Women with infertility at higher risk of mortality than women without infertility: Study

Both male and female infertility have been associated with greater risks for cancer and chronic disease, which are the leading causes of morbidity and mortality. These associations suggest that infertility provides a window into future health and has effects beyond the reproductive years.

Although nulliparity and infertility are distinct, the former has been associated with an increased risk for mortality in large, population-based linkage studies.

Murugappan G, Li S, Alvero RJ, et al sought to build on this previous work by presenting results from a contemporary cohort of women with infertility and examining the differential effects of infertility and fertility treatment on the subsequent risk for mortality.

They carried a retrospective analysis comparing 72,786 women with infertility, identified in the Optum Clinformatics Datamart from 2003 to 2019 by infertility diagnosis, testing, and treatment codes, with 3,845,790 women without infertility seeking routine gynecologic care. The baseline comorbidities were assessed using the presence of ≥1 metabolic syndrome diagnoses and the Charlson Comorbidity Index.

"The primary outcome, which was all-cause mortality, was identified by linkage to the Social Security Administration Death Master File outcomes and medical claims. The association between infertility and mortality was examined using a Cox proportional hazard regression by adjusting for age, hypertension, hyperlipidemia, type II diabetes, year of evaluation, smoking, number of visits per year, nulliparity, obesity, region of the country, and race."

Results:

• The study population included 72,786 women with infertility and 3,845,790 women without infertility. Women with and without infertility were similar in age at the time of enrollment.

• Women with infertility were more likely to be nulliparous (16.6% vs 8.1%), obese (20.2% vs 14.9%), and smokers (7.3% vs 5.4%) than women without infertility.

• 37% of the women in the cohort underwent infertility testing, 90% of women in the cohort had an infertility diagnosis and 23% of the infertile cohort underwent fertility treatment.

• Among 16,473,458 person-years of follow-ups, 13,934 women died. Women with infertility had a 32% higher relative risk for death from any cause (0.42% vs 0.35%, adjusted hazard ratio, 1.32) than women without infertility.

• When stratified by age of <35 or ≥35 years or baseline medical comorbidity, the association between infertility and mortality remained. Women with infertility who delivered a child during the follow-up period faced a similar increased risk for mortality than the overall infertile group.

Finally, receiving fertility treatment was not associated with a higher risk for death than receiving an infertility diagnosis or testing alone.

• From a contemporary cohort of 3,918,576 women aged between 20 and 45 years, authors reported a small absolute risk for death, but a 32% relative increase in the risk for death among women with infertility when compared with women without infertility.

Authors found that the risk for mortality among patients with infertility persisted across different age ranges (<35 or ≥35 years) and comorbidities (number of MetS diagnoses or CCI score). These findings suggest that a biologic difference may exist among women with infertility that leads to an increased risk for mortality that is not solely attributed to increasing age and medical comorbidities. Childbearing has a protective effect on mortality and is influenced by a myriad of factors that are biologic, social, and economic. Having children before ART treatment has been associated with a reduced risk of mortality. This association can be attributed to better health among previously fertile women, or a less severe form of infertility among parous women that is associated with a lower risk for death.

Disparate birth outcomes including stillbirth, multiple birth, and birth of a child with significant abnormality can all increase physical and emotional stress, which in turn can influence the health and mortality risk among both women with and without infertility.

Counseling a patient with infertility who is planning to undertake fertility treatment typically includes a discussion about the attendant risks. Current counseling largely focuses on periprocedural and pregnancy-related risks. The growing body of work demonstrating an association between both female and male infertility and an increased risk for morbidity and mortality suggests that continued evaluation of patients with infertility may be warranted after reproductive pursuits conclude. The fertility evaluation offers an opportunity to screen for additional factors that may affect future health, implement additional periodic health screening measures, and provide counseling regarding the implications of an infertility diagnosis on a woman's short and long-term health.

Although the absolute risk for death was low in both groups, women with infertility face a higher relative risk for mortality than women without infertility, reinforcing the disease burden associated with this diagnosis and its potential for long-term health sequelae. Moreover, the association remained across all age, race and ethnicity groups, morbidities, and delivery strata. Importantly, fertility treatment was not associated with an increased risk for death. Long-term studies are needed to address the time course of this association.

Source: Murugappan G, Li S, Alvero RJ, et al. Association between infertility and all-cause mortality: analysis of US claims data. Am J Obstet Gynecol 2021;225:57.e1-11.

https://doi.org/10.1016/j.ajog.2021.02.010