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Drugs during pregnancy and breast feeding in women diagnosed with Cystic Fibrosis - An update

Open ArchivePublished:December 07, 2017DOI:https://doi.org/10.1016/j.jcf.2017.11.009

      Keywords

      1. Introduction

      Over the past decades life expectancy of people with Cystic Fibrosis (CF) has significantly improved as a result of improved antimicrobial treatment, management strategies aimed at improved nutritional status and facilitating mucus clearance, neonatal screening and standardization of care in multidisciplinary CF care centers. The median age of CF patients in developed countries has increased to over 40 years. Improved survival and overall health has led to an increased number of women reaching reproductive age. In contrast to men, the majority of women with CF have near-normal fertility. Correspondingly, the number of pregnancies in women with CF has been rising during the last decades [
      Cystic fibrosis foundation patient registry annual report.
      ]. The pregnancy rate remained constant the last years resulting in 25,5 pregnancies per 1000 woman-years [
      • Heltshe S.L.
      • Godfrey E.M.
      • Josephy T.
      • Aitken M.L.
      • Taylor-Cousar J.L.
      Pregnancy among cystic fibrosis women in the era of CFTR modulators.
      ]. To insure the best outcomes for mother and baby, well planned management of pregnancy becomes increasingly important, including knowledge of medication safety during pregnancy and breast feeding.
      In 2008, Edenborough et al. published guidelines for the management of pregnancy in women with CF [
      • Edenborough F.P.
      • Borgo G.
      • Knoop C.
      • Lannefors L.
      • Mackenzie W.E.
      • Madge S.
      • et al.
      Guidelines for the management of pregnancy in women with cystic fibrosis.
      ]. They address many aspects of pregnancy, from the preconceptual period until after delivery. Appendix C of their paper discusses the risks of drug use during pregnancy and lactation in CF patients along with recommendations. Since this paper, new prescription medications have been approved for treating CF resulting in the need of an update of Appendix C. This report provides an update on recommendations for safe use of prescription medication in CF patients during pregnancy and breast feeding.

      2. Methods

      All prescription medication mentioned in Appendix C of the Edenborough paper were evaluated whether or not new information about their safety during pregnancy and lactation was available. When new information was found, a new recommendation was formulated. Newly registered prescription medication after the publication of Edenborough et al. have been added to offer an up-to-date evaluation of safety data for the most current prescription medication used in CF patients.
      The Cystic Fibrosis Foundation, FDA, EMA EPAR and uptodate.com provided information on prescription medication registered for CF. This provided an insight in the current use of prescription medication on the market and showed which prescription medication are currently in clinical trial stage 3. After the initial review of prescription medication that were acknowledged for treating CF, a thorough PubMed search using the MeSH terms ‘drug name’, ‘drug class’, ‘pregnancy’, ‘breastfeeding’ and ‘breast milk’ was conducted. Abstracts were included up to April 2017 if it was apparent that a class of prescription medication was used in the management of CF. The possible effect on the pregnancy in first, second and third trimester data was also evaluated and included from both animal and human studies. Databases like LactMed and Briggs ‘Drugs in Pregnancy and Lactation’ were used to formulate a recommendation on breast feeding. Case reports provided insight if there were no findings on the effects of new prescription medication on pregnancy and lactation, bearing in mind that single case reports cannot provide adequate information to formulate recommendations.

      3. Results

      The update of Appendix C of the Edenborough paper is presented in Table 1. References corresponding to Table 1 are presented in Appendix A. Where Edenborough et al. were unable to present a recommendation due to lack of information, a new recommendation was formulated if possible and displayed in italics. Prescription medication where a new recommendation has been formulated belong to the H2 antagonists, Proton Pump Inhibitors (PPI's), antibacterial drugs, antimycotic drugs, anti-viral drugs, blood glucose lowering drugs, bisphosphonates, anticholinergic drugs, bronchodilator drugs, and immunosuppressant drugs. New developed drug classes added since the Edenborough paper are prokinetics, laxatives, pancreatic enzymes, rhDNase, CFTR modulators, osmotic agents, anti-inflammatory agents and vaccines.
      Table 1Overview and recommendations on drug use in pregnant and breast feeding patients diagnosed with CF. New recommendations have been displayed in italics.
      Risk in first trimesterRisk in second/third trimesterRisk at deliveryRecommendationBreast feeding
      Acid inhibitory drugs
      H2 antagonistsNo risk shownPossible increased risk for asthmaNoPossible increased risk for asthma1Possible compatible – low concentrations present in milk
      Proton pump inhibitorsNo risk shownNot shownNoPPI preferredCompatible - low concentration in milk
      Prokinetics
      MetoclopramideNo increased risk shown2Monitor extrapyramidal syndrome in neonates in third trimesterUnknown3Probably safe – first choice is meclozine second choice is metoclopramide5Possible compatible4 – passes blood-brain-barrier, short term use possible
      DomperidonLimited human dataLimited human dataNoProbably safe – meclozine preferred during pregnancyLow dose present – does not cross Blood-Brain-Barrier, monitor QT-interval
      Constipation
      PEG +/− electrolytes

      Macrogol
      No data – systemic exposure neglible6No data – systemic exposure negligibleNoNo absorption is taking place – probably safeCompatible – no oral absorption
      LubiprostoneAdverse effects in animals (fetal loss) – limited human data7Adverse effects in animals (fetal loss) – limited human dataUnknownLimited human data – avoid during pregnancy, Macrogol preferredAvoid – no data
      Contact laxative
      SennaLimited human data shown no adverse effects8Limited human data shown no adverse effects8NoShort term use onlyPossible compatible – low concentration in milk9
      BisacodylAnimal studies show no adverse effects – limited human data10Animal studies show no adverse effects – limited human dataNoShort term use only11Compatible – no GI absorption
      Antibacterial drugs
      Aminoglycosides
       Gentamycin

       Tobramycin

       (i.v., inhal.)
      Associated with fetal nephro- and ototoxicityAssociated with eighth cranial nerve damage in fetus but not in CF literatureNoReserve for life threatening infections – inhaled causes minimal risk due to limited systemic absorptionProbably compatible12 – monitor infant on GI flora effects i.e. diarrhea, candidiasis, beware of hypersensitivity
      Cephalosporins
       Ceftazidim (and other cephalosporins)No risk shownNo risk shownNoProbably safe – only on strict indicationCompatible - excreted in low concentrations13
      Fluoroquinolones
       Ciprofloxacin (and other fluorquinolones)UnknownCartilage damage and arthropathy shown in animals14NoAvoid during pregnancy, if needed ciprofloxacin drug of choiceAvoid - high concentration

      Ciprofloxacin - probably compatible12
      Lincomycins
       ClindamycinNo risk shownNo risk shownNoProbably safe – use in absence of safer alternativePossible Compatible – cases of bloody stool, monitor infant GI flora12,15
      Macrolides
       ErythromycinNo risk shown16No risk shownNoUse as first choicePossible Compatible12
       AzithromycinProbably no riskNo risk shownNoErythromycin first choiceProbably compatible12
       RoxithromycinNo risk shown16Probably no riskNoErythromycin first choicePossible compatible
       ClarithromycinNo risk shownNo risk shownNoErythromycin first choicePossible compatible – low concentration in milk, monitor infant
      Penicillins
       Amoxicillin (and other penicillins + clavulanate or tazobactam)No risk shownNo risk shownNoProbably safeCompatible – trace in milk, beware hypersensitivity
      Polymyxins
       Colistin (i.v., inhal.)Limited human dataLimited human dataNoIV avoid if possible - Inhalation probably safeInhaled -possible compatible

      IV – caution (poorly absorbed from gut)
      Rifamycins
       Rifampicin (and other rifamycins)Animal studies show adverse effect, no adequate human data17Associated with risk of bleeding by mother and neonate in last trimesterNoAvoid during pregnancy, if necessary, treatment with phytomenadione of mother and neonateExcretion in milk – discontinue nursing or drug based on importance of therapy
      Sulphonamide/trimethoprim

      Sulphamethoxazole/trimethoprim
      Trimethoprim is associated with neural defects – reduced by folic acidSulphonamide use in the last trimester is associated with icterus of the neonateSulphonamide use at delivery associated with fetal hemolytic anemiaAvoid during first and third trimester and at deliveryCompatible in healthy term babies – avoid if G6PD deficient or jaundiced
      TrimethoprimTrimethoprim is associated with neural defects – reduced by folic acidProbably no risk if have normal folate statusNoAvoid during first trimester if needed, ensure adequate folate supplementationProbably compatible12 – low concentration in milk
      Tetracyclins
       Doxycycline (and other tetracylines)Risk of neural defects, reduced by folic acidTetracyclines associated with tooth discolorations and delayed osteogenesisAssociated with tooth and bone discolorationAvoid during 2nd/3rd trimester and at delivery should not be first choice (amoxicillin, cephalexin or erythromycin) – doxycycline possible safePossible compatible12 – prolonged use tooth discoloration
      Carbapenems
       ImipenemLimited human dataNo fetal damage in animals – limited humans studies18NoPreferable drugs are penicillin, cephalosporin or erythromycin19Possible compatible – present in milk, unlikely to be absorbed20
       MeropenemFetal damage in animals – limited human studies21No fetal damage found in animals – limited human studies21UnknownPreferable drugs are penicillin, cephalosporin or erythromycin22Possible compatible – present in milk, unlikely to be absorbed23,24
      Other antibacterials
       ChloramphenicolNo fetal damage found in animals – limited human studies21Use in last trimester associated with neonatal cyanosis and hypothermia (grey-baby syndrome)Associated with grey-baby syndromeAvoid during last trimester and at deliveryAvoid – vomiting, excessive intestinal gas and falling asleep25
       MetronidazoleNo increased risk26,27No increased risk26,27NoNo proof for adverse effects on fetusProbably compatible12 – discontinue for 12 h after intake
       PhosphomycinAnimal data show adverse effects at maternal dose - Limited human data show no risk28,29Animal data show adverse effects at maternal dose - Limited human data show no risk28,29NoDrug of choice is nitrofurantoïne (not during delivery)

      Second choice amox/clav30
      Possible compatible – low levels in breastmilk31
       VancomycinUnknown – no evidence of fetal damageUnknown – no evidence of fetal damageNoAvoid during pregnancyCompatible – present in milk, but absorption unlikely
       TeicoplaninAnimal studies show reproductive toxicity – limited human data32Animal studies show reproductive toxicity – limited human dataUnknownAvoid – no dataPossible compatible – limited data, poor oral availability due to high protein binding – monitor infant for GI problems33
       Aztreonam (i.v./inhal.)IV animal studies show no adverse reproductive effect – limited human studies34IV administration crosses placenta and enter fetal circulation – limited human studies35UnknownOnly give when potential benefit outweighs any potential risk – inhaled causes negligible systemic effectPossible compatible36 – inhaled poor systemic absorption
      Antihistamines
      Cinnarizine (and other antihistamines)No increased risk shown – meclozine drug of choiceNo increased risk shown – meclozine drug of choiceNoProbably safe to useAvoid – limited data,

      meclozine drug of choice
      Antimycotic drugs
      FluconazoleAnimal studies show major congenital anomalies – limited human data shows the same37Increase of spontaneous abortion in human37YesDose>300mg contraindicated – lower doses avoid during first trimesterPossible compatible – present in milk (less than neonatal dosage)38
      Itraconazole, voriconazoleAnimal studies show teratogenicity – limited human data show increased spontaneous abortion37No data availableUnknownAvoidAvoid – limited data38
      PosaconazoleAnimal studies show toxicity – no human data37Animal studies show toxicity – limited human dataUnknownAvoidAvoid – no data
      AmphotericinCase reports show no increased risk39Case reports show no increased risk39NoDrug of choice during pregnancyPossible compatible – high protein bound, poor oral absorption
      NystatinProbably safeProbably safeNoProbably safeCompatible – no oral absorption
      Anti-viral drugs
      AciclovirNo risk shownUse in second half of pregnancy to avoid transfer of virus to fetusNoDrug of choiceCompatible40
      ValaciclovirNo risk shown - limited human dataNo risk shown – limited human dataNoLarger bioavailability – aciclovir preferredCompatible
      GanciclovirAnimal studies reveal teratogenicityNo human dataUnknownContraindicatedAvoid – no data
      Blood glucose lowering drugs
      Insulins/insulin analoguesNo riskNo riskNo riskHuman insulins preferredCompatible12
      GlibenclamideAnimal studies reveal teratogenicity – limited human dataIncreased risk for respiratory distress, NICU, neonatal hypoglycemia, large for gestational age41Increased risk for neonatal hypoglycemiaHuman insulins preferredPossible compatible – monitor infant blood glucose
      Tolbutamide, netaglinide, repaglinideAnimal studies reveal teratogenicity – Limited human dataNo adequate human studies – expected to cross placentaIncreased risk for neonatal hypoglycemiaHuman insulins preferredPossible compatible – monitor infant blood glucose
      MetforminNo increased risk42Probably no risk but avoid – insulin preferredNeonatal hypoglycemiaHuman insulins preferredCompatible12
      Pioglitazone and other thiazolidinedionesFetal toxicity in animalsFetal toxicity in animals43Neonatal hypoglycemiaHuman insulins preferredAvoid – no data
      Bisphosphonates
      Risedronate etc.Limited human data show no substantial fetal risk44

      Animal reproduction studies shown adverse effect on fetus
      Limited human data show no substantial fetal risk – marginal decrease gestational age, birth weight and transient neonatal electrolytes45UnknownLimited human data shows no serious fetal or neonatal damage45 – Use with cautionAvoid – no data40
      Cholelithiasis drugs
      Ursodeoxycholic acidNo dataHuman data show no increased risk46NoAvoid during first trimesterCompatible – low levels in breast milk
      Contrast media
      GastrografinNo risk anticipated with oral useNo risk anticipated with oral useNoProbably no riskPossible compatible – poor oral absorption, unlikely to reach infant bloodstream
      Corticosteroids
      SystemicFetal damage in animals (mainly schisis), not in humans – Prednisolone, hydrocortisone drugs of choiceFetal damage in animals (intrauterine growth restriction in prolonged treatment, not in humans)NoSystemic corticosteroids used for supplementation therapy in adrenal insufficiency. Neonate should be monitored for growth retardation, adrenal insuf., hypoglycemiaCompatible – monitor infant adrenal function if maternal dose exceeds 40 mg prednisolone – delay feeding for 4–6 h after dose
      DermalNot probable to cause fetal damageNot probable to cause fetal damageNoClass I and Class II dermatocorticoids are preferred. Intermittend use. Class III/IV max. 1 week in acute phaseCompatible
      Nasal, tracheal steroid metered dose inhalers and dropsNo increased risk shown47No increased risk shownNoCan be used in pregnancyCompatible
      Bronchodilator drugs
      Sympathicomimetics inhaledLABA – limited data

      SABA – probably safe (data shows malformations – due to asthma?)
      LABA – limited data

      SABA – probably safe (data shows malformations – due to asthma?)
      NoSABA – salbutamol/albuterol

      LABA – Salmeterol/formeterol
      Compatible – limited systemic absorption
      Anticholinergic inhaledAnimal studies show no teratogenicity – limited human data48Animal studies show no teratogenicity – limited human data48NoIpratropium preferredProbably compatible – limited systemic absorption
      Aminophylline/theophyllineProbably safeProbably safeNeonatal irritability, cardiac arrhythmias and apneas reportedControl theophylline plasma level in third trimesterCaution — present in milk: irritability in infants reported. Give modified release preparations after feeding
      Pancreatic enzymes
      Pancreatic enzymesNo animal/human data shown – probably no risk49No animal/human data shown – probably no riskNoProbably no risk since no maternal absorptionCompatible – no maternal absorption
      rhDNase
      Dornase alfaNo fetal harm in animal studies, no human data50No fetal harm in animal studies, no human data50Unlikely/NoDue to inhaling no fetal harm expected – probably safe51Possible compatible – due to large protein molecule absorption is low52
      Vitamins
      Vitamin AUse of recommended dose of 800 RE safe53Use of recommended dose of 800 RE safe53NoUse of bètacarotene preferable – conversion rate adjusted to the amount of retinol is neededCompatible – at prophylactic doses
      Vitamin B groupProbably safeProbably safe except high doses of B6 (neonatal convulsions)NoProbably safe – use of high dose B6 contraindicatedCompatible
      Vitamin C,E,KProbably safeProbably safeNoProbably safe – High doses of vitamin C may cause paradoxical neonatal deficiencyCompatible
      Vitamin DProbably safe in prophylactic doseSafe in prophylactic dosesNoSafe in prophylactic dosesCompatible – at prophylactic doses, high doses may cause hypercalcemia in infant
      Immunosuppressant drugs
      CyclosporineAdverse effects in animals – Human data show no increased risk of malformation54Adverse effects in animals – Human data show no increased risk of malformation54Risk of premature delivery - low birth weightMaybe not teratogen – risk of premature delivery, low birth weight, developmental delay, increased risk on development of auto-immune diseasesPossible compatible – low levels in infant55 monitor infant for liver and blood values, avoid breastfeeding 4–6 h after dose
      TacrolimusFetal damage in animals – limited human data show no increased risk56Fetal damage in animals – limited human data show no increased risk56Risk of premature delivery - low birth weightMonitor infant on effect on kidneys, hyperkalemiaPossible compatible – present in low concentrations57 monitor infant for liver and blood values, avoid breastfeeding 4–6 h after dose
      AzathioprineSmall increase of fetal malformations in animalsSmall risk of neonatal immune and bone marrow suppression, premature delivery and low birth weight – monitor, weigh benefit for mother against possible effect on fetusRisk of premature delivery - low birth weightConflicting outcomes studies - monitor blood during third trimester for leukopenia and pancytopeniaPossible compatible – avoid breastfeeding 4–6 h after dose, monitor infant for liver and blood values
      MycophenolateAnimal studies show reproductive toxicity – teratogen in humans58Animal studies show reproductive toxicity – teratogen in humansRisk of spontaneous abortionsAvoid – contraindicated59Avoid – no data60
      CFTR modulators
      Class II modulator
      LumacaftorNo adverse effects in animal studies61No adverse effects in animal studiesUnknownAvoid – limited human dataAvoid – no human data
      Class III modulator
      IvacaftorLimited human data – no adverse effects in animal studiesLimited human data – no adverse effects in animal studiesUnknownAvoid – limited human dataAvoid – no human data
      Class IV modulator
      IvacaftorSee Class III CFTR modulatorsSee Class III CFTR modulatorsSee Class III CFTR modulatorsSee Class III CFTR modulatorsSee Class III CFTR modulators
      Osmotic agents
      Mannitol (inhal.)Animal studies show no malformations – limited human data63,64Animal studies show no malformations – limited human data63,64UnknownDue to local absorption, limited systemic effect -

      Possible hyper reactive response unknown64
      Avoid - unknown
      Anti-inflammatory agents
      IbuprofenHuman data show no significant increase in birth defect risk65Avoid – contraindicated due to increased risk of renal failure and premature closing ductus arteriosus and cryptorchism66YesCan be used during first trimester – avoid during second/third trimesterCompatible
      Vaccines
      InfluenzaNo known adverse effects found67Limited data show no adverse effects67NoLimited data suggest vaccination is safe in the first trimesterCompatible68 - antibodies present in milk, vaccinate child in routine schedules
      PneumococcalAnimal studies show no adverse effects – limited human data suggest also no adverse effects69Animal studies show no adverse effects – limited human data suggest also no adverse effects69NoUse with cautionCompatible68 – antibodies present in milk, vaccinate child in routine schedules
      Two of the recently developed prescription medication since the Edenborough paper are the CFTR modulators ivacaftor and lumacaftor. CF is caused by mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR) protein [
      • Sheppard D.N.
      • Welsh M.J.
      Structure and function of the CFTR chloride channel.
      ]. These mutations in the cAMP regulated anion channel, expressed on the apical membrane of epithelial cells, cause an absent or reduced activity of chloride and bicarbonate transepithelial ion transport [
      • Sheppard D.N.
      • Welsh M.J.
      Structure and function of the CFTR chloride channel.
      ]. This reduced or absent activity results in thickened secretions, obstruction and eventually organ failure. Ivacaftor, as potentiator, and lumacaftor, as corrector, bind to these specific mutations in the CFTR receptor resulting in more chloride transport and thus reducing the thickened secretions and obstructions.
      So far little is known about the safety of CFTR modulators during pregnancy and lactation. Ladores et al. reported a case of a 20-year-old woman with CF who became pregnant five months after initiating ivacaftor [
      • Ladores S.
      • Kazmerski T.M.
      • Rowe S.M.
      A case report of pregnancy during use of targeted therapeutics for cystic fibrosis.
      ]. Following the discovery of her pregnancy, she discontinued Ivacaftor. After 40 and 2/7 weeks gestation she gave birth via spontaneous vaginal delivery to a healthy son. The authors stated that ivacaftor could have had a beneficial effect on the woman's fertility. They did not provide any scientific evidence for their statement, however suggesting that ivacaftor caused vaginal mucus to become less viscous and thereby increasing fertility. Heltshe et al. showed a small decrease of the overall pregnancy rate among women with CF during the introduction of CFTR modulators. This may be related to the fact that women with CF participating in these trials are on strict birth control [
      • Heltshe S.L.
      • Godfrey E.M.
      • Josephy T.
      • Aitken M.L.
      • Taylor-Cousar J.L.
      Pregnancy among cystic fibrosis women in the era of CFTR modulators.
      ]. It was unknown whether this was a reflection of the overall US trend in pregnancies or due to factors specific in the CF community. They showed, however, a small increase in pregnancy rate amongst woman with certain CFTR mutations. These findings stress the need for more vigilance in CF registries worldwide.
      There is only one case report describing a CF patient using ivacaftor during her entire pregnancy [
      • Kaminski R.
      • Nazareth D.
      A successful uncomplicated CF pregnancy while remaining on Ivacaftor.
      ]. The woman gave birth to a healthy full term infant via an uncomplicated spontaneous vaginal delivery, no clear adverse effects were noted in the infant.
      Concerning lactation during the use of CFTR-modulators, both ivacaftor and lumacaftor are excreted in milk of lactating female rats and it cannot be ruled out that they are also excreted in human breast milk [
      • Heltshe S.L.
      • Godfrey E.M.
      • Josephy T.
      • Aitken M.L.
      • Taylor-Cousar J.L.
      Pregnancy among cystic fibrosis women in the era of CFTR modulators.
      ]. Furthermore, ivacaftor is suspected of causing cataract in young children. However, the mechanism behind this is still not clear [
      • McColley S.A.
      A safety evaluation of ivacaftor for the treatment of cystic fibrosis.
      ]. Therefore, ivacaftor and lumacaftor should be avoided during breastfeeding.

      4. Discussion

      Although much research is done for evaluating the safety of medication use, knowledge about drug risks for pregnant or lactating women is still scarce. Pregnant and lactating women are usually excluded in studies evaluating effectiveness and safety. This leads to a challenge for the management of patients during pregnancy and lactation.
      A lot of progress has been made during the last decades in the management of CF. New prescription medication have been approved for the treatment in CF of which the CFTR modulators are the most significant. In addition, new information about drug safety during pregnancy has become available, leading to this update of Appendix C of the Edenborough paper. Recommendations based on case reports need great consideration since they are based on sole events and do not reflect inter-individual differences. Therefore, there is an urgent need to use CF databanks of patients and investigate the possible effects prescription medication have on the child.

      5. Conclusion

      The drug of choice should depend on therapeutic benefits for the mother versus the possible adverse effects for the fetus/infant. The majority of clinical trials have strict exclusion criteria regarding pregnant or breastfeeding women. A pressing need for careful observations combined with reporting of experience of medication use is needed in women with CF who are pregnant, especially in the era of novel CFTR Modulators who have not yet been fully studied for their effect on the unborn child.

      Conflicts of interest

      The authors state that they have no conflicts of interest.

      Appendix A. References of Table 1

      References

      1. Cystic fibrosis foundation patient registry annual report.
        cff.org
        Date: 2014
        • Heltshe S.L.
        • Godfrey E.M.
        • Josephy T.
        • Aitken M.L.
        • Taylor-Cousar J.L.
        Pregnancy among cystic fibrosis women in the era of CFTR modulators.
        J Cyst Fibros. 2017; 16: 687-694
        • Edenborough F.P.
        • Borgo G.
        • Knoop C.
        • Lannefors L.
        • Mackenzie W.E.
        • Madge S.
        • et al.
        Guidelines for the management of pregnancy in women with cystic fibrosis.
        J Cyst Fibros. 2008; 7: 2-32
        • Sheppard D.N.
        • Welsh M.J.
        Structure and function of the CFTR chloride channel.
        Physiol Rev. 1999; 79: 23-45
        • Ladores S.
        • Kazmerski T.M.
        • Rowe S.M.
        A case report of pregnancy during use of targeted therapeutics for cystic fibrosis.
        J Obstet Gynecol Neonatal Nurs. 2017; 46: 72-77
        • Kaminski R.
        • Nazareth D.
        A successful uncomplicated CF pregnancy while remaining on Ivacaftor.
        J Cyst Fibros. 2016; 15: 133-134
        • McColley S.A.
        A safety evaluation of ivacaftor for the treatment of cystic fibrosis.
        Expert Opin Drug Saf. 2016; 5: 709-715