Pregnancy in women with cystic fibrosis

Cystic fibrosis (CF) is an autosomal disorder arising from a defect on chromosome 7 in the region coding for the cystic fibrosis transmembrane regulator (CFTR) protein (1). Disordered production or function of this protein results in abnormal ion and water transport across cells in glands in many organ systems throughout the body resulting in desiccated, tenacious secretions which may in turn cause obstruction and organ damage and loss of function. The prevalence of disordered genes is around 1:25 in many Caucasian populations and with recessive inheritance an incidence of ∼1:2500 live births is seen (2). The clinical picture is dominated by early and persistent infection of the airways with recurrent infective exacerbations leading to bronchiectasis. Respiratory failure causes over 90% of CF-related deaths at an average age ∼30 years in Western populations (3). CF lungs are susceptible to infection with various organisms, particularly Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia (4). Despite attempts to delay the time at which chronic infection becomes established by clinical segregation of those with particular organisms from those without, attempts at eradicating organisms when first cultured and aggressive treatment of infective exacerbations, chronic infection and inexorable decline in lung function is inevitable (5). More recently lung transplantation has offered the chance of prolonged survival and is likely to offer hope to many in the future (6). The second key feature of CF is early obstruction of the pancreatic ducts leading to pancreatic insufficiency (PI) requiring sufferers to take enzyme supplementation from birth (7). Further, the intestine is also affected resulting in maldigestion and malabsorption leading to poor growth, poor weight for height and weight loss in adults, contributing significantly to the morbidity and mortality (8). Less common, but increasingly prevalent, complications include biliary cirrhosis from bile ductule occlusion (9), glucose intolerance and CF-related diabetes (CF-RD) from pancreatic endocrine deficiency (10), and osteoporosis (11) leading to fracture the causes of which are multifactorial. In a typical adult population 85% will be pancreatic insufficient, 35% will have some degree of impaired glucose tolerance and 15% some degree of liver impairment. The treatment of the protean manifestations of CF is complex and has been refined over recent decades with the development of specialized center care, attention to nutrition resulting in near normal growth, prevention and treatment of infection with preservation of lung function into adulthood, and surveillance and early intervention for other complications. As a consequence median survival has increased from early teens in the 1960s to the fourth decade and beyond this century (2). Hence women with a disease once the realm of pediatricians are now seen by adult physicians with the expanding population over the age of 16 being increasingly healthy and able to participate in work, relationships, marriage and the considerations of raising a family, both before and, more recently, after lung transplantation. The male Wolffian ducts are particularly sensitive to CFTR abnormalities and male infertility is almost universal (12) [indeed congenital bilateral absence of the vas deferens, a common cause of male infertility is frequently associated with at least one abnormal CF gene (13)]. Male infertility will not be discussed further. CFTR is found on the cervix, the endometrium and Fallopian tubes (14) and simple mechanical obstruction of the uterine os by tenacious cervical mucus is probably the most common cause of fertility problems in women with CF (15). The endometrium and Fallopian tubes are structurally normal, perhaps because they are open at both ends and have a high flow of relatively protein poor secretions (16) compared with organs closed at one end, which may be affected by occlusion. The ovaries contain little CFTR and their structure and exocrine function in otherwise healthy women with CF is near normal (17). Much of the early infertility (18) noted in CF women may have been associated with anovulatory cycles seen in sick undernourished women, but even when nutrition is optimal, growth is impaired, puberty and menarche delayed and the intriguing discovery of CFTR in the hypothalamus (19) may help to explain these phenomena and account for reduced fecundity still seen in these women. The true potential fertility of women with cystic fibrosis will never be known as many choose not to become pregnant as reported in the first of two articles in this journal (21). Attitudes towards fertility issues and pregnancy in women with CF have been reported (22, 23). Some fear the effect of cystic fibrosis on the pregnancy, with potential harm to the child, including inheritance of CF. Others fear the potential effect of the pregnancy on their CF, their ability to care for that child and the consequences if the mother were to die while the child was still young. It is this author's experience that some women have received very poor advice on these matters (24) and it behoves CF physicians and obstetricians attached to CF Units to tailor advice to the individual woman's situation. Experience suggests that women with advanced cystic fibrosis – even on transplant lists – may become pregnant and reinforces the need to consider contraception in any woman not actively wishing to become pregnant and at any stage of the disease. Pregnancy in a woman with CF was first described in 1960 (25) and a series reviewed in 1966 (26). Subsequent series have been published from the USA (27, 28), Canada (29, 30), the UK (31, 32), Germany (33), and now, in the second paper in this journal, Scandinavia (34). Supplemented by numerous case reports, many hundreds of CF pregnancies have been described and a number of comprehensive reviews have now appeared (35, 36). From the literature it is clear that healthy women with CF can have normal pregnancies without detriment to their condition. While this message remains the same there have been changes in its detail. In the earliest series 'healthy' women were often diagnosed late and were pancreatic sufficient; pancreatic insufficiency and its attendant poor weight were considered markers of poor outcome. As enzyme supplementation, nutrition and pediatric care have developed, pancreatic insufficiency has become less of a concern as an increasing majority of women have near normal weight and are able to maintain body weight during pregnancy, even attaining the 10–12 kg gain expected in healthy women. To achieve this some may require nutritional supplementation orally, by nasogastric or gastrostomy feeding or rarely by parenteral feeding. Those with poor weight (BMI < 18 kg/m2) may have reduced fertility, but if pregnant data is achieved still suggest they do less well (32). Sicker women may struggle, experiencing preterm delivery either spontaneous or as required obstetric or medical intervention, and their infants the consequences of their prematurity. Even the very sickest women, including those on transplant lists may become pregnant and therapeutic termination may be required for medical reasons. Therefore despite concerns that fertility may be reduced in the CF population, contraception must be considered for each individual at every stage of the disease. There is little evidence to suggest miscarriage or ectopic pregnancy is more likely in CF, recent studies confirm a very low perinatal mortality (32, 37) despite the high proportion of preterm births. Diabetes mellitus adversely affects normal pregnancies, and gestational diabetes may develop in health women (38). Early CF pregnancies in the face of diabetes did poorly (39), but again management has improved; however, it is perhaps unsurprising that overall outcome remains poorer for those with CF-RD compared with those without (40). There are no detailed reports describing outcome of pregnancy in the context of CF liver disease; however, many women have abnormal transaminases, or ultrasound scans and pregnancy is probably only contraindicated in severe disease with failure of synthetic function. The only other absolute contraindications include right heart failure due to cor pulmonale and pulmonary hypertension (37). Recently it has been suggested that sputum colonization with Burkholderia cepacia complex is a relative contraindication (41) although this advice may be refined to Genomovar III as microbial typing and understanding of the behavior of these subtypes improves (42). The issue surrounding pregnancy outcome according to prepregnant lung function is yet to be resolved. Those with poor lung function are likely to do less well than those with good lung function and while an absolute cut-off of percent predicted (for age, sex and height) forced expiratory volume in the first second (%FEV1) is impractical, an FEV1 of 60% (28) is generally regarded as the minimum desirable. Some data suggests that infants, though preterm may otherwise do well down to a maternal prepregnant %FEV1 of 50% (32). Anecdotal evidence, alluded to in a number of papers, suggests that even when lung function is good, some women experience a deterioration out of keeping with their prepregnant lung function indicating that pregnancy may have a deleterious effect on the mother. Few studies comparing outcome of pregnant women with non-pregnant severity matched controls have been reported: two are too small to have statistical power (43, 44) and the other two are at odds (45, 46). The UK study (45) suggested that women with poorer lung function were more likely to deliver preterm than those with good lung function and when taken as a group those that delivered preterm lost more lung function than severity matched non-pregnant controls. A much larger study based on returns to the North American CF Foundation database (46) suggested that there was no deleterious effect of pregnancy on long-term survival at any level of lung function. While this study is statistically more powerful, it does seem biologically plausible that a woman sick with more advanced CF could be at risk from the metabolic and physiological demands placed on her by a pregnancy. Certainly great care should be taken when counselling a women with advanced disease that the outcome of her pregnancy might be affected, that her CF could suffer and her survival – and hence the time she may have with the child – may be shortened. Further confusion may occur when comparing study populations. The women studied in the UK (32) had a profile of CF disease almost identical to that of the UK adult CF population as a whole. A recent paper from Toronto (30) describes very much improved outcome of pregnancy but careful study reveals that these patients have a different genotypic and phenotypic composition to UK study and therefore comparison of outcomes is not strictly valid. The second paper presented (34) here describes 33 pregnancies in 26 women, including one who had four successful pregnancies. Again it shows that pregnancy is well tolerated in women who are essentially well, and supports the contention that preterm delivery is associated in particular with a low prepregnant FEV1 although no further light is shed on the discussion as to whether pregnancy per se adversely affects women with poor lung function. Of note, a substantial proportion were diagnosed late, the proportion of the serious Delta F508 genotype was relatively low as was the prevalence of diabetes although, as expected, the majority were pancreatic insufficient. This, coupled with the relatively old age (27 years) at first pregnancy, suggests this group has a higher proportion of healthy women and is more akin to the Canadian group (30) than that of the UK (32). A further area likely to be of greater interest in the future is pregnancy following double lung transplantation for CF. Though still relatively rare, increasing numbers are being reported. An early series (47) in 29 heart and three heart lung transplants reported 27 live births, 41% born preterm, 33% by cesarean section, several with low birth weight, but with no still births, perinatal deaths or fetal anomalies. A later series (48) included three women with CF post lung transplant with two live preterm infants who required intensive support but went on to do well. One mother underwent termination at 16 weeks due to pre-existing transplant rejection. Both groups reported maternal complications during pregnancy but there were no episodes of rejection of graft failure. While experience is limited, current opinion, supported by greater experience in other solid organ transplants, seems to be that ideally pregnancy be delayed by at least 2 years post transplant, rejection and infection are treated conventionally if they occur, and there appears to be little additional risk of rejection, organ failure or fetal anomalies. This author is unaware of any National CF Association guidelines on the management of pregnancy in women with CF. Clearly management should be within a specialized CF center with close collaboration with obstetricians used to managing high-risk pregnancies. Preconceptual genetic counselling of the potential mother and her partner is desirable, and chorionic villus sampling or amniocentesis should be offered where there is doubt about the partners genetic status and if the woman may consider termination if the foetus has CF. Women can be advised that there is very little evidence that the child will be affected by the mothers CF or medication and obstetric complications are no more common than in non-CF pregnancies although there is an increased risk of premature delivery. The ability of a mother to carry a pregnancy to term appears to be related primarily to her prepregnant lung function, although body weight, presence of CF-related diabetes, liver disease or other complications must be considered in the individual. Those with cor pulmonale, pulmonary hypertension and possibly genomovar III B. cepacia should be counselled against pregnancy. None the less, by careful attention to the details of CF care, the majority of CF women who wish to become a mother can have a successful pregnancy, and many will experience no detriment to their overall CF health.

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