Management of pregnancy in cystic fibrosis

Fertility in women with CF

Many, but not all, women with CF are able to conceive without medical intervention. While the rate of subfertility is 5–15% in the general population, researchers have shown the rate of subfertility to be as high as 35% in a cohort of women with CF, with pancreatic insufficiency and advanced maternal age being risk factors [12]. In addition to the overall impact of CF on a woman's health and nutritional status, CFTR may directly influence female fertility. The CFTR protein acts as both a chloride and bicarbonate channel and thus affects both the hydration and pH of secretions not only in the airways and gastrointestinal tract but also in the female reproductive tract, including vagina, cervix, uterus and fallopian tubes. Normal CFTR function leads to thin, watery secretions in the reproductive tract to facilitate passage of sperm through the cervix and uterus and the alkaline pH impacts capacitation (or activation) of sperm to allow fertilisation of the egg. CFTR modulator therapy may be able to directly reverse some of these barriers to conception in CF [1].

Preconception considerations

With the increasing number of pregnancies being observed in people with CF, discussions regarding pregnancy and parenthood should begin early and occur often. Similar to the management of pregnancy in other chronic illnesses, preconception discussions in people with CF should begin during early adolescence in the paediatric CF care setting and continue into adulthood to allow time for optimisation of preconception health [13, 14]. An integral aspect of preconception health includes genetic testing. Carrier screening should be offered to potential reproductive partners to identify the risk of having an infant born with CF. Next-generation genetic sequencing provides a comprehensive CFTR gene mutation evaluation and is recommended for all potential reproductive partners of people with CF [3, 15]. If the reproductive partner is identified as a carrier, a referral to genetic counselling is recommended to discuss further reproductive options as well as additional diagnostic testing [3].

Nutritional status, glucose control and pulmonary function are important aspects to optimise in people with CF to mitigate maternal and infant morbidity, and often require a multidisciplinary team of CF clinicians and high-risk obstetric expertise. Pancreatic insufficiency, a common extrapulmonary manifestation of CF that impacts up to 85% of individuals, can result in poor nutritional status and weight loss secondary to malabsorption [16]. Poor nutritional status is associated with premature and low birth weight infants [17, 18]. Nutrition optimisation through diet, vitamin repletion and pancreatic enzyme replacement therapies should be a priority in the preconception period. A body mass index (BMI) of at least 22 kg·m⁻² is the ideal goal prior to conception [3, 19]. Furthermore, up to 50% of people with CF of gestational capacity have CF-related diabetes (CFRD) [3]. Hyperglycaemia preconception is associated with an increased risk of fetal malformations and hyperglycaemia during pregnancy has been associated with fetal macrosomia, neonatal hypoglycaemia and hyperbilirubinaemia as well as increased caesarean delivery [2, 20]. The mainstay of treatment for CFRD is subcutaneous insulin as oral agents have been shown to be less effective [3]. Thus, adequate glucose control with insulin should be achieved prior to conception as well as throughout the duration of pregnancy with target haemoglobin A1c (HbA1c) of <6.5% at the time of conception and <6.0% during pregnancy [21, 22]. To screen for CFRD prior to pregnancy, woman with CF should have a 75-g oral glucose tolerance test (OGTT) done when pregnancy is confirmed unless they have had a OGTT within the prior 6 months. Gestational diabetes is more common in women with CF, occurring in 10–36% of pregnancies versus in <10% of pregnancies in the general population. Care guidelines for CFRD, which include guidance for pregnant women with and without CFRD, recommend that OGTT should be performed at 12–16 weeks and at 24–28 weeks of pregnancy to screen for development of gestational diabetes [23].

Pulmonary function, as measured by forced expiratory volume in 1 s (FEV₁) % predicted, is a commonly used marker of lung health for people with CF. Preconception discussions surrounding the potential impact of pregnancy on lung function, and therefore on both maternal and infant health are needed. Disease severity and the implications for maternal and neonatal outcomes has also been a focus of recent research. When stratified by disease severity, individuals with moderate-to-severe disease (defined as FEV₁ ≤60% predicted and/or BMI ≤21 kg·m⁻² prior to pregnancy) experience more disease-related complications throughout pregnancy [24]. In addition, studies have shown that more severe disease is associated with a higher risk of preterm delivery, need for caesarean delivery, as well as low fetal birthweight [24, 25]. While lung function may improve with use of CFTR modulators in the preconception period, use of modulator therapies has allowed even those with very severe lung disease to conceive [5], thus potential complications associated with advanced lung disease and pregnancy continue to be important to discuss. Therapies aimed at maintaining lung health, such as inhaled mucolytics and antibiotics during the preconception period should be a priority. In addition, it is important to discuss the potential impact of pregnancy on maternal lung health, including discussion of potential increased morbidity such as more frequent need for acute intervention, prior to conception. Historical reports of the impact of pregnancy on lung function vary. In some historical small, single-centre studies, and in a nested-cohort study and a registry study in which pregnant people had higher baseline lung function than that of those who did not become pregnant, there was no significant difference in lung function in pregnant people with CF when compared from baseline to post-partum follow-up visits [26–29]. However, in a modern cohort, Jain et al. [30] examined the impact of pregnancy on lung function, including the interplay of moderately and highly effective CFTR modulators. The results demonstrated a small (∼2%), but statistically significant decline in FEV₁ % predicted in pregnant people not using modulators or using moderately effective modulators that was mitigated by use of highly effective modulators. Future analyses will focus on differences in baseline health status, modulator use by trimester and modulator withdrawal in this cohort [30].

Medication management during pregnancy

Pulmonary exacerbation treatment

Despite recent advances in therapies, pulmonary exacerbations, characterised by acute worsening of pulmonary symptoms and/or a decrease in lung function warranting antibiotic treatment, occur in people with CF and are associated with increased morbidity, decreased quality of life and ultimately, decreased survival [39]. As pregnancy rates in women with CF have increased over time, researchers have evaluated pulmonary exacerbations in pregnancy. While some retrospective data show no differences in pulmonary exacerbation rates between pregnant and non-pregnant women with CF, data from the Epidemiologic Study of CF demonstrated that pregnancy was associated with increased antibiotic use as well as increased outpatient and inpatient hospital visits which were likely multifactorial [40]. Furthermore, researchers have shown when stratified by disease severity, individuals with more severe disease require more days of intravenous antibiotics compared to those with mild disease [24]. Closer surveillance for pulmonary exacerbation treatment as well as for non-CF related obstetric complications could explain these finding, although it is unknown whether hormonal fluctuations or other physiological changes of pregnancy contributed.

General approaches for pulmonary exacerbation treatment in people with CF consists of optimising airway clearance as well as use of oral or i.v. antibiotics against the individual's current or most recently cultured respiratory pathogens. Although contemporary standardised guidelines do not exist for pulmonary exacerbation treatment, oral antibiotics are generally used for mild symptoms while i.v. antibiotics are used for moderate-to-severe symptoms and in those who are critically ill [39]. We showed that CF clinicians prefer to treat a mild pulmonary exacerbation with oral antibiotics and a severe pulmonary exacerbation with two i.v. antibiotics, which aligns with practice patterns in non-pregnant people with CF [34, 39]. Systemic antibiotic use in pregnancy is challenging due to placental transfer and risk for associated teratogenesis. See table 2 for considerations when prescribing the most commonly used antibiotics in pulmonary exacerbation treatment. Staphylococcus aureus and P. aeruginosa are the two most prevalent pathogens in people with CF, and antibiotic directed therapy against these two agents are commonly required [2, 8, 9]. Systemic antibiotics typically used in CF to target methicillin-susceptible S. aureus (MSSA) include the classes of penicillins and cephalosporins, both of which are compatible to use throughout pregnancy and lactation [11]. Treatment of methicillin-resistant S. aureus (MRSA) in non-pregnant people with CF includes trimethoprim/sulfamethoxazole, vancomycin or linezolid. While trimethoprim/sulfamethoxazole is a commonly prescribed oral option for non-pregnant patients with CF, this medication is avoided during pregnancy due to potential harmful effects of both components. Specifically, trimethoprim may impair folic acid metabolism and sulfonamide has been associated with fetal haemolytic anaemia and neonatal hyperbilirubinaemia and is contraindicated in pregnancy [11]. Thus, the two most widely used antimicrobials include i.v. vancomycin and oral and/or i.v. linezolid. Human studies of vancomycin have been limited in use during the first trimester, but no teratogenic effects have been associated with its use. Thus, vancomycin is considered “probably safe” during the first trimester and is compatible throughout the remainder of pregnancy and lactation [11]. Linezolid is another option to treat MRSA if allergies or intolerance prevent use of vancomycin. While animal reproductive models have not shown any teratogenic effects of linezolid use during pregnancy, there is a lack of human controlled studies and data have been limited to published and post-marketing case reports. Thus, use during pregnancy is suggested if the potential benefits outweigh the risks. Furthermore, linezolid is present in human breast milk, and while there are no data evaluating use of linezolid in lactation, data have shown that the two most commonly reported adverse events in infants receiving linezolid are diarrhoea and vomiting. It is recommended that if systemic linezolid is required during lactation, infants exposed are monitored for diarrhoea and vomiting throughout the duration of therapy [41, 42].

The standard approach for systemic treatment of P. aeruginosa in non-pregnant people with CF has been use of two antipseudomonal agents to increase intrapulmonary activity and minimise development of resistance of pathogens [39]. Fluoroquinolones including levofloxacin and ciprofloxacin, are commonly used oral antibiotics used to treat P. aeruginosa. Their use has been typically avoided in pregnancy given concern for cartilage damage in animal studies. However, recent studies have shown low risk of teratogenesis in human data and fluoroquinolones are considered “possibly safe” during pregnancy and lactation, and ciprofloxacin is the preferred agent to use if clinically indicated [11]. Aminoglycosides are typically used in conjunction with another antipseudomonal agent including β-lactams, cephalosporins and carbapenems. Aminoglycoside use throughout pregnancy is not recommended unless the mother has failed alternative therapies or is critically ill. β-lactams and cephalosporins are compatible throughout pregnancy and lactation and are widely used. However, there are limited data on the use of carbapenems during pregnancy. Case reports of meropenem are limited to the second and third trimester and suggest no increased risk. Thus, meropenem is considered “possibly safe” during the first trimester and “probably safe” during the remainder of pregnancy and lactation [11]. However, treating clinicians should be aware that women with CF have been shown to be more likely to develop severe pre-eclampsia, and carbapenems lower the seizure threshold [43]. The complexities of dual antipseudomonal treatment in pregnancy highlight whether monotherapy or dual therapy should be considered the standard of care. Prior studies addressing this question in non-pregnant people with CF have shown insufficient evidence to recommend one strategy over another [39]. Thus, monotherapy may be the appropriate strategy in pregnancy in someone with mild lung disease who is not critically ill, while dual therapy is reserved for those individuals with moderate-to-severe lung disease or who are critically ill. Continuous assessment will be needed with a low threshold to revise the strategy based on the mother's symptoms and response to treatment. Furthermore, use of inhaled antibiotics during pulmonary exacerbation management has not been evaluated in pregnancy and there has not been sufficient evidence to recommend for or against use in management in non-pregnant people with CF [39]. Inhaled antibiotic therapies during pregnancy may be another alternative given the minimal systemic absorption and minimal risk of inhaled therapies. Although use of highly effective CFTR modulator therapy has substantially reduced the occurrence of pulmonary exacerbations in people with CF, it has not eliminated them [6]. Therefore, future studies evaluating pulmonary exacerbation management during pregnancy in CF should be considered to help guide best practices for pulmonary exacerbation management during pregnancy.

Lactation

CF clinicians reported that over half of the individuals under their care with CF chose to breastfeed after delivery [34]. Lactation impacts both the mother and infant, and clinicians must routinely assess lactation status in the post-partum period. Lactation impacts the nutritional status of the mother, and generally an additional 500 kilocalories per day is recommended for lactating mothers in the non-CF population [44]. Caloric needs will be higher in people with CF who are lactating due to increased caloric expenditure associated with pancreatic insufficiency and CFRD [45]. Thus, careful assessment of the nutritional status and weight in the post-partum period are required in order to balance the benefit of lactation for the infant with potential accelerated weight loss of the mother. Weight loss in some people with CF has been rapid in the post-partum period resulting in return of pre-pregnancy weight within the first 6 weeks [3]. While this rapid weight loss does not occur for all people with CF, weight and BMI need to be monitored closely to optimise post-partum health. In addition, many medications commonly prescribed in CF are excreted in breast milk. Discussing the maternal and infant risks of continuing CF therapies that may be transmitted to the infant through breast milk, such as antimicrobials and CFTR modulators, is necessary. The majority of antibiotics are considered “probably safe” or compatible during lactation. Regarding CFTR modulators, data have shown that each individual modulator component is present in breast milk [35–38]. While no complications have been noted in infants exposed to CFTR modulators during lactation, animal models have demonstrated the occurrence of neonatal cataracts in juvenile rats exposed to IVA [4, 5]. Thus, it is recommended that infants exposed to IVA alone or in combination (LUM/IVA, TEZ/IVA or ETI) in utero or during breastfeeding receive ophthalmologic screening examinations for neonatal cataract evaluation. Furthermore, based on the known metabolism of CFTR modulators in the liver, reflexive or routine evaluation of infant liver function tests should be considered for infants exposed to modulators during breastfeeding.

Management of pregnancy in individuals with CF following organ transplantation

A small subset of those with CF are individuals who have undergone organ transplantation, most commonly bilateral lung transplant [2]. Most transplant centres counsel against post-transplant pregnancy because maternal and fetal complications associated with pregnancy after a lung transplantation are unfortunately high. This high rate of adverse outcomes was reported in a registry analysis in 2012 using data from the US National Transplantation Pregnancy Registry [46]. Investigators found that in 30 pregnancies (12 of whom had CF), the incidence of preterm birth was 60%, and there were 11 infant complications and two neonatal deaths [46]. There was a higher rate of rejection during pregnancy in those with CF (25% in CF versus 11% in those without CF), but there was a lower rate of spontaneous abortion in CF (25% in CF versus 33% in those without CF). Mean gestational age was similar in all groups, but mean birth weight was lower in CF (1980 g in CF versus 2349 g in those without CF). From a study using the Transplant Pregnancy Registry International, 7% of 51 post-transplant pregnancies resulted in graft loss within 2 years of pregnancy [47]. This immune phenomenon may occur spontaneously or due to providers and recipients decreasing immunosuppressive medications to protect the fetus, or rarely due to antibody-mediated rejection from human leukocyte antigen (HLA) sensitisation [48]. As noted above, many lung transplant centres request that recipients avoid pregnancy all together. Other centres recommend waiting at least 2 years after transplantation in order to safely achieve the lowest possible doses of immunosuppressive medicines prior to pregnancy, because immunosuppressive agents such as mycophenolate mofetil are not recommended during pregnancy due to potential fetal toxicity. Although successful pregnancies in transplant recipients may be possible, discussing reproductive goals and family-building options in the pre-transplant evaluation is warranted. Adoption and surrogacy may be alternative options if parenthood is desired in this population.

Conclusion

Pregnancy rates in people with CF are increasing as people are living longer and healthier lives, and we anticipate that these numbers will continue to increase with more widespread use of ETI and new therapeutic advances. With optimisation of preconception health and judicious use of chronic maintenance therapies and antibiotics for the treatment of acute pulmonary exacerbations, people with CF can have successful pregnancies with healthy infants. However, in the setting of markedly higher pregnancy rates in people with a wide range of baseline disease, prospective data collection to more clearly delineate risk factors for adverse maternal and fetal outcomes, including the use or withdrawal of modulators is needed. Generation of such data is crucial to aid clinicians in the provision of evidence-based recommendations to individuals with CF as they pursue all the avenues afforded by the likelihood of longevity.