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Dose-Dependent Teratology in Humans: Clinical Implications for Prevention

Published on Aug 1, 2018in Pediatric Drugs 1.76
· DOI :10.1007/s40272-018-0294-0
Gideon Koren83
Estimated H-index: 83
,
Mati Berkovitch28
Estimated H-index: 28
(TAU: Tel Aviv University),
Asher Ornoy52
Estimated H-index: 52
(HUJI: Hebrew University of Jerusalem)
Cite
Abstract
Since the inception of clinical teratology, the vast majority of scientific work has focused on identification of drugs and environmental agents causing malformations in humans as a dichotomous variable (i.e. yes or no), as well as the relative and absolute risks of such occurrences. Generally, the dose dependency of such events has not been investigated. With the establishment of large pregnancy databases, dose-dependence relationships are being uncovered for increasing numbers of medications, including valproic acid, carbamazepine, phenobarbital, lamotrigine, topiramate, and lithium. In this review we discuss newly recognized dose-dependent human teratogens and the implications to counseling and clinical management of pregnant women. The option of limiting the dose below a teratogenic threshold for women who may need these drugs may be important in managing such pregnancies. Similarly, in women that were exposed before they realized they had conceived, this new knowledge may lead to significant improvement in risk assessment. A common denominator of all studies calculating dose-dependent teratogenicity in humans is their use of total daily drug dose. None of these studies have standardized their calculations for women’s body weight. It is quite possible that the teratogenic dose threshold may be below the clinically effective dose levels for specific women, and hence such information needs to be considered and applied individually. With large administrative databases now reporting on drug safety in pregnancy, more accurate data will likely emerge on dose dependency of human teratogens, and these will likely increase the accuracy of risk assessment.
  • References (23)
  • Citations (2)
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References23
Newest
Published on Dec 27, 2017in Neurology 8.69
Sonia Hernandez-Diaz54
Estimated H-index: 54
,
Krista F. Huybrechts35
Estimated H-index: 35
+ 5 AuthorsElisabetta Patorno15
Estimated H-index: 15
Objective To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications. Methods This population-based study nested in the US 2000–2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in c...
Published on Feb 1, 2017in Epilepsia 5.56
Sanjeev V Thomas27
Estimated H-index: 27
,
Manna Jose4
Estimated H-index: 4
+ 1 AuthorsPrabhakaran Sankara Sarma2
Estimated H-index: 2
SummaryObjective Kerala Registry of Epilepsy and Pregnancy had been prospectively evaluating the reproductive issues of women with epilepsy since April 1998. This analysis aimed to estimate the relative risk of major congenital malformations (MCM) to the registrants. Methods All pregnancies with known outcome in this register until December 2013 were included. Malformation status was evaluated by antenatal ultrasonography, physical examination at birth, echocardiography, and abdomen ultrasonogra...
Published on Nov 7, 2016in Cochrane Database of Systematic Reviews 7.75
Jennifer Weston9
Estimated H-index: 9
(University of Liverpool),
Rebecca L. Bromley18
Estimated H-index: 18
(University of Manchester)
+ 7 AuthorsAnthony G Marson43
Estimated H-index: 43
(University of Liverpool)
Background There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available. Objectives To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child. Search methods We se...
Published on Sep 8, 2015in Neurology 8.69
Torbjörn Tomson63
Estimated H-index: 63
(KI: Karolinska Institutet),
Dina Battino29
Estimated H-index: 29
+ 6 AuthorsF. J. E. Vajda35
Estimated H-index: 35
(University of Melbourne)
Objective: To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose. Methods: The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. ...
Published on Jan 1, 2015in Pakistan Journal of Pharmaceutical Sciences 0.60
Said Said Elshama2
Estimated H-index: 2
,
Osman He1
Estimated H-index: 1
,
El-Kenawy Ael-M1
Estimated H-index: 1
Carbamazepine use is the first choice of antiepileptic drugs among epileptic pregnant females. There are many inconclusive studies regard the safety of carbamazepine use during pregnancy. This study aims to investigate the morphological and histopathological teratogenic effects of carbamazepine use during pregnancy. The healthy pregnant females mice divided into equal five groups (each n=20). The first (control) group received distilled water/day. Second, third, fourth and fifth group received 8...
Published on Oct 1, 2014in Acta Neurologica Scandinavica 2.85
F. J. E. Vajda35
Estimated H-index: 35
(Royal Melbourne Hospital),
Terence J. O’Brien58
Estimated H-index: 58
(Royal Melbourne Hospital)
+ 2 AuthorsM. J. Eadie38
Estimated H-index: 38
(UQ: University of Queensland)
Objective To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate. Materials and methods Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester. Results Compared with the foetal malformation rate in women with epilepsy wh...
Published on Sep 10, 2013in Neurology 8.69
F. J. E. Vajda35
Estimated H-index: 35
(University of Melbourne),
Terence J. O’Brien58
Estimated H-index: 58
(University of Melbourne)
+ 2 AuthorsM. J. Eadie38
Estimated H-index: 38
(UQ: University of Queensland)
Objective: To study the relationships between maternal valproate dose in pregnancy and the pattern of various fetal malformations. Methods: Analysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy collected from 1999 to 2012. The specific type of fetal malformation in offspring exposed to valproate in utero was correlated with the dose of valproate taken by the mother in the first trimester. Results: Compared with other malformations, the mean dose of valproate taken durin...
Published on Jun 1, 2013in Journal of Neurology, Neurosurgery, and Psychiatry 8.27
Rebecca L. Bromley18
Estimated H-index: 18
(University of Liverpool),
George Mawer15
Estimated H-index: 15
(University of Manchester)
+ 7 AuthorsGus A. Baker67
Estimated H-index: 67
(University of Liverpool)
The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regressio...
Cited By2
Newest
Published in PLOS ONE 2.78
Andrea V. Margulis11
Estimated H-index: 11
,
Sonia Hernandez-Diaz54
Estimated H-index: 54
+ -3 AuthorsAnna Sara Oberg6
Estimated H-index: 6
Published on Mar 12, 2019in bioRxiv
Andrea V. Margulis11
Estimated H-index: 11
(RTI International),
Sonia Hernandez-Diaz54
Estimated H-index: 54
+ 5 AuthorsAnna Sara Oberg6
Estimated H-index: 6
BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.nnMethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logi...
Published on Sep 1, 2018in Reproductive Toxicology 3.20
Asher Ornoy52
Estimated H-index: 52
(HUJI: Hebrew University of Jerusalem),
Gideon Koren3
Estimated H-index: 3
(HUJI: Hebrew University of Jerusalem),
Joseph Yanai28
Estimated H-index: 28
(HUJI: Hebrew University of Jerusalem)
Abstract We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, a...