High prevalence of micropenis in 2710 male newborns from an intensive-use pesticide area of Northeastern Brazil

International Journal of Andrology

Volumn 35, Issue 3, 2012, Pages 253-264

  Gaspari, L ^a,b   Sampaio, D R ^c,d   Paris, F ^a,b   Audran, F ^b   Orsini, M ^e   Neto, J B ^c   Sultan, C ^a,b  

^a HÔPITAL ARNAUD DE VILLENEUVE   (France)

^b LAPEYRONIE HOSPITAL   (France)

^c FEDERAL UNIVERSITY OF RIO GRANDE DO NORTE   (Brazil)

^d FEDERAL UNIVERSITY OF CAMPINA GRANDE   (Brazil)

^e NÎMES UNIVERSITY HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN RECEPTOR; ENDOCRINE DISRUPTOR; PESTICIDE; TESTOSTERONE;

ARTICLE; BRAZIL; CLINICAL ARTICLE; CRYPTORCHISM; DISEASE ASSOCIATION; ENDOCRINE FUNCTION; ENVIRONMENTAL EXPOSURE; GENE MUTATION; HEREDITY; HUMAN; HYPOSPADIAS; MALE; MICROPENIS; NEWBORN; OCCUPATIONAL EXPOSURE; PRENATAL EXPOSURE; PREVALENCE; PRIORITY JOURNAL; QUESTIONNAIRE;

BRAZIL; CRYPTORCHIDISM; ENDOCRINE DISRUPTORS; ENVIRONMENTAL EXPOSURE; FEMALE; GENITAL DISEASES, MALE; HUMANS; HYPOSPADIAS; INFANT; INFANT, NEWBORN; MALE; MATERNAL EXPOSURE; PATERNAL EXPOSURE; PENIS; PESTICIDES; PREGNANCY; PREVALENCE;

EID: 84861455815     PISSN: 01056263     EISSN: 13652605     Source Type: Journal    
DOI: 10.1111/j.1365-2605.2011.01241.x     Document Type: Article

References (104)

1. Abdullah NA, Pearce MS, Parker L, Wilkinson JR, Jaffray B & McNally RJ. (2007) Birth prevalence of cryptorchidism and hypospadias in northern England, 1993-2000. Arch Dis Child 92, 576-579.
2. Acerini CL, Miles HL, Dunger DB, Ong KK & Hughes IA. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Arch Dis Child 94, 868-872.
3. Akre O, Lipworth L, Cnattingius S, Sparen P & Ekbom A. (1999) Risk factor patterns for cryptorchidism and hypospadias. Epidemiology 10, 364-369.
4. Anderson HA & Wolff MS. (2000) Environmental contaminants in human milk. J Expo Anal Environ Epidemiol 10, 755-760.
5. Arteaga CE. (1993) Prevalencia y factores asociados a las anomalias congénitas y enfermedades de instalación prenatal en el Instituto Materno Infantil de Bogotá (tesis). Universidad Nacional de Colombia, Bogotá.
6. Barros FC, Huttly SR, Victora CG, Kirkwood BR & Vaughan JP. (1992) Comparison of the causes and consequences of prematurity and intrauterine growth retardation: a longitudinal study in southern Brazil. Pediatrics 90, 238-244.
7. Baskin LS, Himes K & Colborn T. (2001) Hypospadias and endocrine disruption: is there a connection? Environ Health Perspect 109, 1175-1183.
8. Berkowitz GS, Lapinski RH, Dolgin SE, Gazella JG, Bodian CA & Holzman IR. (1993) Prevalence and natural history of cryptorchidism. Pediatrics 92, 44-49.
9. Berkowitz GS, Lapinski RH, Godbold JH & Holzman IR. (1995) Maternal and neonatal risk factors for cryptorchidism. Epidemiology 6, 127-131.
10. Bhangoo A, Paris F, Philibert P, Audran F, Ten S & Sultan C. (2010) Isolated micropenis reveals partial androgen insensitivity syndrome confirmed by molecular analysis. Asian J Androl 12, 561-566.
11. Bianca S, Li Volti G, Caruso-Nicoletti M, Ettore G, Barone P, Lupo L & Li Volti S. (2003) Elevated incidence of hypospadias in two sicilian towns where exposure to industrial and agricultural pollutants is high. Reprod Toxicol 17, 539-545.
12. Boisen KA, Kaleva M, Main KM, Virtanen HE, Haavisto AM, Schmidt IM et al. (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet 363, 1264-1269.
13. Boisen KA, Chellakooty M, Schmidt IM, Kai CM, Damgaard IN, Suomi AM, Toppari J, Skakkebaek NE & Main KM. (2005) Hypospadias in a cohort of 1072 Danish newborn boys: prevalence and relationship to placental weight, anthropometrical measurements at birth, and reproductive hormone levels at three months of age. J Clin Endocrinol Metab 90, 4041-4046.
14. Brock JW, Melnyk LJ, Caudill SP, Needham LL & Bond AE. (1998) Serum levels of several organochlorine pesticides in farmers correspond with dietary exposure and local use history. Toxicol Ind Health 14, 275-289.
15. Campaña H, Pawluk MS, López Camelo JS & Grupo de Estudio del ECLAMC. (2010) Prevalencia al nascimiento de 27 anomalías congénitas seleccionadas, en 7 regiones geográficas de la Argentina. Arch Argent Pediatr 108, 409-417.
16. Canning DA. (1999) Hypospadias trends in two US surveillance systems. Rise in prevalence of hypospadias. J Urol 161, 366.
17. Carbone P, Giordano F, Nori F, Mantovani A, Taruscio D, Lauria L & Figa-Talamanca I. (2006) Cryptorchidism and hypospadias in the Sicilian district of Ragusa and the use of pesticides. Reprod Toxicol 22, 8-12.
18. Castilla EE, Campaña H, Camelo JS & ECLAMC ECOTERAT Group. (2000) Economic activity and congenital anomalies: an ecologic study in Argentina. Environ Health Perspect 108, 193-197.
19. Christiansen S, Scholze M, Axelstad M, Boberg J, Kortenkamp A & Hass U. (2008) Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat. Int J Androl 31, 241-248.
20. Clark RL, Anderson CA, Prahalada S, Robertson RT, Lochry EA, Leonard YM, Stevens JL & Hoberman AM. (1993) Critical developmental periods for effects on male rat genitalia induced by finasteride, a 5 alpha-reductase inhibitor. Toxicol Appl Pharmacol 119, 34-40.
21. Cortes D, Kjellberg EM, Breddam M & Thorup J. (2008) The true incidence of cryptorchidism in Denmark. J Urol 179, 314-318.
22. Czeizel A, Toth J & Czvenits E. (1986) Increased birth prevalence of isolated hypospadias in Hungary. Acta Paediatr Hung 27, 329-337.
23. Edwards TM, Moore BC & Guillette LJ Jr. (2006) Reproductive dysgenesis in wildlife: a comparative view. Int J Androl 29, 109-121.
24. Elder JS. (1998) Congenital anomalies of the genitalia. In: Campbell's Urology, 7th edn (eds PC Walsh, AB Retik, ED Vaughan & AJ Wein .). Hardcover; W.B Saunders Company, Orlando, USA. chap. 69, pp. 2120-2143. W.B. Saunders Company, Philadelphia.
25. Elert A, Jahn K, Heidenreich A & Hofmann R. (2003) The familial undescended testis. Klin Padiatr 215, 40-45.
26. Feldman KW & Smith DW. (1975) Fetal phallic growth and penile standards for newborn male infants. J Pediatr 86, 395-398.
27. Fernandez MF, Olmos B, Granada A, Lopez-Espinosa MJ, Molina-Molina JM, Fernandez JM, Cruz M, Olea-Serrano F & Olea N. (2007) Human exposure to endocrine-disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias: a nested case-control study. Environ Health Perspect 115, 8-14.
28. Flatau E, Josefsberg Z, Reisner SH, Bialik O & Iaron Z. (1975) Letter: Penile size in the newborn infant. J Pediatr 87, 663-664.
29. Foster W, Chan S, Platt L & Hughes C. (2000) Detection of endocrine disrupting chemicals in samples of second trimester human amniotic fluid. J Clin Endocrinol Metab 85, 2954-2957.
30. Francois R, David L & Gugliemi A. (1980) Micropenis: survey of 88 cases (author's transl). Ann Pediatr (Paris) 27, 123-128.
31. Gabrich PN, Vasconcelos JSP, Damião R & da Silva EA. (2007) Penile anthropometry in Brazilian children and adolescents. J Pediatr (Rio J) 83, 441-446.
32. Galera MF, Serafini C, de Campos Matos T, Camacho P, Araújo C, Duarte EC & Borsatto Galera B. (2010) Vigilância epidemiológica de anomalias conge nitas em um Hospital Universitário de Mato Grosso, Brasil. Pediatria (Sãn Paulo) 32(1):28-36.
33. Garcia H, Salguero GA, Moreno J, Arteaga C & Giraldo A. (2003) Fracuencia de anomalias congenitas en el Instituto Materno Infantil de Bogota. Biomedica 23, 161-172.
34. Gaspari L, Paris F, Philibert P, Audran F, Orsini M, Servant N, Maïmoun L, Kalfa N & Sultan C. (2011a) "Idiopathic" partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine-disruptor chemicals? Eur J Endocrinol 165, 579-587.
35. Gaspari L, Paris F, Jandel C, Kalfa N, Orsini M, Daurès JP & Sultan C. (2011b) Prenatal environmental risk factors for genital malformations in a population of 1, 442 French male newborns: a nested case-control study. Hum Reprod 26, 3155-3162.
36. Ghirri P, Ciulli C, Vuerich M, Cuttano A, Faraoni M, Guerrini L, Spinelli C, Tognetti S & Boldrini A. (2002) Incidence at birth and natural history of cryptorchidism: a study of 10, 730 consecutive male infants. J Endocrinol Invest 25, 709-715.
37. Ghirri P, Scaramuzzo RT, Bertelloni S, Pardi D, Celandroni A, Cocchi G et al. (2009) Prevalence of hypospadias in Italy according to severity, gestational age and birthweight: an epidemiological study. Ital J Pediatr 35, 18.
38. González-Andrade F & López-Pulles R. (2010) Congenital malformations in Ecuadorian children: urgent need to create a national Registry of Birth Defects. Appl Clin Genet 3, 29-39.
39. Gray LE Jr, Wilson VS, Stoker T, Lambright C, Furr J, Noriega N, Howdeshell K, Ankley GT & Guillette L. (2006) Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals. Int J Androl 29, 96-104. discussion 105-108.
40. Guillette LJ Jr & Gunderson MP. (2001) Alterations in development of reproductive and endocrine systems of wildlife populations exposed to endocrine-disrupting contaminants. Reproduction 122, 857-864.
41. Gulledge CC, Burow ME & McLachlan JA. (2001) Endocrine disruption in sexual differentiation and puberty. What do pseudohermaphroditic polar bears have to do with the practice of pediatrics?. Pediatr Clin North Am 48, 1223-1240.
42. Hayes TB, Collins A, Lee M, Mendoza M, Noriega N, Stuart AA & Vonk A. (2002) Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses. Proc Natl Acad Sci USA 99, 5476-5480.
43. Husmann DA. (2002) Micropenis: an animal model and its human correlates. Adv Exp Med Biol 511, 41-54. discussion 54-56.
44. International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). (2009) Annual Report with Data for 2007.
45. Jacobson JL, Fein GG, Jacobson SW, Schwartz PM & Dowler JK. (1984) The transfer of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) across the human placenta and into maternal milk. Am J Public Health 74, 378-379.
46. John Radcliffe Hospital Cryptorchidism Study Group (J.R.H. Study Group). (1992) Cryptorchidism: a prospective study of 7500 consecutive male births, 1984-8. Arch Dis Child 67, 892-899.
47. Kalfa N, Liu B, Klein O, Audran F, Wang MH, Mei C, Sultan C & Baskin LS. (2008a) Mutations of CXorf6 are associated with a range of severities of hypospadias. Eur J Endocrinol 159, 453-458.
48. Kalfa N, Liu B, Klein O, Wang MH, Cao M & Baskin LS. (2008b) Genomic variants of ATF3 in patients with hypospadias. J Urol 180, 2183-2188. discussion 2188.
49. Kalfa N, Philibert P & Sultan C. (2009) Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation? Int J Androl 32, 187-197.
50. Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP & Sultan C. (2011) Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertil Steril 95, 2574-2577.
51. Koifman S, Koifman RJ & Meyer A. (2002) Human reproductive system disturbances and pesticide exposure in Brazil. Cad Saude Publica 18, 435-445.
52. Kojima Y, Kohri K & Hayashi Y. (2010) Genetic pathway of external genitalia formation and molecular etiology of hypospadias. J Pediatr Urol 6, 346-354.
53. Kortenkamp A. (2008) Low dose mixture effects of endocrine disrupters: implications for risk assessment and epidemiology. Int J Androl 31, 233-240.
54. Lee PA, Mazur T, Danish R, Amrhein J, Blizzard RM, Money J & Migeon CJ. (1980) Micropenis. I. Criteria, etiologies and classification. Johns Hopkins Med J 146, 156-163.
55. Ludwig G. (1999) Micropenis and apparent micropenis - a diagnostic and therapeutic challenge. Andrologia 31, 27-30.
56. MaÏmoun L, Philibert P, Cammas B, Audran F, Pienkowski C, Kurtz F, Heinrich C, Cartigny M & Sultan C. (2010) Undervirilization in XY newborns may hide a 5α-reductase deficiency: report of three new SRD5A2 gene mutations. Int J Androl 33, 841-847.
57. Main KM, Skakkebaek NE, Virtanen HE & Toppari J. (2010) Genital anomalies in boys and the environment. Best Pract Res Clin Endocrinol Metab 24, 279-289.
58. Martin OV, Shialis T, Lester JN, Scrimshaw MD, Boobis AR & Voulvoulis N. (2008) Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis. Environ Health Perspect 116, 149-157.
59. Mazen I, El-Ruby M, Kamal R, El-Nekhely I, El-Ghandour M, Tantawy S & El-Gammal M. (2010) Screening of genital anomalies in newborns and infants in two Egyptian governorates. Horm Res Paediatr 73, 438-442.
60. Minuci EG & Márcia Furquim de Almeida MF. (2009) Birth weight intra-urban differentials in the city of São Paulo. Rev Saúde Pública 43:1-9.
61. Money J, Lehne GK & Pierre-Jerome F. (1984) Micropenis: adult follow-up and comparison of size against new norms. J Sex Marital Ther 10, 105-116.
62. Monteleone Neto R, Castilla EE & Paz JE. (1981) Hypospadias: an epidemiological study in Latin America. Am J Mad Genet 10, 5-19.
63. Montes LPB, Waliszewski S, Hernández-Valero M, Sanín-Aguirre L, Infanzón-Ruiz RM & Jañas AG. (2010) Exposición prenatal a los plaguicidas organoclorados y criptorquidia. Ciênc Saúde Coletiva 15, 1169-1174.
64. de Muinck Keizer-Schrama SM. (1987) Consensus on management of the undescended testis. Ned Tijdschr Geneeskd 131, 1817-1821.
65. Nair A, Mandapati R, Dureja P & Pillai MK. (1996) DDT and HCH load in mothers and their infants in Delhi, India. Bull Environ Contam Toxicol 56, 58-64.
66. Nassar N, Bower C & Barker A. (2007) Increasing prevalence of hypospadias in Western Australia, 1980-2000. Arch Dis Child 92, 580-584.
67. Nelson CP, Park JM, Wan J, Bloom DA, Dunn RL & Wei JT. (2005) The increasing incidence of congenital penile anomalies in the United States. J Urol 174, 1573-1576.
68. de Nobrega FJ, Lopez FA & Segre CAM. (1989) Anthropometry in Brazilian Newborn Infants: Studies of Association with Some Maternal Factors. In: Intrauterine Growth Retardation, (ed Jacques Senlerre .). Nestle Nutrition Workshop Series. Vol. 18. Nestec Ltd. Vevey/Raven Press, Ltd., New York.
69. Paris F, Servant N, Terouanne B, Balaguer P, Nicolas JC & Sultan C. (2002) A new recombinant cell bioassay for ultrasensitive determination of serum estrogenic bioactivity in children. J Clin Endocrinol Metab 87, 791-797.
70. Paris F, De Ferran K, Bhangoo A, Ten S, Lahlou N, Audran F, Servant N, Poulat F, Philibert P & Sultan C. (2011) Isolated 'idiopathic' micropenis: hidden genetic defects? Int J Androl 34, e518-e525.
71. Paulozzi LJ, Erickson JD & Jackson RJ. (1997) Hypospadias trends in two US surveillance systems. Pediatrics 100, 831-834.
72. Pierik FH, Burdorf A, Nijman JM, de Muinck Keizer-Schrama SM, Juttmann RE & Weber RF. (2002) A high hypospadias rate in The Netherlands. Hum Reprod 17, 1112-1115.
73. Pierik FH, Burdorf A, Deddens JA, Juttmann RE & Weber RF. (2004) Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect 112, 1570-1576.
74. Pierik FH, Burdorf A, de Muinck Keizer-Schrama SM, Wolffenbuttel KP, Nijman JM, Juttmann RE & Weber RF. (2005) The cryptorchidism prevalence among infants in the general population of Rotterdam, the Netherlands. Int J Androl 28, 248-252.
75. Porter MP, Faizan MK, Grady RW & Mueller BA. (2005) Hypospadias in Washington State: maternal risk factors and prevalence trends. Pediatrics 115, e495-E499.
76. Preiksa RT, Zilaitiene B, Matulevicius V, Skakkebaek NE, Petersen JH, Jorgensen N & Toppari J. (2005) Higher than expected prevalence of congenital cryptorchidism in Lithuania: a study of 1204 boys at birth and 1year follow-up. Hum Reprod 20, 1928-1932.
77. Sant'Ana LS, Vassilieff I & Jokl L. (1989) Levels of organochlorine insecticides in milk of mothers from urban and rural areas of Botucatu, SP, Brazil. Bull Environ Contam Toxicol 42, 911-918.
78. da Silva Costa CM, Granado Nogueira da Gama S & do Carmo Leal M. (2006) Congenital malformations in Rio de Janeiro, Brazil: prevalence and associated factors. Cad Saúde Pública 22, 2423-2431.
79. Silva AA, Barbieri MA, Gomes UA & Bettiol H. (1998) Trends in low birth weight: a comparison of two birth cohorts separated by a 15-year interval in Ribeirão Preto, Brazil. Bull World Health Org 76, 73-84.
80. Silva M, de Castro Felismino D & Coelho Dantas I. (2008) Malformações fetais: estudo retrospectivo na maternidade da fundação assistencial da Paraíba no município de Campina Grande. Rev Biol Ciênc Terra 8, 232-239.
81. Singh I & Glassberg K. (1993) Congenital anomalies of the penis. In: The Penis (eds AI Hashmat & S Das .), pp. 25-34. Lea & Febiger, Philadelphia.
82. Skakkebaek NE, Rajpert-De Meyts E & Main KM. (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16, 972-978.
83. Smith D. (1999) Worldwide trends in DDT levels in human breast milk. Int J Epidemiol 28, 179-188.
84. Sonawane BR. (1995) Chemical contaminants in human milk: an overview. Environ Health Perspect 103, 197-205.
85. Sultan C, Balaguer P, Terouanne B, Georget V, Paris F, Jeandel C, Lumbroso S & Nicolas J. (2001a) Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation. Mol Cell Endocrinol 178, 99-105.
86. Sultan C, Paris F, Terouanne B, Balaguer P, Georget V, Poujol N, Jeandel C, Lumbroso S & Nicolas JC. (2001b) Disorders linked to insufficient androgen action in male children. Hum Reprod Update 7, 314-322.
87. Sultan C, Paris F, Jeandel C, Lumbroso S, Galifer RB & Picaud JC. (2004) Ambiguous genitalia in the newborn: diagnosis, etiology and sex assignment. Endocr Dev 7, 23-38.
88. Thong M, Lim C & Fatimah H. (1998) Undescended testes: incidence in 1, 002 consecutive male infants and outcome at 1 year of age. Pediatr Surg Int 13, 37-41.
89. Toppari J & Skakkebaek NE. (1998) Sexual differentiation and environmental endocrine disrupters. Baillieres Clin Endocrinol Metab 12, 143-156.
90. Toppari J, Virtanen HE, Main KM & Skakkebaek NE. (2010) Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birth Defects Res A: Clin Mol Teratol 88, 910-919.
91. Van den Driesche S, Scott HM, Macleod DJ, Fisken M, Walker M & Sharpe RM. (2011) Relative importance of prenatal and postnatal androgen action in determining growth of the penis and anogenital distance in the rat before, during and after puberty. Int J Androl 34, e578-e586.
92. Velasquez-Urzola A, Leger J, Aigrain Y & Czernichow P. (1998) Hypoplasia of the penis: etiologic diagnosis and results of treatment with delayed-action testosterone. Arch Pediatr 5, 844-850.
93. Vidaeff AC & Sever LE. (2005) In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence. Reprod Toxicol 20, 5-20.
94. Virtanen HE, Kaleva M, Haavisto AM, Schmidt IM, Chellakooty M, Main KM, Skakkebaek NE & Toppari J. (2001) The birth rate of hypospadias in the Turku area in Finland. APMIS 109, 96-100.
95. Vos JG, Dybing E, Greim HA, Ladefoged O, Lambre C, Tarazona JV, Brandt I & Vethaak AD. (2000) Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation. Crit Rev Toxicol 30, 71-133.
96. Waliszewski SM, Aguirre AA, Infanzon RM & Siliceo J. (2000) Carry-over of persistent organochlorine pesticides through placenta to fetus. Salud Publica Mex 42, 384-390.
97. Weidner IS, Moller H, Jensen TK & Skakkebaek NE. (1999) Risk factors for cryptorchidism and hypospadias. J Urol 161, 1606-1609.
98. Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB & Sharpe RM. (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118, 1479-1490.
99. Welsh M, MacLeod DJ, Walker M, Smith LB & Sharpe RM. (2010) Critical androgen-sensitive periods of rat penis and clitoris development. Int J Androl 33, e144-e152.
100. Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD & Tashiro M. (1982) Fetal growth and perinatal viability in California. Obstet Gynecol 159, 624-632.
101. World Health Organization Expert Committee. (1995) Physical Status: The Use and Interpretation of Anthropometry. World Health Organization Expert Committee, Geneva (WHO-Technical Report Series, 854).
102. Yiee JH & Baskin LS. (2010) Environmental factors in genitourinary development. J Urol 184, 34-41.
103. Zambonato AMK, Pinheiro RT, Horta BL & Tomasi E. (2004) Risk factors for small-for-gestational-age births among infants in Brazil. Rev Saude Publica 38, 24-29.
104. Zarante Montoya I, Castillo MC, García N, Suárez F, Gutiérrez CA & Umaña A. (2002) Análisis clínico epidemiológico de factores asociados a malformaciones congénitas ECLAMC - Hospital Universitario San Ignacio junio-diciembre de 2001. Univ. Med 43:121-127.