Reproductive Toxicology 50 (2014) 117–121
Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Esophageal atresia and prenatal exposure to mycophenolate M.C. Martín a,f , E. Cristiano b,f , M. Villanueva c , M.L. Bonora d,f , N. Berguio d,f , A. Tocci e,f , B. Groisman a,f , M.P. Bidondo a,f , R. Liascovich a,f , P. Barbero a,f,∗ a
National Center of Medical Genetics “Dr Eduardo Castilla”, Buenos Aires, Argentina Neonatology Service, Penna Hospital, Buenos Aires, Argentina Medical Genetics Service, Elizalde Hospital, Buenos Aires, Argentina d Neonatology Service, Regional Hospital of Río Cuarto, Córdoba, Argentina e Neonatology Service, Argerich Hospital, Buenos Aires, Argentina f National Registry of Congenital Anomalies of Argentina (RENAC), Argentina b c
a r t i c l e
i n f o
Article history: Received 29 May 2014 Received in revised form 8 October 2014 Accepted 14 October 2014 Available online 25 October 2014 Keywords: Mycophenolate mofetil Drug induced abnormalities Teratogen Esophageal atresia
a b s t r a c t Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a congenital anomaly observed with a frequency of 1 in 3500 births [1]. The great majority of cases of EA/TEF occur as sporadic events, and together with the low recurrence risk (approximately 1%) and the low twin concordance rate (2.5%), its evidence for a primarily non-genetic etiology [2]. However, to date, few environmental agents have been suggested as risk factors for the development of tracheoesophageal anomalies like maternal diabetes, maternal exposure to methimazole, exogenous sex
∗ Corresponding author at: Centro Nacional de Genética Médica “Dr. Eduardo Castilla”, Hospital Rivadavia, Av. Gral. Las Heras 2670, 3◦ piso, C1425ASQ, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. Tel.: +54 11 4809 0799. E-mail addresses: maria cecilia [email protected] (M.C. Martín), [email protected] (E. Cristiano), [email protected] (M. Villanueva), [email protected] (M.L. Bonora), [email protected] (N. Berguio), anatocci [email protected] (A. Tocci), [email protected] (B. Groisman), [email protected] (M.P. Bidondo), [email protected] (R. Liascovich), [email protected] (P. Barbero). http://dx.doi.org/10.1016/j.reprotox.2014.10.015 0890-6238/© 2014 Elsevier Inc. All rights reserved.
hormones and maternal alcohol and smoking. So far, no specific environmental risk factor has consistently been identified [3]. Mycophenolate mofetil (MMF) or its metabolite mycophenolic acid (MPA) is an immunosuppressive drug that acts as a selective, non-competitive and reversible inhibitor of the enzyme inosine monophosphate dehydrogenase. This drug is widely used for the management of solid organ transplants and autoimmune diseases, among others. MMF showed teratogenic effects in preclinical studies [4] and in vitro studies [5,6]. In 2007, MMF was reclassified from class C to D because the FDA acted proactively in response to postmarketing studies indicating potential increased risk of first trimester miscarriage and specific birth defects with predominant craniofacial abnormalities [4]. At present, information on the human teratogenic effect of mycophenolate includes at least 19 case reports with malformations observed after exposure in early pregnancy [7] and a prospective study that identified a 26% of malformations incidence and a rate of spontaneous abortion about twice as high than in low-risk pregnancies [8]. The complete clinical pattern is still being delineated. Esophageal atresia has been described only in a few cases, so their inclusion in mycophenolate embryopathy is not clear [8–11].
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M.C. Martín et al. / Reproductive Toxicology 50 (2014) 117–121
The aims of this paper are to describe four cases of newborns with esophageal atresia and other congenital malformations exposed to mycophenolate during the first trimester of pregnancy, and to contribute to delineate the mycophenolate embryopathy.
2. Cases presentation The four cases were reported to the National Registry of Congenital Anomalies of Argentina (RENAC) [12]. The RENAC is a public health surveillance system of major structural birth defects working in 143 maternity hospitals in Argentina, covering up to 350,000 annual births. Neonatologists in each hospital send monthly reports to the RENAC coordination with a verbatim description of cases affected by birth defects and a core set of variables: sex, birth status (live birth, stillbirth), twinning, condition when sending data (discharged alive, dead, not discharged yet, referred to another hospital), gravidity, gestational age, weight, maternal age, prenatal diagnosis and place of residence of the mother. Monthly reports are sent on-line in a web based forum which allows sending pictures of patients and the discussion of the cases. RENAC does not collect systematically or routinely information about exposures, but neonatologists can voluntarily send information about exposures along with the basic report. After being reported to the RENAC coordination the four cases were evaluated by a medical geneticist. Since RENAC does not collect information about exposures we cannot rule out if other children with esophageal atresia or other malformations were exposed to MMF. 2.1. Case 1 The patient was the first child of nonconsanguineous parents. The mother was 23-years-old woman with kidney transplant because of polycystic kidney disease. The mother was exposed to mycophenolate throughout pregnancy. She also received tacrolimus, meprednisone, erythropoietin, and diltiazem throughout pregnancy, enalapril during the first month of pregnancy, and amlodipine from the second month of gestation until delivery. Polyhydramnios was detected by fetal ultrasound. This patient was born by c-section at 35 weeks gestation. Birth weight was 1550 g (
Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Esophageal atresia and prenatal exposure to mycophenolate M.C. Martín a,f , E. Cristiano b,f , M. Villanueva c , M.L. Bonora d,f , N. Berguio d,f , A. Tocci e,f , B. Groisman a,f , M.P. Bidondo a,f , R. Liascovich a,f , P. Barbero a,f,∗ a
National Center of Medical Genetics “Dr Eduardo Castilla”, Buenos Aires, Argentina Neonatology Service, Penna Hospital, Buenos Aires, Argentina Medical Genetics Service, Elizalde Hospital, Buenos Aires, Argentina d Neonatology Service, Regional Hospital of Río Cuarto, Córdoba, Argentina e Neonatology Service, Argerich Hospital, Buenos Aires, Argentina f National Registry of Congenital Anomalies of Argentina (RENAC), Argentina b c
a r t i c l e
i n f o
Article history: Received 29 May 2014 Received in revised form 8 October 2014 Accepted 14 October 2014 Available online 25 October 2014 Keywords: Mycophenolate mofetil Drug induced abnormalities Teratogen Esophageal atresia
a b s t r a c t Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a congenital anomaly observed with a frequency of 1 in 3500 births [1]. The great majority of cases of EA/TEF occur as sporadic events, and together with the low recurrence risk (approximately 1%) and the low twin concordance rate (2.5%), its evidence for a primarily non-genetic etiology [2]. However, to date, few environmental agents have been suggested as risk factors for the development of tracheoesophageal anomalies like maternal diabetes, maternal exposure to methimazole, exogenous sex
∗ Corresponding author at: Centro Nacional de Genética Médica “Dr. Eduardo Castilla”, Hospital Rivadavia, Av. Gral. Las Heras 2670, 3◦ piso, C1425ASQ, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. Tel.: +54 11 4809 0799. E-mail addresses: maria cecilia [email protected] (M.C. Martín), [email protected] (E. Cristiano), [email protected] (M. Villanueva), [email protected] (M.L. Bonora), [email protected] (N. Berguio), anatocci [email protected] (A. Tocci), [email protected] (B. Groisman), [email protected] (M.P. Bidondo), [email protected] (R. Liascovich), [email protected] (P. Barbero). http://dx.doi.org/10.1016/j.reprotox.2014.10.015 0890-6238/© 2014 Elsevier Inc. All rights reserved.
hormones and maternal alcohol and smoking. So far, no specific environmental risk factor has consistently been identified [3]. Mycophenolate mofetil (MMF) or its metabolite mycophenolic acid (MPA) is an immunosuppressive drug that acts as a selective, non-competitive and reversible inhibitor of the enzyme inosine monophosphate dehydrogenase. This drug is widely used for the management of solid organ transplants and autoimmune diseases, among others. MMF showed teratogenic effects in preclinical studies [4] and in vitro studies [5,6]. In 2007, MMF was reclassified from class C to D because the FDA acted proactively in response to postmarketing studies indicating potential increased risk of first trimester miscarriage and specific birth defects with predominant craniofacial abnormalities [4]. At present, information on the human teratogenic effect of mycophenolate includes at least 19 case reports with malformations observed after exposure in early pregnancy [7] and a prospective study that identified a 26% of malformations incidence and a rate of spontaneous abortion about twice as high than in low-risk pregnancies [8]. The complete clinical pattern is still being delineated. Esophageal atresia has been described only in a few cases, so their inclusion in mycophenolate embryopathy is not clear [8–11].
118
M.C. Martín et al. / Reproductive Toxicology 50 (2014) 117–121
The aims of this paper are to describe four cases of newborns with esophageal atresia and other congenital malformations exposed to mycophenolate during the first trimester of pregnancy, and to contribute to delineate the mycophenolate embryopathy.
2. Cases presentation The four cases were reported to the National Registry of Congenital Anomalies of Argentina (RENAC) [12]. The RENAC is a public health surveillance system of major structural birth defects working in 143 maternity hospitals in Argentina, covering up to 350,000 annual births. Neonatologists in each hospital send monthly reports to the RENAC coordination with a verbatim description of cases affected by birth defects and a core set of variables: sex, birth status (live birth, stillbirth), twinning, condition when sending data (discharged alive, dead, not discharged yet, referred to another hospital), gravidity, gestational age, weight, maternal age, prenatal diagnosis and place of residence of the mother. Monthly reports are sent on-line in a web based forum which allows sending pictures of patients and the discussion of the cases. RENAC does not collect systematically or routinely information about exposures, but neonatologists can voluntarily send information about exposures along with the basic report. After being reported to the RENAC coordination the four cases were evaluated by a medical geneticist. Since RENAC does not collect information about exposures we cannot rule out if other children with esophageal atresia or other malformations were exposed to MMF. 2.1. Case 1 The patient was the first child of nonconsanguineous parents. The mother was 23-years-old woman with kidney transplant because of polycystic kidney disease. The mother was exposed to mycophenolate throughout pregnancy. She also received tacrolimus, meprednisone, erythropoietin, and diltiazem throughout pregnancy, enalapril during the first month of pregnancy, and amlodipine from the second month of gestation until delivery. Polyhydramnios was detected by fetal ultrasound. This patient was born by c-section at 35 weeks gestation. Birth weight was 1550 g (
