A descriptive cohort study of pregnancy and parenthood in women with cystic fibrosis

Highlights

• •Women with cystic fibrosis are experiencing improved health on modulator treatments and are increasingly undertaking pregnancy.
• •Outcomes are good but they have an increased rate of diabetes, premature birth and delivery by caesarean section.
• •Safe pregnancy involves pre-conception planning, careful management in pregnancy and ongoing support in parenthood.

Abstract

Women with cystic fibrosis (wwCF) are increasingly undertaking pregnancy. This study assessed the current state of relationships, fertility, pregnancy and parenthood in a total cohort of 217 wwCF. Overall, 64% of wwCF were in long-term heterosexual relationships, 32% were single and 4% were in same-sex relationships; 64 wwCF had 111 children; 97 (87.4%) were conceived naturally and 10 (9%) by assisted reproduction. One woman had two children by surrogacy, one couple adopted a child and six wwCF had a role as a step-parent. Of the 217 wwCF, 31 (14%) died at a mean age of 41.4 years; they had 18 children, and eight of these children (44%) were younger than 18 years old when their mother died. There was a marked increase in pregnancies associated with the introduction of CF modulator medications, from three in 2020 to 16 in 2023. There were 50 pregnancies between 2020 and 2024; 17 (34%) were not planned (five were terminated); and 15 (30%) partners did not have CF genetic tests pre-conception. There were eight miscarriages. Exacerbations of lung disease occurred in 11 (31%) completed pregnancies, gestational diabetes in 12 (34%), one gastrointestinal bleeding, and one pre-eclampsia. Delivery was by caesarean section in 14 pregnancies (40%), and four (11%) births were premature (<37 weeks gestation). Although outcomes are generally good, pre-conception planning is suboptimal, pregnancy is associated with increased complications and parenthood raises complex issues regarding prognosis. CF teams should have close links with maternal medicine services to meet the specific needs of wwCF.

Introduction

Cystic fibrosis (CF) is an autosomal-recessive condition caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein that regulates chloride and bicarbonate transport in epithelial cells.¹ Reduced ion transport results in viscid secretions and organ damage in the respiratory, gastrointestinal, pancreatic, hepatobiliary and reproductive tracts. Historically, women with CF (wwCF) rarely survived into the reproductive years to undertake pregnancy.^2,3 As the prognosis improved with intensive multidisciplinary care in specialist centres, wwCF achieved pregnancy and parenthood, but some did not live to see their child reach adulthood. In 2020, triple-combination CFTR modulator therapy (elexacaftor/tezacaftor/ivacaftor: ETI) was introduced into clinical practice. These medications treat the underlying cause by improving the function of the CFTR protein and have resulted in major improvements in the health and prognosis of people with CF.¹ This has been associated with a remarkable increase in pregnancy rates, with UK CF Registry data recording 58 births in wwCF in 2019, rising to a peak of 140 in 2022, and 116 in 2023.⁴

We, therefore, undertook this descriptive cohort study of all wwCF attending our CF centre to assess the current state of relationships, fertility, pregnancy and parenthood, and to plan for the provision of maternal medicine services in this modern era of CF.

Material and methods

Data were collected on relationships, fertility, pregnancy and parenthood status of a total cohort of women who attended our CF centre from 2014 to 2024. Patients underwent a formal annual review process that addressed many aspects of the disease. Patients gave signed consent for collection of data for research and submission to the national CF Registry, with approval by the regional ethics committee. During the annual review, patients were asked about their family life, relationships, and history or plans for parenthood. Relationships were documented as ‘single’, in a ‘long-term heterosexual relationship’ (married or co-habiting), in a ‘same-sex relationship’, ‘divorced/separated’, or ‘widowed’. Data on key medical parameters, including forced expiratory volume in one second (FEV₁) and body mass index, were collected at their annual review consultation in 2024, or from their last data for deceased patients. Further detailed data were collected prospectively on women undertaking pregnancy in the CFTR modulator era (2020–2024).

Results

Relationships: The relationship status and medical characteristics of the 217 wwCF who attended the CF centre between 2014 and 2024 are shown in Table 1. They were at different stages in their lifecourse and had a wide range of disease severity in terms of lung function and nutritional status; 17 (7.8%) had lung transplantation for advanced CF lung disease; 31 (14%) died during the study period. Overall, 64% had been in long-term heterosexual relationships, 32% were single and 4% were in same-sex relationships. Two identified as transgender female to male.

Table 1.

Medical characteristics and relationship status.

Total number wwCF  - Alive  - Deceased  - Post-lung transplantation Mean age (range) Mean FEV1 (range) Mean body mass index (range) Pancreatic insufficient CF diabetes Pseudomonas aeruginosa infection	217 186 (86%) 31 (14%) 17 (7.8%) 34.2 (18–82) years 67.3 (13–120) % predicted 24.1 (14.5–48.5) kg/m2 185 (85.2%) 65 (30%) 106 (48.8%)
Relationship status  - Single  - Long-term heterosexual relationship  - Divorced/separated  - Widowed  - Same-sex relationship  - Transgender female to male	69 (32%) 113 (52%) 21 (9.6%) 5 (2.3%) 9 (4%) 2 (0.9%)

wwCF: women with cystic fibrosis; FEV₁: forced expiratory volume in one second. Data from annual review consultation in 2024, or last data for deceased.

Fertility: 64 (29.5%) of 217 wwCF had 111 children; 97 (87.4%) were conceived naturally and 10 (9%) by assisted reproduction with in vitro fertilisation; in nine women this was for subfertility; in one case the male partner was a carrier of CF, and the couple underwent in vitro fertilisation with pre-implantation genetic testing (Table 2). Two women in same-sex relationships each had a child by insemination with donor sperm. One further woman had two children by surrogacy, having previously had a termination of pregnancy because of poor lung function. One couple adopted a child. The mean age at first pregnancy was 27.4 (range 16–37) years. None of the children had CF. Over the study period 12 wwCF had 13 terminations of pregnancy: two as the fetus had CF, two because of fetal anomalies, six unwanted pregnancies, and three because maternal health was too poor to tolerate pregnancy. Six wwCF had some parental role for nine step-children from their partner’s previous relationships.

Table 2.

Children of women with cystic fibrosis (wwCF).

65 women

Children 111 28 wwCF had one child 29 wwCF had two children Six wwCF had three children Two ww CF had four children Mean age (range) at first pregnancy: 27.4 (16–37) years

Conception 97 naturally conceived 10 by assisted reproduction  - Nine for subfertility  - One pre-implantation genetic testing Two by surrogacy Two donor sperm insemination

Other parental roles Adoption: one Step-parent: six wwCF for nine children Foster parent: none

Prognosis and parenthood

In the year after delivery, four of 28 (14%) wwCF had an exacerbation requiring intravenous antibiotics, mean FEV₁ fell by 2.1% (range -24% to +12%) and BMI changed from mean 24.8 (range 17.7–34.8) to 24.2 (17.5–31.6) kg/m². Of the 217 wwCF, 31 (14%) died over the study period at a mean age of 41.4 (range 21–82) years. The causes of death were CF lung disease in 18, CF liver disease in one and chronic lung allograft dysfunction after lung transplantation in five; seven women died from other causes (two of dementia, two of degenerative neurological disease, and one each of brain tumour, alcohol liver disease and cervical carcinoma). The 31 women who died had 18 children. At the time of the mother’s death, eight (44%) of the children were younger than 18 years old, at a mean age of 10.4 (range 1.5–17) years. One further woman who died had an adopted child, aged 5.5 years at the time of the mother’s death. Two women who died had termination of pregnancy because of their advanced CF lung disease. Two women were on a transplant waiting list, but died before donor lungs became available. Two wwCF with children went on to have subsequent successful lung transplantation. One wwCF undertook pregnancy after lung transplantation, but suffered lung rejection with a permanent deterioration in lung function.

Pregnancies in the CFTR modulator era

There were 50 pregnancies in 34 women between 2020 and 2024 (Table 3); 17 (34%) of these pregnancies were not specifically planned, and four underwent termination for unwanted pregnancy and one because of fetal anencephaly. Genetic testing of the partner had been undertaken in 35 (70%) before conception, and after conception in six; in nine cases, the partner did not have genetic testing. There were eight miscarriages. Exacerbations of lung disease occurred in 11 (31%) completed pregnancies, and gestational diabetes in 12 (34%); one wwCF developed gastrointestinal bleeding on aspirin, and one developed pre-eclampsia. Delivery was by caesarean section in 14 (40%), and four (11%) births were premature (<37 weeks gestation). Overall, 46 wwCF (94%) were on ETI CFTR modulators and 41 (89%) opted to continue this treatment in pregnancy; two of the women who stopped ETI showed a deterioration in their FEV₁ and resumed treatment later in pregnancy. None of the children had CF, congenital anomalies or cataracts. One child had transient elevation of liver function tests.

Table 3.

Pregnancies and outcomes in the CFTR modulator era 2020–2024.

Characteristics 50 pregnancies in 34 wwCF Mean age (range) Mean BMI (range) Mean FEV1 (range) CF diabetes Pancreatic insufficiency Pseudomonas aeruginosa infection On ETI CFTR modulator  - ETI continued in pregnancy	28.7 (18.5–43) years 23.47 (18.6–34.4) kg/m2 81 (32–121) % predicted 12 (24%) 41 (82%) 23 (46%) 46 (92%) 41 (89%)
Number of pregnancies 2020–2024  - 2020  - 2021  - 2022  - 2023  - 2024 Terminations  - Unwanted pregnancy  - Fetal anomaly Miscarriages Ongoing pregnancy	50 3 11 8 16 12 5 4 1 8 3
Complications in 35 completed pregnancies Gestational diabetes Exacerbations CF lung disease Gastrointestinal bleeding Pre-eclampsia	12 (34%) 11 (31%) 1 1
Deliveries Caesarean section Premature birth (<37 weeks)	14 (40%) 4 (11%)

wwCF: women with cystic fibrosis. ETI: elexacaftor/tezacaftor/ivacaftor. FEV1: forced expiratory volume in one second. BMI: body mass index

Discussion

This study provides comprehensive data on the current state of relationships, fertility, pregnancy and parenthood for a complete cohort of women attending a CF centre. There are over 2,000 variants of the CF gene, such that CF is a diverse condition that varies considerably in complexity, clinical course and prognosis.⁴ These women were at different stages in their lifecourse and had a wide range of disease severity and stage. Advice regarding pregnancy and pregnancy prevention needs to be individualised to the woman’s particular circumstances.

Nearly all men with CF are infertile because of congenital bilateral absence of the vas deferens, but can achieve biological fatherhood by assisted reproduction.⁵ In contrast, wwCF are usually fertile but have lower rates of pregnancy than the general population and may take longer to achieve pregnancy. When forming relationships, wwCF face the issue of disclosure of their diagnosis to a partner. Some may voluntarily avoid pregnancy and parenthood. Ill health and reproductive decisions might impair their relationships, although our data suggest that wwCF are successful in forming and sustaining relationships. Shteinberg et al⁶ reported a multinational study showing that 40% of wwCF attempted pregnancy; 35% had subfertility in that they did not achieve pregnancy within 1 year of trying, compared to about 5–15% in the general population, but 80% of these women subsequently achieved pregnancy. CFTR is expressed in the genital tract and thickened cervical mucus may impair fertility.³ The remarkable increase in the rate of pregnancy in the CFTR modulator era is reflected in our study.⁴ This may indicate a direct effect of CFTR function in the reproductive tract with improved fertility, but it is also likely to reflect improved overall health and wellbeing.^7,8 wwCF currently undertaking pregnancy have already sustained lung damage, but experience a substantial improvement in health on CFTR modulators. However, about 10% of people with CF have mutations that are not amenable to treatment with CFTR modulators.⁴

Ideally, pregnancy should be planned such that maternal health can be optimised, advice regarding medications can be given, and genetic testing of the partner can be performed. Some wwCF have severe disease such that they are unlikely to sustain a pregnancy. Alternative options for parenthood include adoption, surrogacy, foster care or acting as a step-parent, although these are relatively uncustomary, and are still influenced by the prognosis of the woman.⁹

The rate of unplanned pregnancy and terminations in our study is similar to that reported in other studies of wwCF and in the general population.^8,12 Many contraceptive methods are equally suitable for wwCF as for the general population, but consideration should be given to specific CF-related complications such as osteoporosis, liver disease and diabetes.^10,11 As wwCF transition through adolescence to adulthood, they need accurate information on their sexual health and reproductive options. Sexual orientation and gender identity need to be considered to enhance discussions in a sensitive and individualised way.¹²

The current outcomes of pregnancy in CF are generally good, but wwCF have increased rates of preterm births, low birth weight, diabetes and delivery by caesarean section, compared to the general population. An Obstetric Surveillance System study of 71 pregnancies in wwCF receiving antenatal care in the UK between 2015 and 2017 reported live birth of 69 infants, one infant death, no maternal deaths, one early miscarriage, four terminations and three sets of twins.¹³ The mean gestation at delivery was 36.2 weeks, and mean birth weight was the 61st centile. Thirty babies (43%) were born by unassisted vaginal delivery, 14 had assisted vaginal deliveries and 25 (36%) babies were born by caesarean section. This study was performed before triple CFTR modulator therapy was in clinical practice. Outcomes may improve further in the CFTR modulator era, although this may depend on whether women opt to undertake high-risk pregnancies at lower levels of lung function.^14,15 Pregnancy is already quite common in wwCF with poor lung function, below levels of FEV₁ of 60%, which is a commonly used guide for ‘safe pregnancy’.¹⁶ Baseline CF severity has an adverse impact on pregnancy and infant outcomes, but does not affect the rate of disease progression.¹⁷

There is then the impact on the child and the woman’s partner of possible decline in maternal health and premature death. Lung transplantation offers the possibility of improved prognosis. Pregnancy after transplant surgery is also an achievable goal in selected women, but guidance recommends that allograft function should have been stable for 2 years.¹⁸

Pre-conception counselling for wwCF depends on the stage and severity of the disease. Often when the woman’s health is good and her CF is well controlled, the advice can be optimistic, supporting the couple to achieve parenthood. If the couple have difficulty in achieving pregnancy, timely referral for assessment and assisted reproduction may be needed. Folic acid supplementation is recommended before conception and during the first trimester to reduce the risk of neural tube defects. Most of the standard CF medications are considered safe in pregnancy and guidelines recommend continuation of inhaled antibiotics and mucolytics.^19,20 Clinicians usually avoid ciprofloxacin, co-trimoxazole, doxycycline and aminoglycosides in pregnancy and use safer alternatives. Maintaining maternal health is important to improve fetal outcomes and there are risks to both mother and child in stopping some medications. CFTR modulators cross the placenta and are present in breast milk, and they are not licensed in pregnancy. Initial experience is reassuring about their safety in pregnancy and shows that stopping treatment often causes a decline in lung function and an increased risk of exacerbations.^21,22 Most women, therefore, now opt to continue CFTR modulators in pregnancy. Neonatal cataracts have been observed in rats exposed to CFTR modulators in utero. Thus, it is recommended that babies exposed to CFTR modulators should be examined for cataracts and should also have measurement of liver function for potential hepatotoxicity. There is also the possibility of false negative newborn CF screening, measuring immunoreactive trypsinogen.

wwCF may have CF diabetes, which is associated with an increased risk of congenital anomaly. Diabetes in pregnancy is associated with fetal growth abnormalities, macrosomia and increased perinatal morbidity and mortality. An oral glucose tolerance test should be performed in the first trimester and at 24–28 weeks if there is no pre-existing CF diabetes. An individual management plan for delivery should be made, depending on gestational age, disease severity and fetal wellbeing. If maternal health is well maintained and the fetus is growing well, vaginal delivery at term can be anticipated.

It is important that wwCF are well supported in the postnatal period and throughout parenthood, as they are at risk of a decline in their health as they struggle to manage the dual roles of parent and patient.^23,24

Undertaking pregnancy and parenthood is an important life achievement, but should involve pre-conception planning, careful management during pregnancy and ongoing support in parenthood. Limitations of our study are that it is a single-centre study and the wwCF were at different stages in their lifecourse. Prospective studies, such as the MAYFLOWERS and HOPeCF studies, are now in progress to provide further guidance on pregnancy and parenthood in this new era of CF.^25,26

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Ethics approval and consent to participate

Patients gave written informed consent for collection of data for research and submission to the national CF Registry, with approval by the ethics committee (East of England – Cambridge East Research Ethics Committee REC 24/EE/0012 IRAS project 209459).

Data availability statement

The data that support the findings in this study are available from the corresponding author upon reasonable request.

CRediT authorship contribution statement

Aleksandra Duffy: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Conceptualization. Susan Parker: Writing – review & editing, Data curation, Conceptualization. Simon Williams: Writing – review & editing, Data curation, Conceptualization. Kenneth Hodson: Writing – review & editing, Data curation. Simon Doe: Writing – review & editing, Data curation. Carlos Echevarria: Writing – review & editing, Data curation. Stephen J. Bourke: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.