C ORR ES POND ENCE
Correspondence
Folic Acid Antagonists during Pregnancy and Risk of Birth Defects To the Editor: Hernández-Díaz and colleagues (Nov. 30 issue)1 suggest that the use of folic acid antagonists in pregnant women increases the risk of oral clefts and cardiovascular and urinary tract defects in their infants. The possible role of trimethoprim in increasing the risk of malformations of the cardiovascular and urinary systems has practical implications. Trimethoprim is one of the most commonly prescribed drugs in the United States. Furthermore, it is commonly given in the early stages of pregnancy, often before women are aware that they are pregnant. In their report, Hernández-Díaz and colleagues group together data on trimethoprim, triamterene, and sulfasalazine. We wonder why the data on trimethoprim were not highlighted and reported separately, considering the widespread use of this drug. YONA AMITAI, M.D. ALEX LEVENTHAL, M.D., M.P.H. Ministry of Health 91010 Jerusalem, Israel 1. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-14.
To the Editor: A key principle of case–control studies in pharmacoepidemiology is that the control subjects should be “comparable with the cases in all relevant ways, except that they do not have the illness under study.”1 In examining the association of folic acid antagonists with three types of birth defect, Hernández-Díaz et al. excluded infants with “chromosomal or mendelian anomalies” from the group of case subjects but included many infants with such defects in the control group.
This imbalance could have influenced the study’s results if exposure to the study drugs were associated with these genetic conditions. For example, couples with an increased risk of having an infant with a chromosomal or mendelian defect might have sought additional medical attention before conception and then been advised not to take folic acid antagonists and other drugs thought to worsen birth outcome. (The study included infants born through 1998, after the importance of folic acid in reducing the occurrence of birth defects was widely recognized.2) Lower rates of exposure to folic acid antagonist drugs among the control infants because of the medical advice received by their mothers would have resulted in an overestimation of the effect of the drugs. To address this concern, the authors should demonstrate either that the mothers of the two types of control infants had equivalent use of the study drugs or should present data showing that the exclusion of infants with chromosomal or mendelian defects from the control group would not alter the analysis. JOSHUA M. SHARFSTEIN, M.D. Boston University School of Medicine Boston, MA 02118 1. Jick H, Vessey MP. Case-control studies in the evaluation of druginduced illness. Am J Epidemiol 1978;107:1-7. 2. Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847-52.
To the Editor: Hernández-Díaz et al. describe an association between oral clefts and cardiovascular and urinary tract defects and the maternal ingestion of dihydrofolate reductase inhibitors, such as trimethoprim, in early pregnancy. These findings should be of interest to those charged with the control of the AIDS epidemic in Africa. Prophylactic trimethoprim–sulfamethoxazole has been endorsed by the Joint United Nations Programme on HIV/ AIDS as part of the “minimum package of care” for adults and children in Africa who have human immunodeficiency virus (HIV) infection or AIDS.1 Pregnant women are not exempted from this recommendation. Several issues of concern have already been raised about the routine provision of prophylactic trimethoprim–sulfa-
INSTRUCTIONS FOR LETTERS TO THE EDITOR Letters to the Editor are considered for publication (subject to editing and abridgment) provided they do not contain material that has been submitted or published elsewhere. Please note the following: •Your letter must be typewritten and triple-spaced. •Its text, not including references, must not exceed 250 words if it is in reference to a recent Journal article, or 400 words in all other cases (please provide a word count). •It must have no more than five references and one figure or table. •It must not be signed by any more than three authors. •Letters referring to a recent Journal article must be received within four weeks of its publication. •Please include your full address, telephone number, fax number, and e-mail address. •You may send us your letter by standard mail, fax, or e-mail.
Our address: Letters to the Editor • New England Journal of Medicine • 10 Shattuck St. • Boston, MA 02115 Our fax numbers: 617-739-9864 and 617-734-4457 Our e-mail address:
[email protected] We cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. We are unable to provide prepublication proofs. Financial associations or other possible conflicts of interest must be disclosed. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’ s various print and electronic publications and in collections, revisions, and any other form or medium.
N Engl J Med, Vol. 344, No. 12 · March 22, 2001 · www.nejm.org · 933 The New England Journal of Medicine Downloaded from nejm.org on March 16, 2016. For personal use only. No other uses without permission. Copyright © 2001 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
methoxazole to patients in Africa who have AIDS, among them the potential emergence of drug resistance and the possibility that the regimen’s effectiveness may vary with the local incidence of opportunistic infections and with the drug-sensitivity profiles of important bacterial pathogens.2 The possibility that trimethoprim–sulfamethoxazole prophylaxis may increase the incidence of serious birth defects in infants whose protection from the vertical transmission of HIV is still not ensured and whose mothers may not receive periconceptional folate supplementation must now be included in the debate. PAULA E. BRENTLINGER, M.D., M.P.H. Doctors of the World New York, NY 10012 1. Joint United Nations Programme on HIV/AIDS. Provisional WHO/ UNAIDS secretariat recommendations on the use of cotrimoxazole prophylaxis in adults and children living with HIV/AIDS in Africa. (See http: //www.unaids.org/whatsnew/others/cotrimoxazole.html.) 2. Boeree MJ, Harries AD, Zijlstra EE, Taylor TE, Molyneux ME. Co-trimoxazole in HIV-1 infection. Lancet 1999;354:334-5.
To the Editor: We wish to highlight an important finding in the study of Hernández-Díaz et al. — namely, that exposure to folic acid antagonists in the second and third trimesters of pregnancy was not associated with an increased risk of birth defects. This finding has important policy implications for malaria-control programs in Africa. In areas where malaria is endemic and where rates of transmission of Plasmodium falciparum are high, infection in pregnant women is usually asymptomatic. However, malaria infections of the placenta are common and are associated with anemia in the mother and low birth weight in the infant.1 One valuable strategy for the prevention of malaria in pregnant women is preventive intermittent treatment with an effective antimalarial drug. Because resistance of P. falciparum to chloroquine is widespread in Africa, folic acid antagonists such as sulfadoxine– pyrimethamine are mainstays for both prevention and treatment of malaria during pregnancy. Preventive treatment often consists of the directly observed administration of two doses of sulfadoxine–pyrimethamine, one during the second trimester and one early in the third trimester. Because this regimen reduces anemia in the pregnant woman and low birth weight in the newborn,2,3 the World Health Organization recommends it as part of antenatal care. Some African countries have been reluctant to adopt this policy, however, in part because of concern about the safety of sulfadoxine–pyrimethamine during pregnancy. The findings of Hernández-Díaz et al. should reassure policymakers and health care providers about the use of trimethoprim and other folic acid antagonists during the second and third trimesters of pregnancy. ROBERT D. NEWMAN, M.D., M.P.H. MONICA PARISE, M.D. Centers for Disease Control and Prevention Atlanta, GA 30333
BERNARD NAHLEN, M.D. World Health Organization CH-1211 Geneva, Switzerland
1. Steketee RW, Wirima JJ, Campbell CC. Developing effective strategies for malaria prevention programs for pregnant African women. Am J Trop Med Hyg 1996;55:Suppl 1:95-100. 2. Shulman CE, Dorman EK, Cutts F, et al. Intermittent sulphadoxine– pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet 1999;353:632-6. 3. Verhoeff FH, Brabin BJ, Chimsuku L, Kazembe P, Russell WB, Broadhead RL. An evaluation of the effects of intermittent sulfadoxine–pyrimethamine treatment in pregnancy on parasite clearance and risk of low birthweight in rural Malawi. Ann Trop Med Parasitol 1998;92:141-50.
The authors reply: To the Editor: Specific results for trimethoprim are presented in Table 1. These findings are based on relatively few infants and must be evaluated together with results from other studies.1-5 We shared Dr. Sharfstein’s concern about the biased selection of control infants. We originally used three groups of infants as controls: infants with structural malformations, infants with chromosomal malformations, and infants with no malformations. The results in all three groups were similar, and therefore we combined all infants with malforma-
TABLE 1. USE OF TRIMETHOPRIM (COMBINED WITH A SULFONAMIDE) DURING THE SECOND OR THIRD MONTH AFTER THE LAST MENSTRUAL PERIOD IN THE MOTHERS OF INFANTS WITH SELECTED DEFECTS AND IN THE MOTHERS OF CONTROL INFANTS.
VARIABLE
TOTAL NO.
USE OF TRIMETHOPRIM
RELATIVE RISK (95% CI)*
no. (%)
Control Cardiovascular defects Oral clefts Urinary tract defects
8387 3870 1962 1100
6 12 3 1
(0.1) (0.3) (0.2) (0.1)
1.0 4.2 (1.5–11.5) —† —†
*The relative risk has been adjusted for the year of the interview, the geographic region, maternal age, and the presence or absence of diabetes mellitus, multivitamin supplementation, and urinary tract or other infections during the first trimester of pregnancy. CI denotes confidence interval. †We estimated the relative risk only when there were at least five case infants who were exposed during the second or third month.
tions into a single control group. Furthermore, the risks were similar when we excluded women with either previous affected pregnancies or a family history of birth defects, suggesting that preferential advice to couples who are known to have an increased risk does not explain the results. We agree with Dr. Brentlinger and with Dr. Newman and colleagues that the risk of birth defects (and of other potential adverse effects) must be weighed against the benefits of these drugs in specific populations. Although it is biologically plausible that pyrimethamine would not increase the risk of the types of birth defects we studied when taken after the etiologically relevant period, too few women
934 · N Engl J Med, Vol. 344, No. 12 · March 22, 2001 · www.nejm.org The New England Journal of Medicine Downloaded from nejm.org on March 16, 2016. For personal use only. No other uses without permission. Copyright © 2001 Massachusetts Medical Society. All rights reserved.
C ORR ES POND ENCE
in our study had taken pyrimethamine to enable us to evaluate this specific folic acid antagonist. SONIA HERNÁNDEZ-DÍAZ, M.D., DR.P.H. ALLEN A. MITCHELL, M.D. Boston University School of Public Health Brookline, MA 02446 1. Brumfitt W, Pursell R. Trimethoprim–sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis 1973;128:Suppl:S657-S663. 2. Bailey RR. Single-dose antibacterial treatment for bacteriuria in pregnancy. Drugs 1984;27:183-6. 3. Czeizel A. A case-control analysis of the teratogenic effects of co-trimoxazole. Reprod Toxicol 1990;4:305-13. 4. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to pregnancy use of folic acid antagonists. Am J Epidemiol (in press). 5. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore: Williams & Wilkins, 1998.
Screening for Lung Cancer To the Editor: The review by Patz et al. (Nov. 30 issue)1 on screening for lung cancer omits mention of a major historical change over the past three decades: the most common cell type has shifted from squamous-cell to adenocarcinoma — a shift that appears to result from the physicochemical changes in late-20th-century cigarette smoke (e.g., increased levels of tobacco-specific nitrosamines).2 For example, 21 of the 27 (78 percent) peripheral stage I carcinomas detected by computed tomography (CT) among the 1000 smokers in the recent Early Lung Cancer Action Project screening study were adenocarcinoma, 3 (11 percent) were adenosquamous, and 1 (4 percent) was squamous.3 In the lung, primary adenocarcinoma grows more slowly than squamous carcinoma; data on doubling time indicate that, on average, adenocarcinoma grows from 1 cm in diameter to 3 cm in 35 months and that squamous carcinoma grows that much in 16 months.4 The shift to a more slowly growing cell type lengthens the window of opportunity for presymptomatic diagnosis. The surgical literature amply documents a five-year survival among persons with resected stage IA (
