Sleep Length and Euploid Embryo Transfer Prospective Study

Infertility is a devastating disease affecting 1 in 8 couples in the United States and over 80 million people worldwide. Despite significant improvements in the treatments available to infertile individuals in recent decades, there is a high dropout rate due to treatment cost, and treatment success is variable. Even in the setting of a genetically normal embryo, live birth rates after chromosomally normal (i.e. euploid) embryo transfers hover around 60%. Infertility is also associated with significant morbidities among those affected, ranging from emotional suffering, anxiety and depression, to overwhelming financial burden and isolating social stigma.

Although the underlying etiologies of infertility vary greatly, a common denominator shared by a disproportionate number of infertile women is poor sleep. Physicians routinely screen for diabetes and thyroid disease, yet rarely consider the contribution of sleep to healthy reproductive outcomes. This is partially due to the challenges with studying, measuring and quantifying sleep. However, with the advent of commercially available wearable devices, the scientific community has a new and exciting opportunity to quantify the potential harm of poor sleep and identify a new treatment avenue for infertile couples.

Sleep is a critical component of daily life that significantly influences health and well-being. On average, humans spend one third of life asleep. Yet, with the increasing pressures toward high-productivity, and that demand slowly turning us into a '24-hour society,' many Americans are becoming chronically under slept in the last several decades. Recent estimates purport that over 1 in 3 people in the U.S. sleep less than the recommended minimum of 7 hours a night. Among women of reproductive age, a similarly large group has chronic sleep deficits, with approximately 30% of women self-reporting no more than 6 hours of nightly sleep. Poor sleep quality has been linked to multiple co-morbidities, including anxiety, depression, obesity, diabetes, hypertension, myocardial infarct, and stroke. Moreover, deficits in the most important stage of sleep known as rapid-eye-movement (REM) sleep, have been linked to increased mortality and cognitive decline. Thus, sleep represents an important modifiable risk factor in human well and disease states across the lifespan.

Despite the integral role sleep plays in life, its effect on women's reproductive health, and its subsequent impact on fertility, is largely understudied. Animal models of disrupted sleep have shown significant effects of circadian rhythm alterations on reproductive hormone function, leading to both ovulatory dysfunction and sub-fertility. A murine knock-out model of certain circadian rhythm genes (known as 'Clock' genes) found lower rates of embryo implantation due to decreased steroid hormone production. Human subjects research has largely focused on night-shift workers as a model for abnormal sleep. Women in this group have demonstrated higher rates of irregular menstrual cycles and infertility. Moreover, women with circadian disruption due to working at night had increased rates of pregnancy loss compared to women working during the day. Even among women with night-time sleeping schedules, less sleep has been noted as a risk factor for first and second trimester miscarriages. Based on these studies, sleep and circadian rhythms may play a role in both achieving and sustaining pregnancy.

While studies have shown high rates of both psychological distress and poor sleep among women presenting to fertility clinics, a direct link between sleep and fertility has yet to be demonstrated. This proposed study aims to investigate if this link exists, as understanding the relationship between a 'good night's sleep' and one's reproductive potential could inform future therapies to modify sleep as a risk factor and decrease rates of infertility in women across the lifespan.

There are few studies exploring the complex relationship between infertility, sleep, and reproductive outcomes. Prior studies relied on subjective measures of sleep (e.g. sleep diaries and questionnaires) to measure total sleep time prior to and after in vitro fertilization and embryo transfer. Self-reported sleep estimates are notoriously inaccurate and over-report total sleep time compared to polysomnography and actigraphy measures. Furthermore, only one study used actigraphy, a non-invasive, wrist-mounted device, to objectively measure sleep, but was limited by a small sample size and use of surrogate measures of success (e.g. number of oocytes retrieved and embryos made during IVF), rather than pregnancy or live birth rates, compromising an ability to draw meaningful conclusions and implications for pregnancy rates.

This proposal will be the first adequately powered prospective study to comprehensively measure sleep quality and quantity prior to embryo transfer. Validated sleep questionnaires in combination with continuous actigraphy data collected by the Oura ring will be used, a finger-mounted multi-sensor sleep tracker that performs well compared to the gold-standard in sleep tracking of laboratory polysomnography. This study will prospectively follow participants from the 3-4 weeks preceding an embryo transfer, into the weeks following an embryo transfer and early pregnancy. Comprehensive and objective data generated by the Oura ring will be leveraged to characterize the effects of sleep on pregnancy outcomes.

The investigators hypothesize that lower average total sleep time in the month preceding a frozen embryo transfer will be associated with lower implantation, clinical pregnancy, and ongoing pregnancy rates after single euploid embryo transfers. The investigators further hypothesize that lower average total sleep time in the month after frozen euploid embryo transfer will be associated with higher rates of miscarriage. Secondary hypotheses will assess whether or not additional sleep parameters (sleep onset, wake time, sleep midpoint, amount of night time awakenings, and nighttime heart rate variability) are associated with the same positive or negative pregnancy outcomes.