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The molecular biology of Valproic Acid in the etiology of autism: Evidence from molecular genetic studies in a rat model of autism
Free communications and posters / Reproductive Toxicology 31 (2011) 255–268
help us better understand the molecular mechanisms that are associated with DM induced birth defects. Supported by the RW & MS Goode Trust, US–Israel BiNational Foundation (0374352), and the Israeli Science Foundation (0394193). doi:10.1016/j.reprotox.2010.12.049 The molecular biology of Valproic Acid in the etiology of autism: Evidence from molecular genetic studies in a rat model of autism C.J. Stodgell a , G. Glazko b a
Department of Obstetrics/Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14618, USA b Department of Biostatistics/Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14618, USA Valproic Acid (VPA) has long been an effective treatment for certain seizure disorders. More recently, the indications for use have increased to include mania associated with bipolar disorder, migraine headaches and as a chemotherapeutic agent for cancer. VPA has long been known to be teratogenic in both humans and animal models with variable presentation of terata ranging from profound neural tube defects, to delays in developmental and learning milestones, as well as developmental behavioral disorders such as autism spectrum disorders (ASDs). Some have recommended that women of reproductive age on VPA cease taking VPA if they wish to become pregnant. However, this may not be practical in all cases, especially if VPA is effective in its treatment of the conditions for which it is prescribed. The risk for autism spectrum disorders (ASDs) is increased as much as 20-fold when the fetus is exposed to VPA. Further, evidence supporting VPA’s role in ASD’s stems from the neuroanatomical and behavioral similarities seen between cases of ASDs, and rats exposed to VPA in utero. Having a better understanding of the molecular and genetic and molecular mechanisms that are affected in the embryo and fetus may provide important information about VPA’s teratogenicity. This may, in turn, allow for the development of better alternatives of VPA. This presentation will discuss the evidence for VPA’s involvement in ASDs, and how we are using rodent models to understand the molecular genetic events that lead to the neuroanatomical and behavioral deficits seen after exposure. Supported in part by RW & MS Goode Trust. doi:10.1016/j.reprotox.2010.12.050 Pregnancy outcome after in-utero exposure to methylphenidate: A prospective comparative cohort study Rebecka Wajnberg a , Orna Diav-Citrin a , Svetlana Shechtman a , Asher Ornoy a,b,∗ a
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel b The Hebrew University Hadassah Medical School, Jerusalem, Israel
Introduction: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention deficit disorder with or without hyperactivity (ADD/ADHD). The prevalence rate of ADD/ADHD is estimated to be 5–8% of school-aged children. In recent years, methylphenidate is increasingly prescribed in children and young adults. Pregnancy human experience with methylphenidate is scant and partly derived from women who abused it. In a study examining IV pentazocine and methylphenidate abuse there was a high rate of preterm deliveries, growth restriction and withdrawal symptoms after birth. The
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primary objective of the present study was to evaluate the risk of major anomalies after pregnancy exposure to methylphenidate for medical indications. Methods: Callers who contacted the Israeli teratology information service (TIS) between 2005 and 2009 in regard to methyphenidate exposure during pregnancy were prospectively collected and followed-up. Results: We followed-up 54 methylphenidate-exposed pregnancies [52/54 (96%) in the first trimester]. The outcome was compared to that of 54 pregnancies who contacted the Israeli TIS in regard to exposure not known to be teratogenic, matched by maternal age, gestational age at initial contact, and year. The rate of major congenital anomalies was comparable between the groups [0/46 (0%) in the methylphenidate first trimester exposed group vs. 2/51 (3.9%), p = 0.496]. Genetic or cytogenetic anomalies were excluded from the analysis. There were no significant differences in the rate of live-births, miscarriages, or elective terminations of pregnancy between the groups. The median gestational age at delivery [39 (38–40) in both groups, p = 0.310] and birth weight [3293 (2990–3500) methylphenidate vs. 3300 (3000–3600), p = 0.879] were also comparable. Conclusion: The present study suggests that treatment with methylphenidate in pregnancy does not seem to be a major human teratogen and does not adversely affect the gestational age at delivery or neonatal birth weight. Further studies are required to establish its pregnancy safety. doi:10.1016/j.reprotox.2010.12.051 Pregnancy outcomes in women exposed to adalimumab or infliximab: The experience of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy Corinna Weber-Schoendorfer ∗ , Juliane Fritzsche, Christof Schaefer Pharmakovigilanzzentrum Embryonaltoxikologie BBGes/Charité Universitätsmedizin Berlin, Germany Introduction: Infliximab and adalimumab are TNF-␣ blocking, IgG1 monoclonal antibodies (mabs) mainly used in the treatment of severe rheumatoid arthritis, Crohn’s disease, and other autoimmune diseases. Women of reproductive age are often affected, but experience of mabs in pregnancy is still limited, although their use has been steadily increasing. This is reflected by an increasing number of inquiries to our institute: 0.04% of all consultations in 1999, and 1.3% in 2010. IgGs are large molecules that can hardly reach the embryo during the 1st trimester. This is consistent with the experience with infliximab during the 1st trimester not suggesting teratogenicity so far. Later in pregnancy, transplacental transfer is well documented for infliximab. However, it is unknown, whether or not the inhibition of TNF-␣ affects the development of the fetus. Experience with adalimumab during the 1st trimester is scarce and transplacental transfer has been assumed but not been demonstrated by now. The aim of our study is to screen for teratogenic signals and for possible effects after long-term exposure. Methods: Prospectively ascertained case series with pregnancy outcome after infliximab or adalimumab exposure during pregnancy. Results: In 85 cases we could initiate the follow-up procedure, which has been completed in 28 adalimumab and in 25 infliximab exposed pregnancies. There were 2 miscarriages each and 2 voluntary terminations of pregnancy in the adalimumab and 1 in the infliximab cohort. Four of 24 live born infants exposed to adalimumab, and 4 of 22 exposed to infliximab were premature. There were 1 infant after intrauterine adalimumab exposure with an autosomal dominant disease inherited from his father and 2 after infliximab exposure with a major birth defect (ventricular
help us better understand the molecular mechanisms that are associated with DM induced birth defects. Supported by the RW & MS Goode Trust, US–Israel BiNational Foundation (0374352), and the Israeli Science Foundation (0394193). doi:10.1016/j.reprotox.2010.12.049 The molecular biology of Valproic Acid in the etiology of autism: Evidence from molecular genetic studies in a rat model of autism C.J. Stodgell a , G. Glazko b a
Department of Obstetrics/Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14618, USA b Department of Biostatistics/Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14618, USA Valproic Acid (VPA) has long been an effective treatment for certain seizure disorders. More recently, the indications for use have increased to include mania associated with bipolar disorder, migraine headaches and as a chemotherapeutic agent for cancer. VPA has long been known to be teratogenic in both humans and animal models with variable presentation of terata ranging from profound neural tube defects, to delays in developmental and learning milestones, as well as developmental behavioral disorders such as autism spectrum disorders (ASDs). Some have recommended that women of reproductive age on VPA cease taking VPA if they wish to become pregnant. However, this may not be practical in all cases, especially if VPA is effective in its treatment of the conditions for which it is prescribed. The risk for autism spectrum disorders (ASDs) is increased as much as 20-fold when the fetus is exposed to VPA. Further, evidence supporting VPA’s role in ASD’s stems from the neuroanatomical and behavioral similarities seen between cases of ASDs, and rats exposed to VPA in utero. Having a better understanding of the molecular and genetic and molecular mechanisms that are affected in the embryo and fetus may provide important information about VPA’s teratogenicity. This may, in turn, allow for the development of better alternatives of VPA. This presentation will discuss the evidence for VPA’s involvement in ASDs, and how we are using rodent models to understand the molecular genetic events that lead to the neuroanatomical and behavioral deficits seen after exposure. Supported in part by RW & MS Goode Trust. doi:10.1016/j.reprotox.2010.12.050 Pregnancy outcome after in-utero exposure to methylphenidate: A prospective comparative cohort study Rebecka Wajnberg a , Orna Diav-Citrin a , Svetlana Shechtman a , Asher Ornoy a,b,∗ a
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel b The Hebrew University Hadassah Medical School, Jerusalem, Israel
Introduction: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention deficit disorder with or without hyperactivity (ADD/ADHD). The prevalence rate of ADD/ADHD is estimated to be 5–8% of school-aged children. In recent years, methylphenidate is increasingly prescribed in children and young adults. Pregnancy human experience with methylphenidate is scant and partly derived from women who abused it. In a study examining IV pentazocine and methylphenidate abuse there was a high rate of preterm deliveries, growth restriction and withdrawal symptoms after birth. The
267
primary objective of the present study was to evaluate the risk of major anomalies after pregnancy exposure to methylphenidate for medical indications. Methods: Callers who contacted the Israeli teratology information service (TIS) between 2005 and 2009 in regard to methyphenidate exposure during pregnancy were prospectively collected and followed-up. Results: We followed-up 54 methylphenidate-exposed pregnancies [52/54 (96%) in the first trimester]. The outcome was compared to that of 54 pregnancies who contacted the Israeli TIS in regard to exposure not known to be teratogenic, matched by maternal age, gestational age at initial contact, and year. The rate of major congenital anomalies was comparable between the groups [0/46 (0%) in the methylphenidate first trimester exposed group vs. 2/51 (3.9%), p = 0.496]. Genetic or cytogenetic anomalies were excluded from the analysis. There were no significant differences in the rate of live-births, miscarriages, or elective terminations of pregnancy between the groups. The median gestational age at delivery [39 (38–40) in both groups, p = 0.310] and birth weight [3293 (2990–3500) methylphenidate vs. 3300 (3000–3600), p = 0.879] were also comparable. Conclusion: The present study suggests that treatment with methylphenidate in pregnancy does not seem to be a major human teratogen and does not adversely affect the gestational age at delivery or neonatal birth weight. Further studies are required to establish its pregnancy safety. doi:10.1016/j.reprotox.2010.12.051 Pregnancy outcomes in women exposed to adalimumab or infliximab: The experience of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy Corinna Weber-Schoendorfer ∗ , Juliane Fritzsche, Christof Schaefer Pharmakovigilanzzentrum Embryonaltoxikologie BBGes/Charité Universitätsmedizin Berlin, Germany Introduction: Infliximab and adalimumab are TNF-␣ blocking, IgG1 monoclonal antibodies (mabs) mainly used in the treatment of severe rheumatoid arthritis, Crohn’s disease, and other autoimmune diseases. Women of reproductive age are often affected, but experience of mabs in pregnancy is still limited, although their use has been steadily increasing. This is reflected by an increasing number of inquiries to our institute: 0.04% of all consultations in 1999, and 1.3% in 2010. IgGs are large molecules that can hardly reach the embryo during the 1st trimester. This is consistent with the experience with infliximab during the 1st trimester not suggesting teratogenicity so far. Later in pregnancy, transplacental transfer is well documented for infliximab. However, it is unknown, whether or not the inhibition of TNF-␣ affects the development of the fetus. Experience with adalimumab during the 1st trimester is scarce and transplacental transfer has been assumed but not been demonstrated by now. The aim of our study is to screen for teratogenic signals and for possible effects after long-term exposure. Methods: Prospectively ascertained case series with pregnancy outcome after infliximab or adalimumab exposure during pregnancy. Results: In 85 cases we could initiate the follow-up procedure, which has been completed in 28 adalimumab and in 25 infliximab exposed pregnancies. There were 2 miscarriages each and 2 voluntary terminations of pregnancy in the adalimumab and 1 in the infliximab cohort. Four of 24 live born infants exposed to adalimumab, and 4 of 22 exposed to infliximab were premature. There were 1 infant after intrauterine adalimumab exposure with an autosomal dominant disease inherited from his father and 2 after infliximab exposure with a major birth defect (ventricular