Potential Teratogenic Effects Research Articles

Animal-free assessment of developmental toxicity: Combining PBPK modeling with the ReproTracker assay

in vitro screening platforms to assess teratogenic potential of compounds are emerging rapidly. ReproTracker is a human induced pluripotent stem cells (hiPSCs)-based biomarker assay that is shown to identify the teratogenicity potential of new pharmaceuticals and chemicals reliably. In its current state, the assay is limited to identifying the potential teratogenic effects and does not immediately quantify a clinical dose relevant to the exposure of chemicals or drugs observable in mothers or fetuses. The goal of this study was to evaluate whether the ReproTracker assay can be extrapolated in vivo and quantitatively predict developmental toxicity exposure levels of two known human teratogens, thalidomide, and carbamazepine. Here, we utilized Physiologically Based Pharmacokinetic (PBPK) modeling to describe the pharmacokinetic behavior of these compounds and conducted an in vitro to in vivo extrapolation (IVIVE) approach to predict human equivalent effect doses (HEDs) that correspond with in vitro concentrations potentially associated with adverse outcomes in ReproTracker. The HEDs derived from the ReproTracker concentration predicted to cause developmental toxicity were close to the reported teratogenic human clinical doses and the HED derived from the rat or rabbit developmental toxicity study. The ReproTracker derived-HED revealed to be sensitive and protective of humans. Overall, this pilot study demonstrated the importance of integrating PBPK model in extrapolating and assessing developmental toxicity in vitro. The combination of these tools demonstrated that they could improve the safety assessment of drugs and chemicals without animal testing.

Neonatal outcomes of pregnant women attending integrated and standard substance use treatment programs in Ontario, Canada.

Substance use in pregnancy raises concern given its potential teratogenic effects. Given the unique needs of parenting people and the potential impact for developing children, specialized substance use treatment programs are increasingly being implemented for this population. Substance use treatment is associated with more positive neonatal outcomes compared with no treatment, however treatment models vary limiting our understanding of key treatment components/modelsFew studies have explored the influence of treatment model type (i.e., integrated treatments designed for pregnant clients compared with standard treatment models) and no studies have examined the influence of treatment model on neonatal outcomes using Canadian data. We conducted a population-based cohort study of clients who were pregnant when initiating integrated (n = 564) and standard (n = 320) substance use treatment programs in Ontario, Canada. Neonatal outcomes did not significantly differ by treatment type (integrated or standard), with rates of adverse neonatal outcomes higher than published rates for the general population, despite receipt of adequate levels of prenatal care. While this suggests no significant impact of treatment, it is notable that as a group, clients engaged in integrated treatment presented with more risk factors for adverse neonatal outcomes than those in standard treatment. While we controlled for these risks in our analyses, this may have obscured their influence in relation to treatment type. Findings underscore the need for more nuanced research that considers the influence of client factors in interaction with treatment type. Pregnant clients engaged in any form of substance use treatment are at higher risk of having children who experience adverse neonatal outcomes. This underscores the urgent need for further investment in services and research to support maternal and neonatal health before and during pregnancy, as well as long-term service models that support women and children beyond the perinatal and early childhood periods.

Effect of the Aqueous Extract of Chrysobalanus icaco Leaves on Maternal Reproductive Outcomes and Fetal Development in Wistar Rats.

Toxicological studies on medicinal plants are essential to ensure their safety and effectiveness in treating various diseases. Despite the species Chrysobalanus icaco L. being popularly used in the treatment of several diseases due to the pharmacological properties of its bioactive compounds, there are few studies in the literature regarding its toxicity regarding reproduction. Therefore, the purpose of this study was to assess the potential embryotoxic and teratogenic effects of the aqueous extract of C. icaco leaves (AECi) on Wistar rats. Animals were given AECi at doses of 100, 200, and 400 mg/kg during the pre-implantation and organogenesis periods. Data were analyzed using ANOVA followed by Tukey's test and Kruskal-Wallis. Pregnant rats treated during the pre-implantation period showed no signs of reproductive toxicity. Rats that received AECi at 100, 200, and 400 mg/kg during organogenesis did not exhibit any signs of maternal systemic toxicity or significant differences in gestational and embryotoxic parameters. Some skeletal changes were observed in the treated groups. Therefore, it can be suggested that AECi at doses of 100, 200, and 400 mg/kg is safe for treated animals and does not induce reproductive toxicity under the experimental conditions applied, but it also caused low systemic toxicity.

Teratogenic effects of environmental concentration of plastic particles on freshwater organisms

Given the widespread presence of plastics, especially in micro- and nanoscale sizes, in freshwater systems, it is crucial to identify a suitable model organism for assessing the potential toxic and teratogenic effects of exposure to plastic particles. Until now, the early life stage of freshwater organisms and the regeneration capacity in relation to plastic particles exposure is a still poorly investigated topic. In this study, we examine the teratogenic effect on diatom Cocconeis placentula and cnidarian Hydra vulgaris under controlled exposure conditions of poly(styrene-co-methyl methacrylate) (P(S-co-MMA)) particles. Significant effects were observed at the lowest concentrations (0.1 μg/L). A significant increase in the teratological frequency in C. placentula and a significant decrease in the regeneration rate in H. vulgaris were found at the lowest concentration. The delay in hydra regeneration impaired the feeding capacity and tentacles reactivity at 96 h of exposure. No effects on diatom growth were observed upon exposure to P(S-co-MMA) particles (0.1, 1, 100, 10,000 μg/L) for 28 days and these findings agree with other studies investigating algal growth. The application of the Teratogenic Risk Index, modified for diatoms, highlighted a moderate risk for the lowest concentration evaluating C. placentula and low risk at the lowest and the highest concentrations considering H. vulgaris. This study suggests the importance of testing organisms belonging to different trophic levels as diverse teratogenic effects can be found and the need to evaluate environmentally relevant concentrations of plastic particles.

Complete degradation of di-n-butyl phthalate by Glutamicibacter sp. strain 0426 with a novel pathway.

Di-n-butyl phthalate (DBP) is widely used as plasticizer that has potential carcinogenic, teratogenic, and endocrine effects. In the present study, an efficient DBP-degrading bacterial strain 0426 was isolated and identified as a Glutamicibacter sp. strain 0426. It can utilize DBP as the sole source of carbon and energy and completely degraded 300mg/L of DBP within 12h. The optimal conditions (pH 6.9 and 31.7°C) for DBP degradation were determined by response surface methodology and DBP degradation well fitted with the first-order kinetics. Bioaugmentation of contaminated soil with strain 0426 enhanced DBP (1mg/g soil) degradation, indicating the application potential of strain 0426 for environment DBP removal. Strain 0426 harbors a distinctive DBP hydrolysis mechanism with two parallel benzoate metabolic pathways, which may account for the remarkable performance of DBP degradation. Sequences alignment has shown that an alpha/beta fold hydrolase (WP_083586847.1) contained a conserved catalytic triad and pentapeptide motif (GX1SX2G), of which function is similar to phthalic acid ester (PAEs) hydrolases and lipases that can efficiently catalyze hydrolysis of water-insoluble substrates. Furthermore, phthalic acid was converted to benzoate by decarboxylation, which entered into two different pathways: one is the protocatechuic acid pathway under the role of pca cluster, and the other is the catechol pathway. This study demonstrates a novel DBP degradation pathway, which broadens our understanding of the mechanisms of PAE biodegradation.

Impact of the Anti-Tuberculosis Drug Rifampicin on the Feeding, Growth and Embryonic Developmental Profile of the Mosquitofish <i>Gambusia affinis</i>

Although the accumulation of pharmaceutical drugs in aquatic bodies has increased rapidly in recent years, the effect of rifampicin (RIF), a first-line anti-tuberculosis drug, on fish feeding, growth, and embryonic development is unknown. This investigation aimed to determine the impact of RIF on growth and embryonic developmental profile in the mosquitofish Gambusia affinis. Experimental groups included controls, which were kept in normal water for 21 days, whereas those in the second, third, and fourth groups were exposed to 50, 200, and 500 mg RIF/L water, respectively. The food intake rate and Specific Growth Rate (SGR) showed a concentration-dependent significant decrease in RIF-treated fish compared with controls, and a strong positive correlation was found between food consumption and SGR. A significant decrease in the number of embryos at an early stage of development and the total number of embryos in RIF-treated fish was associated with several congenital anomalies such as lack of vitellogenin accumulation, yolk sac regression, decreased pigmentation, aggregations of blood vessels, and curvature of the spinal cord compared with controls. Together, these results reveal for the first time that RIF treatment not only impacts feeding and growth, but also exerts potential teratogenic effect on embryonic developmental stages in the mosquitofish G. affinis.

Maternal antipsychotic use during pregnancy and congenital malformations

Existing data may underestimate the potential teratogenic effects of prenatal antipsychotic exposure because of lacking data on miscarriages and induced abortions. This study aimed to present a comprehensive analysis based on information on pregnancies ending in termination, miscarriage, stillbirth, and live birth. We conducted a population-based cohort study in Denmark of clinically recognized singleton pregnancies with the first-trimester scan performed from 2008 to 2017. We compared the risk of major malformations between pregnancies exposed to antipsychotics in the first trimester and unexposed pregnancies. In secondary analyses, the comparison was made with pregnancies of women who used antipsychotics before but not during pregnancy (discontinuers). We used weighted log-binomial regression to estimate adjusted prevalence ratios and propensity score fine stratifications for confounding control. We performed 4 sensitivity analyses, including a sibling-controlled analysis. Of the 503,158 pregnancies, 1252 (0.2%) were of women who filled an antipsychotic prescription in the first trimester. Major malformations were present in 7.3% of antipsychotic-exposed pregnancies, 5.1% of unexposed pregnancies, and 6.0% of discontinuers' pregnancies. The adjusted prevalence ratio was 1.23 (95% confidence interval, 1.01-1.50) among exposed pregnancies compared with unexposed pregnancies. The prevalence ratio was attenuated to 1.14 (95% confidence interval, 0.88-1.48) compared with discontinuers and 1.08 (95% confidence interval, 0.47-2.49) in the sibling analysis. Similar findings were observed with cardiac malformations. Results were consistent for classes and individual antipsychotics, and remained robust across the 4 sensitivity analyses. Our findings suggest limited or no overall teratogenic effect of first-trimester antipsychotic exposure. For individual antipsychotics, with estimations based on very few cases, further studies with sufficient sample sizes are warranted.

Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy.

Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women. We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic. The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy. Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

Perception, knowledge, practices and training regarding the risk of exposure to antineoplastic drugs in three French compounding units.

Healthcare workers are exposed to hazardous drugs such as antineoplastic drugs, which have potential carcinogenic, mutagenic and teratogenic effects. Protective measures must be taken after appropriate staff training to handle antineoplastic drugs in a safe way. The objective was to assess perception, knowledge, practices and training regarding the risk of exposure of healthcare workers in three French compounding units. This descriptive study was based on a questionnaire made of 33 questions divided into five sections related to the handling of antineoplastic drugs: perception of the risks, knowledge of the risks, protection practices, specific training and general questions. Among the 39 participants, over half considered their overall risk of exposure to antineoplastic drugs not being very low. Inhalation was known to 69.2% of them as possible route of contamination. The breakroom was identified by 28.9% of them as a place of contamination. The procedure in case of accidental exposure to antineoplastic drugs was known by 69.2%, but only half could explain it. Only 38.5% said they changed their gloves every 30 min as recommended. Barely half said that they had been trained specifically for the handling of antineoplastic drugs during an initial training. Over half wished to be informed, trained and aware of the proper handling of antineoplastic drugs. Although some of these results are encouraging, specifically when compared to the other settings where antineoplastic drugs are handled, there is still room for improvement. Efforts to build an adapted and impactful training program must pursue. Study CONTACT, ref. 19-504.

MANAGING ANTI-EPILEPTIC DRUGS DURING PREGNANCY ; EVOLVING CONCEPT

Epilepsy is one of the few neurological disorders that require a constant treatment during pregnancy.Besides epilepsy Anti-epileptic drugs (AEDs) are also commonly used for psychiatric disorders,pain disorders,and migraines. No Anti-epileptic drugs is safe during pregnancy . Anti-epiletic drugs exposure during pregnancy causing intra- uterine growth retardation,cognitive dysfunction,low IQ,microcephaly,major conjenital anomalies and infant mortality. Use of anti-epileptic drugs (AEDs) in pregnant women with epilepsy requires monitorning and maintaining a balance between limiting seizures and decreasing fetal exposure to the potential teratogenic effects. In this review we analysed the data on the pharmacokinetics of various AEDs in pregnancy, neurological teratogenic effects and providing a basis for management of safety of AEDs during pregnancy

Prevalence, predictors and pregnancy outcomes of unprescribed and herbal medicine use in Ibadan, Nigeria

BackgroundUnprescribed and herbal medicines use among pregnant women is a public health concern in low and middle-income countries because of the potential teratogenic effects, insufficient safety and weak drug regulatory systems. Unprescribed and herbal medicines are common among pregnant women in Nigeria, and only a few researchers have documented the prevalence and the risk factors. However, evidence on the associated pregnancy outcomes is still lacking. We assessed the prevalence, predictors and pregnancy outcomes of unprescribed and herbal medicines use among pregnant women in Ibadan, Nigeria.MethodsThis study was a component of the Ibadan Pregnancy Cohort Study, a prospective cohort study, among pregnant women in Ibadan, Nigeria, who were enrolled at ≤ 20 weeks gestation at their first antenatal visit and followed up till delivery. In all, 571 women participated in the maternal drug use assessment during the third trimester using a pretested interviewer-administered questionnaire. The primary outcomes were unprescribed and herbal medicines use and pregnancy outcomes, secondary outcomes, were abstracted from medical records. The predictors assessed included sociodemographic, obstetric, antenatal care utilization, and lifestyle characteristics. Bi-variate logistic and Poisson regression analyses were used to evaluate the predictors and relative risk for the pregnancy outcomes of unprescribed and herbal medicines at 5% significance.ResultsThe prevalence of unprescribed and herbal medicine use was 31.9% and 21.7%, respectively. On bivariate analysis, the significant predictors of unprescribed medicine (which were protective) were tertiary education, increasing income, adequate antenatal care (≥ 4 visits), and at least two doses of sulfadoxine-pyrimethamine. However, high parity and having an antenatal admission increased the risk. However, after adjusting for confounders, the significant factors associated with unprescribed medicines were; tertiary education (AOR) = 0.23; 95% CI: (0.06 – 0.95); p-value: 0.043] and obtaining at least two doses of sulfadoxine-pyrimethamine [AOR = 0.33; 95% CI: (0.29 – 3.60); p-value: 0.048]. For herbal medicines, the predictors were similar to unprescribed drugs. However, after adjusting for confounders, none was significant for herbal medicines. Unprescribed and herbal medicines were not significantly associated with pregnancy outcomes.ConclusionsUnprescribed and herbal medicines use were common among pregnant women in Ibadan, Nigeria, particularly among women with low economic status and those with poor utilization of antenatal care services. These significant predictors can be targeted for public health intervention. Specifically, health education that discourages the use of unprescribed and herbal medications to pregnant women during antenatal care.

ВЛИЯНИЕ ЦИКОРИЯ ОБЫКНОВЕННОГО (CICHORIUM INTYBUS L.) НА РЕПРОДУКТИВНУЮ ФУНКЦИЮ КРЫС

Currently, the development of new domestic medicines-hepatoprotectors for veterinary medicine is an urgent task because liver diseases of various genesis in animals occupy a leading place in the list of non-infectious pathologies. Of particular interest are medicinal plants and substances based on them, which influence the main mechanisms of the development of liver diseases. Such plants include chicory – from the aerial part of which a dry extract with a pronounced hepatoprotective effect has been obtained and standardized at the All-Russian Research Institute of Medicinal and Aromatic Plants. The objective of our study was to study the effect of dry extract of chicory aerial part on the reproductive function of rats in order to preclinically assess the safety of its use during pregnancy. The article presents the results of studying the potential embryotoxic and teratogenic effects of extract recorded in the antenatal and postnatal periods of development of the offspring of rats receiving the studied extract intragastrically at doses of 100 and 500 mg/kg from the 1st to the 6th and from the 6th to the 19th days of pregnancy. When administered in both periods of pregnancy in the tested doses, the dry extract of cichory did not cause a decrease in the body weight of pregnant women, an increase in pre- and post-implantation mortality of embryos, did not affect the body weight and craniocaudal size of 20-day-old rat fetuses, the rate of ossification of cartilaginous bone bookmarks, the condition of the internal organs of embryos. The introduction of the dry extract in the first six days of pregnancy does not have a negative effect on the postnatal development of offspring. However, when the studied extract is administered at the maximum tested dose from 6-19 days of pregnancy, it helps to slow down the formation of sensory-motor reflexes in the offspring. Taking into account the changes obtained, the administration of drugs based on the studied extract to pregnant animals during organo- and fetogenesis should be carried out under the supervision of a veterinarian in compliance with the therapeutic dose.

Ameloriate Effect of Glucose Monohydrate on Nicotine Sulfate-induced Toxicity and Teratogenicity in Xenopus embryos: an Experimental Study

It is well documented that nicotine causes low birth weight, preterm birth, pregnancy difficulties, lower fertility, inhibition of spermatogenesis, and decreased steroidogenesis and potassium channels conductance of Xenopus oocytes. Lung cancer is the most well-known adverse impact of nicotine. This work used a 96-hour FETAX test to examine how concurrent administration of glucose monohydrate modifies the effects of exposure to nicotine, nicotine sulfate, and/or glucose on ion channels and membrane potential in Xenopus leavis embryos at an early stage of development. In-vitro fertilised embryos were treated with nicotine and glucose alone or in combination for this aim, and the effects of those treatments were then assessed for potential teratogenic effects. At the conclusion of the FETAX technique, the ratios of healthy, abnormal, and dead embryos were calculated, and the length of embryos in each treatment group was assessed. The ratios of abnormal and dead embryos were considerably higher with nicotine treatment alone compared to controls. Compared to the results of the nicotine-alone treatment group, the ratio of aberrant embryos was marginally reduced by concurrent glucose and nicotine therapy. In contrast, the ratio of normal embryos was raised. Additionally, treatments with glucose, nicotine, and Nic+Glu significantly altered the resting membrane potentials of fertilised oocytes (p < 0.001). Our findings indicated that the simultaneous treatment groups that also received glucose had a protective impact on embryos. Such structured, more sophisticated research is required to confirm these findings.

Incidence of Herbal Use among Pregnant Women Attending Family Care Center

Background and Aim: Numerous investigations around the globe verified the increasing trend of medicine and complementary use in pregnant women. Pregnant women are not informed of potential teratogenic effects from traditional medicines; some herbal products may cause birth defects in humans. Pregnant women's use of traditional medicine has not yet been evaluated in Pakistan. The present study aimed to determine the incidence of herbal use among pregnant women attending family care centers. Material and Methods: This hospital-based cross-sectional study was conducted on 320 pregnant women attending Family care centers in Jamshoro Hyderabad and Mirpur AJK for the duration of six months from January 2022 to June 2022. Pregnant women attending antenatal care and volunteering to respond were enrolled and those with mental illness and were unwilling to respond were excluded. Herbal medicine self-medication was a dependent variable whereas gestational age, sociodemographic details, and herbal medicine history were independent variables. A questionnaire was designed for determining prior history of herbal use, types of herbal medicine, herbal used in current pregnancy. SPSS version 26 was used for data analysis. Results: Of the total 320 pregnant women, the incidence of herbal use was 86 (26.9%). Based on age, pregnant women were grouped as follows: 64 (20%) in 17-25 years, 148 (46.2%) in 26-35 years, and 108 (33.8%) 35-45 years. The prevalence of herbal usage in the first, second, and third trimesters was 62 (72.1%), 9 (10.5%), and 8 (9.3%), respectively, among 86 herbal-using pregnant women. About 7 (8.1%) pregnant women used herbs in all trimesters. Garlic (Allium sativum) 32 (37.2%), Ginger (zingiberofcinale) 40 (46.5%), Eucalyptus 6 (7%), and tenaadam 8 (9.3%) were different types of herbs used by pregnant women. Conclusion: The present study found that about 26.9% pregnant women used herbal medicine during pregnancy. Majority of women used herbal medicine in the first trimester followed by second and third. Ginger was the most commonly used herbal medicine followed by garlic and tenaadam. Nausea, morning sickness, and vomiting was the most prevalent clinical indications. Keywords: Herbal Medicine, Prevalence, Trimester, Pregnant women

Lymphocytic choriomeningitis virus: An under-recognized congenital teratogen.

BACKGROUNDLymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne arenavirus associated with transplacental transmission and fetal infection. AIMTo summarize the epidemiological, clinical, and diagnostic features of reported patients with congenital LCMV infection.METHODSA literature search was conducted in PubMed, Medline, Google Scholar, and ResearchGate. The keywords used were ‘congenital lymphocytic choriomeningitis virus,’ and 48 studies were included. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com).RESULTSThe results have shown 27 reports of congenital LCMV infection in 86 patients, with 52.73% of them being males. Patients presented with chorioretinitis (83.53%), hydrocephalus (54.12%), and psychomotor retardation or developmental delay (54.12%). Computed tomography and/or magnetic resonance imaging most often demonstrated ventriculomegaly (74.07%), periventricular calcifications (66.67%), and microcephaly (40%). Most mothers of congenitally infected infants were exposed to rodents during pregnancy, predominantly mice, with flu-like symptoms mainly occurring during the first two trimesters of gestation. Mortality in congenitally infected children was 16.47%. The diagnosis of congenital LCMV infection was confirmed serologically in most patients (86.67%).CONCLUSIONLCMV is still an insufficiently recognized fetal teratogen that often leads to long-term neurologic sequelae. Clinicians need to be familiar with LCMV and its potential teratogenic effect and as well as to effectively differentiate LCMV from other TORCH (T: Toxoplasma gondii, O: Other pathogens, R: Rubella virus, C: Cytomegalovirus, H: Herpes simplex virus) pathogens.

Cytogenetic Analysis of a Mare and Her Foal with Suspected Genetic Causes of Disability

Abstract Hereditary diseases represent a serious problem in horses, especially in terms of sport use and breeding. Nowadays, we know the genetic basis of several breed-specific inherited diseases. In this study, we focused on the cytogenetic analysis of the clinical case of a healthy mare and her foal with numerous malformations in order to confirm or disprove the suspicion of genetic causes of a disability in this offspring. We used conventional metaphase staining to analyse chromosomal aberrations – breaks and gaps. In general, the number of breaks exceeding the norm (2—3 breaks/100 meta-phases) may indicate the influence of the external environment with a potential teratogenic effect on the offspring during its mother gravidity. Compared to the norm, we found a slightly increased percentage of chromosomal aberrations in both the mother and the foal. As another method, we used karyotyping to assess the number and morphology of chromosomes, where in addition to conventional staining, we also applied differential staining of metaphases (G-banding). Multiplication, loss or rearrangement of chromosome segments are almost always associated with pathology. In the karyotypes we constructed, we observed changes in both individuals, compared to the international standard; in the mare, we probably recorded the mosaic form of her karyotype. In the foal, we found 64, XX with a suspected morphological change which was probably related to autosomal chromosome pair 31. The cytogenetic analysis of suspected individuals is also very beneficial for horse owners and breeders. Thanks to the combination of cytogenetic and modern molecular-genetic methods, we were able to identify individuals unsuitable for breeding.

Persistently Raised Serum Titanium Levels After Spinal Instrumentation in Children.

Prospective study of patients undergoing elective spinal deformity surgery with repeated testing for circulating metal ions including preoperative levels acting as controls. The aim was to determine if levels of particular circulating metal ions are maintained to two years postsurgery including different implant systems and rods. Adults having hip replacements, especially metal-on-metal bearings, may develop high metal ion levels. Pediatric spinal implants are known to cause circulating metal ions, notably titanium, chromium, cobalt, and nickel. Fifty-six children having spinal deformity surgery were studied with repeated testing for circulating metal ions, using high-resolution inductively coupled plasma mass spectrometry. Linear mixed-effects models adjusting for repeated measurements over time were used to analyze levels of titanium, cobalt, chromium, and nickel. Titanium levels showed a rapid increase by seven days and a peak at 30 days that was essentially maintained at the two-year assay. At two years, titanium levels were 5.14 times greater compared with the presurgery control level (P<0.0001). Cobalt levels were shown to gradually rise to a peak at 30 days and then slowly decline but remained 1.74 times above mean baseline level at two years (P=0.0004), with a declining trajectory. Chromium and nickel levels rose immediately postoperatively and then steadily declined to baseline by six months and remained at baseline at two years. The five implant systems tested had generally equivalent results. The persistent and rising levels of titanium, in a predominantly female population, is concerning. Titanium is known to cross the placental barrier and enter the circulation of the fetus in rodents and humans, and to accumulate in solid organs especially the liver, spleen, heart, and lymph nodes in humans. This potentially exposes the offspring of mothers with spinal implants to titanium, with potential teratogenic effects.

In vivo pharmacokinetic analyses of placental transfer of three drugs of different physicochemical properties in pregnant rats

Although the use of medication during pregnancy is common, information on exposure to the developing fetus and potential teratogenic effects is often lacking. This study used a rat model to examine the placental transfer of three small-molecule drugs with molecular weights ranging from approximately 300 to 800 Da with different physicochemical properties. Time-mated Sprague Dawley (Hsd:SD) rats aged 11–13 weeks were administered either glyburide, rifaximin, or fentanyl at gestational day 15. Maternal blood, placentae, and fetuses were collected at 5 min, 30 min, 1 h, 4 h, 8 h, 24 h, 48 h, and 96 h post-dose. To characterize the rate and extent of placental drug transfer, we calculated several pharmacokinetic parameters such as maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration–time curve (AUC), half-life (t1/2), clearance (CL), and volume of distribution (Vd) for plasma, placenta, and fetus tissues. The results indicated showed that fetal exposure was lowest for glyburide, accounting for only 2.2 % of maternal plasma exposure as measured by their corresponding AUC ratio, followed by rifaximin (37.9 %) and fentanyl (172.4 %). The fetus/placenta AUC ratios were found to be 10.7 % for glyburide, 11.8 % for rifaximin, and 39.1 % for fentanyl. These findings suggest that although the placenta acts as a protective shield for the fetus, the extent of protection varies for different drugs and depends on factors such as molecular weight, lipid solubility, transporter-mediated efflux, and binding to maternal and fetal plasma proteins.

Effect of Rythmol (propafenone HCl) administration during pregnancy in Wistar rats.

Propafenone is a well-known Class 1C antiarrhythmic agent that has sodium channel blocking properties as well as the ability to block 13 other channels and a modest calcium antagonistic effect. Propafenone has a profound electrophysiologic effect on auxiliary atrioventricular circuits and in patients with atrioventricular nodal reentry tachycardia can obstruct conduction in the fast conducting pathway. Furthermore, propafenone is less likely than other Class 1C drugs to cause proarrhythmia. However, although this medicine can pass through the placenta, the effects during pregnancy remain unknown. Here, we investigated the potential teratogenic and genotoxic effects of Rythmol during rat development. Pregnant Wistar rats received 46.25 mg/kg body weight of propafenone daily by gavage from Gestation Day (GD) 5 to GD 19. At GD 20, the dams were dissected, and their fetuses were assessed via morphologic, skeletal, and histologic investigation. In addition, a comet assay was used to measure DNA impairment of fetal skull osteocytes and hepatic cells. The study showed that propafenone treatment of pregnant rats led to a marked decrease in gravid uterine weight, number of implants/litter, number of viable fetuses, and bodyweight of fetuses but a clear increase in placental weight and placental index in the treated group. Frequent morphologic abnormalities and severe ossification deficiency in the cranium bones were observed in the treatment group. Various histopathological changes were observed in the liver, kidney, and brain tissues of maternally treated fetuses. Similarly, propafenone induced DNA damage to examined samples. Thus, our study indicates that propafenone may be embryotoxic in humans.

P030 Quality improvement project on awareness in patients to stop teratogenic disease-modifying anti-rheumatic drugs (DMARDs) while planning pregnancy and need for highly effective contraception

Abstract Background/Aims The MHRA (Medicines and Healthcare Products Regulatory Agency) published guidelines in February 2018 on highly effective contraception (injectable/IUCD/partner vasectomy) for women of childbearing age consuming potentially teratogenic DMARDs (disease-modifying anti-rheumatic drugs) which might result in increased risk of birth defects. Objective: A quality improvement project was carried out in the rheumatology department at James Cook University Hospital, Middlesbrough to assess patient awareness of the potential teratogenicity of the DMARDS like methotrexate, leflunomide and mycophenolate mofetil and need for highly effective contraception to avoid foetal complications. Methods A spot audit was carried out from June to September 2019, through patient questionnaires to assess awareness in women of childbearing age (15- 45 years) about the potential teratogenic effects of these DMARDs and the need for highly effective contraception. Following this audit more tailored consent forms were introduced in February 2020 to increase awareness of potential teratogenicity at initiation of DMARDs with robust counselling. Subsequent to this we carried out quality improvement project to accumulate similar data between June and September 2021. Results Data were collected from 43 patients during the spot and 27 patients during the second cycle. 88% patients were on methotrexate, 9% on MMF, 2% on leflunomide and 2% on multiple DMARDS during the first audit compared to 66.6% on methotrexate, 16.6% on leflunomide and 6% on MMF during the second cycle. It was very positive to see 74% of patients reporting increased awareness about potential teratogenicity of the DMARDS gained through counselling compared to the 37% previously. 90% of the patients were aware to stop these DMARDs when planning pregnancy compared to the 88% previously. We achieved 100% awareness that the medication should be stopped in pregnancy compared to 90% previously. Rates of contraception use were comparable across cycles - 54% during the first cycle and 56.7% during the second. Of patients using contraception, 33.3% were using highly effective contraception the first cycle which improved to 37% during the second cycle. Nearly 44.4% patients were not on any contraception. Reasons why contraception was not used was not explored which was beyond remit of this project. Since this is a significant proportion there is certainly a need for further assessment and analysis. Conclusion Overall this quality improvement project has highlighted the need for robust counselling as well as structured and informative consent forms to improve the awareness of teratogenicity with certain DMARDs therapy in woman of childbearing age. In spite of increased awareness of the teratogenicity of these DMARD 44.4% patients were not on any form of contraception. There is definitely room for improvement in effectively disseminating information regarding highly effective form of contraception to prevent inadvertent exposure during pregnancy which may result in foetal birth defects. Disclosure F.A. Khan: None.