Teratogenic Risk Research Articles

Brief intervention reduces prescription of sodium valproate in women of childbearing age.

Sodium valproate's teratogenicity has prompted increasing restrictions to its use. Our initial audit 2years prior demonstrated continuing hazardous prescription to women of childbearing age in a New Zealand psychiatric inpatient unit, consistent with nationwide dispensing data. Following a service-wide educational intervention and application of "black box" warnings, we conducted a follow-up audit of valproate prescription in the same inpatient unit by reviewing records of women admitted over a 10-month period (March 2020-January 2021). Results were compared with local and international guidelines, and against data from our initial audit. Two hundred and sixty-one women of childbearing age were admitted over the sampling period, 26 of whom (10%) were prescribed valproate on discharge. Over three quarters (77%) of these patients had diagnoses other than bipolar affective disorder, valproates only approved psychiatric indication in New Zealand. Following intervention, significant improvements were observed in several key indicators of prescribing quality: pregnancy testing, documentation of contraception status, and discussion of teratogenic risk. Following intervention, re-audit demonstrated reduced prescription of valproate and improved management of its teratogenic risk in women of childbearing age receiving inpatient psychiatric care. These results demonstrate the value of a systematic approach to improve prescribing practice.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

Abstracts 13th PCNE Working Conference “Pharmacies' new roles in pharmaceutical care: bridging research and practice”

Abstracts 13th PCNE Working Conference “Pharmacies' new roles in pharmaceutical care: bridging research and practice”

Developmental Toxicity Studies: The Path towards Humanized 3D Stem Cell-Based Models

Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification.

Lithium management in pregnant patients with bipolar disorder

IntroductionWomen with bipolar disorder often ask their treating clinician for information about family planning, as they are concerned about the impact of their illness on offspring. Pregnancy places additional stress on patients, and physiological changes are particularly acute during postpartum. On the other hand, the risk of abnormalities and teratogenicity from psychotropic drugs is significant. The decision wether resuming or discontinuating lithium is discussed.ObjectivesWe present a theoretical review on the topic.MethodsA bibliographic review is presented.ResultsThe choice to continue medication during pregnancy balances the risks of an untreated illness with the risks of medication exposure. Abrupt discontinuation of psychotropic medications is associated with an increased risk for illness recurrence. Women with BD who discontinue their medications before or during pregnancy have a 71% risk of recurrence with new episodes occurring most frequently in the first trimester. Recurrent illness during pregnancy is associated with a 66% increase in the risk of postpartum episodes. Untreated or under-treated BD during pregnancy is associated with poor birth outcomes independent of pharmacotherapy exposure, including preterm birth, low birth-weight, intrauterine growth retardation, small for gestational age, fetal distress, and adverse neurodeve- lopmental outcomes. Women with untreated BD also have behavioral risk factors such as decreased compliance with prenatal care, poor nutrition, and high-risk behaviors. Impaired capacity to function may result in loss of employment, health care benefits, and social support. The biological and psychosocial risks of a BD episode are the justification for the risk of medication exposure.Fetal exposure to lithium has been associated with an increased risk for cardiac abnormalities. The risk for Ebstein’s anomaly with first trimester exposure is 1 (0.1%) to 2 in 1000 (0.2%), but the absolute risk remains low. Folate supplementation with 5 mg reduces the risk and severity of congenital heart disease. Lithium toxicity causes lethargy, hypotonia, tachycardia, coma, cyanosis, and chronic twitching in the newborn.Strategies to minimize fetal exposure and maintain efficacy include using the lowest effective dose, prescribing lithium twice daily to avoid high peak serum concentrations, and regular monitoring of lithium serum concentrations. The effective serum concentration must be established before pregnancy. If a therapeutic concentration has not been established, the lithium dose is titrated to a concentration within the therapeutic range. Breast feeding is discouraged in women taking lithium because of the high rate of transmission to the infant.ConclusionsTreatment decisions for pregnant women with mood disorders must weigh the potential for increased risks of lithium during pregnancy, especially during the first trimester, against its effectiveness at reducing relapse.Disclosure of InterestNone Declared

Using Rabbit Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Investigate Drug-Induced Fetal Heart Malformations

Introduction: Teratogenic events such as fetal heart malformations are serious and tragic drug-induced toxicities. Preclinical studies conducted during drug safety evaluation are intended to identify teratogenic risks using rodent and nonrodent models, largely based on the experience with thalidomide, which is teratogenic in humans and rabbits but refractory in rodents. Methods: To study the teratogenic properties of thalidomide in rabbit, a novel method was designed to develop cardiomyocytes (CMs) from rabbit induced pluripotent stem cells (rbiPSCs). Throughout the course of differentiation, rbiPSC-CMs were examined by real time polymerase chain reaction, high-content analysis, calcium flux measurements, and electrophysiology to confirm the cell's mature CM phenotype. The effects of thalidomide were then measured in each of the endpoints when present throughout differentiation. Results: As early as differentiation day (DD) 3 of the differentiation, rbiPSCs begin to express early CM markers (e.g., NXK2.5) and mesodermal markers (e.g., FOXF1). By DD 21, rbiPSC-CMs expressed messenger RNA (mRNA) and protein of mature CM genes, including TNNT2, HCN4, and KCNJ2. Spontaneous beating was observed by microscopy and electrophysiology as early as DD 8, and live cell calcium probes demonstrated pulsatile calcium flux. Thalidomide treatment to rbiPSC-CMs downregulated mRNA and protein of early and mature cardiac markers, suggesting suppressed differentiation. In addition, thalidomide treatment abrogated the onset of spontaneously beating cells. Conclusions: Taken together, these data indicate that rbiPSC-CMs can recapitulate thalidomide-induced cardiac teratogenicity observed in rabbits. Moving forward, this model can be deployed to investigate the underlying mechanisms of rabbit teratogenicity and better understand species-specific differences in drug-induced fetal heart malformations.

Antiseizure Medications in Pregnancy.

Epilepsy affects up to 15 million of people assigned female at birth of childbearing age globally. Up to 65% of these people with epilepsy and gestational capacity have an unplanned pregnancy. Seizure control during pregnancy is important for both the childbearer's and fetus' safety. There are multiple antiseizure medications (ASMs) that can be used to control epilepsy; however, each medication has its own teratogenic risk profile, which must be considered. The majority of these ASMs will require frequent plasma concentration monitoring during pregnancy with corresponding dosage adjustments. Dosages can be reduced back to prepregnancy levels within 3weeks postpartum. Breastfeeding on ASMs is recommended.

Determination and risk assessment of pharmaceutical residues in the urban water cycle in Selangor Darul Ehsan, Malaysia.

The environmental fate of non-steroidal anti-inflammatory drugs (NSAIDs) in the urban water cycle is still uncertain and their status is mainly assessed based on specific water components and information on human risk assessments. This study (a) explores the environmental fate of NSAIDs (ibuprofen, IBU; naproxen, NAP; ketoprofen, KET; diazepam, DIA; and diclofenac, DIC) in the urban water cycle, including wastewater, river, and treated water via gas chromatography-mass spectrophotometry (GCMS), (b) assesses the efficiency of reducing the targeted NSAIDs in sewage treatment plant (STP) using analysis of variance (ANOVA), and (c) evaluates the ecological risk assessment of these drugs in the urban water cycle via teratogenic index (TI) and risk quotient (RQ). The primary receptor of contaminants comes from urban areas, as a high concentration of NSAIDs is detected (ranging from 5.87 × 103 to 7.18 × 104 ng/L). The percentage of NSAIDs removal in STP ranged from 25.6% to 92.3%. The NAP and KET were still detected at trace levels in treated water, indicating the persistent presence in the water cycle. The TI values for NAP and DIA (influent and effluent) were more than 1, showing a risk of a teratogenic effect. The IBU, KET, and DIC had values of less than 1, indicating the risk of lethal embryo effects. The NAP and DIA can be classified as Human Pregnancy Category C (2.1 > TI ≥ 0.76). This work proved that these drugs exist in the current urban water cycle, which could induce adverse effects on humans and the environment (RQ in high and low-risk categories). Therefore, they should be minimized, if not eliminated, from the primary sources of the pollutant (i.e., STPs). These pollutants should be considered a priority to be monitored, given focus to, and listed in the guideline due to their persistent presence in the urban water cycle.

The Awareness and Adherence of the Valproate Pregnancy Prevention Program: A Questionnaire Survey among Healthcare Professionals, Pharmacists, and Patients in Denmark.

The European Medicine Agency (EMA) provided additional recommendations regarding the use of valproate during pregnancy in 2018 by introducing a pregnancy prevention program (PPP). This study aimed to investigate the adherence and the impact of the PPP and the awareness of valproate teratogenicity among Danish healthcare professionals (HCPs) and patients. As part of the EMA initiated multi-country survey, web-based questionnaires were distributed among Danish general practitioners (GPs), medical specialists, pharmacists, and patients. A total of 90 prescribers, 98 pharmacists, and 103 patients were included in the study. Some 95.0% of the prescribers, 78.6% of the pharmacists, and 81.6% of the patients were aware of the teratogenic risks of valproate. The patient guide (27.8%), the HCP guide (23.3%), direct healthcare professional communication (23.3%), and the warning sign on the outer medication package (23.5%) were the most applied measures from the PPP. A total of 54.4% of the prescribers and 32.7% of the pharmacists informed patients about the importance of effective contraception during the use of valproate. The study showed that in Denmark HCPs and patients are highly aware of the teratogenic effects of valproate. However, adherence to and the impact of the measures included in the PPP were low.

Trends in antiseizure medications utilization among women of childbearing age with epilepsy in Poland between 2015 and 2019

PurposeTo determine trends in the use of antiseizure medications (ASMs) among women of childbearing age (WOCA) and girls aged 12–14 years with epilepsy between 2015 and 2019 in Poland. MethodsThe study used data from the Pex database, which captures information on prescriptions dispensed from 85% of community pharmacies in Poland. The prescriptions issued by neurologists who provide epilepsy care in Poland were studied. Six of the most commonly prescribed ASMs were analyzed: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate. ResultsThe use of valproate and carbamazepine decreased in all age groups. Among the newer ASMs, the use of lamotrigine, levetiracetam, and topiramate increased and oxcarbazepine decreased significantly in WOCA. The only subgroup with statistically significant changes in all ASMs prescriptions were women aged 19–34 years. For girls aged 12–14 years, significant changes were found only for valproate and carbamazepine. In the last year of observation (2019) valproate and lamotrigine accounted for two-thirds of ASMs units prescribed to WOCA. Valproate accounted for half of the prescribed drug units in girls aged 12–14 years. The lowest rates of VPA prescriptions were found in women aged 19–34 years. ConclusionsThere is a change in prescribing habits in WOCA with epilepsy in Poland with trends toward using less teratogenic ASMs. However, many WOCAs are treated with valproate and topiramate despite their known teratogenicity risk. Valproate is still the most commonly prescribed ASM in WOCA and girls aged 12–14 years. Educational interventions for healthcare professionals are needed to improve prescribing practices in WOCA with epilepsy in Poland.

Genetic Influences on Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorder (FASD) encompasses the range of deleterious outcomes of prenatal alcohol exposure (PAE) in the affected offspring, including developmental delay, intellectual disability, attention deficits, and conduct disorders. Several factors contribute to the risk for and severity of FASD, including the timing, dose, and duration of PAE and maternal factors such as age and nutrition. Although poorly understood, genetic factors also contribute to the expression of FASD, with studies in both humans and animal models revealing genetic influences on susceptibility. In this article, we review the literature related to the genetics of FASD in humans, including twin studies, candidate gene studies in different populations, and genetic testing identifying copy number variants. Overall, these studies suggest different genetic factors, both in the mother and in the offspring, influence the phenotypic outcomes of PAE. While further work is needed, understanding how genetic factors influence FASD will provide insight into the mechanisms contributing to alcohol teratogenicity and FASD risk and ultimately may lead to means for early detection and intervention.

EmbryoTox: Using Graph-Based Signatures to Predict the Teratogenicity of Small Molecules.

Teratogenic drugs can lead to extreme fetal malformation and consequently critically influence the fetus's health, yet the teratogenic risks associated with most approved drugs are unknown. Here, we propose a novel predictive tool, embryoTox, which utilizes a graph-based signature representation of the chemical structure of a small molecule to predict and classify molecules likely to be safe during pregnancy. embryoTox was trained and validated using in vitro bioactivity data of over 700 small molecules with characterized teratogenicity effects. Our final model achieved an area under the receiver operating characteristic curve (AUC) of up to 0.96 on 10-fold cross-validation and 0.82 on nonredundant blind tests, outperforming alternative approaches. We believe that our predictive tool will provide a practical resource for optimizing screening libraries to determine effective and safe molecules to use during pregnancy. To provide a simple and integrated platform to rapidly screen for potential safe molecules and their risk factors, we made embryoTox freely available online at https://biosig.lab.uq.edu.au/embryotox/.

Management of epilepsy in pregnancy: What we still need to learn

Safe pregnancies have been a major concern for women with epilepsy. With more than 50 years of research, we have learned that antiseizure medications (ASMs) differ in their teratogenic risk. Valproate is associated with greater risks for malformations and adverse neurodevelopmental outcomes than other ASMs. Furthermore, seizure control is important for maternal health in pregnancy and it can be affected by a decline in serum concentrations of many ASMs during pregnancy.However, significant knowledge gaps remain. First, there is insufficient evidence about the relative teratogenic risks of most newer generation ASMs, as well as diverse ASM combinations. Similarly, information on gestation-induced changes in maternal serum levels and transfer into breastmilk is inadequate for the majority of the newer ASMs. Further, the optimal dose of folate supplementation remains unknown for women with epilepsy. Finally, most of previous studies on epilepsy and pregnancy come from Europe or North America. Efforts should be made to include more countries in collaboration with existing prospective epilepsy and pregnancy studies to increase the cohort size while at the same time enhancing the generalizability of the results. Large countries, such as China, present great potential to shorten the time to obtain answers to important unsolved questions.

Analysis of bisphenol-propane in dialyzer and its effect on human body

The effect of trace solvent bisphenol A (BPA) in polyether sulfone hollow fiber membrane Enttex™-16LF (E60) (produced by 3 M) low-throughput dialyzer was tested in this study. Animal experiments were conducted to evaluate its genotoxicity, carcinogenicity, and teratogenicity upon chronic exposure. The dialyzer was operated at 200 mL/min and 400 mL/min and coupled with LC-20AT liquid chromatography to detect BPA, which showed that the BPA content was less than 5 μg/kg/d at both flow rates. In animal experiments, the tolerable intake (T.I.) was calculated to be 0.5 μg/kg/d. With hemodialysis three times per week, the average patient weight was calculated at 70 kg, and the average daily BPA exposure was 0.0306 μg/kg/d. The risk of residual BPA was within the acceptable limit with polyether sulfone membrane Enttex™-16LF (E60) hollow fiber dialyzer from 3 M, without inducing risk for disability, teratogenicity, or genotoxicity.

Successful delivery using interferon α for molecular relapse of chronic myeloid leukemia after interruption of tyrosine kinase inhibitor

A tyrosine kinase inhibitor (TKI) was used to treat the patient, a 35-year-old woman who was diagnosed with chronic myeloid leukemia at the age of 22 years. Since a four-year deep molecular response (DMR) was obtained, spontaneous pregnancy was planned under TKI withdrawal. Even though her disease had advanced to MR2.0 at the time of pregnancy confirmation, 2 months from TKI cessation, interferon α therapy was initiated in light of the patient's history. Later, the patient reached MR3.0, gave birth to a healthy baby, and maintained MR3.0-4.0. TKI was resumed after about 6 months of breastfeeding. Treatment-free remission (TFR) is required for natural conception despite the teratogenicity and miscarriage risks associated with BCR::ABL1 TKIs. When planning a pregnancy, it is also necessary to take the patients' backgrounds, disease states, and medical history into account.

PS-P07-1: TERATOGENIC RISK OF FIRST TRIMESTER EXPOSURE TO ANTIHYPERTENSIVES, INCLUDING AMLODIPINE AND METHYLDOPA: AN ANALYSIS OF AN ADMINISTRATIVE DATABASE 2010–2019

Objective: No firm conclusions on the teratogenic risk of antihypertensives have been drawn, although methyldopa and amlodipine are relatively frequently prescribed in the first trimester (FT) in Japan [1]. The primary objective was to evaluate the teratogenic risk of FT exposure to antihypertensives, including amlodipine and methyldopa. Design and method: This study used a large claims database from JMDC Inc. The dates of pregnancy onset and delivery were estimated using published algorithms [2] and infant birth months. The prevalence of antihypertensive prescriptions during pregnancy was described in 91,390 women who gave birth between 2010 and 2019. The time trends of antihypertensive prescription were evaluated using a multivariate logistic regression model adjusted for maternal age. The teratogenic risk of FT antihypertensive exposure was evaluated in 1,185 women diagnosed with hypertensive disorders in the FT. The teratogenic risk of FT exposure to amlodipine and methyldopa was evaluated in 178 women who were prescribed antihypertensives in the FT. Logistic regression analysis was used to estimate the odds ratios (ORs) for overall major congenital malformations (MCMs). The results were presented for analyses adjusted for multiple confounding factors. The MCMs in claims were validated and the overall positive predictive value was 91.5% [3]. Results: Antihypertensives were prescribed to 278 (0.30%) women during their FT. The prescription prevalence in the FT was highest for methyldopa (0.13%), followed by amlodipine (0.06%), oral hydralazine (0.03%), and nifedipine (0.02%). Antihypertensives were prescribed to 2,955 (3.23%) pregnant women. Nifedipine (0.99%) was the most frequently prescribed oral antihypertensive medication, with a significant increase in annual prevalence (P < 0.0001), followed by methyldopa (0.78%), hydralazine (0.34%), and furosemide (0.14%) during pregnancy. Nicardipine (0.83%) was the most frequently prescribed injectable antihypertensive agent, with a significant increase in annual prevalence (P < 0.0001), followed by furosemide (0.42%), nitroglycerin (0.26%), and hydralazine (0.20%) during pregnancy. The adjusted OR (aOR) of MCMs in the FT prescription of any antihypertensive medication was 1.096 (95% confidence interval [CI], 0.612–1.964). The aORs of MCMs in the FT prescription of amlodipine and methyldopa were 1.161 (95% CI, 0.347–3.882) and 0.937 (0.313–2.809), respectively. Conclusions: FT exposure to antihypertensive drugs, including amlodipine and methyldopa, was not associated with MCM risk in infants. REFERENCE 1. Pharmacoepidemiol Drug Saf 2018; 27:1325–1334.2. Pharmacoepidemiol Drug Saf 2018; 27:751–762.3. Pharmacoepidemiol Drug Saf 2021; 30:975–978.

Effect of vinpocetine on embryonic heart rate in vitro

Vinpocetine is a readily available nutritional supplement claimed to improve memory and weight loss.However, it blocks the Ikr current essential for cardiac action potential repolarisation and Ikr inhibition can cause “torsade de pointes” arrhythmias and sudden death. Moreover, Ikr blockers have exhibited teratogenic effects in reproductive toxicology studies, leading to increased birth defects and embryonic mortality. The FDA advises against vinpocetine use in pregnant and prospective mothers based on animal studies showing dose-dependent fetal mortality in rats and rabbits, and cardiovascular malformations in surviving fetuses. However, the mechanisms responsible for vinpocetine's fetal toxicity remain unclear.The present study used rat embryo culture to evaluate vinpocetine and its major metabolite, apovincaminic acid, on embryonic heart rate, a possible causative factor behind its adverse effects. Both compounds induced embryonic bradycardia in a concentration-dependent manner, with vinpocetine proving more potent.The minimum vinpocentine concentration to induce bradycardia was 100 nM, a level unlikely to be reached in humans following typical doses. Embryonic arrhythmias were also observed at the highest concentrations.These results suggest that the FDA's cautionary statement may generate undue anxiety, although re-evaluation of teratogenicity risk associated with vinpocetine should be revisited if a link to cardiac arrhythmias in adults is established.

Alprazolam safety in pregnancy

Benzodiazepines are commonly prescribed for the treatment of anxiety disorders, including in pregnant women. There is conflicting information in the research literature, however, regarding benzodiazepines’ safety when used during pregnancy, with concern over both pregnancy and neonatal outcomes. Animal data have suggested potential teratogenic risk associated with alprazolam exposure, including occurrence of cleft lip and palate and limb abnormalities in rat offspring.

The quality and the accuracy of codes for terminations of pregnancy for fetal anomalies recorded in hospital databases in three countries in northern Europe.

The number of terminations of pregnancy for fetal anomalies in Europe (TOPFA) has increased over recent decades. Therefore, it is important that TOPFAs, in addition to all other birth outcomes, are included in the surveillance of congenital anomalies and in studies on possible teratogenic risks of pregnancy exposures. The aim of this study was to evaluate the quality and the accuracy of codes identifying TOPFA cases in hospital databases. TOPFA cases recorded in three EUROCAT congenital anomaly registries (Finland, 2010-2014; Funen in Denmark, 2005-2014; and northern Netherlands, 2013-2014) were linked to hospital databases using maternal IDs. A total of 2,114 TOPFA cases over the study period were identified in the registries and 2,096 (99%) of these pregnancies were identified in the hospital databases. An end of pregnancy code was present for 91% of the cases and a code for a congenital anomaly was present for 82% (with some differences across registries). The proportion of TOPFA cases with a code for a specific congenital anomaly was <50% for cases with a structural anomaly (range 0%-50%) and 70% for cases with a chromosomal anomaly. Hospital databases have limited information or codes to identify TOPFAs for specific anomalies and the data are not detailed enough for surveillance of congenital anomalies or for studies analyzing pregnancy exposures and risk of congenital anomalies. However, hospital data may be used to identify the occurrence of a TOPFA to enable more detailed information to be obtained from the medical records.

The Effect of Herbal Therapy on Emesis Gravidarum

Handling emesis gravidarum using conventional drugs has a teratogenic risk, so another effort is to provide subscriptions using herbal therapy. This study was conducted to determine the effect of herbal therapy in reducing the frequency of emesis gravidarum Method: This type of research is a literature review using the Pubmed, Research Gate, SINTA database. Literature collection strategy using the PICO framework was then analyzed until there were 16 literature that could be used. The review method used is to compare and contrast to find similarities in the types of herbal therapy and the dissimilarities of the most effective herbs. There are differences in the frequency of emesis gravidarum in the use of ginger, mint, lemon, quince, lavender, orange herbs which are provided in the form of extracts and aromatherapy. Giving herbal therapy in the form of ginger, mint, lemon, quince, lavender, orange with aromatherapy and extract preparations can reduce the frequency of emesis gravidarum.