Elexacafator/tezacaftor/ivacaftor resolves subfertility in females with CF: A two center case series

Abstract

Infertility and subfertility are commonly faced by females with cystic fibrosis (FwCF) and resulting in decreased contraceptive use and increased utilization of reproductive technologies. Elexacaftor-tezacaftor-ivacaftor (ETI) is a CFTR modulator that affects common causes of subfertility.

Two CF centers conducted a retrospective chart review on females with CF who were receiving ETI and became pregnant. We analyzed obstetrical-gynecological history, genotype, and clinical response to ETI therapy. Fourteen FwCF on ETI became pregnant. Half (7) of the FwCFs were previously attempting to conceive, but only three were using contraceptives. Four FwCF had a history of infertility; two were reconsidering use of reproductive technologies (IUI). Patients achieved conception at mean 8 weeks after initiating ETI. ETI may lessen CF-associated factors that affect fertility; however, its exact mechanism is unknown. This warrants counseling on contraceptive use and family planning prior to initiation of therapy and at routine intervals while utilizing ETI.

Introduction

Female persons with CF (FwCF) exhibit infertility and subfertility (defined as achieving conception after greater than 1 year of unprotected intercourse or utilization of reproductive technologies after a preceding year of infertility) at 24–35% compared to healthy control populations at 5–15% [1,2]. Most FwCF exhibit subfertility with a median time to conception of 12 months [3]. The perception of subfertility partially propagates habits of contraceptive underutilization with 35% of sexual encounters employing contraceptives compared to > 50% of the general public [1].

The mechanisms associated with subfertility in FwCF are heterogenous. One potential driver of CF-related subfertility is at the level of the cervical epithelium where dysfunctional CFTR results in impairments to sperm penetration due to alterations of the cervical mucus viscosity and pHJ [4]. In addition to direct effects on the cervical epithelium, secondary amenorrhea is common in the setting of a stress state due to chronic illness, frequent infection, persistent inflammation, uncontrolled diabetes and malnutrition [1]. Furthermore, characteristics common to many patients with CF, including low FEV₁, low Body Mass Index (BMI), pancreatic insufficiency, and bacterial colonization, have been identified as risk factors for infertility [1,2].

The recent therapeutic advancement of elexacaftor-tezacaftor-ivacaftor (ETI) restores CFTR function systemically and was shown to improve lung function, BMI, and quality of life [5 Extra-pulmonary effects from ETI have been hypothesized, including ameliorating subfertility secondary to increased CFTR function at the level of the cervical epithelium and improvements of overall health. With these encouraging outcomes, there has been rapid expansion in the use of ETI for eligible FwCF. Previously, several case reports on chronic ivacaftor and lumacaftor/ivacaftor therapy for responsive CFTR mutations have suggested that positive health effects resulted in increased fertility and higher rates of unexpected pregnancies [6, 7, 8]. Thus, ETI therapy may also reduce causes of subfertility. However, pregnant FwCF and those lacking highly effective birth control methods were excluded from the original CFTR modulator therapy studies. This absence of safety data represents an important void in our knowledge. Following widespread initiation of ETI in the fall of 2019 at two academic centers, a rapid increase in pregnancy was noted among females from our centers. The purpose of this article is to describe two CF Centers’ initial experience with increased pregnancies amongst FwCF taking ETI using a case series.

Methods

We performed a retrospective chart review of patients from two large academic centers located in the southeastern United states (University of Alabama at Birmingham and Medical University of South Carolina). Using the electronic medical record we assessed baseline demographics including genotype, BMI, lung function (FEV₁ % predicted), and obstetrical – gynecological history (contraceptive usage, prior pregnancies, utilization of advanced reproductive technologies and attempts at conception) of all adult females with child-bearing potential who became pregnant following the initiation of ETI.

Statistical analysis

Continuous data including BMI and FEV₁ were compared pre and post initiation of ETI for all subjects. Fertility history, contraceptive utilization rates and obstetrical rates were described from historical data. Descriptive statistics were conducted utilizing GraphPad Prism 8 and Excel ®.

Ethics statement

This retrospective analysis of patient demographics and outcomes was conducted after approval of the institutional review boards of the University of Alabama at Birmingham and the Medical University of South Carolina.

Results

From the census of two centers, 201 FwCF were identified as eligible for and received ETI based on CFTR genetics and of child-bearing potential. 14 individuals with childbearing potential (premenopausal females who have not had surgical sterilization) conceived after initiating ETI during our review period (October 2019 to May 2020). Review of gynecological history of this subset of patients revealed that two individuals pursued prior fertility treatments for a total of three attempts without success. Two other FwCF had not sought reproductive therapies despite greater than five years of infertility. Seven of the 14 patients reported they were not attempting to conceive with self-reported utilization of contraceptive prophylaxis including: condoms (2), natural family planning (1), or lack of prophylaxis (4). After initiation of ETI, time to pregnancy was established with a median of 8 weeks (range 1–17 weeks). Of note, one patient had a similar experience with her first child while enrolled in an open label lumacaftor/ivacaftor trial despite multiple years of infertility. 10 of the 14 FwCF on ETI elected to continue therapy after conceiving despite lack of clinical trials validating safety outcomes in pregnancy. This data is summarized in Table 1.

Table 1.

Obstetric and Gynecological History (n = 14).

Contraceptive UsageYesNo	311
Attempting to ConceiveYesNo	77
Previous PregnancyYesNo	77
History of Infertility	4
Prior Fertility Treatments	2

In those on ETI, the mean percent predicted FEV₁ at baseline was 58.5 (range 27–98% predicted). Baseline ppFEV₁ improved by 6% (range of 0–43% predicted) on ETI at a median of 4 weeks of follow-up after initiating ETI. BMI also increased during this time as shown in Table 2. However, not enough data was available account for pregnancy-related weight gain. At the time of this review, no exacerbations requiring hospitalizations were identified. One FwCF suffered a spontaneous abortion at 6 weeks which may or may not be attributed to ETI. Clinical outcome data on the 10 FwCF who elected to continue ETI after conception is summarized in Table 2.

Table 2.

Continued ETI Population Baseline Demographics (n = 10),

	Pre-ETI	Post-ETI
Genotype
Homozygous F508delHeterozygous F508del	82	–
Age (median, range, year)	32 (22–37)	–
FEV1 (median, range, % predicted)	61 (27–98)	67 (34–104)
BMI (median, range, kg/m2)	21(16.9–29.47)	22 (19.5–29.66)

BMI, Body Mass Index; ETI, elexacaftor-tezacaftor-ivacaftor

Discussion

In our case series we describe 14 instances of conception after initiation of ETI therapy. This occurred in 7 patients attempting conception, all of whom had a history of subfertility or infertility. Moreover, there were 7 instances of conception in FwCF not attempting to conceive and using various methods of contraception. A review of literature has noted decreased efficacy of chemical contraceptives with lumacaftor/ivacaftor through an unknown mechanism [9]. As our patients were not utilizing oral contraceptives the unknown interaction between ETI and chemical contraceptives did not alter our findings.

The median time to conception was 8 weeks but noted to be as early as 1 week for one patient. Timing was determined off of retrospective review of the EMR which inherently has a degree of inaccuracy. However, the effects of ETI are rapid in the first weeks of therapy initiation and may impact the cervical mucosa early on creating an improved environment for insemination.

While the etiology for increased fertility is unclear in our data, increasing evidence with similar outcomes due to several direct and indirect effects on CFTR activation involving F508del from highly effective modulators have demonstrated a change in fertility in FwCF [10]. Subsequent larger studies will determine if a similar increase in pregnancy rates observed after the initial ivacaftor approval for G551D will be observed and sustained in the post approval period for ETI [6].

ETI prescribing in an unstudied population highlights important clinical questions. Without study directed outcomes the provider must substitute clinical judgement for evidence-based medicine to determine if risks of the medication offset the risk of pulmonary decline. We cannot ascertain if l the benefit of decreased exacerbations, potential weight gain and improved FEV₁ (factors that improve pregnancy outcomes and fertility) outweigh unknown teratogenic potential and breast-feeding complications. Due to limited data some individuals will elect to suspend therapy during pregnancy which can lead to worsening pulmonary status and increased embryo risk. While the ETI combination on pregnancy outcomes has not been studied, minimal reports of harm have been documented with monotherapy and dual therapy. In a retrospective study with 61 patients from 31 international CF centers only 2 events were deemed to be secondary to modulator therapy (a pulmonary exacerbation and post-partum diagnosis of acute myelocytic leukemia) [11]. Within our own center we lack sufficient longitudinal data to make definitive statements. However, thus far we have not observed markers of worsening pulmonary or other health instability such as decline in FEV₁ or BMI, increased frequency of pulmonary exacerbations, or obstetric complications. Instead, we noted increases in BMI and FEV₁ which will be protective to mother and baby. We lack data on post-partum care with those taking TCT. Despite these limitations, of those involved in this study physician preference is for continued therapy throughout pregnancy to optimize pulmonary status. Due to the absence of large-scale evidence-based data, we encourage a shared decision-making process between clinicians and patients regarding pre-conception planning and fertility. Our clinical teams have expanded counselling regarding fertility in ETI-treated FwCF to include education on potentially increased fertility, safe sex practices and the consideration for reattempting natural conception prior to pursuing costly reproductive technologies. Since the effect of ETI on fertility is unknown, continued counseling beyond the initiation period of ETI may be prudent in a population who may underutilize contraception prophylaxis.

We recognize that this study has some noted limitations. We conducted a retrospective chart review without blinding. In addition, this data is drawn from only two CF centers within a limited geographic region of the southeastern United States. An untreated comparative cohort was not presented due to low numbers of patients not on ETI. This limitation is being addressed by a larger longitudinal study currently being conducted. The duration of therapy and sample size is small and may not reflect the outcomes of a larger study with longer duration. We also were unable to account for compliance with therapy, prior modulator therapy or fertility history of the male partners. All patients were reported equally whether actively attempting to conceive or not. Further investigation may show the observed fertility rate was not due to medication changes but the act of intent. While this study confirmed some key clinical parameters and suggests increased fertility, weight gain and FEV₁ improvement while on ETI, we are unable to ascertain if these clinical improvements are solely due to ETI therapy alone. Further clarification could be obtained with studies focusing on optimization of nutritional status and assessment of cervical mucosal function

In conclusion, this data demonstrates the need for further study to better understand the reproductive implications of ETI therapy and enhanced patient pre-conception counselling.