Pregnancy and cystic fibrosis
Recent studies have shown that women with CF have similar sexual lifestyles to their peer group with equal numbers getting married and with no difference in the frequency of sexual intercourse or age at first intercourse (Fair et al, 2000; Sawyer et al, 2005). The first successful pregnancy in CF was reported in 1960 (Siegel & Siegel, 1960). The outlook for mother and baby has improved considerably since that time. Increasing numbers of women with CF are having babies.
Thirty infants, including one set of twins, have been born to women with CF attending our adult CF Unit in Leeds. To the best of our knowledge all but one of the children are in good health and developing normally. We and others have achieved good foetal outcomes with intensive antenatal care. The Toronto Unit report a good outcome for 74 babies born to 49 women. Mean gestational age and birth weight were comparable to the non-CF population (Gilljam et al, 2000). In Seattle, USA most women delivered at 33 weeks gestation or later (Cheng et al, 2006).
Women with CF should discuss their intention to become pregnant with the CF physician who will arrange referral for genetic and obstetric advice, and check that all the prescribed treatment is safe in pregnancy. The partner must be screened for CF carrier status. If the father is a carrier, there is a one in two chance that the baby will have CF. In such circumstances antenatal or pre-implantation screening can be offered to the couple. The former allows the option of terminating the pregnancy at about twelve weeks if the baby has CF. The latter allows selection of embryos that have only the one CFTR gene mutation that will always be inherited from the mother. Pre-implantation diagnosis involves routine assisted reproduction techniques. The ovaries, stimulated by fertility drugs, produce several eggs. These are surgically removed at the time of ovulation and injected with the partner’s sperm. If successfully fertilised, the eggs are examined at a very early stage of cell division for the presence of any CFTR gene mutations. Those with one mutation only (inevitably inherited from the mother), are implanted into the womb. Pre-implantation genetic diagnosis is only available at a limited number of Centres of Reproductive Medicine.
All women with CF who are planning to become pregnant should see a CF dietitian to undergo a thorough nutritional assessment and to optimise their nutritional status (Cystic Fibrosis Trust, 2002). A low pre-conceptional weight is a risk factor for poor pregnancy outcome. A survey of mothers with CF in the UK has shown that those who received nutritional advice before conceiving had significantly greater weight gain during pregnancy and gave birth to significantly heavier babies (Morton et al, 1996). Maternal health post-partum is directly related to nutritional status during pregnancy (Kent & Farquharson, 1993). They must also be given general advice, e.g. folic acid supplementation before conception (Department of Health, 1992) which protects against neural tube defects (spina bifida) and advice about food safety.
Serum vitamin levels should be checked in the preconceptional period. If levels of vitamin A are normal it would appear prudent to continue vitamin A supplements at a dose of less than 10,000 IU/day (the maximum recommended daily supplement of vitamin A during pregnancy), (World Health Organisation, 1998). Women with CF and unknown glycaemic status planning a pregnancy should have an oral glucose tolerance test in the preconceptional period to determine their glycaemic status (Cystic Fibrosis Trust, 2004).
Though it is unusual to be weighed in the routine antenatal clinic, for women with CF regular monitoring of nutritional status and weight gain is essential throughout pregnancy. Oral supplementation or nasogastric feeding may be required. For normal weight gain in pregnancy an extra 200 kcal/day is needed in the last three months. Patients with poor nutrition and a low BMI prior to conception may need even more energy. Pregnant women who are pancreatic sufficient and not receiving supplemental vitamin D should be prescribed 400 IU per day, the recommended dosage for women without CF. The amount of additional vitamin D needed in pregnancy in women with CF and pancreatic insufficiency is currently unknown but is likely to exceed 400 IU/day.
The usual gastrointestinal problems of pregnancy; indigestion, reflux, vomiting and constipation may be particularly troublesome for women with CF. Pregnancy may affect glucose tolerance and blood glucose should be monitored. Many women with CF will develop diabetes by about 28 weeks (Hardin et al, 2005). Diagnosis and treatment of gestational diabetes improves maternal nutritional outcome. An oral glucose tolerance test should be performed in each trimester to 30 weeks (Verma et al, 2002; Cystic Fibrosis Trust, 2004).
The pregnancy should be closely supervised by the CF team and an obstetrician familiar with the problems caused by CF in pregnancy. Patients with CFRD or gestational diabetes are referred to the diabetic antenatal clinic for additional specialist advice. It is essential that the CF team and the obstetric teams work closely together to optimise the time of delivery with regard to the demands of the baby and the mother’s CF status. The CF team should be very flexible in organising care for pregnant women with CF. In Leeds we try and see patients approximately every two weeks. We generally work around the antenatal care, seeing patients in our Unit either before or after their routine antenatal clinic appointment so that they do not have to make separate visits to the hospital for antenatal and CF care.
Women chronically infected with P. aeruginosa are likely to need several courses of intravenous antibiotics during the pregnancy. It is our policy to use ceftazidime at a reduced dose of two grams three times a day. If the patient is not responding, meropenem can be added. Although aminoglycosides have a potential for ototoxicity, they can be used if the prescribing physician concludes that the risk:benefit ratio is favourable, but levels should be carefully monitored (Canny, 1993). Both during pregnancy and in the early years of motherhood, women with CF may need a greater level of medical care to maintain their clinical well being. They should be counselled about this probability (Cheng et al, 2006). Mothers in our Unit had significantly more outpatient visits, intravenous antibiotic courses and days of intravenous antibiotic treatment during pregnancy than a matched control group (Clifton et al, 2003).
Both chest and nutritional problems may require all the expertise of the combined medical and obstetric teams even though the patient may appear to have relatively mild CF at the start of the pregnancy. Studies have shown a significant decline in respiratory function during the pregnancy with return to pre-pregnancy levels in the weeks following delivery of the baby (Edenborough et al, 1995; Jankelson et al, 1998; McMullen et al, 2006). As expected, women with more severe respiratory disease are likely to have the worst outcome with a greater loss in respiratory function, a higher incidence of premature labour and delivery and more neonatal complications (Kent 1993; Edenborough et al, 1995; Jankelson et al, 1998; Cheng et al, 2006).
After delivery we encourage patients to come into the Unit for one to two weeks so that they can receive “top up” chest physiotherapy and intravenous antibiotics and have plenty of nursing help on hand for the new baby. The new mother may lose weight very rapidly after delivery. Cheng reported all women were back to their pre-pregnancy weight by two months post partum (Cheng et al, 2006). This probably reflects all the new demands on the mother’s time and emphasises the need for proper support so that she can continue to properly attend to her own medical needs. We found that more and longer courses of intravenous antibiotic treatment were required up to two years after delivery to maintain clinical stability. At four years after childbirth the annual cost of care for the mothers was twice that of the controls (Clifton et al, 2003). McMullen and colleagues reported similar results from a larger epidemiological study (McMullen et al, 2006).
Large population studies show that statistically pregnancy is safe for most women with CF with good lung function. Data from the US CF Foundation database and the Epidemiologic Study of CF show that women with CF who become pregnant are as a group healthier at baseline than women who do not become pregnant (Goss et al, 2003; McMullen et al, 2006). Goss showed that even after adjusting for differences in various prognostic indices, pregnant women with CF have a greater 10 year survival than non-pregnant women with CF, 77% vs. 58% (because as a rule those who become pregnant have less severe disease). Pregnancy was not associated with an increased risk of death, nor was it harmful in any subgroup including women with FEV1 less than 40% predicted normal (Goss et al, 2003). Similarly, Fitzsimmons found the rate of decline in FEV1 two years post pregnancy was not significantly greater when mothers with CF were compared to matched controls. Across the board survival was worse in women with poor respiratory function and poor nutrition but pregnancy did not add any greater risk (Fitzsimmons et al, 1996). In the Toronto study, 10 years after delivery 79% of the mothers were still alive. The yearly rate of decline in FEV1 was comparable to that of the clinic as a whole and the average BMI before pregnancy was not different from that after pregnancy (Gilljam et al, 2000). In the Minneapolis clinic pregnancy had no impact on long term survival (Billings et al, 2000). Gillet reported the outcome of 75 pregnancies in French women with CF between 1980 and 1999. There were 64 live births with a prematurity rate of 18%, five spontaneous and five medical terminations and one maternal death in pregnancy. Those who carried their babies to term had better respiratory function and nutritional status than those who delivered prematurely. At one year after delivery the mothers showed no accelerated decline in lung function. As in the American experience, pulmonary status was better in the mothers before pregnancy compared to the non-pregnant control group (Gillet et al, 2002). Contrary to Fitzsimmons (Fitzsimmons et al, 1996), Goss did not find pregnancy harmful in women with CF and diabetes mellitus, although the prevalence of treatment for diabetes may more than double (McMullen et al, 2006).
On the other hand Edenborough felt that an FEV1 below 60% predicted normal was a cut off point for a worse prognosis and stated that lung function is the most significant predictor of outcome (Edenborough et al, 1995). Women with poor lung function may lose precious respiratory reserve with long term effects (Edenborough, 2001). It is difficult nonetheless to predict individual outcomes and we have seen maintenance of stable lung function throughout pregnancy in women with pre-conception FEV1 values of less than 40% predicted normal. Gilljam found a reduced mortality rate when the pre-pregnancy FEV1 was greater than 50% predicted, but also reported long term survival in two women with pre-pregnancy FEV1 values of 35% predicted (Gilljam et al, 2000).
A balanced approach to the available evidence is needed. Our policy is to caution against pregnancy for women with an FEV1 value of less than 60% predicted although our experience is that when a child is seriously wanted this advice is mostly ignored. Women with CF should have individual counselling about the suitability of pregnancy. Some of our patients have had an accelerated decline after giving birth. We feel this may be related to the support structure at home for the mother and new baby and the difficulties that the mother finds in maintaining her CF care as well as attending to the demands of a new baby. We believe it is essential that the social worker of the Unit is intimately involved in establishing a care plan for mother and baby well in advance of delivery.
• Most women with CF become pregnant without any difficulty
• Pregnancy is not associated with an accelerated decline in health in large North American studies
• Women with an FEV1 value less than 60% predicted should be counselled against pregnancy
• Pregnancy should be planned and discussed with the CF multidisciplinary team before conception
• A care plan for mother and baby should be in place well before the expected delivery date
Billings JC, Dunitz JM, Warwick WJ. Longterm survival of women with cystic fibrosis following pregnancy. Pediatr Pulmonol 2000; Suppl 20: A483.
Canny GJ. Pregnancy in patients with cystic fibrosis. CMAJ 1993; 149: 805-806. [PubMed]
Cheng EY, Goss CH, McKone EF, et al. Aggressive prenatal care results in successful fetal outcomes in CF women. J Cyst Fibros 2006; 5: 85-91. [PubMed]
Clifton I, Bodey S, McIntosh G, et al. Pregnancy and motherhood in cystic fibrosis: the financial cost to the health service and the health cost to the mother. J Cyst Fibros 2003; 2: S102.
Cystic Fibrosis Trust Diabetes Working Group. Management of Cystic Fibrosis Related Diabetes Mellitus. London. Cystic Fibrosis Trust, June 2004. [Link]
Cystic Fibrosis Trust Nutrition Working Group. Nutritional Management of Cystic Fibrosis. London. Cystic Fibrosis Trust, April 2002. [Link]
Department of Health, 1992. Folic acid and the Prevention of Neural Tube Defects.
Edenborough FP, Stableforth DE, Webb AK, et al. Outcome of pregnancy in women with cystic fibrosis. Thorax 1995; 50: 170-174. [PubMed]
Edenborough F. Women with cystic fibrosis and their potential for reproduction. Thorax 2001; 56: 649-655. [PubMed]
Fair A, Griffiths K, Osman LM. Attitudes to fertility issues among adults with cystic fibrosis in Scotland. The Collaborative Group of Scottish Adult CF Centres. Thorax 2000; 55: 672-677. [PubMed]
Fitzsimmons SC, Fitzpatrick S, Thompson D, et al. A longitudinal study of the effects of pregnancy on 325 women with cystic fibrosis. Pediatr Pulmonol 1996; Suppl 13: 99-101.
Gillet D, de Braekeleer M, Bellis G, et al. Cystic fibrosis and pregnancy. Report from French data (1980-1999). Br J Obstet Gynecol 2002; 109: 912-918. [PubMed]
Gilljam M, Antoniou M, Shin J, et al. Pregnancy in cystic fibrosis. Fetal and maternal outcome. Chest 2000; 118: 85-91. [PubMed]
Goss CH, Rubenfeld GD, Otto K, et al. The effect of pregnancy on survival in women with cystic fibrosis. Chest 2003; 124: 1460-1468. [PubMed]
Hardin DS, Rice J, Cohen RC, et al. The metabolic effects of pregnancy in cystic fibrosis. Obstet Gynaecol 2005; 106: 367-375. [PubMed]
Jankelson D, Robinson M, Parsons S. Cystic fibrosis and pregnancy. Aust NZ J Obstet Gynaecol 1998; 38: 180-184. [PubMed]
Kent NE, Farquharson DF. Cystic fibrosis in pregnancy. CMAJ 1993; 149: 809-813. [PubMed]
McMullen AH, Pasta DJ, Frederick PD, et al. Impact of pregnancy on women with cystic fibrosis. Chest 2006; 129: 706-711. [PubMed]
Morton A, Wolfe S, Conway SP. Dietetic intervention in pregnancy in women with CF -the importance of pre-conceptional counselling. Israel J Med Sci 1996; 32(Suppl): S271.
Sawyer SM, Farrant B, Cerritelli B, et al. A survey of sexual and reproductive health in men with cystic fibrosis: new challenges for adolescent and adult services. Thorax 2005; 60: 326-330. [PubMed]
Siegel D, Siegel S. Pregnancy and delivery in a patient with Cystic Fibrosis of the pancreas. Obstet Gynecol 1960; 16: 439-440.
Verma A, Das M, Ahluwalia A, et al. Gestational dibetes in cystic fibrosis. J Cyst Fibros 2002; 1: S155-S156.
World Health Organisation. Safe vitamin A dosage during pregnancy and lactation: recommendations and report of a consultation. Document NUT/98.4. Geneva: WHO, 1998.