Abstract
BACKGROUND
Little is known about how new therapies that partially correct the basic cystic fibrosis (CF) defect (ivacaftor and lumacaftor) might alter hormonal contraceptive effectiveness, impact pregnancy outcomes, or affect pregnancy timing. Examination of pregnancy rates among CF women during periods of CFTR modulator therapy initiation will provide foundation for further research in this area.
METHODS
The Cystic Fibrosis Foundation Patient Registry was used to examine pregnancy rates and outcomes by genotype class before, during, and after the introduction of CFTR modulator therapies between 2005 and 2014.
RESULTS
Among women with CF, ages 15–44 years, there was a slight downward trend in annual pregnancy rates from 2005 to 2014 (2% reduction per year, p=0.041) Among women with G551D, pregnancy rates during phase 3 ivacaftor trial years was 14.4/1000 women/year compared to 34.0/1000 prior to the trial period (relative risk [RR]=0.65; 95% CI=0.43–0.96; p=0.011) and 38.4/1000 after drug approval in June 2012 (RR=1.52 post approval compared to trial period; 95% CI=1.26, 1.83; p<0.001). Pregnancy outcomes did not significantly change between 2005 and 2014 for any genotype class.
CONCLUSION
Evidence of significantly increased numbers of pregnancies among women taking approved CFTR modulators is important because of the unknown risk to pregnancy and fetal outcomes. Increases may be temporary following pregnancy prevention during controlled clinical trials, or from altered perceptions about maternal survival with new approved treatments. As more women with CF become eligible to receive modulators, the CF community must study their effect on contraceptive efficacy and safety during pregnancy. With increased health and survival due to modulation, family planning topics will become more common in CF.
Keywords: pregnancy, G551D, ivacaftor, lumacaftor
INTRODUCTION
Cystic fibrosis (CF) is a heritable, primarily Caucasian disease caused by a defect in the CF transmembrane conductance regulator (CFTR) gene on each allele (1). There are five classes of mutations and each combination of classes can yield varying degrees of disease severity (2). The presence of a class IV or V mutation such as R117H is generally associated with milder disease than exclusive class I–III mutation pairings such as homozygous F508del –the most common CF causing genotype. While CF was historically a fatal pediatric respiratory and digestive disease, new therapies mean that patients live longer, healthier lives. With more than half the CF patients in the U.S. now over the age of 18 years (3), conversations about family planning, contraception and pregnancy have become an everyday occurrence in adult CF clinics (4–6). There are some known complications of pregnancy in CF (5, 7), but generally, maternal outcomes are not significantly altered by pregnancy and childbirth (8, 9). However, little is known about the intersection of contraception and chronic CF medications on pregnancy and fetal and maternal outcomes. CFTR modulators were recently approved for a subset of CF patients: those who are class II homozygous F508del, those with at least one class III gating mutation (the most common being G551D with a prevalence of approximately 4%), and patients with a milder class IV R117H CFTR mutation (<2% prevalence) (10–12). Chronic use of modulators is increasing but their impact on hormonal contraception effectiveness and their safety during pregnancy (designated category B rating by the United States [US] Food and Drug Administration [FDA]) has not been rigorously investigated (13, 14). Currently, the information included in the package inserts for the approved modulators suggests that physicians counsel women with CF on modulator therapy to use an alternative to hormonal contraception if they wish to avoid pregnancy (13, 14); however there are no data evaluating contraceptive effectiveness during CFTR modulator use. Similarly, there are limited data on the effects of modulators on the fetus, although a recent case report suggests that the modulator, ivacaftor, did not adversely affect the pregnancy nor the newborn infant (15). It is unknown how many women with CF might choose to stay on modulators throughout their pregnancies.
Our objective was to examine overall annual pregnancy rate by genotype, as well as report the characteristics associated with those who were pregnant between 2005–2014. Additionally, we sought to compare pregnancy rates and outcomes by genotype before and after the CFTR modulator clinical trials. We examined pregnancy by CFTR genotype between 2005 and 2014 –a period of time spanning pre-CFTR modulator availability, controlled clinical trials of ivacaftor (Kalydeco®) and lumacaftor/ivacaftor (Orkambi®) for heterozygote G551D and homozygous F508del, respectively, and post approval of ivacaftor for G551D patients. We hypothesized that 1) overall pregnancy rate would mimic temporal trends of the general US population, and 2) pregnancy trends through time would differ by genotype because of differing disease severity and access to CFTR modulators. Specifically, we hypothesized that the pregnancy rate would be reduced during periods of active clinical trials where pregnancy is an exclusion criterion.
MATERIALS AND METHODS
Patients and design
This was a retrospective, observational analysis of pregnancy rates and pregnancy outcomes by genotype among all women with CF of childbearing age (15–44 years (16)) at the end of each year in the US CF Foundation Patient Registry (CFFPR) (17) between 2005 and 2014. The pregnancy rate is the number of pregnancies recorded per 1000 women with CF aged 15–44. The CFFPR ascertains pregnancy as a binary event in a given review year with possible outcomes: live birth, still birth, spontaneous abortion, therapeutic abortion, undelivered and unknown. Women who were pregnant two consecutive years with outcome “undelivered” in the former year were counted as a pregnancy case in the former year –but not the latter. CF pregnancy rates were compared to overall US trends during the same period as reported by the National Center for Health Statistics (18). Clinical features such as race/ethnicity, age (at end of year woman became pregnant), body mass index (BMI), pancreatic enzyme use, CF related diabetes status, percent predicted forced expiratory volume in 1 second (FEV1) (19), pulmonary exacerbations during the year, and respiratory microbiology including Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (MRSA) were ascertained via the annualized CFFPR data (17).
Phase 3 trials of ivacaftor in those with at least one G551D allele were conducted from June 2009 through January 2011 (12); a singular phase 3 trial of ivacaftor in those with at least one R117H CFTR mutation was performed in 2012–2013 (ClinicalTrials.gov NCT01614457), and among those with a non-G551D gating mutation in 2013 (ClinicalTrials.gov NCT01614470). The phase 3 trials of lumacaftor/ivacaftor in homozygous F508del were conducted from April 2013 to April 2014 (10). Pregnancy rates through time and by genotype groups, defined as homozygous delta F508, heterozygous delta F508 (not G551D or R117H), at least one G551D, at least one R117H (no G551D allele), and others (including unknown genotype) were calculated. Pregnancy outcomes as recorded in the CFFPR were tabulated by genotype and year groupings: 2005–2009 are pre-CFTR modulator years, and 2010–2013 are the first years that CFTR modulators were available (2014 was omitted because not all pregnancies had a realized outcome by end of the reporting year).
Statistics
Annual pregnancy rates through time and by group were estimated with 95% confidence intervals. Generalized estimating equations (GEE) were used to compare and test year-over-year changes in overall pregnancy rate. The relative risks (RR) of pregnancy (expressed as a proportion) for periods pre, during, and post modulator trials were tested with Fisher’s Exact test for within genotype comparisons. All reported p-values are two-sided and analyses were performed using SAS V9.4 (SAS Institute, Cary, NC, USA) or R V 3.16 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
CF pregnancy compared to US national averages
In the US CFFPR, the number of women with CF of childbearing age steadily increased annually from 5,335 to 7,164 between 2005 and 2014 (Table 1). Overall, 46.7% were homozygous F508del, 32.9% heterozygous F508del, 4.2% had at least one G551D allele, 1.7% had at least one R117H allele and 14.4% of the women were “other” or had unknown CFTR mutations. The pregnancy rate was 25.5 per 1000 women with CF (95% confidence interval [CI]= 24.3– 26.7). There was a slight downward trend in annual pregnancy rates from 2005 to 2014 (2% reduction per year, p=0.041) (Figure 1). The decline was consistent with overall US trends, which also declined over this period; however, the CF pregnancy rate was a fraction of that in the general population (2009 CF rate 27.2 versus 102.1 per 1000 US women aged 15–44) (18). The 1,726 pregnancies reported in the CFFPR between 2005 and 2014 were among 1,296 women in which 73.2% reported having one pregnancy, 21.7% two, 4.0% three, and 1.1% reported having 4 or more pregnancies. Demographic and clinical characteristics were fairly constant through time among the pregnant CF women with the exception of lung function (FEV1 % predicted) increasing from 68.5% in 2005 to 73.3% in 2014 (Table 2).
Table 1.
Number of women of child bearing age (15–44 years) and pregnancy rate by year in the US Cystic Fibrosis Foundation Patient Registry
| Year | All | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2005 | 2006 | 2007 | 2008 | 2009 | 2010 | 2011 | 2012 | 2013 | 2014 | |||||||||||||
| Genotype Group |
N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % |
| F508del Homozygous |
2467 | 46.2 | 2640 | 46.7 | 2762 | 46.9 | 2861 | 46.5 | 2982 | 46.8 | 3026 | 47.1 | 3105 | 47.1 | 3196 | 46.8 | 3260 | 47.1 | 3353 | 46.8 | 31989 | 46.7 |
| F508del Heterozygous |
1672 | 31.3 | 1786 | 31.6 | 1885 | 32.0 | 2002 | 32.5 | 2101 | 33.0 | 2147 | 33.4 | 2221 | 33.7 | 2332 | 34.1 | 2347 | 33.9 | 2423 | 33.8 | 22533 | 32.9 |
| G551D | 221 | 4.1 | 227 | 4.0 | 231 | 3.9 | 247 | 4.0 | 263 | 4.1 | 264 | 4.1 | 276 | 4.2 | 292 | 4.3 | 311 | 4.5 | 322 | 4.5 | 2860 | 4.2 |
| R117H | 83 | 1.6 | 97 | 1.7 | 96 | 1.6 | 112 | 1.8 | 115 | 1.8 | 115 | 1.8 | 110 | 1.7 | 112 | 1.6 | 130 | 1.9 | 134 | 1.9 | 1182 | 1.7 |
| Other | 892 | 16.7 | 900 | 15.9 | 912 | 15.5 | 934 | 15.2 | 913 | 14.3 | 879 | 13.7 | 883 | 13.4 | 901 | 13.2 | 876 | 12.7 | 932 | 13.0 | 9884 | 14.4 |
| All | 5335 | 5650 | 5886 | 6156 | 6374 | 6431 | 6595 | 6833 | 6924 | 7164 | 68448 | |||||||||||
| Pregnancy ate (Pregnancies per 1000 woman-years) |
28.7 | 29.4 | 30.6 | 29.1 | 27.2 | 26.1 | 24.4 | 27.8 | 29.3 | 23.5 | 25.5 | |||||||||||
Figure 1. Pregnancies among women with CF ages 15–44.
Pregnancy rate (per 1000 woman-years) by year and genotype group. Thick gray line=rate for entire population; gray shaded region = 95% confidence interval for entire population; cyan line=R117H; blue line=Other; green line=G551D; red line=F508del homozygous; pink line =F508del heterozygous. Indicators for timing of Phase 3 trials in that genotype group (~10% of G551D women and ~5% of F508del homozygous women).
Table 2.
Demographic and clinical characteristics of pregnant CF women by year
| Year (number of women pregnant) | All (N=1726) |
||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2005 (n=152) |
2006 (n=165) |
2007 (n=178) |
2008 (n=177) |
2009 (n=172) |
2010 (n=166) |
2011 (n=160) |
2012 (n=188) |
2013 (n=201) |
2014 (n=167) |
||||||||||||||
| Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | Mea n |
Std | ||
| Age at year end | 26.2 | 5.5 | 26.5 | 5.4 | 25.8 | 5.4 | 26.4 | 5.2 | 27.1 | 6.1 | 27.6 | 5.5 | 26.8 | 5.7 | 27.3 | 5.5 | 27.7 | 5.8 | 28.1 | 5.6 | 27 | 5.6 | |
| Body mass index (kg/m2) |
22.9 | 4.2 | 22.4 | 3.3 | 22.5 | 3.9 | 23.4 | 4.9 | 23.6 | 4.8 | 22.8 | 3.9 | 23.4 | 4.2 | 23 | 3.6 | 23 | 3.9 | 23.8 | 4.4 | 23.1 | 4.1 | |
| FEV1 % Predicteda | 68.5 | 22. 7 |
68.1 | 21. 5 |
66.7 | 22. 1 |
67.4 | 21. 6 |
72 | 19. 3 |
67.7 | 22 | 72 | 21. 9 |
72.8 | 22. 3 |
74.9 | 21. 3 |
73.3 | 20. 4 |
70.4 | 21. 7 |
|
| N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | N | % | ||
| Caucasian Race | 144 | 94. 7 |
158 | 95. 8 |
167 | 93. 8 |
167 | 94. 4 |
168 | 97. 7 |
155 | 93. 4 |
150 | 93. 8 |
178 | 94. 7 |
188 | 93. 5 |
157 | 94 | 163 2 |
94. 6 |
|
| Hispanic Ethnicity | 9 | 5.9 | 3 | 1.8 | 11 | 6.2 | 7 | 4 | 10 | 5.8 | 6 | 3.6 | 16 | 10 | 12 | 6.4 | 4 | 2 | 16 | 9.6 | 94 | 5.4 | |
| CF Related Diabetes | 32 | 21. 1 |
38 | 23 | 40 | 22. 5 |
28 | 15. 8 |
37 | 21. 5 |
42 | 25. 3 |
37 | 23. 1 |
46 | 24. 5 |
38 | 18. 9 |
37 | 22. 2 |
375 | 21. 7 |
|
| Pancreatic Enzyme usage |
127 | 83. 6 |
138 | 83. 6 |
153 | 86 | 143 | 80. 8 |
127 | 73. 8 |
123 | 74. 1 |
114 | 71. 3 |
143 | 76. 1 |
151 | 75. 1 |
123 | 73. 7 |
134 2 |
77. 8 |
|
|
Pseudomonas aeruginosa |
99 | 65. 1 |
116 | 70. 3 |
120 | 67. 4 |
113 | 63. 8 |
102 | 59. 3 |
97 | 58. 4 |
99 | 61. 9 |
119 | 63. 3 |
118 | 58. 7 |
101 | 60. 5 |
108 4 |
62. 8 |
|
| Methicillin Resist. Staph aureus |
27 | 17. 8 |
32 | 19. 4 |
49 | 27. 5 |
47 | 26. 6 |
29 | 16. 9 |
48 | 28. 9 |
49 | 30. 6 |
50 | 26. 6 |
58 | 28. 9 |
46 | 27. 5 |
435 | 25. 2 |
|
| Num. PEb treated by IV antibiotics |
|||||||||||||||||||||||
| 0 | 73 | 48 | 73 | 44. 2 |
80 | 44. 9 |
83 | 46. 9 |
92 | 53. 5 |
84 | 50. 6 |
84 | 52. 5 |
99 | 52. 7 |
107 | 53. 2 |
84 | 50. 3 |
859 | 49. 8 |
|
| 1 | 36 | 23. 7 |
42 | 25. 5 |
41 | 23 | 33 | 18. 6 |
35 | 20. 3 |
41 | 24. 7 |
27 | 16. 9 |
47 | 25 | 41 | 20. 4 |
32 | 19. 2 |
375 | 21. 7 |
|
| 2 or more | 43 | 28. 3 |
50 | 30. 3 |
57 | 32 | 61 | 34. 5 |
45 | 26. 1 |
41 | 24. 6 |
49 | 30. 6 |
42 | 22. 4 |
53 | 26. 4 |
51 | 30. 6 |
492 | 28. 6 |
|
Global Lung Initiative Equations (19)
PE=Pulmonary exacerbation
Genotype specific pregnancy during periods of CFTR modulator trials
Phase 3 trials of ivacaftor in those with at least one G551D allele were conducted from June 2009 through January 2011 (12). Pregnancy incidence among women with G551D during the trial years (2009–2011) was 14.4/1000 woman-years compared to 34.0/1000 prior to the trial period (2005–2008) (relative risk [RR]=0.65; 95% CI=0.43–0.96; p=0.011). Pregnancy rebounded to 38.4/1000 among G551D genotypes after FDA approval in June 2012 (years 2012–2014) (RR=1.52 post approval compared to trial period; 95% CI=1.26, 1.83; p<0.001; Figure 1).
The pregnancy rate was 23.2/1000 among women homozygous for F508del during periods of large phase 3 trials from April 2013 to April 2014 (10) compared to 25.1/1000 prior to the trials (2005–2012) (RR=0.94; 95% CI=0.81, 1.08; p=0.39). No post-FDA approval (March, 2015) data are yet available for homozygous F508del patients. A small study of ivacaftor in patients (total n=69 age 6 and above with n=50 adults) carrying the R117H allele (a milder mutation of altered CFTR conductance) was conducted in 2012 and 2013, leading to its approval in this subgroup of patients by the FDA in January, 2015 (ClinicalTrials.gov NCT01614457). There were no significant changes in pregnancy in this subgroup of women.
Pregnancy outcomes
The proportion of live births among pregnant CF women was 70.1% from 2005 through 2009 and 73.4% 2010--2013 (Table 3). According to national data, 64.6% of pregnancies in 2008 ended in live births among all races. Since the CF population included in this analysis was predominantly Caucasian (94.6%), we compared the 2008 percent distribution of national live births among US non-Hispanic Caucasian women ages 15–44, which was 69.2% (20). Pregnancy outcomes were grouped by genotype and year in Table 3 (2014 pregnancies were excluded because 39% were undelivered by the end of the reporting year, and thus outcome was unknown). The proportion of live births increased in recent years compared to 2005–2009 for each genotype group except those with other or unknown CFTR class; none were significant, but R117H saw the biggest increase (93.6% versus 75.0% live births, p=0.052).
Table 3.
Pregnancy outcomes by genotype and by CFTR modulator access years
| 2005–2009 (Pre-CFTR modulators) | 2010–2013 (CFTR modulator trials and post-approval) | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| live birth | still birth | miscarriage | termination | unknown | All | live birth | still birth | miscarriage | termination | unknown | All | |||||||||||
| Genotype Group |
n | % | n | % | n | % | n | % | n | % | N | n | % | n | % | n | % | n | % | n | % | N |
| F508del Homozygous |
245 | 66.2 | 2 | 0.5 | 40 | 10.8 | 39 | 10.5 | 44 | 11.9 | 370 | 208 | 71.7 | 2 | 0.7 | 40 | 13.8 | 18 | 6.2 | 22 | 7.6 | 290 |
| F508del Heterozygous |
194 | 72.1 | 4 | 1.5 | 27 | 10.0 | 17 | 6.3 | 27 | 10.0 | 269 | 185 | 74.9 | 2 | 0.8 | 30 | 12.2 | 10 | 4.1 | 20 | 8.1 | 247 |
| G551D | 19 | 61.3 | 1 | 3.2 | 5 | 16.1 | 4 | 12.9 | 2 | 6.5 | 31 | 20 | 74.1 | 0 | 0.0 | 0 | 0.0 | 3 | 11.1 | 4 | 14.8 | 27 |
| R117H | 27 | 75.0 | 1 | 2.8 | 4 | 11.1 | 1 | 2.8 | 3 | 8.3 | 36 | 29 | 93.6 | 1 | 3.2 | 1 | 3.2 | 0 | 0.0 | 0 | 0 | 31 |
| Other | 107 | 77.5 | 0 | 0.0 | 8 | 5.8 | 9 | 6.5 | 14 | 10.2 | 138 | 83 | 69.2 | 0 | 0.0 | 8 | 6.7 | 17 | 14.2 | 12 | 10.0 | 120 |
| All | 592 | 70.1 | 8 | 1.0 | 84 | 10.0 | 70 | 8.3 | 90 | 10.7 | 844 | 525 | 73.4 | 5 | 0.7 | 79 | 11.1 | 48 | 6.7 | 58 | 8.1 | 715 |
Year groupings: 2005–2009 and 2010–2013 (2014 excluded because 39% not full term by end of reporting year)
Reported ivacaftor usage among non-G551D women of childbearing age was scant in the CFFPR through 2014 (21 R117H, 74 F508del heterozygous, and 32 F508del homozygous women). However, reported ivacaftor usage had increased among G551D women from 17.0% in 2011 (prior to FDA approval), to 75.4% in 2012 (the year of FDA approval), to 87.9% in 2014 in the CFFPR. There were 40 pregnancies among 1188 G551D woman-years during this period and pregnancy outcomes appeared no different from the pre-modulator period (2005–2009) (Table 3).
DISCUSSION
CFTR modulator thearapies are being used by increasing numbers of patients with CF and their effects on pregnancy and contraceptives are unknown Our goal was to examine pregnancy rates and outcomes by CF genotype class before, during, and after the introduction of CFTR modulator therapies. We found that the overall pregnancy rate among women with CF of childbearing age has slightly decreased in recent years –a time that coincides with the introduction of CFTR modulators. Specifically, pregnancy was reduced among the genotype classes that were eligible for registration trials between 2010 and 2014 (G551D and F508del homozygous), but a rebound in pregnancy rate was observed post FDA approval in the G551D population. Pregnancy outcomes reported in the CFFPR remained relatively unchanged in the years of controlled trials and post-approval compared to the years before CFTR modulators were available.
Despite a better prognosis for CF men and women over the last decade, pregnancy rates have decreased. It cannot be determined if this is a reflection of the overall US trend in pregnancy or some other factor specific to the CF community. Reduced pregnancy among the genotype classes that were eligible for registration trials over the last five years (G551D and F508del homozygous) suggests that contraceptive use may have been impacted by patient involvement in trials that strictly enforce birth control method use to prevent pregnancy. The overall US proportion of a given genotype class enrolled in the phase 3 trials was small (approximately 10% for G551D and 5% for F508del homozygous), but enthusiasm for the studies was extremely high and anticipation of possible inclusion may have influenced the reproductive life goals of women with CF. A separate but very small study of ivacaftor in non-G551D gating mutations was conducted in 2013 (n=18 aged 6 and older; ClinicalTrials.gov NCT01614470) and Kalydeco® was eventually approved for these genotypes but the population was so small that we did not include them in this analysis.
Thus far, CF patients with a G551D CFTR mutation have had the most experience with modulator therapy (FDA approved in 2012). This investigation found that pregnancy rates were reduced in this group during controlled trials but have returned to pre-2009 trial levels. That, taken in combination with our finding that the majority of G551D women of childbearing age report ivacaftor use within the same year of becoming pregnant, underscores the need to better understand CFTR modulators given their unknown risk to pregnancy and fetal outcomes. Ivacaftor is classified as a category B pregnancy risk by the FDA, a classification that is given when there are no data to support its potential harm during pregnancy, nor human studies that evaluate the safety profile during pregnancy (14). A single case of a complication-free pregnancy and normal full term infant in a CF woman taking ivacaftor has been reported (15); however a corresponding editorial highlighted the pressing need for more data to support the safety or risk to infants born to women taking CFTR modulators (6). Phase 2 data of CFTR modulators show that sweat chloride, a measure of CFTR function, rapidly returns to baseline after cessation of CFTR modulators (21, 22), therefore discontinuation of a modulator throughout pregnancy may compromise maternal health. Due to the epidemiologic nature of the CFFPR data, it was impossible to determine whether women discontinued ivacaftor during pregnancy but further research could inform decision making for modulator use during pregnancy to reduce both maternal and fetal risks.
We observed a higher rate of pregnancy among women with CF with a mutation that confers mild disease (R117H) compared to other CF genotypes. While this finding is intriguing and might provide insight into differences in reproductive life planning goals depending on disease severity, the number of women in this group is quite small (<150), and therefore results should be interpreted with care. With evolving expectations about the impact of CFTR-modulation on improved disease prognosis and increased life expectancy, pregnancies and births among women with CF may further increase.
While this study focused on pregnancy, because of the inherent link between pregnancy, contraception and fertility, there is also a need to understand modulator impact on fertility and contraception. However there is a paucity of data on contraceptive use in CF. There has been some speculation that CFTR modulators could make a woman with CF more fecund by altering hormonal response and regulating female menses (23), and current recommendations state that lumacaftor/ivacaftor may render hormonal contraceptive methods ineffective (13), but there are no data supporting or refuting these claims. Other diseases have used a contraceptive registry to understand the impact of contraceptive methods on disease, and the effect of certain medications on contraceptive effectiveness (24). Both the World Health Organization and US Centers for Disease Control have issued recommendations for contraceptive use among men and women with certain medical conditions (25), but data on contraceptive efficacy and safety in CF are scant (26–28). Detailed data collection on contraception, pregnancy, dates of CFTR modulator usage, and pregnancy complications and outcomes could be ascertained through post-marketing phase 4 trials, national registries, or targeted questionnaires to CF Center Directors. Such data would help researchers differentiate planned pregnancies from potentially failed contraceptive methods due to modulator use, in addition to better understanding the safety profile of modulators during pregnancy and lactation.
The strength of this study is that it leveraged the largest single epidemiological database of CF patients to examine recent pregnancy trends and outcomes in the modern era of CFTR modulators. Nonetheless, there were limitations. While intriguing findings emerged to show that pregnancy increases in certain genotypes post-modulator approval, the retrospective nature of the data and the small subgroup size limit inference, especially with regards to pregnancy outcomes by genotype. Among women with the G551D CFTR mutation, only 40 pregnancies after 2010 were reported. Eighty percent (n=32) of these pregnancies were in women reporting ivacaftor usage during the year of incident pregnancy, but neither the precise timing of ivacaftor usage nor the start of gestation was captured in the CFFPR, therefore the overlap of the two is unknown. It is also impossible to determine whether the observed increases in pregnancy were planned, unplanned, were term or pre-term, or simply deferred due to strict contraception criteria during clinical trials.
With the recent approval of lumacaftor/ivacaftor for F508del homozygous patients, CFTR modulators are reaching a larger patient population, and thus the consequences for contraception and pregnancy may be profound. Future data, if collected with sufficient detail, can elucidate CFTR modulator effects on hormonal contraceptive method efficacy and pregnancy outcomes in as many as 3,500 women of child bearing age who are homozygous for the F508del mutation (Table 1), and double that (approximately 7,000 US women) if modulators are approved in all genotypes. The findings could have lasting implications on medication choices for women with CF. A patient-centered approach that includes women with CF, their partners, CF clinicians, obstetricians and family planning experts must be undertaken to develop research that addresses community-wide concerns and needs pertaining to female reproductive life planning and motherhood.
Supplementary Material
Highlights.
Analysis of US Registry data show that pregnancy rates differ by genotype.
Increases in pregnancy were seen after periods of CFTR modulator trials in G551D.
Increases may be due to deferral during trials or new perceptions about survival.
From 2005–2014, there were no apparent trends in pregnancy outcomes by genotype.
Acknowledgments
The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry data to conduct this study. Additionally we would like to thank the patients, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CF Foundation Patient Registry.
FUNDING: This work was supported by the United States National Institutes of Health [grant numbers: P30DK089507]; the Cystic Fibrosis Foundation, Bethesda, MD USA [grant numbers: RAMSEY03YO; GOAL13K0].
ABBREVIATIONS
- CF
cystic fibrosis
- CFTR
cystic fibrosis transmembrane conductance regulator
- CFFPR
Cystic Fibrosis Foundation Patient Registry
- US
United States
- FDA
Food and Drug Administration
- ANOVA
analysis of variance
- GEE
generalized estimating equations
- RR
relative risk
- PE
pulmonary exacerbation
- FEV1
forced expiratory volume in 1 second
- RR
relative risk
Footnotes
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REFERENCES
- 1.Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992–2001. doi: 10.1056/NEJMra043184. [DOI] [PubMed] [Google Scholar]
- 2.Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annual review of genetics. 1995;29:777–807. doi: 10.1146/annurev.ge.29.120195.004021. [DOI] [PubMed] [Google Scholar]
- 3.Cystic Fibrosis Foundation Patient Registry: Annual Data Report 2014. Bethesda, MD: Cystic Fibrosis Foundation; 2014. [Google Scholar]
- 4.Simcox AM, Duff AJ, Morton AM, Edenborough FP, Conway SP, Hewison J. Decision making about reproduction and pregnancy by women with cystic fibrosis. British journal of hospital medicine. 2009;70(11):639–643. doi: 10.12968/hmed.2009.70.11.45053. [DOI] [PubMed] [Google Scholar]
- 5.Tonelli MR, Aitken ML. Pregnancy in cystic fibrosis. Curr Opin Pulm Med. 2007;13(6):537–540. doi: 10.1097/MCP.0b013e3282f01120. [DOI] [PubMed] [Google Scholar]
- 6.Goss CH, VanDevanter DR. CFTR modulators and pregnancy: Our work has only just begun. J Cyst Fibros. 2016;15(1):6–7. doi: 10.1016/j.jcf.2015.12.019. [DOI] [PubMed] [Google Scholar]
- 7.Goss CH, Rubenfeld GD, Otto K, Aitken ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest. 2003;124(4):1460–1468. doi: 10.1378/chest.124.4.1460. [DOI] [PubMed] [Google Scholar]
- 8.Ahluwalia M, Hoag JB, Hadeh A, Ferrin M, Hadjiliadis D. Cystic fibrosis and pregnancy in the modern era: a case control study. J Cyst Fibros. 2014;13(1):69–73. doi: 10.1016/j.jcf.2013.08.004. [DOI] [PubMed] [Google Scholar]
- 9.Gilljam M, Antoniou M, Shin J, Dupuis A, Corey M, Tullis DE. Pregnancy in cystic fibrosis. Fetal and maternal outcome. Chest. 2000;118(1):85–91. doi: 10.1378/chest.118.1.85. [DOI] [PubMed] [Google Scholar]
- 10.Wainwright CE, Elborn JS, Ramsey BW. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(18):1783–1784. doi: 10.1056/NEJMc1510466. [DOI] [PubMed] [Google Scholar]
- 11.Sawicki GS, Dasenbrook E, Fink AK, Schechter MS. Rate of Uptake of Ivacaftor Use after U.S. Food and Drug Administration Approval among Patients Enrolled in the U.S. Cystic Fibrosis Foundation Patient Registry. Annals of the American Thoracic Society. 2015;12(8):1146–1152. doi: 10.1513/AnnalsATS.201504-214OC. [DOI] [PubMed] [Google Scholar]
- 12.Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663–1672. doi: 10.1056/NEJMoa1105185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Incorporated VP, editor. Package Insert Label: Product Monograph — Orkambi®. 2015. [Google Scholar]
- 14.Incorporated VP, editor. Package Insert Label: Product Monograph — Kalydeco®. 2012. [Google Scholar]
- 15.Kaminski R, Nazareth D. A successful uncomplicated CF pregnancy while remaining on Ivacaftor. J Cyst Fibros. 2016;15(1):133–134. doi: 10.1016/j.jcf.2015.11.013. [DOI] [PubMed] [Google Scholar]
- 16.Graham L. CDC Releases Guidelines on Improving Preconception Health Care. Am Fam Physician. 2006;74(11):1967–1970. [Google Scholar]
- 17.Knapp EA, Fink AK, Goss CH, Sewall A, Ostrenga J, Dowd C, et al. The Cystic Fibrosis Foundation Patient Registry: Design and Methods of a National Observational Disease Registry. Annals of the American Thoracic Society. 2016;13(7):1173–1179. doi: 10.1513/AnnalsATS.201511-781OC. [DOI] [PubMed] [Google Scholar]
- 18.Curtin SC, Abma JC, Ventura SJ, Henshaw SK. Pregnancy rates for U.S. women continue to drop. Hyattsville, MD, USA: National Center for Health Statistics; 2014. [Google Scholar]
- 19.Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–1343. doi: 10.1183/09031936.00080312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ventura SJ, Curtin SC, Abma JC. Estimated preganancy rates and rates of pregnancy outcomes for the United States, 1990–2008. Hyattsville, MD, USA: National Center for Health Statistics; 2012. Contract No.: 7. [PubMed] [Google Scholar]
- 21.Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. The New England journal of medicine. 2010;363(21):1991–2003. doi: 10.1056/NEJMoa0909825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014;2(7):527–538. doi: 10.1016/S2213-2600(14)70132-8. [DOI] [PubMed] [Google Scholar]
- 23.Jones GH, Walshaw MJ. Potential impact on fertility of new systemic therapies for cystic fibrosis. Paediatr Respir Rev. 2015;16(Suppl 1):25–27. doi: 10.1016/j.prrv.2015.07.013. [DOI] [PubMed] [Google Scholar]
- 24.Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA, Davis AR. Contraceptive practices of women with epilepsy: Findings of the epilepsy birth control registry. Epilepsia. 2016;57(4):630–637. doi: 10.1111/epi.13320. [DOI] [PubMed] [Google Scholar]
- 25.Centers for Disease C, Prevention. U S. Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep. 2010;59(RR-4):1–86. [PubMed] [Google Scholar]
- 26.Plant BJ, Goss CH, Tonelli MR, McDonald G, Black RA, Aitken ML. Contraceptive practices in women with cystic fibrosis. J Cyst Fibros. 2008;7(5):412–414. doi: 10.1016/j.jcf.2008.03.001. [DOI] [PubMed] [Google Scholar]
- 27.Roe AH, Traxler S, Schreiber CA. Contraception in women with cystic fibrosis: a systematic review of the literature. Contraception. 2016;93(1):3–10. doi: 10.1016/j.contraception.2015.07.007. [DOI] [PubMed] [Google Scholar]
- 28.Thorpe-Beeston JG. Contraception and pregnancy in cystic fibrosis. J R Soc Med. 2009;102(Suppl 1):3–10. doi: 10.1258/jrsm.2009.s19002. [DOI] [PMC free article] [PubMed] [Google Scholar]
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