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The Effect of Pregnancy on Survival in Women With Cystic Fibrosis^*

^* From the Division of Pulmonary and Critical Care Medicine (Drs. Goss, Rubenfeld, and Aitken), Department of Medicine, University of Washington Medical Center, Seattle, WA; and Statistical Consulting (Ms. Otto), Seattle, WA.

Correspondence to: Christopher H. Goss, MD, MS, Assistant Professor of Medicine, University of Washington Medical Center, Campus Box 356522, 1959 NE Pacific, Seattle, WA 98195; e-mail: goss{at}u.washington.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Study objectives: Patients with cystic fibrosis (CF) are currently living to their fourth decade and are making reproductive decisions. Information concerning the reproductive health of women with CF has been limited to small or single-center studies.

Design: We conducted a matched parallel-cohort study to assess the impact of pregnancy on the survival of women with CF.

Participants: A parallel-cohort study included all women > 12 years of age who were enrolled in the US Cystic Fibrosis Foundation National Patient Registry from 1985 to 1997.

Measurements and results: Six hundred eighty of the 8,136 women in the cohort became pregnant. These 680 women were matched on an index year to 3,327 control women with CF. At the inception of entry into the cohort, women who reported pregnancy were more likely to have had a higher percentage of predicted FEV₁ (67.5% predicted vs 61.7% predicted, respectively; p < 0.001) and a higher weight (52.9 vs 46.4 kg, respectively; p < 0.001). Using Kaplan-Meier survival curves, the 10-year survival rate in pregnant women (77%; 95% confidence interval [CI], 71 to 82%) was higher than in those women who did not become pregnant (58%; 95% CI, 55 to 62%). A separate analysis, matching pregnant patients on FEV₁ percent predicted, age, Pseudomonas aeruginosa colonization, and pancreatic function, obtained similar results. Using Cox proportional hazard modeling to adjust for baseline age, FEV₁ percent predicted, weight, height, and pulmonary exacerbation rate per year, pregnancy was not associated with an increase risk of death. Pregnancy was not harmful in any subgroup including patients with FEV₁ < 40% of predicted or diabetes mellitus.

Conclusions: Women with CF who became pregnant were initially healthier and had better 10-year survival rates than women with CF who did not become pregnant. After adjustment for the initial severity of illness, women who became pregnant did not have a significantly shortened survival.

Key Words: cystic fibrosis • outcome • pregnancy • survival

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Cystic fibrosis (CF) is an autosomal-recessive disease with an incidence of approximately 1 in 3,200 live births.¹ Over the past 30 years, the median age of survival has improved from 14 years in 1969 to 32 years in 2000 in the United States.² Despite the increasing age and survival of this patient population, little is known about the long-term consequences of pregnancy, or whether some subsets of patients are at a particularly high risk from pregnancy. Medical opinion regarding the risks related to pregnancy in women with CF has shifted over the last 4 decades from recommendations for sterilization to guarded optimism.^{3 4 5 6 7 8 9 10}

However, care providers have had limited information on which to base their counseling to individual women with CF about the risks of pregnancy both for themselves and for their unborn child. Most of the studies have been small case series with one case control study.^{6 9 11 12 13 14 15 16} Uncontrolled studies found that other factors including pancreatic insufficiency, nutritional status, and low Shwachman or Taussig score were predictors of poor prognosis in pregnancy. The largest study was a survey performed in the United States and Canada¹⁷ that found that moderate-to-severe pulmonary disease with exacerbations during pregnancy, dyspnea, and cyanosis was associated with shortened gestation and increased perinatal mortality. In the present study, we used prospectively collected data from the US Cystic Fibrosis Foundation (CFF) National Patient Registry to assess the effect of pregnancy on survival in women with CF.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Participants
The US CFF National Patient Registry database contains demographic and clinical data collected at CFF-accredited centers in the United States since 1966, using an annual questionnaire. A full description of the database has been published previously.¹⁸ Study subjects were women with CF who had been seen at a CFF-accredited care center in the United States between January 1, 1985, and December 31, 1997. All women who reported pregnancy during this 13-year period were considered for this analysis. Subjects were excluded from the analysis if they were < 12 years of age or > 45 years of age at the time of the diagnosis of CF, or if they reported a pregnancy in the first year of observation. Patients were excluded if they had become pregnant in the first year of observation because they would not have baseline data prior to pregnancy. Subjects who had only 1 year of observation were excluded. Verification of pregnancy status was not possible, because the data in the CFF National Patient Registry is anonymous. The institutional review board at the University of Washington approved this study.

Design and Procedures
The data were analyzed in two ways. The first study design was a matched parallel-cohort study comparing women who reported pregnancy to those who did not. The index date was inferred to be the first day of the year of the first pregnancy. The comparison subjects were women with CF who had been randomly selected from the population, did not report a pregnancy, and were matched on the index date of the pregnant case at a 5:1 ratio. Comparison patients had to be alive on January 1 of the index year. The index date was chosen for this matched analysis to control for temporal changes. Subject survival time was censored (ie, subjects no longer accrued survival time) at the time when they were lost to follow-up or underwent lung, heart-lung, or liver transplantation. The primary outcome was the time from the index date to death from any cause. Demographic and physiologic characteristics from these two cohorts were assessed at 1 year prior to the index date. A second analysis was performed matching nonpregnant control patients to pregnant patients at a 5:1 ratio. Patients were matched on age (± 1.5 years), FEV₁ percent predicted (± 5% predicted), pancreatic sufficiency, and Pseudomonas aeruginosa colonization. The values for the matching variables were obtained from the pregnant patients in the year prior to the index date for the pregnant patients.

Body mass index (BMI) was calculated using weight (in kilograms) divided by height (in meters squared). The FEV₁ and FVC values used were the highest ones observed during a given year, with percent predicted values calculated using the equations of Knudson et al.¹⁹ Pancreatic insufficiency was defined as the use of pancreatic enzymes during the year. Genotype was classified as homozygous for the delta F508 mutation, heterozygous for the delta F508 mutation, genotyped with other mutations, or not genotyped. Measures of health-care utilization included the total number of CF-related hospital admissions, the total number of CF-related hospital days, the total number of courses of home IV antibiotic treatments, the total number of home IV antibiotic treatment days, the total number of outpatient visits, and the total number of CF pulmonary exacerbations.

Statistical Analysis
For comparisons between groups, the unpaired t test, Mann-Whitney rank-sum test, and ² analysis of contingency tables were used. These statistics were used after confirming that adjusting for the matching variable had no effect on the level of significance.²⁰ The Kaplan-Meier product limit estimator was used to describe the proportion of patients surviving to any time point during the follow-up, and the log-rank statistic was used to assess differences in survival between groups.

The Cox proportional hazards model was used with and without time-varying covariates to look at differences in survival after controlling for confounders, as well as to assess potential interactions.²¹ Those variables that violated the proportional hazards assumption were used in a stratified Cox proportional hazards model. All clinically relevant variables were added to the model and were assessed by their magnitude of effect on the primary predictor variable, pregnancy status. The variable with the largest impact on the primary predictor was subsequently kept in the model, and the process was repeated until the addition of further variables had minimal effect (ie, a < 10% change) on the coefficient of the predictor of interest, pregnancy status.²¹ Clinically relevant interactions were decided a priori to their statistical assessment in the model and subsequently were tested. The model was refit with organ transplantation used as a time-dependent covariate to assess whether the decision to censor at the time of organ transplantation was appropriate. Given that our original matched analysis did not use all of the available data, we first modeled pregnancy as a time-varying covariate. We used the same rules to decide which covariates and interactions to include in this model. We used statistical software packages (1996: SAS, version 6.12 for Windows; SAS Institute; Cary, NC; and 1999: STATA, version 6.0; STATA Corp; College Station, TX).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
There were 8,136 women with CF enrolled in the CFF National Patient Registry who were > 12 years of age. Sixty-three women reported pregnancy in the first year of enrollment, 37 women were diagnosed after the age of 45 years, and 930 had only 1 year of observation during the study period. These patients were excluded from the analyses. Six hundred eighty women (9.6%) became pregnant, 313 of whom (3.9%) had multiple pregnancies (median, two pregnancies; range, one to six pregnancies). A majority of pregnancies ended in a live birth (455 pregnancies; 67%). The remainder of the first pregnancies resulted in the following: 39 spontaneous abortions (6%); 103 therapeutic abortions (15%); 16 stillbirths (2%); and 67 unknown pregnancy outcomes (10%). These percentages are similar to those for the United States in 1996, as follows: live births, 63%; spontaneous abortions, 13.8%; therapeutic abortions, 22%; and fetal loss, 15%.^{22 23}

After randomly matching pregnant women by index date (ie, year of first pregnancy) at a 1:5 ratio with nonpregnant women, there were 680 pregnant women with CF and 3,327 nonpregnant women with CF. Complete 1:5 matching was not achieved, but the results did not differ from 1:4 matching. The median follow-up time was 4 years (interquartile range, 2.5 to 7.0). Baseline characteristics 1 year prior to the index date showed that the subjects who reported pregnancy, when compared to the nonpregnant cohort, were older, had higher FEV₁ percent predicted values, had higher BMIs, and had fewer CF-related complications (Table 1 ). There was no statistically significant difference in pancreatic insufficiency or P aeruginosa infection. Pregnant women had similar rates of being uninsured (3.4% vs 2.5%, respectively; p = 0.22), but were more likely to have Medicaide insurance (17.5% vs 14.0%, respectively; p = 0.02). At 2 years after the index date, there was no difference in the rate of FEV₁ decline or in weight loss in the two groups (-2.2% vs -1.8% per year, respectively [p = 0.18]; and -1.7 vs -1.1 kg, respectively [p = 0.06]). The pregnant women whose first pregnancy ended in a live birth had the following characteristics: mean age, 23.3 (SD, 5.0); mean FEV₁, 70.6% predicted (SD, 22.1% predicted); mean BMI, 20.7 (SD, 3.1); pancreatic insufficiency, 88%; and P aeruginosa colonization, 67%.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Top, A: Kaplan-Meier estimates of survival comparing women who became pregnant to those who did not become pregnant. Bottom, B: Kaplan-Meier estimates of survival comparing women who became pregnant based on the outcome of the pregnancy. All p values relate to the results of the log-rank test comparing survival curves.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Kaplan-Meier estimates of survival for patients stratified by age, with the following three age groupings: (top, A) age 25 years; (middle, B) age 18 years to > 25 years; and (bottom, C) age < 18 years. The age used was the one at the index time (ie, January 1 of the year of first pregnancy). All p values relate to the results of the log-rank test comparing survival curves.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 3.. Kaplan-Meier estimates of survival for specific subgroups of patients. Top, A: graph showing those women (both pregnant and nonpregnant) with FEV1 < 40% of predicted. Bottom, B: graph showing those women (both pregnant and nonpregnant) with insulin-dependent diabetes mellitus. All p values relate to the results of the log-rank test comparing survival curves.

Since the above results might be explained by the differences noted at study initiation and because using stratified analysis and matching analysis limits the number of variables that may be assessed and may limit the power to detect differences, a Cox proportional hazards model was used to adjust for these baseline differences. The variables included in the model were age, FEV₁, weight, height, and annual number of CF pulmonary exacerbations. A Cox regression analysis, stratified on the FEV₁ percent predicted category (based on deciles) was used (Table 2 ). There was an interaction between pregnancy status and age. After adjusting for the effect of the FEV₁ percent predicted category, weight, height, and exacerbation rate, the pregnant cohort had differing relative hazards of death, ranging from reductions of 11 to 45%, depending on their age (Table 3 ). Adjustment for delta F508 genotype and the presence of insulin-dependent diabetes mellitus had no effect on the model. No significant interaction was found between pancreatic insufficiency and Burkholderia cepacia colonization on the impact of pregnancy and survival. In an attempt to address unmeasured confounders, an extremely ill subset of patients was selected. Survival was not worse in pregnant subjects with FEV₁ < 40% predicted, pancreatic insufficiency, insulin-dependent diabetes, and P aeruginosa detected in their sputum. To confirm this finding, another model using a time-varying Cox model containing all eligible women was used. In this model, pregnancy was not associated with a worse survival (relative hazard ratio, 0.92; 95% CI, 0.68 to 1.25) after adjustment for lung function, age, weight, and number of exacerbations. When the interaction between age and pregnancy was modeled, a significant reduction in the hazard of death was found in women with CF in patients 20 years of age.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
This study shows that women with CF who reported pregnancy were older, had higher FEV₁ percent predicted values, and had higher BMIs than a randomly selected sample of women with CF who did not report pregnancy. It also shows that after adjusting for these initial demographic differences, women with CF who became pregnant did not have worse survival. Several techniques were utilized to adjust for confounding variables, including selecting specific subsets, stratification, full matching, and multivariate adjustment. All of these techniques produced similar results, both in all patients who became pregnant and in those patients whose first pregnancy resulted in a live birth.

Historically, pregnancy had been discouraged in women with CF because of the concern of its impact on the life of both the mother and fetus. With improved survival in CF patients, more women now reach an age at which they may conceive. When questioned about sexual practices and pregnancy, women with CF have been found to be as sexually active as their non-CF peers and to have relatively high rates of unplanned pregnancies, and many express the desire to become pregnant.²⁴ In a separate study, > 70% of women with CF questioned thought that having children was important now or would be in the future. But despite this finding, > 25% of these women had never discussed fertility with any care provider.²⁵

Twenty years ago, Cohen and colleagues¹⁷ noted that severe pulmonary dysfunction was associated with shortened gestation and increased perinatal mortality when compared to pregnant women with preserved lung function. Their study noted an 18% mortality rate within 24 months after delivery. Since the time of the study by Cohen et al,¹⁷ the care of patients with CF has changed with the development of CF centers, antipseudomonal antibiotics, improved nutritional support, and improved care for high-risk obstetric patients.

Investigators^{4 26 27} have suggested previously that pregnancy be terminated in women with CF in whom the FVC was < 50% of predicted or the FEV₁ is < 60% of predicted. A number of more recent retrospective cohort studies have tried to clarify the risk of pregnancy in patients with CF to guide clinicians and patients. Edenborough and colleagues⁶ studied 20 selected CF patients who had undergone 22 pregnancies and noted that FEV₁ percent predicted was the most important predictor of outcome in pregnancy. Jankelson and colleagues⁸ retrospectively evaluated 13 pregnancies in 11 patients and found better outcomes for patients with FEV₁ > 80% of predicted. However, there are a number of case reports^{12 15} of women with severely diminished spirometry who gave birth without complications. Frangolias and colleagues¹⁴ attempted to address the lack of comparison groups by conducting a small case-controlled study, evaluating seven pregnant women with CF with seven nonpregnant women with CF matched control subjects. The authors concluded that pregnancy had little impact on patients with mild disease but resulted in poor outcomes for those with advanced disease. Gilljam and colleagues⁹ compared 54 pregnant women with CF to nonpregnant women with CF and found no difference in survival between the two groups. We found that improved survival was seen only in women 18 years of age. Pancreatic insufficiency, insulin-dependent diabetes mellitus, or B cepacia infection were not found to be a worse prognostic factors in women who got pregnant as had been previously described.^{12 28} Two additional case series^{29 30 31} recently have been published documenting the experience with pregnancy in CF patients in France, Norway, and Sweden noting similar findings to earlier studies.

In previously published information from the CFF National Patient Registry regarding the outcome of pregnant women with CF, there was no difference in the rate of hospital admissions, the use of home IV antibiotics, supplemental oxygen, and supplemental feedings in the year after pregnancy.⁵ An abstract³² presented at the Tenth Annual 1996 North American Cystic Fibrosis Conference matched each pregnant woman with CF with three to four control patients, based on age, FEV₁ percent predicted, and National Center for Health Statistics weight percent. This analysis compared 325 pregnant women with CF registered between 1986 and 1994 to matched control subjects and found no difference in the 1-year or 2-year survival rate. The current study extends the observation period from 1985 to 1997 and utilizes survival techniques to show that women with CF who became pregnant did not experience worse adjusted survival rates compared to nonpregnant control subjects.

Our analysis has several important limitations that affect the interpretation of these data. The medical and psychosocial events prior to the pregnancy that influence patients to choose to become pregnant could not be evaluated. Since no randomized controlled trial assessing the effect of pregnancy on survival in CF can be done, this limitation will never be fully addressed. Another important limitation is that censoring occurred at different rates in the two groups. To address this problem, a sensitivity analysis was performed looking at the most conservative assumptions of survival in the censored groups, and still, pregnancy did not appear to be associated with a worse survival. A third important limitation is that the registry only began collecting data in 1986 on women who became pregnant. Thus, women who had been pregnant before that time could have been classified as control subjects. There is no clear evidence that such misclassification would have been nonrandom. Thus, the effect of potential misclassification would have been to bias our results to the null. Last, unmeasured confounders, such as socioeconomic status, could account for the differences seen. The only measure for socioeconomic status obtained throughout the study was insurance status. Insurance status has been associated with decreased life expectancy in patients with CF and may represent a good surrogate for socioeconomic status.^{33 34} The survival benefit seen in this analysis, especially in the patients who had their first pregnancy at 18 years of age, does not imply causality. This finding could have been due to residual confounding or the possibility that women with CF who are 18 years of age are better able to cope with their disease and a new child. There is reasonable evidence, however, that pregnancy in women with CF is not detrimental to their health or survival, as has been thought previously.^{6 7 8} While there are case reports^{8 17 35} of declines in pulmonary function during the latter half of pregnancy, there is no clear link to a specific cutoff for prepregnancy spirometry.

Pregnancy adds many different physiologic stresses to the body by increasing circulating blood volume by 40% and cardiac output by 40 to 45%.¹⁵ Pregnancy also is associated with a decrease in residual volume, expiratory reserve capacity, and to a lesser extent functional residual capacity. It is also associated with increased nutritional needs (approximately 300 kcal/d).³⁶ In a CF patient with pulmonary hypertension or in a patient with poor nutritional status, these added stresses could significantly affect survival regardless of pulmonary function.

This study is not designed to address the psychosocial responsibility of women with CF. No one is guaranteed the opportunity to witness the growth of their children, but mothers with CF must face the possibility of their own early death with more than just vague concern. Overall, 20% of mothers with CF will be dead prior to the child’s 10th birthday, and this number increases to 40% if the FEV₁ is < 40% of predicted. Discussions regarding these possibilities optimally should occur before conception. However, it is imperative for health-care providers to recognize that they should not impose their own views on an individual patient’s reproductive decision making but, rather, should present the patient with medical information to allow them to make their own informed decision.

	Conclusions

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Women with CF who became pregnant were initially healthier and had better 10-year survival rates than did women with CF who did not become pregnant. After adjustment for initial severity of illness, women who became pregnant did not have a significantly shortened survival compared to nonpregnant women with CF. No specific subsets of pregnant patients were identified in this analysis who had worse survival than the comparison group.

	Acknowledgements

 
We are indebted to Preston Campbell, III, MD, Executive Vice President for Medical Affairs, Cystic Fibrosis Foundation, for his support of this project and for making the CFF National Patient Registry data available to us. We are also indebted to Stacey FitzSimmons for her early work on the CFF National Patient Registry data.

	Footnotes

 
Abbreviations: BMI = body mass index; CF = cystic fibrosis; CFF = Cystic Fibrosis Foundation; CI = confidence interval

This research was supported by the Leroy Matthew Physician Scientist Award from the Cystic Fibrosis Foundation and by Firlands Foundation.

Received for publication September 10, 2002. Accepted for publication March 12, 2003.

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TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Goss, C. H. Articles by Aitken, M. L. Search for Related Content PubMed PubMed Citation Articles by Goss, C. H. Articles by Aitken, M. L.