Pregnancy outcomes in patients from a Scottish Adult Cystic Fibrosis Unit taking elexacaftor/tezacaftor/ivacaftor,2020

Abstract

Background

Elexacaftor/tezacaftor/ivacaftor (ETI) was made available to eligible women in September 2020 by NHS Scotland.

Methods

Retrospective data collection for the 13 pregnancies in women taking ETI from the West of Scotland Adult Cystic Fibrosis Unit, September 2020–December 2023.

Results

Mean pre-pregnancy FEV1 was 2.26L, 70% predicted (range 1.25–3.19); (38–86% predicted). Mean FEV1 post-pregnancy was 2.29L, 71% predicted (range 1.49–3.40); (45–92% predicted). The mean age at conception (29 years) and mean percentage predicted FEV1 (70%) were higher than in other UK studies. Two pregnancies resulted in miscarriage, the remaining 11 pregnancies resulted in a live birth. Seven women had a pulmonary exacerbation of CF during pregnancy. Three of four women with FEV1 < 60% predicted had uncomplicated pregnancies with no pulmonary exacerbations.

Conclusion

We demonstrate that people with CF and varying spectrums of lung disease who take CFTR modulators can have uncomplicated pregnancies with positive lung function outcomes.

Keywords

Cystic fibrosis pregnancy CFTR modulator fertility

Background

The UK Cystic Fibrosis (CF) Registry Annual Data Report for 2021 demonstrates that across the UK, 103 women with CF had babies in 2021, relative to 58 in 2019.¹ Today, with the introduction of transformative Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators and improvements in genetic testing, there is a known increase in the number of adults living with CF past their fourth decade.² This positive increase in median survival of women with CF reverberates to those of child-bearing age. This population must tackle subfertility, genetic counselling, and uncertainty in their decision to conceive.³ Materno-fetal outcomes in the era of CFTRs remain a grey area in the UK and worldwide, with the anticipation of clinical trials such as Mayflowers to provide needed answers.⁴

Elexacaftor/tezacaftor/ivacaftor (ETI) combination therapy was made available to eligible women by NHS Scotland in September 2020.⁵ Previous studies on pregnancy and CF in the UK have yielded data on maternal and fetal outcomes – lung function, complications of pregnancy, gestation, birthweight – but none with CFTR modulator use in pregnancy.^6–8 This is the first Scottish report of pregnancy outcomes in women taking ETI.

Method

Data was collected retrospectively from the West of Scotland Adult CF Unit's clinical information system from September 2020 to December 2023. Data included patient demographics; ETI use before, during and after pregnancy; pulmonary exacerbations; complications during pregnancy; birth outcome and breastfeeding. A pulmonary exacerbation was defined as requiring oral or IV antibiotics, with or without hospitalisation.

The best pre-pregnancy FEV1 (forced expiratory volume in 1 s) was taken in the first 12 months prior to conception. For postpregnancy FEV1, the best result from 24 months following birth was taken, depending on clinic attendance. Body mass index (BMI) was collected 12 months before and 12 months after conception.

Results

Thirteen pregnancies (12 unassisted) were identified from September 2020 to April 2023 (present) in the West of Scotland Adult CF Unit. Data collection continued until December 2023 to account for the delivery of all women.

Keywords: Pregnancy complications, infectious, puerperal disorders

Demographics

Table 1 describes patient characteristics. Of the 13 women, all Caucasian, 62% were ΔF508/ΔF508 homozygote. Nine were colonised with Pseudomonas Aeruginosa, four had CF-related diabetes (CFRD). The mean duration of ETI use prior to conception was 16 months. The mean age of conception was 29 years (17–37 years), with 54% conceiving over the age of 30 years; 77% of women were primiparous; 46% of pregnancies were unplanned.

Table 1.

Patient characteristics.

Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8	Patient 9	Patient 10	Patient 11	Patient 12	Patient 13
Age of conception	27	36	31	36	17	34	23	20	30	36	22	22	37
Planned pregnancy	Yes	Yes	No	Yes	No	No	Yes	Yes	Yes	No	No	No	Yes
CF genetics	ΔF508/ΔF508	ΔF508/R560T	ΔF508/ΔF508	ΔF508/ΔF508	ΔF508/ΔF508	ΔF508/G542X	ΔF508/c.2052dupAA	ΔF508/ΔF508	ΔF508/ΔF508	ΔF508/ΔF508	ΔF508/ΔF508	P67L/S492F	ΔF508/R560T
Microbial colonisation	P. aeruginosa ^a	P. aeruginosa	P. aeruginosa	P. aeruginosa	nil	P. aeruginosa	P. aeruginosa	Staphylococcus aureus	P. aeruginosa	P. aeruginosa	Mycobacterium abscessus	H. influenzae	P. aeruginosa
ETI use in pregnancy: #Months prior to conception	Yes: 1 month	Yes: 10 months	Yes: 23 months	Yes: 13 months	Yes: 11 months	No: 23 months^b	Yes: 8 months	Yes: 4 months	Yes: 22 months	Yes: 26 months	Yes: 29 months	Yes: 20 months	Yes: 26 months
#Prior pregnancies	0	0	0	1	0	0	0	0	1	0	0	0	1
Gestational diabetes	Yes	CFRD^c	CFRD	yes	No	CFRD	No	No	Yes	No	No	No	CFRD
Live birth	Yes	Yes	No	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes

Pseudomonas aeruginosa (P. aeruginosa).

Took ETI at time of conception however advised to stop and discontinued throughout pregnancy.

CF-related diabetes (CFRD).

Pregnancy outcomes

Of the 13 pregnancies, two resulted in a miscarriage (13 + 5/40 and 13 + 0/40). Furthermore, 12 women elected to continue ETI during their pregnancy and 1 patient was advised to discontinue ETI, this pregnancy ended in miscarriage. For the 11 live births on ETI, the mean pre-pregnancy BMI was 23.5 kg/m² (range 20.4–28.1) and the mean post-pregnancy BMI was 23.8 kg/m² (range 21.5–28.8). Three women developed gestational diabetes. Recorded complications of pregnancy resulting in hospital admission prior to labour were recurrent kidney calculi (10 days); anaemia and hypertension (1 day); PV bleeding (2 days). Six women (54%) had no complications of pregnancy and no hospitalisation prior to labour.

Lung function

Graph 1 shows changing FEV1 values per patient before and after birth, for the 11 live births in women taking ETI from the sample. Mean pre-pregnancy FEV1 was 2.26L, 70% predicted (range 1.25–3.19); (38–86% predicted). Three women had pre-pregnancy FEV1 < 60% predicted. Mean FEV1 post-pregnancy was 2.29L, 71% predicted (range 1.49–3.40); (45–92% predicted). Of these 11 pregnancies, 7 had at least 1 pulmonary exacerbation requiring oral antibiotic treatment, of them 5 women had exactly 1 pulmonary exacerbation. No women required intravenous antibiotics during pregnancy.

Graph 1.

FEV1 pre- and post-pregnancy.

Birth outcomes and breastfeeding

Table 2 summarises birth outcomes, there was one twin birth. Four women had a spontaneous vaginal delivery (SVD), five had elective caesareans, one had a planned caesarean (failed induction of labour) and one had an emergency caesarean (delay in the second stage of labour). The mean gestation of spontaneous vaginal delivery was 37 + 0/40 weeks. The reasons for elective caesarean were malpresentation and previous caesarean. For singleton pregnancies, the mean birth weight was 3279 g (range 2180–3863 g). Other than the twins, one neonate had a low birthweight <2500 g. Nine neonates (82%) had no complications at delivery; one required a neonatal intensive care unit (NICU) stay for 9 days with respiratory support and transient neonatal jaundice and was discharged with no ongoing complications. The twins spent 17 days in the NICU, discharged with no ongoing complications. Six women breastfed for a mean duration of 3 months on ETI. No ongoing health concerns have been reported in the 12 infants born to women who took ETI during pregnancy.

Table 2.

Live birth outcomes for patients taking ETI.

Birth Outcomes	Patient 1	Patient 2	Patient 4	Patient 5	Patient 7	Patient 8	Patient 9	Patient 10	Patient 11	Patient 12	Patient 13
Gestation at birth	39 + 4/40	35 + 1/40	37 + 4/40	38 + 2/40	32 + 1/40	34 + 3/40	38 + 0/40	38 + 0/40	35 + 1/40	38 + 0/40	37 + 0/40
Delivery type	SVD vertex	Elective caesarean	Elective caesarean	SVD vertex	Emergency caesarean	SVD breech	Elective caesarean	Planned caesarean	Elective caesarean	SVD vertex	Elective caesarean
Singleton or multiple	singleton	singleton	singleton	singleton	twin	singleton	singleton	singleton	singleton	singleton	singleton
Birth weight (grams)	3704	3447	3478	3863	Baby 1: 1885 Baby 2: 1755	2180	3066	3048	2750	3554	3708
Breastfed?	Yes, 2 months	Yes, 3 months	no	No	Yes, 4 months	Yes, 5 months	Yes, 4 weeks	No	No	No	Yes, 3 months

Discussion

Fertility

The 6 unplanned pregnancies (46%) had a mean duration of ETI use of 22 months prior to conception. The 7 planned pregnancies had a mean duration of ETI use of 12 months prior to conception. Our sample would suggest that the chance of unplanned pregnancy increases with prolonged ETI use. Unlike men, women with CF have anatomically normal reproductive tracts. CFTR modulators improve CFTR function at the fallopian tubes, cervical epithelium and endometrial epithelium, which in turn improves cervical mucus consistency and pH.^9,10 Is the increasing rate of unplanned pregnancy in this population taking ETI due to overall health improvement, fertility improvement or both – an area for further research? CF healthcare professionals should advise women and their partners about increased fertility when taking ETI.

Lung function

Pre-pregnancy lung function is the singular most important factor that predicts birth outcomes. Pre-CFTR modulator era studies have shown that pregnancy in women with FEV1 of <60% predicted can lead to increased risk of materno-fetal complications such as maternal lung infections, increased risk of preterm birth, low birthweight and perinatal death.^11,12 In our sample, women are conceiving at a higher mean age of 29 and with a higher mean predicted FEV1 of 70% relative to other UK studies. The overall change in FEV1 for those who continued to take ETI during their pregnancy was negligible. Interestingly, a previous case study reports that 5 of 6 women who ceased ETI on conceiving resumed therapy during pregnancy due to significant respiratory deterioration.¹³ This, along with our data, suggests that continuing ETI during pregnancy contributes to clinical stability. Our three women with FEV1 < 60% predicted had uncomplicated pregnancies with no inpatient admissions prior to delivery and no pulmonary exacerbations. Templeton et al. report 28 pregnancies within the same Scottish CF unit in 2008–2018, prior to the introduction of CFTR modulators.¹⁴ While pre-pregnancy lung function in the two patient groups is similar, there were fewer complications in the current group of women who took ETI during pregnancy, with fewer respiratory exacerbations and less hospitalisation. This shows that pre-pregnancy lung function as a predictor of pregnancy outcome may be variable in the current CFTR modulators era. In our sample the 3 multiparous women had 1 previous birth each, of note research has shown CF women with ≥3 pregnancies can have accelerated respiratory deterioration and higher rates of prematurity and newborn complications.¹⁵

Birth and neonatal outcomes

There is limited data on the safety of ETI during pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.¹⁶ A previous case series of 45 ETI-exposed pregnancies reported complications in 2 mothers and 3 infants, of unknown relatedness to ETI according to clinicians.¹³ As per LactMed^®, ETI use is probably safe during breastfeeding, but data is limited.¹⁷ Results from two maternal-infant pairs indicate low levels of ETI in milk and infant serum whereas an international survey found no adverse effects in 26 breastfed infants of ETI-exposed mothers.¹⁷ Examination for cataracts and infant monitoring of bilirubin and liver enzymes have been recommended in breastfeeding with maternal CFTR modulator use.¹⁷ Currently, the contribution of ETI breastfeeding to congenital cataracts cannot be determined and there is limited data on ETI breastfeeding and its association with liver enzyme abnormalities. In our sample, no pregnancy or neonatal complications were felt to be related to ETI use. Only one neonate had adverse outcomes but was discharged with no long-term complications. We provide further data to support discussions between CF healthcare professionals and women deciding whether to continue ETI during pregnancy.

Pregnancy outcomes in CF with ETI vs no modulator

Table 3 summarises previously published research comparing pregnancy outcomes in CF with ETI versus no modulator.^14,18–20 Similar to our findings, Etherington et al. show a significant increase in unplanned pregnancies (67% vs. 40%, p = 0.003) in the ETI group, along with a reduction in antibiotic use during pregnancy with a trend towards a reduced rate of decline in FEV1.¹⁸ Moreover, 19% of the ETI group had preterm birth vs. 43% in the non-ETI group, p = 0.03, and 50% of ETI-babies were breastfed.¹⁸ Jain et al. show an overall decline in percent predicted FEV1 from pre-pregnancy to post-pregnancy in the non-ETI group, which was not observed in the ETI group.¹⁹ Interestingly, BMI increased from pre-pregnancy to during pregnancy in both groups but with no significant change post-pregnancy.¹⁹ Dau et al. also had significantly higher post-pregnancy BMI in the ETI group (28.1 kg/m²) relative to the non-ETI group (22.8 kg/m², p = 0.003).²⁰ This suggests closer weight monitoring in pregnant women with CF is needed. Dau et al. show longer gestation (non-ETI 34.4 weeks vs. ETI 36.8 weeks, p = 0.01) and significantly higher birthweight in the ETI group (non-ETI 2744 g vs. ETI 3187 g, p = 0.03).²⁰ Our data provides further evidence to suggest that continuing ETI during pregnancy maintains FEV1 and BMI at pre-pregnancy levels and results in fewer pre-term births with increased infant birth weight.

Table 3.

Pregnancy outcomes ETI /no modulator.

Authors	Jain et al.	Etherington et al.	Dau et al.	Valcheva/Templeton et al.
n (ETI/no modulator)	77/193	24/26	12/8	12/28
Mean age at conception (years)	28.5/28.6	27.5/28.9	28.6/26.3	29/-
Unplanned pregnancy (%)	46/39	67/40	–	46/-
Unplanned pregnancy (%)	46/39	p = 0.003	–	46/-
Pre-pregnancy BMI (kg/m²)	22.2/22.4	24.5/21.7	–	23.5/-
Pre-pregnancy BMI (kg/m²)	22.2/22.4	p = 0.01	–	23.5/-
Post-pregnancy BMI (kg/m²)	–	–	28.1/22.8	23.8/-
Post-pregnancy BMI (kg/m²)	–	–	p = 0.003	23.8/-
Change BMI pre- to post-pregnancy	2.05/0.07	–	–	0.3/-
Pre-pregnancy FEV1 (%)	71.2/74.9	–	–	70/74
Post-pregnancy FEV1 (%)	–	–	73.8/62.1	71/60
Post-pregnancy FEV1 (%)	–	–	p = 0.18	71/60
Change pp FEV1 pre to during pregnancy (%)	2.6/-2.36	–	–	1/-14
Change in pulmonary exacerbations pre- to during pregnancy	0.61–1.1	–	–	–
Antibiotic use during pregnancy (days)	–	7/24	–	–
Antibiotic use during pregnancy (days)	–	p < 0.01	–	–
Preterm birth %	29.8/34.5	19/43	–	36/52
Preterm birth %	29.8/34.5	p = 0.03	–	36/52
Gestation birth (weeks)	–	–	36.8/34.4	37/36
Gestation birth (weeks)	–	–	p = 0.003	37/36
Mean birthweight (g)	–	–	3187/2744	3279**/-
Mean birthweight (g)	–	–	p = 0.03	**for singleton pregnancies
Low birthweight (%)*	21.7/21.1	No data	No data	27/-
*defined to be <2.5kg	21.7/21.1	No data	No data	27/-
Breastfed (%)	–	50/35	–	55/-
Breastfed (%)	–	p = 0.04	–	55/-

Conclusion

We demonstrate that ETI may improve fertility in women with CF and that continuing ETI during pregnancy results in no deterioration in lung function or BMI; fewer respiratory exacerbations; and a reduced rate of pre-term birth compared to studies of CF pregnancies where ETI was not taken. Our study is the first of its kind for Scotland.

Footnotes

Acknowledgements

The authors would like to acknowledge all the hard-working staff at the West of Scotland Adult Cystic Fibrosis Unit.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable.

Informed consent

Not applicable.

Guarantor

Ivaila Valcheva.

ORCID iD

Ivaila Valcheva

Iona Paterson

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Pregnancy outcomes in patients from a Scottish Adult Cystic Fibrosis Unit taking elexacaftor/tezacaftor/ivacaftor,2020–present

Abstract

Background

Methods

Results

Conclusion

Keywords

Background

Method

Results

Demographics

Pregnancy outcomes

Lung function

Birth outcomes and breastfeeding

Discussion

Fertility

Lung function

Birth and neonatal outcomes

Pregnancy outcomes in CF with ETI vs no modulator

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

Ethical approval

Informed consent

Guarantor

ORCID iD

References