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STUDY QUESTION What are the roles of maternal preconception diabetes and related periconceptional hyperglycemia on the risk of major congenital malformations (MCMs) in offspring? SUMMARY ANSWER Maternal periconceptional glycated hemoglobin (HbA1c) levels over 5.6% were associated with an increased risk of congenital heart defects (CHD) in the offspring, and maternal preconception diabetes was associated with an increased risk of CHD, including when HbA1c levels were within euglycemic ranges. WHAT IS KNOWN ALREADY Maternal preconception diabetes has been linked with MCMs in the offspring. However, evidence concerning associations with specific periconception serum measures of hyperglycemia, and susceptibility of different organ systems, is inconsistent. Moreover, limited evidence exists concerning the effectiveness of antidiabetic medications in mitigating diabetes-related teratogenic risks. STUDY DESIGN, SIZE, DURATION A large Israeli birth cohort of 46 534 children born in 2001–2020. PARTICIPANTS/MATERIALS, SETTING, METHODS Maternal HbA1c test results were obtained from 90 days before conception to mid-pregnancy. Maternal diabetes, other cardiometabolic conditions, and MCMs in newborns were ascertained based on clinical diagnoses, medication dispensing records, and laboratory test results using previously validated algorithms. Associations were modeled using generalized additive logistic regression models with thin plate penalized splines. MAIN RESULTS AND THE ROLE OF CHANCE Maternal periconceptional HbA1c value was associated with CHD in newborns, with the risk starting to increase at HbA1c values exceeding 5.6%. The association between HbA1c and CHD was stronger among mothers with type 2 diabetes mellitus (T2DM) compared to the other diabetes groups. Maternal pre-existing T2DM was associated with CHD even after accounting for HbA1C levels and other cardiometabolic comorbidities (odds ratio (OR)=1.89, 95% CI 1.18, 3.03); and the OR was materially unchanged when only mothers with pre-existing T2DM who had high adherence to antidiabetic medications and normal HbA1c levels were considered. LIMITATIONS, REASONS FOR CAUTION The rarity of some specific malformation groups limited the ability to conduct more granular analyses. The use of HbA1c as a time-aggregated measure of glycemic control may miss transient glycemic dysregulation that could be clinically meaningful for teratogenic risks. WIDER IMPLICATIONS OF THE FINDINGS The observed association between pre-existing diabetes and the risk of malformations within HbA1c levels suggests underlying causal pathways that are partly independent of maternal glucose control. Therefore, treatments for hyperglycemia might not completely mitigate the teratogenic risk associated with maternal preconception diabetes. STUDY FUNDING/COMPETING INTEREST(S) The work was supported by NIH grants K99ES035433, R01HD097778, and P30ES000002. None of the authors reports competing interests. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

This report is the first comprehensive update on the activities of existing epilepsy‐pregnancy registries since 2010. The primary aim of these registries, which were initiated by independent international research groups some 25 years ago, has been to assess the risk of major congenital malformations (MCMs) in offspring exposed in utero to different antiseizure medications (ASMs). Progress reports are provided here from the five original registries (the International Registry of Antiepileptic Drugs and Pregnancy EURAP, the North American Antiepileptic Drug Pregnancy Registry, the UK and Ireland Epilepsy and Pregnancy Register, the Kerala Registry of Epilepsy and Pregnancy, and the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs) plus the more recently initiated West China Registry. Since their inception, the registries have published a wealth of data revealing important differences in risks across the most frequently used ASM treatments, thereby facilitating rational management of women with epilepsy who are of childbearing potential. Although the number of pregnancies enrolled in the different registries has more than doubled since the 2010 report, many questions remain. These include outcomes following prenatal exposure to most of the newer ASMs or different ASM combinations, as well as associations with specific MCMs rather than MCMs as a collective. All the registries, therefore, remain active and continue to enroll pregnancies. Administrative health care databases have been utilized more recently for the assessment of MCM risks and other adverse pregnancy outcomes associated with in utero exposure to ASMs. Although these can provide population‐based complementary information, they cannot replace the specific epilepsy‐pregnancy registries with their more detailed validated individual information. Given the multiple newer ASMs that are increasingly used and the continuing multiple knowledge gaps for the older ASMs, epilepsy‐pregnancy registries will continue to play an important role in the future. [ABSTRACT FROM AUTHOR]

Background: About 80% of pregnant women use at least one medication during their pregnancy period. Many drugs that are not allowed to be used during pregnancy (from FDA Pregnancy Categories D and X) were used. Irrational use of these drugs during pregnancy may result in different birth defects, as explained by thalidomide and diethylstilbestrol's tragedy. Knowledge of drug utilization and associated factors that affect the pattern is important to enhance rational prescribing. But information about prescription patterns and associated factors among pregnant women is scarce in the Debre Tabor area and generally in Ethiopia. Objective: This study was aimed at assessing drug prescription patterns, potential teratogenicity, and associated factors among pregnant women attending the antenatal care unit at Debre Tabor Comprehensive Specialized Hospital, Debre Tabor, Northwest Ethiopia. Methods: A retrospective cross‐sectional study design was performed on 359 pregnant women attending antenatal care units from June 01, 2022, to August 30, 2022, in the hospital. Necessary data were obtained through a questionnaire by reviewing the medical charts of the women. Analysis of the data was performed using SPSS Version 23. The association of the independent variables to medication use was assessed using multivariate logistic regression. A p value of less than 0.05 was considered significant. Results: Most of the study participants (325/359) were married (90.5%). From a total of 359 participants, 350 (97.5%) were prescribed with drugs. About 64% (385/602) of the prescribed medications were iron and vitamins. The most commonly prescribed medications are iron and folic acid combination (340/602, 56.5%), albendazole (48/602, 8%), mebendazole (37/602, 6.1%), omeprazole (33/602, 5.5%), followed by amoxicillin (32/602, 5.3%). The majority (79.3%) of the drugs were from FDA Pregnancy Categories A and B. Prescribed drug utilization was more probable in women who first visited the facility at their second (AOR = 2.91, 95% CI [1.12–6.64]) and third trimesters (AOR = 4.32, 95% CI [1.37–6.81]), had chronic illness (AOR = 7.54, 95% CI [2.34–14.68]), and live in rural areas (AOR = 2.47, 95% CI [1.56–8.43]). Conclusion: The study revealed that the prescription pattern in the hospital is in line with the WHO reference. Age, gravidity, number of ANC visits, first visit to the facility, presence of chronic illness, educational status, and residency were significantly associated with prescription drug use in pregnant mothers. But still, some pregnant women received drugs that may have teratogenicity risk (FDA Category C). [ABSTRACT FROM AUTHOR]

Background: Famotidine, a histamine2-receptor antagonist (H2Ras), is widely used to treat and prevent gastrointestinal symptoms during pregnancy. Although several studies have reported the use of H2Ras during pregnancy, limited data on famotidine were included in these reports. Therefore, we analyzed pregnancy outcome data to evaluate the effects of famotidine use during pregnancy on the fetus. Methods: Pregnancy outcome data were used for females enrolled in two Japanese facilities that provided counseling on drug use during pregnancy between April 1988 and December 2017. For the primary endpoint, the incidence of congenital malformations was calculated from the data of live birth to pregnant women who took famotidine (n = 330) or drugs considered to exert no teratogenic risk (control, n = 1,407) during the first trimester of pregnancy. Considering secondary endpoints, the incidence of obstetric outcomes, including preterm delivery, was calculated from data on the use of famotidine (n = 347) and controls (n = 1,476) during the entire pregnancy. The crude odds ratios (cORs) for the incidence of congenital malformations were calculated using univariate logistic regression analysis, with the control group used as the reference. Adjusted ORs (aORs) were calculated using multivariate logistic regression analysis adjusted for various other factors. Results: The incidences of congenital malformations in the famotidine and control groups were 3.9% and 2.8%, respectively. There was no significant difference between the famotidine and control groups (cOR: 1.40 [95% CI:0.68–2.71], aOR: 1.06 [95% CI:0.51–2.16]). Conversely, the preterm delivery rates were 8.1% and 3.8% in the famotidine and control groups, respectively, indicating a significant difference (cOR: 2.00 [95% CI:1.20–3.27]). However, the multivariate analysis eliminated famotidine use as a confounding factor. Conclusions: This observational cohort study revealed that exposure to famotidine during the first trimester of pregnancy was not associated with an increased risk of congenital malformations in infants. Although a higher rate of preterm delivery was detected in famotidine users when compared with controls, this could be attributed to confounding factors, such as complications. [ABSTRACT FROM AUTHOR]

Iprodione (IDN) is a broad-spectrum fungicide used to treat various fungal infections in plants. Despite its extensive use, assessment of its toxicity in aquatic organisms remains incomplete. This study investigated the deleterious effects of IDN using zebrafish (ZF) as a model organism. ZF embryos, beginning at 2 h post-fertilization (hpf), were exposed to IDN (3.75–40 mg/L), and both mortality and deformities were assessed. The impact of IDN on mortality was concentration-dependent and significant from 14 mg/L. Importantly, IDN induced several deformities at sublethal concentrations, including abnormal somites, reduced retinal pigment accumulation, yolk sac edema, hatching failure, abnormal swim bladders, and spinal curvature. The EC50 values for IDN-induced deformities were 3.44 ± 0.74 to 21.42 ± 6.00 mg/L. The calculated teratogenic index values for all deformities were above 1, indicating that IDN is teratogenic to ZF. IDN-exposed ZF also displayed abnormalities in touch-evoked escape responses. IDN significantly affected heart rate and blood flow, and induced pericardial edema and hyperemia in a concentration-dependent manner, suggesting its influence on cardiac development and the function of ZF. In conclusion, these results suggest that IDN exerts toxic effects on ZF embryos, affecting mortality, development, and behavior. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the risk of an undetected natural conception pregnancy during luteal phase ovarian stimulation, and how does it impact the pregnancy's course? SUMMARY ANSWER The risk for an undetected, natural conception pregnancy in luteal phase ovarian stimulation is low and it appears that ovarian stimulation is unlikely to harm the pregnancy. WHAT IS KNOWN ALREADY Random start ovarian stimulation appears to be similarly effective as early follicular stimulation start; and it allows ovarian stimulation to be started independent of the cycle day and throughout the cycle, in accordance with the patients' and clinics' schedule as long as there is no intention of a fresh embryo transfer in the same cycle. Starting ovarian stimulation in the luteal phase bears the possibility of an—at the timepoint of stimulation start—undetected, natural conception pregnancy that has already occurred. There is scarce data on the incidence of this event as well as on the possible implications of ovarian stimulation on the course of an existing pregnancy. STUDY DESIGN, SIZE, DURATION This retrospective observational study, performed between June 2017 and January 2024, analyzed luteal phase stimulations, in which a natural conception pregnancy was detected during the ovarian stimulation treatment for IVF/ICSI. Luteal phase stimulation was defined as ovarian stimulation started after ovulation and before the next expected menstrual bleeding, with a serum progesterone (P4) level of >1.5 ng/ml on the day of stimulation start or 1 day before. PARTICIPANTS/MATERIALS, SETTING, METHODS Women who underwent a luteal phase ovarian stimulation in a tertiary referral ART center. MAIN RESULTS AND THE ROLE OF CHANCE A total of 488 luteal phase stimulation cycles were included in the analysis. Luteal phase stimulation was only started after a negative serum hCG measurement on the day or 1 day before commencement of ovarian stimulation. Ten patients (2.1%) had an undetected natural conception pregnancy at the time of luteal phase stimulation start. Eight of these patients underwent an ovarian stimulation in a GnRH-antagonist protocol and two in a progestin-primed stimulation protocol (PPOS). Recombinant FSH was used as stimulation medication for all patients, the patients with a PPOS protocol received additional recombinant LH. One pregnancy (0.2%) was detected after the oocyte retrieval, the other nine pregnancies were detected either due to persistent high serum progesterone levels or due to an increasing progesterone level after an initial decrease before oocyte retrieval. In the cycles with an undetected natural conception pregnancy, the median number of stimulation days was 8 days (range: 6–11 days) and median serum hCG at detection of pregnancy was 59 IU hCG (range: 14.91–183.1). From 10 patients with a pregnancy, three patients delivered a healthy baby, two patients had ongoing pregnancies at the time of summarizing the data, three patients had biochemical pregnancies (patient age: 30, 39, and 42 years), one patient had an ectopic pregnancy which required a salpingectomy, and one patient (age: 34 years) had an early pregnancy loss. LIMITATIONS, REASONS FOR CAUTION The retrospective study design and the small sample size can limit the accuracy of the estimates. WIDER IMPLICATIONS OF THE FINDINGS Overall, there is a small risk of undetected natural conception pregnancies when luteal phase stimulation is undertaken. It appears that there are no adverse effects through either direct effect on the embryo or indirectly through a detrimental effect on the corpus luteum function on the pregnancy in our cohort. STUDY FUNDING/COMPETING INTEREST(S) This study did not receive funding. The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Abstract Background Famotidine, a histamine2-receptor antagonist (H2Ras), is widely used to treat and prevent gastrointestinal symptoms during pregnancy. Although several studies have reported the use of H2Ras during pregnancy, limited data on famotidine were included in these reports. Therefore, we analyzed pregnancy outcome data to evaluate the effects of famotidine use during pregnancy on the fetus. Methods Pregnancy outcome data were used for females enrolled in two Japanese facilities that provided counseling on drug use during pregnancy between April 1988 and December 2017. For the primary endpoint, the incidence of congenital malformations was calculated from the data of live birth to pregnant women who took famotidine (n = 330) or drugs considered to exert no teratogenic risk (control, n = 1,407) during the first trimester of pregnancy. Considering secondary endpoints, the incidence of obstetric outcomes, including preterm delivery, was calculated from data on the use of famotidine (n = 347) and controls (n = 1,476) during the entire pregnancy. The crude odds ratios (cORs) for the incidence of congenital malformations were calculated using univariate logistic regression analysis, with the control group used as the reference. Adjusted ORs (aORs) were calculated using multivariate logistic regression analysis adjusted for various other factors. Results The incidences of congenital malformations in the famotidine and control groups were 3.9% and 2.8%, respectively. There was no significant difference between the famotidine and control groups (cOR: 1.40 [95% CI:0.68–2.71], aOR: 1.06 [95% CI:0.51–2.16]). Conversely, the preterm delivery rates were 8.1% and 3.8% in the famotidine and control groups, respectively, indicating a significant difference (cOR: 2.00 [95% CI:1.20–3.27]). However, the multivariate analysis eliminated famotidine use as a confounding factor. Conclusions This observational cohort study revealed that exposure to famotidine during the first trimester of pregnancy was not associated with an increased risk of congenital malformations in infants. Although a higher rate of preterm delivery was detected in famotidine users when compared with controls, this could be attributed to confounding factors, such as complications.

Misoprostol, a synthetic analogue of prostaglandin E1, is commonly used in gynecology, particularly in combination with mifepristone for elective abortion. Although its use is widespread, the potential teratogenic effects of misoprostol in cases of failed medical abortion have not been sufficiently explored in the medical literature. Severe congenital malformations, although rare, have been reported, raising concerns about the impact of this drug on fetal development. We present a rare case of femoral agenesis observed in a woman who experienced a failed medical abortion with Misoprostol (Cytotec®), highlighting the need for a better understanding of the risks associated with fetal exposure to this drug and the implementation of rigorous follow-up measures after its use.

Background: Silver nanotechnology is widely applied in industry and medicine, with an increased likelihood of environmental and food contamination. Aim: This study aimed to explore the adverse effects of orally administering silver nanoparticles (AgNPs) to pregnant or lactating female rats on adults and the development of their offspring. Methods: Forty female albino rats were used to assess the immediate impacts of AgNPs in two separate experiments. The experimental group received 1 mL of AgNPs, dissolved in deionized water, at doses of 0, 50, and 100 mg/kg of body weight from the 6th to the 15th day of gestation in pregnant albino rats. After a 20-day gestation period, euthanasia was performed on the female rats, followed by a gross examination post-dissection. Results: The feti were preserved in ethyl alcohol and Poin's solution for the identification of skeletal and visceral malformations. It was noticed that feti of dams that received AgNPs showed teratogenicities such as delayed ossification and deletion of bones or ribs. Notably, dams showed necrosis and satellitosis with evidence of behavioral alteration. While rats' pups showed only brain edema and no behavioral changes. Conclusion: AgNPs at a dose of 50 or 100 mg/kg induced teratogenic effect in terms of delayed ossification, abnormal limb formation, and brain edema in rat pups, however induced necrosis and satellitosis in dam rats. Hence, greater emphasis should be placed on preventing exposure to Ag-NPs, especially among pregnant females. [Open Vet J 2024; 14(8.000): 1999-2006]

Abstract Bulk zinc oxide (ZnO-BPs) and its nanoparticles (ZnO-NPs) are frequently used in various products for humans. Helisoma duryi embryos can serve as effective model organisms for studying the toxicity of NPs. This study aimed to compare the teratogenic potency of ZnO-BPs and ZnO NPs in the embryonic stages of H. duryi to evaluate the utility of this snail as a bioindicator for ZnO-NPs in the aquatic environment. The mechanisms of teratogenesis were evaluated by determination of the LC50, studying the effect of sub-lethal concentrations of both ZnO forms on the embryos, and studying their enzyme activity, oxidative stress, and biochemical analysis. The SDS-PAGE electrophoresis was undertaken to assess the effect of ZnO-BPs and ZnO NPs on protein synthesis. The results revealed that the veliger stage of H. duryi is the specific stage for bulk and nano ZnO. ZnO-NPs proved to be more toxic to snails’ embryos than ZnO-BPs. Exposure to ZnO influences specific types of defects in development, which in the case of BPs are far less drastic than those caused by NPs. Thus, the toxicity of ZnO-NPs in embryonic development is due to their unique physicochemical properties. The observed malformations include mainly hydropic malformation, exogastrulation, monophthalmia, shell misshapen, and cell lyses. Almost all tested oxidative biomarkers significantly changed, revealing that ZnONPs display more oxidative stress than ZnO-BPs. Also, the low concentration of ZnO induces many disturbances in the organic substances of veliger larvae, such as a decrease in the total protein and total lipid levels and an increase in the glycogen level. The results indicated that ZnO-BPs increase the number of protein bands. Conversely, ZnO-NPs concealed one band from treated egg masses, which was found in the control group. Embryos of snail are an appropriate model to control freshwater snails. This study demonstrates that H. duryi embryos can serve as effective model organisms to study the toxicity of ZnO-NPs.

Drug use during pregnancy is an important issue that must be investigated due to its adverse effects on maternal and foetal health. This study aimed to determine the embryotoxic and teratogenic effects of in‐ovo administered metamizole (dipyrone), which can be used when needed during pregnancy and has potent analgesic, antipyretic, anti‐inflammatory, and long bone (tibia and femur) effects. This study used 240 fertile eggs from Atak S breed chickens, divided into eight equal groups: control, vehicle control, and 15.62, 31.25, 62.5, 125, 250 and 500 mg/kg metamizole. The eggs were hatched on the 21st day of incubation, and the chicks' body weights and mortality rates were determined. The right and left femur and tibia bones were resected from the chicks. Anatomical reference points were determined after removing the soft tissues of the bones, and necessary morphometric measures were taken from these points with a 0.01 mm precision using digital callipers. The 100% lethal dose (LD100) was identified in the highest examined dose (500 mg/kg) in the Chicken Embryotoxicity Screening Test (CHEST)‐I stage. The CHEST‐II stage determined the 50% lethal dose (LD50). High‐dose metamizole affected skeletal development, significantly decreasing tibia and femur lengths and corpus thicknesses and increasing mortality. [ABSTRACT FROM AUTHOR]

Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for investigating pharmacological effects and toxicity during vertebrate development. Several studies have suggested the use of zebrafish embryos for the assessment of malformations or embryo-fetal lethality (MEFL). However, a reproducible protocol as a standard for the zebrafish MEFL test method that fulfills global requests has not been established based on the International Council of Harmonisation (ICH) S5 (R3) guidelines. To establish such a toxicity test method, we developed a new and easy protocol to detect MEFL caused by chemicals, especially those with teratogenic potential, using fertilized zebrafish eggs (embryos) within 5 days of development. Our toxicity test trials using the same protocol in two to four different laboratories corroborated the high inter-laboratory reproducibility. Our test method enabled the detection of 18 out of 22 test compounds that induced rat MEFL. Thus, the prediction rate of our zebrafish test method for MEFL was almost 82% compared with that of rat MEFL. Collectively, our study proposes the establishment of an easy and reproducible protocol for the zebrafish MEFL test method for reproductive and developmental toxicity that meets ICH guideline S5 (R3), which can be further considered in combination with information from other sources for regulatory use. [ABSTRACT FROM AUTHOR]

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Background: Silver nanotechnology is widely applied in industry and medicine, with an increased likelihood of environmental and food contamination. Aim: This study aimed to explore the adverse effects of orally administering silver nanoparticles (AgNPs) to pregnant or lactating female rats on adults and the development of their offspring. Methods: Forty female albino rats were used to assess the immediate impacts of AgNPs in two separate experiments. The experimental group received 1 ml of AgNPs, dissolved in deionized water, at doses of 0, 50, and 100 mg/kg of body weight from the 6th to the 15th day of gestation in pregnant albino rats. After a 20-day gestation period, euthanasia was performed on the female rats, followed by a gross examination post-dissection. Results: The feti were preserved in ethyl alcohol and Poin’s solution for the identification of skeletal and visceral malformations. It was noticed that feti of dams that received AgNPs showed teratogenicities such as delayed ossification and deletion of bones or ribs. Notably, dams showed necrosis and satellitosis with evidence of behavioral alteration. While rats’ pups showed only brain edema and no behavioral changes. Conclusion: AgNPs at a dose of 50 or 100 mg/kg induced teratogenic effect in terms of delayed ossification, abnormal limb formation, and brain edema in rat pups, however, induced necrosis and satellitosis in dam rats. Hence, greater emphasis should be placed on preventing exposure to Ag-NPs, especially among pregnant females. [ABSTRACT FROM AUTHOR]

The effect of the lipid extract isolated from the tunic of the marine hydrobiont Halocynthia aurantium was studied. Its administration during hypothermia, hyperthermia, muscle load, introduction of hexenal, and the vertical fixation by the dorsal neck fold, as well as its embryotoxic and teratogenic effects, was evaluated. The impact of stress (vertical fixation of rats by the dorsal neck fold) was accompanied by an increase in the plasma levels of total lipids, total cholesterol, cholesterol/phospholipid ratios, and a decrease in the total phospholipids, as well as by a change in the quantitative characteristics of classes of neutral and phospholipids. A correction of the developed changes by a lipid extract of ascidia and a commercial reference preparation Omega-3 was carried out. The lipid extract of H. aurantium showed a higher efficiency in restoring the lipid composition of the blood plasma under stress impact compared to the preparation Omega-3 due to the wider range of neutral and phospholipid classes, polyunsaturated fatty acids of the n-3 and n-6 families. The tunic of ascidian can be used as a raw material for obtaining preparations with stress-protector and lipid-correcting properties. [ABSTRACT FROM AUTHOR]

Background: Porcine bile powder (PBP) is a traditional Chinese medicine that has been used for centuries in various therapeutic applications. However, PBP has not previously undergone comprehensive component analysis and not been evaluated for safety through standard in vivo toxicological studies. Methods: In our study, we characterized the component of PBP by liquid chromatography-mass spectrometry. The acute and subchronic oral toxicity, genotoxicity, and teratogenicity studies of PBP were designed and conducted in Kunming mice and Sprague-Dawley (SD) rats. Results: The chemical analysis of PBP showed that the main components of PBP were bile acids (BAs), especially glycochenodeoxycholic acid. There were no signs of toxicity observed in the acute oral test and the subchronic test. In the genotoxicity tests, no positive results were observed in the bacterial reverse mutation test. Additionally, in the mammalian micronucleus test and mouse spermatocyte chromosomal aberration test, no abnormal chromosomes were observed. In the teratogenicity test, no abnormal fetal development was observed. Conclusion: Our findings demonstrate that PBP, composed mainly of BAs, is non-toxic and safe based on the conditions tested in this study. [ABSTRACT FROM AUTHOR]

Antibiotics are the major therapeutic arsenal against bacterial infections. Yet, beneath this medical triumph lies an under investigated challenge of the potential teratological and toxicological impacts associated with the use of antibiotics. In the present study, we have explored the teratogenic potential of five commonly used antibiotics (streptomycin, metronidazole, tigecycline, doxycycline and norfloxacin) on Drosophila melanogaster Oregon-R strain. Except norfloxacin, all other tested antibiotics significantly delayed the onset of pupariation. Consistently, metronidazole, doxycycline and tigecycline resulted in statistically significant drops in egg-to-adult viability and adversely affected egg-to-pupa transition. In comparison, embryonic exposure of streptomycin impeded pupa-to-fly transition. All tested antibiotics induced morphological defects in antenna, wings, proboscis, eye, head, thorax, haltere and abdomen. Interestingly, developmental exposure of antibiotics resulted in statistically significant decrease in the lifespan of both male and female flies. This suggests an increased incidence of teratogenic faults at the systemic level, which are otherwise not manifested morphologically, due to the exposure of tested antibiotics during development. Taken together, our data show that developmental exposure of antibiotics may induce varying degrees of teratogenicity in D. melanogaster. Given the genomic homology and conservation of major molecular pathways that underpin development in humans and D. melanogaster, the findings do hold translational potential.

Nausea and vomiting of pregnancy (NVP), associated as „morning sickness”, is a problem faced by approximately 70% of pregnant women. The exact mechanism of NVP is not known, research suggests that growth and differentiation factor 15 (GDF 15) secreted by the placenta has a significant impact on these symptoms. Various scales and indices are used to describe the condition in NVP: the PUQE index, the Rhodes index, the McGill nausea questionnaire, and the visual-analogue scale. Depending on the severity of the disease course, therapy may include the non-pharmacological and/or pharmacological sphere. In this article, reports on the treatment of NVP worldwide, therapeutic preparations registered on the Polish market and current recommendations for their safety were presented. Non-pharmacological recommendations for NVP include a change in diet, avoidance of spicy foods, supplementation with preparations containing ginger rhizome or acupressure. Pyridoxine, antihistamines, dopamine D2 receptor antagonists, serotonin 5-HT₃ receptor antagonists and glucocorticosteroids are used to treat vomiting. Despite the wide range of antiemetics, there is still a search for effective NVP therapies, drugs with few side effects and, above all, adequate safety. Multicenter studies on a large population are particularly valuable in assessing teratogenicity, based on which are used to recommend whether a medicine can be used during pregnancy, especially in the first trimester. A two-component product containing pyridoxine and doxylamine was launched on the Polish market in December 2021. This drug was withdrawn from the US market in the 1980s because of suspicions that it was harmful. It is now recommended by both the US Food and Drug Administration and the Polish Society of Obstetricians and Gynaecologists as a first-line treatment for NVP. If treatment with this drug is ineffective, promethazine, in severe cases, metoclopramide and corticosteroids are also used in this indication. In some pregnant women, persistent vomiting leads to dehydration and malnutrition. In these cases, additional fluid therapy and clinical nutrition should be given.

Following two requests from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for preformed vitamin A and β‐carotene. Systematic reviews of the literature were conducted for priority adverse health effects of excess vitamin A intake, namely teratogenicity, hepatotoxicity and endpoints related to bone health. Available data did not allow to address whether β‐carotene could potentiate preformed vitamin A toxicity. Teratogenicity was selected as the critical effect on which to base the UL for preformed vitamin A. The Panel proposes to retain the UL for preformed vitamin A of 3000 μg RE/day for adults. This UL applies to men and women, including women of child‐bearing age, pregnant and lactating women and post‐menopausal women. This value was scaled down to other population groups using allometric scaling (body weight0.75), leading to ULs between 600 μg RE/day (infants 4–11 months) and 2600 μg RE/day (adolescents 15–17 years). Based on available intake data, European populations are unlikely to exceed the UL for preformed vitamin A if consumption of liver, offal and products thereof is limited to once per month or less. Women who are planning to become pregnant or who are pregnant are advised not to consume liver products. Lung cancer risk was selected as the critical effect of excess supplemental β‐carotene. The available data were not sufficient and suitable to characterise a dose–response relationship and identify a reference point; therefore, no UL could be established. There is no indication that β‐carotene intake from the background diet is associated with adverse health effects. Smokers should avoid consuming food supplements containing β‐carotene. The use of supplemental β‐carotene by the general population should be limited to the purpose of meeting vitamin A requirements. [ABSTRACT FROM AUTHOR]

Background: The individual teratogenicity profiles of Lumacaftor and Ivacaftor are known, but the combined effects remain unexplored. Purpose: To evaluate the teratogenic profile of a combination of Lumacaftor and Ivacaftor in Sprague-Dawley Rats. Materials and Methods: This study adhered to the Committee for Control and Supervision of Experiments on Animals (CCSEA) and Organisation for Economic Co-operation and Development (OECD) guidelines. Sprague–Dawley rats were acclimated and housed individually under controlled conditions. A polygamous breeding scheme was implemented, and pregnant female rats were assigned to control, vehicle control or treatment group following OECD Test Guideline 414. Lumacaftor and Ivacaftor were administered to pregnant rats at various doses, such as MRHD, 5MRHD, 8MRHD and 10MRHD, from gestation days 6 to 17. Clinical observations, body weight and food consumption of pregnant rats were monitored. Postmortem examinations included caesarean section, reproductive performance (the number of corpora lutea, implantation sites, early and late resorptions and live foetuses) and assessment of foetal analysis. The foetal analysis incorporated external malformation evaluation, visceral examination and skeletal examination using alizarin red solution. Results: In pregnant rats exposed to Lumacaftor and Ivacaftor, the external examination was conducted on 206, 209, 199, 184, 198 and 201 foetuses in their respective groups, each consisting of 19 litters. Within this cohort, approximately 33% of foetuses underwent visceral examination. Additionally, across six groups approximately 50% of foetuses underwent skeletal examination. Importantly, no abnormalities were detected in skeletal, visceral or histopathological assessments across the treatment groups encompassing doses of a combination of Lumacaftor and Ivacaftor at MRHD, 5MRHD, 8MRHD and 10MRHD. Additionally, no significant morbidity or mortality related to the treatment was observed. Conclusion: In conclusion, the study indicates that the combination of Lumacaftor and Ivacaftor at doses equivalent to MRHD, 5MRHD, 8MRHD and 10MRHD did not induce significant teratogenic effects, affirming their safety during pregnancy in rats. [ABSTRACT FROM AUTHOR]

AbstractIn recent years, the presence of pharmaceuticals in the aquatic environment has gained a significant attention. Carbamazepine, a commonly prescribed antiepileptic drug, has been consistently found in aquatic environments at concentrations ranging from nanograms to micrograms, raising concerns about its potential negative impacts on aquatic organisms. The study examined the acute and chronic neurotoxic effects of environmentally relevant and sublethal concentrations of carbamazepine in the mosquitofish Gambusia affinis. After a 96-hour exposure period, the median lethal concentration (LC50) of carbamazepine for G. affinis was determined as 24 mg L − 1. For the current study, sublethal concentrations i.e., one-tenth (2.4 mg L − 1) and one-fifth (4.8 mg L − 1) of the LC50 value were chosen for assessing the neurotoxic effects along with the environmentally relevant concentration (13 ng L − 1). The research findings indicated that carbamazepine had a disruptive impact on the typical growth and behavior of the fish. During the acute exposure phase, physical deformities were observed in the fish, resulting in neonatal and postneonatal fatalities. Furthermore, the neurotoxic effects of carbamazepine were clearly demonstrated through alterations in various neurological parameters, including acetylcholinesterase, dopamine, gamma-aminobutyric acid, serotonin, monoamine oxidase, 5-hydroxyindole acetic acid, adrenaline, and nor-adrenaline. These findings raise concerns about the survival of fish populations in their natural environment. [ABSTRACT FROM AUTHOR]

To assess the risk of major birth defects after first‐trimester exposure to carbocisteine and ambroxol during pregnancy, we conducted a prospective cohort study using counseling data for drug use during pregnancy provided by the Japan Drug Information Institute in Pregnancy and Toranomon Hospital. Counseling information, including drug usage and participants' demographic information, was collected between April 1988 and December 2017. Pregnancy outcome data, including major birth defects, were obtained using a questionnaire administered 1 month after delivery. The risks of major birth defects after first‐trimester exposure to carbocisteine (n = 588) and ambroxol (n = 341) were compared with those of nonteratogenic drug use during the first trimester (n = 1525). The adjusted odds ratio (aORs) for major birth defects was calculated using a multiple logistic regression analysis adjusted for confounders. The incidence of major birth defects was 1.2% (7/588) and 2.1% (7/341) in the carbocisteine and ambroxol groups, respectively, which was comparable to the control group (26/1525, 1.7%). Results of multiple logistic regression demonstrated similar nonsignificant risks for both carbocisteine (aOR: 0.66, 95% confidence interval [CI]: 0.40–1.1, p = 0.11) and ambroxol (aOR: 1.1, 95% CI: 0.18–7.2, p = 0.88). No specific major birth defects were reported in the carbocisteine or ambroxol groups. This study demonstrated that carbocisteine and ambroxol exposure during the first trimester was not associated with an increased risk of major birth defects. These results could help in counseling for the use of these drugs during pregnancy and further alleviate anxiety in patients. [ABSTRACT FROM AUTHOR]

Bambusa vulgaris is a commonly consumable plant, which is widely utilized by indigenous peoples as a source of food. Consumption of these plant products in various forms is typically acceptable due to their distinct tastes, and aromatic flavor. However, there is little information on the plant's safety and toxicity profile. Although toxicity information on B. vulgaris is readily available, the impact of plants during pregnancy has yet to be fully explored. To determine the possible mechanism behind teratogenicity, pregnant albino Wistar rats are administered aqueous extracts of B. vulgaris in a dose‐dependent manner. For determining the structural malformations, Teratogenicity indices include maternal common physiological parameters, number of implantations and fetal indices, number of live, resorpsed, and dead somites, morphological malformations, and skeletal malformations of different organs are evaluated by comparing different test groups with control groups. Most developmental indices, including implantation and fetalindices, vertebral, organ, and skeletal structures are significantly altered by the crude extract at higher dosages in treated as compared to control animals. The administration of aqueous extract of B. vulgaris during the organogenesis phase in rats has a considerable deleterious effect on embryonic and fetal developmental indices. It ruthlessly impacts the embryo's numerous organs as well as their typical physiological processes in a dose‐dependent way. The present investigation validates the capacity of B. vulgaris to cause developmental toxicity in Wistar rats, as evidenced by significant alterations in their gestational morphological, structural, and skeletal anatomy and physiology. It is recommended that further scientific studies be conducted to evaluate the more advanced mechanisms of teratogenicity associated with B. vulgaris. [ABSTRACT FROM AUTHOR]

Aspartame, a widely used artificial sweetener, is present in many food products and beverages worldwide. It has been linked to potential neurotoxicity and developmental defects. However, its teratogenic effect on embryonic development and the underlying potential mechanisms need to be elucidated. We investigated the concentration- and time-dependent effects of aspartame on zebrafish development and teratogenicity. We focused on the role of sirtuin 1 (SIRT1) and Forkhead-box transcription factor (FOXO), two proteins that play key roles in neurodevelopment. It was found that aspartame exposure reduced the formation of larvae and the development of cartilage in zebrafish. It also delayed post-fertilization development by altering the head length and locomotor behavior of zebrafish. RNA-sequencing-based DEG analysis showed that SIRT1 and FOXO3a are involved in neurodevelopment. In silico and in vitro analyses showed that aspartame could target and reduce the expression of SIRT1 and FOXO3a proteins in neuron cells. Additionally, aspartame triggered the reduction of autophagy flux by inhibiting the nuclear translocation of SIRT1 in neuronal cells. The findings suggest that aspartame can cause developmental defects and teratogenicity in zebrafish embryos and reduce autophagy by impairing the SIRT1/FOXO3a axis in neuron cells. [ABSTRACT FROM AUTHOR]

Sodium valproate (SV), as a common anti-epileptic drug, causes teratogenic effects on skeletal system by reactive oxygen species (ROS) generation. Herbal extract of Prosopis Farcta (PF), as a natural antioxidant necessary for many physiological activities, can probably ameliorate the teratogenic effects of SV during pregnancy. This study aimed to investigate the possible anti-teratogenic role of PF and Vitamin E (VE) on skeletal anomalies caused by SV in rat fetuses. Adult female rats (n=30) were categorized into 6 groups including control, SV (400 mg/kg), SV+VE (100mg/kg), and three doses of PF (50, 100, and 150 mg/kg) + SV. Each male rat mated with three adult female rats. The rats received SV, PF and VE at the 8th and 9th days of pregnancy by intraperitoneal injection. The animals were anesthetized and the laparotomy was applied at the 20th day of pregnancy. Skeletal abnormalities were analyzed using Alizarin red and Alcian blue staining. The expression of Runx2 and BMP2 genes was assessed using qPCRTM analysis in limbs bones. SV showed significant teratogenic effects including decrease in the rate of animal weight, Crown-rump length (CRL), various skeletal anomalies. The mRNA expression of Runx2 and BMP2 was also reduced in SV exposed animals. Administration of PF (especially 100mg/kg) in SV-exposed animals increased the weight of animals, CRL index, expression of Runx2 and BMP2, and reduced skeletal anomalies. The body weight, CRL index, Runx2 and BMP2 mRNA expression significantly increased, and skeletal anomalies decreased in VE group compared to the SV group. The results showed that PF could ameliorate the skeletal abnormalities and thus decreased osteogenic associated genes induced by SV in rat offsprings. [ABSTRACT FROM AUTHOR]

Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development characterized by numerous developmental anomalies that are restricted to the head and neck. Most TCS cases are inherited in an autosomal dominant manner. The diagnosis of TCS relies on clinical and radiographic findings. The four genes involved in TCS are TCOF1, POLR1D, POLR1C, and POLR1B.

Iprodione (IDN) is a broad-spectrum fungicide used to treat various fungal infections in plants. Despite its extensive use, assessment of its toxicity in aquatic organisms remains incomplete. This study investigated the deleterious effects of IDN using zebrafish (ZF) as a model organism. ZF embryos, beginning at 2 h post-fertilization (hpf), were exposed to IDN (3.75–40 mg/L), and both mortality and deformities were assessed. The impact of IDN on mortality was concentration-dependent and significant from 14 mg/L. Importantly, IDN induced several deformities at sublethal concentrations, including abnormal somites, reduced retinal pigment accumulation, yolk sac edema, hatching failure, abnormal swim bladders, and spinal curvature. The EC50 values for IDN-induced deformities were 3.44 ± 0.74 to 21.42 ± 6.00 mg/L. The calculated teratogenic index values for all deformities were above 1, indicating that IDN is teratogenic to ZF. IDN-exposed ZF also displayed abnormalities in touch-evoked escape responses. IDN significantly affected heart rate and blood flow, and induced pericardial edema and hyperemia in a concentration-dependent manner, suggesting its influence on cardiac development and the function of ZF. In conclusion, these results suggest that IDN exerts toxic effects on ZF embryos, affecting mortality, development, and behavior.

Objective: Many cultures use herbal medicines in pregnancy as a safer treatment than traditional medicine to promote the mother and/or baby health. Horse chestnut, a medicinal herb that mainly contains aescin, is used for its vagotonic impact, vascular protection, and antiedematous properties. This research sought to assess the impact of prenatal administration of horse chestnut extract on fetal development of rats, which is a novel achievement in teratogenesis studies. Methods: Pregnant rats were allocated randomly into four groups. Horse chestnut extract was administered through oral gavage to the animals from day 0 to day 16 of pregnancy at doses of 10, 20, and 40 mg/kg. On day 18, after the cesarean process, the effects of the extract were estimated by morphological, skeletal, and histological studies. Results: Administration of the extract resulted in a substantial decrease in weight, head diameter, tail diameter, and crown-rump length of fetuses. There were no malformations and no lack of toes and legs, and all internal organs of the fetus were completely formed. Also, there was no difference in the overall skeletal opacity and density between the control and treatment groups. Moreover, heart cells and neurons were seen in all the groups but the formation of the central vein, portal area, and hepatic sinusoids were not observed in groups that received the extract. Conclusion: The result of this study revealed that oral administration of horse chestnut extract in pregnant rats could cause teratogenicity. However, some additional clinical studies may be necessary but according to our data, consumption of this herbal extract during pregnancy is not recommended. [ABSTRACT FROM AUTHOR]

Diflubenzuron (DFB) and pyriproxyfen (PPF) are larvicides used in crops to control insect plagues. However, these pesticides are known to impact non-target organisms like fish and mammals. Here, we aimed at assessing the embryotoxicity of purified DFB, PPF, and their mixtures in a non-target organism—zebrafish. Zebrafish embryos were exposed to different concentrations for 120 h: 0.025, 0.125, 0.25, 1.25, 2.5, and 10 mg/L of purified PPF and purified DFB, while we used 0.025 mg/L PPF + 10 mg/L DFB (Mix A), 0.125 mg/L PPF + 10 mg/L DFB (Mix B), and 0.25 mg/L PPF + 10 mg/L DFB (Mix C) for the mixtures of PPF + DFB. We observed mortality, teratogenicity, and cardiotoxicity. For the neurotoxicity tests and evaluation of reactive oxygen species (ROS) levels in the brain, embryos were exposed for 120 h to 0.379 and 0.754 mg/L of PPF and 0.025 and 0.125 mg/L of DFB. We established the LC50 for PPF as 3.79 mg/L, while the LC50 for DFB was not determinable. Survival and hatching were affected by PPF concentrations above 0.125 mg/L, DFB concentrations above 1.25 mg/L, and the lower pesticide mixtures. PPF exposure and mixtures induced different types of malformations, while a higher number of malformations were observed for the mixtures, suggesting a potentiating effect. Pesticides diminished avoidance responses and increased the levels of ROS across all concentrations, indicating neurotoxicity. Our findings underscore the detrimental impact of PPF and DFB exposure, spanning from biochemistry to morphology. There is a critical need to reconsider the global use of these pesticides and transition to more ecologically friendly forms of pest control, raising an alarm regarding repercussions on human and animal health and well-being. [ABSTRACT FROM AUTHOR]

Purpose of Review: Selection of antiretroviral therapy during pregnancy must consider maternal physiology and resulting pharmacokinetic changes in pregnancy, resistance and efficacy profiles, tolerability and frequency of adverse effects, teratogenicity, and maternal, neonatal, and pregnancy outcomes. The objective of this review is to summarize the underlying data that informs the current clinical perinatal guidelines in the USA. Recent Findings: Data now supports the use of dolutegravir at all stages of pregnancy with no significant increase in neural tube defects. Safety and pharmacokinetic data on newer antiretroviral medications in pregnancy continue to lag behind the general population. Summary: While there are multiple safety and tolerability concerns with older regimens, there are now multiple options of regimens that are highly efficacious and have good safety data in pregnancy. Most pregnant patients who are virally suppressed on a well-tolerated regimen are able to safely continue those medications during pregnancy. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are particles released not only from blood cells but also from various organs. EVs, which are lipid bilayer vesicles, contain proteins, DNAs, and RNAs. The RNA and proteins within EVs display cell-specific characteristics. EVs derived from tumor cells are identified as biomarkers with diagnostic accuracy exceeding 90% for early cancer detection. Furthermore, EV RNA in serum has serves as a biomarker for toxicity. EVs have been found in various body fluids, including saliva, tears, urine, and amniotic fluid. In this study, we aimed to investigate the potential use of EV RNA in amniotic fluid as an indicator of developmental toxicity. Pregnant mice were exposed to valproic acid (VPA), a developmental toxicant, at concentrations of 0, 300, or 600 mg/kg/day on gestational days (GDs) 9-11. The study involved measuring VPA concentration in maternal plasma and fetuses on GD11, fetal weight on GD15 and 18, and assessing external morphological abnormalities on GDs11, 15 and 18. Additionally, EVs were collected from fetal amniotic fluid, and a comprehensive gene expression analysis of EV RNA was conducted on GD15. As a result, the concentration of VPA in the fetuses was not associated with the implantation location. Additionally, the VPA-treated group exhibited intrauterine growth retardation and teratogenic effects, including neural tube defects and digit malformations. EV RNA analysis identified differentially expressed EV small RNAs, both suppressed and induced, in the VPA-treated group compared with the control (vehicle, 0.5% Methylcellulose) group. These findings suggest that EV RNA in amniotic fluid serve as an indicator of developmental toxicity. [ABSTRACT FROM AUTHOR]

Background: Palliative care patients frequently present with clinically significant gastrointestinal bleeding. Due to the existence of confounding comorbidities and a remarkably reduced state of general health in many cases, the management of gastrointestinal bleeding in this population is often challenging. Summary: This review summarizes and discusses the role of thalidomide in gastrointestinal bleeding with a special focus on palliative care patients. In addition, an illustrative case report is presented. Thalidomide may be beneficial in gastrointestinal bleeding by exerting antiangiogenic effects. The drug has an acceptable safety profile. Side effects like neurotoxicity may limit its use but can be monitored safely. Due to thalidomide's thrombin generation potential, patients managed with thalidomide-containing regimes should be closely monitored for deep venous thrombosis. Given its teratogenicity, thalidomide should not be administered to women of childbearing potential who are not using adequate contraception. Key Message: Physicians caring for patients in a palliative care setting should be aware of thalidomide as an effective therapeutic option when endoscopy fails to find a bleeding source or for those patients who cannot or refuse to undergo endoscopy but present with recurrent or obscure gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Abstract Following two requests from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for preformed vitamin A and β‐carotene. Systematic reviews of the literature were conducted for priority adverse health effects of excess vitamin A intake, namely teratogenicity, hepatotoxicity and endpoints related to bone health. Available data did not allow to address whether β‐carotene could potentiate preformed vitamin A toxicity. Teratogenicity was selected as the critical effect on which to base the UL for preformed vitamin A. The Panel proposes to retain the UL for preformed vitamin A of 3000 μg RE/day for adults. This UL applies to men and women, including women of child‐bearing age, pregnant and lactating women and post‐menopausal women. This value was scaled down to other population groups using allometric scaling (body weight0.75), leading to ULs between 600 μg RE/day (infants 4–11 months) and 2600 μg RE/day (adolescents 15–17 years). Based on available intake data, European populations are unlikely to exceed the UL for preformed vitamin A if consumption of liver, offal and products thereof is limited to once per month or less. Women who are planning to become pregnant or who are pregnant are advised not to consume liver products. Lung cancer risk was selected as the critical effect of excess supplemental β‐carotene. The available data were not sufficient and suitable to characterise a dose–response relationship and identify a reference point; therefore, no UL could be established. There is no indication that β‐carotene intake from the background diet is associated with adverse health effects. Smokers should avoid consuming food supplements containing β‐carotene. The use of supplemental β‐carotene by the general population should be limited to the purpose of meeting vitamin A requirements.

Exposure to teratogenic agents during pregnancy can lead to fetal abnormalities. Establishing histological, hematological, and biochemical parameters is pivotal to enhancing the evaluation of the effect of any substance on embryo-fetal development. The present study investigated the maternal toxicity of aqueous extract of Bambusa vulgaris Schrad. ex J.C. Wendl shoots in pregnant Wistar rats. The pregnant rats were then allocated into four groups (n=6): a control group (without treatment) and three test groups (treated with the extract 250, 500, and 1000 mg/Kg, respectively). The treatment was initiated on gestational day (GD) 6 and continued until the 15th day. On GD 20, all the rats were anesthetized and subjected to laparotomy. Blood samples were collected from the pregnant rats for hematological and biochemical analyses, while various organs were isolated for histopathological studies. The study demonstrates dose-dependent toxicity of the extract, with significant variations (P

ObjectiveTo evaluate mutagenic and teratogenic effects of lanthanum nitrate for providing evidence to safe use of the rare earth element. MethodsThe mutagenicity of lanthanum nitrate was evaluated by micronucleus assay on mouse bone marrow cells, in vitro chromosome aberration test, and Salmonella typhimurium strains bacterial reverse mutation test and the teratogenic effect of lanthanum nitrate was assessed with teratogenicity test in rats. The micronucleus assay on mouse bone marrow cells was performed in three groups of ICR mice (10 in each group, half male and half female) administrated with lanthanum nitrate at concentrations (mg/kg·BW) of 875, 437.5, 218.75 for the male mice and 1015, 507.5, 253.75 for the female mice according to the median lethal dose (LD50) of lanthanum nitrate for the mice. The chromosome aberration test of mammalian cells in vitro was conducted on Chinese hamster lung (CHL) cells (with good growth during logarithmic division and inoculated into 25 mL cell culture bottle, 1 × 106 cells per bottle) treated with lanthanum nitrate at concentrations of 1 × 10 – 3, 1 × 10 – 4, 1 × 10 – 5 mol (without S9 mixture) and 5 × 10 – 3, 2.5 × 10 – 4,1.25 × 10 – 5 mol (with S9 mixture) based on the median inhibition concentration (IC50) of lanthanum nitrate on CHL cells. Five lanthanum nitrate dose groups (5, 1, 0.2, 0.04, 0.008 mg/dish, respectively) were set up to carry out Salmonella typhimurium (TA97, TA98, TA100, TA102, TA1535) strains bacterial reverse mutation test in the presence or absence of S9 metabolic activation system. In teratogenicity test on pregnant Sprague-Dawley (SD) rats (at least 15 in each group), three lanthanum nitrate dosages of (9, 36, 144 mg/kg·BW) were determined and the growth and implantation ability and the offspring rats′ weight and length, rate of skeletal malformation, rate of organ malformation and total rate of viscera malformation were oberserved. ResultsIn micronucleus assay, the micronucleus formation rates of bone marrow cells in each lanthanum nitrate dose group were similar with that of vehicle control group (P > 0.05) . In vitro chromosome aberration test, the rate of cells with chromosome aberration in 1 × 10 – 5 M lanthanum nitrate group significantly increased in the absence of S9 compared to that of the control group (χ2 = 12.109, P < 0.01); however, the proportion of cells with chromosome aberration was less than 5%, indicating a biological insignificance; in the presence of S9, there was no significant difference in chromosome aberration the between each lanthanum nitrate dose group and the control group (all P > 0.05). The results of Salmonella typhimurium strains bacterial reverse mutation test showed that there were no significant differences in the mutagenicity among lanthanum nitrate dose groups and the control group in both the presence and absence of S9 mixture. The results of teratogenic test showed that there were no significant differences in the growth and the implantation ability of pregnant rats among all dose groups and the vehicle group; lanthanum nitrate at concentration of 144 mg/kg BW inhibited fetal body weight and length significantly (both P < 0.05) and increased skeletal malformation of fetal rat compared with those of the vehicle group (χ2 = 9.939, P < 0.05). However, there was no significant difference in organ-specific and total visceral malformation among the dose groups (P > 0.05 for all). ConclusionsThe mutagenic effect of lanthanum nitrate was not observed under the conditions of this study and the study resulted in a no observable adverse effect level (NOAEL) of 36 mg/kg BW for lanthanum nitrate (15.38 mg/kg BW in terms of lanthanum).

Objective: There is limited safety data on the use of everolimus during pregnancy. In this study, we present the maternal and neonatal outcomes of everolimus used throughout the course of pregnancy and conducted a systematic review of reports of everolimus use after organ transplantation during pregnancy. Case report: A woman with type 1 diabetes who underwent kidney transplantation was treated with tacrolimus, everolimus, and prednisolone. Two years later, she became pregnant. At 27 weeks of gestation, an emergent cesarean delivery was performed owing to severe preeclampsia and fetal distress. No congenital malformation was noted in the baby at a corrected age of 4 months, and the maternal renal function remained stable. Conclusion: Our systematic review did not identify evidence of teratogenicity in babies exposed to everolimus as an immunosuppressant after transplantation. To better assess the risk of exposure to everolimus during pregnancy, all cases of new pregnancies occurring in transplant recipients receiving treatment with mammalian target of rapamycin inhibitor inhibitors should be reported.

The incidence of coronavirus disease (COVID-19) is increasing each day worldwide and the clinico-pharmacological dynamics of it is also changing with time. Pregnant women do also get infected though mostly mild to moderate in nature. To date, there is no specific drug against the severe acute respiratory syndrome coronavirus disease-2 (SARS-CoV-2), more so its drug management in pregnancy in view of adverse maternal and fetal effects. There are different treatment modalities described in literature. Here, we present a case of severe COVID-19 pneumonia in second trimester pregnancy managed successfully with “off label” use of tofacitinib along with steroid pulse therapy in preventing her from going to invasive mechanical ventilation and probable catastrophe due to hyperinflammatory syndrome characterised by surge of cytokines.

Abstract Background There is growing concern regarding teratogenic effect of antipsychotics. Previous research assessing association between antipsychotics and congenital malformations (CMs) yielded mixed results and were all derived from Western countries. We aimed to examine risk of major and organ/system-specific CMs associated with prenatal antipsychotic exposure in Hong Kong. Methods This population-based study identified women aged 15–50 years who delivered their first/singleton child between 2003–2018 from public healthcare service database. Propensity score (PS)-weighted logistic-regression analyses were performed to examine risk of CMs following first-trimester exposure to antipsychotic classes (second- and first-generation antipsychotic; SGA and FGA) and six most frequently-prescribed individual antipsychotics. Results Of 465,069 women, 419 and 420 redeemed ≥1 prescription of SGA and FGA during first-trimester, respectively. Prevalence of any CMs was 4.9% (95%CI:4.9–5.0%) in unexposed-infants, 9.1% (6.7–12.3%) in SGA-exposed infants, and 6.2% (4.3–9.0%) in FGA-exposed infants. SGA exposure (adjusted-odds-ratio: 2.11 [95%CI:1.19–3.86]) was associated with increased risk of CMs. This finding was consistent with sensitivity analyses addressing exposure misclassification and confounding by treatment indication, but not with PS-matched sensitivity analysis. Elevated risk of CMs was observed in infants exposed to high-dose olanzapine (7.50 [1.65–36.13]) and high-dose quetiapine (15.03 [4.86–56.72]), but with wide-CIs. Organ/system-specific malformations were not associated with SGA, FGA or individual antipsychotics. Conclusion We observed a small increased risk of major malformations associated with SGA, but was not consistently affirmed in sensitivity analyses, precluding firm conclusions. Research with large sample size clarifying comparative safety of individual antipsychotics on specific malformations is warranted.