Is Depression Associated With Reduced Fertility in the Developed World?

Question:

"Is there any evidence that depression in the ‘non-infectious’ developed world decreases fertility? Don’t individuals with depression who reach sexual maturity pass their genes on at the same frequency as non-carriers?"

Charles Raison, MD:

For folks like me who often skim the beginning and end of articles or blogs, let me cut to the chase: yes, there is significant evidence that depression is associated with reduced fertility in the developed world, and people who are infertile are more depressed than are fertile individuals, with this effect being especially strong for women. If you want to know the details, and how this might link to adaptive advantages of depression in the ancestral environment (as well as fertility and survival in the royalty of Europe), read on.

Williams and colleagues reviewed the world’s literature on this topic in 2007. ¹ At that time a number of studies suggested that people with both bipolar and unipolar mood disorders had reduced fertility, as measured by number of offspring, when compared with matched controls. Importantly, the bulk of the evidence suggested that this effect was seen even prior to the onset of the psychiatric illness, suggesting that the link between mood disturbances and fertility may cut deeper than a simple association between being too unhappy to have sexual relations and reduced number of children.

In the years since 2007, studies from around the world have continued to observe an association between mood disorders and reduced fertility. ^2-3 For example, women from Sardinia with carefully assessed DSM-IV mood disorders (N=1,975) had 17% fewer children/person than the comparable general population of the island. ⁴ Reproductive rates were lowest for those with bipolar I disorder, followed by bipolar II disorder, followed by recurrent unipolar major depression. The effect was more pronounced in women than in men and in individuals with an early onset to their mood disorder. There is any number of reasons why people with depression might have fewer children, but a study from Turkey suggests biological contributions to the association. In women, depressive symptoms were correlated with reduced oocyte numbers. ⁵ Whether depression affects oocyte biology or whether factors that affect oocyte biology affect the brain, or both, remains unknown.

Most of the studies that have examined associations between depression and fertility have not asked whether people with depression have fewer children, but have reversed the question by asking whether people with infertility have higher rates of depression than do fertile people. There are far too many studies to review one by one, but a strong pattern emerges from the overall data. People with infertility have higher rates of depression than do their fertile counterparts, whether studies are conducted in the United States, Europe, or the Middle East. ^{1, 6-9}

Yet another way of getting at associations between depression and fertility is to enquire whether infertile individuals with depressive symptoms have a more difficult time conceiving than their non-depressed infertile counterparts. The data are mixed, with one recent meta-analysis finding no association between depressive or anxiety symptoms and the success of a single cycle of assisted reproduction technology (ART), ¹⁰ and another meta-analysis finding small, but significant associations between these symptoms and failure to conceive following ART. ¹¹

Associations between depression and reduced fertility help highlight a question that has increasingly captured my attention as a researcher: if depression is at least partly a genetically-driven condition, and if it reduces fertility (in addition to increasing mortality), why haven’t the genes that contribute to the disorder been removed from the human genome by natural selection? Why, in fact, are the risk genes for depression both common and increasing in prevalence?

One potential answer to this question points to evidence that these genes may have undergone positive selection because they produced biochemical and behavioral changes that may have helped individuals either avoid or better survive infections in the ancestral environment. Said differently, while bad for social functioning and fertility, depressive symptoms, and their underlying biology, may have had survival-relevant effects in environments when most individuals died early in life from infectious causes. The full argument that supports this idea is way beyond the scope of this Q&A, but if you are interested you can download the article . ¹² I would like to make a few comments specific to infertility, depression, inflammation, and survival.

Significant data suggest that, while contributing too many late-life diseases in the modern world, inflammatory processes provide protection against death from infectious causes. Thus, as one might predict, people with higher levels of inflammation are more likely to live to old age in high-pathogen environments, but die at younger ages from inflammatory conditions in environments in which infection is no longer a primary source of mortality. ¹³ But even in high pathogen environments, higher levels of inflammation extract costs for one’s reproductive success, given ample evidence that inflammation impairs fertility. ^14-15 Studies in European royalty prior to the development of modern medicine demonstrate a strong relationship between survival into advanced age and reduced fertility, over and above mortality directly related to childbirth. The most parsimonious explanation for these findings is that individuals with increased inflammatory activity were more likely to survive infectious death, but also less able to conceive. Of course, this connection between inflammation and infertility makes sense from an evolutionary point of view. Inflammation signals the brain and body that an infection has occurred, and it makes no sense to get pregnant if one needs all available resources just to fight the infection and survive.

Inflammation also produces depression, and as a group, individuals with depression have elevations in a range of inflammatory biomarkers. ¹⁶ For this reason alone, one would predict that depression should be associated with reduced fertility. In fact, if depression wasn’t associated with impaired fertility it would be a challenge to what has come to be known as the cytokine hypothesis of major depression.

References

1. Williams KE, Marsh WK, Rasgon NL. Mood disorders and fertility in women: a critical review of the literature and implications for future research. Hum Reprod Update. 2007;13(6):607-616.
2. Yates WR, Meller WH, Lund BC, Thurber S, Grambsch PL. Early-onset Major Depressive Disorder in men is associated with childlessness. J Affect Disord. 2010;124(1-2):187-190.
3. Laursen TM, Munk-Olsen T. Reproductive patterns in psychotic patients. Schizophr Res. 2010;121(1-3):234-240.
4. Tondo L, Lepri B, Baldessarini RJ. Reproduction among 1975 Sardinian women and men diagnosed with major mood disorders. Acta Psychiatr Scand. 2011;123(4):283-289.
5. Gurhan N, Akyuz A, Atici D, Kisa S. Association of depression and anxiety with oocyte and sperm numbers and pregnancy outcomes during in vitro fertilization treatment. Psychol Rep. 2009;104(3):796-806.
6. Noorbala AA, Ramezanzadeh F, Abedinia N, Naghizadeh MM. Psychiatric disorders among infertile and fertile women. Soc Psychiatry Psychiatr Epidemiol. 2009;44(7):587-591.
7. Volgsten H, Skoog Svanberg A, Ekselius L, Lundkvist O, Sundstrom Poromaa I. Prevalence of psychiatric disorders in infertile women and men undergoing in vitro fertilization treatment. Hum Reprod. 2008;23(9):2056-2063.
8. Sbaragli C, Morgante G, Goracci A, Hofkens T, De Leo V, Castrogiovanni P. Infertility and psychiatric morbidity. Fertil Steril. 2008;90(6):2107-2111.
9. Domar AD, Broome A, Zuttermeister PC, Seibel M, Friedman R. The prevalence and predictability of depression in infertile women. Fertil Steril. 1992;58(6):1158-1163.
10. Boivin J, Griffiths E, Venetis CA. Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies. BMJ. 2011;342:d223.
11. Matthiesen SM, Frederiksen Y, Ingerslev HJ, Zachariae R. Stress, distress and outcome of assisted reproductive technology (ART): a meta-analysis. Hum Reprod. 2011;26(10):2763-2776.
12. Raison CL, Miller AH. The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry. Jan 31 2012.
13. Kuningas M, May L, Tamm R, et al. Selection for genetic variation inducing pro-inflammatory responses under adverse environmental conditions in a Ghanaian population. PLoS One. 2009;4(11):e7795.
14. Westendorp RG, van Dunne FM, Kirkwood TB, Helmerhorst FM, Huizinga TW. Optimizing human fertility and survival. Nat Med. 2001;7(8):873.
15. Van Bodegom D, May L, Meij HJ, Westendorp RG. Regulation of human life histories: the role of the inflammatory host response. Ann N Y Acad Sci. 2007;1100:84-97.
16. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.