Journal of Cystic Fibrosis 18 (2019) S95 S104

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Journal of Cystic Fibrosis

journal homepage: www.elsevier.com/locate/jcf

Female reproductive health in cystic fibrosis

Kara S. Hughana,*, Tanicia Daleyb, Maria Socorro Rayasc, Andrea Kellyd, Andrea Roee
a
Division of Pediatric Endocrinology and Diabetes, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue,
Pittsburgh, PA, USA
b
Division of Pediatric Endocrinology and Metabolism, Emory Children’s Pediatric Institute, Emory University School of Medicine, 1400 Tullie Road, Atlanta, GA, USA
c
Division of Pediatric Endocrinology and Diabetes, University of Texas Health San Antonio, 7703 Floyd Curl, San Antonio, TX, USA
d
Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania,
2716 South Street, Philadelphia, PA, USA
e
Division of Family Planning, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, 1000 Courtyard,
3400 Spruce Street, Philadelphia, PA, USA

A R T I C L E I N F O A B S T R A C T

Article History: Women with cystic fibrosis (CF) are living longer and healthier lives, and opportunities for childbearing are
Received 8 July 2019 increasingly promising. However, this population can also face sexual and reproductive health concerns,
Revised 21 August 2019 including menstrual irregularities, unplanned pregnancies, infertility and pregnancy complications. Addi-
Accepted 22 August 2019
tionally, more women are entering menopause and are at risk for the consequences of estrogen deficiency.
The exact mechanisms involved in female reproductive health conditions in CF are not clearly understood,
but are thought to include cystic fibrosis transmembrane regulator (CFTR)-mediated abnormalities, changes
Keywords: in female sex hormones, and other CF health-related factors. In the era of CFTR modulator therapy, new data
Cystic fibrosis
are necessary to understand the impact of CFTR modulation on contraceptive effectiveness, fertility, and
Reproductive health
pregnancy outcomes to help guide future clinical care. This article reviews the current scientific knowledge
Menstruation
Amenorrhea of major reproductive health issues for women with CF.
Fertility © 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open
Contraception access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Pregnancy

1. Background
As health improves for people with cystic fibrosis (CF), women are
increasingly living into their reproductive years and into menopause.
CF patients often lack knowledge about sexual and reproductive
health, but desire increased attention to these aspects of their well-
being [1,2]. As primary caregivers for this population, CF providers
require familiarity with the breadth of female reproductive health
pathophysiology seen in CF [3,4]. In this article intended for members
of the CF provider team in pulmonology, endocrinology, obstetrics
and gynecology and primary care, we review menstruation, fertility,
contraception, pregnancy, and menopause related issues that affect
Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane regulator; OC,
oral contraceptives; FEV1, forced expiratory volume; GnRH, gonadotropin releasing
hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone; BMD, bone min-
eral density; DXA, dual x-ray absorptiometry; BMI, body mass index; IUD, intrauterine
device; DMPA, depot medroxyprogesterone acetate; VTE, venous thromboembolism;
CFRD, cystic fibrosis-related diabetes; PK, pharmacokinetic; MRHD, maximum recom-
mended human dose
*Corresponding author at: Division of Pediatric Endocrinology and Diabetes, UPMC
Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401
Penn Avenue, Pittsburgh, PA 15224, USA.
E-mail address: kara.hughan@chp.edu (K.S. Hughan).
women with CF. We also summarize existing data on the interaction
between cystic fibrosis transmembrane regulator (CFTR) modulators
and oral contraceptives (OC) and the impact of CFTR modulation on
fertility and pregnancy outcomes.
2. Impact of sex hormones on CF lung disease
Women with CF experience more pulmonary exacerbations after
puberty than men [5] according to Sutton et al., as well as increased
colonization with the mucoid form of the commonly acquired CF
pathogen Pseudomonas aeruginosa [6,7]. Gonadal hormones may con-
tribute to these sex differences. Female sex hormones (estrogen and
progesterone) are expressed in lung tissue [8,9], as are their hormone
receptors [8,10]. In vitro studies demonstrate that estradiol upregu-
lates mucus production in human airway epithelial cells [11] and
inhibits airway chloride secretion, resulting in airway surface dehy-
dration and decreased mucociliary clearance [12].
Recent work by Abid and colleagues evaluated the impact of
estrogen on inflammation and innate immunity in murine models
and in humans with and without CF. [13] They demonstrated that
female wild-type and CFTR-deficient mice infected with P. aeruginosa
had lower bacterial lung clearance rates and died earlier than male
mice [13]. The estrogen effect on murine mortality was confirmed

https://doi.org/10.1016/j.jcf.2019.08.024
1569-1993/© 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license.
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
S96 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104

when both estradiol-supplemented ovariectomized female and male
mice had an impaired ability to clear the Pseudomonal lung pathogen
and had decreased survival [13]. While estrogen had no direct effect
on Pseudomonal growth or mucoid conversion, estrogen treatment
induced a neutrophil-predominant host immune response against
Pseudomonas but hindered the neutrophil killing capacity [13],
implying neutrophils may modulate the host response to the bacte-
rial pathogen in CF through the estrogen receptor [13].
In women with CF, the various stages of the menstrual cycle
(Fig. 1) may also differentially impact lung health. To explore this
possible influence, a small group of women with CF were studied lon-
gitudinally and found to have lower forced expiratory volume (FEV1)
in the ovulatory and menstrual phases of the cycle [14]. Subse-
quently, Chotirmall and colleagues found that naturally-cycling
women had a higher frequency of pulmonary exacerbations during
the pre-ovulatory phase of the menstrual cycle, whereas the use of
OCs was associated with a decreased exacerbation rate that was simi-
lar to the rate in men [6]. In addition, estradiol has been shown to
trigger mucoid conversion of P. aeruginosa [6]. In women with CF,
high pre-ovulatory phase estradiol concentrations may alter the
inflammatory milieu and innate immune response; may disrupt
airway chloride, bicarbonate and water balance, leading to thick
tenacious mucus; and may enhance mucin production and impair
mucin clearance.
3. Menstruation
3.1. Definition of menstrual irregularity
Women with CF can experience a range of menstrual irregulari-
ties. Oligomenorrhea is infrequent menstrual periods (fewer than
nine periods per year or cycle length >35 days). Secondary amenor-
rhea is the cessation of menses for >3 months after menarche has
occurred. Primary amenorrhea is less common among girls with CF,
and is defined as menstruation that is absent at 16 years of age or
3 years after onset of secondary sexual characteristics [15].
3.2. Prevalence of menstrual irregularity
According to reports from the 1980s, menarche occurred signifi-
cantly later among adolescent girls with CF [16]. However, current
data suggest that menarche occurs at the same age or only slightly

Fig. 1. Gonadotropin control of the ovarian and endometrial cycles.

Reproduced with permission from Williams Obstetrics (Fig. 5 1) McGraw-Hill Education.
Figure legend. The ovarian-endometrial cycle has been structured as a 28-day cycle. The follicular phase (days 1 to 14) is characterized by rising estrogen levels, endometrial
thickening, and selection of the dominant “ovulatory” follicle. During the luteal phase (days 14 to 21), the corpus luteum (CL) produces estrogen and progesterone, which prepare
the endometrium for implantation. If implantation occurs, the developing blastocyst begins to produce human chorionic gonadotropin (hCG) and rescues the corpus luteum, thus
maintaining progesterone production. FSH = follicle-stimulating hormone; LH = luteinizing hormone.
 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104
later for girls with CF compared to their healthy peers [17,18].
According to a recent estimate, girls with CF have a mean age at men-
arche of 13.1 years, compared to 12.4 years in the general population
[18]. In the 1980s, approximately one-quarter to one-half of women
with CF were estimated to have oligomenorrhea [16,19] or dysfunc-
tional uterine bleeding [16] and one-quarter to one-third of women
with CF were estimated to have a history of secondary amenorrhea
[19,20]. However, these women with CF were likely significantly less
healthy than current-day women with CF; therefore, further studies
are necessary to identify modern estimates.
3.3. Pathophysiology of menstrual irregularity
Oligomenorrhea and amenorrhea may have a variety of etiologies,
including polycystic ovary syndrome and thyroid dysfunction. In
women with CF, menstrual irregularity is most commonly associated
with hypothalamic suppression, the etiology of which is multifacto-
rial. Undernutrition, increased energy expenditure, chronic stress
[21], poorly controlled diabetes, recurrent infections and chronic
hypoxemia are all determinants of hypothalamic amenorrhea in the
non-CF population and are common in CF. Classically, suppression of
hypothalamic gonadotropin releasing hormone (GnRH) pulsatility
leads to decreased gonadotropin (LH, FSH) pulse frequency and con-
centrations. The mid-cycle luteinizing hormone (LH) surge is absent,
follicle stimulating hormone (FSH) is low or normal, ovarian follicular
development is absent, anovulation occurs, and sex steroids are low
[22]. This hypogonadal state may arise from defective CFTR in areas
enriched in sex hormone receptors, including the hypothalamus and
pituitary [23]. Abnormal hypothalamic CFTR protein may disrupt
GnRH pulsatility [23] and contribute to menstrual irregularity in CF.
3.4. Diagnostic workup of menstrual irregularity
In the non-CF population, hypothalamic amenorrhea is associated
with greater risk for various chronic adverse health outcomes associ-
ated with lower sex steroid levels (Table 1), including low bone min-
eral density (BMD). Any woman with CF should be evaluated further
if she meets criteria for oligo- or amenorrhea (Table 2), is identified
to have low BMD by dual x-ray absorptiometry (DXA), or has symp-
toms of vaginal dryness or dyspareunia indicative of hypoestrogen-
ism. Laboratory evaluation and radiologic testing should be selected
(Table 2) based upon the medical history and physical exam of the
woman.
3.5. Routine management of menstrual irregularity
Ideally, amenorrhea is reversed by addressing the underlying con-
dition or stress. This approach can include lifestyle changes to
encourage increased caloric intake and psychological support to
improve emotional state. Nutritional recovery, re-activation of the
hypothalamic-pituitary-ovarian axis, and calcium and vitamin D sup-
plementation may be needed to support bone health. Exogenous
Table 1
Adverse health outcomes associated with amenorrhea.
Body system Health outcomes
Endocrine Primary or secondary amenorrhea
Anovulatory infertility
Metabolic Reduced energy expenditure
Musculoskeletal Decreased bone accrual in adolescence
Low bone mineral density (BMD) in adulthood
Long bone and vertebral fractures
Genitourinary Vaginal dryness
Dyspareunia
Psychiatric Impacts on cognition, anxiety and mood
Abbreviations: BMD, bone mineral density.
S97
Table 2
Evaluation for oligo- and amenorrhea.
Medical history Menstrual, weight and exercise history
Chronic illness history
Fracture history
Uterine instrumentation history
Galactorrhea
Acne or hirsutism
Hypothyroid symptoms
Hypo-estrogen symptoms
Physical exam External gynecologic exam
Laboratory evaluation Serum beta-human chorionic gonadotropin
FSH, LH and estradiol
TSH and free T4
Testosterone
Prolactin
25-OH vitamin D
Radiologic imaging Pelvic ultrasound
Dual x-ray absorptiometry (DXA) scan
Abbreviations: FSH, follicle stimulating hormone; LH, luteinizing hor-
mone; TSH, thyroid stimulating hormone; DXA, dual x-ray
absorptiometry.
estrogen therapy may be necessary. In postmenopausal women with-
out CF, Weissberger et al. showed continuous transdermal estradiol
patches with cyclic oral progesterone for endometrial protection are
preferred [24] over combined OCs [25], which have limited to no ben-
efit on BMD.
4. Fertility
4.1. Definition of infertility
Infertility is defined as the inability of a couple to conceive after
12 months of regular sexual intercourse without use of contraception
in women <35 years of age, and after 6 months in women 35 years
and older [26]. Subfertility is defined as requiring assisted reproduc-
tion after one year of infertility or achieving spontaneous pregnancy
after over one year of unprotected intercourse [26].
4.2. Prevalence of infertility
Published pregnancy rates in the US and UK are up to 40/1000-per
year in reproductive aged women with CF (compared to 80/1000-per
year in the general population) [27,28], and 2 4% of women with CF
are estimated to become pregnant per year [18,29]. In a recent multi-
center, multinational study of women with CF, 40% of women with
CF attempted pregnancy [30]. The authors report a subfertility and
infertility rate of 35% in CF women attempting to conceive (average
age 30.4 years) [30] in comparison to 5 15% in the general popula-
tion [31,32] and in comparison to 14% among women of similar age
in the general population [31].
4.3. Pathophysiology of infertility
Women with CF may experience reduced fertility for a variety of
reasons, including etiologies unrelated to CF, and it is unclear which
mechanisms are most salient. As discussed above, hypothalamic sup-
pression resulting from nutritional deficiencies [23,33] and other dis-
ease-related stresses can result in anovulation, which reduces
fertility. In the cervix, defective CFTR in the epithelium promotes pro-
duction of cervical mucus that is thick and dehydrated. This mucus
blocks the cervical os and impairs sperm entry [34 37]. In the endo-
metrium, defective CFTR in the epithelium can alter bicarbonate
secretion, reducing uterine fluid volume and impairing sperm fertili-
zation capacity [36,38]. Finally, women with CF may have lower ovar-
ian reserve compared to age-matched controls [39,40].
S98 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104
4.4. Risk factors for infertility
Limited data are available to inform discussion surrounding fertil-
ity in CF, and the existing literature does not differentiate those
women who choose to avoid pregnancy and those who try but are
not successful. These issues may be further confounded by the sub-
group of women for whom pregnancy is not recommended (such as
very low lung function or post-lung or liver transplant). Shteinberg
and colleagues recently found pancreatic insufficiency and age
>31 years at first attempt of conception are independent risk factors
for subfertility in CF [30]. In contrast, chronic colonization with
Pseudomonas aeruginosa, body mass index (BMI), lung function and
pulmonary exacerbations were not associated with infertility [30].
4.5. Diagnostic workup and management of infertility
In women with fertility concerns, ovulatory function and anatomy
will be assessed. Clomiphene citrate and/or injectable gonadotropins
can be administered to stimulate ovarian follicle production, with or
without the use of intrauterine insemination, which can bypass thick
cervical mucus. In vitro fertilization is an additional option should
less invasive techniques fail. It is more costly, but can also offer the
opportunity for preimplantation genetic screening of embryos for
those at risk for CF. However, these treatments have never been stud-
ied in CF, and therefore the impact of these treatments on the health
of people with CF is unknown.
5. Sexual activity
Women with CF have similar age of onset of sexual activity, num-
ber of partners, and sexual activity rate [41] and are equally likely to
engage in risky sexual behaviors as the general population [18,42].
Two US CF centers reported 43% of adolescents with CF and 83% of
adult women with CF are sexually active [43,44].
6. Contraception
6.1. Contraceptive use
Women with CF underutilize contraception (35%) compared to
the general population (up to 51%) [43]. Differing pregnancy inten-
tions from the general population, as well as misconceptions about
contraception and fertility, may contribute to their lower rates of
contraceptive use [45]. The most commonly used methods of contra-
ception are condoms (12 18%) and hormonal contraceptive pills
(19 26%) [43,46]. As in the general population, long-acting reversible
contraceptives, including copper and progestin intrauterine devices
(IUD) and the progestin subdermal implant, are less frequently used.
See Table 3 for available methods of contraception in the United
States [47,48].
6.2. Contraceptive safety
Research on contraceptive safety specific to women with CF has
been systematically reviewed but remains limited [49]. Most proges-
tin-only methods, such as the progestin IUD, progestin subdermal
implant, and progestin-only OCs, as well as non-hormonal methods,
such as the copper IUD and barrier methods, carry no theoretical risks
in the setting of CF. However, estrogen-containing contraception,
including combined OCs, the transdermal patch, and the vaginal ring,
as well as the depot medroxyprogesterone acetate (DMPA) injection,
have additional considerations for use among women with CF.
Exogenous estrogen from combined OCs is associated with a
2 3 times increased risk of venous thromboembolism (VTE) in the
general population [50], and cases of VTE with OC use have been
reported in CF [51,52]. Combined OCs may not be the optimal
contraceptive method in those with CF-related risk factors for VTE,
including implantable vascular access devices, liver disease (which
may impact metabolism of contraceptive hormones and may also
be associated with vitamin K deficiency and hypercoagulability),
acquired thrombophilia secondary to inflammation, CF-related diabe-
tes (CFRD), sinus disease, and prolonged hospitalizations [51,53,54].
Combined OC use is contraindicated in CF with pulmonary hyperten-
sion [54].
DMPA use results in BMD loss via inhibition of gonadotropins,
leading to decreased estrogen production [55]. In the general popula-
tion, BMD recovers completely after discontinuation of DMPA use.
However, in adolescents and adults without CF with >2 years of
DMPA use, the speed and completeness of recovery varies by dura-
tion of treatment and by anatomic site, with the hip and femoral
neck recovery generally taking longer than the lumbar spine [55].
DMPA may not be the optimal contraceptive choice for women with
CF who have osteopenia or osteoporosis.
With regard to lung health, combined OCs do not impair disease
severity as measured by change in pulmonary function [56] and
exacerbation rates [6,57]. In fact, prospective observation over
36 months by Chotirmall et al. revealed a potential protective effect
of OCs against CF exacerbations [6].
6.3. Contraceptive effectiveness
In theory, women with CF may have gastrointestinal dysfunction
and pancreatic insufficiency that may impair metabolism of hor-
monal contraception [58]. Data on the effectiveness of combined hor-
monal contraception in women with CF are sparse [46,49,57,59,60].
A small study (n = 10) reported no pregnancies within 6 12 months
after initiating OCs in CF patients [57], and another study reported a
contraceptive patch failure resulting in pregnancy in one of 26
patients on hormonal contraception [46]. Recent data following 8
women post-lung transplant, 7 of whom had CF, reported no preg-
nancies after a mean duration of 12.5 months of combined hormonal
contraception use (using OCs, the patch, or the ring) and no graft dys-
function, rejection or side effects associated with immunosuppres-
sive agents [59]. A study of combined 50 mg ethinyl estradiol/250 mg
levonorgestrel pills found similar pharmacokinetic (PK) data in
women with and without CF [61]. No studies exist regarding the
effectiveness of other contraceptive methods in the CF population,
although there are fewer mechanistic concerns about their methods
of action and metabolism.
6.4. Medication interactions
Rifamycin antibiotic use (including rifampin, rifabutin, rifaximin
and rifalazil) in the general population has been associated with a
theoretical risk for reduced OC effectiveness [62] due to induction of
hepatic cytochrome P450 enzymes involved in OC metabolism as
well as concurrent increased hepatic sex hormone binding globulin
production, leading to reductions in bioactive hormones [62,63], but
has not been exclusively studied in women with CF. A recent system-
atic review of non-rifamycin antibiotic use in the general population
(including penicillins, tetracyclines, fluoroquinolones, macrolides,
metronidazole, nitrofurantoin and trimethoprim/sulfamethoxazole)
demonstrated no differences in ovulation suppression or progestin
PK during co-administration of hormonal contraception [64]. Ethinyl
estradiol area under the curve decreased with administration of diri-
thromycin, but no other non-rifamycin antibiotic. No differences in
pregnancy rates are reported in women in the general population
who used OCs with and without antibiotics [64] and data are lacking
specifically in women with CF.
Mycophenolate may decrease serum estrogen and progestin con-
centrations, potentially reducing the effectiveness of hormonal con-
traception. Therefore, the drug's package insert recommends any
 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104 S99

Table 3
Contraceptive methods.

Contraceptive method Effectiveness Duration of use Side effects

Surgical
Female permanent contraception 99.5% lifelong
Tubal ligation or salpingectomy

Hormonal
Progestin subdermal implant 99.95% 3 years Irregular bleeding
Injectable progestin/depot medroxyprogesterone 94% 12 weeks Irregular bleeding, headache, nausea; may cause increased loss of
acetate (DMPA) bone mineral density
Combined oral contraceptive pill 91% Daily Spotting, breast tenderness, bloating, VTE risk
Progestin only pill 91% Daily
Estrogen-progestin transdermal patch 91% Weekly Spotting, breast tenderness, nausea, skin irritation, VTE risk
Estrogen-progestin vaginal ring 91% Monthly Spotting, breast tenderness, nausea, increased vaginal discharge, VTE risk
Emergency contraception: Take within:
Plan B 56 89% 72 h of sex Nausea, spotting, fatigue, headache, dizziness
Ulipristal acetate 62 85% 120 h of sex Nausea, spotting, fatigue, headache, dizziness
Copper intrauterine device (IUD)a 99.2% 120 h of sex Pelvic pain, spotting, uterine perforation, infection
Progestin IUD 99.8% 3 5 years

Barrier
Diaphragm or cervical cap 88 94% Per each encounter
Male condom 82% Per each encounter
Female condom 79% Per each encounter
Sponge 88% Per each encounter Vaginal irritation or dryness, vaginal/urinary infection
Spermicide 72% Per each encounter Genital tissue sensitivity

Other
Copper IUD 99.2% 10 years Pelvic pain, spotting uterine perforation, infection
Withdrawal 78% Per each encounter
Fertility awareness based methods 76% Per each encounter
Abbreviations: DMPA, depot medroxyprogesterone acetate injection; VTE, venous thromboembolism; IUD, intrauterine device.
a
Off-label indication.

woman using mycophenolate and hormonal contraception should
consider additional or alternative contraceptive methods [65].
Seidegard et al. showed short-term administration (7 days) of
prednisolone in combination with hormonal contraceptives
increased plasma concentrations of prednisone [66], but the long-
term impact of concurrent steroid and hormonal contraceptive use
on bone health in women with CF is not known.
The impact of CFTR modulators on contraception is discussed in
this manuscript's section 9.2.
7. Pregnancy
should be carefully adjusted for nutritional density of the diet. The CF
care team may need to introduce or maximize oral/enteral nutritional
supplements to optimize BMI, as low pre-pregnancy BMI is associ-
ated with intrauterine growth restriction, low birth weight, and pre-
term delivery [72]. Diabetes has adverse effects in pregnancy,
including fetal anomaly, preterm delivery, and maternal complica-
tions such as pre-eclampsia [73].
A comprehensive update is available on the safety of prescription
medications used in the management of CF during pregnancy and
lactation [74]. Limited data are available on CFTR modulators during
pregnancy and are reviewed in this manuscript's section 9.4.

7.1. Pre-conceptual care 7.2. Management of the antenatal period

The first report of successful pregnancy in a woman with CF was
in 1960 but resulted in death of the woman postpartum [67]. Today,
maternal and fetal pregnancy outcomes are significantly improved,
although pregnancy can still carry health risks that warrant increased
attention pre-conceptually and in the antenatal and postpartum peri-
ods. There is no convincing evidence that pregnancy is associated
with increased mortality or declining FEV1 [68]. Women with CF are
at greater risk of preterm birth (18 46%) and Cesarean delivery, but
neonates are generally healthy [69]. Open discussions about patients'
childbearing desires facilitate planning prior to pregnancy, and pro-
viders should be prepared to address the unique physical and social
difficulties of pregnancy and parenthood for women with CF [70,71].
Women with CF may want to pursue genetic testing for a male
partner in order to assess risk for CF disease or carrier status in future
offspring. Referral to maternal-fetal medicine is recommended for
genetic testing and counseling. For women with CF who choose to
pursue pregnancy, their health, including lung function, nutrition,
CFRD, and medications, should be optimized prior to conception.
Baseline pulmonary function is associated with pulmonary and
pregnancy outcomes during pregnancy [69], therefore airway man-
agement should be emphasized prior to conception. Dietary intake
All pregnancies in women with CF are considered high-risk, and
therefore a referral to maternal-fetal medicine should occur early in
pregnancy, if not prior to conception. The primary CF provider and
the maternal-fetal medicine specialist should lead a multidisciplinary
team approach for the pregnancy, delivery and postpartum period.
Individualized care is supported by the respiratory therapist, dieti-
cian and clinical psychologist. While comprehensive 2008 guidelines
commissioned by European Cystic Fibrosis Society on the manage-
ment of pregnancy in CF exist, much is based on expert consensus
[29].
During pregnancy, the increasing size of the uterus can have nega-
tive impacts on the mechanics of the chest cavity and pelvic floor.
Adherence to chest treatment regimens becomes increasingly impor-
tant and alterations to the timing and frequency of physiotherapy
may be necessary compared to prior to pregnancy. Due to the high
prevalence of gastroesophageal reflux in adults with CF, head-down
tilted postural drainage is not recommended in pregnancy [75].
Upright sitting position throughout pregnancy and supine horizontal
positioning in the first trimester may be preferred positioning for air-
way clearance [76]. Several airway clearance techniques are useful
during pregnancy (Table 4) [76]. In the setting of declining function
S100 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104
or infection, interventions and antibiotic treatment should be aggres-
sive and early. Short-term maternal/neonatal outcomes are closely
related to the absolute lung function and the stability of lung function
over time.
Prognostic factors for poor pregnancy outcomes in CF in the litera-
ture are robust and include poorly controlled diabetes, poor nutrition
(BMI <18 kg/m2), FEV1 <40% or forced vital capacity <50%, Burkhol-
deria cepacia complex infection and liver disease [77].
For women without CFRD, screening for gestational diabetes
should occur early, and again at a routine screening interval if
negative. With new gestational diabetes or existing CFRD, glycemic
control throughout pregnancy is important, involving daily glucose
monitoring and may require initiation of insulin therapy.
Urinary incontinence is also common in females with CF [78]. As a
result, women can be hesitant to perform chest physiotherapy and/or
spirometry, and the incontinence may also inhibit their social activi-
ties. Women can begin daily pelvic floor muscle exercises early to
better assist with airway clearance maneuvers.
7.3. Management of delivery
Preterm birth is the most common complication of pregnancy
among women with CF [27,69,77], and this may be the result of med-
ical recommendation in the setting of worsening maternal or fetal
status, in addition to spontaneous preterm labor. Vaginal delivery is
preferred to Cesarean when possible, as surgical recovery can
heighten atelectasis and retention of airway secretions. However, a
woman's ability to tolerate labor should be assessed by her high-risk
obstetrician [69].
7.4. Management of postpartum period
Women with CF require ongoing effort to maintain nutritional
and pulmonary health during the postpartum period and benefit
from increased social support. Breastfeeding may have some infant
benefits and breastmilk in women with CF has normal composition
[79], but breastfeeding requires significant time and calories and may
not be appropriate for women with CF, especially those with nutri-
tional failure. Contraception is recommended to prevent unintended
pregnancy and a short inter-pregnancy interval. As in the general
population, postpartum women with CF should be screened for
depression.
7.5. Post-transplantation pregnancy
CF patients who undergo lung transplant may be at higher risk
during pregnancy for graft rejection (25%) [80], hypertension, pre-
eclampsia [81,82], gestational diabetes [83] and death after preg-
nancy (40%) [80]. Fetal complications include higher rates of preterm
birth and low birth weight compared to other organ recipients [80].
Risk of congenital infections in offspring of lung and liver transplant
Table 4
Airway clearance techniques useful in pregnancy.
Active cycle of breathing techniques (ACBT)
Autogenic drainage (AD)
Positive expiratory pressure (PEP) therapy
Oscillating positive expiratory pressure (OscPEP) therapy
Intrapulmonary percussive ventilation (IPV) including MetanebÒ device
Physical exercise
Effective huffing from different lung volumes avoiding dynamic collapse
Abbreviations: ACBT, active cycle of breathing techniques; AD, autogenic
drainage; PEP, positive expiratory pressure; OscPEP, oscillating positive
expiratory pressure; IPV, intrapulmonary percussive ventilation.
Adapted from Blue Booklet: Physiotherapy for People with Cystic Fibrosis:
from Infant to Adult [76].
recipients are similar to the general population [84], but rates in off-
spring of lung transplant recipients with CF have not been reported.
The European Cystic Fibrosis Society recommend that pregnancy
be delayed after lung transplant for at least 1 2 years to minimize
graft rejection and loss and to reduce infection as well as to manage
co-existing conditions [81,82]. Many transplant programs in the
United States in fact strongly advise against women from becoming
pregnant post lung transplant. All immunosuppressive agents cross
the placenta. In particular, mycophenolate mofetil, sirolimus and
everolimus are relatively contraindicated in any pregnancy and
should be stopped prior to conception. In contrast, other immuno-
suppressive agents including tacrolimus, cyclosporine, prednisone
and azathioprine are associated with low prevalence of congenital
anomalies comparable to the general population. In women who are
post-transplant, acid reflux treatment should be optimized prior to
pregnancy as reflux can increase rejection [85].
After delivery, contraceptive options should avoid exogenous
estrogen if the patient experiences rejection or graft failure [54].
Breastfeeding may be compatible with use of the immunosuppressive
agents tacrolimus, cyclosporine, azathioprine and prednisone [74],
but some sources recommend a 4 6 h delay after medication dosing
[86] and infant monitoring of kidney function (cyclosporine) and
blood counts (cyclosporine, azathioprine) due to potential risks of
nephrotoxicity and myelosuppression [86,87]. Breastfeeding should
be avoided with use of mycophenolate, sirolimus and everolimus in
women with CF, due to lack of data [74].
7.6. Termination of pregnancy
Unintended pregnancy rates in women with CF are high at
26 50% [41,88] and are likely underreported for various reasons.
One study reported that 15% of pregnancies resulted in abortion [89].
Cor pulmonale and pulmonary hypertension are considered contrain-
dications to carrying a pregnancy in CF. However, a woman may
choose to terminate a pregnancy due to other medical or social com-
plications. Options for termination include medication abortion with
mifepristone and misoprostol, surgical abortion with uterine aspira-
tion or dilation and evacuation, and induction termination with a
vaginal delivery. Referral to a gynecologist with expertise in family
planning is recommended for management of termination, especially
for women with CF with poor health status.
8. Menopause
8.1. Definition of menopause
Clinically, menopause is recognized after 12 months of amenor-
rhea. Its onset is variable with ~95% of women in the general popula-
tion undergoing menopause between 45 and 55 years of age
(average at 51 years of age).
8.2. Onset of menopause and clinical presentation
To date, one study has shown lower anti-Mu € llerian hormone lev-
els in women with CF compared to controls, suggestive of lower ovar-
ian reserve which may predict earlier menopausal onset [40];
however, the age of menopause in women with CF is unknown. Simi-
lar to the general population, if a woman with CF presents with con-
cerns of early menopause (<45 years of age), referral for evaluation
by a women's health provider is warranted.
Symptoms of menopause include hot flashes, palpitations, chills,
vaginal dryness and itching, dyspareunia, reduced sexual function
and sleep disturbances. Symptoms are more common at night and
occur several times per day. In the year leading up to the final men-
strual period, bone loss is accelerated. Additional long-term
 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104
consequences of menopause include loss of lean mass, gain in fat
mass and decrease in skin collagen [90].
8.3. Routine management of menopause
In the general population, treatment of vasomotor symptoms
associated with menopause with oral or transdermal estrogen may
be indicated in those younger than 60 years or within 10 years since
the onset of menopause. An individualized evaluation of benefits and
cardiovascular and breast cancer risks should be completed before
initiating hormone therapy [91]. Contraindications to menopausal
estrogen therapy specific to CF outside of usual contraindications
(such as history of VTE or liver disease) include CFRD with microvas-
cular complications, other vascular disease or CFRD for over 20 years.
Vaginal atrophy is preferentially treated with local estrogen therapy
rather than more systemic routes of administration. Given the accel-
erated BMD loss associated with onset of menopause, postmeno-
pausal women 65 years and older regardless of their diagnosis of CF
or risk factors should undergo osteoporosis screening via DXA. Sev-
eral medical societies also recommend BMD testing in women older
than 50 years with any clinical risk factor for fracture.
9. Potential impact of CFTR modulation on reproductive health
9.1. Mechanism of action and CFTR genotype indications
In the last decade, the Food and Drug Administration has
approved three drugs in the CFTR modulator class. Ivacaftor, a CFTR
potentiator, increases the channel gating activity of CFTR at the epi-
thelial surface to enhance chloride transport. It is approved for
patients with G551D and similar gating mutations. Ivacaftor is also
currently formulated in combination with one of two CFTR correc-
tors, lumacaftor and tezacaftor, for patients who are homozygous for
F508del or compound heterozygous for F508del and G551D or, for
tezacaftor/ivacaftor, who have at least one copy of a CFTR gene muta-
tion responsive to the drug combination. These correctors increase
processing and trafficking of CFTR to the epithelial cell membrane,
resulting in increased chloride transport.
9.2. Interactions with oral contraceptives
In vitro studies demonstrated ivacaftor and tezacaftor competi-
tively inhibit the hepatic CYP3A enzyme [92,93]. Combined OCs are
also partially metabolized by CYP3A with ethinyl estradiol undergo-
ing extensive hepatic first-pass effect [94]. Human PK studies with
co-administration of ivacaftor or tezacaftor/ivacaftor and a combined
OC demonstrate non-clinically significant PK increases in ethinyl
estradiol and norethindrone [93,94] with adequate suppression of
ovulation [94]. Therefore, co-administration of ivacaftor or tezacaf-
tor/ivacaftor with a combined OC is not expected to impact safety or
efficacy of the combined OC and dose adjustment of the combined
OC is not necessary. Additionally, tezacaftor has the advantage that it
does not induce CYP3A enzymes and therefore reduces drug-drug
interactions and dosing complexities [93].
In contrast, the CFTR modulator lumacaftor is a strong inducer of
CYP3A and forms a component of the combination drug lumacaftor/
ivacaftor, indicated for CF patients with homozygous F508del muta-
tions. This drug decreases serum concentrations of estrogen deriva-
tives that are the substrates of CYP3A, decreasing the contraceptive
effect of combined OCs. In addition, this interaction increases the
incidence of dysmenorrhea, menorrhagia and menstrual irregularity
(27% lumacaftor/ivacaftor+combined OC vs. 3% lumacaftor/ivacaftor
alone) [95]. Therefore, combined hormonal contraceptives (OCs,
patch, and ring) should not be relied upon as an effective method of
contraception when co-administered with lumacaftor/ivacaftor [96].
S101
9.3. Effects on fertility
Animal studies of ivacaftor show decreased embryo viability and
implantation with drug exposures in early pregnancy at 5 times the
maximum recommended human dose (MRHD), but no effects with
exposures at 3 times the MRHD [92]. Studies of lumacaftor in female
rodents resulted in no effects on fertility and reproductive perfor-
mance with drug exposures in early pregnancy at 8 times the MRHD
[96]. Human fertility data in the setting of CFTR therapy are currently
lacking.
9.4. Effects on pregnancy and lactation
Very limited pregnancy studies of ivacaftor and lumacaftor in ani-
mals have thus far demonstrated no teratogenicity or adverse effects
on fetal development, delivery or growth in offspring from organo-
genesis through lactation [92,96]. Animals given tezacaftor at mater-
nally toxic doses had offspring with lower fetal body weight and
early developmental delays [93]. Ivacaftor was found to cross the pla-
centa and ivacaftor and tezacaftor were excreted in the animal's milk
[92]. Ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor are preg-
nancy class B [74] and destabilization after modulator withdrawal
has been reported. Therefore, benefits and risks of modulator therapy
during pregnancy and lactation should be assessed with each woman
individually. Women with CF who are attempting pregnancy have
been excluded from participating in CFTR modulator clinical trials,
therefore clinical experience with these drugs in pregnancy is limited
to case reports, which all describe full-term deliveries and no major
reported maternal or fetal complications [60,97 99]. Lumacaftor/iva-
caftor has been noted to result in transient postnatal infant hepatic
function abnormalities during breastfeeding, and its use during lacta-
tion warrants further investigation in the infants [99].
10. Future directions in CF female reproductive health research
 Reproductive health decision-making tools should be explored as
a way to enhance patient-provider communication surrounding
reproductive health topics.
 CF providers themselves should be studied in order to find opti-
mal mechanisms of provider reproductive health education and
care coordination across specialties.
 Given sex differences in disease, further studies are necessary to
explore menstrual cycle physiology and the impact of disease
cyclicity on lung health.
 Another unexplored but potentially significant issue is ovarian
reserve and function.
 Larger studies of hormonal contraception are needed to confirm
contraceptive safety and effectiveness in CF, especially in women
with severe disease.
 Women with CF are newly entering menopause and the natural
history of this transition needs to be described.
 The impact of CFTR modulation on menstruation, fertility, bone
health and pregnancy should be studied.
11. Clinical practice points
11.1. Menstruation
 Refer any woman with CF with menstrual irregularities to a
gynecologist or endocrinologist, especially if she is identified as
having low BMD or has symptoms of hypo-estrogenism.
11.2. Fertility
 Estimated prevalence of subfertility in women with CF is higher
(35%) compared to the general population (5 15%).
S102 K.S. Hughan et al. / Journal of Cystic Fibrosis 18 (2019) S95 S104
 Pancreatic insufficiency and older age at first attempt of concep-
tion are associated with increased subfertility, but BMI, coloniza-
tion with Pseudomonas aeruginosa, lung function and pulmonary
exacerbations are not.
 Refer any woman with CF to a fertility specialist if she presents
with concerns of infertility, in order to explore assisted reproduc-
tive technology options.
11.3. Sexual activity and contraception
 Adolescent and young adults with CF have similar age of onset of
sexual activity, number of partners, and sexual activity rate and
are equally likely to engage in risky sexual behaviors compared
to the general population.
 Refer any adolescent or adult woman with CF to an adolescent
medicine specialist or women's health provider if contraceptive
use and choice cannot be provided by the CF care team.
11.4. Pregnancy and delivery
 As unplanned pregnancy rates in CF are high, preconceptual
health and pregnancy planning should be discussed at the wom-
an's annual CF review.
 Prognostic factors for poor pregnancy outcomes include poorly
controlled diabetes, poor nutrition (BMI <18 kg/m2), FEV1 <40%
or FVC <50%, Burkholderia cepacia complex infection, and liver
disease.
 The most common complications of CF pregnancies are Cesarean
delivery and preterm birth, but neonates are generally healthy.
 All pregnancies in women with CF are considered high-risk,
therefore refer any pregnant woman with CF to a high-risk obste-
trician for antenatal care.
11.5. Menopause
 Refer any woman with CF with concerns of early menopause
(<45 years of age) to a women's health provider to evaluate the
amenorrhea.
 Treatment of vasomotor symptoms associated with menopause
with estrogen may be indicated (transdermal preferred) in those
<60 years or under 10 years since the onset of menopause.
11.6. CFTR modulator therapy and reproductive health
 Co-administration of daily lumacaftor/ivacaftor with combined
hormonal contraceptives decreases contraceptive effectiveness
and increases the incidence of menstrual adverse reactions.
 More clinical data is needed to assess the impact of tezacaftor,
lumacaftor and ivacaftor during pregnancy and lactation on
maternal and fetal outcomes due to their crossing the placenta
and passing into the breastmilk.
 CFTR modulators are pregnancy class B, therefore, benefits and
risks of modulator therapy during pregnancy and lactation
should be assessed with each woman individually.
12. Summary
The CF care team now has increasing responsibility to recognize
and refer for sexual and reproductive health issues of menstruation,
fertility, sexual activity, contraception, pregnancy planning and pre-
vention, and menopause. Further registry and clinical trial data are
urgently needed to better inform care related to these issues. CF pro-
viders should coordinate sexual and reproductive health care with
general gynecologists and relevant specialists in reproductive endo-
crinology, maternal-fetal medicine, and family planning to maximize
the reproductive health of women with CF.
Declaration of Competing Interest
The authors declare no conflict of interest.
Funding
This paper is part of a Supplement supported by the Cystic Fibrosis
Foundation.
Acknowledgements
The authors would like to thank the Cystic Fibrosis Foundation for
grant support and the faculty mentor members of the EnVision:
Emerging Leaders in CF Endocrinology Program for their ongoing
mentorship of the program awardees.
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