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(Chest. 2006;129:706-711.)
© 2006 American College of Chest Physicians

Impact of Pregnancy on Women With Cystic Fibrosis*

Ann H. McMullen, RN, MS; David J. Pasta, MS; Paul D. Frederick, MPH, MBA; Michael W. Konstan, MD; Wayne J. Morgan, MD; Michael S. Schechter, MD, MPH, FCCP; Jeffrey S. Wagener, MD; for the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis

* From the University of Rochester Medical Center (Ms. McMullen), Rochester, NY; Ovation Research Group (Mr. Pasta and Mr. Frederick), Highland Park, IL; Rainbow Babies and Children’s Hospital (Dr. Konstan), Cleveland, OH; the University of Arizona (Dr. Morgan), Tucson, AZ; Brown University (Dr. Schechter), Providence, RI; and the University of Colorado Health Sciences Center (Dr. Wagener), Denver, CO.

Correspondence: Ann McMullen, MS, CPNP, Senior Advanced Practice Nurse, Division of Pediatric Pulmonology and Allergy, Department of Pediatrics, University of Rochester Medical Center, Associate Professor of Clinical Nursing, University of Rochester School of Nursing, 601 Elmwood Avenue, Rochester, NY 14642, Phone: 585-275-2464, Fax: 585-275-8706, Email: ann_mcmullen{at}urmc.rochester.edu

Abstract

Background: Improvements in the health and survival of patients with cystic fibrosis (CF) have led to increasingly normal lifestyles, including successful pregnancies in women with CF. Concern exists among care providers about the impact of pregnancy on the health of women with CF.

Study objectives: We examined data from a large longitudinal observational study, the Epidemiologic Study of Cystic Fibrosis (ESCF), to characterize health outcomes and CF-related therapies in women who became pregnant.

Design: This analysis was conducted using ESCF data from 1995 to 2003.

Patients: A total of 216 women, aged 15 to 38 years, who met the criteria for a qualifying pregnancy, were compared with a matched group of never-pregnant women during three time periods (ie, baseline, during pregnancy, and follow-up).

Interventions: None.

Results: The baseline pulmonary function (FEV1) values were 74.5% and 66.4% predicted, respectively, in the pregnant and nonpregnant women. Declines in FEV1 values of 6.8% and 4.7%, respectively, were observed from baseline to follow-up in the pregnant and nonpregnant women (p = 0.61). During pregnancy, outpatient visits were 33% more frequent compared to baseline and 62% more frequent than in the nonpregnant group (7.19 vs 4.45, respectively, visits annually). Annual rates of respiratory exacerbation and hospitalization were similar at baseline but increased during pregnancy. The prevalence of treatment for diabetes more than doubled, from 9.3% at baseline to 20.6% during pregnancy, and was 14.4% at follow-up. In contrast, 18.7% of the never-pregnant women were being treated for diabetes at baseline, rising to 25.2% at follow-up.

Conclusions: These findings suggest that, over the same time period, women with CF who become pregnant experienced similar respiratory and health trends as nonpregnant women. However, pregnant women use a greater number of therapies and receive more intense monitoring of their health. These findings have implications for clinicians providing prepregnancy counseling for women with CF.

Key Words: cystic fibrosis • pregnancy • therapy

Both survival and health outcomes have improved for individuals with cystic fibrosis (CF) over the past 2 decades. In 2002, the median expected survival age for CF patients in the United States was 31.6 years; women had a lower median survival age of 29.0 years.1 Because of these improvements, clinicians are now required to address fertility, family planning, and pregnancy issues with their patients. Although early case reports and surveys of pregnant women documented poorer health outcomes during and following pregnancy, investigators have subsequently reported more favorable outcomes.23456 In these reports of matched cohorts, no difference in lung function decline was noted between pregnant and nonpregnant patients. In the largest of these analyses,5 pregnancy was not an independent predictor of survival; however, women with lower lung function, diabetes, or poorer nutritional status in both the pregnant and nonpregnant groups had decreased survival.

In a more recent analysis of the Cystic Fibrosis Foundation patient registry data (1987 to 1997),6 women who became pregnant did not demonstrate a significantly shortened survival time, even in the subgroup of patients with an FEV1 of < 40% predicted. These findings are supported by reports from Canada,28 the University of Minnesota ,9 and Scandinavia.1011 The Scandinavian report11 also suggested that CF-related therapies to treat pulmonary and nutritional needs are used more intensively during pregnancy.

Taken together, these reports suggest that, at least for women who have mild CF lung disease, pregnancy may present minimal additional risk. However, in counseling patients and their partners, it is incumbent on clinicians to present a balanced picture, a view not only of the risks of pregnancy and the impact of childbearing on the health of the mother with CF, but also of the additional care that might be anticipated during and following the pregnancy. We used data from the Epidemiologic Study of Cystic Fibrosis (ESCF) longitudinal encounter-based data set to identify changes in care that occurred during and after pregnancy as well as nutritional and pulmonary outcomes in pregnant women with CF.

Materials and Methods

We examined data from the ESCF that documented the clinical course and treatment of 24,000 individuals with CF living in the United States and Canada who were followed up for up to 9 years. Sites providing care for ≥ 10 patients with a documented diagnosis of CF who elected to participate obtained patient consent, as required by local investigational review boards, and collected data, including those on specific pulmonary and nutritional therapies for each patient encounter. All patient therapy decisions were made at the discretion of the local care providers, although the use of guidelines developed by the Cystic Fibrosis Foundation was encouraged. With the analyses reported here, we sought to characterize health outcomes and CF-related therapies in pregnant women with CF.

We considered all women between 14 and 40 years of age who had at least 10 encounters recorded in the ESCF.12 Because the database does not capture the dates of the last menstrual period, delivery, or termination of pregnancy and does not record fetal outcomes, pregnancy was identified if a woman was reported as being pregnant on at least two visits > 30 days apart. The clinic visit prior to the first visit recording the pregnancy was considered to be the index visit and was required to occur within 180 days before the first pregnancy visit. We then considered the 18 months of time up to and including the index visit to be the baseline period; the 12 months of time following the index visit as the during pregnancy period; and the subsequent 18 months as the follow-up period (Fig 1 ). In addition to the two pregnancy visits occurring at least 30 days apart, patients were required to have an index visit and at least one visit in the follow-up period. For women with multiple pregnancies, defined by a span of > 300 days from the first to the last reported visit in which the patient was pregnant, the first qualifying pregnancy was included. A qualifying pregnancy required that the woman not be pregnant for 18 months before the pregnant visit and for 18 months after the pregnancy period was completed.


Figure 1
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  		Figure 1.. Timeline and required visits during the three periods of the study (baseline, during pregnancy, and follow-up).

 
Pregnant women were stratified according to their age in years at the index visit. For each group (women with qualifying pregnancies ranged in age from 15 to 38 years), a comparison cohort was constructed from among the women who had never been pregnant. To select a comparison group that was as similar as possible to the pregnant women, we defined an index visit for each comparison case as the last visit (within 180 days) before she reached her half-birthday. In addition to the index visit, the comparison cases were required to have at least one visit each in the 12-month during-pregnancy period and the 18-month follow-up period. This requirement ensured that there was a minimum of two visits in the during-pregnancy period for women in both the pregnant and the nonpregnant groups.

Because a comparison cohort was constructed separately for each annual age group, and data were available for individual women over a period of several years, it was possible for a single patient to contribute to the comparison cohort for more than one age group. Thus, a total of 13,259 comparison cases were included, representing 3,896 individual never-pregnant patients. The number of comparison cases including patients at each age varied from 146 to 1,556, and the ratio of comparison cases to pregnant patients was at least 19.7:1 (median, 57:1).

Outcome variables were summarized for each patient according to the predetermined time period (ie, baseline, during, or follow-up). Lung function measures (FEV1 percent predicted and FVC percent predicted) were presented as the average value for each time period. In the ESCF, each visit identifies whether the patient is sick or stable; for the purposes of lung function analyses, only the lung function values from visits during which the patient was stable were used. The number of exacerbations, hospitalizations, and clinic visits, as well as the frequency of therapies, including inhaled antibiotics, IV antibiotics, oral quinolone antibiotics, and dornase alfa (Pulmozyme; Genentech Inc; South San Francisco, CA), were recorded for each patient during each time period. Similarly, the average weight in kilograms and the percentage of ideal body weight were calculated for each patient.

Analyses of variance were used to compare treatments and outcomes for the pregnant women with those of the never-pregnant women for each single year of age, treating the three periods as repeated measures within each patient. All analyses were performed using a statistical software package (SAS, version 8.2; SAS Institute; Cary, NC). All of the p values that were reported are two-tailed; values < 0.05 were considered to be statistically significant.

Results

A total of 216 women aged 15 to 38 years met the criteria for at least one qualifying pregnancy reported during the 9 years of the study (Fig 2 ). Single pregnancies occurred in 192 women (89%). The remaining 24 pregnancies included in this analysis represented multiple pregnancies (first pregnancy, 15 pregnancies; second pregnancy, 8 pregnancies; or third pregnancy, 1 pregnancy). The median age at the time of pregnancy was 24 years; three fourths of pregnancies occurred in women who were between 18 and 29 years of age. The index visit occurred at a mean (± SD) time of 72 ± 38 days before the first reported pregnancy visit.


Figure 2
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  		Figure 2.. Age distribution of 216 pregnant CF patients who were enrolled in the ESCF.

 
Baseline pulmonary function was better in women who became pregnant than in the never-pregnant comparison group (Table 1 ). Baseline FEV1 values covered a wide range but were unimodal. The lower and upper quartiles for FEV1 were 54% and 83% predicted, respectively, for pregnant patients, and 45% and 82% predicted, respectively, for never-pregnant patients. Thus, the difference in mean values can be attributed to there being disproportionately fewer pregnant women at the lower FEV1 values. Compared to nonpregnant women, pregnant women demonstrated significantly higher FEV1 (p < 0.001) and FVC (p < 0.001) values during each time period. During pregnancy, pulmonary function decreased, and this decrease persisted during the 18 months following pregnancy (Fig 3 ). Although this decline in FEV1 was greater in women in the pregnant than in those in the nonpregnant group (–6.8% vs –4.7%, respectively), the overall difference was not significant (p = 0.61).


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  		Table 1.. Percent Predicted Lung Function and Nutritional Measures in Pregnant and Nonpregnant Women With CF at Three Separate Time Periods*

 

Figure 3
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  		Figure 3.. FEV1 trends in pregnant and nonpregnant women with CF during three separate time periods (at baseline, during pregnancy, and at follow-up). Pregnant patients had higher lung function during each time period compared to nonpregnant patients (p < 0.001); however, trend lines were not different (p = 0.61).

 
Nutritional status, as determined by mean body weight and the percentage of the predicted ideal body weight, was better in the pregnant patients than in the nonpregnant patients (Table 1). During the baseline period, pregnant women had higher actual body weights (p = 0.01) but similar percent ideal body weights (p = 0.09) compared to the nonpregnant women. As expected, pregnant women gained a substantial amount of weight during the pregnancy and lost it following pregnancy, returning to their prepregnancy weight. During the follow-up period, women who had been pregnant demonstrated a significantly higher percent ideal body weight (p = 0.04) compared to nonpregnant women.

During the baseline period, the women who later became pregnant were seen an average of 5.4 times per year for outpatient clinical care compared to 4.7 times per year for the nonpregnant cohort (p < 0.001). Clinic visits were 33% more frequent during pregnancy compared to the baseline period (7.2 vs 5.4 visits per year, respectively; p < 0.001). However, in the follow-up period, the frequency of visits decreased to levels below baseline values (p = 0.002). Women who became pregnant were also seen more frequently during pregnancy (p < 0.001) and during the follow-up period compared with control subjects (p = 0.002).

Hospitalizations for the pregnant group were minimally higher during the baseline period (p = 0.43). Hospital admissions increased by 37% during pregnancy (from 0.81 to 1.11 hospital admissions per year; p = 0.02); however, this increase did not persist during the 18 months after pregnancy. Hospitalizations for nonpregnant women increased by 11% over the same time period. The overall difference between groups was not significant (p = 0.21) (Table 2) .


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  		Table 2.. Annual Clinic Visits and Hospital Admissions*

 
A variety of drug therapies were administered to pregnant and nonpregnant patients (Table 3 ). In general, pregnant women received more IV and inhaled antibiotics before and during pregnancy than did nonpregnant women, while the use of oral quinolone antibiotics decreased during pregnancy. Dornase alfa use decreased during pregnancy and remained low during the follow-up period. Medical treatment for diabetes was twice as common in nonpregnant patients during the baseline period (Table 4 ). During pregnancy, the number of women receiving diabetes therapy more than doubled. In the follow-up period, nearly half of those patients who began treatment for diabetes during pregnancy continued to require therapy. In the nonpregnant group, the number of patients being treated for diabetes increased by 35%, compared to the 55% increase in the pregnant group between the baseline and follow-up periods.


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  		Table 3.. Pregnant and Nonpregnant Women With CF Receiving Respiratory Therapies During Three Separate Time Periods*

 

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  		Table 4.. Pregnant and Nonpregnant Women With CF Receiving Other Therapies During Three Separate Time Periods*

 
The percentage of women receiving both oral and parenteral nutritional supplements increased markedly during pregnancy and persisted following pregnancy (Table 4). There was no change in the nutritional support provided over the same time period in the nonpregnant control group.

To further test the reliability of the differences that we observed, we examined the same variables for the 18 to 36 months before the index visit and for the 18 to 36 months following the pregnancy period in a subgroup of patients with available data (n = 83). Group differences remained similar across all five time periods of comparison, indicating a constant difference between the pregnant and control groups. Additionally, results did not change when multiple pregnancies were excluded from the analysis.

Discussion

Because of improved health outcomes in patients with CF, an increasing number of affected women are interested in bearing children. Investigators have previously reported56789 that the outcomes associated with these pregnancies include healthy infants, a slight deterioration in maternal pulmonary function, and uncompromised long-term survival. Our findings are consistent with these reports and, in addition, show a substantial increase in therapy both during and after the pregnancy in women with CF.

Women with CF who become pregnant generally have better pulmonary function than women who do not become pregnant; women in the former group generally have only mild-to-moderate lung disease (average FEV1, 74.5% predicted). During the baseline period, they received more therapy than women who did not become pregnant. This finding is perhaps related to the patients’ expressed desire to become pregnant and an associated motivation to improve and maintain their health, as well as to the clinician’s goal of maximizing lung health prior to pregnancy. In addition, women who become pregnant have a better nutritional status, and there is little evidence that fertility is reduced in healthy women with CF except by the mechanical barrier of cervical mucus plugging.13 These observations may also correlate with the general finding in CF care that better outcomes are associated with more aggressive therapy.14

Because the ESCF is an encounter-based study, we were able to assess the use of specific therapies before, during, and after pregnancy. Despite an increase in hospital admissions during pregnancy, the use of IV antibiotics for respiratory exacerbations did not increase during this time. This suggests that hospitalizations occurred for other than respiratory indications, such as obstetric complications. The increased hospitalization rate may also indicate that the clinician is less comfortable treating the pregnant woman at home during a respiratory exacerbation.

During pregnancy, there was a significant decrease in the use of both oral quinolones and inhaled dornase alfa, while inhaled antibiotic use remained constant. The decreased use of quinolone antibiotics is probably the result of pulmonologists’ concerns about the effect of these drugs on fetal cartilage development.15 The decreased use of dornase alfa is more difficult to rationalize. Perhaps other airway clearance therapies are being substituted. In addition, the demands of pregnancy and child rearing may reduce the patient’s adherence to routine therapies. This issue is of concern, since reduction in airway clearance could be contributing to the observed decrease in lung function associated with pregnancy.

We noted an increase in the use of nutritional therapies during and after pregnancy. This finding is consistent with the increasing caloric needs associated with pregnancy and breastfeeding; recommendations for these therapies are supported by both obstetric and CF caregivers.

The increased frequency of CF clinic visits is likely due to the perceived need for increased monitoring of disease status as well as the need to closely monitor for complications of the pregnancy. The most frequently documented complication was the need for the management of diabetes. Almost one pregnant woman in five was treated with either insulin or an oral hypoglycemic agent during pregnancy. The detection of diabetes during pregnancy might have been higher because of ascertainment bias; that is, women are routinely screened for diabetes during pregnancy, whereas not all CF centers routinely screen for diabetes in adolescents and adults. In this study, at least half of the women who were first identified as diabetic during pregnancy continued to require diabetes therapy following the pregnancy. Diabetes in CF patients has been associated with a higher risk of pulmonary decline,1617 and it is appropriate to communicate these risks to a woman with CF who is contemplating pregnancy. Nonpregnant women also had an increase in the use of antidiabetic medications during the same period, although at a slightly lower rate of increase.

These analyses were limited by the available variables in the ESCF database. All women who were pregnant were alive for the 18-month follow-up period; however, long-term outcomes for these women, including survival, were not examined. Because the database did not include the date of conception, we had to estimate the actual time of pregnancy. Our use of a 1-year period was designed to ensure that we included the entire pregnancy. No data on associated infant outcomes are available from the ESCF database, and we are unable to comment on whether the mother was breastfeeding following delivery, which might represent an added nutritional burden after pregnancy.

Conclusions

Analyses of data from this large cohort demonstrate that women with CF can experience a pregnancy with the impact on their overall respiratory and nutritional health being similar to nonpregnant women. Pregnant women with CF will likely require increased use of various therapies and more hospitalizations, and receive more intensive monitoring of their health. In addition, these women will have an increased chance of requiring treatment for diabetes both during and after pregnancy. There is also some suggestion that, with the demands of pregnancy and motherhood, women with CF may not maintain their previous levels of adherence to maintenance therapies, which may contribute to the observed decline in lung function in this group. Recognition and communication of these realities should be a part of prepregnancy counseling for women with CF.

Footnotes

Abbreviations: CF = cystic fibrosis; ESCF = Epidemiologic Study of Cystic Fibrosis

Supported by Genentech, Inc., South San Francisco, CA.

References

  1. . Cystic Fibrosis Foundation. (2002) Patient registry annual report. Cystic Fibrosis Foundation. Bethesda, MD:
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  5. FitzSimmons, SC, Fitzpatrick, S, Thompson, B, et al A longitudinal study of the effects of pregnancy on 325 women with cystic fibrosis. Pediatr Pulmonol Suppl 1996;13,99-101
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  10. Odegaard, I, Stray-Pedersen, B, Hallberg, K, et al Maternal and fetal morbidity in pregnancies of Norwegian and Swedish women with cystic fibrosis. Acta Obstet Gynecol Scand 2002;81,698-705[CrossRef][ISI][Medline]
  11. Odegaard, I, Stray-Pedersen, B, Hallberg, K, et al Prevalence and outcome of pregnancies in Norwegian and Swedish women with cystic fibrosis. Acta Obstet Gynecol Scand 2002;81,693-697[CrossRef][ISI][Medline]
  12. Konstan, MW, Butler, SM, Schidlow, DV, et al Patterns of medical practice in cystic fibrosis: part I. Evaluation and monitoring of health status of patients. Pediatr Pulmonol 1999;28,242-247[CrossRef][ISI][Medline]
  13. Edenborough, FP Women with cystic fibrosis and their potential for reproduction. Thorax 2001;56,649-655[Free Full Text]
  14. Johnson, C, Butler, SM, Konstan, MW, et al Factors influencing outcomes in cystic fibrosis: a center-based analysis. Chest 2003;123,20-27[Abstract/Free Full Text]
  15. Grady, R Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J 2003;22,1-9[Medline]
  16. Finklestein, SM, Wielinski, CL, Elliott, GR, et al Diabetes mellitus associated with cystic fibrosis. J Pediatr 1988;112,373-377[CrossRef][ISI][Medline]
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