Cystic fibrosis (prenatal screening and diagnosis and care of pregnant women with CF)

1. What every clinician should know

Clinical features and incidence

Cystic fibrosis (CF) is an autosomal recessive disorder resulting in a progressive multisystem disease that affects primarily the pulmonary and digestive systems, but with notable dysfunction of the reproductive, musculoskeletal and biliary systems as well. The incidence in the United States ranges from 1 in 2500 to 1 in 3300 live births. CF is caused by mutations in the cystic fibrosis conductance transmembrane regulator (CFTR) protein complex encoded on chromosome 7, which lead to an inability to conduct chloride and other anions.

The major issue facing obstetricians is screening for CF in the pregnant and preconception populations. The frequency of carriers varies widely; the most common rate of carriers being found in the Caucasian and European populations (specifically those of Ashkenazi Jewish descent) at approximately 1 in 25. African Americans, Hispanics and Asian Americans are significantly less likely to be carriers; however increasing rates of mixed ethnicity, both identified and not, make it difficult to assess the risk of carrier status for a given individual.

Improved medical care has resulted in patients with CF living to reproductive age with an average life expectancy in the fifth decade for mild variants. Although men with CF are largely infertile, female infertility is much less common and appears to be largely related to nutritional status and maternal weight. Pregnant women with CF are at risk for respiratory compromise and possible worsening of their underlying disease as well as perinatal complications including antepartum hospitalization, preterm birth and diabetes.

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Maternal mortality for those with modest respiratory function does not appear to be higher than for women who do not become pregnant, but 20-40% of women with CF who are pregnant will be deceased within 10 years of the delivery, so continuation of a pregnancy has many medical and psychosocial implications. In addition to maternal health, all children of a woman with CF will be at least CF carriers and the risk of a fetus affected by CF can increase from the baseline of 1 in 2500 to 1 in 50, making paternal screening and prenatal testing paramount in prenatal care.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

The diagnosis of CF is made largely in infancy, requiring both clinical symptoms consistent with CF (chronic upper and lower respiratory tract infection and dysfunction, pancreatic insufficiency, meconium ileus, intestinal obstruction and biliary disease) and an elevated primary diagnostic test for CF, the sweat chloride test. This test must be performed and be abnormally high (greater than 60 mmol/L) on two separate occasions. Alternatively, the diagnosis may be made in a symptomatic individual with two abnormal copies of the CFTR gene or with the nasal potential difference test.

Obstetrician-gynecologists are unlikely to be involved in the initial diagnosis of an affected woman; however, milder cases of CF can go unrecognized. A suspicion for the disease in a woman with chronic lung disease in the absence of another diagnosis is prudent. Some men may be diagnosed with azoospermia and, more specifically, bilateral congenital absence of the vas deferens during the course of a primary infertility work-up of a patient. In this instance, the patient and the partner should be referred for CF screening as this may be the presenting symptom.

The American College of Obstetricians and Gynecologists as well as the American College of Medical Genetics recommend that screening for CF be offered to all women who are pregnant or considering pregnancy. Currently, there are more than 1700 recognized mutations in the CFTR gene that can lead to CF with marked variation in the prevalence of mutations by ethnicity. A panel of the most common 23 mutations is recommended for most patients, although extended panels may be obtained in patients at risk for less common mutations.

Using the 23-mutation panel, 88% of Caucasian carriers will have their mutation detected; however, only 49% of the Asian Americans with a mutation will be screen positive. This underscores the importance of pre-screening discussions regarding the possibility of a false-negative screening test. If a patient has a positive screening panel, the partner should next be screened. If the partner is unavailable, genetic counseling and invasive testing should be considered.

If there is a family history of CF, ideally the mutation should be identified and then the related patient and/or partner should be tested for that mutation. If the partner is CF affected (almost always after assisted reproductive technology is used), the patient should undergo screening. If both parents are found to be carriers or one parent is known to be affected and the other is a carrier, genetic counseling and invasive testing should be considered.

Invasive genetic testing can be performed through chorionic villus sampling (11-14 weeks’ gestation), amniocentesis (more than 15 weeks’ gestation) or fetal blood sampling (more than 20 weeks’ gestation). The fetal sample would then be sequenced for the CFTR gene mutations. There is increasing evidence that single-gene disorders can be diagnosed noninvasively using cell-free fetal DNA in the maternal serum; however, these tests are not yet clinically available or adequately studied.

CF is included in all states on the newborn screening panel. The infant’s blood is analyzed for elevated immunoreactive trypsinogen (IRT). Although the sensitivity for detection of CF is 95%, there are still many false positives, so counseling after a positive screen is important for parental assurance. If the screen is positive, confirmatory DNA sequencing of the CFTR gene should be performed. The newborn screen does not mitigate the need for prenatal maternal screening both from a pregnancy option viewpoint and given that it does not provide information for the patient for future pregnancies.

Cystic fibrosis may rarely be diagnosed based on ultrasound findings antenatally due to echogenic bowel. This can be noted at any point in the pregnancy, although it is most commonly seen in the second trimester. Upon sonographic evaluation the bowel, with the gain at the lowest level, appears as bright as bone. If this finding is present, assessment for other causes of echogenic bowel (see differential diagnosis) and maternal screening for CF, if not previously performed, are warranted.

Differential Diagnosis

The confluence of chronic respiratory disease and pancreatic insufficiency should prompt investigation for CF. Approximately 10% of cases are mild, with patients presenting later than infancy, sometimes with only one organ system involved, such as male factor infertility. Other possible diagnoses are primary ciliary dyskinesia, primary immunodeficiency such as IgA deficiency, asthma, GERD, chronic aspiration, failure to thrive, celiac disease or a protein-losing enteropathy. The diagnosis of these conditions is beyond the scope of this chapter, but patients suspected of having CF or any chronic pulmonary or gastrointestinal disorder should be seen and evaluated in conjunction with an internal medicine physician or appropriate subspecialist.

The differential diagnosis of echogenic bowel on ultrasound includes fetal CF, fetal ingestion of blood (from a subchorionic hematoma or abruption), fetal viral infection (most commonly CMV), aneuploidy and unknown etiology. Only 3% of fetuses with echogenic bowel will be diagnosed with CF, so investigation including maternal history, maternal viral titers and amniocentesis for infection and karyotype are all recommended in the setting of echogenic bowel detected on ultrasound.

3. Management


For all pregnant women and women desiring conception

All women should be offered CF carrier screening with partner screening when appropriate and available. Women with a negative CF screening, particularly those of non-Caucasian descent, should be aware that a negative screening does not entirely eliminate the possibility of carrier status and thus an affected child.

Pregnant women with positive carrier screening and positive partner screening or unavailable partner testing should undergo genetic counseling. Women may undergo chorionic villus sampling, amniocentesis or, in select cases, fetal blood sampling for DNA sequencing and definitive diagnosis.

Women with a fetus diagnosed with CF should have counseling with the appropriate subspecialists regarding short- and long-term health and care implications before making decisions regarding the pregnancy. If the pregnancy is continued, serial assessment for fetal growth and consideration of referral for delivery at a facility with the ability to care for a neonate with CF is recommended. There are no specific indications for cesarean delivery of an infant with CF apart from general obstetric practice. Siblings of an affected child should be screened for carrier status as well as atypical or mild phenotypic CF.

Women and their partners who are both known to be carriers (or if a patient or her partner is affected with CF) may consider pregestational diagnosis using ART or use of donor egg or sperm to avoid conception with an affected fetus. Women who have CF and are not interested in pregnancy should be counseled and encouraged to use an adequate form of contraception.

For women affected with CF who are pregnant or desiring conception

There is a growing volume of literature regarding pregnancy outcomes of women with CF. Several important considerations should be explained to a pregnant CF patient and strong consideration of the implications should be encouraged for a woman desiring conception.

First, women with CF who are considering pregnancy or are diagnosed with an intrauterine pregnancy should consider the possible implications of the disease including early death. In one series of 41 patients with 48 pregnancies, 8 women (7 of whom had an FEV1 below 50%) died within 8 years of their delivery and 4 died within 2 years. Even with cases of mild CF, the average lifespan is only 56, so a discussion with the patient, her partner and her subspecialists will improve patient and provider expectations for the pregnancy and beyond.

Second, patients with CF should be optimized from a respiratory and pancreatic standpoint before or early in pregnancy. Women with an FEV1 below 40% have a significantly higher rate of mortality within the next 2 years with or without pregnancy and in some series have an even further increase in the risk of perinatal death.

Approximately 40-50% of women with CF will be diabetic during their reproductive years. Preconception optimization of glucose control is necessary to reduce the risk of diabetic teratogenicity as well as the complications of diabetes in pregnancy including growth disorders, preeclampsia, stillbirth, macrosomia and neonatal complications such as RDS and hypoglycemia. Women with CF who are not diabetic prior to pregnancy are significantly more likely to have gestational diabetes and should be screened in the first and second trimesters for diabetes.

Finally, the prenatal care of a patient with CF will require coordination with pulmonary and GI specialists and should include antenatal consultation with anesthesia and nutrition. Fetuses are at an elevated risk for CF, and patients should be referred for genetic counseling, partner screening and invasive testing as indicated. Patients should be monitored closely for adequate weight gain, assessed for diabetes if not previously diagnosed, and hospitalized with involvement of a multidisciplinary team for respiratory complications.

In some series, preterm birth rates are as high as 50%; however, the deliveries were largely iatrogenic due to worsening maternal condition. Serial assessment of fetal growth as well as consideration for antenatal testing are reasonable given the likely suboptimal nutritional and oxygenation status of the patient.


Intrapartum care of a patient with CF

As with prenatal care, intrapartum care for a patient with CF will necessitate involvement of pulmonary and anesthesia specialists. Delivery should ideally occur in a facility with close access to critical care facilities and specialists. Continuous maternal oxygen saturation monitoring and continuous fetal monitoring are prudent for labor. If diabetes is present, standard monitoring and treatment of blood glucose is recommended.

In the absence of other obstetric indications, cesarean delivery is not indicated for the disease alone; however, maternal respiratory compromise may preclude Valsalva and pushing efforts. Ideally, the CF status of the fetus would be known prior to delivery, with pediatrician involvement for affected neonates.

Intrapartum care of a patient carrying a fetus with CF

The intrapartum care of a fetus with CF should not differ from standard obstetric management, although labor and delivery should be undertaken only at a facility with capabilities to care for an affected neonate. Pediatrician involvement from the time of delivery is recommended.


Women with CF should be monitored closely in the postpartum period. In one series, approximately 20% of the postnatal maternal deaths occur within a week of delivery. Postpartum fluid shifts superimposed on lung disease with possible complications related to diabetes and preeclampsia can lead to severe and catastrophic maternal morbidity in the immediate postpartum period. Follow-up with the appropriate subspecialists should be coordinated during the delivery admission to optimize long-term care for the patient and improve her longevity for the neonate. Postpartum contraception is especially important in these high-risk patients.

4. Complications

Complications of women with CF who are pregnant

Patients with CF who become pregnant are at high risk for obstetric complications as well as perinatal death. All studies show an increased incidence of respiratory exacerbations and hospitalizations. Miscarriage rates are not apparently higher than the general population. The preterm birth rate ranges from 5-50%, although most of these are not spontaneous. Pregestational diabetes rates range from 3-54% with as much as a third of women requiring insulin. Cesarean delivery rates are as high as 40%, likely related to gestational age at delivery and maternal respiratory status. There is a theoretical risk of fetal growth restriction due to maternal malnutrition; however, this has not been seen in the largest cohorts studied.

The most important consideration for maternal care is the rate of perinatal maternal mortality, which has been noted as high as almost 10%. Additionally, one series showed 13% death rate within 2 years of delivery. As many as 20-40% of women with CF will be deceased by 10 years after delivery, most commonly from respiratory complications.

Complications of prenatal screening and diagnosis

Complications of any prenatal screening are false-positive screens leading to invasive testing, which appear to be uncommon in CF screening. However, the frequency of false-negative tests will vary by the prevalence of the disease in a patient population; therefore all patients should be counseled that a negative screening test does not completely eliminate the chance of being a CF carrier.

Should both partners or the patient alone (if partner testing is not possible) be diagnosed as carriers, invasive genetic testing would be recommended. The pregnancy loss rates for chorionic villus sampling and amniocentesis range from 1 in 200 to 1 in 1500 depending on the series reviewed.

5. Prognosis and outcome

Maternal and fetal/neonatal outcomes

The prognosis for patients who are pregnant with CF has been studied in several large retrospective series. Overall, the risk of preterm birth and operative delivery were higher than in the general population, but there was not a significantly increased risk of miscarriage or stillbirth. Patients with CF have a significantly shortened lifespan when compared with healthy adults and thus will have a significantly higher incidence of perinatal mortality and maternal death in the years following pregnancy, but in the largest series, this does not seem to be worsened by the pregnancy itself.

Neonates born with CF face a lifetime of chronic disease requiring frequent care and subspecialty interventions.

Impact on long-term health

Women with CF do not appear to have long-term changes in respiratory status secondary to pregnancy. Studies regarding the impact on health for women with extremely poor prepregnancy function (FEV1 less than 40%) have been conflicting with the largest series showing no difference in outcome. However, as would be expected, those women have a significantly higher rate of death within 10 years of delivery compared with women with better lung function regardless of whether they became pregnant.

6. What is the evidence for specific management and treatment recommendations

Ratjen, F, Döring, G. “Cystic fibrosis”. Lancet. vol. 361. 2003. pp. 681-9. (A general overview of cystic fibrosis, including the pathophysiologic basis of disease, diagnosis, management and outcomes.)

“American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis”. Obstet Gynecol. vol. 117. 2011. pp. 1028(Recommendations by the American College of Obstetricians and Gynecologists regarding screening.)

Castellani, C, Picci, L, Tamanini, A, Girardi, P, Rizzotti, P, Assael, BM. “Association between carrier screening and incidence of cystic fibrosis”. JAMA. vol. 302. 2009. pp. 2573-9. (A review of the impact of an effective screening program on CF disease incidence.)

Thorpe-Beeston, JG, Madge, S, Gyi, K, Hodson, M, Bilton, D. “The outcome of pregnancies in women with cystic fibrosis—single centre experience 1998–2011”. BJOG. vol. 120. 2013. pp. 354-61. (A review of the complications in pregnancy in women with CF.)

Goss, CH, Rubenfeld, GD, Otto, K, Aitken, ML. “The effect of pregnancy on survival in women with cystic fibrosis”. Chest. vol. 124. 2003. pp. 1460-8. (A review of the impact of pregnancy on CF.)

(For patient information regarding CF screening and testing as well as an informative handout for health care providers reviewing newborn CF carrier screening.)