Obstructive sleep apnea increases risk of female infertility: A 14-year nationwide population-based study.

Obstructive sleep apnea (OSA) is a widely prevalent but often underdiagnosed respiratory disorder characterized by recurrent upper airway obstruction during sleeping. Approximately 5% of the general population experiences OSA; among those aged 30–60 years, the prevalence is 9% in women and 24% in men [ 1 , 2 ]. The risk of OSA is higher with a family history of OSA, obesity, hypertension, menopause, cigarette smoking, and alcohol consumption [ 3 ]. OSA results in sleep fragmentation and repetitive hypoxemia and is associated with various comorbidities, including hypertension, diabetes mellitus, ischemic heart disease, and obesity [ 4 , 5 ]. According to the American College of Obstetricians and Gynecologists (ACOG), the definition of infertility is the failure to conceive after 1 year or more of regular unprotected sexual intercourse [ 6 ]. The prevalence of infertility has increased since 1990; in 2010, approximately 48.5 million individuals worldwide suffered from infertility [ 7 ]. Moreover, according to the data published by Taiwan’s Ministry of the Interior, the fertility rates of women within childbearing age decreased from 1.680 births per woman in 2000 to 1.080 births per woman in 2018, with the mean age of the women at their first birth increasing from 22.88 years to 30.90 years during that period. Female infertility can result from various conditions, including endometriosis, pelvic adhesion, polycystic ovary syndrome, tubal blockage, hyperprolactinemia, and congenital or acquired uterine or ovarian abnormalities [ 8 ]. Infertility can be associated with multiple factors, such as inflammation, obesity, intermittent hypoxia and sympathetic activation [ 9 , 10 ]. In our previous study, we have found an increased risk of infertility in female patients with non-apnea sleep disorder [ 11 ]. However, little is known about whether OSA is associated with a risk of female infertility. The aim of the present study was to investigate whether women with OSA had an increased risk of subsequent female infertility. Accordingly, we used Taiwan’s National Health Insurance Research Database (NHIRD) for conducting the largest retrospective study to date discussing the association of female infertility with OSA.

We identified 4,078 female patients in the database who had been diagnosed with infertility by the end of the study. After applying the exclusion criteria, 2,400 patients were included and assigned as the study group in the analysis. The control group comprised 4,800 matched women without infertility. The mean ages in the study groups were 32.19 ± 6.20 years, whereas the mean ages in the control groups were 32.24 ± 6.37 years. Table 1 summarizes the characteristics of the study and the control groups. There were significantly more patients who had been diagnosed with OSA in the study group than in the control group (1.38% vs. 0.63%; p = .002). In addition, we have found that 33 patients in the study group and 30 patients in the reference group, who have had prior exposure to OSA. Women aged 26–30 years and 31–35 years were more than other aged groups in our study population (28.0% and 32.29% respectively). P : Chi-square / Fisher exact test on category variables and t-test on continue variables Multivariable logistic regression analysis was used in this retrospective study. We listed factors for female infertility in Table 2 . There were no significant differences in the risk of female infertility between patients with and without gynecological disorders, endocrine disorders, or concomitant comorbidities, including hypertension, diabetes mellitus, hyperlipidemia, COPD, chronic kidney disease, coronary heart disease, stroke, obesity, anxiety, and depression ( Table 2 ). The increased likelihood of subjects with OSA to be infertile was also showed in Table 2 (adjusted odds ratio, 2.101; p<0.001). ICD-9-CM and correlation analysis were listed in S1 and S2 Tables, respectively. OR = odds ratio, CI = confidence interval, Adjusted OR: Adjusted variables listed in the table

In conclusion, this study showed that OSA is more commonly seen in infertile women and increases the odds that a woman will be infertile. Therefore, infertile women should be screened for signs and symptoms of OSA, which may help to increase female fertility rate.

Taiwan launched its National Health Insurance program in 1995. This program covers approximately 99% of the 23.74 million individuals in Taiwan, and 97% of clinics are covered by the system [ 12 ]. Taiwan’s health care system is insurance-based, and is characterized by its good accessibility, high efficiency, comprehensive population coverage (99% of the 23.74 million residents in Taiwan), relatively low costs and short waiting times [ 13 ]. The NHIRD contains health registration records for most of the general population in Taiwan, including details of outpatient, inpatient, and emergency department visits, with diagnoses coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9). The high accuracy and validity of diagnoses in the NHIRD have been demonstrated in previous studies, confirming that the NHIRD offers representative data for medical and health-related research [ 14 – 16 ]. A subset of approximately 1 million patient records from the NHIRD was randomly chosen for inclusion in the Longitudinal Health Insurance Database as an aid to research projects. The privacy of all individuals registered in the program is ensured via the encryption and conversion of the identification numbers of all records. The protocol for this study was approved by the Institutional Review Board of the Tri-Service General Hospital (TSGHIRB No. 1-106-05-169). From the outpatient and inpatient data of 989,753 individuals for the period 2000 to 2013 in Taiwan’s Longitudinal Health Insurance Database, we identified female patients aged 20–45 years who were diagnosed with infertility. We excluded women who received radiation therapy, chemotherapy, and genital organ surgery ( Fig 1 ). Patients who met the criteria were assigned to the study group. We used two-fold propensity score matching to create a control group by matching each case group member with two other women from the database according to age (by 5-year span) and index date, applying the same exclusion criteria [ 17 , 18 ]. We compared differences between both groups for the prior exposure of OSA. Both groups were followed until the end of 2013. Our study was conducted by extracting the ICD-9 codes from the NHIRD. The diagnosis of OSA is made by polysomnography and the diagnosis of female infertility is confirmed by the obstetrician and gynecologists. We listed several covariates in our study, including season (Spring, Summer, Autumn, Winter), urbanization level of residence and level of care (medical center, regional, and local hospital). Moreover, common comorbidities as well as endocrine and gynecological diseases, such as obesity, Cushing’s syndrome, thyroid disease, PCOS, and endometriosis, were used in the analysis to evaluate the cause of infertility and their effects on OSA. We compared the study and control groups with regard to characteristics and common comorbidities, including hypertension, diabetes mellitus, hyperlipidemia, and COPD, by using chi-squared tests. The mean ages of the two groups were compared using Student’s t-test. The odds ratio (OR) for factors potentially associated with female infertility were evaluated using multivariable logistic regression with and without stratification. The variables that adjusted in the odds ratio were the variables that listed in the table. Correlation analysis was used to study the strength of a relationship between age groups and the variables listed in S2 Table . All comparisons were two-tailed, and p-values <0.05 were considered statistically significant. The statistical analyses were performed using IBM SPSS v 22.0 software.

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