As reviewed in a previous blog, infertility is a growing global problem, with record low fertility rates reported in the U.S. While there are a number of contributing factors, perhaps most notably exposure to environmental toxins, a systematic review published in BMC Women’s Health examined the association between poor sleep and infertility in women. Nineteen studies were included in this review, grouped into one of three categories: those related to (1) sleep disturbance and infertility among reproductive-age women, (2) sleep disturbance and women receiving fertility treatments, and (3) obstructive sleep apnea (OSA) and infertility. The studies ranged in both size and type; for example, there were 9 studies included in the first category, a mix of prospective cohort and cross-sectional studies, ranging in size from just over 200 to over 50,000 women. A variety of measures of sleep were utilized across these studies, including subjective measurements such as the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index, as well as objective measurements including polysomnography (the gold standard) and actigraphy. The studies included in the first category generally reported a positive association between sleep disturbances (excluding sleep apnea) and infertility, with a nearly 4-fold higher risk for developing infertility among women reporting sleep disorders versus those without. Cross-sectional data from both China and the U.S. suggests a U-shaped association between sleep and fertility among women, with approximately 7 hours of sleep per night at the lowest point of the U (another study based in the U.S. also found a U-shaped association, with 8.5 hours as the ideal, and regular sleeping/waking times as protective). It’s important to note that this cross-sectional data cannot rule out reverse causation, i.e., that infertility may interfere with sleep.
Among women receiving fertility treatment, 24-57% report sleep disturbances, including 42-69% receiving in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments, suggesting sleeping problems are quite common among these women. Subjective measures of sleep have been shown to impair the effectiveness of fertility treatments. For example, in one prospective cohort which included nearly 1300 women receiving IVF/ICSI, poor sleep (such as shorter or longer duration, difficulty falling asleep, inappropriate sleep time, etc.) had a significant reduction in the number of retrieved and mature oocytes. Another prospective study that included more than 3000 women found a higher pregnancy and live birth rate among those with good sleep quality. While not all studies found an association, generally, a duration of 7-8 hours of sleep per night was associated with the highest treatment success.
OSA is a well-recognized risk factor for infertility, particularly for polycystic ovarian syndrome (PCOS); women with PCOS are 4 times more likely to have OSA. One 14-year long study based in Taiwan found a more than 2-fold higher prevalence of OSA among women with infertility. Sleep apnea has also been linked to lower levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and to be associated with Anti-Müllerian hormone (AMH) levels among women with PCOS. Women with OSA have also been shown to need higher levels of gonadotropin and to have lower peak estradiol, fewer retrieved oocytes, as well as high-quality and available embryos.
There are a number of limitations of this analysis, including a lack of a meta-analysis (studies were only reviewed in isolation), heterogeneity in methodology, reliance on self-reporting, etc., as well as the real possibility of reverse causation. For example, anxiety and depression are more common among women with subfertility and/or receiving fertility treatments, which may, in turn, impact normal sleeping patterns.
This systematic review also discusses potential mechanisms for the influence of disturbed sleep on fertility. This includes disruptions in the circadian system, which is also involved in regulating the reproductive system. For example, recent evidence indicates that the pituitary gland, ovary, uterus, and oviduct have functional molecular clocks, and the function of these clocks influences gonadotropin secretion, ovulation, and parturition. Circadian clocks may influence steroid biosynthesis, the sensitivity of the endometrium to steroids, LG gene expression, etc. Indeed, small studies have found that polymorphisms within clock genes (ARNTL and NPAS2) have been associated not only with miscarriages and pregnancy rates, but also with mood, seasonal variations, and sleep length. Melatonin has been suggested as a possible adjunctive therapy for women attempting to improve fertility with mixed results. For example, a prospective cohort study found that melatonin supplementation more than doubled clinical pregnancy rates, ongoing pregnancy rates, and live birth rates when dosed at 2mg per day. However, a systematic review found that despite a significant increase in fertilization rates, melatonin supplementation was not linked to higher clinical pregnancy rates.
Other possible mechanisms discussed in this review include higher reactive oxygen species damage and increased inflammation, as potential factors that impair fertility. Other recent studies suggest elevated homocysteine and polymorphisms in the MTHFR gene may also influence fertility rates. Collectively, these studies suggest that therapies targeting improved sleep duration and quality, as well as anti-inflammatory and antioxidant regimens, should be considered for women attempting to improve fertility.