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More growth-chart confusion
THE LANCET
More growth-chart confusion SIR—WHO has published new reference figures for mid-upper-arm circumference (MUAC), based on data collected by the US National Center for Health Statistics (NCHS).1,2 The timing is curious—29 years after the publication by Jelliffe of the previous standard for MUAC,3 22 years after much of the NCHS data were collected, 17 years after WHO adopted NCHS data for weight-for-age, height-for-age, and weight-for-height,4 and at a time when WHO is initiating the development of a new single international reference for anthropometry of young children.1 MUAC, thought of as an index of wasting, is commonly measured with a tape and a single cut-off for children between 1 and 5 years of age. Many have challenged the assumption of age independence; however, although other reference figures have been published for developed countries, reservations have been expressed about their applicability to populations with lower levels of fatness. The NCHS MUAC-for-age reference seems to have been selected by WHO on the grounds of consistency with the NCHS/WHO weight and height reference. However, WHO concludes that the NCHS/WHO reference itself has such “significant technical drawbacks” that “it should be updated or replaced in the near future”; in particular, a new reference for infants should reflect WHO feeding recommendations.1 If the same were true for MUAC, the new reference will have a short life. WHO and the US Centers for Disease Control and Prevention are preparing NCHS reference data for MUAC-for-height, intended as a proxy for MUAC-for-age in situations in which age is not known? Nothing is known about the changing relation with age between MUAC-for-age, MUACfor-height, and weight-for-height in the NCHS population nor in populations which are breast fed or which have high levels of wasting. Until such information is available, it is difficult to know the equivalence between assessments on the basis of any of these indices and between different populations and age groups. Yet international references are usually justified as means of standardising anthropometric indices to facilitate comparisons of nutritional status between communities. A change of reference can cause confusion on the ground. Lessons should be learned from the problems introduced by the change from the Harvard standard to the NCHS/WHO
150
reference, and by the move from calculating indices as percentages of the median to standard deviation scores.5 For the time being, if MUAC is to be measured, the simplicity and transparency of cautious use of an ageindependent cut-off, however flawed, remains more attractive than an unexplored MUAC-for-age or MUACfor-height reference. Sarah B J Macfarlane Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
1
2
3
4
5
WHO Expert Committee. Physical status: the use and interpretation of anthropometry. WHO Tech Rep Ser 1995, no 854. de Onis M, Yip R, Mei Z. The development of MUAC-for-age reference data recommended by the WHO Expert Committee. Bull WHO 1997; 75: 11–18. Jelliffe DB. The assessment of the nutritional status of the community. WHO Monog Ser 1966; no 53. WHO. A growth chart for international use in maternal and child health care. Geneva: WHO, 1978. Grant K, Seaman J. Growth chart confusion. Lancet 1979; ii: 102.
Inclusion of women in clinical trials of antiretroviral agents for HIV/AIDS during pregnancy SIR—In the past, women of childbearing age were excluded from clinical trials of new drugs for fear of pregnancy and subsequent fetal damage. Inclusion of women in such trials is now regarded as essential for the promotion of women’s health; doctrine is to avoid pregnancy, with withdrawal should it occur. Between 1990 and 1994, an NIAID-sponsored trial, ACTG 076, was targeted at antiretroviral naive, HIV-infected pregnant women. Zidovudine or placebo was given during the later trimesters and intrapartum, and to infants post-partum. Transmission rates were 8·3% and 25·5%, respectively—a 67·5% risk reduction with zidovudine.1 Reported cases of perinatally acquired AIDS in the USA have subsequently declined strikingly since the peak in 1992, 2 despite an increasing incidence of HIV infection among women of childbearing age. On Jan 14, 1997, an NIH panel reaffirmed the USPHS recommendation to treat HIV-infected pregnant women with zidovudine. Currently, this drug, which lowers viral load two-fold to ten-fold in antiretroviral naive patients, is regarded as suboptimum treatment compared with combinations of newer agents which lower viral load by 100-fold to 1000-fold, often to undetectable levels, with appreciable clinical benefit.3 A
recent analysis of the ACTG 076 data revealed the transmission rates were lower among mothers with a lower viral load.4 We can only hope that more potent regimens will further reduce perinatal transmission rates without adverse effects on the fetus. The Antiretroviral Pregnancy Registry5 was initiated in 1989 to provide an early signal of teratogenicity associated with prenatal use of antiretroviral agents. Initially for zidovudine, it has been expanded to include voluntarily reported outcomes of pregnancies among patients receiving zalcitabine, didanosine, stavudine, lamivudine, saquinavir, and most recently indinavir. So far, there has been no increase in the number of birth defects among the prospective reports of first-trimester zidovudine exposures when compared with that expected in the general population. Zidovudine use in any trimester led to a risk of 3·8% birth defects with no uniqueness of pattern to suggest a common cause. Although data for other drugs are limited, there have been no birth defects reported from exposure to them, either alone or in combinations, among prospectively reported pregnancies. Although insufficient data exist to conclude that antiretroviral drugs are not teratogenic,5 we believe that the benefit/risk ratio favours allowing HIVinfected pregnant women enrolled in clinical trials with potent antiretrovirals to continue participation, if they choose to do so. Those who were withdrawn would probably seek treatment with the same or similar agents, without the advantages of careful observation and the accumulation of important information. Supported in part by NIAID Grant No. A125924.
*Julie E Mangino, Robert J Fass Ohio State University Medical Center, Columbus, OH 43210, USA
1
2
3
4
5
Connor EM, Sperling RS, Gelber RG, et al. Reduction of maternal-infant transmission of HIV with zidovudine treatment. N Engl J Med 1994; 331: 1173–80. AIDS among children—United States, 1996. MMWR Morb Mortal Wkly Rep 1996; 45: 1005–10. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996. JAMA 1996; 276: 146–54. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 1996; 335: 1621–29. A collaborative project managed by: BristolMyers Squibb Co, Glaxo Wellcome, Hoffman-La Roche Inc, and Merck and Co, Inc. Antiretroviral pregnancy registry for didanosine, indinavir, lamivudine, saquinavir, stavudine, zalcitabine, and zidovudine. Interim report—Jan 1, 1989, to Dec 31, 1996.
Vol 350 • July 12th, 1997
More growth-chart confusion SIR—WHO has published new reference figures for mid-upper-arm circumference (MUAC), based on data collected by the US National Center for Health Statistics (NCHS).1,2 The timing is curious—29 years after the publication by Jelliffe of the previous standard for MUAC,3 22 years after much of the NCHS data were collected, 17 years after WHO adopted NCHS data for weight-for-age, height-for-age, and weight-for-height,4 and at a time when WHO is initiating the development of a new single international reference for anthropometry of young children.1 MUAC, thought of as an index of wasting, is commonly measured with a tape and a single cut-off for children between 1 and 5 years of age. Many have challenged the assumption of age independence; however, although other reference figures have been published for developed countries, reservations have been expressed about their applicability to populations with lower levels of fatness. The NCHS MUAC-for-age reference seems to have been selected by WHO on the grounds of consistency with the NCHS/WHO weight and height reference. However, WHO concludes that the NCHS/WHO reference itself has such “significant technical drawbacks” that “it should be updated or replaced in the near future”; in particular, a new reference for infants should reflect WHO feeding recommendations.1 If the same were true for MUAC, the new reference will have a short life. WHO and the US Centers for Disease Control and Prevention are preparing NCHS reference data for MUAC-for-height, intended as a proxy for MUAC-for-age in situations in which age is not known? Nothing is known about the changing relation with age between MUAC-for-age, MUACfor-height, and weight-for-height in the NCHS population nor in populations which are breast fed or which have high levels of wasting. Until such information is available, it is difficult to know the equivalence between assessments on the basis of any of these indices and between different populations and age groups. Yet international references are usually justified as means of standardising anthropometric indices to facilitate comparisons of nutritional status between communities. A change of reference can cause confusion on the ground. Lessons should be learned from the problems introduced by the change from the Harvard standard to the NCHS/WHO
150
reference, and by the move from calculating indices as percentages of the median to standard deviation scores.5 For the time being, if MUAC is to be measured, the simplicity and transparency of cautious use of an ageindependent cut-off, however flawed, remains more attractive than an unexplored MUAC-for-age or MUACfor-height reference. Sarah B J Macfarlane Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
1
2
3
4
5
WHO Expert Committee. Physical status: the use and interpretation of anthropometry. WHO Tech Rep Ser 1995, no 854. de Onis M, Yip R, Mei Z. The development of MUAC-for-age reference data recommended by the WHO Expert Committee. Bull WHO 1997; 75: 11–18. Jelliffe DB. The assessment of the nutritional status of the community. WHO Monog Ser 1966; no 53. WHO. A growth chart for international use in maternal and child health care. Geneva: WHO, 1978. Grant K, Seaman J. Growth chart confusion. Lancet 1979; ii: 102.
Inclusion of women in clinical trials of antiretroviral agents for HIV/AIDS during pregnancy SIR—In the past, women of childbearing age were excluded from clinical trials of new drugs for fear of pregnancy and subsequent fetal damage. Inclusion of women in such trials is now regarded as essential for the promotion of women’s health; doctrine is to avoid pregnancy, with withdrawal should it occur. Between 1990 and 1994, an NIAID-sponsored trial, ACTG 076, was targeted at antiretroviral naive, HIV-infected pregnant women. Zidovudine or placebo was given during the later trimesters and intrapartum, and to infants post-partum. Transmission rates were 8·3% and 25·5%, respectively—a 67·5% risk reduction with zidovudine.1 Reported cases of perinatally acquired AIDS in the USA have subsequently declined strikingly since the peak in 1992, 2 despite an increasing incidence of HIV infection among women of childbearing age. On Jan 14, 1997, an NIH panel reaffirmed the USPHS recommendation to treat HIV-infected pregnant women with zidovudine. Currently, this drug, which lowers viral load two-fold to ten-fold in antiretroviral naive patients, is regarded as suboptimum treatment compared with combinations of newer agents which lower viral load by 100-fold to 1000-fold, often to undetectable levels, with appreciable clinical benefit.3 A
recent analysis of the ACTG 076 data revealed the transmission rates were lower among mothers with a lower viral load.4 We can only hope that more potent regimens will further reduce perinatal transmission rates without adverse effects on the fetus. The Antiretroviral Pregnancy Registry5 was initiated in 1989 to provide an early signal of teratogenicity associated with prenatal use of antiretroviral agents. Initially for zidovudine, it has been expanded to include voluntarily reported outcomes of pregnancies among patients receiving zalcitabine, didanosine, stavudine, lamivudine, saquinavir, and most recently indinavir. So far, there has been no increase in the number of birth defects among the prospective reports of first-trimester zidovudine exposures when compared with that expected in the general population. Zidovudine use in any trimester led to a risk of 3·8% birth defects with no uniqueness of pattern to suggest a common cause. Although data for other drugs are limited, there have been no birth defects reported from exposure to them, either alone or in combinations, among prospectively reported pregnancies. Although insufficient data exist to conclude that antiretroviral drugs are not teratogenic,5 we believe that the benefit/risk ratio favours allowing HIVinfected pregnant women enrolled in clinical trials with potent antiretrovirals to continue participation, if they choose to do so. Those who were withdrawn would probably seek treatment with the same or similar agents, without the advantages of careful observation and the accumulation of important information. Supported in part by NIAID Grant No. A125924.
*Julie E Mangino, Robert J Fass Ohio State University Medical Center, Columbus, OH 43210, USA
1
2
3
4
5
Connor EM, Sperling RS, Gelber RG, et al. Reduction of maternal-infant transmission of HIV with zidovudine treatment. N Engl J Med 1994; 331: 1173–80. AIDS among children—United States, 1996. MMWR Morb Mortal Wkly Rep 1996; 45: 1005–10. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996. JAMA 1996; 276: 146–54. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 1996; 335: 1621–29. A collaborative project managed by: BristolMyers Squibb Co, Glaxo Wellcome, Hoffman-La Roche Inc, and Merck and Co, Inc. Antiretroviral pregnancy registry for didanosine, indinavir, lamivudine, saquinavir, stavudine, zalcitabine, and zidovudine. Interim report—Jan 1, 1989, to Dec 31, 1996.
Vol 350 • July 12th, 1997