- Email: [email protected]
Vitamin A supplementation and HIV-1 mother-to-child transmission in Africa
CORRESPONDENCE
overzealous resections. If they do, then the lesson from large randomised studies showing the equivalence of conservative surgery over mastectomy would be ignored. Drew and colleagues suggest that multicentric foci left behind are adequately treated by radiotherapy and tamoxifen, resulting in a recurrence rate of 8·5%, but then go on to suggest that it would be unacceptable to deliberately leave behind enhancing foci detected on MRI. These two statements seem to contradict each other and highlight the degree of uncertainty generated by the assumptions made. To establish the natural history of breast-cancer multicentricity, C R M Boggis and co-workers (May 2, p 1362)5 suggest that a prospective series of patients in whom MRI is not allowed to influence patient management will answer the question we asked.1 Although this is a feasible study, it will not tell us whether removal of the enhancing foci on MRI (probable cancer foci) is necessary. The prospective trial that we envisaged is conceptually different. To ascertain the value of MRI in clinical management we propose randomising patients with enhancing foci to either surgical excision of these foci along with the primary tumour, or excision of the primary alone and MRI follow-up. In this way we would establish not only the natural history of enhancing foci but also whether removing these foci is feasible by conservative surgery and whether this practice would ultimately influence local recurrence rates. *M Douek, J S Vaidya, M Baum, I Taylor University College London Medical School, London W1P 7LD, UK 1
2
3
4
5
Douek M, Vaidya JS, Lakhini SR, et al. Can magnetic-resonance imaging help elucidate natural history of breast cancer multicentricity? Lancet 1998; 351: 801–02. Drew PJ, Turnbull, LW, Kerin MJ. Magnetic resonance imaging for breast cancer. Lancet 1998; 351: 1661–62. Fisher ER, Anderson S, Redmond C, Fisher B. Ipsilateral breast tumour recurrence and survival following lumpectomy and irradiation: pathological findings from NSABP protocol B-06. Semin Surg Oncol 1992; 8: 161–66. Baum M, Vaidya JS, Mittra I. Multicentricity and recurrence of breast cancer. Lancet 1997; 349: 208. Boggis CRM, Bundred NJ. Magnetic resonance imaging in breast cancer. Lancet 1998; 352: 1362.
Correspondents’ reply Sir—M Douek and colleagues1 suggest that MRI is detecting small enhancing foci of malignant disease distant to the
THE LANCET • Vol 352 • July 4, 1998
primary tumour. Their proposed study involves leaving these enhancing foci untreated with no further evaluation other than follow-up with MRI. In view of our results, which show that the rate of recurrence after breast conserving therapy seems to be lower than the incidence of MRI detected multifocality in patients with primary disease, the clinical relevance of these small enhancing foci remains in question.2 However, no conclusion should be drawn from case series alone, and until a prospective randomised trial has shown no difference in outcome for patients treated on the basis of MRI evaluation or by standard triple assessment, we do not think that these enhancing foci can be left untreated. Suspicious mammographic lesions are always evaluated to expedite early intervention. Until proven to the contrary, we believe that lesions which are suspicious on MRI should be treated in the same way. Furthermore, whatever the theoretical arguments about the nature of multicentricity, the proposed trial is flawed on radiological grounds. It has already been established that the inflammation and distortion caused by surgery and radiotherapy during breast conserving treatment results in a substantial reduction in the specificity of contrast-enhanced MRI for up to 18 months after treatment.3 We have an 85–90% specificity for the detection of primary disease with our MRI technique, which uses a fast dynamic sequence. Even this specificity is reduced if the scan is done too soon after breast conserving therapy.4 It also seems unlikely that women would accept a non-interventional wait-andsee policy, even if there was some doubt over the original MRI diagnosis. In addition, if these lesions are left insitu, when does a clinically irrelevant enhancing focus become an invasive cancer that has an adverse prognostic effect? A more acceptable approach would be to undertake a randomised, controlled trial comparing the longterm outcome in women who have been evaluated with MRI with those who have not. Such a trial would compare the established gold standard with the new technique and would also answer some of the outstanding questions about the clinical usefulness of MRI. MRI of the breast has now advanced to the stage at which we can relatively confidently detect multifocal disease that is undetectable by conventional imaging.2 Although we accept that the technique may be oversensitive and that some of these foci may be
clinically irrelevant, the fact remains that the foci are present. Until an appropriately designed prospective trial establishes whether treatment planning with MRI affects outcome, we do not feel that suspicious foci can be left in situ solely to elucidate their natural history,5 especially when no accurate imaging follow-up is possible in the early post-treatment phase. We cannot leave aside ethics, as Douek and colleagues suggest, because we believe that this should be one of the primary concerns of any clinical research. However, we agree that a prospective multicentre trial is needed.2 *P J Drew, L W Turnbull, M J Kerin *University of Hull Academic Surgical Unit, Castle Hill Hospital, Hull HU16 5JQ, UK; and Centre for MR Investigations, Hull Royal Infirmary 1
2
3
4
5
Douek M, Vaidya JS, Lakhani SR, Hall-Craggs MA, Baum M, Taylor I. Can magnetic resonance imaging help elucidate natural history of breast cancer multicentricity. Lancet 1998; 351: 801–02. Drew PJ, Turnbull LW, Kerin MJ, Carleton PJ, Fox JN. Multicentricity and recurrence of breast cancer. Lancet 1998; 349: 208–09. Heywang-Koebrunner SH, Schlegel A, Beck R, et al. Contrast enhanced MRI of the breast after limited surgery and radiation therapy. JCAT 1993; 17: 891–900. Drew PJ, Kerin MJ, Turnbull LW, et al. Routine screening for local recurrence following breast conserving therapy for cancer with dynamic contrast enhanced magnetic resonance imaging of the breast. Ann Surg Onc 1998; 5: 265–70. Drew PJ, Turnbull LW, Kerin MJ. Magnetic-resonance imaging for breast cancer. Lancet 1998; 351: 1661–62.
Vitamin A supplementation and HIV-1 mother-to-child transmission in Africa Sir—Wafaie Fawzi and colleagues (May 16, p 1477)1 conclude that multivitamin supplementation had beneficial effects on pregnancy outcomes (fetal deaths and neonatal characteristics) and on maternal T cell counts in HIV-1 infected women in Tanzania. In this study, there was no evidence for similar benefits of vitamin A supplementation alone. The absence of an effect of vitamin A supplement is, however, questionable. First, the sample size was calculated for an expected reduction of the HIV-1 mother-to-child transmission rate of 30%, with a baseline risk of 30%. This sample was likely to be insufficient to identify vitamin A benefits on outcomes with a frequency as low as 3% for very-low-birthweight or 14% for
653
CORRESPONDENCE
small-for-gestational-age babies. Second, the comparability of the two groups during pregnancy is not described, and possible differences might have occurred despite randomisation, especially in a factorial design. Third, the reported compliance of 91% is very high for a trial with 4 months of treatment in an African population, but no objective information was presented about a possible difference of compliance between the group of women who received multivitamins and the group who did not. Women receiving multivitamins may have rapidly felt in better shape (especially for vitamin C supplementation), and their compliance could have been better than in the group who did not receive this intervention, in which there were women receiving vitamin A alone. Moreover, we have no details of the maternal characteristics at the beginning and end of pregnancy: some that could affect pregnancy outcome, such as maternal body weight gain or other clinical indices, and be improved by multivitamin supplementation, could have reduced the power to detect a difference in the vitamin A comparison. We also have reservations about the feasibility of such an intervention early in pregnancy since most African women use prenatal services late in pregnancy.2 In this Tanzanian trial setting, the selection process of eligible women and the characteristics of women enrolled could have partly accounted for some of the positive results—eg, high HIV-1 screening and trial acceptability, or high drug compliance. Finally, Fawzi and co-workers offer reasons for the absence of beneficial effects of vitamin A supplementation. However, the essential objective of their trial has not yet been achieved— namely, a benefit of vitamin A supplementation on maternal and infant morbidity, as has already been suggested in other such trials.3,4 We, as are many researchers in prevention of vertical transmission of HIV-1 in developing countries,5 are pleased to hear about the potential benefit effect of multivitamin supplementation but are waiting for information on the association between vitamin A supplementation and evolution of women’s health, HIV-1 mother-tochild transmission, and child morbidity. *Katia Castetbon, Valériane Leroy, François Dabis INSERM U330, Université Victor SegalenBordeaux 2, 33 076 Bordeaux, France
654
1
2
3
4
5
Fawzi WW, Msamanga GI, Speigelman D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 1998; 351: 1477–82. Mtimavalye L, Biggar RJ, Taha TE, Chiphangwi J. Maternal-infant transmission of HIV-1. N Engl J Med 1995; 332: 890–91. Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Publ Hlth 1995; 85: 1076–81. Coutsoudis A, Moodley D, Pillay K, et al. Effects of vitamin A supplementation on viral load in HIV-1-infected pregnant women. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 15: 86–87. Dabis F, Msellati P, Newell ML, et al. Methodology of intervention trials to reduce mother to child transmission of HIV with special reference to developing countries. AIDS 1995; 9 (suppl A): S67–74.
Sir—Wafaie Fawzi and colleagues’ results1 bring potent arguments for the use of vitamin supplements to reduce adverse pregnancy outcome in African HIV-1 infected women. Data and interpretation of the effect of vitamins on T-cell counts, however, raise questions that should be addressed before such an intervention is applied. Can the mechanism by which vitamins increase CD4 cell counts slow the process of HIV disease progression? It is well known that HIV-induced alterations are distinct according to the T cell subsets, mainly including a concomitant rise in CD8 activated T cells and a fall in CD4 cells, this last event being a multifactorial process. Peripheral cell loss results from decreased proliferation, increased cell death by apoptosis, increased emigration to lymph nodes, and, but this last mechanism is controversial, reduced central T cell production.2 The global rise noted by Fawzi and co-workers in all peripheral mature T subsets, rather than in CD4 cells alone, suggests an impact on the last process—ie, proliferation of leucocyte progenitors.3 Data on total white blood cells, differential white cell counts, total lymphocyte counts (which are often proposed as an alternative to CD4 counts in the African setting4), and CD4/CD8 ratio should be discussed. A trophic effect on both fetal cells and haematological precursors, rather than a real immunological T cell improvement, could well result from the use of folic acid and vitamin B12, micronutrients which have key roles in the metabolism of proliferating cells. Is the increase seen in CD4 cells, resulting from this whole T lymphocyte population enlargement, protective against opportunistic diseases? The value of absolute CD4 cell count as a surrogate marker of
progression to AIDS has been confirmed in a prospective study. 5 Nevertheless, this fact does not anticipate the functional value of expanded CD4 cells during treatment. In fact, the relation between the gain in CD4 and the protection against pathogens in treated patients is being intensively researched. Could generalisation of multivitamin supplementation in HIVinfected people have adverse effects? Although an increase in viral load is not likely to occur, this load should be monitored. Alternatively, a theoretical risk of some protozoal opportunistic diseases such as toxoplasmosis should result from the widespread use of folate supplementation. Indeed, this risk could undermine folic acid antagonists administration, one of the rare weapons for the prevention of AIDS in developing countries.4 Eric Ledru Viral Oncology Unit, Pasteur Institute, 75724 Paris, France (e-mail: [email protected]) 1
2
3
4
5
Fawzi WW, Msamanga GI, Spiegelman D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 1998; 351: 1477–82. Rosenberg YJ, Anderson AO, Pabst R. HIV-induced decline in blood CD4/CD8 ratios: viral killing or altered lymphocyte trafficking? Immunol Today 1998; 19: 10–17. Beutler E, Lichtman MA, Coller BS, Kippl TJ. Williams hematology, fifth ed. New York: McGraw-Hill, 1995. Ledru E, Diagbouga S, Meda N, et al. A proposal for basic management of HIV disease in West-Africa. Use of clinical staging and haemogram data. Int J STD AIDS (in press). Perneger TV, Yerly S, Perrin L. Transforming laboratory test results to improve clinical outcome predictors in HIV patients. J Acq Immun Defic Syndr Hum Retroviral 1998; 17: 442–49.
Authors’ reply Sir—We agree with Katia Castetbon and colleagues that we have limited power to detect small effects of vitamin A on adverse pregnancy outcomes. We also stated that the confidence intervals of our results are compatible with a modest protective assocation of vitamin A, although it was smaller than the effect of multivitamins and was not statistically significant. In addition, we reported that there were no significant differences between treatment arms in various baseline characteristics. There were also no differences in compliance between treatment arms, as measured by pill counts of supplements or ingestion of the vitamin A dose at delivery. Women who received vitamin A supplements had significant
THE LANCET • Vol 352 • August 22, 1998
overzealous resections. If they do, then the lesson from large randomised studies showing the equivalence of conservative surgery over mastectomy would be ignored. Drew and colleagues suggest that multicentric foci left behind are adequately treated by radiotherapy and tamoxifen, resulting in a recurrence rate of 8·5%, but then go on to suggest that it would be unacceptable to deliberately leave behind enhancing foci detected on MRI. These two statements seem to contradict each other and highlight the degree of uncertainty generated by the assumptions made. To establish the natural history of breast-cancer multicentricity, C R M Boggis and co-workers (May 2, p 1362)5 suggest that a prospective series of patients in whom MRI is not allowed to influence patient management will answer the question we asked.1 Although this is a feasible study, it will not tell us whether removal of the enhancing foci on MRI (probable cancer foci) is necessary. The prospective trial that we envisaged is conceptually different. To ascertain the value of MRI in clinical management we propose randomising patients with enhancing foci to either surgical excision of these foci along with the primary tumour, or excision of the primary alone and MRI follow-up. In this way we would establish not only the natural history of enhancing foci but also whether removing these foci is feasible by conservative surgery and whether this practice would ultimately influence local recurrence rates. *M Douek, J S Vaidya, M Baum, I Taylor University College London Medical School, London W1P 7LD, UK 1
2
3
4
5
Douek M, Vaidya JS, Lakhini SR, et al. Can magnetic-resonance imaging help elucidate natural history of breast cancer multicentricity? Lancet 1998; 351: 801–02. Drew PJ, Turnbull, LW, Kerin MJ. Magnetic resonance imaging for breast cancer. Lancet 1998; 351: 1661–62. Fisher ER, Anderson S, Redmond C, Fisher B. Ipsilateral breast tumour recurrence and survival following lumpectomy and irradiation: pathological findings from NSABP protocol B-06. Semin Surg Oncol 1992; 8: 161–66. Baum M, Vaidya JS, Mittra I. Multicentricity and recurrence of breast cancer. Lancet 1997; 349: 208. Boggis CRM, Bundred NJ. Magnetic resonance imaging in breast cancer. Lancet 1998; 352: 1362.
Correspondents’ reply Sir—M Douek and colleagues1 suggest that MRI is detecting small enhancing foci of malignant disease distant to the
THE LANCET • Vol 352 • July 4, 1998
primary tumour. Their proposed study involves leaving these enhancing foci untreated with no further evaluation other than follow-up with MRI. In view of our results, which show that the rate of recurrence after breast conserving therapy seems to be lower than the incidence of MRI detected multifocality in patients with primary disease, the clinical relevance of these small enhancing foci remains in question.2 However, no conclusion should be drawn from case series alone, and until a prospective randomised trial has shown no difference in outcome for patients treated on the basis of MRI evaluation or by standard triple assessment, we do not think that these enhancing foci can be left untreated. Suspicious mammographic lesions are always evaluated to expedite early intervention. Until proven to the contrary, we believe that lesions which are suspicious on MRI should be treated in the same way. Furthermore, whatever the theoretical arguments about the nature of multicentricity, the proposed trial is flawed on radiological grounds. It has already been established that the inflammation and distortion caused by surgery and radiotherapy during breast conserving treatment results in a substantial reduction in the specificity of contrast-enhanced MRI for up to 18 months after treatment.3 We have an 85–90% specificity for the detection of primary disease with our MRI technique, which uses a fast dynamic sequence. Even this specificity is reduced if the scan is done too soon after breast conserving therapy.4 It also seems unlikely that women would accept a non-interventional wait-andsee policy, even if there was some doubt over the original MRI diagnosis. In addition, if these lesions are left insitu, when does a clinically irrelevant enhancing focus become an invasive cancer that has an adverse prognostic effect? A more acceptable approach would be to undertake a randomised, controlled trial comparing the longterm outcome in women who have been evaluated with MRI with those who have not. Such a trial would compare the established gold standard with the new technique and would also answer some of the outstanding questions about the clinical usefulness of MRI. MRI of the breast has now advanced to the stage at which we can relatively confidently detect multifocal disease that is undetectable by conventional imaging.2 Although we accept that the technique may be oversensitive and that some of these foci may be
clinically irrelevant, the fact remains that the foci are present. Until an appropriately designed prospective trial establishes whether treatment planning with MRI affects outcome, we do not feel that suspicious foci can be left in situ solely to elucidate their natural history,5 especially when no accurate imaging follow-up is possible in the early post-treatment phase. We cannot leave aside ethics, as Douek and colleagues suggest, because we believe that this should be one of the primary concerns of any clinical research. However, we agree that a prospective multicentre trial is needed.2 *P J Drew, L W Turnbull, M J Kerin *University of Hull Academic Surgical Unit, Castle Hill Hospital, Hull HU16 5JQ, UK; and Centre for MR Investigations, Hull Royal Infirmary 1
2
3
4
5
Douek M, Vaidya JS, Lakhani SR, Hall-Craggs MA, Baum M, Taylor I. Can magnetic resonance imaging help elucidate natural history of breast cancer multicentricity. Lancet 1998; 351: 801–02. Drew PJ, Turnbull LW, Kerin MJ, Carleton PJ, Fox JN. Multicentricity and recurrence of breast cancer. Lancet 1998; 349: 208–09. Heywang-Koebrunner SH, Schlegel A, Beck R, et al. Contrast enhanced MRI of the breast after limited surgery and radiation therapy. JCAT 1993; 17: 891–900. Drew PJ, Kerin MJ, Turnbull LW, et al. Routine screening for local recurrence following breast conserving therapy for cancer with dynamic contrast enhanced magnetic resonance imaging of the breast. Ann Surg Onc 1998; 5: 265–70. Drew PJ, Turnbull LW, Kerin MJ. Magnetic-resonance imaging for breast cancer. Lancet 1998; 351: 1661–62.
Vitamin A supplementation and HIV-1 mother-to-child transmission in Africa Sir—Wafaie Fawzi and colleagues (May 16, p 1477)1 conclude that multivitamin supplementation had beneficial effects on pregnancy outcomes (fetal deaths and neonatal characteristics) and on maternal T cell counts in HIV-1 infected women in Tanzania. In this study, there was no evidence for similar benefits of vitamin A supplementation alone. The absence of an effect of vitamin A supplement is, however, questionable. First, the sample size was calculated for an expected reduction of the HIV-1 mother-to-child transmission rate of 30%, with a baseline risk of 30%. This sample was likely to be insufficient to identify vitamin A benefits on outcomes with a frequency as low as 3% for very-low-birthweight or 14% for
653
CORRESPONDENCE
small-for-gestational-age babies. Second, the comparability of the two groups during pregnancy is not described, and possible differences might have occurred despite randomisation, especially in a factorial design. Third, the reported compliance of 91% is very high for a trial with 4 months of treatment in an African population, but no objective information was presented about a possible difference of compliance between the group of women who received multivitamins and the group who did not. Women receiving multivitamins may have rapidly felt in better shape (especially for vitamin C supplementation), and their compliance could have been better than in the group who did not receive this intervention, in which there were women receiving vitamin A alone. Moreover, we have no details of the maternal characteristics at the beginning and end of pregnancy: some that could affect pregnancy outcome, such as maternal body weight gain or other clinical indices, and be improved by multivitamin supplementation, could have reduced the power to detect a difference in the vitamin A comparison. We also have reservations about the feasibility of such an intervention early in pregnancy since most African women use prenatal services late in pregnancy.2 In this Tanzanian trial setting, the selection process of eligible women and the characteristics of women enrolled could have partly accounted for some of the positive results—eg, high HIV-1 screening and trial acceptability, or high drug compliance. Finally, Fawzi and co-workers offer reasons for the absence of beneficial effects of vitamin A supplementation. However, the essential objective of their trial has not yet been achieved— namely, a benefit of vitamin A supplementation on maternal and infant morbidity, as has already been suggested in other such trials.3,4 We, as are many researchers in prevention of vertical transmission of HIV-1 in developing countries,5 are pleased to hear about the potential benefit effect of multivitamin supplementation but are waiting for information on the association between vitamin A supplementation and evolution of women’s health, HIV-1 mother-tochild transmission, and child morbidity. *Katia Castetbon, Valériane Leroy, François Dabis INSERM U330, Université Victor SegalenBordeaux 2, 33 076 Bordeaux, France
654
1
2
3
4
5
Fawzi WW, Msamanga GI, Speigelman D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 1998; 351: 1477–82. Mtimavalye L, Biggar RJ, Taha TE, Chiphangwi J. Maternal-infant transmission of HIV-1. N Engl J Med 1995; 332: 890–91. Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Publ Hlth 1995; 85: 1076–81. Coutsoudis A, Moodley D, Pillay K, et al. Effects of vitamin A supplementation on viral load in HIV-1-infected pregnant women. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 15: 86–87. Dabis F, Msellati P, Newell ML, et al. Methodology of intervention trials to reduce mother to child transmission of HIV with special reference to developing countries. AIDS 1995; 9 (suppl A): S67–74.
Sir—Wafaie Fawzi and colleagues’ results1 bring potent arguments for the use of vitamin supplements to reduce adverse pregnancy outcome in African HIV-1 infected women. Data and interpretation of the effect of vitamins on T-cell counts, however, raise questions that should be addressed before such an intervention is applied. Can the mechanism by which vitamins increase CD4 cell counts slow the process of HIV disease progression? It is well known that HIV-induced alterations are distinct according to the T cell subsets, mainly including a concomitant rise in CD8 activated T cells and a fall in CD4 cells, this last event being a multifactorial process. Peripheral cell loss results from decreased proliferation, increased cell death by apoptosis, increased emigration to lymph nodes, and, but this last mechanism is controversial, reduced central T cell production.2 The global rise noted by Fawzi and co-workers in all peripheral mature T subsets, rather than in CD4 cells alone, suggests an impact on the last process—ie, proliferation of leucocyte progenitors.3 Data on total white blood cells, differential white cell counts, total lymphocyte counts (which are often proposed as an alternative to CD4 counts in the African setting4), and CD4/CD8 ratio should be discussed. A trophic effect on both fetal cells and haematological precursors, rather than a real immunological T cell improvement, could well result from the use of folic acid and vitamin B12, micronutrients which have key roles in the metabolism of proliferating cells. Is the increase seen in CD4 cells, resulting from this whole T lymphocyte population enlargement, protective against opportunistic diseases? The value of absolute CD4 cell count as a surrogate marker of
progression to AIDS has been confirmed in a prospective study. 5 Nevertheless, this fact does not anticipate the functional value of expanded CD4 cells during treatment. In fact, the relation between the gain in CD4 and the protection against pathogens in treated patients is being intensively researched. Could generalisation of multivitamin supplementation in HIVinfected people have adverse effects? Although an increase in viral load is not likely to occur, this load should be monitored. Alternatively, a theoretical risk of some protozoal opportunistic diseases such as toxoplasmosis should result from the widespread use of folate supplementation. Indeed, this risk could undermine folic acid antagonists administration, one of the rare weapons for the prevention of AIDS in developing countries.4 Eric Ledru Viral Oncology Unit, Pasteur Institute, 75724 Paris, France (e-mail: [email protected]) 1
2
3
4
5
Fawzi WW, Msamanga GI, Spiegelman D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 1998; 351: 1477–82. Rosenberg YJ, Anderson AO, Pabst R. HIV-induced decline in blood CD4/CD8 ratios: viral killing or altered lymphocyte trafficking? Immunol Today 1998; 19: 10–17. Beutler E, Lichtman MA, Coller BS, Kippl TJ. Williams hematology, fifth ed. New York: McGraw-Hill, 1995. Ledru E, Diagbouga S, Meda N, et al. A proposal for basic management of HIV disease in West-Africa. Use of clinical staging and haemogram data. Int J STD AIDS (in press). Perneger TV, Yerly S, Perrin L. Transforming laboratory test results to improve clinical outcome predictors in HIV patients. J Acq Immun Defic Syndr Hum Retroviral 1998; 17: 442–49.
Authors’ reply Sir—We agree with Katia Castetbon and colleagues that we have limited power to detect small effects of vitamin A on adverse pregnancy outcomes. We also stated that the confidence intervals of our results are compatible with a modest protective assocation of vitamin A, although it was smaller than the effect of multivitamins and was not statistically significant. In addition, we reported that there were no significant differences between treatment arms in various baseline characteristics. There were also no differences in compliance between treatment arms, as measured by pill counts of supplements or ingestion of the vitamin A dose at delivery. Women who received vitamin A supplements had significant
THE LANCET • Vol 352 • August 22, 1998