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Risk of Hypospadias in Newborn Infants Exposed to Valproic Acid During the First Trimester of Pregnancy

A Case-Control Study in Spain

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Abstract

Background: Hypospadias is one of the most frequently occurring genital anomalies described in infants prenatally exposed to valproic acid (VA). However, to our knowledge, only one publication has studied a potential causal relationship between VA and hypospadias, only estimating the unadjusted global risk. Here we present the results of a multivariate case-control study aimed at analysing and quantifying the specific risk of hypospadias in newborn infants exposed to VA during the first trimester of pregnancy.

Methods: The data analysed here were derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC), an ongoing, hospital-based, case-control study and surveillance system in which collaborating paediatricians identify case and control infants. The paediatricians collect the same data for both case and control infants, blinded to information on any prenatal exposure. The information includes 312 items related to many prenatal exposures, including drug exposure, reproductive and family history, and other characteristics. The sample analysed included 2393 infants with hypospadias and 12 465 male controls.

Results: The results showed that the unadjusted risk of hypospadias in infants prenatally exposed to VA was 5.23 (95% CI 2.31, 11.86; p < 0.00001). Once adjusted for 13 potential confounding factors using conditional logistic regression analyses, the value of the risk was of a similar magnitude (odds ratio = 5.71; 95% I 1.78, 18.36; p = 0.003). In addition, the frequency of hypospadias in the study population was approximately 1.8/1000 births. This allowed us to calculate the specific risk for an infant with hypospadias to be born to an exposed mother, which was 1 child in 97 births to mothers using VA during the first trimester of pregnancy. We consider this information much more useful for risk assessment than the risk value itself.

Conclusions: An alteration of placental gonadotrophic stimulation caused by changes in gonadotropin-releasing hormone release produced by the effects of VA on GABA is a possible pathogenic mechanism. Our results support the relationship between prenatal exposure to VA and hypospadias.

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References

  1. Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects [letter]. Lancet 1982; 2: 937

    Article  PubMed  CAS  Google Scholar 

  2. Bjerkedal TA, Czeizel A, Goujard J, et al. Valproic acid and spina bifida [letter]. Lancet 1982; 2: 1096

    Article  PubMed  CAS  Google Scholar 

  3. Martínez-Frías ML, Rodríguez-Pinilla E, Salvador J. Valproate and spina bifida [letter]. Lancet 1989; 1: 611

    Google Scholar 

  4. Prieto L, Martínez-Frías ML. Case-control studies using only malformed infants: are we interpreting the results correctly? Teratology 1999; 60: 1–2

    Article  PubMed  CAS  Google Scholar 

  5. DiLiberti JH, Farndon PA, Dennis NR, et al. The fetal valproate syndrome. Am J Med Genet 1984; 19: 473–81

    Article  PubMed  CAS  Google Scholar 

  6. Jager-Roman E, Deichi A, Jacob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986; 108: 997–1004

    Article  PubMed  CAS  Google Scholar 

  7. Lammer EJ, Sever LE, Oakley Jr GP. Teratogen update: valproic acid. Teratology 1987; 35: 465–73

    Article  PubMed  CAS  Google Scholar 

  8. Ardinger HH, Atkin JF, Blackston RD, et al. Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988; 29: 171–85

    Article  PubMed  CAS  Google Scholar 

  9. Martínez-Frías ML. Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic information. Am J Med Genet 1990; 37: 277–82

    Article  PubMed  Google Scholar 

  10. Rodríguez-Pinilla E, Arroyo I, Fondevilla J, et al. Prenatal exposure to valproic acid during pregnancy and limb deficiencies: a case-control study. Am J Med Genet 2000; 90: 376–81

    Article  PubMed  Google Scholar 

  11. Bertollini R, Kallen B, Mastroiacovo P, et al. Anticonvulsant drugs in monotherapy: effect on the fetus. Eur J Epidemiol 1987; 3: 164–71

    Article  PubMed  CAS  Google Scholar 

  12. Winter RM, Donnai D, Burn J, et al. Fetal valproate syndrome: is there a recognisable phenotype? J Med Genet 1987; 24: 692–5

    Article  PubMed  CAS  Google Scholar 

  13. Lindhout D, Omtzigt JG, Cornel MC. Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992; 42: 111–8

    Article  PubMed  CAS  Google Scholar 

  14. Bradaï R, Robert E. Diagnostic anténatal échographique chez la mereèpiléptique sous acide valproice. Etude rétrospective ou 161 cas de Registre France/Centre-Est de malformations congenitales. J Gynecol Obstet Biol Reprod 1998; 27: 413–9

    Google Scholar 

  15. Wyszynski DF, Nambisan M, Surve T, et al. Increased rate of major malformations in offspring exposed to valpoate during pregnancy. Neurology 2005; 64: 961–965

    Article  PubMed  CAS  Google Scholar 

  16. Arpino C, Brescianini S, Robert E, et al. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure [MADRE]. Epilepsia 2000; 41: 1436–43

    Article  PubMed  CAS  Google Scholar 

  17. The Centre of the ICBDSR. International Clearinghouse for Birth Defects Surveillance and Research (ICBDRS): annual report [online]. 2005; Rome. ISSN 0743-5703 Available from URL: http://www.icbdsr.org [2008 May 5]

  18. Bermejo E, Cuevas L, Mendioroz J, et al. Anomalías congénitas en Espana: vigilancia epidemiológica en elúltimo cuarto de siglo [1980–2004]. Boletín del ECEMC: Revista de Dismorfología y Epidemiología 2005; V (4): 62–85 [online]. Available from URL: http://bvs.isciii.es/mono/pdf/CIAC_04.pdf [Accessed 2008 May 5]

  19. Prieto L, Martinez-Frias ML. Case-control studies using only malformed infants who were prenatally exposed to drugs: what do the results mean? Teratology 2000; 62(1): 5–9

    Article  PubMed  CAS  Google Scholar 

  20. Martínez-Frías ML. Postmarketing analysis of medicines: methodology and value of the Spanish case-control study and surveillance system in preventing birth defects. Drug Safety 2007; 30(4): 307–16

    Article  PubMed  Google Scholar 

  21. Martínez-Frías ML. Interviewer bias and maternal bias. Teratology 1993; 47: 531–2

    Article  PubMed  Google Scholar 

  22. Källén B. Valproic acid is known to cause hypospadias in man but not reduce anogenital distance or causes hypospadias in rats. Basic Clin Pharmacol Toxicol 2004; 94(1): 51–4

    Article  PubMed  Google Scholar 

  23. Licht P, Harbarth P, Merz WE. Evidence for modulation of human chorionic gonadotropin [hCG] subunit messenger ribonucleic acid levels and hCG secretion by ?-aminobutyric acid in human first trimester placenta in vitro. Endocrinology 1992; 130: 490–6

    Article  PubMed  CAS  Google Scholar 

  24. Bhasin S, Heber D, Steiner BS, et al. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III: effects of long term combined treatment with GnRH agonist and androgen. J Clin Endocrinol Metab 1985; 60(5): 998–1003

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant from the Fundación Raul González-Salas (a Non Governmental Organization to promote Science and Culture), Spain. The authors have no conflicts of interest that are directly relevant to the content of this study.

The ECEMC Working Group that participated in this project in 2005 by Spanish region are as follows. Andalucía: Barcia JM (Cabra), Cózar JA (Huércal Overa), Esteban MV (Jaen), Fernández E (Antequera), Gallardo FL (Montilla), Gomar JL (La Línea), Lara A (Ubeda), Rodríguez A (Motril), Tapia JM (Puerto Real). Aragón: Muñoz MS (Teruel), Calvo MJ (Barbastro), Oliván del Cacho MJ (Huesca). I. Baleares: Gómez F (Mahón), Jiménez F (Manacor). Canarias: López Mendoza S (Tenerife). Cantabria: Canduela V (Laredo), Gomez-Ullate J (Santander). Castilla-La Mancha: Félix V (Toledo), García A (Guadalajara), García MJ (Cuenca), Huertas H (Valdepenas), Salvat F (Hellín), Sánchez C (Puertollano), Suay M (Cuenca), Vázquez MS (Albacete). Castilla y Leon: Aparicio P (Burgos), Burón E (Valladolid), Centeno F (Valladolid), Marugán VM (Zamora) Mousallem AG (Medina del Campo), Nieto C (Segovia). Cataluña: Alsina MN (Calella), Martínez S (Girona), Marco JJ (Lleida), Moral A (Terrassa), Rosal J (Tortosa), García MM (Figueres), Foguet A (Olot), Caubet I (Vielha), Puig I (Girona), Martí JJ (Santa Coloma de Gramanet), Serrano A (Mora ’d Ebre), Torres JM (Palamós). Comunidad de Madrid: Conde JF (Madrid), Martín F (Madrid), Martínez MN (Leganés), Gallegos S (El Escorial). Comunidad Foral de Navarra: Egüés J (Pamplona). Comunidad Valenciana: Andrés M (Valencia), Beseler B (Denia), Climent S (Xátiva y Ontinyent), García C (Valencia), González de Dios J (San Juan de Alicante), Jovani C (Vila-Real), Martínez A (Requena), Pi G (Alzira), Sanchis A (Valencia), Vizcaíno C (Elche). Extremadura: Arroyo I (Cáceres), Galán E (Badajoz), Contreras J (Coria), Gómez H (Llerena), RotaL (Navalmoral de la Mata). Galicia: Blanco M (Vigo), Martínez MA (Vilagarcía de Arousa), Silveira M (Burela). Principado de Asturias: Rodríguez MC (Riaño), Mayoral B (Cangas del Narcea), Suarez ME (Avilés). País Vasco: PaisánL (San Sebastián), Pérez JL (Basurto), Zuazo E (Zumarraga). Región de Murcia: Contessotto C (Santiago de la Ribera), Hernandez F (Murcia), López JA (Lorca), Martín JM (Murcia), Penas A (Yecla), Rubio MJ (Murcia). La Rioja: Garijo C (Calahorra).

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  1. Spanish Collaborative Study of Congenital Malformations (ECEMC), Research Center on Congenital Anomalies (CIAC), Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain

    Elvira Rodríguez-Pinilla, Consuelo Mejías, David Prieto-Merino, Paloma Fernández & María L

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  1. Elvira Rodríguez-Pinilla
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  2. Consuelo Mejías
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  3. David Prieto-Merino
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  4. Paloma Fernández
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  5. María L
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the ECEMC Working Group

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Correspondence to Elvira Rodríguez-Pinilla.

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Rodríguez-Pinilla, E., Mejías, C., Prieto-Merino, D. et al. Risk of Hypospadias in Newborn Infants Exposed to Valproic Acid During the First Trimester of Pregnancy. Drug-Safety 31, 537–543 (2008). https://doi.org/10.2165/00002018-200831060-00008

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  • DOI: https://doi.org/10.2165/00002018-200831060-00008

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