetrics and gynaecology, 127(9), 1090–1099.
[8] Basit, S., Wohlfahrt, J., & Boyd, H. A. (2019). Pregnancy loss and risk of later dementia: A nationwide cohort study, Denmark, 1977-2017. Alzheimer’s & dementia (New York, N. Y.), 5, 146–153.
[9] Gong, J., Harris, K., Peters, S. A. E., & Woodward, M. (2022). Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants. PLoS medicine, 19(4), e1003955.
[10] Yagi, S., & Galea, L. A. M. (2019). Sex differences in hippocampal cognition and neurogenesis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44(1), 200–213.
[11] Liang, C., Chung, H. F., Dobson, A. J., Hayashi, K., van der Schouw, Y. T., Kuh, D., Hardy, R., Derby, C. A., El Khoudary, S. R., Janssen, I., Sandin, S., Weiderpass, E., & Mishra, G. D. (2022). Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women. BMJ (Clinical research ed.), 377, e070603.
[12] Kolte, A. M., Olsen, L. R., Mikkelsen, E. M., Christiansen, O. B., & Nielsen, H. S. (2015). Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss. Human reproduction (Oxford, England), 30(4), 777–782.
[13] Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C., & Scheltens, P. (2006). Risk of dementia in diabetes mellitus: a systematic review. The Lancet. Neurology, 5(1), 64–74.
