Title: Sleep disturbances and female infertility: a systematic review
Version: 1 Date: 24 Jun 2024
Reviewer:  Alan H. Decherney
Reviewer's report:
Introduction:
• Paragraph 1: A brief, general statement elaborating on the relationship between risk factors
for infertility (diabetes, thyroid disease, obesity, PCOS) and disordered sleep would make this
paragraph stronger.
• Paragraph 3: “Explore” instead of “export”.
Methods
• Clear description of methodology and excellent adherence to PRISMA guidelines. The authors
are encouraged to work with a copy editor or English language consultant to address minor
grammatical and syntax errors.
• Section “How to measure sleep”
o This section acknowledges the heterogeneity of sleep assessment methods across the literature
surveyed, which is an important discussion but less appropriate for the “Methods” section. We
recommend briefly acknowledging this heterogeneity in the discussion with an emphasis on how
this affected the interpretation of the literature, and either delete or move a detailed description
of these methods (PSG, polygraphy, actinography, and sleep quality survey instruments) in the
Supplemental information.
o
o Results
• Multiple references are made to “sleep breathing disorders” (such as Table 3 and paragraphs
that mention Table 3). All these references are studying obstructive sleep apnea (OSA) alone.
Consider referring specifically to OSA instead of the generic “sleep breathing disorder” since
studies examining other disorders are not listed.
• Section “Sleep disturbance and infertility among reproductive-age females”
o Would specify that the discussion regarding “conflicting” results of cross-sectional studies are
examining sleep duration as a risk factor, rather than sleep disturbance. From this paragraph it
appears that there is conflicting evidence regarding the association between sleep duration and
infertility, and while the association between sleep disturbance and infertility is more consistent.
o Please specify “U-shaped association between female sleep duration” and probability of
conception.
• Section “Sleep disturbance and female receiving fertility treatment”
o “Potentially jeopardize reproductive outcomes” is somewhat of a strong claim to make, given
the evidence in the surveyed literature. Consider “may be associated with poorer treatment
outcomes” or something more conservatively worded.
o “One study demonstrated that shorter sleep duration (<7 h), later bedtime and sleep midpoint
significantly decreased the likelihood of completing the IVF cycles” – this study is missing a
reference. Please add a citation.
o Could there be a brief discussion on how patient “sleep chronotypes” are determined in these
studies, and how this affects study validity and generalizability? This is an interesting question,
but research into this may be limited by how reproducibly patients can be assigned to one
chronotype vs. another for the purposes of research.
• Section “Sleep breathing disorder and female infertility”
o As above, consider replacing mentions of “sleep breathing disorder” with “OSA” since this is
the only diagnosis that is considered in these studies.
o Please comment on whether how studies on PCOS and OSA adjusted for obesity or BMI,
which is an obvious confounder. Are these associations purely mediated by obesity, or is there
another physiologic relationship between OSA and oligo-ovulatory endocrinopathy?
o The point about poor OSA screening rates in academic centers does not belong in this
paragraph or section. Perhaps this can be moved later in the discussion arguing for greater
provider awareness of how disordered sleep may be associated with infertility or reduced IVF
outcomes.
o Discussion on oxidative stress, inflammation, and LH/FSH levels seems misplaced as well
in this section – these mechanistic hypotheses are better and more concisely addressed in the
discussion. Consider deleting.
o Reference 10 (Llaneza et al) and 24 (Walter et al) are not peer reviewed articles, but conference
abstracts. If the inclusion criteria of this systematic review are meant to include non-peer
reviewed articles, it is important to specify this. Otherwise, I recommend excluding these articles
from the discussion.
Discussion: “Causes and managements of sleep disturbance in infertile females”
• Good comprehensive discussion on potential comorbidities that can confound the relationship
between sleep disturbance and infertility, including depression/anxiety, and obesity.
• Important discussion on the heterogeneity in methods when assessing sleep duration, sleep
quality, and the presence of a sleep disorder diagnosis, as well as when assessing for infertility
and reproductive outcomes. For this reason, some of the claims across this manuscript should be
softened and qualified to reflect the heterogeneity and limited number and quality of available
evidence.
• Section “Circadian dysrhythmia”
o Consider editing to provide a more concise summary of circadian rhythms, while also going
into more depth re: references 59 and 60. Summarizing some key mechanisms of circadian
regulation of reproductive function would be helpful than a summary of circadian rhythms.
• Section “Clock systems”
o Similar to the above point, the discussion on clock genes and reproduction requires much less
explanation on CLOCK genes and circadian rhythm regulation, and more focus on how these
systems may be implicated in fertility. This is an opportunity to make this manuscript far more
concise.
• Section “Metabolic disorders and sleep breathing disorder.”
o More discussion on the role of disordered sleep and OSA on insulin resistance would be helpful
here, rather than just identifying insulin resistance as a risk factor for developing OSA. What I
believe is more established in the literature is how disordered sleep may affect insulin resistance.
• Various references to “Oxidate stress” – consider the more common terminology “Oxidative
stress”.
• Section “Immune inflammatory response”
o Consider adding 1-2 more sentences to discuss how inflammation may affect specific
aspects of IVF or natural fertility (folliculogenesis, oocyte quality, endometrial receptivity and
implantation, miscarriage risk).