The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

Including prenatal and antenatal diagnosis, pregnancy, influence on incidence,



1979 Brock DJ, Hayward C. Methylumbelliferyl-reactive proteases and prenatal diagnosis of cystic fibrosis. Lancet 1979; i: 1245-1246.[PubMed]
The titration of trypsin like proteases in cell free amniotic fluid against an artificial substrate, 4methylumbelliferyl-guanidinobezoate which had been proposed as a means of antenatal diagnosis by Nadler et al (Lancet 1980; ii: 96-97; Nadler HL, Walsh MMJ. Pediatrics 1980; 66:690-692.[PubMed]) looked hopeful but could not be reproduced in other centres resulting in an unacceptable number of false negative and false positive results (Tummler B et al. Clin Chem Acta 1982; 125:219-232 [PubMed])


1983 Carbens NJB, Gosden G, Brock DJH. Microvillar peptidase activity in amniotic fluid: possible use in prenatal diagnosis of cystic fibrosis. Lancet 1983; i: 329-331.[PubMed]
The activities of two amniotic fluid peptidases were significantly depressed in the second trimester amniotic fluid supernatant in the presence of a fetus affected by cystic fibrosis. Eventually David Brock, of Edinburgh, used monoclonal antibody specific for isoenzyme of alkaline phosphatase (see below). Both methods were superseded by superior DNA based methods.


1983 Brock DJH. Amniotic fluid alkaline phosphatase isoenzymes in early prenatal diagnosis of cystic fibrosis. Lancet 1983; ii: 941-943. [PubMed]
Antenatal diagnosis in families with a known CF child was possible by assay of the microvillus enzymes at 17-18th week of pregnancy. In pregnancies with a CF fetus there was a profound deficiency of one form of alkaline phosphatase (the phenylalanine-inhibitable form). When phenylalanine and homoarginine were used to define the alkaline phosphatase isoenzymes in stored amniotic fluid, 9 out of 10 cases of CF were identified (Brock DH et al, Hum Genet 1984; 65: 248-251.[PubMed]; Brock DH et al, Hum Genet 1988; 78:271-275. [PubMed]).

David Brock later (1993) commented that assay of microvillar enzymes in the second trimester amniotic fluid supernatant had a rational physiological basis and had stood the test of time but eventually it was superseded by superior DNA-based methods.


1985 Brock DJH, Befgood D, Barron L, Haward C. Prospective prenatal diagnosis of cystic fibrosis. Lancet 1985;I: 1175-1178. [PubMed]
An immunoassay based on monoclonal antibodies with specificity for the three major isoenzymes of alkaline phosphatase (ALP) was used in second-trimester prenatal diagnosis of cystic fibrosis. When prospective and retrospective data were summed the sensitivity of the test was 91% (39 of 43) and the false-positive rate 6% (5 of 81). The authors concluded that this was probably an acceptable form of prenatal diagnosis of CF for the high-risk mother at the time.

David Brock of Edinburgh pioneered antenatal diagnosis prior to the identification of the probes in close proximity to the CF gene in 1985. He had previously made major contributions to the antenatal recognition of spina bifida.


1986 Farrell M, Law HY, Rodeck CH, Warren R, Stanier P, Super M, Lissens W, Scambler P, Watson E, Wainwright B, et al. First-trimester prenatal diagnosis of cystic fibrosis with linked DNA probes. Lancet 1986; i: 1402-1405. [PubMed]
More accurate antenatal diagnosis using the new linked probes was described in 1985. Linkage analysis with cloned gene probes has shown that the mutation causing cystic fibrosis was located in the middle of the long arm of chromosome 7.

In this paper first-trimester diagnosis of cystic fibrosis is reported in four informative families and second-trimester diagnosis in one family with fetal DNA prepared from chorionic villi, hybridised with the tightly linked DNA probes, pJ3.11 and met. Risk calculations show that the expected false-negative and false-positive rates are approximately 2% and 6%, respectively, for typical nuclear families with one affected living child.
The authors considered existing probes to be sufficiently informative now to allow full diagnosis in about two-thirds of couples presenting with at least one affected child. In half of the remainder, the inheritance of one parental mutant chromosome could be deduced.


1992 Handyside AH, Lesko JG, Tarin JJ, Winston RM, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med 1992; 327:905-909. [PubMed]
Preimplantation genetic diagnosis of cystic fibrosis was attempted in three couples, both members of which carried the delta F508 deletion. In vitro fertilisation techniques were used to recover oocytes from each woman and fertilize them with her husband's sperm. Three days after insemination, embryos in the cleavage stage underwent biopsy and removal of one or two cells for DNA amplification and analysis. Only two oocytes from one woman were fertilized normally; DNA analysis of one of the embryos failed and cystic fibrosis was diagnosed in the other (i.e. it was homozygous for delta F508), so neither was transferred. The oocytes of each of the other two women produced non-carrier, carrier, and affected embryos. Both couples chose to have one non-carrier embryo and one carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes.

This is the first report of preimplantation genetic diagnosis to identify the delta F508 deletion causing cystic fibrosis using in vitro fertilisation, biopsy of a cleavage-stage embryo, and amplification of DNA from single embryonic cells (also Handyside et al, 1988 above). Subsequent reports indicated an approximately 30% chance of a successful pregnancy after such an embryo had been implanted.


1992 Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I, Whyte DA, Brock DJH. Prenatal screening for cystic fibrosis. Lancet 1992; 340:214-216. [PubMed]
This is the first report of antenatal couple screening for CF in the Edinburgh maternity hospitals. Of 4348 women, 14% declined prenatal screening and 13% were not screened for other reasons. Amongst 3165 women there were 111 carriers detected of whom four had carrier partners and all 4 couples opted for prenatal diagnosis. One pregnancy with an affected fetus was terminated. The importance of adequate counselling was stressed.

Antenatal screening for CF became routine in Edinburgh but was eventually discontinued in 2005 for various reasons including the improving prognosis for CF and also the introduction of neonatal screening in Scotland (also Brock 1985 above; Livingstone et al, 1994 below). National antenatal CF carrier screening had not been introduced in the UK by 2012 although it had been accepted in principle by the UK National Screening Committee.


1994 Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G. Active cascade screening for carriers of cystic fibrosis gene. BMJ 1994; 308:1462-1467. [PubMed]

Dr Maurice Super (1936-2006) first encountered CF in Windhoek in South West Africa (Namibia) in 1967 where he started a CF clinic. He subsequently became a leading geneticist and paediatrician in the UK working in Manchester. Maurice was a major protagonist of carrier screening in the extended families of people with cystic fibrosis – so-called “cascade screening”. The present paper describes 15 carrier couples detected out of 1563 relatives of people with CF who were tested; eight had prenatal tests and three pregnancies were terminated. An average of 16 people per family had been tested. Cascade screening was acceptable to relatives, particularly on the mother’s side of the family and 10 times more successful in detecting carrier couples than unfocused screening.

The genetic testing of all potential child-bearing relatives of a person with CF is now provided by the UK NHS if the individuals wish to be tested.


1994 Livingstone J, Axton RA, Gilfillan A, Mennie M, Compton M, Liston WA, Liston WA, Calder AA, Gordon AJ, Brock DJ. Antenatal screening for cystic fibrosis: a trial of the couple model. BMJ 1994; 308:1459-1462. [PubMed]
The second report of antenatal screening of 8536 couples in Edinburgh. 8.4% were “ineligible”, 1900 declined screening for various reasons and 5922 (69.4%) were screened. There were four positives (i.e. both partners were CF carrier heterozygotes) and all four couples opted for prenatal diagnosis. There were three terminations where the fetus was affected and one couple elected to have the CF infant. There was 99% satisfaction by those screened.

Antenatal CF screening was pioneered in Edinburgh by David Brock and his colleagues and this is one of the first reports (also Mennie et al, 1992 first report above). Screening was introduced into the two Edinburgh trial hospitals following this report. However, the service was eventually discontinued in 2005 soon after neonatal CF screening was introduced into Scotland. As the outlook for CF improved parental attitudes changed to antenatal diagnosis and termination, also the mutations tested differed from the neonatal ones, and finally funding for both antenatal and neonatal screening was inadequate. It has been estimated from various studies that for every CF fetus detected by antenatal screening the cost is between £50K and £100K.


1996 Brock DJH. Prenatal screening for cystic fibrosis: 5 years’ experience reviewed. Lancet 1996; 347:148-150. [PubMed]
Antenatal screening had been available at two maternity clinics in Edinburgh, UK, since January, 1992, first on a research basis and then routinely. 25,000 couples had been screened. The take-up rates for the two-step and couple models of delivery were very similar at about 70%. Of 22 high-risk couples identified entirely through screening, 20 (91%) opted for prenatal diagnosis. Four couples returned for second and two for third monitored pregnancies. In all eight cases where affected fetuses were identified, pregnancy was terminated.

David Brock concluded that “these data remove one of the few remaining obstacles to a general implementation of prenatal screening for CF”.

However, although prenatal screening was recommended in the UK by a Health Technology Assessment (Murray et al, 1999) and after this was accepted in principle by the National Screening Committee, prenatal screening had not been introduced in the UK by 2012. Furthermore, antenatal CF screening was discontinued in the Edinburgh hospitals in 2005 on grounds of both cost and also the introduction of neonatal screening and the evidence of improving prognosis for infants with CF diagnosed soon after birth (also Mennie et al, 1992 above; Livingstone et al, 1994 above).


1998 Cunningham S, Marshall T. Influence of five years of antenatal screening on the paediatric cystic fibrosis population in one region. Arch Dis Child 1998; 78:345-348.[PubMed]
The incidence of CF in the five years before and after antenatal screening was introduced in Edinburgh decreased from 4.6 to 1.6 infants per year – a reduction greater than could be accounted for by prenatal diagnosis and termination.



2005 Dupuis A, Hamilton D, Cole DE, Corey M. Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing. J Pediatr 2005; 147:312-315. [PubMed]
The overall CF birth rate from 1971-1987 was 1 in 2714 with no increasing or decreasing trend. Beginning in 1988, 1 year before identification of the CF transmembrane conductance regulator gene, estimated CF birth rates followed a linear decline to an estimated rate of 1 in 3608 in 2000. CF birth rates may have stabilized in the last few years, but further decline may occur with implementation of carrier screening in the general population. These results demonstrate the temporal association of genetic testing and declining CF birth rates in Canada.

Both neonatal screening in East Anglia (Green et al,1993 above) and antenatal screening in Edinburgh (Cunningham & Marshall, 1998 above) have been associated with a subsequent reduction in the incidence of CF in newborns in those areas – which perhaps is not surprising.


2006 Saker A, Benachi A, Bonnefont JP, Munnich A, Dumez Y, Lacour B, Paterlini-Brechot P. Genetic characterisation of circulating fetal cells allows non-invasive prenatal diagnosis of cystic fibrosis. Prenatal Diagnosis 2006; 26:906-916. [PubMed]
The purpose of this study from Paris was to develop a molecular method to characterise both paternal and maternal CFTR alleles in DNA from circulating fetal cells (CFCs) isolated by ISET (isolation by size of epithelial tumour/trophoblastic cells). This protocol was validated in 12 pregnant women, at 11 to 13 weeks of gestation, whose offspring had a 1 in 4 risk of CF. Results showed that one fetus was affected, seven were heterozygous carriers of a CFTR mutation, and four were healthy homozygotes. These findings were consistent with those obtained by chorionic villus sampling (CVS).

This test affords a reliable method prenatal diagnosis for high risk couples and avoids the risks associated iatrogenic miscarriage with chorionic biopsy (also note Fetal DNA detected at 13 weeks of a Q890X carrier fetus by Gonzalez-Gonzalez MC et al. Prenatal diagnosis 2002; 22:946-948.[PubMed]).

2009 Christie LM. Ingrey AJ. Turner GM. Proos AL. Watts GE. Outcomes of a cystic fibrosis carrier testing clinic for couples. M J Australia 2009; 191:499-501 [PubMed]
To review the outcomes of offering carrier testing for cystic fibrosis (CF) to couples considering pregnancy, and to women in early pregnancy and their partners. An after-hours clinic was established in Newcastle (Australia) for discussion of issues related to prenatal testing.

Couples were offered CF carrier testing by extracting DNA from a mouthwash sample. An expanded one-step model was used with both partners being tested initially for the p.F508del cystic fibrosis transmembrane conductance regulator gene (CFTR) mutation. If one partner was a p.F508del carrier, the other partner was tested for an additional 28 CFTR mutations. Of 1000 individuals who were offered CF carrier testing, none declined. No re-collections of mouthwash samples were required, and results were available within 14 days.

There were 730 individuals who had no family history of CF (73%); 27 were carriers (4%; 95% CI, 2.4%-5.3%), and there were two high-risk couples where both partners were carriers of p.F508del. There were 270 individuals who had an affected family member with CF or a child identified as a CF carrier through newborn screening; 126 were carriers (46%; 95% CI, 40.6%-52.8%), and there were two high-risk couples - one couple where both partners were carriers of p.F508del, and another couple where the woman was homozygous for p.F508del and the man was a p.F508del carrier. The information on carrier status led the four high-risk couples to change their reproductive decisions to avoid having a child with CF.

The authors concluded that CF carrier testing for couples using an expanded one-step model will detect about 80% of high-risk couples and enables various reproductive choices. They believe that all couples considering pregnancy, and women in early pregnancy and their partners, should be offered CF carrier testing.



1960 Siegel B, Siegel S. Pregnancy and delivery in a patient with cystic fibrosis of the pancreas. Obstet Gynecol 1960; 16:438-440.

This was the first report of pregnancy in a lady with CF; the patient died six weeks after the birth. The authors concluded, “cystic fibrosis is seriously complicated by pregnancy”. As the survival and condition of patients with CF improved, an increasing number of women with CF had successful pregnancies (Cohen et al, 1980 below [PubMed]; Gilliam et al, 2000 below [PubMed]; Edenborough et al, 2000 below [PubMed]), even some who had undergone lung transplantations (Gyi KM et al. J Cyst Fibros 2006; 5:171-175.[PubMed]).


1980 Cohen LF, Di Sant’Agnese PA, Friedlander J. Cystic fibrosis and pregnancy: a national survey. Lancet 1980; ii: 842-844. [PubMed]

First large national survey of pregnancies in women with CF attending 119 CF centres in the U.S.A. and Canada, reporting 129 pregnancies in 100 women. Ninety seven pregnancies were completed resulting in 86 viable infants, only one of whom had cystic fibrosis. Shortened gestation and increased maternal and perinatal mortality were related to severe maternal pulmonary infection. There were no congenital anomalies in this series in spite of frequent use of antibiotics by these mothers.

The first pregnancy in a woman with CF was by Siegel & Siegel (1960 above) and she died six weeks after the birth. Even in 1980 pregnancy was still a hazardous undertaking for women with CF and the authors advised that unless the clinical condition was good, pregnancy should be avoided in women with cystic fibrosis. Fortunately, although there were still problems, the outlook continued to improve (Gilljam M, et al. Chest 2000; 118:85-91. [PubMed]; Edenborough FP, et al. Brit J Obstet Gynaec 2000; 107:254-261. [PubMed]).


2000 Gilljam M, Antoniou M, Shin J, Dupuis A, Corey M, Tullis DE. Pregnancy in cystic fibrosis. Fetal and maternal outcome. Chest 2000; 118:85-91. [PubMed]
From 1963 to 1998, there were 92 pregnancies in 54 women known to the Toronto clinic. There were 11 miscarriages and 7 therapeutic abortions. Forty-nine women gave birth to 74 children. The overall mortality rate was 19% (9 of 48 patients). Absence of Burkholderia cepacia (p < 0.001), pancreatic sufficiency (p = 0.01), and pre-pregnancy FEV1 > 50% predicted (p = 0.03) were associated with better survival rates. When adjusted for the same parameters, pregnancy did not affect survival compared to the entire adult female CF population.

The maternal and fetal outcome is good for most women with CF. However, it is important that pregnancies are planned so that there is opportunity for counselling and optimization of the medical condition. Good communication between the CF team and the obstetrician is important. Both these papers emphasise the need to plan pregnancies, that severity of the mothers’ chest determines the maternal outcome but that most infants are normal. The women should be closely supervised by the team at a specialist CF centre working closely with an obstetrician with experience in CF pregnancies. Ideally the woman with CF should discuss with the CF team, particularly the dietitian, before she becomes pregnant (also Edenborough et al, 2000 above; Edenborough et al, 2008 below).


2000 Rodgers HC, Knox AJ, Toplis PJ, Thornton SJ. Successful pregnancy and birth after IVF in a woman with cystic fibrosis. Hum Reproduct 2000; 15:2152-3. [PubMed]
The first woman with CF to be successfully treated with in vitro fertilisation (IVF) after repeated failed attempts at intrauterine insemination.

As survival increases, patients with CF are often confronted with reproductive issues. Initial reports gave conflicting advice regarding the outcome of pregnancy in CF; however two more recent large longitudinal studies of pregnancies in CF women suggested that in recent years most pregnancy has little impact on morbidity or mortality (Edenborough et al. 2000 [PubMed]; Gilljam et al. 2000 [PubMed]).

Reduced fertility in women with CF has been described, considered possibly due to thick cervical mucus, and intrauterine insemination has been used to overcome this. In the present case IVF was used - a technique first described by Professor Robert Edwards and used successfully in 1978. Professor Edwards was awarded the Nobel Prize for his work in 2010. The technique first described by Edwards and Steptoe (Steptoe PC, Edwards RG. Birth after the re implantation of a human embryo. Lancet 1978; 2:366. [PubMed]) has proved valuable for people with CF as representing an essential step in performing preimplantation genetic diagnosis and also in pregnancies following intracytoplasmic sperm injection of samples from men with cystic fibrosis.


2000 Edenborough FP, Mackenzie WE, Stableforth DE. The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977-1996. Brit J Obstet Gynaec 2000; 107:254-261). [PubMed]
Frank Edenborough (figure 1), Director of the Adult CF Centre in Sheffield, reviews 72 pregnancies in women with CF in the UK, the outcomes were known for 69; there were 48 live births (70%) of which 22 were premature (46%); 14 therapeutic abortions (20%); and 7 miscarriages (10%). There were no stillbirths, neonatal or early maternal deaths. Three major fetal anomalies were seen, but no infant had cystic fibrosis.

The outcomes for the infants of women with CF are generally good but are variable for the mother - lung function being the most significant determining factor. All pregnancies should be planned with prior counselling and monitored by dedicated cystic fibrosis teams, including obstetricians who are experienced in managing high risk pregnancies (also Siegel & Siegel, 1960 above; Cohen et al, 1980 above [PubMed]; Gilljam et al, 2000 above [PubMed]).

Fig. 1: Frank Edenborough

There are more recent European guidelines - Edenborough et al. Guidelines for management of pregnancy in women with cystic fibrosis. J Cyst Fibros 2008; Suppl 1:S1-32.) [PubMed]


2003 Simon-Bouy B, Satre V, Ferec C, Malinge MC, Girodon E, Denamur E, Leporrier N, Lewin P, Forestier F, Muller F. French Collaborative Group. Hyperechogenic fetal bowel: a large French collaborative study of 682 cases. Am J Med Genet 2003; Part A. 121A:209-213. [PubMed]
Hyperechogenic fetal bowel is detected in 0.1-1.8% of pregnancies during the second or third trimester. This 1997-1998 multicenter study in 22 molecular biology laboratories identified 682 cases of hyperechogenic fetal bowel detected by routine ultrasound examination during the second (86%) or third trimester. The fetal bowel was considered hyperechogenic when its echogenicity was broadly similar to, or greater than, that of the surrounding bone. Karyotyping, screening for viral infection, and screening for cystic fibrosis mutations were performed in all cases. Pregnancy outcome and postnatal follow-up were obtained in 656 of the 682 cases (91%). In 447 cases (65.5%), a normal birth was observed. Multiple malformations were observed in 47 cases (6.9%), a significant chromosomal anomaly was noted in 24 (3.5%), cystic fibrosis in 20 (3%), and viral infection in 19 (2.8%). In utero unexplained fetal death occurred in 1.9% of cases, toxemia in 1.2%, IUGR in 4.1%, and premature birth in 6.2%.

This study demonstrates that this ultrasound sign is potentially associated with medically significant outcomes. Having established that the bowel is hyperechogenic, recommended investigations should include a detailed scan with Doppler measurements, fetal karyotyping, cystic fibrosis screening, and infectious disease screening. After birth, newborns require pediatric examination because a surgical treatment may be necessary. This should be combined with clear counseling of the parents.

A very clear and practically useful paper from a large multicentre French study which indicates the significance of hyperechogenic bowel during pregnancy.


2008 Edenborough FP, Borgo G, Knoop C, Lannefors L, Mackenzie WE, Madge S, Morton AM, Oxley HC, Touw DJ, Benham M, Johannesson M. Guidelines for the management of pregnancy in women with cystic fibrosis. J Cyst Fibros 2008: S2-S32. [PubMed]
Optimal treatment of all aspects of CF needs to be maintained from the pre conceptual period until after the baby is born. Clinicians must be prepared to modify their treatment to accommodate the changing physiology during pregnancy and to be aware of changing prescribing before conception, during pregnancy, after birth and during breast feeding.

This supplement offers detailed consensus guidelines based on review of the literature and experience of paediatricians, adult and transplant physicians, and nurses, physiotherapists, dietitians, pharmacists and psychologists experienced in CF and anaesthetists and obstetricians with experience of CF pregnancy.


2013 Thorpe-Beeston JG, Madge S, Gyi K, Hodson M, Bilton D. The outcome of pregnancies in women with cystic fibrosis-single centre experience 1998-2011. BJOG: An International Journal of Obstetrics & Gynaecology. 2013; 120:354-61. [PubMed]

Forty one women with CF had 48 pregnancies - two miscarriages, 44 singleton pregnancies and two sets of twins. All babies were live born and survived, mean gestational age was 35.9 +/- 3.3 weeks. There were no fetal abnormalities or terminations of pregnancy. The median birth weight centile was 31.9. Twenty-five (52.1%) of the women had pancreatic insufficiency and 17 (35.4%) required insulin. Women with FEV (1) <=60% were more likely to deliver earlier and by caesarean section compared with women with FEV(1) >60%. Three of the seven women with an FEV(1) <40% died within 18 months of delivery. Four of the eight women with FEV(1) 40-50% died between 2 and 8 years after delivery.

The authors confirmed that pregnancy for women with cystic fibrosis results in favourable maternal and fetal outcomes, but the incidence of preterm delivery and caesarean section is increased. However, women with pre-existing poor lung function should be counselled antenatally to ensure that they understand the implications of their shortened life-expectancy and parenthood.

Her is further data from the world’s largest adult CF unit, at the Royal Brompton in London, that pregnancy becomes increasingly risky for the mother as the respiratory involvement becomes more severe.


2013 Kernan NG, Alton EW, Cullinan P, Griesenbach U, Bilton D. Oral contraceptives do not appear to affect cystic fibrosis disease severity. Eur Resp J 2013; 41:67-73. [PubMed]

A retrospective study of the effects of oral contraceptive (OCs) on clinical outcomes in females with CF. Data from 681 females were available, of whom 42% had taken OCs for varying periods of time. There were no differences between the two groups. Nor did an an intra-patient analysis of the same outcomes over a 3-yr period. The authors concluded that the use of OCs does not affect CF disease severity.

A reassuring report for women with CF of experience from a major adult CF Centre.




1968 Denning CR, Sommers SC, Quigley HJ. Infertility in male patients with cystic fibrosis. Pediatrics NY 1968; 41:7-17. [PubMed]
This is the first report that men with CF were infertile. Repeated sperm analyses in 8 male patients with CF always showed aspermia with low volume and increased turbidity. All the men were in reasonable general condition. In nine patients at autopsy and in one biopsy specimen the testes showed active spermatogenesis but half the sperms had malformed heads.

Various explanations for the infertility were discussed including malnutrition, vitamin deficiencies and genetic causes – but not at this stage were abnormalities of the vas deferens suggested as a cause.
Although “transport difficulties” of the sperms due to viscid secretions in the male are mentioned there is no mention of the maldevelopment of the vas deferens which was eventually found to be the main reason for the infertility; this was described first by Kaplan et al, in 1968 (below) and also by Valman and France in 1969 (below).


1968 Kaplan E, Shwachman H, Perlmutter AD, Rule A, Khaw KT, Holsclaw DS. Reproductive failure in males with cystic fibrosis. N Eng J Med 1968; 279:65-69. [PubMed]
Histological abnormalities of the testis and structural abnormalities of the vas deferens are described; this is the first correct explanation of the male infertility. Twenty five patients aged 17 to 31 years all had aspermia. The authors could not identify the vas deferens in necropsy specimens from patients aged 5 to 20 years nor in 6 patients during repair of inguinal hernias. These findings provided an explanation for the previously reported infertility of men with CF (Denning et al, 1968 above). The vas deferens was represented by a thin fibrous cord or could not be located; the body of the epididymis was small or absent and the seminal vesicles were either absent, fused or represented in a dilated or bifid sac.

The authors considered these were development changes rather than the result of duct obstruction as occurred in the pancreas (See Denning et al, 1968 above; Valman HB, France NE. 1969 below). Later a survey of US CF centres suggested that some 2-3% of men with CF may be fertile (Taussig LM et al. N Eng J Med 1972; 287:586-589.[PubMed]).

With regard to this paper Elvin Kaplan later recalled - “My year as a fellow with him (Harry Shwachman) was rich in clinical and personal growth. Harry expected each fellow to write a paper and he eventually suggested the topic he wanted me to explore. It was his idea, his insight and his direction that lead this paper that was published in the New England Journal of Medicine (Kaplan et al, 1968). But he insisted that I be the senior author. It was at that time quite a breakthrough in our understanding of why males were sterile, but Harry took none of the credit. I think this typified his devotion and nurturing of his staff” (Fanos JH. Am J Med Genet 2008; Part A164A:284-293. [PubMed]).


1969 Valman HB, France NE. The vas deferens in cystic fibrosis. Lancet 1969; ii: 566-567. [PubMed]
One of the early reports of the abnormalities of the vas deferens which explained the infertility first reported in detail by Carolyn Denning et al - first at the CF Club 1966 and later published in 1968 (above). Also this paper confirmed the abnormalities of the vasa differentia described by Kaplan et al, 1968 (above) as the cause of the infertility and showed the changes could be variable.

In Bernard Valman’s study the post mortem appearance of the vasa differentia in 10 boys with CF were reported. In all the vasa were either absent or reduced to a fibrous or muscular band suggesting that the mesonephric duct had been obliterated during the 10th or 12th week of fetal life (figure in main text).


1969 Feigelson J, Pecau Y, Shwachman H. A propos d’une paternite chez un malade attient de mucoviscidose: Tudes des fonctions genitals et de la filiation. Arch Fr Pediatr 1969; 26:937-944. [PubMed]
Jean Feigelson told me this was the first instance of proven fertility in a man with cystic fibrosis. Shwachman reviewed the details with Feigelson and agreed with the diagnosis – hence Shwachman was included as an author. It is usually stated that 2-3% of men with CF are fertile and this is more likely with particular genotypes such as 3849-10kb C->T mutation (Dryfus DH et al. Am J Resp Crit Care Med 1996; 153:858-860. [PubMed]).


1971 Holsclaw DS, Permutter AD, Jockin H, Shwachman H. Congenital abnormalities in male patients with cystic fibrosis. J Urol 1971; 106:568-574. [PubMed]
The genetic link between men with CF and those with men whose main problem was congenital absence of the vas deferens (CBAVD) was first postulated by Douglas Holsclaw and colleagues and subsequently confirmed following the availability of genetic analysis after the identification of the CF gene in 1989 (Dumur V et al, Lancet 1990; 336:512 [PubMed]; Rigot JM et al. N Eng J Med 1991; 325:64-65 [PubMed]; Anguiano A et al. JAMA 1992; 267:1794-1797. [PubMed])


1972 Taussig LM, Lobeck C, di Sant’Agnese PA, Ackerman DR, Kattwinkel J. Fertility in males with cystic fibrosis. N Eng J Med 1972; 287:586. [PubMed]
Some 2% of 117 men with CF appeared to be fertile and the authors emphasised they should be given genetic counselling. They documented relatively normal semen analysis in only two men with CF and note a further report of male fertility by Feigelson et al, (1969 above) (on male infertility also Denning et al, 1968 above; Kaplan et al, 1968 above).


1992 Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher TA, White MB, Milunsky A. Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA 1992; 267:1794-1797. [PubMed]
It had been suggested that otherwise healthy men with congenital bilateral absence of the vas deferens (CBAVD), previously considered a distinct genetic entity, have an increased frequency of CF gene mutations (Dumur V et al. Abnormal distribution of CF delta F508 allele in azospermic men with congenital aplasia of epididymis and vas deferens. Lancet 1990; 336:512 [PubMed]; Rigot JJM et al. Cystic fibrosis and congenital absence of the vas deferens. N Eng J Med 1991; 325:64-65. [PubMed]). The association was first suggested by Douglas Holsclaw (Holsclaw DS, et al. Congenital abnormalites in male patients with cystic fibrosis. J Urol 1871; 106:568-574.[PubMed]).

The present report of 25 unselected men with CBAVD found 16 (64%) had at least one detectable CF mutation, 16 times the expected frequency; 3 men were compound heterozygotes.
Some, if not all, otherwise healthy men with CBAVD reflect a newly recognized, primarily genital, phenotype of CF. A very important practical suggestion was that prior to sperm aspiration to remedy infertility, CF mutation analysis should be recommended for them and their partners, as well as for their relatives.

In a later study (Chillon M et al. NEJM 1995; 332:1475-1480.[PubMed]) 19 of 102 (18.6%) CBAVD patients had 2 CF mutations and none had the 5T allele. 54 had one copy and 34 had the 5T allele in the other CFTR gene. 29 had no CF mutations but 7 of them had the 5T allele.

So most men with CBAVD have mutations in the CFTR gene. The combination of the 5T allele in one copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most common cause of CBAVD. The 5T allele mutation has a wide range of clinical presentations, occurring in patients with CBAVD or moderate forms of cystic fibrosis and also in fertile men.


1992 Handyside AH, Lesko JG, Tarin JJ, Winston RM, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med 1992; 327:905-909. [PubMed]
Preimplantation genetic diagnosis of cystic fibrosis was attempted in three couples, both members of which carried the delta F508 deletion. In vitro fertilisation techniques were used to recover oocytes from each woman and fertilize them with her husband's sperm. Three days after insemination, embryos in the cleavage stage underwent biopsy and removal of one or two cells for DNA amplification and analysis. Only two oocytes from one woman were fertilized normally; DNA analysis of one of the embryos failed and cystic fibrosis was diagnosed in the other (i.e. it was homozygous for delta F508), so neither was transferred. The oocytes of each of the other two women produced non-carrier, carrier, and affected embryos. Both couples chose to have one non-carrier embryo and one carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes.

This is the first report of preimplantation genetic diagnosis to identify the delta F508 deletion causing cystic fibrosis using in vitro fertilisation, biopsy of a cleavage-stage embryo, and amplification of DNA from single embryonic cells (also Handyside et al, 1988 above). Subsequent reports indicated an approximately 30% chance of a successful pregnancy after such an embryo had been implanted.



*1994  Liu J, Lissens W, Silber SJ, Devroey P, Liebaers I, Van Steirteghem A. Birth after preimplantation diagnosis of the cystic fibrosis delta F508 mutation by polymerase chain reaction in human embryos resulting from intracytoplasmic sperm injection with epididymal sperm. JAMA. 1994; 21; 272:1858-60.[PubMed]

Men with congenital bilateral absence of the vas deferens (CBAVD) have been regarded as presenting a mild form of cystic fibrosis (CF). In this article, we report a case of male-factor infertility, in which both partners are carriers of the delta F508 mutation and the male partner has CBAVD. Microsurgical epididymal sperm aspiration (MESA) was performed to obtain spermatozoa; intracytoplasmic sperm injection (ICSI) was carried out on the oocytes since the motility of the spermatozoa was severely impaired; and embryo biopsy and a polymerase chain reaction (PCR) were carried out for preimplantation diagnosis of the CF delta F508 mutation. Single-blastomere analysis was performed and indicated that two embryos were affected (homozygous delta F508) and three embryos were carriers. After transfer of the latter three embryos, a singleton pregnancy was established. At amniocentesis, the delta F508 carrier status of the fetus with a 46, XY karyotype was confirmed. A healthy boy was born and the presence of vasa deferentia, bilaterally, was confirmed. The CF sweat test was also normal. Successful fertilization can be obtained by combination of MESA and ICSI in patients with CBAVD. Preimplantation diagnosis of CF is indicated. Pregnancy and birth of normal children can ensue in such patients.


*2000  McCallum TJ, Milunsky JM, Cunningham DL, Harris DH, Maher TA, Oates RD.  Fertility in men with cystic fibrosis: an update on current surgical practices and outcomes. Chest 2000; 118:1059-62.[PubMed]

To describe patient anatomy and semen characteristics and to determine the pregnancy rates of couples in whom the male partner has CF and who have undergone microsurgical epididymal sperm aspiration coupled with in vitro technology, specifically intracytoplasmic sperm injection              All 13 men had low-volume azoospermia, absent vasa, and aplasia/hypoplasia of the seminal vesicles. CF mutation analysis was carried out in 11 of 13 men, and 9 of 11 were DeltaF508 homozygous. Eight men underwent microsurgical sperm aspiration, and their partners underwent one or more cycles of ICSI. Five couples (62.5%) achieved a pregnancy, with four couples delivering (three sets of twins and one singleton).                                                                                                                                     CF in men is accompanied by bilateral vasal aplasia. The resultant obstructive azoospermia can be treated quite successfully with a combination of sperm aspiration and ICSI. It is important for physicians involved in the care of men with CF to convey the message that prospects for fatherhood are excellent with current technology.