Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Explain the genetic basis of cystic fibrosis to couples anticipating pregnancy.
2. Assess perinatal complications associated with cystic fibrosis.
3. Describe the postpartum and long-term course of cystic fibrosis.
Pregnancy is associated with numerous physiologic changes in women. Even before considering becoming pregnant, a woman should undergo a considerable amount of planning to optimize the outcome for both her fetus and herself. This process usually involves counseling from a primary care provider or an obstetrician. Patients can begin taking prenatal vitamins, have immunization status checked, have a standard panel of laboratory tests drawn, get screened for selected genetic disease, and undergo screening for infection. Patients with underlying health conditions shall receive individual counseling and planning to support their bodies during the changes that take place during pregnancy. Cystic fibrosis (CF) represents a significant health condition that can affect both mother and baby in pregnancy. The goal of this article is to update the practitioner on the impact and management of CF, as this condition relates to pregnancy.
Cystic Fibrosis Historical Anecdote
As health care and medical management of chronic medical conditions advance, more women become willing to pursue pregnancy. CF, in particular, has carried a poor prognosis, and many women were counseled against attempting pregnancy. According to a case report published in 1960, although the first successful pregnancy in a woman with CF resulted in a healthy premature baby, the mother "died five weeks postpartum from respiratory failure."1 Subsequent literature described a high rate of maternal mortality and discouraged pregnancy.2,3 However, due to medical improvements and increasing acceptance of the importance of patient autonomy over the last several decades, there has been a rise in pregnancy among women with CF. "The majority of women with CF have near normal fertility, although ovulation disturbances may occur in patients with more severe disease."4 In addition, it is important to consider the median predicted survival of 39.3 years for patients with CF in the United States, according to the Cystic Fibrosis Foundation 2014 Registry Report.5 As such, the consequences of pregnancy on maternal health must still be considered. With more women with CF becoming pregnant, it is important for physicians to know how to generate the appropriate multidisciplinary team, counsel, and navigate the complexities of pregnancy.
Biology of Cystic Fibrosis
CF is inherited in an autosomal recessive pattern due to mutated variants of a portion of the genes on chromosome 7 that encode the cystic fibrosis transmembrane conductance regulator (CFTR) protein. As such, a person must inherit a defective copy of CFTR on chromosome 7 from each parent. The most common cause of CF is a mutation at the [DELTA]F508, and is found in 90% of patients with CF. The CFTR works as a chloride channel that regulates sodium and chloride on the cell surface. As a result of this genetic disease, secretions become thickened and difficult to clear.
CF affects many organ systems throughout the body including the lungs, pancreas and digestive system, and reproductive tract. In the gastrointestinal system, bile and pancreatic enzymes are poorly secreted. This pathology causes nutritional deficiency, diabetes, liver disease, and intestinal obstruction. The lungs suffer from chronic obstruction due to the viscous secretions. This chronic obstruction results in constant bacterial infections of the lung, which causes a chronic inflammatory response that results in bronchiectasis. In the reproductive organs, men are infertile due to an absence of vas deferens, but they have normal spermatogenesis. Although women have a slightly unfavorable, thickened cervical mucus, they have normal fertility.6
Fertility
A study published in 2000 examined the attitudes on the importance of having children among patients with CF. According to the study, "72% of women and 85% of men interviewed felt that it was important to have children."7 As discussed, approximately 97% of men with CF are infertile due to absence of the vas deferens, epididymis, and seminal vesicles.
Although women with CF have thickened cervical mucus, there is a misconception that this results in slightly decreased fertility. This seems not to be true, so women with CF who wish to avoid pregnancy should be informed of the need for contraception. Although women with CF do not a priori have reduced fertility, they can often have amenorrhea due to a variety of causes. "Menstruation generally occurs slightly later in girls with cystic fibrosis and bodyweight is the most significant determinant of menarche. Once menstruation is established, the majority of young women have regular cycles, with amenorrhea most likely to occur in those with poor lung function."8 Other considerations for amenorrhea include poor nutrition and the burden of chronic disease. Thus, it is important to maintain nutrition and a healthy body mass index (BMI) to promote ovulation if a woman wants to have a child.
Genetics
As CF is inherited in an autosomal recessive manner, women with CF who desire pregnancy should undergo genetic screening for her and the partner. There are more than 1700 different genetic mutations that can lead to CF, and they must be investigated before pregnancy in order for patients to understand the risk of passing the disease to a child.9 As an example, if two people who were carriers for the CF mutation were to have children, they would be counseled that they have a 25% chance that their child would have CF and a 50% chance that a child would be a carrier. Further, if one person has CF, and the partner is a carrier for the disease, there would be a 50% chance that the offspring would have CF and a 100% chance that the unaffected offspring would be a carrier. This information should be thoroughly explained and investigated before attempting pregnancy.
Prenatal Counseling: Prenatal Visits, Multidisciplinary Team, Nutrition, and Medication
Accurate counseling for patients with CF is critical to their ability to make informed decisions. Among many things, patients with CF must be counseled on pulmonary function, nutrition status, and long-term prognosis. According to a study published in 2009, it is also important to establish a multidisciplinary team to help manage all aspects of care.10 This multidisciplinary team should ideally include input from a cystic fibrosis specialist, obstetrician, dietician, diabetes team, specialist cystic fibrosis nurse, and physiotherapist. The most important aspect to investigate is the severity and burden of disease for a patient with CF. Included in this discussion should be the genetic screening options. In women who are already pregnant, prenatal testing can be performed to determine whether the fetus is affected by CF if the patient wishes to do so.
Like all women, nutritional status must be adequate for pregnancy. Women with CF generally follow similar guidelines as women without CF. Nevertheless, it is advisable for patients with CF to meet with a nutritionist before conception to determine nutritional needs and advice for appropriate maternal weight gain.11 Severe malnutrition with a BMI of less than 18 kg/m2 is considered an absolute contraindication.9 As discussed, many patients with CF have pancreatic disease; thus, glycemic control must be ensured before conception. All patients should be screened for diabetes.
Patients with CF are commonly on a number of medications before conception. Most medications that are required to treat patients with CF are safe to use during pregnancy, but all should be screened for teratogenicity. Like many women who are on medications for chronic medical conditions, there must be a risk-benefit discussion with the mother to weigh the risk of cessation of a medication against the risk of adverse fetal outcome. One study published in 2010 examined commonly used drugs in CF to assess safety; the results are summarized in Table 1.12
Baseline pulmonary function should be assessed before conception as a predictor for pregnancy outcome. One study in 1995 demonstrated that patients with a forced expiratory volume in 1 second (FEV1) less than 60% before pregnancy produced more preterm infants, experienced greater loss of lung function, and mortality compared with patients with milder disease.13 The data further suggested that the milder the pulmonary disease burden of CF on a mother, the better the prognosis for the fetus. This suggests that patients with poor lung function are at an increased risk for poor outcomes, though there is no consensus regarding an absolute cutoff for attempting pregnancy. However, cor pulmonale with pulmonary hypertension remains a contraindication to pregnancy.12
Intrapartum Care: Pregnancy Through Delivery
Pregnancy in patients with CF provides a unique set of challenges. Currently, more than 45% of women with CF are living long enough to enter their reproductive years.14 This percentage continues to rise as treatments develop and advance. A common question women with CF will ask is whether their pregnancy will affect their long-term survival. A study published in 2003 examined 680 women with CF to compare changes in survival rate after pregnancy; after adjusting for disease severity, it was concluded that patients did not experience a statistically significant decrease in survival.15
In normal pregnancy, the gravid uterus expands upward into the abdominal cavity, which leads to the upward displacement of the diaphragm. This upward displacement leads to a reduction in both the pulmonary and functional residual volumes as measured by pulmonary function testing. Further, there is an increase in resting minute ventilation. Finally, there is a widened alveolar-arterial oxygen gradient.14 Healthy pregnant women are typically able to compensate and adjust to these pregnancy-induced physiologic changes. However, in women with CF, these physiologic changes can create enough stress to cause pulmonary decompensation including pulmonary hypertension and infection. In addition, a retrospective study published in 2002 examined lung infections during pregnancies over 2 decades. They found that 77.5% of pregnant women with CF received IV antibiotics as compared with 59.1% before pregnancy. This observation suggests either an increased risk of exacerbation/severity during pregnancy or a lowered threshold for administering IV antibiotics in this group.16 Interestingly, despite all these changes and increased risk, it has been demonstrated that pregnant women with CF generally do well from a pulmonary standpoint. However, it should be noted that the pregnant women with CF compared with controls required more physician visits and respiratory therapy to achieve this outcome.14
Nutrition and weight during pregnancy should be followed closely. It may be difficult for women with CF to keep up with the typical increased requirement of 300 kcal/day to support the changes of pregnancy and the developing fetus. This is due both to chronic disease and to difficulty in digestion and malabsorption related to pancreatic insufficiency. Therefore, women with CF must have their nutrition and weight gain monitored closely to ensure caloric intake is appropriate. Poor weight gain and low BMI in pregnancy are associated with both premature delivery and low birth weight.17 If nutritional status optimization is unsuccessful, it is sometimes necessary to consider a nasogastric tube, gastrostomy, or parental nutrition to support weight gain.18
There is an increased risk of uteroplacental insufficiency, intrauterine growth restriction, and preterm birth in patients with CF. The obstetrician must therefore increase antenatal monitoring in these patients. In general, antenatal testing should be initiated at about 32 weeks unless there is a suggestion of maternal or fetal compromise before that time. Maternal status should be followed for deterioration of pulmonary function, right-sided heart failure, refractory hypoxemia, or hypercapnia resulting in respiratory acidosis.14 Early delivery may be indicated for maternal indications; betamethasone can be used as needed in patients with CF.
Intrapartum management should include close monitoring of oxygenation and cardiac function. Pain, anxiety, and shallow breathing can lead to hypercapnia and hypoxia. Adequate analgesia, generally by conduction anesthesia, is advocated to improve gas exchange and decrease both pulmonary and cardiac work.9 Mucus clearing between contractions may be necessary to ensure adequate oxygenation.
Postnatal Care
The burden of a newborn can be exacerbated by pulmonary challenges experienced by a woman with CF. The typical exhaustion can be made much worse by both the chronic disease and hypoxia. When possible, postpartum visits should be coordinated with any visits to her pulmonologist or internist. Breast feeding is encouraged, though data suggest that many women with CF are unable to maintain prolonged breast feeding due to inadequate caloric intake.9 Finally, these patients may be at even higher than usual risk of postpartum depression, so providers should be particularly attentive to signs of depression or anxiety.
Information and Resources
The changing medical landscape has seen many advancements recently, and as a result, people with chronic medical conditions are living longer. In women with CF, these longer life expectancies allow women to experience new chapters in their lives. From going to college, to family planning and parenting, many women with CF face new questions and on balancing CF with the challenges of life. Unfortunately, there was a lag between the medical advancement and the support systems and information. However, resources such as the Cystic Fibrosis Foundation offer families the tools necessary to make informed decisions. From discussions of the biology of pregnancy and CF to pregnancy tips, this information empowers women. Foundations and websites such as these allow women to anticipate and plan for obstacles they will face. Women with CF can connect to share tips and generate a network of information sharing.
Current Research and Development
From a maternal standpoint, additional research continues to produce progress in improving the quality of life in patients with CF. Further, there are constant advances in preventing exacerbation of lung and pancreatic disease. Gene therapy using genetic transfer and gene editing to replace the mutated and dysfunctional CFTR gene with a normal variant is being studied extensively.19 One hopes that these advances will make pregnancy more achievable and safer in the future for women with CF.
In utero gene therapy of affected fetuses may provide a new avenue for potential treatment and even cure from a fetal standpoint as well.20 There is experimental basis in animal models for this proof of concept. Once the diagnosis is made antepartum, it may be feasible to initiate genetic transfer to produce normal as opposed to defective CFTR genes. In this manner, the fetal genetic code could be identified and modified before birth. Gene therapy could prevent the disease from passing on to the child.
Conclusion
There are numerous considerations when counseling a patient who desires pregnancy, and special consideration must be taken in patients with CF. Although the medical infrastructure to support a woman with CF was often lacking until recently, many woman are now able to find the support needed for pregnancy. At the heart of patient care lies a strong interdisciplinary team; it is important to develop this interdisciplinary team to help with each facet of the patient's care and life. Physicians must maintain open, objective, and honest conversations about the potential complications of pregnancy.
Among many considerations, patients must be made aware of the potential complications they might face during pregnancy, as well as the risk of passing the disease to the child. Further, although difficult, there must be a discussion about the shortened life expectancy in patients with CF; this counseling must be provided in a delicate manner and provide the patient with the information to make informed decisions. Unfortunately, as stated earlier, the median life expectancy is around 40 years; thus, many patients will not live long enough to see their child grow up.
The difficulties of parenting should be talked about during counseling as well as discussing the difficulties of managing complex chronic medical conditions with a newborn. Despite challenges that these women will face, the interdisciplinary team must support the patient. Finally, psychological counseling should be offered to patients who might suffer from depression, anxiety, or frustration during challenging aspects of care.
REFERENCES