Male fertility in cystic fibrosis

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infarction associated with antihypertensive drug therapies, JAMA

1995; 274: 620-25. 2 Buring JE, Glynn RJ, Hennekcns CH. Calcium channel blockers and myocardial infarction: a hypothesis formulated but not yet tested. JAMA 1995; 274: 654-55.

Iron supplementation: is less better? deficiency affects more than a quarter of the world’s population.’ The optimum long-term intervention strategy is iron fortification of food, but in developing countries where iron deficiency is most prevalent it is often difficult to identify a foodstuff that is centrally processed and widely consumed. Consequently, distribution of iron tablets is the mainstay of efforts to alleviate iron deficiency despite its dismal record of success. Among several reasons why iron supplementation programmes are ineffective,2 poor compliance is generally believed to be the most important. A proposed innovation in iron supplementation programmes is a reduction in frequency of administration to less than once daily. The efficacy of intermittent supplementation was evaulated recently by Schultink and colleagues3 who compared daily with twice weekly iron Iron

administration in in

a

, , ,. ,

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50 mg of iron as ferrous sulphate when subjects were given oral iron for the preceeding six days.’ Whilst any increase in iron intake is likely to be of some benefit, a central question with intermittent supple-mentation is whether a 3-7-fold reduction in the weekly dose of iron will have an impact on the prevalence of iron deficiency anaemia. Estimations from isotopic measurements show that 50 mg of iron given twice weekly with food provides less than 10% of the iron requirements during the third trimester of pregnancy.’ More effective approaches to circumventing the gastrointestinal side-effects of iron would be to use formulations that delay iron release in the stomach"" or perhaps to reduce the daily dose of iron." More than twenty studies have been planned or are in progress in developing countries to assess the efficacy of intermittent iron supplementation schedules." This heavy investment in a theoretical concept may not represent the best use of limited resources. James D Cook Department of Internal Medicine, University

of Kansas Medical Center,

Kansas City, Kansas, USA

DeMaeyer E, Adiels-Tegman M. The prevalence of anaemia in the world. World Health Stat Quart 1985; 38: 302-16. Gillespie S, Kevany J, Mason J. Controlling iron deficiency: a report based on a ACC/SCN workshop. Lavenham, Suffolk: Lavenham Press,

1

2

randomised double-masked field trial

in eastern Jakarta, Indonesia. 87 children with a baseline haemoglobin concentration of less than 112 g/L were given anthelminthic treatment and then randomly assigned to receive 30 mg iron as liquid ferrous sulphate either daily or twice weekly for 2 months. Correction of iron deficiency as measured by an increase in haemoglobin or decrease in erythrocyte protoporphyrin concentration was two-fold greater in 32 children given iron daily than in 33 children given iron twice daily. However, after statistical adjustment for the lower initial haemoglobin concentration in children given iron daily, the difference was not statistically significant. The researchers concluded that the effectiveness of daily and intermittent administration schedules was equivalent. Their findings would have been strengthened if a control group had been included to assess the haematological effects of deworming and the magnitude of regression to the mean of laboratory iron administration was measurements. Because supervised by health workers in the home, compliance was not evaluated in this study. However, the fact that a quarter of the children in both groups refused to continue in the trial suggests that there was a high frequency of gastrointestinal side-effects from iron doses as high as 4 mg/kg body weight. A more important question is whether a busy mother will be more consistent with intermittent than with daily iron administration; compliance has been a major limitation with weekly antimalarial prophylaxis as a public health measured An argument in support of intermittent supplementation is derived from rat studies showing that iron absorption is inhibited when preceded by massive doses of oral iron that would be highly toxic in human beings if given on a body weight basis.5" This mucosal block to iron absorption is assumed to occur with daily dosage. Theoretically, less frequent adminstration of iron should enhance absorption sufficiently to offset the reduction in weekly dose of iron. However, in a recent radioisotopic study, there was no significant difference in absorption of

",

2-5-year-old preschoolchildren

1991: 1-93.

SchultinkW, Gross R, Gliwitzki M, Karyadi D, Matulessi P. Effect of

3

twice weekly iron supplementation in Indonesian preschool children with low iron status. Am J Clin Nutr 1995; 61: 111-15. 4 Heymann DL, Steketee RW, Wirima JJ, McFarland DA, Khoromana CO, Campbell CC. Antenatal chloroquine chemoprophylaxis in Malawi: chloroquine resistance, compliance, protective efficacy and cost. Trans R Soc Trop Med Hyg 1990; 84: 496-98. 5 Wright AJ, Southon S. The effectiveness of various ironsupplementation regimens in improving the iron status of anaemic rats. Br J Nutr 1990; 63: 579-85. 6 Fairweather-Tait SJ, Swindell TE, Wright AJ. Further studies in rats on the influence of previous iron intake on the estimation of bioavailability of iron. Br J Nutr 1985; 54: 79-86. 7 Cook JD, Reddy MB. Efficacy of weekly versus daily iron supplementation. Am J Clin Nutr 1995; 62: 117-20. 8 Cook JD, Carriaga M, Kahn SG, Schalch W, Skikne BS. Gastric delivery system for iron supplementation. Lancet 1990; 335: 1136-39. 9 Simmons WK, Cook JD, Bingham KC, et al. Evaluation of a gastric delivery system for iron supplementation in pregnancy. Am J Clin Nutr

daily vs

1993; 58: 622-26. 10

11

Fogelholm M, Suominen M, Rata H. Effects of low-dose iron supplementation in women with low serum ferritin concentration. Eur J Clin Nutr 1994; 48: 753-56. Viteri FE. The consequences of iron deficiency and anaemia in pregnancy on maternal health, the foetus and the infant. SCN News 1994; 11: 14-18.

Male

fertility

in

cystic fibrosis

Infertility in males, which is generally accepted as an almost inevitable component of cystic fibrosis (CF), results from congenital bilateral absence or atrophy of the vas deferens (CBAVD).’ The body of the epididymis is also affected but the testicular efferent ducts tend to be spared and some may be dilated.These features are usually established by the time of birth, although there is evidence of postnatal progression in some individuals. Semen analysis reveals azoospermia in almost all adult males with CF.’J CBAVD may also occur as an isolated abnormality.’5 In a study of 102 patients without any other clinical manifestations of CF who were investigated for abnormalities in the CFTR gene, 19 had mutations in

587

both

copies of the gene while 54 had a mutation in an of a single copy. 34 (63%) of these "heterozygotes" were shown to have a DNA variant in a non-coding sequence of their other CFTR gene ("the 5T allele") which reduces the production of normal CFTR messenger RNA.6 Such mutations in non-coding regions of the gene may thus result in low levels of expression of normal CFTR protein, although the amount produced exon

may be sufficient to prevent or postpone disease in the organs classically affected by CF such as lungs and pancreas. These findings highlight the acute sensitivity of

deferens to CFTR dysfunction. Obstructive azoospermia has been proposed as a major diagnostic criterion in atypical patients with mild features of CF and normal or equivocal sweat chloride concentrations.3 Anecdotal reports of occasional fertile males with atypical CF were often regarded as unproven, sometimes with mention of a similar but distinct disease (phenocopy), until the advent of molecular genetic analysis revealed that some compound heterozygotes with CF gene mutations are unquestionably fertile.’ The Cleveland group who promoted the diagnostic value of azoospermia3 lately reported 4 adult male patients with CF and patency of the vas deferens. These individuals were all hemizygous for a splice mutation in an intron, 3849+lOkb C—/T. There is a further reference to semen analyses showing satisfactory sperm counts, and fertility, in patients with the same mutation.9 Although of the Cleveland patients had pancreatic none insufficiency, they had variable degrees of lung disease. Pancreatic insufficiency was present in 33% of patients with 3849+lOkb C-T and another "severe" mutation in an Israeli series.’° These observations add further support to the view that pancreatic insufficiency, bronchial infection, and lung damage in CF are determined not only by the level of expression and function of CFTR but also by environmental and perhaps other genetic factors.",12 Even for men with CBAVD there is now hope that they may be able to become fathers. After microsurgical epididymal sperm aspiration (MESA)’3 followed by intracytoplasmic sperm injection into oocytes in vitro, a man with CF fathered a healthy child." This case was the more remarkable because the female partner was a carrier of the A F508 mutation, and implantation of the fertilised ovum was carried out only after single-blastomere analysis of the embryo had shown it to be heterozygous. Other instances of successful pregnancies with sperm from CF men by the same technique have been reported.15 The high frequency of CF mutations and the 5T allele in men with CBAVD, together with the empirical carrier frequency of about 1 in 25 in their female partners, makes it essential that both partners should be screened for CF mutations before MESA and in-vitro fertilisation are contemplated. Sympathetic counselling of infertile couples requesting MESA and in-vitro fertilisation where the male partner has classic CF with lung disease should also address the likelihood that the potential father will have a reduced life expectancy, and that his partner may therefore have to cope with a dependent husband as well as a young child. In addition, in-vitro fertilisation has a high failure rate. Fortunately, two recent reports confirm continued and substantial improvements in CF survival’6 and the success of in-vitro fertilisation.17 Increasing

vas

588

numbers of affected couples will the new option for parenthood.

JA

surely wish

to

explore

Dodge

Nuffield Department of Child Health, Queen’s University of Belfast, Belfast, UK Shwachman H, Perlmuter AD, Rule A, Khaw K-T, Holsclaw DS. Reproductive failure in males with cystic fibrosis. N Engl J Med 1968; 279: 65-69. 2 Landing BH, Wells TR, Wang CI. Abnormality of the epididymis and vas deferens in cystic fibrosis. Arch Pathol 1969; 88: 569-90. 3 Stern RC, Boat TF, Doershuk CF. Obstructive azoospermia as a diagnostic criterion for cystic fibrosis syndrome. Lancet 1983; i: 1401-04. 4 Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas deferens: a primary genital form of cystic fibrosis. JAMA 1992; 267: 1794-97. 5 Augarten A,YahavY, Kerem B-S, et al. Congenital bilateral absence of vas deferens in the absence of cystic fibrosis. Lancet 1994; 344: 1473-74. 6 Chillon M, Casals T, Mercier B, Bassas L, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995; 332: 1475-80. 7 Barreto C, Marques Pinto L, Duarte A, Lavinha J, Ramsay M. A fertile male with cystic fibrosis: molecular genetic analysis. J Med Genet 1991; 28: 420-21. 8 Stern RC, Doershuk CF, Drumm M. 3849+10kb C→T mutation and disease severity in cystic fibrosis. Lancet 1995; 346: 274-76. 9 Highsmith WE, Burch LH, Zhou Z, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994; 331: 974-80. 10 Augarten A, Kerem B-S, Yahav Y, et al. Mild cystic fibrosis and normal or borderline sweat test in patient with the 3849+10kb C→T mutation. Lancet 1993; 342: 25-26. 11 Dean M, Santis G. Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations. Hum Genet 1994; 93: 364-68. 12 Veeze HJ, Halley DJJ, Bijman J, et al. Determinants of mild classical symptoms in cystic fibrosis patients: residual chloride secretion measured in rectal biopsies in relation to the genotype. J Clin Invest 1994; 93: 461-66. 13 Oates RD, Honig S, Berger MJ, Harris D. Microscopic epididymal sperm aspiration (MESA): a new option for treatment of the obstructive azoospermia associated with cystic fibrosis. J Assist Reprod Genet 1992; 9: 36-40. 14 Liu J, Lissens W, Silber SJ, et al. Birth after preimplantation diagnosis of the cystic fibrosis &Dgr;F508 mutation by polymerase chain reaction in human embryos resulting from intracytoplasmic sperm injection with epididymal sperm. JAMA 1994; 272: 1858-60. 15 Fogdestam I, Hamberger L, Ludin K, Sjögren A, Hjelte L, Strandvik B. Successful pregnancies after in vitro fertilization with sperm from men with cystic fibrosis. 19th European Cystic Fibrosis 1

Kaplan E,

Conference, Paris, 1994 (abstr). 16 UK Cystic Fibrosis Survey 1995 Report, June 1995. 17 Human Fertilisation and Embryology Authority. annual London: HFEA, 1994.

Treatment of AIDS

opportunistic

Report.

infections in

Opportunistic infections are responsible for much of the morbidity and mortality in AIDS patients and are mostly attributable to a small number of pathogens.’ Because these infections had previously been encountered in patients with other types of immune deficiency, effective had often been established before the onset of epidemic.’ Optimum therapy for AIDS-related opportunistic infections is frequently reviewed.3 A comparison of the treatments for these common opportunistic infections in 1981, when the AIDS epidemic was first identified, versus 1995 shows what has been achieved in the 14 year interval (table). Pneumocystis carinii pneumonia (PCP) was once the AIDS-defining infection in 60% of HIV-infected persons and occurred in up to 80% of individuals. With aggressive

treatments

the AIDS