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A case-control study on pregnancy in Italian Cystic Fibrosis women. Data from the Italian Registry

Open ArchivePublished:November 13, 2018DOI:https://doi.org/10.1016/j.rmed.2018.11.009

      Highlights

      • The mean age at pregnancy was 31ys;
      • Decrease on nutritional status and lung function among pregnant women.
      • Difference in median age at diagnosis: pregnant (8.1 yrs) and non-pregnant (2.0 yrs).
      • Difference in change between cases and controls for the nutritional status.

      Abstract

      Background

      Pregnancy in CF women is no longer an exceptional event, but few information on its effect on clinical status in European CF patients are available. This study describes Italian CF pregnant population, to investigate its effect on CF woman.

      Methods

      Data were collected (2010–2015) by the Italian CF Registry. A case-control study was performed between pregnant and never pregnant women.

      Results

      A total of 81 pregnant women (aged 18-45ys) were identified with a mean age at pregnancy of 31ys. Median age at diagnosis resulted higher in cases (P = 0.010). A decline from 6 to 12 months before pregnancy to one year after delivery in BMI (P = 0.034), in FEV1 (P < 0.001) and FVC (P < 0.001) was registered among cases. Difference in change between cases and controls was found for the BMI (P = 0.006); weak evidence of difference in FEV1 (p = 0.080) and FVC (p = 0.056) were noted between the groups.

      Conclusion

      Data from ICFR show that CF women can become mother with only slight adverse effect on their nutritional status. Further study should be carried out to investigate long term effect of pregnancy on lung function.

      Keywords

      1. Introduction

      Cystic Fibrosis (CF) is the most frequent autosomal recessive disease in Caucasian, due to alterations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. This multi-organ disease reduces the life expectancy of affected individuals. A noticeable improvement in the prognosis of CF patients has occurred in recent decades, due to concomitant factors, as early diagnosis by neonatal screening, management improvements, and use of new personalized therapies improving CFTR protein function lead to an average survival predicted over 50 years for subjects born after 2000 [
      • Keogh R.H.
      • Szczesniak R.
      • Taylor-Robinson D.
      • Bilton D.
      Up-to-date and projected estimates of survival for people with cystic fibrosis using baseline characteristics: a longitudinal study using UK patient registry data.
      ].
      The improvement in survival is already well documented by the increase in the adult CF population reported by the various national and supranational registers. In USA, in 2016 adults accounted for 53% of total population [

      Cystic Fibrosis Foundation Patient Registry 2016 Annual Data Report, Bethesda, Maryland ®2017 Cystic Fibrosis Foundation.

      ], in Europe for 52.1% in 2015 [
      • Zolin A.
      • Naehrlich L.
      Van Rens J ECFSPR Annual Report.
      ], similarly in 2013, in Australia adults were 49.9% of CF population [
      • CF in Australia
      16th Annual Report Australian CF Data Registry.
      ]. In Italy, CF Data Registry Report for years 2011–2014 [
      • Giordani B.
      • Amato A.
      • Majo F.
      • Ferrari G.
      • Quattrucci S.
      • Minicucci L.
      • Padoan R.
      • Floridia G.
      • Puppo Fornaro G.
      • Taruscio D.
      • Salvatore M.
      • Gruppo di lavoro R.I.F.C.
      Italian cystic fibrosis registry. Report 2011-2014.
      ] shows that the adult population in 2014 accounts for 55.5% of the total CF population, with 54.2% of females being over 18 years old in the CF Italian women population.
      Fertility, impaired in 95–98% of male subjects [
      • Ahmad A.
      • Ahmed A.
      • Patrizio P.
      Cystic fibrosis and fertility.
      ], is not in women, and cases of pregnancies in CF women have begun to be reported in the scientific literature since 1960 as single case reports [
      • Siegel B.
      • Siegel S.
      Pregnancy and delivery in a patient with cystic fibrosis of the pancreas.
      ,
      • Grand R.J.
      • Talamo R.C.
      • Di Sant' Agnese P.A.
      • Schwartz R.H.
      Pregnancy in cystic fibrosis of the pancreas.
      ]. In the following years pregnancy in CF patients became a more common occurrence as a result of improving survival rates in females, as documented in several paper since 1980 [
      • Corkey C.W.
      • Newth C.J.
      • Corey M.
      • Levison H.
      Pregnancy in cystic fibrosis: a better prognosis in patients with pancreatic function?.
      ,
      • Cohen L.F.
      • di Sant'Agnese P.A.
      • Friedlander J.
      Cystic fibrosis and pregnancy.
      ]. Women with CF have a longer life expectancy and therefore, since adolescence, they may pose questions about their fertility and the possibilities of motherhood. As a consequence, a decade ago, guidelines have been published [
      • Edenborough F.P.
      • Borgo G.
      • Knoop C.
      • Lannefors L.
      • Mackenzie W.E.
      • Madge S.
      • Morton A.M.
      • Oxley H.C.
      • Touw D.J.
      • Benham M.
      • Johannesson M.
      European Cystic Fibrosis Society
      Guidelines for the management of pregnancy in women with cystic fibrosis.
      ] to improve management and treatments in CF women wishing to become pregnant.
      Up to now, no information exists for the Italian CF female population in relation to pregnancy and its effect on mother's clinical condition. The aim of this paper is therefore, by using data from the Italian CF Registry (ICFR), to describe a group of Italian women, evaluating clinical status of who became pregnant over the period 2010–2015.
      Furthermore, as several previous papers showed in pregnant women a better clinical status than never pregnant women [
      • Gillet D.
      • de Braekeleer M.
      • Bellis G.
      • Durien I.
      French Cystic Fibrosis Registry
      Cystic Fibrosis and pregnancy. Report from French data (1980-1999).
      ,
      • Goss C.H.
      • Rubenfeld G.D.
      • Otto K.
      Aitken ML the effect of pregnancy on survival in women with cystic fibrosis.
      ], we conducted a case-control study to clarify if women who became pregnant were initially healthier than never pregnant patients and to assess the effect, if any, of pregnancy on maternal clinical conditions.

      2. Methods

      Clinical data of CF women who had at least one pregnancy over the study period 2010–2015 were retrospectively collected, using records from ICFR. Data refer to patients in charge to Italian specialized CF Centers: registry collects data on demographic characteristics, diagnosis, genotype, lung function, nutrition, respiratory microbiology, complications, therapies, transplantation, mortality. Data on pregnancy outcomes were also collected (pregnancy duration, type of labor, newborn's CF diagnosis and weight).
      To assess whether the pregnancy could have medium-term effects on maternal clinical conditions, a matched case-control study was performed, comparing clinical trend of women who had children to never pregnant ones.
      Pregnant women were matched, by age and genotype, with never pregnant control subjects, at a ratio of 1:2; where it was not possible, the matching was done by functional classes of CFTR, otherwise cases were excluded from the study.
      Demographic and diagnosis data (age at diagnosis, sweat chloride, genotype, age at pregnancy) were obtained for cases and controls and the following outcomes were also investigated in the year of conception: respiratory function (FEV1% and FVC% of predicted [
      • Quanjer P.H.
      • Stanojevic S.
      • Cole T.J.
      • Baur X.
      • Hall G.L.
      • Culver B.H.
      • Enright P.L.
      • Hankinson J.L.
      • Ip M.S.
      • Zheng J.
      • Stocks J.
      ERS Global Lung Function Initiative
      Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012.
      ]), chronic infections and complications occurrence, pancreatic function (i.e. pancreatic insufficiency), body mass index (BMI).
      Clinical data on lung function and BMI referred to 6–12 months prior pregnancy and one year after delivery were also analyzed.

      2.1 Statistical analysis

      Data was explored and missing information was collected from CF Centers. A descriptive analysis of variables was first carried out to describe the study population in the year of conception.
      Potential associations between demographic or clinical variables and pregnancy were explored through the conditional logistic regression.
      Pre (6–12 months prior pregnancy) and post-delivery (one year after delivery) changes for clinical outcome, calculated as percentage changes, were tested with a paired t-test within each comparison group. Differences in nutritional status and lung function changes between the two comparison groups were also assessed. Results were considered statistically significant when the two-sided P value was <0.05. Statistical analyses were performed using the Stata Statistical Software: Release12 (College Station, TX, USA: StataCorp LP).

      3. Results

      In Italy, over the study period, women with a diagnosis of CF in their childbearing age (15–49) increased by 32.8% (from 1086 in 2010 to 1442 in 2015), accounting for 57% of the whole female CF Italian population in 2015. On average, the pregnancy rate was 10.6 per 1000 CF women-year.
      A total of 84 pregnancies were identified in 81 women: 85.2% of women reported one single pregnancy while 3.7% reported two pregnancies; nine women (11.1%) reported interruptions, equally distributed between miscarriage and voluntary or medical terminations.
      Data on pregnancy outcome and newborn health status was available for 79% of pregnancies: the mean gestational age was 37.2 ± 2.5 weeks; 65% of pregnancies had a cesarean delivery. The mean birth weight was 2780 ± 520 g; only 2 newborns were diagnosed as CF.
      Among the 81 women (aged between 18 and 45 years), identified within the ICFR for the study purposes, 2 cases, not meeting the CF diagnostic criteria (sweat chloride ≥60 mmol/L and/or two CF-causing mutations [
      • Farrell P.M.
      • White T.B.
      • Ren C.L.
      • Hempstead S.E.
      • Accurso F.
      • Derichs N.
      • Howenstine M.
      • McColley S.A.
      • Rock M.
      • Rosenfeld M.
      • Sermet-Gaudelus I.
      • Southern K.W.
      • Marshall B.C.
      • Sosnay P.R.
      Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation.
      ]), were excluded from the study. Seven additional cases, were not included in the study since no control women could be matched due to their very rare genotype. None of cases and controls had received lung transplant.
      A total of 72 women (out of the 81 identified, 89%) were definitively included in all the analyses performed.
      Table 1 describes genotypes of women with a pregnancy grouped by functional classes. As shown, 45.8% of women were characterized by a genotype conferring absent or minimal CFTR function; 41.7% by at least one CFTR mutation with residual function, while in 12.5% of women the functional effect of genotype is not determined.
      Table 1Genotypes by functional classes.
      Absent or minimal functionNResidual functionNNot determined functionN
      [delta]F508[delta]F5089[delta]F5082789+5G>A4[delta]F508c.1584 + 18672A->G2
      [delta]F508N1303K7[delta]F508D1152H3[delta]F508unknown2
      [delta]F508546insCTA1[delta]F508D110H2G542XH139R1
      [delta]F508Delexon22-241[delta]F5083849 + 10kbC->T2G542XL997F1
      [delta]F508E585X1[delta]F508D579G2unknownunknown3
      [delta]F508G1244E1[delta]F508R347H1
      [delta]F5081717-1G->A1[delta]F508T51
      [delta]F508G85E1[delta]F508TG12/T51
      2183AA->G2183AA->G2R347PR347P2
      N1303KN1303K32789+5G>AR1066C1
      G1244EG1244E12789+5G>AL1077P1
      G1244EDelexon2-313849 + 10kbC->TR347P1
      G85E711+1G->T14382delA1259insA1
      G542XG85E1621+1G->TT338I1
      Delexon2-3Delexon2-31G1244ED1152H1
      R1162XQ1476X1G542XD1152H1
      N1303K3849 + 10kbC->T1
      R334W2184insA1
      R334WR117L1
      1717-1G->ATG12/T51
      T338IT338I1
      Total:33 (45.8%)30 (41.7%)9 (12.5%)
      The CFTR allelic distribution in the study population differs from that of the CF Italian population [
      • Giordani B.
      • Amato A.
      • Majo F.
      • Ferrari G.
      • Quattrucci S.
      • Minicucci L.
      • Padoan R.
      • Floridia G.
      • Puppo Fornaro G.
      • Taruscio D.
      • Salvatore M.
      • Gruppo di lavoro R.I.F.C.
      Italian cystic fibrosis registry. Report 2011-2014.
      ]. However, the most frequent CFTR mutation is always the [delta]F508 (35.4% versus 44.8% of the whole Italian CF population) followed by the N1303K (9.7%). Only 12.5% of pregnant women reported [delta]F508 in homozygosis, in contrast with the 21.2% of the Italian CF adult population (referred to ICFR 2015 data, unpublished).
      Clinical and demographic characteristics of cases and controls in the year of conception are presented in Table 2.
      Table 2Demographic and clinical features in pregnant and never pregnant CF women in the year of conception.
      Pregnant (cases)Never pregnant (controls)p-value
      Number of subject72144
      Age (years), mean ± SD7231.0 ± 6.014431.2 ± 7.50.831
      Age at diagnosis (years), median, IQR728.1 (1.1–18.8)1442.0 (0.3–14.2)0.010
      Wilcoxon rank-sum test.
      Reason for diagnosis n(%)721440.164
      Chi-square test.
       Symptoms55 (76.4)100 (69.4)
       Familiarity9 (12.5)11 (7.6)
       Screening5 (6.9)22 (15.3)
       Meconium ileus3 (4.2)11 (7.6)
      Sweat chloride, mean ± SD
      5685.4 ± 25.612789.3 ± 25.70.337
      Nutritional status
       Body Mass Index (kg/m2), mean ± SD7221.8 ± 3.214421.7 ± 4.00.860
       Body Mass Index<22, n(%)41 (56.9)93 (64.6)0.258
      Lung function
      Women who had never had a lung transplant.
       FEV1% predicted, mean ± SD7272.6 ± 22.214272.2 ± 24.80.772
       FEV1% predicted ≥ 70, mild/normal, n(%)40 (55.6%)74 (52.1%)0.666
       FEV1% predicted ≥ 40 and < 70, n(%)27 (37.5%)53 (37.3%)0.917
       FEV1% predicted <40, n(%)5 (6.9%)15 (10.6%)0.382
       FVC% predicted7185.8 ± 18.714285.0 ± 21.50.556
      a Women who had never had a lung transplant.
      b Wilcoxon rank-sum test.
      c Chi-square test.
      The mean age at pregnancy was 31 years (range 18–45 years). There were no differences between cases and controls in sweat chloride value (p = 0.337) and in the reasons for diagnosis (P = 0.164): 76.4% and 69.4% of women were diagnosed from symptoms in cases and controls, respectively. Evidence of difference was found (p = 0.010) in the median age at diagnosis between cases (median age at diagnosis 8.1 years) and non-pregnant matched population (median age at diagnosis 2.0 years). There was no evidence of difference between the two comparison groups in the clinical status, as shown by the mean BMI (p = 0.860), mean FEV1% predicted (p = 0.772) and mean FVC% predicted (p = 0.556). Further comparisons on nutritional status and lung function in the pregnant women group were performed between those with genotypes conferring absent or minimal CFTR function and those with residual CFTR function genotypes. We found evidence of better nutritional status (p = 0.015) and better lung function (FEV1% predicted, p = 0.007; FVC% predicted, p = 0.030) in the residual CFTR function genotypes group of pregnant women.
      No significant difference between the two groups was found for pancreatic insufficiency (55.6% among pregnant women versus 57.6% for never pregnant) and for chronic infectious diseases (Pseudomonas aeruginosa, Staphylococcus aureus and B. Cepacea). Frequency of Pseudomonas aeruginosa respiratory infection resulted more frequent in cases, even if not statistically significant (55.6% among cases versus 48.6% among controls, p = 0.304).
      No difference in prevalence of complication (ABPA, diabetes, liver diseases without cirrhosis, hemoptysis) was observed (p > 0.05); however diabetes and liver disease were more frequent in controls. Neither pneumothorax nor cancer were reported in the year of conception. As regards for the trend of maternal clinical outcome over the study period starting from 6 to 12 months prior the pregnancy to one year after delivery, the changes in pulmonary function (FEV1 and FVC) and nutritional status (BMI) for pregnant and matched never pregnant CF patients are reported in Table 3. We found significant changes among cases in the BMI, which decreased by 1.9% (p = 0.034); changes were also found in the FEV1 (in liters) and FVC (in liters) which significantly fell by 7.3% (p < 0.001) and 6.2% (p = 0.001), respectively.
      Table 3Percentage change ante-post pregnancy.
      pregnantnever pregnant
      Nchange (95% CI)p-valueNchange (95% CI)p-value
      Body Mass Index (kg/m2)64−1.91 (−3.67 to −0.15)0.0341280.94 (−0.19 to 2.06)0.102
      FEV1 (in liters)64−7.32 (−11.27 to −3.38)<0.001128−2.08 (−5.81 to 1.66)0.273
      FVC (in liters)62−6.23 (−9.94 to −2.54)0.001124−2.04 (−4.50 to 0.42)0.104
      The prevalence of chronic Staphylococcus aureus or Pseudomonas aeruginosa infections among pregnant women remained stable over the study period, as well as prevalence of diabetes or complications. One woman reported a diagnosis of cancer after one year from delivery. One maternal death was reported at 14 months post-delivery for causes not related to CF.
      There was no evidence (p > 0.05) of change in the nutritional status or pulmonary function among never pregnant group over the same study period.
      Difference in change of BMI was found between cases and controls (p = 0.006). Moreover, there was weak evidence of differences between the two comparison groups in the lung function decline for FEV1 (p = 0.080) and FVC (p = 0.056).
      As regards for worsening of nutritional status or pulmonary function over the year after delivery, no association was found with the presence of Pseudomonas chronic respiratory infections, the presence of complications or pancreatic insufficiency, the presence of moderate-severe lung disease (FEV1<70% predicted) (p > 0.05) or genotype (absent or minimal CFTR function versus residual function genotypes) in both groups.

      4. Discussion

      This paper describes, for the first time, clinical features of CF Italian women who became pregnant in the period 2010–2015, using the Italian CF Registry data, and compared maternal health status and outcomes after delivery with a group of CF never pregnant women, matched for age and genotype. It also represents one of the most numerous case-control study on pregnancy clinical effect in a European CF population.
      In Italy, in the studied period, the number of CF women in their childbearing age (15–49 yrs) increased of more than 30%, predicting an increase in number of CF pregnant women in the coming years. Pregnancy in CF women seems to be a not so frequent event in Italy with a pregnancy rate of 10.6 per 1000 women-year with CF, less than the rate reported in the US CF population (25,5 per 1000 women)] [
      • 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 may be possible an underestimation of pregnancy rate in Italian CF women, as ICFR does not collect information on any pregnancies that occurred before CF diagnosis and a consistent number of patients received CF diagnosis in adulthood [
      • Giordani B.
      • Amato A.
      • Majo F.
      • Ferrari G.
      • Quattrucci S.
      • Minicucci L.
      • Padoan R.
      • Floridia G.
      • Puppo Fornaro G.
      • Taruscio D.
      • Salvatore M.
      • Gruppo di lavoro R.I.F.C.
      Italian cystic fibrosis registry. Report 2011-2014.
      ].
      The series of pregnant women described in our paper differs, with respect to the genotype, from other reported case series [
      • 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.
      ,
      • Girault A.
      • Blanc J.
      • Gayet V.
      • Goffinet F.
      • Hubert D.
      Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis—a single centre case-control study.
      ], as more than 40% have a genotype with at least one allele that guarantees a CFTR residual function. This allelic diversity might explain some of the differences observed in comparison with other case series described previously. In our population, the mean age at conception was 31 years, older than that reported by several Authors (22.8yrs-30.5yrs) and, moreover, their clinical conditions seem to be better than those reported for other CF pregnant women series. Indeed, mean FEV1 in our study was 72% predicted, higher than those previously reported (57.3%–71.3% predicted) and also mean BMI was higher (21.8) than those previously reported [
      • Gillet D.
      • de Braekeleer M.
      • Bellis G.
      • Durien I.
      French Cystic Fibrosis Registry
      Cystic Fibrosis and pregnancy. Report from French data (1980-1999).
      ,
      • Girault A.
      • Blanc J.
      • Gayet V.
      • Goffinet F.
      • Hubert D.
      Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis—a single centre case-control study.
      ,
      • Edenborough F.P.
      • Mackenzie W.E.
      • Stableforth D.E.
      The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977-1996.
      ,
      • Ahluwalia M.
      • Hoag J.
      • Hadeh A.
      • Ferrin M.
      • Hadjiliadis D.
      Cystic fibrosis and pregnancy in the modern era: a case control study.
      ]. Moreover, a lower percentage (12.5%) of pregnant women required insulin if compared to those reported in other cases: this may be explained by the high percentage of pancreatic sufficient patients (44,4%) in whom CFRD is less frequent, compared to other papers which reported higher frequency of pancreatic insufficient patients (68.2%–89.0%) and of CFRD (21.7%–35.4%) (Table 4).
      Table 4Demographic details and clinical data of CF women before pregnancy: different case series.
      Author (ref.)YearCountryNr.mean age (years)Mean FEV1%Mean FVC %mean BMICFRD %Pancreatic Insufficiency (%)Ps.aer. (%)
      Edenborough [
      • Edenborough F.P.
      • Mackenzie W.E.
      • Stableforth D.E.
      The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977-1996.
      ]
      2000UK5522.871.087.020.314.089.0
      Odergaard [
      • Ødegaard J.
      • Stray-Pedersen B.
      • Hallberg K.
      • Haanaes O.C.
      • Storrøsten O.T.
      • Johannesson M.
      Maternal and fetal morbidity in Norwegian and Swedish women with cystic fibrosis.
      ]
      2002NORV/SW2317.0
      Gillet [
      • Gillet D.
      • de Braekeleer M.
      • Bellis G.
      • Durien I.
      French Cystic Fibrosis Registry
      Cystic Fibrosis and pregnancy. Report from French data (1980-1999).
      ]
      2002France
      National Registry.
      8027.4
      At delivery.
      61.870.519.3149.068.364.3
      Goss [
      • Goss C.H.
      • Rubenfeld G.D.
      • Otto K.
      Aitken ML the effect of pregnancy on survival in women with cystic fibrosis.
      ]
      2003USA
      National Registry.
      68067.5
      McMullen [
      • McMullen A.H.
      • Pasta D.J.
      • Frederick P.D.
      • Konstan M.W.
      • Morgan W.J.
      • Schechter M.S.
      • Wagener J.S.
      Impact of pregnancy on women with cystic fibrosis.
      ]
      2006USA
      Epidemiologic Cystic Fibrosis Study.
      21624 (median)74.587.39.3
      Burden [
      • Burden C.
      • Ion R.
      • Chung Y.
      • Henry A.
      • Downey D.G.
      • Trinder J.
      Current pregnancy outcome in women with Cystic Fibrosis.
      ]
      2012UK1528.963.657.0
      Thorpe-Beeston [
      • Thorpe-Beeston J.G.
      • Madge S.
      • Gyi K.
      • Hodson M.
      • Bilton D.
      The outcome of pregnancy in women with Cystic fibrosis- single center experience 1998-2011.
      ]
      2012UK4829.560.921.935.454.268.7
      Ahwuralia [
      • Ahluwalia M.
      • Hoag J.
      • Hadeh A.
      • Ferrin M.
      • Hadjiliadis D.
      Cystic fibrosis and pregnancy in the modern era: a case control study.
      ]
      2014USA2230.568.287.521.531.868.262.5
      Renton [
      • Renton M.
      • Priestley L.
      • Bennett L.
      • Mackillop L.
      • Chapman S.J.
      Pregnancy outcomes in cystic fibrosis: a 10-year experience from a UK centre.
      ]
      2015UK826.968.184.124.013.373.386.7
      Girault [
      • Girault A.
      • Blanc J.
      • Gayet V.
      • Goffinet F.
      • Hubert D.
      Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis—a single centre case-control study.
      ]
      2016France3328.7
      At delivery.
      57.075.019.530.379.382.7
      Heltshe [
      • 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.
      ]
      2016USA
      National Registry.
      17262770.423.121.777.862.8
      Giordani2018Italy723172.685.821.812.555.655.6
      a National Registry.
      b At delivery.
      c Epidemiologic Cystic Fibrosis Study.
      Eighty-nine percent of women had carried out pregnancies resulting in birth, including those who had a severe genotype (about 50%), who reported severe condition of pulmonary function (7% of cases reported a FEV1 less than 40% predicted) or who were chronically colonized by Pseudomonas aeruginosa and Staphylococcus aureus. This might suggest that pregnancy is feasible in CF women and that the integrated care provided by CF specialized centers following specific recommendations, may provide successful management for CF pregnant women.
      Percentage of interruptions (10.7%) is similar to that reported for other case series (4–14%) [
      • Thorpe-Beeston J.G.
      • Madge S.
      • Gyi K.
      • Hodson M.
      • Bilton D.
      The outcome of pregnancy in women with Cystic fibrosis- single center experience 1998-2011.
      ].
      Therefore, in Italy, pregnancy occurs in CF women in an acceptable health status, reflecting maybe the tendency of clinicians to discourage pregnancy in CF subjects who do not present an optimal clinical status; or to improve CF women's health through a preconception intensive management.
      A case-control study, allows to clarify the effect of pregnancy on clinical status trend and several criteria may exist to select controls. In our study we have chosen to match cases and controls by age and genotype and not on clinical basis (by similar lung function and/or nutritional status). Only for seven patients (8.6%), then excluded from the study, we failed to find any control, due to their rare genotype. We have therefore conducted our case-control study on what appears to be the largest European CF population of pregnant women (72 cases versus 144 controls) (Table 5).
      Table 5Case control studies on pregnant CF women versus never pregnant CF women.
      Author (ref.)yearCountryMatchNr (ratio case-controls)Outcome in pregnant women
      Ahmed [
      • Ahmed R.
      • Wielensku C.L.
      • Warwick W.J.
      Effect of pregnancy on CF.
      ]
      1995USAAge, Clinical13 (1:1)more exacerbations
      FitzSimmons [
      • FitzSimmons S.C.
      • Fitzpatrick S.
      • Thompson B.
      A longitudinal study of the effects of pregnancy on 325 women with cystic fibrosis.
      ]
      1996CFF USA RegistryAge, Clinical258 (1:4)no negative effects of pregnancy
      Frangolias [
      • Frangolias D.D.
      • Nakielmna E.M.
      • Wilcox P.G.
      Prenancy and cystic fibrosis: a case-controlled study.
      ]
      1997CanadaAge, Clinical7 (1:1)no difference
      Gillet [
      • Gillet D.
      • de Braekeleer M.
      • Bellis G.
      • Durien I.
      French Cystic Fibrosis Registry
      Cystic Fibrosis and pregnancy. Report from French data (1980-1999).
      ]
      2002France, RegistryAge,Genotype18 (1:1)slight adverse effect in pregnant women
      Goss [
      • Goss C.H.
      • Rubenfeld G.D.
      • Otto K.
      Aitken ML the effect of pregnancy on survival in women with cystic fibrosis.
      ]
      2003CFF USA RegistryAge, Clinical680:3327better survival
      McMullen [
      • McMullen A.H.
      • Pasta D.J.
      • Frederick P.D.
      • Konstan M.W.
      • Morgan W.J.
      • Schechter M.S.
      • Wagener J.S.
      Impact of pregnancy on women with cystic fibrosis.
      ]
      2006ESCF USAAge, Clinical216:3896no difference/more therapies and visits
      Schechter M [
      • Schechter M.S.
      • Quittner A.L.
      • Konstan M.W.
      • Millar S.J.
      • Pasta D.J.
      • McMullen A.
      Epidemiologic Study of Cystic Fibrosis. Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis.
      ]
      2013ECFS USAPropensity Score119–1190No difference in long-term outcome/more hospital visits and more courses of intravenous antibiotics
      Ahluwalia [
      • Ahluwalia M.
      • Hoag J.
      • Hadeh A.
      • Ferrin M.
      • Hadjiliadis D.
      Cystic fibrosis and pregnancy in the modern era: a case control study.
      ]
      2014Phyladelphia, USAAge, Clinical22 (1:1)no worse outcome
      Giordani2018Italy, RegistryAge,Genotype72 (1:2)decline in BMI
      Our study reported no difference between cases and controls on health status at conception, unlike what is reported by others [
      • Gillet D.
      • de Braekeleer M.
      • Bellis G.
      • Durien I.
      French Cystic Fibrosis Registry
      Cystic Fibrosis and pregnancy. Report from French data (1980-1999).
      ,
      • Goss C.H.
      • Rubenfeld G.D.
      • Otto K.
      Aitken ML the effect of pregnancy on survival in women with cystic fibrosis.
      ,
      • Schechter M.S.
      • Quittner A.L.
      • Konstan M.W.
      • Millar S.J.
      • Pasta D.J.
      • McMullen A.
      Epidemiologic Study of Cystic Fibrosis. Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis.
      ], who found a better clinical status in pregnant women. The only significant difference was found for mean age at diagnosis, higher in cases. We suggest that it may be due to a lower outbreak of the disease, during pediatric age, in the pregnant group, in absence of neonatal screening policies.
      Only a few studies [
      • Goss C.H.
      • Rubenfeld G.D.
      • Otto K.
      Aitken ML the effect of pregnancy on survival in women with cystic fibrosis.
      ,
      • McMullen A.H.
      • Pasta D.J.
      • Frederick P.D.
      • Konstan M.W.
      • Morgan W.J.
      • Schechter M.S.
      • Wagener J.S.
      Impact of pregnancy on women with cystic fibrosis.
      ,
      • Schechter M.S.
      • Quittner A.L.
      • Konstan M.W.
      • Millar S.J.
      • Pasta D.J.
      • McMullen A.
      Epidemiologic Study of Cystic Fibrosis. Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis.
      ,
      • FitzSimmons S.C.
      • Fitzpatrick S.
      • Thompson B.
      A longitudinal study of the effects of pregnancy on 325 women with cystic fibrosis.
      ], conducted on USA population, explored the medium and long term effect of pregnancy on clinical status of women in larger number of cases finding no or slight negative effect of pregnancy together with a greater therapeutic and assistance load. Another study, with a limited case series, showed no negative effects of pregnancy, besides an increasing number of exacerbations during pregnancy [
      • Ahluwalia M.
      • Hoag J.
      • Hadeh A.
      • Ferrin M.
      • Hadjiliadis D.
      Cystic fibrosis and pregnancy in the modern era: a case control study.
      ]. On the contrary, a significant decline in nutritional status and lung function was found in Italian CF women in the period over the 6–12 months prior pregnancy to the first year after delivery, sign of the potential risk of worsening that pregnancy has on the health status of women. However, between the two comparison groups, the study showed difference in the BMI change and weak evidence of difference for lung function change.
      In our study, age at pregnancy is older than that reported in previous studies which is not linked to an overall worsen pre-pregnancy lung function as seen by Thorpe [
      • Thorpe-Beeston J.G.
      • Madge S.
      • Gyi K.
      • Hodson M.
      • Bilton D.
      The outcome of pregnancy in women with Cystic fibrosis- single center experience 1998-2011.
      ]. On the contrary, mean FEV1% predicted resulted higher than that reported in other series (Table 4).
      The mean age at conception over 30 years could in part explain the significant decline in BMI and in pulmonary function over the study period. On the other hand, the reduced time women spend to their own healthcare (due to breastfeeding and childcare), at an age which presumably more time to therapies or clinical assessments is required, can contribute to the slight differences when compared with never pregnant women.
      It would be challenging to understand whether that is specifically due to the pregnancy itself or simply to the method of calculation of lung function changes.
      As regard outcomes, the majority were caesarian delivery, with a duration of pregnancies slightly shorter than normal, and therefore the weight of newborns is lower than normal.
      The strength of this study is the number of subjects, which makes it the largest case-control study on a European CF pregnant population.
      However, this study has also several limitations.
      Unfortunately, ICFR does not collect data on number of pulmonary exacerbations and estimation of difference between pregnant and never pregnant women was not possible. Due to the limited follow up time, estimation pregnancy effect on long term CF survival is not possible. No data on socio-economic status, on education or marital status is collected by ICFR, thus we don't known the effect of these variables on pregnancies in CF women.
      On the other hand, ICFR for both cases and controls provided accurate information about several clinical variables necessary to evaluate the women's state of health; this will make possible to carry out a medium-term study of the pregnancy effect on different clinical outcomes. Moreover data on pregnancy in CF women are unfortunately not collected by the European CF Patients' Registry as well. Information on pregnancies in European CF women is reported only on a center's basis [
      • Edenborough F.P.
      • Mackenzie W.E.
      • Stableforth D.E.
      The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977-1996.
      ,
      • Thorpe-Beeston J.G.
      • Madge S.
      • Gyi K.
      • Hodson M.
      • Bilton D.
      The outcome of pregnancy in women with Cystic fibrosis- single center experience 1998-2011.
      ,
      • Burden C.
      • Ion R.
      • Chung Y.
      • Henry A.
      • Downey D.G.
      • Trinder J.
      Current pregnancy outcome in women with Cystic Fibrosis.
      ,
      • Renton M.
      • Priestley L.
      • Bennett L.
      • Mackillop L.
      • Chapman S.J.
      Pregnancy outcomes in cystic fibrosis: a 10-year experience from a UK centre.
      ,
      • Ødegaard J.
      • Stray-Pedersen B.
      • Hallberg K.
      • Haanaes O.C.
      • Storrøsten O.T.
      • Johannesson M.
      Maternal and fetal morbidity in Norwegian and Swedish women with cystic fibrosis.
      ] o by the national French registry surveys [
      • Gillet D.
      • de Braekeleer M.
      • Bellis G.
      • Durien I.
      French Cystic Fibrosis Registry
      Cystic Fibrosis and pregnancy. Report from French data (1980-1999).
      ].
      In conclusion, analyses of ICFR data from this large cohort showed that Italian CF women may became parent with a slight impact of pregnancy on their lung function in the medium term follow up, though their nutritional status appears to be negatively impacted by pregnancy. A more careful monitoring of nutritional status during pregnancy is then desirable in the Italian CF population.
      Parenthood is therefore becoming a normal expectation, rather than an exception in CF women and number of pregnancies will be increasing in the future due to the better clinical conditions of CF women.

      Declarations of interest

      None.

      Acknowledgement

      We thank Lega Italiana Fibrosi Cistica ONLUS - LIFC to trust and to financially support all activities of the Italian Cystic Fibrosis Registry (ICFR).
      We thank Dr. Manuela Seia (Medical Genetics Laboratory, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy) for her comments on the definition of genotypes.
      We thank the patients who allowed the collection of their data by the Italian Registry and the Directors of the Italian Cystic Fibrosis Centers that contribute to the registry by sending data.
      We would like to thank the ICFR scientific board: Laura Minicucci, MD ( Genoa CF Center ), Donatello Salvatore, MD ( Potenza CF Center ), Domenica Taruscio MD (National Center for Rare Diseases, Istituto Superiore di Sanità, Rome) and Giovanna Floridia PhD ( National Center for Rare Diseases, Istituto Superiore di Sanità, Rome ) and the technical committee: Gianluca Ferrari (National Center for Rare Diseases, Istituto Superiore Sanità) and Fabio Majo, MD ( Ospedale Pediatrico Bambino Gesù CF Center, Rome ) for their support in conducting this research.

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