Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in a multisystem disease. CF most commonly affects the respiratory, hepatobiliary, digestive and reproductive systems, though the majority of morbidity and mortality results from progressive obstructive lung disease and chronic pulmonary infection. In recent years, the survival of patients with CF has increased significantly with a recently reported median survival of up to 51.8 years of age.
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in a multisystem disease. CF most commonly affects the respiratory, hepatobiliary, digestive and reproductive systems, though the majority of morbidity and mortality results from progressive obstructive lung disease and chronic pulmonary infection.1 In recent years, the survival of patients with CF has increased significantly with a recently reported median survival of up to 51.8 years of age.2 With increased survival, there has been a concurrent increase in the incidence of pregnancy in patients with CF. The Cystic Fibrosis Foundation Patient Registry in the United States reported 124 pregnancies in 1990 and 235 pregnancies in 2015.3 Despite the increased incidence of pregnancy in patients with CF, the evidence for optimal treatment is scarce.
In men, almost universally, CF causes infertility due to congenital absence of the vas deferens.4 In women, the CFTR protein is present throughout the reproductive tract, which can result in reduced fertility in CF, though this is not universal.5 The first successful pregnancy in a woman with CF was published in 1960. The patient was 20 years old and delivered a healthy baby girl at 34 weeks’ gestational age by spontaneous vaginal delivery. Unfortunately, the patient died four months later due to a pulmonary CF exacerbation and right heart failure.6 At that time, and for decades later, pregnancy in patients with CF was discouraged due to presumed poor outcomes and poor maternal survival. However, evidence shows that pregnancy does not have a negative impact on the prognosis of CF.7
When counselling patients with CF who are planning a pregnancy, fertility, the status of the patients’ health prior to conception (including lung function, clinical stability and co-morbidities), the risk of exacerbations and other complications, access to specialized obstetric care and the risk of having a child with CF are all factors to consider. Given the complexity of care these patients require, careful planning and regular review of a pregnancy with a specialist CF centre and their multidisciplinary team, and an obstetric team with experience in high-risk pregnancies is advised.8
Fertility
The CFTR protein is expressed throughout the reproductive tract.9 This results in infertility in 95% of men with CF due to congenital absence of the vas deferens.4 However, women with CF may experience normal fertility, while in others it may be reduced. Multiple aetiologies for reduced fertility in women with CF have been identified and include:
Thickened cervical secretions10
Altered fluid regulation in the uterus impairing sperm transport10
Altered HCO3– in the uterus impairing sperm capacitation11
Reduced ovarian reserve12
Increased anovulatory cycles13
Delayed menarche due to malnutrition and/or chronic inflammation.14
In both men and women, infertility can be overcome by reproductive technologies. Men commonly undergo microepididymal or testicular sperm aspiration followed by intracytoplasmic sperm injection. These techniques have been reported to have a 60% success rate.15,16 Women with CF and reduced fertility can often achieve pregnancy with interventions such as follicular stimulation, intrauterine insemination, in vitro fertilization and intracytoplasmic sperm injection.17
Our practice is to refer couples to fertility specialists if the couple is unable to conceive after 6–12 months of unprotected intercourse.
Genetic Counselling
CF is an autosomal recessive disorder. Therefore, the child of a parent with CF will either be a CF carrier or will have CF. The risk of the child having CF depends on the carrier status of the patient’s partner, and therefore carrier screening is universally recommended.8,18,19
Standard screening panels for CFTR mutations include only the most common mutations found in the CF population. However, 2000 CFTR mutations have been identified, of which 281 are presently considered to be disease causing.20,21 Some of the disease-causing mutations are very rarely reported, and are therefore not included in standard screening panels for CFTR mutations. This equates to an 84% detection rate of CF carrier status in a diverse ethnic population.22 In the case of a positive CF carrier screening test in the partner (i.e. they are a CF carrier), the risk of the baby having CF is 50%. However, if the partner has a negative CF carrier screen the risk is significantly decreased. The risk can be further quantified based on the ethnicity of the partner, as certain CFTR mutations occur at varying frequencies in different ethnicities. This results in a detection rate of CF carrier status with a standard screening that varies by ethnicity23 (see Table 8.1).
| Ethnicity | CF carrier rate | Carrier rate with a negative screen |
|---|---|---|
| Non-Hispanic Caucasian | 1:25 | 1:206 |
| Ashkenazi Jewish | 1:24 | 1:384 |
| Hispanic Caucasian | 1:58 | 1:203 |
| African American | 1:61 | 1:171 |
| Asian American | 1:94 | 1:183 |
Consultation with a medical genetics specialist to discuss the risks of having a child with CF and the need for prenatal screening should be considered. In some patients using in vitro fertilization pre-implantation diagnosis is warranted to prevent having a child with a diagnosis of CF.24
Contraindications to Pregnancy in CF
Clinical guidelines for the management of pregnancy in CF were published in the Journal of Cystic Fibrosis in 2008. Contraindications to pregnancy include pre-existing pulmonary hypertension, cor pulmonale and hypoxia that is not correctable without acidosis. Suggested relative contraindications include:8
Poor nutrition
Diabetes
Chronic infection with Burkholderia cepacia complex
Significant liver disease
Forced expiratory volume in 1 second (FEV1) <60% predicted (though the rate of decline of lung function may be more important than the absolute lung function).
These co-morbid conditions listed as relative contraindications have been associated with mixed outcomes, though the number of patients within these subpopulations in published studies are small.25,26
Chronic infection with B. cepacia complex has not been found to affect the survival of pregnant patients with CF when compared to non-pregnant patients with CF who are also infected with B. cepacia complex.7 However, chronic B. cepacia complex infection in any patient with CF has been associated with decreased survival.27 Of note, there are many different Burkholderia genomovars with varying prognostic significance.
An FEV1 of <50–60% predicted in pregnant women with CF is frequently associated with poor outcomes, though some women with CF and severe obstructive lung disease have successfully carried pregnancies. A low FEV1 in pregnancy has been associated with increased days in hospital, increased days requiring intravenous antibiotics,28 decreased maternal weight gain,29 increased risk of prematurity29,30 and delivery by caesarean section.30. In addition, the 10-year survival after pregnancy of a woman with CF and an FEV1 of <50% predicted is worse than if the FEV1 was >50%. In one study, an FEV1 of >50% was associated with an 89% 10-year survival while an FEV1 of <50% had a 50% 10-year survival.25 These findings are in keeping with the widely accepted dogma that lung function is the most important predictor of mortality in CF31 and therefore should be considered when planning a pregnancy.
There have been no reported pregnancies in women with CF and significant liver disease. For information on the effect of malnutrition and diabetes on the outcomes of pregnancy, see subsequent sections.
Nutrition
Nutritional deficiencies including a low body mass index (BMI) and micronutrient deficiencies are common in CF due to gastrointestinal malabsorption and high caloric requirements. Current guidelines recommend that women with CF aged ≥20 years old maintain a BMI ≥22 kg/m2,32 and although the median BMI for females with CF in Canada in 2016 is 21.68 kg/m2, a cohort of adults with CF remain underweight (12.7% of Canadian females with CF in 2016).33 Monitoring of nutrition in pregnancy in women with CF is important because a low BMI has been associated with adverse fetal outcomes,26 and in one study, mothers who delivered prematurely gained significantly less weight (mean weight gain of 2.6 kg) than those who delivered at term (mean weight gain of 8.9 kg).29 These findings are confounded by their retrospective nature and have not been consistent across studies. In another retrospective study, when compared to patients with CF and a normal BMI, a low pre-pregnancy BMI (<20 kg/m2) was not associated with any difference in infant weight or gestational age. However, the patients with a low BMI required more days in hospital and more days of IV antibiotics.28 Finally, no difference in survival has been found between pregnant women with a BMI <20 kg/m2 and those with a BMI >20 kg/m2.25
Pre-conception, women with CF should be given the same advice as women without CF regarding avoidance of alcohol, smoking, and unpasteurized dairy products. Similarly, to decrease the risk of neural tube defects (NTD) daily folic acid supplementation should be started (0.4 mg (low risk), 1 mg (moderate risk) or 4 mg (high risk)). A common co-morbidity in patients with CF that puts them at moderate risk of having a child with a NTD is diabetes.34 For a complete list of risk factors associated with NTDs see the Society of Obstetricians and Gynaecologists of Canada Clinical Practice Guidelines.34
There are no guidelines on specific weight gain targets for pregnancy in CF, therefore we defer to the Institute of Medicine’s recommendations for weight gain during pregnancy for all women based on their pre-pregnancy BMI (Table 8.2).35
Table 8.2 Suggested weight gain based on pre-pregnancy BMI
| BMI (kg/m2) | Weight Gain (kg) |
|---|---|
| <18.5 | 12.5–18 |
| 18.5–24.9 | 11.5–16 |
| 25–29.9 | 7–11.5 |
| ≥30 | 5–9 |
BMI, body mass index
Weight gain in pregnant patients with CF is likely to require nutritional supplementation. Oral supplements are preferred, however if oral intake is limited by nausea and vomiting, other options for enteral nutrition include using a nasogastric tube or a percutaneous gastrostomy tube. Parenteral nutrition may be required in some cases.28
CF-Related Diabetes
CF-related diabetes (CFRD) affects approximately 20% of adolescents and 40–50% of adults, with the highest prevalence occurring in women aged 30–39 years.36 The prevalence of gestational diabetes mellitus (GDM) is 3–10 times higher than the general population, and affects between 14–26% of pregnant women with CF.25,37,38 Generally, CFRD is associated with a decline in lung function and increased mortality,39 although there is no evidence that CFRD or GDM in patients with CF have negative effects on the outcomes of pregnancy.7, 28
The Clinical Care Guidelines for Cystic Fibrosis-Related Diabetes40 recommend that patients be screened for CFRD within six months prior to pregnancy, or as soon as pregnancy is confirmed, with a 2 hour, 75 g oral glucose tolerance test (OGTT). If negative, the OGTT should be repeated to screen for GDM at the end of the first and second trimesters (12–16 weeks and 24–28 weeks, respectively). Finally, the OGTT should be repeated to screen for CFRD post-partum at 6–12 weeks.40 The recommendations from Guidelines for the Management of Pregnancy in Women with Cystic Fibrosis are similar, though they suggest an OGTT prior to, or at confirmation of, conception and again at 20 weeks’ gestation. Furthermore, they recommend that random blood sugars be done at each clinic visit and during infective exacerbations.8 The diagnostic criteria for CFRD and GDM are shown in Table 8.3.
| Diagnostic test | CFRD result40 | GDM result64 |
|---|---|---|
| Fasting plasma glucose | ≥7.0 mmol/l (126 mg/dl)a | ≥5.1 mmol/l (92 mg/dl) |
| OGTT 1-hour plasma glucose | – | ≥10.0 mmol/l (180 mg/dl) |
| OGTT 2-hour plasma glucose | ≥ 11.1 mmol/l (200 mg/dl) | ≥ 8.5 mmol/l (153 mg/dl) |
| Random glucose |
| – |
| Haemoglobin A1c | ≥ 6.5%a | – |
a If positive, these tests should be confirmed with an OGTT
b Classical symptoms of diabetes include polydipsia and polyuria
CFRD, cystic fibrosis-related diabetes; GDM, gestational diabetes mellitus; OGTT, oral glucose tolerance test
The recommended treatment for CFRD and GDM is insulin, which should be titrated to maintain tight blood sugar control. There are no specific guidelines for plasma glucose or haemoglobin A1c targets for pregnant patients with CF who have either CFRD or GDM. Therefore, guidelines for the management of diabetes mellitus in pregnancy and GDM are generally followed. Prior to pregnancy, The Canadian Diabetes Association Clinical Practice Guidelines advise a haemoglobin A1c target of 7% or normal if this can be safely achieved.41 During pregnancy, the plasma glucose targets are as follows: fasting <5.3 mmol/l (95 mg/dl), 1 hour post-prandial <7.8 mmol/l (140 mg/dl) and 2 hour post-prandial <6.7 mmol/l (120 mg/dl), while monitoring closely for hypoglycaemia.41 Finally, these patients should be referred to an endocrinology specialist for monitoring and treatment.
Medications
There is limited data on the safety of commonly used medications in CF during pregnancy and with breastfeeding, as pregnant patients are almost universally excluded from clinical trials. Therefore, available safety data is typically derived from animal models, case reports or case series. Ideally, prior to conception and throughout pregnancy, each medication taken by a pregnant patient with CF should be reviewed in consultation with a pharmacist and continued only where the expected benefits outweigh the potential risk to the fetus.
Overall, many medications taken by patients with CF are considered to be safe in pregnancy. These include inhaled β-agonists, inhaled corticosteroids, pancreatic enzymes and routine vitamins (in patients with vitamin deficiencies).8 Inhaled antibiotics have low systemic absorption and therefore fetal exposure is thought to be minimal. However, low serum concentrations of tobramycin can be detected with the use of both inhaled tobramycin solution and tobramycin inhalation powder,42 therefore testing of serum levels can be considered. There is limited experience with inhaled colistimethate in pregnancy and therefore changing to a safer alternative medication might be preferred.8
Prevention of CF pulmonary exacerbations is still an important goal, as respiratory extremis and sepsis may adversely affect both the mother and fetus, and treatment requires the addition of systemic medications. In the event of a pulmonary exacerbation, antibiotics should be chosen with care.18 To target Pseudomonas aeruginosa, β-lactam antibiotics are preferred.8,18 Historically, ciprofloxacin was considered contraindicated during pregnancy due to concerns regarding fetal tendinopathies in animal studies. However, studies to date have not demonstrated this finding43,44 and therefore it is often used to treat P. aeruginosa infections, particularly as an outpatient. Aminoglycosides are often avoided for fear of causing fetal nephrotoxicity and ototoxicity.18 However, intravenous tobramycin has been studied in pregnant women without CF in small numbers and has not been found to adversely affect the fetus.45 Generally, sulfamethoxazole/trimethoprim is avoided in the first trimester due to an association with neural tube and cardiovascular defects,8,46 though evidence for teratogenesis is inconsistent. The American College of Obstetricians and Gynecologists Committee on Obstetric Practice opinion advises that sulfonamides may be used in the second and third trimesters routinely, as well as in the first trimester if there are no other suitable antibiotics available.47 Finally, tetracyclines are avoided due to an association with fetal tooth discoloration.48 With each medication, the risks must be weighed against the benefits, and in severe pulmonary exacerbations their use might be warranted.8
There are two published cases of successful pregnancies in the setting of the CFTR modulator ivacaftor. Both patients had normal lung function and had spontaneous vaginal deliveries of full-term babies without complications. In one case, the patient experienced improved quality of life and lung function while taking ivacaftor and therefore it was continued throughout the pregnancy.49 In the second case, the patient ceased ivacaftor after discovering the pregnancy and then restarted it five weeks post-partum.50
For more detailed information on the use of individual medications commonly used in CF during pregnancy and their anticipated risks, see Appendix C in the Guidelines for the Management of Pregnancy in Women with Cystic Fibrosis by Edenborough et al.8
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