Talk:Abnormal Development - Drugs
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Cite this page: Hill, M.A. (2024, May 5) Embryology Abnormal Development - Drugs. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Abnormal_Development_-_Drugs |
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Drug Teratogen
<pubmed limit=10>drug teratogen</pubmed>
2015
Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis
Clin Pharmacol Ther. 2015 Jun 5. doi: 10.1002/cpt.158. [Epub ahead of print]
Tanoshima M1,2, Kobayashi T1,3, Tanoshima R1,4, Beyene J5,6, Koren G1, Ito S1.
Abstract
Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, risks of VPA-associated CMs are 2 to 7 fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics. KEYWORDS: congenital malformations; cumulative meta-analysis; neural tube defects; teratogenicity; valproic acid
PMID 26044279
Statins and congenital malformations: cohort study
BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h1035 (Published 17 March 2015) Cite this as: BMJ 2015;350:h1035
Abstract Objective To examine the teratogenic potential of statins.
Design Cohort study.
Setting United States.
Participants A cohort of 886 996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007.
Methods We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs.
Results 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses.
Conclusions Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.
2014
Fetal valproate syndrome
Indian J Hum Genet. 2014 Apr;20(2):187-8. doi: 10.4103/0971-6866.142898.
Chandane PG, Shah I.
Abstract
Antenatal use of anticonvulsant valproic acid can result in a well-recognized cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. In this report, we describe a case with typical features of fetal valproate syndrome (FVS). A 26-year-old female with epilepsy controlled on sodium valproate 800 mg/day since 3 years, gave birth to a male child with characteristic features of FVS. She also had 3 spontaneous first-trimester abortions during those 3 years. Sodium valproate, a widely used anticonvulsant and mood regulator, is a well-recognized teratogen that can result in facial dysmorphism, craniosynostosis, neural tube defects, and neurodevelopmental retardation. Therefore, we strongly recommend avoidance of valproic acid and supplementation of folic acid during pregnancy. KEYWORDS: Anticonvulsant; pregnancy; sodium valproate
PMID 25400349
2013
Birth Defects After Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study
J Clin Endocrinol Metab. 2013 Oct 22. [Epub ahead of print]
Andersen SL, Olsen J, Wu CS, Laurberg P. Source Department of Endocrinology (S.L.A., P.L.), Aalborg University Hospital, DK-9000 Aalborg, Denmark; and Section for Epidemiology (J.O., C.S.W.), Department of Public Health, Aarhus University, DK-8000 Aarhus, Denmark.
Abstract
Introduction:Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy.Objective:Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects.Methods:This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children.Results:The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]).Conclusions:Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.
PMID 24151287
Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism
JAMA. 2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270.
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. Source Department of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark. jakob@farm.au.dk
Abstract
IMPORTANCE: Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism. OBJECTIVE: To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS: Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES: Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS: Of 655,615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE: Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control. Comment in Risks of in utero exposure to valproate. [JAMA. 2013] PMID 23613074
2012
Propylthiouracil is teratogenic in murine embryos
PLoS One. 2012;7(4):e35213. doi: 10.1371/journal.pone.0035213. Epub 2012 Apr 18.
Benavides VC, Mallela MK, Booth CJ, Wendler CC, Rivkees SA. Source
Section of Developmental Endocrinology and Biology, Yale Pediatric Thyroid Center, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Abstract
BACKGROUND: Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed. METHODS: We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis. RESULTS: When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.
PMID 22529993
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035213
Obstetric toxicology: teratogens
Emerg Med Clin North Am. 2012 Nov;30(4):977-90. doi: 10.1016/j.emc.2012.08.008.
Levine M, O'Connor AD. Source Section of Medical Toxicology, Department of Emergency Medicine, University of Southern California, 1200 North State Street, Room 1011, Los Angeles, CA 90033, USA; Department of Medical Toxicology, Banner Good Samaritan Medical Center, 925 East McDowell Road, Second Floor, Phoenix, AZ 85006, USA. Electronic address: mdlevine@usc.edu.
Abstract
The emergency physician frequently encounters women who seek care because of pregnancy- and nonpregnancy-related complaints. Many medications are safe for use during pregnancy, including several that are listed as potential teratogens based on the Food and Drug Administration's (FDA) pregnancy classification; but it is important that the emergency physician know and recognize which drugs can be given in pregnancy and which drugs are absolutely contraindicated. Expert resources should be identified and used because the FDA's classification of drugs based on pregnancy risk does not represent the most up-to-date or accurate assessment of a drug's safety. Copyright © 2012 Elsevier Inc. All rights reserved.
PMID 23137407
2011
--Mark Hill 13:05, 19 September 2011 (EST) The Teratogen Information System TERIS a computerized database designed to assist physicians or other health care professionals in assessing the risks of possible teratogenic exposures in pregnant women. (subscription only) External link not added to drugs page as information is not freely available.
Abnormal notochord branching is associated with foregut malformations in the adriamycin treated mouse model
PLoS One. 2011;6(11):e27635. doi: 10.1371/journal.pone.0027635. Epub 2011 Nov 21.
Hajduk P1, Sato H, Puri P, Murphy P.
Abstract
Oesophageal atresia (OA) and tracheooesophageal fistula (TOF) are relatively common human congenital malformations of the foregut where the oesophagus does not connect with the stomach and there is an abnormal connection between the stomach and the respiratory tract. They require immediate corrective surgery and have an impact on the future health of the individual. These abnormalities are mimicked by exposure of rat and mouse embryos in utero to the drug adriamycin. The causes of OA/TOF during human development are not known, however a number of mouse mutants where different signalling pathways are directly affected, show similar abnormalities, implicating multiple and complex signalling mechanisms. The similarities in developmental outcome seen in human infants and in the adriamycin treated mouse model underline the potential of this model to unravel the early embryological events and further our understanding of the processes disturbed, leading to such abnormalities. Here we report a systematic study of the foregut and adjacent tissues in embryos treated with adriamycin at E7 and E8 and analysed between E9 and E12, comparing morphology in 3D in 149 specimens. We describe a spectrum of 8 defects, the most common of which is ventral displacement and branching of the notochord (in 94% of embryos at E10) and a close spatial correspondence between the site of notochord branching and defects of the foregut. In addition gene expression analysis shows altered dorso-ventral foregut patterning in the vicinity of notochord branches. This study shows a number of features of the adriamycin mouse model not previously reported, implicates the notochord as a primary site of disturbance in such abnormalities and underlines the importance of the model to further address the mechanistic basis of foregut congenital abnormalities.
PMID 22132119
Valproic Acid Increases Formation of Reactive Oxygen Species and Induces Apoptosis in Postimplantation Embryos: A Role for Oxidative Stress in Valproic Acid-Induced Neural Tube Defects
Mol Pharmacol. 2011 Aug 25. [Epub ahead of print]
Tung EW, Winn L. Source 1 Queen's University;
Abstract
Exposure to the anticonvulsant valproic acid (VPA) during the first trimester of pregnancy is associated with an increased risk of congenital malformations including heart defects, craniofacial abnormalities, skeletal and limb defects, and most frequently, neural tube defects (NTDs). The mechanisms by which VPA induces teratogenic effects are not fully understood, although previous studies support a role for oxidative stress. To investigate the effects of VPA on early development, a whole embryo culture model was used to evaluate the protective effects of antioxidants, measure intracellular reactive oxygen species (ROS) levels, and assess markers of oxidative damage and apoptosis. Furthermore, in vivo teratological evaluations of antioxidant protection were also completed. VPA (0.60 mM in embryo culture, 400 mg/kg s.c. in vivo) induced significant decreases in embryonic growth and increases in NTDs. Of the antioxidants tested, catalase provided partial protection against VPA-mediated reductions in morphological and developmental growth parameters in both whole embryo culture and in vivo systems. VPA exposure resulted in an increase in ROS staining in the head region, as assessed by whole mount staining with CM-H(2)DCFDA. Markers of embryonic oxidative damage including 8-hydroxyguanosine, 4-hydroxynonenal adducts, and 3-nitrotyrosine were not affected by VPA treatment. Increased ROS levels were correlated with increased staining for apoptotic markers, as assessed by western blotting and immunohistochemistry. Addition of catalase to the media attenuated VPA-induced increases in ROS formation and apoptosis. These studies identify regions of the embryo susceptible to ROS and apoptosis induced by VPA, thus establishing a possible molecular pathway by which VPA exerts teratogenicity.
PMID 21868484
Evolving knowledge of the teratogenicity of medications in human pregnancy
Am J Med Genet C Semin Med Genet. 2011 Aug 15;157(3):175-82. doi: 10.1002/ajmg.c.30313. Epub 2011 Jul 15.
Adam MP, Polifka JE, Friedman JM. Source University of Washington in Seattle, and Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105-0371, USA. margaret.adam@seattlechildrens.org
Abstract
A majority of pregnant women take at least one medication during pregnancy, although the safety of such drugs during pregnancy is not always known. We reviewed the safety during pregnancy of 172 drugs approved by the US Food and Drug Administration (FDA) from 2000 to 2010 using the TERIS risk rating system. We also reviewed safety information for 468 drugs approved by the FDA from 1980 to 2000 to determine if revisions in risk categories had been made in the last 10 years. The teratogenic risk in human pregnancy was "undetermined" for 168 (97.7%) of drug treatments approved between 2000 and 2010. Furthermore, the amount of data available regarding safety in pregnancy was rated as "none" for 126 (73.3%) of these drugs. For those drugs approved between 1980 and 2000, only 23 (5%) changed a full risk category or more in the past 10 years. Sources of data that led to a revised risk were derived from exposure cohort studies performed through record linkage studies, teratogen information services, large population-based case-control studies, and pregnancy registries. The mean time for a treatment initially classified as having an "undetermined" risk to be assigned a more precise risk was 27 years (95% confidence interval 26-28 years). The lack of information needed to assess the safety of drug treatments during human pregnancy remains a serious public health problem. A more active approach to post-marketing surveillance for teratogenic effects is necessary.
Copyright © 2011 Wiley-Liss, Inc.
PMID 21766440
Exposure to Non-Steroidal Anti-Inflammatory Drugs during Pregnancy and the Risk of Selected Birth Defects: A Prospective Cohort Study
PLoS One. 2011;6(7):e22174. Epub 2011 Jul 18.
van Gelder MM, Roeleveld N, Nordeng H. Source Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Abstract
BACKGROUND: Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs.
METHODS AND FINDINGS: We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0-12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4-1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9-15.7).
CONCLUSIONS: Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded.
PMID 21789231
Valproic acid inhibits neural progenitor cell death by activation of NF-kappaB signaling pathway and up-regulation of Bcl-XL
J Biomed Sci. 2011 Jul 4;18(1):48. [Epub ahead of print]
Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH.
Abstract ABSTRACT:
BACKGROUND: At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs.
METHODS: Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C.) diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-kappaB p65 was investigated by ChIP assay.
RESULTS: In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IkappaBalpha and increased the nuclear translocation of NF-kappaB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL.
CONCLUSIONS: To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IkappaBalpha and the activation of NF-kappaB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior.
PMID 21722408
2010
The effect of drugs with ion channel-blocking activity on the early embryonic rat heart
Birth Defects Res B Dev Reprod Toxicol. 2010 Oct;89(5):429-40.
Abela D, Ritchie H, Ababneh D, Gavin C, Nilsson MF, Khan MK, Carlsson K, Webster WS.
Department of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, Australia.
Abstract This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing. Birth Defects Res (Part B) 89:429-440, 2010. © 2010 Wiley-Liss, Inc.
PMID: 20973055
Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: an update
Postgrad Med. 2010 Jul;122(4):49-65.
Tuccori M, Montagnani S, Testi A, Ruggiero E, Mantarro S, Scollo C, Pergola A, Fornai M, Antonioli L, Colucci R, Corona T, Blandizzi C. Unit of Pharmacology, University Hospital of Pisa, Pisa, Italy. m.tuccori@ao-pisa.toscana.it Abstract General consensus exists about the need to avoid drug intake as much as possible during pregnancy due to the lack of thorough evidence about the safety of pharmacologic treatments during gestation for both mothers and fetuses. In this respect, the overall safety profile of selective serotonin reuptake inhibitors (SSRIs) in pregnancy remains unclear. This article reviews current evidence about the safety of each SSRI during pregnancy in order to describe their specific teratogenic potential, with a particular focus on major and cardiovascular malformations, and to verify whether such toxicity can be considered as a class effect. The literature review included controlled studies and meta-analyses (retrieved using PsychINFO, EMBASE, and Medline from January 1966 to May 2010) from which the risk of major and/or cardiovascular malformations associated with a specific SSRI (ie, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine) could be estimated. Although there is evidence to support the association between birth defects and first-trimester exposure to paroxetine, findings from the studies reviewed suggest a teratogenic potential of the whole SSRI class, consistent with preclinical evidence. These teratogenic effects are mainly in the heart region, and they are often described as septal defects. It may be suggested that the higher frequency of teratogenic effects reported for paroxetine might depend on specific pharmacologic features of this drug compared with other SSRIs, although it is difficult to test this hypothesis. It is noteworthy that current evidence on SSRI teratogenicity stems from studies affected by several methodological weaknesses (ie, lack of investigations using control groups of untreated depressed mothers, confounding by indication, and recall bias). Accordingly, we are not yet able to rule out the possibility that positive associations, as determined in some studies, result from analyses of poor quality. PMID: 20675971
Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register
Seizure. 2010 Aug 24. [Epub ahead of print]
Vajda FJ, Graham JE, Hitchcock AA, O'Brien TJ, Lander CM, Eadie MJ. Department of Medicine and Neurology, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia. Abstract Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N=118), the incidences for LTG (N=243), carbamazepine (CBZ) (N=302) and VPA (N=224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs. Copyright © 2010. Published by Elsevier Ltd. PMID: 20739196
Are azole fungicides a teratogenic risk for human conceptus?
Toxicol Lett. 2010 Oct 5;198(2):106-11. Epub 2010 Jul 13.
Giavini E, Menegola E. Università degli studi di Milano, Dipartimento di Biologia, Via Celoria, 26, I-20133 Milano, Italy. erminio.giavini@unimi.it Abstract Azole fungicides are widely used in agriculture and in human mycosis. Their antifungal activity is based on their ability to inhibit CYP51, a key enzyme in the formation of fungal wall. Several azole fungicides tested in laboratory animals have been found to possess a common teratogenic potential to induce facial, axial skeleton, and limb defects. The mechanism of the teratogenic effect has been hypothesized to be related to the capability of these substances to alter embryonic retinoic acid catabolism. Although a number of human epidemiological studies were unable to demonstrate a definite relationship between azole exposure during pregnancy and birth defects, some case reports indicate a possible teratogenic effect of high doses of azoles in humans. Because of their common mechanism of action, azole fungicides should be regarded with caution for use in pregnant women. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
PMID 20633616
2001
Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature
Am J Med Genet. 2001 Jan 15;98(2):168-75.
Kozma C. Source Child Development Center/Department of Pediatrics, Georgetown University Medical Center, Washington, DC 20007-3935, USA. kozmac@gunet.georgetown.edu
Abstract
Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid (VPA). It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies, and central nervous system dysfunction. In this study, two siblings who were exposed to monotherapy with VPA are described with documentation of long-term follow up. Both children had craniofacial findings, multiple systemic and orthopedic abnormalities, an overgrowth pattern, and developmental deficits. The literature from 1978-2000 is reviewed. A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified. The clinical manifestations of FVS encompass a wide spectrum of abnormalities including consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth. The facial appearance is characterized by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities. Less frequently encountered abnormalities included brain, eye, kidney, and hearing defects. Neural tube defects were seen in 3% of the sample. Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation. Although 15% of patients had growth retardation, an overgrowth pattern was seen in 9%. The data from this comprehensive review especially the developmental outcome should be added to the teratogenic risk, that arises in association with the use of VPA during pregnancy. Copyright 2001 Wiley-Liss, Inc.
PMID 11223853
1988
Prenatal adverse effects of various drugs and chemicals. A review of substances of frequent concern to mothers in the community
Med Toxicol Adverse Drug Exp. 1988 Jul-Aug;3(4):307-23.
Bologa-Campeanu M1, Koren G, Rieder M, McGuigan M.
Abstract
Using the number of calls to the Canadian Motherisk Program as an indicator of the drugs and chemicals frequently of concern to mothers during pregnancy, the risks to the fetus of exposure to these compounds have been reviewed. The drugs which were of concern, and have been proven to be teratogenic, included alcohol, alkylating and antimetabolite agents, stilboestrol, disulfiram, heparin, lithium carbonate, phenytoin, tretinoin (retinoic acid), troxidone and valproic acid. For other compounds studied, there was either no data in the literature or no clear evidence of teratogenicity. The combination of doxylamine and pyridoxine, for example, has been associated with limb reduction defects in isolated case reports: cohort and case-control studies have failed to show a higher-than-baseline risk of malformations. In some cases of exposure to compounds with no known teratogenic potential, other adverse effects to the fetus are possible, and these effects are discussed in detail. In conclusion, when advising a pregnant woman about the potential teratogenic effect of a particular drug or chemical exposure, the health professional should also discuss other factors such as age, obstetric and medical history and the history of other exposures (including alcohol and smoking). In every pregnancy there is a 1 to 5% risk of mayor malformations, and even if the exposure does not appear to increase the teratogenic risk, such a risk still exists.
PMID 3054428
