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Fertility issues in cystic fibrosis
PAEDIATRIC RESPIRATORY REVIEWS (2002) 3, 236±240 doi: 10.1016/S1526±0542(02)00184-7, available online at http://www.idealibrary.com on
SERIES: NON-RESPIRATORY ASPECTS OF CF
Fertility issues in cystic ®brosis Angela Lyon and Diana Bilton* Adult CF Centre, Papworth Hospital NHS Trust, Cambridge, UK KEYWORDS cystic ®brosis, azoospermia, congenital absence of the vas deferens or CBAVD, pregnancy, fertility
Summary With increasing survival in cystic ®brosis (CF) there is an increasing need to deal with the desires of CF patients to become parents. In the context of 98% male infertility in CF, new techniques offer the prospect of successful parenthood. For females, successful pregnancy is possible but careful planning is required. The practical and ethical aspects of reproductive health in CF are discussed. ß 2002 Elsevier Science Ltd. All rights reserved.
Review articles written 30 years ago referred to cystic ®brosis (CF) as a fatal disease of childhood. CF is now termed a life-limiting disease with median survival at least into the fourth decade. It is in the context of a dramatic alteration in morbidity and mortality of this disease that issues of reproductive health have become important in the management of adolescents and adults with CF. Furthermore, parents are increasingly interested, not simply in the child's survival but in whether ``reproduction'' will be possible.
MALE INFERTILITY The ®rst reports of male infertility in CF appeared in the late 1960s. A 31-year-old male was noted to be childless and requested investigation which revealed bilateral absence of the vas deferens and incomplete development of the epididymis. Subsequently, 25 further male CF adults were investigated and the absence of the vas deferens was con®rmed in all cases.1 Further studies reported similar ®ndings and it became clear that almost all male CF patients are azoospermic secondary to bilateral absence of the vas deferens. In addition the body and tail of the epididymides are rudimentary or absent and the efferent ductules of the head end blindly. The testes may be atrophic or normal. The seminal vesicles display various abnormalities including aplasia, hypoplasia or cystic dilatation. The spectrum of abnormalities described is not surprising considering the common embryological pathway of development from the *
Correspondence to: Dr Diana Bilton, Adult CF Centre, Papworth Hospital NHS Trust, Papworth Everard, Cambridge CB3 8RE, UK. Tel: 44 (0) 1480 830541x4697, Bleep 463; Fax: 44 (0) 1480 364330/466511; E-mail: [email protected] 1526±0542/02/$ ± see front matter
mesonephric (or Wolf®an) duct. It has been proposed that the changes occur as a result of intrauterine obstruction by dehydrated secretions.2 The alternative explanation for the pathogenesis of the male Wolf®an duct abnormalities is that there is a failure of differentiation during the ®rst trimester. Of course both pathways may contribute. It is clear that the cystic ®brosis transmembrane regulator (CFTR) gene is expressed in the epididymis and vas deferens. Furthermore its product, the CFTR protein, a small conductance cAMP-activated chloride channel has been identi®ed in human fetal vas deferens cells. The CF mouse, despite failing to survive because of intestinal obstruction, was found to have structurally normal epididymides and normal fertility despite abolished cAMPmediated chloride secretion, probably because of an alternative Ca2 activated chloride channel that compensates for the lack of CFTR protein.3
CONGENITAL ABSENCE OF THE VAS DEFERENS AND CYSTIC FIBROSIS MUTATIONS Absence of the vas deferens accounts for about 2% of male infertility. Men with congenital absence of the vas deferens (CBAVD) are apparently healthy with normal lung and pancreatic function. The characteristic Wolf®an duct derivative abnormalities that were evident in both CF and CBAVD patients and identical semen analysis suggested a common genetic link. The ®rst report of increased frequency of the commonest CFTR mutation, delta F508, in azoospermic men with CBAVD came in 1990. Following the initial studies of delta F508, a so-called mild mutation, R117H, was found with signi®cantly increased frequency. ß 2002 Elsevier Science Ltd. All rights reserved.
FERTILITY ISSUES IN CYSTIC FIBROSIS A review of 420 published cases of CBAVD indicated that 19% of patients carried two mutations, 47% carried a single mutation and in 34% no mutation could be identi®ed.4 The search to identify a CFTR related pathogenesis in patients carrying a single mutation led to studies of other parts of the gene including introns and promoter regions. In particular the number of thymidine nucleotides found in part of the gene called intron 8, which is important for the control of production of the CFTR protein, will affect the clinical phenotype. Five, seven or nine thymidine (T) nucleotides can be found. The 5T and 7T variants both result in a decrease in the production of functional protein. Thus, the ef®cacy of splicing of exon 9 via the 5T, 7T or 9T repeats is thought to modify the phenotypic expression of the CF genotype. The 5T allele, in combination with a single mutation of the other chromosome, is common in CBAVD and accounts for the observed Wolf®an duct abnormalities.
INVESTIGATION AND TREATMENT OF MALE INFERTILITY IN CF Adults wishing to be investigated should have semen analysis to con®rm or refute azoospermia. Although it is likely that azoospermia is present and the test will be con®rmatory, there are reports of fertility in CF males.5 Transrectal ultrasonography will reveal the status of the seminal vesicles and vasal ampullae. Obstructive azoospermia cannot be surgically corrected and precludes natural conception. The alternatives for a male with CF were adoption (discussed elsewhere) or sperm donation for the partner and assisted fertilisation. The recent advances in reproductive techniques and the awareness that spermatogenesis is largely normal in CF have allowed the development of sperm aspiration coupled with intra-cytoplasmic sperm injection (ICSI). Surgical collection of sperm is achieved by microsurgical epididymal sperm aspiration (MESA: where individual tubules are opened and sperm-rich ¯uid is gently aspirated), or testicular sperm extraction. Sperm retrieval is undertaken on a day remote from an ICSI cycle since sperm samples can be divided and cryopreserved for subsequent use. Following induction of ovulation, oocytes are harvested under ultrasound guidance. Individual sperm are then delivered by micropipette into the oocyte cytoplasm. Fertilisation is assessed at 24 hours and the appropriate number of embryos are transferred to the uterus. In a recent report of 13 CF men undergoing evaluation of infertility, eight of them elected to pursue MESA coupled with ICSI.6 In that report the fertilisation rate (i.e. the number of viable embryos per the number of oocytes injected) was 75 (24)%. A pregnancy rate of 62.5% was quoted re¯ecting ®ve out of the eight couples achieving pregnancy. Pregnancy occurred after the ®rst ICSI cycle in three couples and after the second cycle in two couples. One couple had ®ve ICSI cycles and failed to achieve a pregnancy. Of note, three of the successful pregnancies yielded twins. The authors
237 concluded that it was important for physicians involved in the care of CF males to suggest that the prospects for fatherhood are now excellent given current technology. Clearly this report involves only small numbers but there is cause for optimism about a treatment that enables CF males to father children. In the UK availability of the treatment is variable with funding arrangements currently varying with postcode. The authors also pointed out that it cannot be overemphasised that genetic testing and counselling are a key part of reproductive therapies (see below).
MALE REPRODUCTIVE HEALTH IN CF ± KNOWLEDGE AND ATTITUDES It is clearly important that males with CF are informed about infertility, yet previous studies have suggested that health professionals and parents may not be successful at imparting the correct knowledge at the right time. In one UK study in the early 1990s, only 27% of men and women with CF knew how the reproductive organs were affected.7 Another study in the UK found that 10 out of 37 males thought that men with CF were not infertile.8 In contrast later publications from the USA9 and Scotland10 revealed that patients were more well informed with 90% and 99% of males, respectively, being aware of male infertility in CF. Of more concern was the ®nding in the Scottish study10 of 82 males that 43% of these male CF adults had never discussed fertility issues with a CF health professional. Looking at the problem from another angle, Sawyer et al.'s study9 of 50 males in Boston revealed that only 48% of the 40 adults involved ®rst heard about infertility from their health care provider. Both studies revealed that CF male adults felt that the subject of infertility should be introduced by health professionals during adolescence (age 14 from the Sawyer study9 and age 12±15 from the Scottish study10). The effects of being told about infertility have not been extensively studied. Sawyer et al.9 reported that there was no major distress upon ®rst hearing about infertility during adolescence but that there was increasing signi®cance in adulthood of the inability to father children, which developed with increased maturity. It seems that in adult CF males the inability to father children is associated with strong negative emotions. It is clear that CF males need good information about reproductive health (Table 1). They report wishing to know the facts in early adolescence from a health professional. It would seem sensible to initiate discussions with the young CF adolescent at age 12±15. The changing signi®cance of infertility and associated issues with increasing age and maturity needs to be taken into account so that the issues are reviewed on a regular basis and appropriate information imparted. The ®rst discussion may be a simple explanation of the facts with a requirement to clarify the differences between infertility and impotence. Later, semen analysis can be discussed and all the details of assisted
238 Table 1
A. LYON AND D. BILTON What does a CF male need to know?
95% of CF males are infertile. Infertile does not mean impotent, i.e. sexual function is normal. Spermatogenesis is likely to be normal. Ejaculatory fluid will not contain sperm (i.e. azoospermia) because of the bilateral absence of the vas deferens. Ejaculatory fluid is of low volume. Sperm aspiration and intra-cytoplasmic sperm injection can result in successful pregnancy. Genetic counselling is available.
reproduction. We have found it extremely useful to ensure that knowledge about fertility and the desire for further information and investigation is reviewed in the adult service (age 16 onwards) as part of the routine annual review. This avoids the mishap of ``late'' more devastating discovery. Whilst the authors of reports on MESA and ICSI are extremely positive, it is important that patients are given suf®cient information when appropriate to understand that this technique is not an ``easy'' ®x. Along with discussions of reproductive issues adolescents should receive information about sexual health, including the importance of condom use for protection against sexually transmitted disease even though they may not be required for contraception. Reported barriers to discussions of male infertility and sexual health include lack of training, embarrassment and dif®culty in ®nding ``the right time'' on the part of the health professionals.11
FEMALE FERTILITY AND PREGNANCY IN CF Unlike the CF male, there are no reproductive tract abnormalities in CF females. It is reported that sub-fertility may occur because of the reduction in cervical mucus water content. This may result in a thick mucus plug resistant to the passage of sperm.12,13 However, the true fertility rate in CF females is unknown (Table 2). Females with malnutrition or chest disease have an increase in irregular menstrual cycles and may suffer from ovulatory disturbance and amenorrhoea, but ill patients can still conceive! With increasing survival and improved health of adults with CF, since the ®rst reported pregnancies in the 1960s, there are now more than 100 pregnancies per year in CF females in the USA. Table 2
What does the CF female need to know?
The global fertility rate is not known ± but fertility is most likely. Even people with bad chests can conceive. Successful pregnancies are occurring with increasing frequency in CF nowadays. Pregnancy in CF requires careful planning.
Table 3
Why should pregnancy be carefully planned in CF?
To allow genetic counselling and, if desired, carrier testing for the partner. To allow consideration of severity of lung disease to avoid early post-partum death. To avoid the use of teratogenic drugs or ``toxic'' drugs that may be used in CF treatments.
It is important that pregnancies in CF are carefully planned for several reasons (Table 3). Firstly, the couple must be aware of the potential risks of having a CF child (see Genetic counselling, below). Furthermore, the mother must be aware of the potential consequences of the pregnancy on her own respiratory function and survival. Finally, drugs that may be teratogenic or simply toxic to the fetus should be avoided. Reviews of pregnancies in CF indicate that the decline in pulmonary function that occurs during pregnancy is usually regained post-partum.14±16 Maternal deaths have occurred in women with moderate to severe lung disease, following failure to regain pulmonary function post-partum. Edenborough et al.'s excellent review17 provides a useful basis on which to have discussions with patients about the risks of pregnancy with regard to their lung function and survival. We have found it helpful to discuss pregnancy using this paper directly with the couple. It is critical that the couple are supported in making informed decisions. The risks to the mother are clearly increased with increasing severity of lung disease. Low body weight increases the risk to mother and baby. In addition the risks of pre-term delivery with inherent risks to the fetus are increased. CF pregnancies require careful management in a centre where there is a close working relationship between the CF physician, the CF team and the obstetrician. The mother can be reassured that breastfeeding is possible with normal breast milk composition.
DISCUSSING REPRODUCTIVE HEALTH WITH CF FEMALES CF women theoretically have abnormal cervical mucus but there is no evidence of a ``global'' reduction in fertility in young female CF adults. Therefore, it is important that discussions about pregnancy are begun in early adolescence. With increasing evidence of earlier sexual activity in teenagers it is critical that the CF female is aware of her fertility. Some patients report thinking that all CF sufferers are infertile regardless of gender! Appropriate contraceptive advice should be given along with advice on sexual health measures to avoid sexually transmitted diseases. This advice can be given by someone with the correct training in the CF team, linking up with a family planning unit or the GP. In a similar fashion to checking about the knowledge of male infertility, it is useful to include a discussion about sexual health, contraception
FERTILITY ISSUES IN CYSTIC FIBROSIS and pregnancy at each annual review from the age of 14 upwards.
GENETIC COUNSELLING A man or a woman with CF seeking to be a parent should be fully informed of the risks of having a CF child. Couples may be ignorant of this and welcome the chance to discuss the risks. The likelihood of a child being affected by CF is 50% if the partner of the CF man or woman is a carrier. Genotyping of the partner should therefore be offered ahead of active attempts to become pregnant or to enter assisted reproduction programmes so that the greatest number of reproductive options may be explored. If the partner is a carrier the couple may choose not to seek a pregnancy, to use donor sperm (or oocyte) or to determine the genotype of the fetus in utero. The latter raises the dif®cult option of termination. It is important to understand that counselling should be performed outside any presumption that the couple might consider a CF child as unacceptable. After all, the CF adult has lived life with the disease and would feel severely devalued if such assumptions were made. In this context the feelings of the couple towards a CF affected child should be explored carefully. If the partner is found not to be a carrier the likelihood of the couple having a CF child should be zero. In reality, with so many mutations of the CF gene described, routine testing does not allow for every described mutation to be checked. Local genetics services use the tests that cover the most common mutations found in the local population and will advise on the statistical risks of a patient with CF and a partner who has tested negative for the common mutations having a CF child. Although these are extremely low it is important that the couple realise that there is no 100% guarantee of not having a CF child.
GENERAL COUNSELLING AND ETHICAL ISSUES Before embarking on becoming a parent many patients wish to discuss questions about their own health and longterm issues about the likelihood of premature death of the CF affected parent. Physicians caring for adults with CF should be ready to discuss the effects of the disease process, its potential impact on family life and the prospect of a ``one-parent'' family with openness and honesty without prejudice or assumption. Failing to mention the prospect of earlier death of the CF adult seems irresponsible. These discussions are particularly pertinent when assisted reproduction and adoption are being considered, since the agencies involved will wish to know about the ability of the parent to look after the prospective unborn child. Pregnancy, adoption and assisted reproduction have occurred successfully as described in this paper but it is important that the CF adult and partner discuss all of the issues with
239 the CF physician and team before progressing into the process of becoming a parent. An increasing trend in our clinic is for the CF adult to arrange for us to discuss CF and its effects on fertility, health and survival with the long- term partner or spouse to avoid misinformation or nasty shocks later on. Whilst adult physicians support CF adults in achieving a better quality of life, better survival and the ``normality'' that being a parent achieves are underlying ethical issues that deserve some thought. From a societal viewpoint there is a paradox in considering population screening for CF to reduce the burden of disease whilst increasing the carrier rate in the population by supporting CF adults in parenting children who, by de®nition, will all be carriers. For the future we need to think about educating these children at the right time about their carrier status to ensure that they make their own informed decisions. Some paediatricians would take issue with adult physicians supporting reproduction when children are likely to be motherless or fatherless within 5 years. Adult physicians feel a doctor does not have the right to prevent an adult seeking to be a parent but must be responsible in terms of discussing those issues. Obviously no one is guaranteed survival to witness the growth of their own children into adulthood but CF adults must consider that prospect with more than a vague passing thought. It is for this reason of parental survival, with the primary focus being the longterm interests of the parents, that adoption is rare in the case of a CF adult, although successful adoptions have taken place. Finally the prospect of lung transplantation should not be allowed to bias the debate about whether or not to become a parent. Some young women may have the simplistic view that if things go wrong post-partum the situation can be rescued by a transplant. Thus, discussions about transplantation and clari®cation of the shortage of suitable donors and the survival rates post-transplantation may need to be included in a discussion about parenthood!
CONCLUSIONS As CF patients grow into adulthood in good health rather than just ``survive'' there is an increasing need to be proactive in terms of advice about reproductive health. Paediatricians should start discussions in early adolescence and the transition to the adult clinic provides an opportunity to check the level of knowledge about male infertility and female fertility. It is critical that young men are offered investigation and semen analysis, whilst young women are offered contraceptive advice. At the time the young adult wishes to discuss parenthood, the physician and team should be ready to discuss all of the issues involved from the technical aspects of assisted reproduction to the question of parental survival. Ensuring that patients receive the best advice at the right time provides an exciting challenge for those in CF care.
240
PRACTICE POINTS Information about fertility should be imparted early in adolescence. Roughly 98% of males with cystic fibrosis (CF) are infertile. CF males can now successfully father children as a result of microsurgical epididymal sperm aspiration followed by assisted reproduction. CF females should all be regarded as potentially fertile. Pregnancy in CF females can be successful but should be carefully planned. Counselling about fertility issues is important.
REFERENCES 1. Kaplan E, Swachman H, Perlmutter AD, Rule A, Khan KT, Holsclaw DS. Reproductive failure in males with cystic ®brosis. N Engl J Med 1968; 279: 65±69. 2. Taussig LM, Lobeck CC, Si Saint'Agnese PA, Ackerman DR, Kattwinkel J. Fertility in males with cystic ®brosis. N Engl J Med 1972; 287: 586±589. 3. Leung AYH, Wong PYD, Yankaskas JR, Boucher RC. cAMP but not Ca2 regulated Cl conductance is lacking in cystic ®brosis mice epididymides and seminal vesicles. Am J Physiol 1996; 271: C188±C193. 4. Lissens W, Mercier B, Tournaye H et al. Cystic ®brosis and infertility caused by congenital absence of the vas deferens and related clinical entities. Hum Reprod 1996; 11 (supplement 4): 55±89.
A. LYON AND D. BILTON 5. Barretto C, Pinto LM, Duarte A, Lavinha J, Ramsey M. A fertile male with cystic ®brosis: molecular genetic analysis. J Med Genet 1991; 28: 420±421. 6. McCallum TJ, Milunsky JM, Cunningham DL, Harris DH, Maher TA, Oates RD. Fertility in men with cystic ®brosis ± an update on current surgical practices and outcomes. Chest 2000; 118: 1059±1062. 7. Hames A, Beesley J, Nelson R. Cystic ®brosis what do patients know, and what else would they like to know? Respir Med 1991; 85: 389± 392. 8. Conway SP, Pond MN, Hamnett T et al. Compliance with treatment in adult patients with cystic ®brosis. Thorax 1996; 51: 29±33. 9. Sawyer SM, Tully MM, Dovey ME, Colin AA. Reproductive health in males with cystic ®brosis, knowledge, attributes and experiences of patients and parents. Pediatr Pulmonol 1998; 25: 226±230. 10. Fair A, Grif®ths K, Osman LM. Attitudes to fertility issues among adults with cystic ®brosis in Scotland. Thorax 2000; 55: 672±677. 11. Sawyer SM, Tully MM, Colin AA. Reproductive and sexual health in males with cystic ®brosis: a case for health professional education and training. J Adolesc Health 2001; 28: 36±40. 12. Oppenheimer EH, Esterly JR. Observations on cystic ®brosis of the pancreas V1 ± the uterine cervix. J Paediatr 1970; 77: 991±995. 13. Kotloff RM, Fitzsimmons SC, Fiel SB. Fertility and pregnancy in patients with cystic ®brosis. Clin Chest Med 1992; 13: 623±635. 14. Canny GJ, Corey M, Livingstone RA, Carpenter S, Green L, Levison H. Pregnancy and cystic ®brosis. Obstet Gynecol 1991; 77: 850± 853. 15. Edenborough FP, Stableforth DE, Webb AK, Mackenzie WE, Smith DL. Outcome of pregnancy in women with cystic ®brosis. Thorax 1995; 50: 170±174. 16. Olsen GL. Cystic ®brosis in pregnancy. Semin Perinatol 1997; 21: 307±312. 17. Edenborough FP, Mackenzie W, Stableforth DE. The outcome of 72 pregnancies in 55 women with cystic ®brosis in the UK. BJOG 2000; 107: 254±261.
SERIES: NON-RESPIRATORY ASPECTS OF CF
Fertility issues in cystic ®brosis Angela Lyon and Diana Bilton* Adult CF Centre, Papworth Hospital NHS Trust, Cambridge, UK KEYWORDS cystic ®brosis, azoospermia, congenital absence of the vas deferens or CBAVD, pregnancy, fertility
Summary With increasing survival in cystic ®brosis (CF) there is an increasing need to deal with the desires of CF patients to become parents. In the context of 98% male infertility in CF, new techniques offer the prospect of successful parenthood. For females, successful pregnancy is possible but careful planning is required. The practical and ethical aspects of reproductive health in CF are discussed. ß 2002 Elsevier Science Ltd. All rights reserved.
Review articles written 30 years ago referred to cystic ®brosis (CF) as a fatal disease of childhood. CF is now termed a life-limiting disease with median survival at least into the fourth decade. It is in the context of a dramatic alteration in morbidity and mortality of this disease that issues of reproductive health have become important in the management of adolescents and adults with CF. Furthermore, parents are increasingly interested, not simply in the child's survival but in whether ``reproduction'' will be possible.
MALE INFERTILITY The ®rst reports of male infertility in CF appeared in the late 1960s. A 31-year-old male was noted to be childless and requested investigation which revealed bilateral absence of the vas deferens and incomplete development of the epididymis. Subsequently, 25 further male CF adults were investigated and the absence of the vas deferens was con®rmed in all cases.1 Further studies reported similar ®ndings and it became clear that almost all male CF patients are azoospermic secondary to bilateral absence of the vas deferens. In addition the body and tail of the epididymides are rudimentary or absent and the efferent ductules of the head end blindly. The testes may be atrophic or normal. The seminal vesicles display various abnormalities including aplasia, hypoplasia or cystic dilatation. The spectrum of abnormalities described is not surprising considering the common embryological pathway of development from the *
Correspondence to: Dr Diana Bilton, Adult CF Centre, Papworth Hospital NHS Trust, Papworth Everard, Cambridge CB3 8RE, UK. Tel: 44 (0) 1480 830541x4697, Bleep 463; Fax: 44 (0) 1480 364330/466511; E-mail: [email protected] 1526±0542/02/$ ± see front matter
mesonephric (or Wolf®an) duct. It has been proposed that the changes occur as a result of intrauterine obstruction by dehydrated secretions.2 The alternative explanation for the pathogenesis of the male Wolf®an duct abnormalities is that there is a failure of differentiation during the ®rst trimester. Of course both pathways may contribute. It is clear that the cystic ®brosis transmembrane regulator (CFTR) gene is expressed in the epididymis and vas deferens. Furthermore its product, the CFTR protein, a small conductance cAMP-activated chloride channel has been identi®ed in human fetal vas deferens cells. The CF mouse, despite failing to survive because of intestinal obstruction, was found to have structurally normal epididymides and normal fertility despite abolished cAMPmediated chloride secretion, probably because of an alternative Ca2 activated chloride channel that compensates for the lack of CFTR protein.3
CONGENITAL ABSENCE OF THE VAS DEFERENS AND CYSTIC FIBROSIS MUTATIONS Absence of the vas deferens accounts for about 2% of male infertility. Men with congenital absence of the vas deferens (CBAVD) are apparently healthy with normal lung and pancreatic function. The characteristic Wolf®an duct derivative abnormalities that were evident in both CF and CBAVD patients and identical semen analysis suggested a common genetic link. The ®rst report of increased frequency of the commonest CFTR mutation, delta F508, in azoospermic men with CBAVD came in 1990. Following the initial studies of delta F508, a so-called mild mutation, R117H, was found with signi®cantly increased frequency. ß 2002 Elsevier Science Ltd. All rights reserved.
FERTILITY ISSUES IN CYSTIC FIBROSIS A review of 420 published cases of CBAVD indicated that 19% of patients carried two mutations, 47% carried a single mutation and in 34% no mutation could be identi®ed.4 The search to identify a CFTR related pathogenesis in patients carrying a single mutation led to studies of other parts of the gene including introns and promoter regions. In particular the number of thymidine nucleotides found in part of the gene called intron 8, which is important for the control of production of the CFTR protein, will affect the clinical phenotype. Five, seven or nine thymidine (T) nucleotides can be found. The 5T and 7T variants both result in a decrease in the production of functional protein. Thus, the ef®cacy of splicing of exon 9 via the 5T, 7T or 9T repeats is thought to modify the phenotypic expression of the CF genotype. The 5T allele, in combination with a single mutation of the other chromosome, is common in CBAVD and accounts for the observed Wolf®an duct abnormalities.
INVESTIGATION AND TREATMENT OF MALE INFERTILITY IN CF Adults wishing to be investigated should have semen analysis to con®rm or refute azoospermia. Although it is likely that azoospermia is present and the test will be con®rmatory, there are reports of fertility in CF males.5 Transrectal ultrasonography will reveal the status of the seminal vesicles and vasal ampullae. Obstructive azoospermia cannot be surgically corrected and precludes natural conception. The alternatives for a male with CF were adoption (discussed elsewhere) or sperm donation for the partner and assisted fertilisation. The recent advances in reproductive techniques and the awareness that spermatogenesis is largely normal in CF have allowed the development of sperm aspiration coupled with intra-cytoplasmic sperm injection (ICSI). Surgical collection of sperm is achieved by microsurgical epididymal sperm aspiration (MESA: where individual tubules are opened and sperm-rich ¯uid is gently aspirated), or testicular sperm extraction. Sperm retrieval is undertaken on a day remote from an ICSI cycle since sperm samples can be divided and cryopreserved for subsequent use. Following induction of ovulation, oocytes are harvested under ultrasound guidance. Individual sperm are then delivered by micropipette into the oocyte cytoplasm. Fertilisation is assessed at 24 hours and the appropriate number of embryos are transferred to the uterus. In a recent report of 13 CF men undergoing evaluation of infertility, eight of them elected to pursue MESA coupled with ICSI.6 In that report the fertilisation rate (i.e. the number of viable embryos per the number of oocytes injected) was 75 (24)%. A pregnancy rate of 62.5% was quoted re¯ecting ®ve out of the eight couples achieving pregnancy. Pregnancy occurred after the ®rst ICSI cycle in three couples and after the second cycle in two couples. One couple had ®ve ICSI cycles and failed to achieve a pregnancy. Of note, three of the successful pregnancies yielded twins. The authors
237 concluded that it was important for physicians involved in the care of CF males to suggest that the prospects for fatherhood are now excellent given current technology. Clearly this report involves only small numbers but there is cause for optimism about a treatment that enables CF males to father children. In the UK availability of the treatment is variable with funding arrangements currently varying with postcode. The authors also pointed out that it cannot be overemphasised that genetic testing and counselling are a key part of reproductive therapies (see below).
MALE REPRODUCTIVE HEALTH IN CF ± KNOWLEDGE AND ATTITUDES It is clearly important that males with CF are informed about infertility, yet previous studies have suggested that health professionals and parents may not be successful at imparting the correct knowledge at the right time. In one UK study in the early 1990s, only 27% of men and women with CF knew how the reproductive organs were affected.7 Another study in the UK found that 10 out of 37 males thought that men with CF were not infertile.8 In contrast later publications from the USA9 and Scotland10 revealed that patients were more well informed with 90% and 99% of males, respectively, being aware of male infertility in CF. Of more concern was the ®nding in the Scottish study10 of 82 males that 43% of these male CF adults had never discussed fertility issues with a CF health professional. Looking at the problem from another angle, Sawyer et al.'s study9 of 50 males in Boston revealed that only 48% of the 40 adults involved ®rst heard about infertility from their health care provider. Both studies revealed that CF male adults felt that the subject of infertility should be introduced by health professionals during adolescence (age 14 from the Sawyer study9 and age 12±15 from the Scottish study10). The effects of being told about infertility have not been extensively studied. Sawyer et al.9 reported that there was no major distress upon ®rst hearing about infertility during adolescence but that there was increasing signi®cance in adulthood of the inability to father children, which developed with increased maturity. It seems that in adult CF males the inability to father children is associated with strong negative emotions. It is clear that CF males need good information about reproductive health (Table 1). They report wishing to know the facts in early adolescence from a health professional. It would seem sensible to initiate discussions with the young CF adolescent at age 12±15. The changing signi®cance of infertility and associated issues with increasing age and maturity needs to be taken into account so that the issues are reviewed on a regular basis and appropriate information imparted. The ®rst discussion may be a simple explanation of the facts with a requirement to clarify the differences between infertility and impotence. Later, semen analysis can be discussed and all the details of assisted
238 Table 1
A. LYON AND D. BILTON What does a CF male need to know?
95% of CF males are infertile. Infertile does not mean impotent, i.e. sexual function is normal. Spermatogenesis is likely to be normal. Ejaculatory fluid will not contain sperm (i.e. azoospermia) because of the bilateral absence of the vas deferens. Ejaculatory fluid is of low volume. Sperm aspiration and intra-cytoplasmic sperm injection can result in successful pregnancy. Genetic counselling is available.
reproduction. We have found it extremely useful to ensure that knowledge about fertility and the desire for further information and investigation is reviewed in the adult service (age 16 onwards) as part of the routine annual review. This avoids the mishap of ``late'' more devastating discovery. Whilst the authors of reports on MESA and ICSI are extremely positive, it is important that patients are given suf®cient information when appropriate to understand that this technique is not an ``easy'' ®x. Along with discussions of reproductive issues adolescents should receive information about sexual health, including the importance of condom use for protection against sexually transmitted disease even though they may not be required for contraception. Reported barriers to discussions of male infertility and sexual health include lack of training, embarrassment and dif®culty in ®nding ``the right time'' on the part of the health professionals.11
FEMALE FERTILITY AND PREGNANCY IN CF Unlike the CF male, there are no reproductive tract abnormalities in CF females. It is reported that sub-fertility may occur because of the reduction in cervical mucus water content. This may result in a thick mucus plug resistant to the passage of sperm.12,13 However, the true fertility rate in CF females is unknown (Table 2). Females with malnutrition or chest disease have an increase in irregular menstrual cycles and may suffer from ovulatory disturbance and amenorrhoea, but ill patients can still conceive! With increasing survival and improved health of adults with CF, since the ®rst reported pregnancies in the 1960s, there are now more than 100 pregnancies per year in CF females in the USA. Table 2
What does the CF female need to know?
The global fertility rate is not known ± but fertility is most likely. Even people with bad chests can conceive. Successful pregnancies are occurring with increasing frequency in CF nowadays. Pregnancy in CF requires careful planning.
Table 3
Why should pregnancy be carefully planned in CF?
To allow genetic counselling and, if desired, carrier testing for the partner. To allow consideration of severity of lung disease to avoid early post-partum death. To avoid the use of teratogenic drugs or ``toxic'' drugs that may be used in CF treatments.
It is important that pregnancies in CF are carefully planned for several reasons (Table 3). Firstly, the couple must be aware of the potential risks of having a CF child (see Genetic counselling, below). Furthermore, the mother must be aware of the potential consequences of the pregnancy on her own respiratory function and survival. Finally, drugs that may be teratogenic or simply toxic to the fetus should be avoided. Reviews of pregnancies in CF indicate that the decline in pulmonary function that occurs during pregnancy is usually regained post-partum.14±16 Maternal deaths have occurred in women with moderate to severe lung disease, following failure to regain pulmonary function post-partum. Edenborough et al.'s excellent review17 provides a useful basis on which to have discussions with patients about the risks of pregnancy with regard to their lung function and survival. We have found it helpful to discuss pregnancy using this paper directly with the couple. It is critical that the couple are supported in making informed decisions. The risks to the mother are clearly increased with increasing severity of lung disease. Low body weight increases the risk to mother and baby. In addition the risks of pre-term delivery with inherent risks to the fetus are increased. CF pregnancies require careful management in a centre where there is a close working relationship between the CF physician, the CF team and the obstetrician. The mother can be reassured that breastfeeding is possible with normal breast milk composition.
DISCUSSING REPRODUCTIVE HEALTH WITH CF FEMALES CF women theoretically have abnormal cervical mucus but there is no evidence of a ``global'' reduction in fertility in young female CF adults. Therefore, it is important that discussions about pregnancy are begun in early adolescence. With increasing evidence of earlier sexual activity in teenagers it is critical that the CF female is aware of her fertility. Some patients report thinking that all CF sufferers are infertile regardless of gender! Appropriate contraceptive advice should be given along with advice on sexual health measures to avoid sexually transmitted diseases. This advice can be given by someone with the correct training in the CF team, linking up with a family planning unit or the GP. In a similar fashion to checking about the knowledge of male infertility, it is useful to include a discussion about sexual health, contraception
FERTILITY ISSUES IN CYSTIC FIBROSIS and pregnancy at each annual review from the age of 14 upwards.
GENETIC COUNSELLING A man or a woman with CF seeking to be a parent should be fully informed of the risks of having a CF child. Couples may be ignorant of this and welcome the chance to discuss the risks. The likelihood of a child being affected by CF is 50% if the partner of the CF man or woman is a carrier. Genotyping of the partner should therefore be offered ahead of active attempts to become pregnant or to enter assisted reproduction programmes so that the greatest number of reproductive options may be explored. If the partner is a carrier the couple may choose not to seek a pregnancy, to use donor sperm (or oocyte) or to determine the genotype of the fetus in utero. The latter raises the dif®cult option of termination. It is important to understand that counselling should be performed outside any presumption that the couple might consider a CF child as unacceptable. After all, the CF adult has lived life with the disease and would feel severely devalued if such assumptions were made. In this context the feelings of the couple towards a CF affected child should be explored carefully. If the partner is found not to be a carrier the likelihood of the couple having a CF child should be zero. In reality, with so many mutations of the CF gene described, routine testing does not allow for every described mutation to be checked. Local genetics services use the tests that cover the most common mutations found in the local population and will advise on the statistical risks of a patient with CF and a partner who has tested negative for the common mutations having a CF child. Although these are extremely low it is important that the couple realise that there is no 100% guarantee of not having a CF child.
GENERAL COUNSELLING AND ETHICAL ISSUES Before embarking on becoming a parent many patients wish to discuss questions about their own health and longterm issues about the likelihood of premature death of the CF affected parent. Physicians caring for adults with CF should be ready to discuss the effects of the disease process, its potential impact on family life and the prospect of a ``one-parent'' family with openness and honesty without prejudice or assumption. Failing to mention the prospect of earlier death of the CF adult seems irresponsible. These discussions are particularly pertinent when assisted reproduction and adoption are being considered, since the agencies involved will wish to know about the ability of the parent to look after the prospective unborn child. Pregnancy, adoption and assisted reproduction have occurred successfully as described in this paper but it is important that the CF adult and partner discuss all of the issues with
239 the CF physician and team before progressing into the process of becoming a parent. An increasing trend in our clinic is for the CF adult to arrange for us to discuss CF and its effects on fertility, health and survival with the long- term partner or spouse to avoid misinformation or nasty shocks later on. Whilst adult physicians support CF adults in achieving a better quality of life, better survival and the ``normality'' that being a parent achieves are underlying ethical issues that deserve some thought. From a societal viewpoint there is a paradox in considering population screening for CF to reduce the burden of disease whilst increasing the carrier rate in the population by supporting CF adults in parenting children who, by de®nition, will all be carriers. For the future we need to think about educating these children at the right time about their carrier status to ensure that they make their own informed decisions. Some paediatricians would take issue with adult physicians supporting reproduction when children are likely to be motherless or fatherless within 5 years. Adult physicians feel a doctor does not have the right to prevent an adult seeking to be a parent but must be responsible in terms of discussing those issues. Obviously no one is guaranteed survival to witness the growth of their own children into adulthood but CF adults must consider that prospect with more than a vague passing thought. It is for this reason of parental survival, with the primary focus being the longterm interests of the parents, that adoption is rare in the case of a CF adult, although successful adoptions have taken place. Finally the prospect of lung transplantation should not be allowed to bias the debate about whether or not to become a parent. Some young women may have the simplistic view that if things go wrong post-partum the situation can be rescued by a transplant. Thus, discussions about transplantation and clari®cation of the shortage of suitable donors and the survival rates post-transplantation may need to be included in a discussion about parenthood!
CONCLUSIONS As CF patients grow into adulthood in good health rather than just ``survive'' there is an increasing need to be proactive in terms of advice about reproductive health. Paediatricians should start discussions in early adolescence and the transition to the adult clinic provides an opportunity to check the level of knowledge about male infertility and female fertility. It is critical that young men are offered investigation and semen analysis, whilst young women are offered contraceptive advice. At the time the young adult wishes to discuss parenthood, the physician and team should be ready to discuss all of the issues involved from the technical aspects of assisted reproduction to the question of parental survival. Ensuring that patients receive the best advice at the right time provides an exciting challenge for those in CF care.
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PRACTICE POINTS Information about fertility should be imparted early in adolescence. Roughly 98% of males with cystic fibrosis (CF) are infertile. CF males can now successfully father children as a result of microsurgical epididymal sperm aspiration followed by assisted reproduction. CF females should all be regarded as potentially fertile. Pregnancy in CF females can be successful but should be carefully planned. Counselling about fertility issues is important.
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