[ Education and Clinical Practice CHEST Reviews ]

Sex and Gender in Lung Diseases and Sleep

Disorders
A State-of-the-Art Review: Part 2
Amik Sodhi, MBBS, MPH; Katherine Cox-Flaherty, MD; Meredith Kendall Greer, MD; Tasnim I. Lat, DO; Yuqing Gao, MD;
Deepika Polineni, MD; Margaret A. Pisani, MD, MPH; Ghada Bourjeily, MD; Marilyn K. Glassberg, MD; and
Carolyn D’Ambrosio, MD

There is now ample evidence that differences in sex and gender contribute to the incidence,
susceptibility, presentation, diagnosis, and clinical course of many lung diseases. Some con-
ditions are more prevalent in women, such as pulmonary arterial hypertension and sarcoidosis.
Some life stages—such as pregnancy—are unique to women and can affect the onset and
course of lung disease. Clinical presentation may differ as well, such as the higher number of
exacerbations experienced by women with cystic fibrosis (CF), more fatigue in women with
sarcoidosis, and more difficulty in achieving smoking cessation. Outcomes such as mortality
may be different as well, as indicated by the higher mortality in women with CF. In addition,
response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic
factors are often not adequately addressed in clinical trials. Various aspects of lung/sleep
biology and pathobiology are impacted by female sex and female reproductive transitions.
Differential gene expression or organ development can be impacted by these biological dif-
ferences. Understanding these differences is the first step in moving toward precision medicine
for all patients. This article is the second part of a state-of-the-art review of specific effects of
sex and gender focused on epidemiology, disease presentation, risk factors, and management
of selected lung diseases. We review the more recent literature and focus on guidelines
incorporating sex and gender differences in pulmonary hypertension, CF and non-CF bronchi-
ectasis, sarcoidosis, restless legs syndrome and insomnia, and critical illness. We also provide a
summary of the effects of pregnancy on lung diseases and discuss the impact of sex and gender
on tobacco use and treatment of nicotine use disorder. CHEST 2023; 163(2):366-382

KEY WORDS: cystic fibrosis; gender; nonbreathing sleep disorders; pregnancy; pulmonary
hypertension; sarcoidosis; sex; smoking cessation

ABBREVIATIONS: CF = cystic fibrosis; CFTR = cystic fibrosis trans-
membrane conductance regulator; DHEA = dehydroepiandrosterone;
PAH = pulmonary arterial hypertension; ppFEV1 = percent predicted
FEV1; REM = rapid eye movement; RLS = restless legs syndrome;
TGE = transgender and gender expansive
AFFILIATIONS: From the Division of Allergy, Pulmonary and Critical
Care Medicine (A. S.), University of Wisconsin, Madison, WI; the
Division of Pulmonary, Critical Care and Sleep Medicine (K. C.-F. and
G. B.), Brown University, Providence, RI; the Division of Pulmonary,
Critical Care and Sleep Medicine (M. K. G.), Emory University School
of Medicine, Atlanta, GA; the Division of Pulmonary, Critical Care and
Sleep Medicine (T. I. L.), Baylor Scott & White Health, Temple, TX; the
Division of Pulmonary, Critical Care and Sleep Medicine (Y. G. and M.
K. G.), University of Arizona College of Medicine Phoenix, Phoenix,
AZ; the Division of Pulmonary, Critical Care and Sleep Medicine (D.
P.), Washington University at St. Louis, St. Louis, MO; and the Divi-
sion of Pulmonary, Critical Care and Sleep Medicine (M. A. P. and C.
D’A.), Yale University School of Medicine, New Haven, CT.
CORRESPONDENCE TO: Carolyn D’Ambrosio, MD; email: carolyn.
dambrosio@yale.edu
Copyright Ó 2022 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: https://doi.org/10.1016/j.chest.2022.08.2240

366 CHEST Reviews [ 163#2 CHEST FEBRUARY 2023 ]

“Sex” and “gender” each have specific meaning and
impact respiratory disease in different ways. We have
previously published an article outlining the appropriate
terminology for sex and gender.1
As a recapitulation, sex is a biological construct, whereas
gender is a social construct. The term “sex” indicates an
animal’s or a person’s biological status. A combination
of anatomical features, genetics, sex organs, and
hormones define sex. On the other hand, “gender” is
considered a psychological and social construct, which
reflects behaviors, attitudes, and feelings of a person in
the context of their historical and cultural milieu.
Societal roles, work roles, environmental exposures, and
social support are factors that are encompassed in
describing gender. Thus, it has been recommended that
“sex” be used to describe the biological differences and
influences observed in females compared with males.
“Gender” should be used when describing psychological
and social differences between men and women.2
This is the second part of a series providing a state-of-
the-art review of how these constructs impact specific
respiratory diseases and sleep disorders. Although
there is fluidity and interdependence of sex and
gender, the purpose of this review is to highlight areas
in which the study of sex and/or gender differences in
lung diseases has clinical and research significance. We
also provide a background of the effect of pregnancy
on lung disease and how pregnancy may impact
chronic respiratory conditions. As in our previous
review,1 although we advocate the use of the correct
terminology of sex and gender when discussing data
from the existing literature below, we used the same
terminology used in the published manuscripts, even
when terminology was used incorrectly, to avoid
misrepresenting the cited studies. As an example, for
some citations used in this manuscript, the original
manuscript discusses “sex” as a variable but uses the
words men and women, which usually apply to
gender. In some situations, gender is used when the
effect is clearly biological. It is unclear to us whether
the authors are referring to sex or gender in the above
situations. In these instances, we have marked the data
with an asterisk (*) where we thought there may have
been a discrepancy.
This second review represents a joint venture between
the senior faculty authors and selected fellows and junior
faculty. We believe that initiatives such as this will
chestjournal.org
spearhead strong mentoring relationships and
productive new partnerships.
Pregnancy
Pregnant and postpartum patients represent a unique
population, with some respiratory conditions occurring
more frequently. For example, asthma, the most
commonly diagnosed respiratory condition in
pregnancy, occurs in up to 13% of all pregnancies.3-5
Although uncommonly screened and diagnosed in
pregnancy, breathing disorders during sleep are reported
in 9% of low-risk pregnancies,6,7 in up to 70% of
pregnancies complicated by metabolic or cardiovascular
disorders, and/or in pregnancies carrying a small-for-
gestational-age fetus.8-10 Common causes of severe
maternal morbidity and mortality include pulmonary
infections or pulmonary embolism.11,12 Adverse
perinatal outcomes and neonatal mortality are noted
when respiratory disorders accompany pregnancy,
including preeclampsia, low birth weight, and preterm
birth.3,7,13-16 Hence, the physician should have an
understanding of pregnancy physiology and expected
changes in hemodynamics and ventilation around labor
and delivery. These variations can affect diagnostic test
results and impact appropriate decisions about safely
treating patients through pregnancy, delivery, and the
postpartum period.
Upper airways undergo significant changes in pregnancy
that lead to smaller oropharyngeal and mean pharyngeal
areas17 and nasal congestion. As a result, there may be
decreased airway patency, increasing the risk of difficult
airway intubation. These changes also lead to increased
risk for sleep-disordered breathing. Functional residual
capacity decreases with pregnancy progression but tidal
volume and minute ventilation increase. The increase in
tidal volume is presumed to be related to the increase in
metabolic rate and CO2 production, and the rise in the
secretion of progesterone—a respiratory drive stimulant—
is thought to be related to pregnancy progression. The
ratio of dead space to tidal volume is unchanged in
pregnancy. Hence, dead space ventilation is increased in
pregnancy,18,19 despite the increase in cardiac output and
the improved perfusion to the lung apices.
Labor and delivery are associated with profound changes
in hemodynamics, with increases in cardiac output and
minute ventilation. This physiology may significantly
stress the respiratory and cardiovascular systems,
potentially leading to serious complications around
367
 Modified immune response
Disease states impacted
Infections Nasal congestion
Critical illness Upper airway mucosal edema
Airway patency reduced
Hypercoagulable State Diseases impacted
Disease states impacted Asthma
Pulmonary Embolism Sleep disorders/OSA
Pulmonary Hypertension Difficult intubation
Critical illness
FRC reduced
Increased Cardiac Output Low Oxygen reserve
Disease states impacted Reduced respiratory system compliance
Pulmonary Hypertension Disease states impacted
Critical illness Rapid desaturation
Critical illness
Teratogenic effects of drugs ARDS
Disease states impacted Sleep Disordered Breathing
Chronic Lung Diseases
Sleep Disorders Teratogenic effects of Radiation
Pulmonary Embolism Disease states impacted
Infection Pulmonary Embolism
Critical Illness Critical illness
Lung cancer
Infections
Interstitial Lung Disease

Figure 1 – Impact of physiological changes during pregnancy on respiratory diseases. FRC ¼ functional residual capacity.

labor and delivery and the postpartum period (Fig 1).
Hence, anticipation of the potential complications
around labor and delivery can assist in the management
of chronic conditions during pregnancy. Most of the
physiologic changes that occur in pregnancy return to
baseline in the postpartum period. More detailed reviews
of perinatal physiology can be found elsewhere.20,21
Although radiation is feared in pregnancy because of
potential teratogenicity, most imaging studies such as
multidetector chest CT scan imaging, chest radiographs,
and ventilation-perfusion scans can be performed in
pregnancy and do not exceed the threshold for
teratogenicity.22 Although most physicians aim to keep
cumulative radiation doses during the course of a
pregnancy below 5 rad, a threshold of 10 rad has been
proposed to be acceptable.22 Collaborations with the
radiologist and the medical physicist can help reduce
maternal and fetal radiation exposure during diagnostic
tests. IV iodinated contrast can be used in pregnancy,
and there is minimal risk for thyroid toxicity.23
One of the main challenges in caring for pregnant
patients with lung disease concerns the use of
pharmacotherapies. Because of the systematic exclusion
of pregnant patients from many trials, including drug
trials,24 few drugs have optimal safety data in pregnancy,
leaving the patient and the physician with minimal
information about many first-line treatments. Despite
that, the average number of medications used in
pregnancy has been increasing in the past decades. In
many cases, detailed information about the risk of the
untreated lung condition vs the risk of the drug needs to
be presented to the patient, with shared decision-
making. We have previously published a suggested
approach regarding decision-making on
pharmacotherapy in pregnancy that considers the risk of
the condition, the risk of the medication, and the
availability of drugs with similar efficacies but with
better safety profiles.21
Another way to minimize complications in pregnancy is
to conduct pre-conception counseling in reproductive-age
patients with chronic respiratory conditions, and to
perform counseling repeatedly, as risk in pregnancy
changes with age and disease activity.25 Pre-conception
counseling can set expectations for a potential pregnancy
and aid in devising a monitoring plan during pregnancy
and the postpartum period. For patients with
uncontrolled disease, counseling on risk of pregnancy and
a recommendation for contraception or a delay in
pregnancy until their condition is better controlled should
be discussed. For others, such as patients with pulmonary
arterial hypertension, categorized under the highest risk
by the modified World Health Organization

368 CHEST Reviews [ 163#2 CHEST FEBRUARY 2023 ]

TABLE 1 ] Sex and Gender Differences in Critical Illness
Sex Differences
(Females Compared With Males)
 Less likely to develop sepsis
and septic shock
 Outcomes in sepsis similar
 Less likely to develop ARDS
with COVID-19
Gender Differences
(Women Compared With Men)
Epidemiology
 Less likely to receive aggressive care (mechanical ventilation, ECMO, tracheostomy,
vasopressors) despite similar severity of illness
 More likely to have delays in antibiotic administration in sepsis
Symptoms/disease characteristics
 More likely to have advance directives
 More likely to have DNR orders
 Possibly less likely to develop hyperactive delirium
Management
 Higher tidal volumes for given height, especially in shorter women
 Higher plateau pressures
Outcomes after critical illness
 Lower mortality in patients with ARDS
 More likely to experience disability, depression, trauma, and short-term
institutionalization

DNR ¼ do not resuscitate; ECMO ¼ extracorporeal membrane oxygenation.

classification,26 pregnancy is contraindicated given the
high risk of mortality for the mother, and patients who
become pregnant are advised to terminate their
pregnancy.
Critical Illness
Interest in sex- and gender-based differences in critical
illness presentation, treatment, and outcomes has
appropriately heightened since the onset of the COVID-
19 pandemic. The pandemic increased this attention to
gender differences in critical illness as higher rates of
severe illness and death were seen in male patients.27
Sex hormones may impact the trajectory of critical illness,
with estrogen conjectured to play a protective role.28,29 For
example, there is a male preponderance for the
development of sepsis and septic shock30-32 possibly
mediated by sex hormones, but other studies do not clearly
demonstrate that the mortality rate from sepsis is impacted
by sex and/or gender.32-35 The paucity of research in this
area makes definitive conclusions regarding the effects of
sex hormones in critical illness difficult.
Landmark clinical trials in the management of common
conditions experienced by critically ill patients—such as
those with sepsis and ARDS—have enrolled
predominantly male participants.36-42 Although this
may have been a consequence of more male patients
being admitted to ICUs, the complex interaction
between sex and gender in relation to management and
outcomes of critical illness may have been overlooked.
Multiple retrospective and prospective studies have
demonstrated that critically ill male patients were more
likely to receive life-sustaining treatments such as
mechanical ventilation, vasopressors, intracranial
pressure management, tracheostomy, hemodialysis, and
extracorporeal membrane oxygenation, despite similar
or even higher severity of illness in female patients.43,44
A more recent meta-analysis confirms that women were
less likely to receive mechanical ventilation and renal
replacement therapy than men, even with adjustment for
illness severity.45 Female* patients have delays in the
initiation of early antibiotic therapy in sepsis and are less
likely to receive therapies such as mechanical ventilation
and hemodialysis to treat complications related to sepsis.31
Prepandemic, the LUNG-SAFE (Large Observational
Study to Understand the Global Impact of Severe Acute
Respiratory Failure) trial found that among shorter
patients (height < 1.69 m), women were more likely to
receive higher tidal volume ventilation with higher plateau
pressures than men; women categorized as having severe
ARDS were noted to have higher mortality in this trial.46
End-of-life planning impacts care provided in the ICU
as well; in studies assessing the impact of gender on end-
of-life care, women were more likely to have do-not-
resuscitate orders and were more likely to have advanced
directives.47-49 Cultural beliefs may also influence gender
disparity in the creation of advanced directives and
implementation of do-not-resuscitate orders. The exact
reasons underlying disparity between the sexes in
consumption of ICU resources are unclear; conscious or
unconscious bias in favor of more life-sustaining

chestjournal.org 369
TABLE 2 ] Sex and Gender Differences in Pulmonary Hypertension
Sex Differences (Females Compared With Males) Gender Differences (Women Compared With Men)
 Majority of PAH Symptoms/disease characteristics
 Higher proportion of female BMPR2 mutation carriers develop PAH  Sexual quality of life and overall HRQoL
 More favorable hemodynamic profile (lower PVR and higher RV ejection lower
fraction)  Higher rate of admissions for heart failure
 Better survival exacerbation
 May respond better to prostacyclin analogs
 In preclinical models, DHEA has protective effects on the RV
 Higher estradiol and lower DHEA levels associated with worse outcomes
in both females and males
 Unique challenges during pregnancy
 Some medications may be teratogenic
Diagnosis
 Connective tissue disease-associated PAH
more common
Management
 May respond better to ERAs
 Contraception recommended for preg-
nancy avoidance

BMPR2 ¼ gene encoding bone morphogenetic protein receptor type 2; DHEA ¼ dehydroepiandrosterone; ERA ¼ endothelin receptor antagonist; HRQoL ¼
health-related quality of life; PAH ¼ pulmonary arterial hypertension; PVR ¼ pulmonary vascular resistance; RV ¼ right ventricle.

treatments for male patients by physicians may play a
role and should be investigated.
Outcomes in conditions commonly represented in medical
ICUs may vary by gender, but there are few data on long-
term outcomes in women following critical illness. The
FROG-ICU (French and European Outcome Registry in
Intensive Care Units) study did not find significant
differences in short- and long-term mortality between men
and women when adjusting for comorbidities and severity
of illness.50 On examining delirium, the current literature
does not demonstrate gender differences in the
development, duration, or severity of delirium,51 although
there may be a preponderance of hyperactive delirium in
men.52 The BRAIN-ICU (Bringing to Light the Risk
Factors and Incidence of Neuropsychological Dysfunction
in ICU Survivors) study examined disparities in functional
outcome following critical illness on the basis of gender
and concluded that women were more likely to experience
disability, depression, trauma, and short-term
institutionalization following critical illness compared with
men.53 Table 1 summarizes key impacts of sex and gender
on critical illness.
The impact of sex and gender on critical illness has not
been rigorously explored to date. Our current

TABLE 3 ] Sex and Gender Differences in Cystic Fibrosis and Non-Cystic Fibrosis Bronchiectasis
Sex Differences (Females Compared With Males)
 Lower survival in CF
 Increased estradiol associated with earlier
bacterial colonization in CF
 Higher exacerbations in follicular phase of
menstrual cycle (CF and non-CF)
 Subfertility in females, males usually sterile (CF)
Gender Differences (Women Compared With Men)
Symptoms/disease characteristics (CF)
 Lower quality of life, greater emotional impact of diagnosis
 More body image dysmorphism
 Lower BMI
 Earlier bacterial colonization
 More frequent exacerbations
 Higher rates of decline in percent predicted FEV1
Symptoms/disease characteristics (non-CF bronchiectasis)
 More common in women
 Worse lung function
 Present earlier
Management
 Lower treatment adherence in CF
 Treatment efficacy (exacerbations) equal in non-CF bronchiectasis,
but women note less meaningful improvement by questionnaires

CF ¼ cystic fibrosis.

370 CHEST Reviews [ 163#2 CHEST FEBRUARY 2023 ]

understanding of sex and gender in critical illness is
limited. Failure to explore the impact of these factors on
critical illness impedes understanding of the complex
pathophysiology and psychosocial factors that may
contribute to critical illness. Future directions in
research should focus on prospective studies and
enrolling women in clinical trials, exploration of the
impact of sex hormones on the trajectory of critical
illness, and exploration of post-ICU outcomes by sex
and gender.
Reproductive Health in Critical Care
Critical care for the obstetric patient should be
multidisciplinary and include intensivists, obstetricians,
nurses, pediatricians, and pharmacists. The same
principles in caring for any critically ill patient apply,
recognizing that you are caring for two patients and
that optimizing care and survival for the mother is the
primary objective and one that gives the fetus the best
chance at survival. Hypertensive disorders and
obstetric hemorrhage are the most common reasons
for ICU admission during the pregnancy/postpartum
period, with most admissions occurring in the
postpartum period.54 Critical care in pregnancy relies
predominantly on recommendations from
nonpregnant adult critical care with only limited
research available for obstetric critical care
specifically.55
Data guiding maternal oxygenation, ventilation, and
acid-base status are scarce and mostly extrapolated
from animal studies and case series. Current evidence
suggests that pregnant women’s oxygenation be kept
at approximately 95% saturation or above to avoid
harmful effects of hypoxemia to the fetus. However,
fetal oxygenation is complex and depends on many
factors such as cardiac output, BP, pH, and placental
health. In addition, there is usually a gradient of about
10 mm Hg in PaCO2 between the mother and the fetus
to allow CO2 elimination by the mother. Hence, the
application of strategies of permissive hypercapnia is
complicated in pregnant mothers.56 However, as
previously discussed, the health of the mother is
usually prioritized over the health of the fetus. A
detailed discussion of maternal oxygenation and
ventilation is beyond the scope of this article.
Knowledge of physiologic changes and unique
pathology is critical in the treatment of these patients.
We refer readers to a review on critical care in
obstetric patients.57
chestjournal.org
Pulmonary Hypertension
Sex and gender differences are well recognized in
patients with pulmonary hypertension, especially in
those with pulmonary arterial hypertension (PAH).
Although current registries suggest that 65% to 80% of
individuals with PAH are female,58,59 the prevalence and
incidence of death are higher in males.60,61 Females are
more likely to have idiopathic and heritable PAH.62
Autosomal dominant bone morphogenetic protein
receptor type 2 (BMPR2) mutations are the most
common cause of heritable PAH and have incomplete
penetrance.62 Annually, 3.5% of female BMPR2
mutation carriers develop incident PAH compared with
0.99% of male mutation carriers.62 PAH associated with
connective tissue disease has a substantial female
predilection, as with most autoimmune conditions.63
Females are also at higher risk for the development of
portopulmonary hypertension despite cirrhosis being
more common in males.64
Surprisingly, whereas females are more prone to develop
PAH and have evidence of more vascular remodeling,
they typically exhibit a more favorable hemodynamic
profile including lower pulmonary vascular resistance65
and higher right ventricular ejection fraction66 when
compared with males. Females may have a more
adaptive right ventricle, which could explain their
relative survival benefit. Response to treatment is also
sexually dimorphic. Women respond better to
endothelin receptor antagonists and prostacyclin
analogs, whereas men may respond better to
phosphodiesterase type 5 inhibitors.67-69
Given the clinical differences between males and females
with PAH, chromosomal sex, sex hormones, and sex
hormone receptors likely play a complex role in PAH
pathophysiology. The higher female-to-male ratio is more
pronounced in younger patients with PAH, but as age
increases the ratio becomes more balanced, invoking a
change that occurs later in life, possibly related to
hormonal shifts.70 Higher estradiol and lower
dehydroepiandrosterone (DHEA) levels are associated
with increased risk and severity of PAH in both men and
women.71-73 Paradoxically, preclinical models suggest that
both estrogens and DHEA may have beneficial effects on
right ventricular function.74,75 These types of observations
have led to ongoing randomized clinical trials of an
aromatase inhibitor and DHEA in PAH.76,77
Reproductive Health in Pulmonary Hypertension
The female preponderance in PAH raises several
unique concerns related to sexual health, management
371
TABLE 4 ] Sex and Gender Differences in Sarcoidosis
Sex Differences (Females Compared With Males)
 Higher incidence, especially in older age
 Estrogen exposure may delay sarcoidosis onset
 Lack of estrogen leads to enhanced granuloma formation
HRQoL ¼ health-related quality of life.
of contraception, pregnancy, and delivery. PAH
negatively impacts sexual health-related quality of life
and overall quality of life in women.78 Despite
advances in therapy, maternal and fetal morbidity and
mortality remain high and thus pregnancy avoidance
or termination is still recommended.79 The
consequences of pregnancy and delivery can be life-
threatening for individuals with PAH, and therefore it
is of the utmost importance that they have access to
clear reproductive counseling, contraception, and the
option of safe elective termination, should they
become pregnant. Indeed, patients of reproductive age
diagnosed with PAH are advised to consult their
obstetrician regarding safe and effective contraceptive
options. Individuals with the diagnosis who become
pregnant are advised to have a termination of
pregnancy as early as possible to avoid the impact of
the expected physiologic changes of pregnancy on the
cardiovascular system. Individuals who decide to
continue with pregnancy are treated with pulmonary
vasodilator medications.80 Given the cardiopulmonary
TABLE 5 ] Sex and Gender Differences in Restless Legs Syndrome and Insomnia
Sex Differences (Females Compared With Males)
Sex differences in RLS
 RLS twice as common
 Iron deficiency during premenopause and preg-
nancy worsens symptoms
 Fluctuating levels of estrogen, rather than ab-
solute levels, likely contributory
Sex differences in insomnia
 Insomnia 1.5 to two times more common
 REM latency may be increased in late luteal
phase of menstruation
 Arousal threshold may be reduced in late luteal
phase of menstruation and in menopause
REM ¼ rapid eye movement; RLS ¼ restless legs syndrome.
372 CHEST Reviews
Gender Differences (Women Compared With Men)
Symptoms/disease characteristics
 More fatigue, anxiety, and depression
 Worse HRQoL, especially physical domain
 Fewer pulmonary symptoms
 More hospitalizations, lower lung function
 More likely to have skin and ocular involvement
 More multiorgan involvement
Diagnosis
 Diagnosed later in life
 Fewer biopsies performed
complexity of pregnant individuals with PAH, it is
recommended that they be monitored closely by
multidisciplinary teams with expertise in PAH.
Delivery is frequently tightly coordinated and
performed in an intensive care setting or operating
room with invasive monitoring. A summary of sex
and gender impacts on PAH are presented in
Table 2.81
Cystic Fibrosis and Non-Cystic Fibrosis
Bronchiectasis
Cystic fibrosis (CF), previously considered a pediatric
disease, is now a chronic disease of adulthood. Despite
the marked increase in median survival, female* patients
with CF have a lower quality of life compared with
males, noting greater emotional impacts from diagnosis,
lower treatment adherence, body image dysmorphism,
and lower BMI.82 Whereas morbidity and mortality are
driven by lung disease (ie, development of bronchiectasis
and infectious/inflammatory sequelae), the life
Gender Differences (Women Compared With Men)
Symptoms/disease characteristics in RLS
 More likely to have multiple sleep symptoms (involuntary move-
ments when awake, sleep onset difficulties, and frequent awak-
enings at night) with RLS
 RLS symptoms more severe
 Predominantly sensory symptoms in RLS
 More likely to present with hypothyroidism
Symptoms/disease characteristics in insomnia
 Insomnia can be associated with anxiety and depression
 Shorter sleep times may increase gestational hypertension in
pregnancy
[ 163#2 CHEST FEBRUARY 2023 ]
expectancy of patients with CF is impacted by many
factors, including CFTR genotype, nonpulmonary CF
manifestations, socioeconomic status, age, sex, and
gender.
Sex- and gender-based CF health disparities are well
established, and often referred to as the “CF gender*
gap,” with women* having worse outcomes83,84 and
lower survival as reported in CF registry data from
Canada, the United States, and the United
Kingdom.83,85,86 Historical diagnostic delays in females
have been attributed to possible unconscious gender
bias,87 which modern-day universal newborn screening
should mitigate. Still, females with CF have earlier
bacterial colonization and more frequent pulmonary
exacerbations,88 and epidemiologic studies show worse
rates of decline in the percent predicted FEV1 (ppFEV1).
Several studies implicate the role of estrogens and
estradiol in CF in late adolescence and early adulthood,
when the most rapid FEV1 decline occurs.89 Increased
estradiol levels have been associated with earlier
colonization of mucoid Pseudomonas aeruginosa and
increased CF exacerbations during the follicular phase
(when estradiol peaks).90 A recent prospective study
showed increased inflammatory marker levels during
peak estradiol vs improved ppFEV1 and respiratory
symptoms in patients taking combined estrogen-
progestin oral contraceptives, suggesting estrogen may
be an immunomodulator in CF lung disease.91 Although
highly effective cystic fibrosis transmembrane
conductance regulator (CFTR) modulators have
markedly reduced CF lung function decline, female sex
has been associated with greater reductions in sweat
chloride in patients taking CFTR modulators but no
apparent difference in ppFEV1 changes.92 Further
studies are needed to identify whether the sex and
gender gap in CF mortality persists in the era of CFTR
modulators.
Unlike CF bronchiectasis, non-CF bronchiectasis is a
female-predominant disorder in most countries
worldwide.93 Females* present earlier with symptoms of
non-CF bronchiectasis, and have worse lung disease
with similar contributory factors as in CF.94 Non-CF
bronchiectasis related to nontuberculous mycobacterial
infection occurs largely in postmenopausal women and
those with lower BMI, implicating factors of age, sex
hormones, and nutritional status.95 Treatment of non-
CF bronchiectasis yields similar efficacy in male* and
female patients in terms of reduced frequency of
chestjournal.org
exacerbations, yet women report lower clinically
meaningful improvement when assessed by
questionnaires.96 A retrospective analysis of 28 years of
lung transplantation data found more women* with
non-CF bronchiectasis who were listed for
transplantation; however, posttransplant survival did
not differ significantly from age- and sex-matched
cohorts with other lung diseases.97 The impact of sex
and gender on CF and non-CF bronchiectasis is
summarized in Table 3. The overall sex differences in
non-CF bronchiectasis health have been attributed to
multifactorial causes, as with CF, including sex hormone
effects on inflammation, host defense responses, and
airway microbiota, warranting further studies in both CF
and non-CF bronchiectasis to improve sex-based
discrepancies in health outcomes.
Reproductive Health in Cystic Fibrosis and
Non-Cystic Fibrosis Bronchiectasis
Subfertility in women with CF is significantly higher
than that of the general population and is presumed to
be multifactorial, related to hyperviscosity of cervical
mucus, and effects of chronic illness.98 Higher ppFEV1
pre-conception is associated with improved pregnancy
outcome and lung function recovery after pregnancy,
although no significant differences were noted in
overall maternal outcome.99 Notably, there is evidence
of increased spontaneous pregnancies, especially in the
era of CFTR modulators, between 2015 and 2020.100
Studies are ongoing101 to evaluate the effects of CFTR
during and 2 years after pregnancy. Pregnancy and
parenthood each pose complex challenges to patients
with CF, including family planning and genetic
counseling in the pre-pregnancy phase; managing
pregnancy-related physiologic effects; treating
respiratory system and other, extrapulmonary effects
impacting CF-related diabetes, CF-related liver disease,
and weight-related concerns with lactation; and
managing psychosocial demands.102 Furthermore, little
is known regarding the effects of CFTR modulators on
breastfed infants, and are currently catagorized as
“probably safe” based on expert opinions.103 The full
impact of CFTR modulators requires further study on
maternal/child health in CF.
Sarcoidosis
Sarcoidosis is characterized by noncaseating epithelioid
granulomas that may affect any organ system.
Understanding the effects of sex and gender on
373
TABLE 6 ] Sex and Gender Differences in Smoking Cessation
Sex Differences (Females Compared With Males)
 CYP2A6 enzyme is induced by estrogen (leading to quicker
metabolization of nicotine)
 b2*-nAChR availability higher in male smoker brains
 More vulnerable to relapse during the follicular (low pro-
gesterone) phase of the menstrual cycle
b2*-nAChR ¼ b2* subunit-containing nicotinic acetylcholine receptor.
sarcoidosis is complicated by the variability in
presentation and challenges in making a diagnosis.
Data suggest the age at diagnosis may be
increasing,104,105 with a higher percentage of women
aged more than 50 years receiving a diagnosis of
sarcoidosis. Case-control studies have shown that
symptomatic men aged less than 50 years were
diagnosed approximately 2 years earlier than
women.106 The exact reason for the difference in age
at diagnosis is unknown but is likely due to a
combination of sex-specific hormone factors and
gender-specific environmental exposures. As an
example, there may be genetic differences between the
sexes that lead to disease presentation earlier in life.
There may also be delay in access to health care and
delay in recognizing symptoms that may contribute to
a later diagnosis.
Endogenous hormones, especially estrogens, may delay
sarcoidosis onset and reduce its severity in women
through resetting the imbalanced helper T type 1/helper
T type 2 immune response.107 Estrogen exposure
variables (older age at menopause, age at first pregnancy,
and age at last pregnancy) indicated a protective effect of
estrogen on sarcoidosis risk,108,109 whereas older age at
menarche and first pregnancy and ever use of hormone
replacement therapy were likely to be associated with
increased risk.110
The clinical manifestations associated with sarcoidosis
are quite varied and include both constitutional and
organ-specific presentations. Women have significantly
fewer pulmonary symptoms (36%) compared with
374 CHEST Reviews
Gender Differences (Women Compared With Men)
Exposure
 Targeted advertisements toward women in the 1960s
 Lower use of smoking cessation services
Success of smoking cessation
 Lower rates of overall success with smoking cessation
 More trouble maintaining long-term abstinence
 Higher rates of relapse
 Depression and weight gain are barriers to smoking
cessation
Pharmacotherapy
 Nonnicotine replacement methods should be
considered
 Varenicline may have higher efficacy in women as
compared with other pharmacotherapy
men (51%).111 In a multicenter, prospective study of
1,445 patients, women were more likely to have eye or
skin involvement, whereas men were more likely to
have cardiac involvement.111 Males* were also more
likely to develop hypercalcemia.112,113 Females* with
sarcoidosis were noted to have more multiorgan
involvement as compared with males (OR, 1.238;
95% CI, 1.083-1.415).111 Manifestations of Löfgren’s
syndrome differ between genders: erythema nodosum
is found more commonly in women, whereas a
marked periarticular inflammation of the ankles
without erythema nodosum is seen primarily in
men.114
Females* with sarcoidosis have been reported to have
higher rates of hospitalizations115 and lower lung
function (lower FVC % predicted).116 Mortality rates for
sarcoidosis have increased over time in the United
States, with higher mortality reported in females with
sarcoidosis compared with males.117,118
Gender differences in complaints of fatigue,119 anxiety,
or depression120 are reported in patients with
sarcoidosis. Patients with sarcoidosis often report a
diminished health-related quality of life,121-123 with a
range of symptoms such as emotional distress, pain, and
physical limitations. Women with sarcoidosis seem to
have worse health-related quality of life as compared
with men, particularly regarding pain, sleep, positive
feelings, self-esteem, bodily image, mobility, and daily
life activities.123 A prospective, cross-sectional survey
found that women with sarcoidosis showed a greater
degree of functional impairment than men, particularly
[ 163#2 CHEST FEBRUARY 2023 ]
 General

• Include more women and gender diverse patients in clinical trials

• Stratify study results by sex and gender
• Include pregnant patients in clinical trials

Pulmonary Hypertension

• Understand the biological mechanisms of sex-based differences in Pulmonary vascular resistance and RV remodeling
• Understand the effect of therapeutic agents by sex and gender
• Understand the utility of sex specific omic markers to determine risk for Pulmonary Hypertension and therapeutics

Cystic Fibrosis and Non CF-bronchiectasis

• Understand the biologic mechanisms in sex-based differences in bacterial colonization

• Understand the sex-based differences for lower survival in females with CF and non-CF bronchiectasis
• Understand the sex and gender based differences with available pharmacotherapy and medication use patterns
• Understand the gender-based differences in functional outcomes

Sarcoidosis

• Understand the mechanisms of sex and gender based differences in frequency of sarcoidosis
• Understand the sex-based mechanisms for poorer outcomes in sarcoidosis in men
• Understand sex-based differences in therapeutics for sarcoidosis
• Understand the sex-based pathways leading to fatigue in sarcoidosis

RLS and Insomnia

• Understand the biologic mechanisms that increase RLS rates in menopause and during pregnancy
• Understand the sex-based mechanisms leading to cardiovascular disease in patients with RLS
• Understand the gender-based differences to different pharmacotherapy options
• Understand the mechanism of sex-based differences in sleep architecture

Critical Illness

• Understand the biologic mechanisms that predispose males to sepsis and septic shock
• Understand gender-based differences in symptoms and presentation of critical illness
• Understand the differences in advance care planning between genders
• Understand the sex-based and gender-based mechanisms leading to poorer outcomes in females after critical illness

Smoking Cessation

• Expand our understanding of the biologic mechanisms of sex based differences in smoking cessation
• Understand gender-based barriers to smoking cessation
• Understand sex-based mechanisms of optimal timing of smoking cessation during menstrual cycle
• Understand sex and gender based differences in pharmacotherapy available for smoking cessation

Figure 2 – Recommendations for future research, based on gaps identified in the literature. CF ¼ cystic fibrosis; RLS ¼ restless legs syndrome; RV ¼
right ventricle.

regarding physical health.124 Emotional quality-of-life Methotrexate is commonly used as a steroid-sparing

data have noted variability in men and women.125,126
Table 4 highlights some of the sex and gender
differences in sarcoidosis.127 These factors may
contribute to reports of higher rates of work loss among
women with sarcoidosis as compared with men.128
Studies are needed to evaluate whether the differences
between male and female patients with sarcoidosis are
caused by subject selection bias or lifestyle differences or
potentially have a genetic, hormonal, or biological basis.
Reproductive Health in Sarcoidosis
There are currently no data regarding differences in
management of sarcoidosis based on gender or sex.
agent in sarcoidosis and is an abortifacient; this requires
that pregnancy status be documented along with
provision of contraception counseling. Health advocacy
is required to ensure adequate and timely access to
methotrexate, especially in young females, in whom the
disease impact can be significant, and access may be
limited in some states because of its use as an
abortifacient. Limited data exist regarding sarcoidosis
and pregnancy. One study showed that sarcoidosis
increased the risk of preeclampsia/eclampsia, preterm
birth, cesarean delivery, and some birth defects during
pregnancy.129 It is likely prudent to attempt disease
control before attempting conception.

chestjournal.org 375
Restless Legs Syndrome
Restless legs syndrome (RLS) is described as an
uncomfortable sensation in the legs, worse with
inactivity and partially or totally improved with
movement, occurring most frequently at nighttime.
RLS is twice as prevalent in female* compared with
male patients, with pregnancy and menopause being
associated with higher risk of symptoms.130 This may
be due to association of iron and estrogens with
dopamine and glutamate transmission, the two
neurotransmitters thought to be involved in the
pathophysiology of RLS. The production and
regulation of dopamine require iron as an enzymatic
cofactor.
Reproductive Health in RLS
Premenopausal females are at risk of low iron and ferritin
due to menstruation, and in pregnancy there is a risk of
relative iron deficiency. Interestingly, fluctuating levels of
estrogen—higher in pregnancy, especially in the third
trimester, and lower in menopause—appear to increase
risk of symptoms, indicating that it is the change in
estrogen level rather than the total amount that puts
female patients at risk of RLS.130,131 In the postpartum
state, although many patients’ symptoms resolve, one
study found that up to 34.8% of patients had continued
symptoms132 and others have noted that increased parity
is associated with higher risk of developing RLS later in
life,133 especially if RLS was experienced during
pregnancy.134 There is no difference in the incidence of
RLS in postmenopausal patients taking hormone
replacement therapy.133,135 In transgender patients, a
single study showed a trend toward a higher prevalence of
RLS in those treated with estrogen compared with those
treated with testosterone.136 Thus, estrogens appear to
have a prominent role in RLS, but it is clear that further
studies are needed to investigate sex hormones as a
potential therapeutic target.
Insomnia
Insomnia is one of the most common sleep disorders
and is defined as difficulty initiating and/or
maintaining sleep with associated daytime dysfunction.
It is 1.5 to two times as prevalent in female* patients
than in males, can be associated with depression and
anxiety (more prevalent in females), and may reflect
differences and changes in sex hormone levels with
age. This difference in insomnia prevalence may in
part be related to an increased likelihood of women to
report symptoms and seek care.
376 CHEST Reviews
During menstruation, estrogen rises over the follicular
phase. After ovulation, during the luteal phase, both
estrogen and progesterone rise together for 7 days and
then drop before menses.137 As estrogen is involved with
norepinephrine turnover, it promotes rapid eye
movement (REM) sleep, whereas progesterone is
thought to have sedative effects and decreases arousals.
During the late luteal phase, as these hormones decrease,
REM latency and time spent in REM sleep may be
reduced and the arousal threshold, and thus overnight
awakenings, may be increased. In menopause, there is a
significant decrease in these hormones accompanied by
vasomotor symptoms. These symptoms lead to
increased arousals, which can lead to conditioned
overnight awakenings and contribute to insomnia even
after symptoms have resolved. In addition, it is thought
that the hypothalamic-pituitary-adrenal axis may play a
role with sex differences in cortisol levels potentially
contributing to hyperarousal.137
Reproductive Health in Insomnia
In pregnancy, increased snoring, risk of restless legs
syndrome, nocturia, and overall discomfort lead to
frequent overnight awakenings, especially in the third
trimester. Shorter sleep times during pregnancy have
been associated with higher rates of gestational
hypertension, longer labor times, and need for cesarean
delivery.131 Because of this, it is imperative that we
evaluate pregnant patients for treatable sleep disorders
such as OSA and restless leg syndrome in addition to
insomnia. If treatment for insomnia is indicated,
nonpharmacologic therapy such as sleep hygiene and
cognitive behavioral therapy for insomnia should be
considered as first-line treatments, as in the
nonpregnant population. Lack of safety data limits
treatment choices; however, the use of some medications
such as antihistamines, zolpidem,138,139 or zopiclone
may be justified with counseling regarding potential risk
and appropriate monitoring for neonatal risk of
withdrawal or flaccidity.140 Hormone therapy to treat
insomnia in postmenopausal patients has been
investigated over the years. A recent meta-analysis found
that combined estrogen and progesterone therapy can
improve sleep quality.141 Table 5 summarizes key sex
and gender effects in RLS and insomnia.142,143
Tobacco Use and Treatment of Nicotine Use
Disorder
Cigarette smoking is a leading cause of preventable death
and disease in the United States.144 Tobacco control efforts
[ 163#2 CHEST FEBRUARY 2023 ]
have had remarkable success in the last half-century,
leading to a reduction in the prevalence of smoking.145
Despite this, the risk of mortality from smoking-related
disease is increasing, especially for women.144 Smoking
cessation leads to significant immediate and long-term
reductions in smoking-related disease146 and is key to
addressing smoking-related disease.
Studies have reported observed differences between
men and women in the success with which individuals
achieve smoking cessation in various contexts.147
Compared with men, women report lower use of
smoking cessation services.148 Many studies report
that women have a lower likelihood of achieving
abstinence in clinical trials.149 However, most tobacco
cessation clinical trials are not designed to assess sex
and gender differences, and post-hoc comparisons
may be biased.150 The data regarding the role of sex
and gender in smoking cessation are mixed. Some
studies have found that women have more difficulty
maintaining long-term abstinence than do men,151
whereas others suggest there may not be any
difference.152 Few studies address differences in sex
and gender differences in relapse rate, underscoring
the need for further studies to address barriers to
successful smoking cessation in women.
The exact reason for lower smoking cessation rates for
women is unclear. Women may be less sensitive to the
chemical effects of nicotine and may smoke for other
reasons.147 As a result, women may face different
barriers to smoking cessation, including a greater
likelihood of depression, weight control concerns, and
nonpharmacologic motives for smoking.153,154 Sex-
related factors, such as genetics and sex hormones, may
also play a role. Enzyme functions determine the
nicotine metabolization rate. Estrogen may modify this
function and lead females to metabolize nicotine more
rapidly.155 Fast metabolizers may find it more difficult to
quit and be less responsive to nicotine replacement
therapies.156,157 Pregnancy is also associated with faster
nicotine metabolism, which impacts the dosing of
nicotine replacement and cessation rates.158 Genetic
studies evaluating heritability of smoking cessation
likelihoods have focused primarily on autosomes and
have excluded X and Y chromosomes, thereby leading to
a gap in our understanding of sex effects in smoking
cessation.
Tobacco smoking-induced upregulation of nicotinic
acetylcholine receptors containing the b2* subunit (b2*-
nAChRs) in the brain appears to be different in males
chestjournal.org
and females, with female sex hormones likely playing a
role. b2*-nAChR availability in the striatum, cortex, and
cerebellum was significantly higher in male smokers but
not female smokers, when compared with their same-sex
nonsmoking counterparts.159 Female sex hormones
impact the response to smoking as well as cessation.
Although vulnerability to relapse may be higher in the
follicular phase,160 and progesterone may have a
protective effect against smoking,161 the influence of the
menstrual cycle on smoking cessation requires further
study to determine the best window for cessation among
premenopausal women and to identify potential
therapeutic targets.
There is evidence for the presence of interaction between
gender and pharmaceutical agents used for smoking
cessation. Nicotine replacement therapy has been found
to be less effective for smoking cessation in women.162
In contrast, varenicline appears to be more effective in
women.163,164 The American Thoracic Society clinical
practice guidelines on pharmacologic treatment in
tobacco-dependent adults recommend using varenicline
over nicotine replacement therapies for all patients with
no specific mention of sex or gender differences.165
Transgender and gender-expansive (TGE) individuals,
who have a gender identity, behavior, or mode of self-
expression that is different from their sex assigned at
birth, are twice as likely to smoke cigarettes than
cisgender individuals.166 Research suggests that given
the appropriate resources and opportunities, TGE adult
smokers are just as likely as cisgender smokers to want
to quit.167-169 There is a critical gap in research on
effective and culturally sensitive approaches to reduce
smoking prevalence among TGE adults.
Table 6 summarizes some of the key aspects of sex and
gender interaction on smoking cessation.
Conclusions
Sex and reproductive differences and transitions impact
various aspects of lung/sleep biology and pathobiology.
Better awareness within the health care community of the
increasing burden of respiratory diseases in women is
important to improve diagnosis and treatment.
Education efforts are needed for physicians to understand
the differences in presentation and nuances in
management of diseases by sex and gender. Interaction
with female patients should take into account that their
symptoms may not conform to traditionally accepted sex-
based clinical presentations. Gender- and sex-specific
management options, if available, should also be
377
considered. Challenges exist for female patients at all
levels of health care interaction, and as physicians we
need to acknowledge unconscious biases and work to
eliminate them. Empowering patients to have frank
discussions with their health care team when they
perceive bias is another step to help promote equity.
Differences between men and women underscore the
importance of prompt recognition of possible cases,
suitable diagnostic procedures, accurate assessment of
the severity of the disease, and personalized treatment.
Recommended areas of research based on gaps
identified in the literature are summarized in Figure 2.
Further research should clearly report biological sex
and gender in all aspects of investigation. In addition
to the mandate of the inclusion of sex as a biological
variable by the National Institutes of Health, readily
available resources are needed to guide investigators
on the incorporation of sex and gender issues in
research endeavors. There should be a concerted effort
to include pregnant women in clinical trials. Journals
should screen submissions and should consider
excluding manuscripts that fail to document sex in
methodology and/or exclude or under-enroll specific
sex/gender participants in appropriate clinical trials.
Implementation of consistent reporting and editorial
guidelines related to sex and gender will lead to more
equitable approaches in research and impact advances
in therapies.
Funding/Support
G. B. is funded by the National Institutes of Health
(NIH) [HL-130702, HL-130702 4S, and HL-157288];
M. K. G. is funded by the NIH [NIA-AG060338-NIH-
PASC-ROA-OTA-15B]; K. C.-F. is funded by the NIH
[T32 HL-134625].
Financial/Nonfinancial Disclosures
None declared.
Acknowledgments
Author contributions: All of the authors contributed to the conceptual
design of the review, data analysis, and manuscript writing. All of the
authors approved the manuscript version.
Role of sponsors: The sponsor had no role in the design of the study,
the collection and analysis of the data, or the preparation of the
manuscript.
References
1. Sodhi A, Pisani M, Glassberg MK, Bourjeily G, D’Ambrosio C. Sex
and gender in lung disease and sleep disorders: a state-of-the-art
review. Chest. 2022;162(3):647-658.
378 CHEST Reviews
2. Doyal L. Sex and gender: the challenges for epidemiologists. Int J
Health Serv. 2003;33(3):569-579.
3. Clifton VL, Engel P, Smith R, Gibson P, Brinsmead M, Giles WB.
Maternal and neonatal outcomes of pregnancies complicated by
asthma in an Australian population. Aust N Z J Obstet Gynaecol.
2009;49(6):619-626.
4. Kwon HL, Triche EW, Belanger K, Bracken MB. The epidemiology
of asthma during pregnancy: prevalence, diagnosis, and symptoms.
Immunol Allergy Clin North Am. 2006;26(1):29-62.
5. Mendola P, Laughon SK, Männistö TI, et al. Obstetric
complications among US women with asthma. Am J Obstet
Gynecol. 2013;208(2). 127.e1-8.
6. Bin YS, Cistulli PA, Ford JB. Population-based study of sleep apnea
in pregnancy and maternal and infant outcomes. J Clin Sleep Med.
2016;12(6):871-877.
7. Bourjeily G, Danilack VA, Bublitz MH, et al. Obstructive sleep
apnea in pregnancy is associated with adverse maternal outcomes: a
national cohort. Sleep Med. 2017;38:50-57.
8. Bublitz MH, Monteiro JF, Caraganis A, et al. Obstructive sleep
apnea in gestational diabetes: a pilot study of the role of the
hypothalamic-pituitary-adrenal axis. J Clin Sleep Med. 2018;14(1):
87-93.
9. Fung AM, Wilson DL, Lappas M, et al. Effects of maternal
obstructive sleep apnoea on fetal growth: a prospective cohort
study. PLoS One. 2013;8(7):e68057.
10. Reutrakul S, Zaidi N, Wroblewski K, et al. Interactions between
pregnancy, obstructive sleep apnea, and gestational diabetes
mellitus. J Clin Endocrinol Metab. 2013;98(10):4195-4202.
11. Centers for Disease Control and Prevention, Division of
Reproductive Health, National Center for Chronic Disease
Prevention and Health Promotion. Pregnancy Mortality
Surveillance System. 2020. Accessed October 6, 2022. https://www.
cdc.gov/reproductivehealth/maternal-mortality/pregnancy-
mortality-surveillance-system.htm
12. Rojas-Suarez J, Bello-Munoz C, Paternina-Caicedo A, Bourjeily G,
Carino G, Duenas C. Maternal mortality secondary to acute
respiratory failure in Colombia: a population-based analysis. Lung.
2015;193(2):231-237.
13. Doyle TJ, Goodin K, Hamilton JJ. Maternal and neonatal outcomes
among pregnant women with 2009 pandemic influenza A(H1N1)
illness in Florida, 2009-2010: a population-based cohort study.
PLoS One. 2013;8(10):e79040.
14. Sliwa K, van Hagen IM, Budts W, et al. Pulmonary hypertension
and pregnancy outcomes: data from the Registry of Pregnancy and
Cardiac Disease (ROPAC) of the European Society of Cardiology.
Eur J Heart Fail. 2016;18(9):1119-1128.
15. Bublitz MH, Bourjeily G. Sleep disordered breathing in pregnancy
and adverse maternal outcomes—a true story? US Respir Pulm Dis.
2017;2(1):19-20.
16. Bourjeily G, Danilack VA, Bublitz MH, Muri J, Rosene-Montella K,
Lipkind H. Maternal obstructive sleep apnea and neonatal birth
outcomes in a population based sample. Sleep Med. 2020;66:
233-240.
17. Izci B, Vennelle M, Liston WA, Dundas KC, Calder AA,
Douglas NJ. Sleep-disordered breathing and upper airway size in
pregnancy and post-partum. Eur Respir J. 2006;27(2):321-327.
18. Pernoll ML, Metcalfe J, Kovach PA, Wachtel R, Dunham MJ.
Ventilation during rest and exercise in pregnancy and postpartum.
Respir Physiol. 1975;25(3):295-310.
19. Templeton A, Kelman GR. Maternal blood-gases, (PaO2—PaO2),
physiological shunt and Vd/Vt in normal pregnancy. Br J Anaesth.
1976;48(10):1001-1004.
20. Hegewald MJ, Crapo RO. Respiratory physiology in pregnancy.
Clin Chest Med. 2011;32(1):1-13.
21. Nassikas N, Malhame I, Miller M, Bourjeily G. Pulmonary
considerations for pregnant women. Clin Chest Med. 2021;42(3):
483-496.
[ 163#2 CHEST FEBRUARY 2023 ]
 22. Brent R. The pulmonologist’s role in caring for pregnant women
with regard to the reproductive risks of diagnostic radiological
studies or radiation therapy. Clin Chest Med. 2011;32(1):33-42.
23. Bourjeily G, Chalhoub M, Phornphutkul C, Alleyne TC,
Woodfield CA, Chen KK. Neonatal thyroid function: effect of a
single exposure to iodinated contrast medium in utero. Radiology.
2010;256(3):744-750.
24. Shields KE, Lyerly AD. Exclusion of pregnant women from
industry-sponsored clinical trials. Obstet Gynecol. 2013;122(5):
1077-1081.
25. American College of Obstetricians and Gynecologists. ACOG
Committee Opinion No. 762: Prepregnancy Counseling. Obstet
Gynecol. 2019;133(1):e78-e89.
26. Suwanrath C, Thongphanang P, Pinjaroen S, Suwanugsorn S.
Validation of modified World Health Organization classification
for pregnant women with heart disease in a tertiary care center in
southern Thailand. Int J Womens Health. 2018;10:47-53.
27. Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL.
Considering how biological sex impacts immune responses and
COVID-19 outcomes. Nat Rev Immunol. 2020;20(7):442-447.
28. van Eijk LT, Dorresteijn MJ, Smits P, van der Hoeven JG,
Netea MG, Pickkers P. Gender differences in the innate immune
response and vascular reactivity following the administration of
endotoxin to human volunteers. Crit Care Med. 2007;35(6):
1464-1469.
29. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender
and sex hormones on immune responses following shock. Shock.
2000;14(2):81-90.
30. Campanelli F, Landoni G, Cabrini L, Zangrillo A. Gender
differences in septic intensive care unit patients. Minerva
Anestesiol. 2018;84(4):504-508.
31. Azkárate I, Choperena G, Salas E, et al. Epidemiology and
prognostic factors in severe sepsis/septic shock: evolution over six
years. Med Intensiva. 2016;40(1):18-25.
32. Nachtigall I, Tafelski S, Rothbart A, et al. Gender-related outcome
difference is related to course of sepsis on mixed ICUs: a
prospective, observational clinical study. Crit Care. 2011;15(3):
R151.
33. Xu J, Tong L, Yao J, et al. Association of sex with clinical outcome
in critically ill sepsis patients: a retrospective analysis of the large
clinical database MIMIC-III. Shock. 2019;52(2):146-151.
34. Adrie C, Azoulay E, Francais A, et al. Influence of gender on the
outcome of severe sepsis: a reappraisal. Chest. 2007;132(6):
1786-1793.
35. Pavon A, Binquet C, Kara F, et al. Profile of the risk of death after
septic shock in the present era: an epidemiologic study. Crit Care
Med. 2013;41(11):2600-2609.
36. Goldstein RH, Walensky RP. Where were the women? Gender
parity in clinical trials. N Engl J Med. 2019;381(26):2491-2493.
37. Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-
based care for early septic shock. N Engl J Med. 2014;370(18):
1683-1693.
38. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-
directed resuscitation for septic shock. N Engl J Med. 2015;372(14):
1301-1311.
39. ARISE Investigators; ANZICS Clinical Trials Group; Peake SL,
Delaney A, Bailey M, et al. Goal-directed resuscitation for patients
with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
40. Acute Respiratory Distress Syndrome Network; Brower RG,
Matthay MA, Morris A, et al. Ventilation with lower tidal volumes
as compared with traditional tidal volumes for acute lung injury
and the acute respiratory distress syndrome. N Engl J Med.
2000;342(18):1301-1308.
41. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe
acute respiratory distress syndrome. N Engl J Med. 2013;368(23):
2159-2168.
42. National Heart, Lung, and Blood Institute PETAL Clinical Trials
Network; Moss M, Huang DT, Brower RG, et al. Early
chestjournal.org
neuromuscular blockade in the acute respiratory distress syndrome.
N Engl J Med. 2019;380(21):1997-2008.
43. Blecha S, Zeman F, Specht S, et al. Invasiveness of treatment is
gender dependent in intensive care: results from a retrospective
analysis of 26,711 cases. Anesth Analg. 2021;132(6):1677-1683.
44. Valentin A, Jordan B, Lang T, Hiesmayr M, Metnitz PG. Gender-
related differences in intensive care: a multiple-center cohort study
of therapeutic interventions and outcome in critically ill patients.
Crit Care Med. 2003;31(7):1901-1907.
45. Modra LJ, Higgins AM, Abeygunawardana VS, Vithanage RN,
Bailey MJ, Bellomo R. Sex differences in treatment of adult
intensive care patients: a systematic review and meta-analysis. Crit
Care Med. 2022;50(6):913-923.
46. McNicholas BA, Madotto F, Pham T, et al; LUNG SAFE
Investigators and the ESICM Trials Group. Demographics,
management and outcome of females and males with acute
respiratory distress syndrome in the LUNG SAFE prospective
cohort study. Eur Respir J. 2019;54(4):1900609.
47. Sharma RK, Prigerson HG, Penedo FJ, Maciejewski PK. Male-
female patient differences in the association between end-of-life
discussions and receipt of intensive care near death. Cancer.
2015;121(16):2814-2820.
48. Purcell LN, Tignanelli CJ, Maine R, Charles A. Predictors of change
in code status from time of admission to death in critically ill
surgical patients. Am Surg. 2020;86(3):237-244.
49. Cooney TM, Shapiro A, Tate CE. End-of-life care planning: the
importance of older adults’ marital status and gender. J Palliat Med.
2019;22(8):902-907.
50. Hollinger A, Gayat E, Féliot E, et al; FROG ICU study investigators.
Gender and survival of critically ill patients: results from the
FROG-ICU study. Ann Intensive Care. 2019;9(1):43.
51. Mehta S, Cook D, Devlin JW, et al. Prevalence, risk factors, and
outcomes of delirium in mechanically ventilated adults. Crit Care
Med. 2015;43(3):557-566.
52. Karamchandani K, Schoaps RS, Printz J, Kowaleski JM, Carr ZJ.
Gender differences in the use of atypical antipsychotic medications
for ICU delirium. Crit Care. 2018;22(1):220.
53. Scheunemann LP, Leland NE, Perera S, et al. Sex disparities and
functional outcomes after a critical illness. Am J Respir Crit Care
Med. 2020;201(7):869-872.
54. Vasquez DN, Das Neves AV, Vidal L, et al. Characteristics,
outcomes, and predictability of critically ill obstetric patients: a
multicenter prospective cohort study. Crit Care Med. 2015;43(9):
1887-1897.
55. American College of Obstetricians and Gynecologists. ACOG
Practice Bulletin No. 211: Critical Care in Pregnancy. Obstet
Gynecol. 2019;133(5):e303-e319.
56. Lapinsky SE, Rojas-Suarez JA, Crozier TM, et al. Mechanical
ventilation in critically-ill pregnant women: a case series. Int J
Obstet Anesth. 2015;24(4):323-328.
57. Gaffney A. Critical care in pregnancy—is it different? Semin
Perinatol. 2014;38(6):329-340.
58. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial
hypertension: baseline characteristics from the REVEAL Registry.
Chest. 2010;137(2):376-387.
59. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial
hypertension in France: results from a national registry. Am J
Respir Crit Care Med. 2006;173(9):1023-1030.
60. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting
survival in pulmonary arterial hypertension: insights from the
Registry to Evaluate Early and Long-Term Pulmonary Arterial
Hypertension Disease Management (REVEAL). Circulation.
2010;122(2):164-172.
61. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with
idiopathic, familial, and anorexigen-associated pulmonary arterial
hypertension in the modern management era. Circulation.
2010;122(2):156-163.
379
62. Montani D, Girerd B, Jaïs X, et al. Screening for pulmonary arterial
hypertension in adults carrying a BMPR2 mutation. Eur Respir J.
2021;58(1):2004229.
63. Chung L, Liu J, Parsons L, et al. Characterization of connective
tissue disease-associated pulmonary arterial hypertension from
REVEAL: identifying systemic sclerosis as a unique phenotype.
Chest. 2010;138(6):1383-1394.
64. Kawut SM, Krowka MJ, Trotter JF, et al. Clinical risk factors for
portopulmonary hypertension. Hepatology. 2008;48(1):196-203.
65. Ventetuolo CE, Praestgaard A, Palevsky HI, Klinger JR,
Halpern SD, Kawut SM. Sex and haemodynamics in pulmonary
arterial hypertension. Eur Respir J. 2014;43(2):523-530.
66. Kawut SM, Al-Naamani N, Agerstrand C, et al. Determinants of
right ventricular ejection fraction in pulmonary arterial
hypertension. Chest. 2009;135(3):752-759.
67. Gabler NB, French B, Strom BL, et al. Race and sex differences in
response to endothelin receptor antagonists for pulmonary arterial
hypertension. Chest. 2012;141(1):20-26.
68. Mathai SC, Hassoun PM, Puhan MA, Zhou Y, Wise RA. Sex
differences in response to tadalafil in pulmonary arterial
hypertension. Chest. 2015;147(1):188-197.
69. Frantz RP, Schilz RJ, Chakinala MM, et al. Hospitalization and
survival in patients using epoprostenol for injection in the
PROSPECT observational study. Chest. 2015;147(2):484-494.
70. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients
diagnosed with idiopathic pulmonary arterial hypertension: results
from the COMPERA registry. Int J Cardiol. 2013;168(2):871-880.
71. Ventetuolo CE, Baird GL, Barr RG, et al. Higher estradiol and
lower dehydroepiandrosterone-sulfate levels are associated with
pulmonary arterial hypertension in men. Am J Respir Crit Care
Med. 2016;193(10):1168-1175.
72. Baird GL, Archer-Chicko C, Barr RG, et al. Lower DHEA-S levels
predict disease and worse outcomes in post-menopausal women
with idiopathic, connective tissue disease- and congenital heart
disease-associated pulmonary arterial hypertension. Eur Respir J.
2018;51(6):1800467.
73. Baird GL, Walsh T, Aliotta J, et al. Insights from the menstrual
cycle in pulmonary arterial hypertension. Ann Am Thorac Soc.
2021;18(2):218-228.
74. Alzoubi A, Toba M, Abe K, et al. Dehydroepiandrosterone restores
right ventricular structure and function in rats with severe
pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol.
2013;304(12):H1708-H1718.
75. Frump AL, Goss KN, Vayl A, et al. Estradiol improves right
ventricular function in rats with severe angioproliferative
pulmonary hypertension: effects of endogenous and exogenous sex
hormones. Am J Physiol Lung Cell Mol Physiol. 2015;308(9):
L873-L890.
76. National Institutes of Health Clinical Center. Pulmonary
hypertension and anastrozole trial (PHANTOM). NCT03229499.
ClinicalTrials.gov. National Institutes of Health; 2017. Updated
December 6, 2021. https://clinicaltrials.gov/ct2/show/NCT032294
99
77. National Institutes of Health Clinical Center. Effects of DHEA in
pulmonary hypertension (EDIPHY). NCT03648385. ClinicalTrials.
gov. National Institutes of Health; 2018. Updated March 29, 2022,
https://clinicaltrials.gov/ct2/show/NCT03648385
78. Banerjee D, Vargas SE, Guthrie KM, et al. Sexual health and health-
related quality of life among women with pulmonary arterial
hypertension. Pulm Circ. 2018;8(4):2045894018788277.
79. Banerjee D, Ventetuolo CE. Pulmonary hypertension in pregnancy.
Semin Respir Crit Care Med. 2017;38(2):148-159.
80. Olsson KM, Channick R. Pregnancy in pulmonary arterial
hypertension. Eur Respir Rev. 2016;25(142):431-437.
81. Lakshmanan S, Jankowich M, Wu WC, Blackshear C, Abbasi S,
Choudhary G. Gender differences in risk factors associated with
pulmonary artery systolic pressure, heart failure, and mortality in
blacks: Jackson Heart Study. J Am Heart Assoc. 2020;9(1):e013034.
380 CHEST Reviews
82. McGarry ME, Williams WA II, McColley SA. The demographics of
adverse outcomes in cystic fibrosis. Pediatr Pulmonol.
2019;54(suppl 3):S74-S83.
83. Harness-Brumley CL, Elliott AC, Rosenbluth DB, Raghavan D,
Jain R. Gender differences in outcomes of patients with cystic
fibrosis. J Womens Health (Larchmt). 2014;23(12):1012-1020.
84. Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of
mortality in patients with cystic fibrosis. N Engl J Med.
1992;326(18):1187-1191.
85. Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2020
Annual Data Report. 2022. Accessed October 6, 2022. https://www.
cysticfibrosis.ca/registry/2020AnnualDataReport.pdf
86. Rosenfeld M, Davis R, FitzSimmons S, Pepe M, Ramsey B. Gender
gap in cystic fibrosis mortality. Am J Epidemiol. 1997;145(9):
794-803.
87. Lai HC, Kosorok MR, Laxova A, Makholm LM, Farrell PM.
Delayed diagnosis of US females with cystic fibrosis. Am J
Epidemiol. 2002;156(2):165-173.
88. Maselli JH, Sontag MK, Norris JM, MacKenzie T, Wagener JS,
Accurso FJ. Risk factors for initial acquisition of Pseudomonas
aeruginosa in children with cystic fibrosis identified by newborn
screening. Pediatr Pulmonol. 2003;35(4):257-262.
89. Caley L, Smith L, White H, Peckham DG. Average rate of lung
function decline in adults with cystic fibrosis in the United
Kingdom: data from the UK CF registry. J Cyst Fibros. 2021;20(1):
86-90.
90. Chotirmall SH, Smith SG, Gunaratnam C, et al. Effect of estrogen
on Pseudomonas mucoidy and exacerbations in cystic fibrosis.
N Engl J Med. 2012;366(21):1978-1986.
91. Holtrop M, Heltshe S, Shabanova V, et al. A prospective study of
the effects of sex hormones on lung function and inflammation in
women with cystic fibrosis. Ann Am Thorac Soc. 2021;18(7):
1158-1166.
92. Nichols DP, Paynter AC, Heltshe SL, et al. Clinical effectiveness of
elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a
clinical trial. Am J Respir Crit Care Med. 2022;205(5):529-539.
93. McDonnell MJ, Aliberti S, Goeminne PC, et al. Comorbidities and
the risk of mortality in patients with bronchiectasis: an
international multicentre cohort study. Lancet Respir Med.
2016;4(12):969-979.
94. Vidaillac C, Yong VFL, Jaggi TK, Soh MM, Chotirmall SH. Gender
differences in bronchiectasis: a real issue? Breathe (Sheff).
2018;14(2):108-121.
95. Chan ED, Iseman MD. Underlying host risk factors for
nontuberculous mycobacterial lung disease. Semin Respir Crit Care
Med. 2013;34(1):110-123.
96. Chalmers JD, Boersma W, Lonergan M, et al. Long-term macrolide
antibiotics for the treatment of bronchiectasis in adults: an
individual participant data meta-analysis. Lancet Respir Med.
2019;7(10):845-854.
97. Jung F, Riley L, Lascano J. Outcomes and survival following lung
transplantation in non-cystic fibrosis bronchiectasis. ERJ Open Res.
2022;8(1):00607-2021.
98. Shteinberg M, Taylor-Cousar JL, Durieu I, Cohen-Cymberknoh M.
Fertility and pregnancy in cystic fibrosis. Chest. 2021;160(6):
2051-2060.
99. Cohen-Cymberknoh M, Gindi Reiss B, Reiter J, et al. Baseline cystic
fibrosis disease severity has an adverse impact on pregnancy and
infant outcomes, but does not impact disease progression. J Cyst
Fibros. 2021;20(3):388-394.
100. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient
Registry: Annual Data Report 2020. 2021 Bethesda, MD: Cystic
Fibrosis Foundation. Accessed October 17, 2022. https://www.cff.
org/sites/default/files/2021-11/Patient-Registry-Annual-Data-
Report.pdf
101. National Institutes of Health Clinical Center. Prospective study of
pregnancy in women with cystic fibrosis (MAYFLOWERS).
NCT04828382. ClinicalTrials.gov. National Institutes of Health;
[ 163#2 CHEST FEBRUARY 2023 ]
 2021. Updated August 9, 2022, https://clinicaltrials.gov/ct2/show/
NCT04828382
102. Kazmerski TM, West NE, Jain R, et al. Family-building and
parenting considerations for people with cystic fibrosis. Pediatr
Pulmonol. 2022;57(suppl 1):S75-S88.
103. Middleton PG, Gade EJ, Aguilera C, et al. ERS/TSANZ task
force statement on the management of reproduction and
pregnancy in women with airways diseases. Eur Respir J.
2020;55(2):1901208.
104. Sawahata M, Sugiyama Y, Nakamura Y, et al. Age-related and
historical changes in the clinical characteristics of sarcoidosis in
Japan. Respir Med. 2015;109(2):272-278.
105. Fidler LM, Balter M, Fisher JH, To T, Stanbrook MB, Gershon A.
Epidemiology and health outcomes of sarcoidosis in a universal
healthcare population: a cohort study. Eur Respir J. 2019;54(4):
1900444.
106. Judson MA, Boan AD, Lackland DT. The clinical course of
sarcoidosis: presentation, diagnosis, and treatment in a large white
and black cohort in the United States. Sarcoidosis Vasc Diffuse Lung
Dis. 2012;29(2):119-127.
107. Salem ML. Estrogen, a double-edged sword: modulation of TH1-
and TH2-mediated inflammations by differential regulation of
TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy.
2004;3(1):97-104.
108. Cozier YC, Berman JS, Palmer JR, Boggs DA, Wise LA,
Rosenberg L. Reproductive and hormonal factors in relation to
incidence of sarcoidosis in US Black women: the Black Women’s
Health Study. Am J Epidemiol. 2012;176(7):635-641.
109. Dehara M, Sachs MC, Kullberg S, Grunewald J, Blomberg A,
Arkema EV. Reproductive and hormonal risk factors for
sarcoidosis: a nested case-control study. BMC Pulm Med.
2022;22(1):43.
110. van Manen MJG, Wester VL, van Rossum EFC, et al. Scalp hair
cortisol and testosterone levels in patients with sarcoidosis. PLoS
One. 2019;14(6):e0215763.
111. Zhou Y, Gerke AK, Lower EE, et al. The impact of demographic
disparities in the presentation of sarcoidosis: a multicenter
prospective study. Respir Med. 2021;187:106564.
112. Baughman RP, Teirstein AS, Judson MA, et al. Clinical
characteristics of patients in a case control study of sarcoidosis. Am
J Respir Crit Care Med. 2001;164(10 Pt 1):1885-1889.
113. Ungprasert P, Crowson CS, Matteson EL. Influence of gender on
epidemiology and clinical manifestations of sarcoidosis: a
population-based retrospective cohort study 1976-2013. Lung.
2017;195(1):87-91.
114. Grunewald J, Eklund A. Sex-specific manifestations of Löfgren’s
syndrome. Am J Respir Crit Care Med. 2007;175(1):40-44.
115. Gerke AK, Tangh F, Yang M, Cavanaugh JE, Polgreen PM. An
analysis of seasonality of sarcoidosis in the United States veteran
population: 2000-2007. Sarcoidosis Vasc Diffuse Lung Dis.
2012;29(2):155-158.
116. Rabin DL, Thompson B, Brown KM, et al. Sarcoidosis: social
predictors of severity at presentation. Eur Respir J. 2004;24(4):
601-608.
117. Swigris JJ, Olson AL, Huie TJ, et al. Sarcoidosis-related mortality in
the United States from 1988 to 2007. Am J Respir Crit Care Med.
2011;183(11):1524-1530.
118. Ogundipe F, Mehari A, Gillum R. Disparities in sarcoidosis
mortality by region, urbanization, and race in the United States: a
multiple cause of death analysis. Am J Med. 2019;132(9):1062-1068.
e3.
119. Hinz A, Fleischer M, Brahler E, Wirtz H, Bosse-Henck A. Fatigue
in patients with sarcoidosis, compared with the general population.
Gen Hosp Psychiatry. 2011;33(5):462-468.
120. Hinz A, Brahler E, Mode R, Wirtz H, Bosse-Henck A. Anxiety and
depression in sarcoidosis: the influence of age, gender, affected
organs, concomitant diseases and dyspnea. Sarcoidosis Vasc Diffuse
Lung Dis. 2012;29(2):139-146.
chestjournal.org
121. Cella DF. Quality of life: concepts and definition. J Pain Symptom
Manage. 1994;9(3):186-192.
122. Gwadera L, Bialas AJ, Gorski W, et al. Gender differences in health-
related quality of life measured by the Sarcoidosis Health
Questionnaire. Sci Rep. 2021;11(1):10242.
123. De Vries J, Van Heck GL, Drent M. Gender differences in
sarcoidosis: symptoms, quality of life, and medical consumption.
Women Health. 1999;30(2):99-114.
124. Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. The
Sarcoidosis Health Questionnaire: a new measure of health-related
quality of life. Am J Respir Crit Care Med. 2003;168(3):323-329.
125. Bourbonnais JM, Samavati L. Effect of gender on health related
quality of life in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis.
2010;27(2):96-102.
126. Dudvarski-Ilic A, Mihailovic-Vucinic V, Gvozdenovic B, Zugic V,
Milenkovic B, Ilic V. Health related quality of life regarding to
gender in sarcoidosis. Coll Antropol. 2009;33(3):837-840.
127. Tajima K, Miura K, Ishiwata T, et al. Sex hormones alter Th1
responses and enhance granuloma formation in the lung.
Respiration. 2011;81(6):491-498.
128. Arkema EV, Eklund A, Grunewald J, Bruze G. Work ability before
and after sarcoidosis diagnosis in Sweden. Respir Med. 2018;144S:
S7-S12.
129. Kocher L, Rossides M, Remaeus K, et al. Maternal and infant
outcomes in sarcoidosis pregnancy: a Swedish population-based
cohort study of first births. Respir Res. 2020;21(1):225.
130. Seeman MV. Why are women prone to restless legs syndrome? Int J
Environ Res Public Health. 2020;17(1):368.
131. Silvestri R, Arico I. Sleep disorders in pregnancy. Sleep Sci.
2019;12(3):232-239.
132. Neyal A, Senel GB, Aslan R, et al. A prospective study of Willis-
Ekbom disease/restless legs syndrome during and after pregnancy.
Sleep Med. 2015;16(9):1036-1040.
133. Manconi M, Ulfberg J, Berger K, et al. When gender matters:
restless legs syndrome. Report of the “RLS and woman” workshop
endorsed by the European RLS Study Group. Sleep Med Rev.
2012;16(4):297-307.
134. Cesnik E, Casetta I, Turri M, et al. Transient RLS during pregnancy
is a risk factor for the chronic idiopathic form. Neurology.
2010;75(23):2117-2120.
135. Jehan S, Masters-Isarilov A, Salifu I, et al. Sleep disorders in
postmenopausal women. J Sleep Disord Ther. 2015;4(5):212.
136. Fulda S, Stalla GK, Wetter TC. Prevalence of the restless legs
syndrome in transsexual patients: the hormonal hypothesis
revisited. J Neurol. 2007;254(12):1748-1749.
137. Suh S, Cho N, Zhang J. Sex differences in insomnia: from
epidemiology and etiology to intervention. Curr Psychiatry Rep.
2018;20(9):69.
138. Khazaie H, Ghadami MR, Knight DC, Emamian F, Tahmasian M.
Insomnia treatment in the third trimester of pregnancy reduces
postpartum depression symptoms: a randomized clinical trial.
Psychiatry Res. 2013;210(3):901-905.
139. Hashmi AM, Bhatia SK, Bhatia SK, Khawaja IS. Insomnia during
pregnancy: diagnosis and rational interventions. Pak J Med Sci.
2016;32(4):1030-1037.
140. Miller MA, Mehta N, Clark-Bilodeau C, Bourjeily G. Sleep
pharmacotherapy for common sleep disorders in pregnancy and
lactation. Chest. 2020;157(1):184-197.
141. Pan Z, Wen S, Qiao X, Yang M, Shen X, Xu L. Different regimens
of menopausal hormone therapy for improving sleep quality: a
systematic review and meta-analysis. Menopause. 2022;29(5):
627-635.
142. Bentley AJ, Rosman KD, Mitchell D. Gender differences in the
presentation of subjects with restless legs syndrome. Sleep Med.
2006;7(1):37-41.
143. Holzknecht E, Hochleitner M, Wenning GK, Hogl B, Stefani A.
Gender differences in clinical, laboratory and polysomnographic
features of restless legs syndrome. J Sleep Res. 2020;29(3):e12875.
381
144. US Department of Health and Human Services. The Health
Consequences of Smoking—50 Years of Progress: A Report of the
Surgeon General. 2014. Accessed October 7, 2022. https://www.cdc.
gov/tobacco/sgr/50th-anniversary/index.htm
145. Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smoking-
related mortality in the United States. N Engl J Med. 2013;368(4):
351-364.
146. Jha P, Ramasundarahettige C, Landsman V, et al. 21st-century
hazards of smoking and benefits of cessation in the United States.
N Engl J Med. 2013;368(4):341-350.
147. Gritz ER, Nielsen IR, Brooks LA. Smoking cessation and gender:
the influence of physiological, psychological, and behavioral factors.
J Am Med Womens Assoc (1972). 1996;51(1-2):35-42.
148. Allen AM, Yuan NP, Wertheim BC, Krupski L, Bell ML, Nair U.
Gender differences in utilization of services and tobacco cessation
outcomes at a state quitline. Transl Behav Med. 2019;9(4):663-668.
149. Smith PH, Kasza KA, Hyland A, et al. Gender differences in
medication use and cigarette smoking cessation: results from the
International Tobacco Control Four Country Survey. Nicotine Tob
Res. 2015;17(4):463-472.
150. Killen JD, Fortmann SP, Varady A, Kraemer HC. Do men
outperform women in smoking cessation trials? Maybe, but not by
much. Exp Clin Psychopharmacol. 2002;10(3):295-301.
151. Smith PH, Bessette AJ, Weinberger AH, Sheffer CE, McKee SA.
Sex/gender differences in smoking cessation: a review. Prev Med.
2016;92:135-140.
152. Marqueta A, Nerín I, Gargallo P, Beamonte A. Gender differences
in success at quitting smoking: short- and long-term outcomes.
Adicciones. 2016;29(1):13-21.
153. Torres OV, O’Dell LE. Stress is a principal factor that promotes
tobacco use in females. Prog Neuropsychopharmacol Biol Psychiatry.
2016;65:260-268.
154. Dieleman LA, van Peet PG, Vos HMM. Gender differences within
the barriers to smoking cessation and the preferences for
interventions in primary care a qualitative study using focus groups
in The Hague, The Netherlands. BMJ Open. 2021;11(1):e042623.
155. Higashi E, Fukami T, Itoh M, et al. Human CYP2A6 is induced by
estrogen via estrogen receptor. Drug Metab Dispos. 2007;35(10):
1935-1941.
156. Chenoweth MJ, Tyndale RF. Pharmacogenetic optimization of
smoking cessation treatment. Trends Pharmacol Sci. 2017;38(1):
55-66.
157. Lerman C, Schnoll RA, Hawk LW Jr, et al. Use of the nicotine
metabolite ratio as a genetically informed biomarker of response to
nicotine patch or varenicline for smoking cessation: a randomised,
double-blind placebo-controlled trial. Lancet Respir Med. 2015;3(2):
131-138.
382 CHEST Reviews
158. Bowker K, Lewis S, Coleman T, Cooper S. Changes in the rate of
nicotine metabolism across pregnancy: a longitudinal study.
Addiction. 2015;110(11):1827-1832.
159. Cosgrove KP, Esterlis I, McKee SA, et al. Sex differences in
availability of b2*-nicotinic acetylcholine receptors in recently
abstinent tobacco smokers. Arch Gen Psychiatry. 2012;69(4):
418-427.
160. Franklin TR, Jagannathan K, Wetherill RR, et al. Influence of
menstrual cycle phase on neural and craving responses to appetitive
smoking cues in naturally cycling females. Nicotine Tob Res.
2015;17(4):390-397.
161. Ethier AR, McKinney TL, Tottenham LS, Gordon JL. The
effect of reproductive hormones on women’s daily
smoking across the menstrual cycle. Biol Sex Differ.
2021;12(1):41.
162. Perkins KA, Scott J. Sex differences in long-term smoking cessation
rates due to nicotine patch. Nicotine Tob Res. 2008;10(7):
1245-1250.
163. McKee SA, Smith PH, Kaufman M, Mazure CM,
Weinberger AH. Sex differences in varenicline efficacy for
smoking cessation: a meta-analysis. Nicotine Tob Res.
2016;18(5):1002-1011.
164. Walker NJ, van Woerden HC, Kiparoglou V, Yang Y, Robinson H,
Croghan E. Gender difference and effect of pharmacotherapy:
findings from a smoking cessation service. BMC Public Health.
2016;16(1):1038.
165. Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic
treatment in tobacco-dependent adults: an official American
Thoracic Society clinical practice guideline. Am J Respir Crit Care
Med. 2020;202(2):e5-e31.
166. Buchting FO, Emory KT, Scout, et al. Transgender use of cigarettes,
cigars, and e-cigarettes in a national study. Am J Prev Med.
2017;53(1):e1-e7.
167. Grady ES, Humfleet GL, Delucchi KL, Reus VI,
Munoz RF, Hall SM. Smoking cessation outcomes among
sexual and gender minority and nonminority smokers in
extended smoking treatments. Nicotine Tob Res.
2014;16(9):1207-1215.
168. Matthews AK, Cesario J, Ruiz R, Ross N, King A. A qualitative
study of the barriers to and facilitators of smoking cessation among
lesbian, gay, bisexual, and transgender smokers who are interested
in quitting. LGBT Health. 2017;4(1):24-33.
169. Levinson AH, Hood N, Mahajan R, Russ R. Smoking cessation
treatment preferences, intentions, and behaviors among a large
sample of Colorado gay, lesbian, bisexual, and transgendered
smokers. Nicotine Tob Res. 2012;14(8):910-918.
[ 163#2 CHEST FEBRUARY 2023 ]