Maternal traditional Chinese medicine exposure and risk of congenital malformations: a multicenter prospective cohort study.

INTRODUCTION: The potential teratogenic risk of traditional Chinese medicine (TCM) is of widespread concern; however, related evidence is largely absent in humans. This study aimed to compare the prevalence of congenital malformations between pregnant women with and without TCM exposure. MATERIAL AND METHODS: This was a multicenter prospective cohort study of 17 713 women who participated in a survey on periconceptional TCM exposure. Primary outcome was congenital malformations diagnosed from a survey conducted on the day 42 after delivery. RESULTS: A total of 16 751 pregnant women with 273 congenital malformations were included in the analysis. Fetuses exposed to TCM had an increased risk of congenital malformations compared to those without exposure (odds ratio [OR] 2.10; 95% confidence interval [CI] 1.09-4.02) after controlling for potential confounders. There were significant associations with congenital malformations in women with early pregnant exposure (OR 2.04, 95% CI 1.00-4.20) and for those who received ≥2 TCM formulas (OR 5.84, 95% CI 1.44-23.65). Pre-pregnancy TCM exposure was significantly associated with an increased risk of congenital heart defects (OR 12.69; 95% CI 3.01-53.51). CONCLUSIONS: Periconceptional TCM exposure is associated with an increased risk of congenital malformation. This effect was cumulative and sensitive to periconceptional age. Therefore, TCM deserves more attention and should be used cautiously for pregnant women and those trying to become pregnant.

Differential toxicity and teratogenic effects of the hot water and cold water extracts of Lignosusrhinocerus (Cooke) Ryvarden sclerotium on zebrafish (Danio rerio) embryos.

ETHNOPHARMACOLOGICAL RELEVANCE: The sclerotium of Lignosusrhinocerus (Cooke) Ryvarden is highly valued for its purported medicinal properties. The decoction and macerated materials prepared from the sclerotium are used for treating cancer and other ailments based on extensive traditional knowledge. Scientific evidence from in vitro cytototoxicity, anti-inflammatory and immunomodulatory analyses showed the effectiveness of sclerotial water extracts but toxicity assessment of such preparations has not been reported. AIM OF THE STUDY: This study aimed to compare the differential toxicity and teratogenicity (if any) of the hot water (HW) and cold water (CW) extracts of both wild and cultivated sclerotium on zebrafish (Danio rerio) embryos. MATERIALS AND METHODS: Zebrafish embryos were treated with varying concentrations of the sclerotial HW and CW extracts (0.3-500 µg/mL) for 72 h until hatching. The hatching, mortality and heartbeat rate of the embryos as well as the potential teratogenic effect of the extracts were assessed in embryos post-treatment with the extracts. RESULTS: While the sclerotial HW extracts were nontoxic (LC50 > 500 µg/mL), the sclerotial CW extracts delayed the hatching of the embryos up to 48 h and showed slight toxicity with LC50 values of 398.4 µg/mL and 428.3 µg/mL for the cultivated and wild sclerotium, respectively. The sclerotial CW extracts also induced minor tachycardia in zebrafish larvae. Phenotypic assessment revealed that, while yolk sac edema was observed at high concentrations (300 and 500 µg/mL) of all extracts, curved trunk and bent tail were only observed in the embryos treated with CW extracts of wild sclerotium (300 and 500 µg/mL) but not for CW extracts of cultivated sclerotium at similar concentrations. CONCLUSION: The sclerotial water extracts of L.rhinocerus prepared using different methods have varying degree of toxicity and teratogenicity in zebrafish embryos with the sclerotial CW extracts showed higher toxicity than the HW extracts.

Neurodevelopmental toxicity of alumina nanoparticles to zebrafish larvae: Toxic effects of particle sizes and ions.

The aim of this study was to explore the mechanism of neurodevelopmental toxicity of alumina nanoparticles (AlNPs) on zebrafish larvae, specifically, the toxic effects of AlNPs of different particle sizes and of dissolved aluminum ions. AlNPs with sizes of 13 nm (13 nm-Al) and 50 nm (50 nm-Al) were used as the main research objects; while nanocarbon particles with sizes of 13 nm (13 nm-C) and 50 nm (50 nm-C) as particle-size controls; and an aluminum chloride solution (Al3+) as an ion control. Zebrafish embryos were exposed to different treatments from 6 h post-fertilization (hpf) to 168 hpf. Deformities were observed at different time points. Neurodevelopmental behavior tests were carried out, and oxidative stress responses and transcriptional alterations in autophagy-related genes were assessed. Malformations occurred in the 13 nm-Al, 50 nm-Al, and Al3+ treated groups at different developmental stages of zebrafish larval, but no malformations were observed in the 13 nm-C or 50 nm-C groups. In addition, the average speed, distance travelled and thigmotaxis in zebrafish larvae decreased in the AlNPs treated group, and the effects were related to the particle sizes. Furthermore, increases in the oxidative stress response and autophagy-related genes expression were also related to the particle sizes of AlNPs as well. In conclusion, the mechanism underlying the neurodevelopmental toxicity of AlNPs on zebrafish larvae mainly depended on the size of the nanoparticles, and dissolved Al3+ also contributes to the toxic effects.

Methyl Palmitate-A suitable adjuvant for Sorafenib therapy to reduce in vivo toxicity and to enhance anti-cancer effects on hepatocellular carcinoma cells.

This study focused on evaluating the potency of Methyl Palmitate in reducing in vivo toxicity with enhancement of anti-cancer effects of Sorafenib. In vitro anti-cancer effects on human Hep-G2 cell line were analysed by MTT, Trypan blue, clonogenic, wound scratch migration and TUNEL assays. An in vivo study for anti-angiogenesis effect, toxicity and teratogenicity was analysed in Zebrafish embryos. The combination of Sorafenib (4.5 µmol/L) with Methyl Palmitate (3 mmol/L) significantly enhanced anti-cancer effects on Hep-G2 cell line by increasing cytotoxicity (P ≤ .05 in MTT assay; P ≤ .01 in Trypan blue assay), apoptosis (P ≤ .05) and decreasing the metastatic migration (P ≤ .01) than Sorafenib alone treatment. A prominent inhibition of angiogenesis in vivo was observed for combination treatment. At 5 dpf, only <20% toxicity was observed for 3 mmol/L Methyl palmitate while it was 65.75% for Sorafenib treatment which implies that it is a safer dose for in vivo treatments. A highly significant (P ≤ .001) reduction (43.20%) in toxicity was observed in combination treatment. Thus, the Sorafenib-Methyl Palmitate combination showed a promising treatment effect with significantly reduced in vivo toxicity when compared with Sorafenib alone treatment, and hence the Methyl Palmitate may serve as a good adjuvant for Sorafenib therapy.

Developmental toxicity of Clerodendrum cyrtophyllum turcz ethanol extract in zebrafish embryo.

ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendrum cyrtophyllum Turcz has been used in traditional medicine for the treatment of various diseases. In spite of its therapeutic applications, research on its toxicity and teratogenicity is still limited. AIM OF THE STUDY: The study aimed to investigate the developmental toxicity of the ethanol extract of C. cyrtophyllum (EE) in zebrafish embryo model. MATERIAL AND METHODS: Major compounds from crude ethanol extract of Clerodendron cyrtophyllum Turcz leaves were determined using HPLC-DAD-Orbitrap-MS analysis. The developmental toxicity of EE were investigated using zebrafish embryo model. Zebrafish embryos at 6 h post-fertilization (hpf) were treated with EE at different concentrations. Egg coagulation, mortality, hatching, yolk sac edema, pericardial edema and teratogenicity were recorded each day for during a 5-day exposure. At time point 120 hpf, body length, pericardial area, heartbeat and yolk sac area were assessed. In order to elucidate molecular mechanisms for the developmental toxicity of EE, we further evaluated the effects of the EE on the expression of genes involved on signaling pathways affecting fish embryo's development such as heart development (gata5, myl7, myh6, has2, hand2, nkx 2.5), oxidative stress (cat, sod1, gpx4, gstp2), wnt pathway (ß-catenin, wnt3a, wnt5, wnt8a, wnt11), or cell apoptosis (p53, bax, bcl2, casp3, casp8, casp9, apaf-1, gadd45bb) using qRT-PCR analysis. RESULTS: Our results demonstrated that three major components including acteoside, cirsilineol and cirsilineol-4'-O-ß-D-glucopyranoside were identified from EE. EE exposure during 6-96 h post-fertilization (hpf) at doses ranging from 80 to 200 µg/mL increased embryo mortality and reduced hatching rate. EE exposure at 20 and 40 µg/mL until 72-120 hpf induced a series of malformations, including yolk sac edema, pericardial edema, spine deformation, shorter body length. Based on two prediction models using a teratogenic index (TI), a 25% lethality concentration (LD25) and the no observed-adverse-effect level (NOAEL), EE is considered as teratogenic for zebrafish embryos with TI (LC50/EC50) and LD25/NOAEC values at 96 hpf reaching 3.87 and 15.73 respectively. The mRNA expression levels of p53, casp8, bax/bcl2, gstp2, nkx2.5, wnt3a, wnt11, gadd45bb and gata5 were significantly upregulated by EE exposure at 20 and 40 µg/mL while the expression of wnt5, hand2 and bcl2 were downregulated. CONCLUSIONS: These results provide evidence for toxicity effects of EE to embryo stages and provide an insight into the potential toxicity mechanisms on embryonic development.

Folic acid dose, valproate, and fetal malformations.

OBJECTIVE: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy. METHODS: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy. RESULTS: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409). CONCLUSIONS: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.

Optimizing Isotretinoin Treatment of Acne: Update on Current Recommendations for Monitoring, Dosing, Safety, Adverse Effects, Compliance, and Outcomes.

Acne vulgaris is the most common skin disease treated by dermatologists. It can be severe and result in permanent scars. Isotretinoin is the most effective treatment for acne and has the potential for long-term clearance. Prescribing and monitoring protocols can vary widely among prescribers. Recent studies, reports, and consensus statements help shed light on optimizing the use of isotretinoin for acne. A recent literature review is summarized in this article to help the practitioner optimize isotretinoin use for acne. The article outlines the advantages and disadvantages of standard, high-dose, and low-dose isotretinoin regimens; discusses the current status of controversies surrounding isotretinoin (including depression/suicide, pregnancy, and inflammatory bowel disease); reviews monitoring recommendations and treatment for hypertriglyceridemia and elevated transaminase levels; and discusses common adverse effects seen with isotretinoin, along with their treatment and prevention.

Effects of Erythrosine on Neural Tube Development in Early Chicken Embryos.

OBJECTIVE: Erythrosine (E127), a synthetic food dye containing iodine and sodium, has often been used inside packaged foods and beverages in Turkey and many other countries. We evaluated the effects of erythrosine on neural tube development in early-stage chicken embryos. METHODS: The study included 4 groups, with a total of 80 embryos: a control group, a normal saline group, a half-dose group, and a high-dose group. After 30 hours of incubation, saline and erythrosine solution was injected under the embryonic discs. At the end of 72 hours, the embryos were excised and evaluated macroscopically and histopathologically. RESULTS: Neural tube defects were detected in the erythrosine-administered groups with statistically significant differences. In contrast, the embryos in the control and saline groups displayed normal development. CONCLUSIONS: Erythrosine increased the risk of neural tube defects in early-stage chicken embryos, even at half of the approved dose.

Potential toxicity effects of Anastatica hierochuntica aqueous extract on prenatal development of Sprague-Dawley rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Anastatica hierochuntica (A. hierochuntica) is a plant consumed in folk medicine for the treatment of reproductive system related problems and metabolic disorders. It is of concern that the herb is commonly consumed by pregnant women towards the end of pregnancy to ease the process of labour, despite the lack of studies evaluating its safety. AIM OF THIS STUDY: This study aimed to investigate the potential toxicity effects of A. hierochuntica in pregnant Sprague-Dawley rats and their developing foetuses. MATERIALS AND METHODS: Experiments were conducted in accordance to the Organisation for Economic Co-operation and Development guideline 414. Animals were randomly divided into four groups (n = 10 females per group): negative control (received the vehicle only), experimental animals received 250, 500, and 1000 mg/kg A. hierochuntica aqueous extracts (AHAE), respectively. Treatment was administered daily by oral gavage from gestational day (GD) 6-20, and caesarian section performed on GD21. RESULTS: There were significant reduction in the corrected maternal weight gain of dams and body weight of foetuses in the lowest and highest dose of AHAE-treated animals compared to the control. These findings were associated with the increase in anogenital distance index and multiple congenital anomalies observed in some of the offspring. On the other hand, rats treated with 500 mg/kg showed higher embryonic survival rate with absence of significant treatment-related effect. CONCLUSION: Findings showed that highest and lowest doses of AHAE have prenatal toxicity effects in SD rats. Therefore, AHAE is potentially harmful to the developing foetuses especially when consumed during the period of implantation and organogenesis. As for the rats treated with 500 mg/kg AHAE, there was no significant treatment-related effect. Hence, we postulate that this finding suggests that the disruption on the hormonal regulation could have been compensated by negative feedback response. The compensated effects of AHAE at 500 mg/kg and the presence of lowest observed adverse effect level (LOAEL) at 250 mg/kg has resulted in a non-monotonous dose response curve (NMDRC), which complicates the determination of the value of no-observed-adverse effect level (NOAEL).

Deleterious effects of perinatal exposure to potassium bromate on the development of offspring of Swiss mice.

The present study aimed to investigate the impact of perinatal potassium bromate (KBrO3) exposure on the development of sensorimotor reflexes and redox status, and on the histological architecture of the brain, liver, and kidney of newborn mice. Pregnant mice received 1-ml bottled drinking water daily by oral intubation and served as the control group. Another group of pregnant mice were supplemented orally with 200 mg/kg body weight KBrO3 dissolved in drinking water from gestation day 5 to postnatal day 21. KBrO3 induced a decrease in the postnatal body weight in the newborn mice. KBrO3-exposed newborn mice showed poor performance and delayed development of the sensorimotor reflexes. Histological changes, increased lipid peroxidation, and altered antioxidants were reported in the cerebrum, cerebellum, medulla oblongata, liver, and kidney of the KBrO3-exposed newborn mice. In conclusion, these findings demonstrated that perinatal exposure to bromate induced oxidative stress, histological and behavioral alterations, and was a potential teratogen in newborn mice.

Teratogenicity of valproic acid and its constitutional isomer, amide derivative valnoctamide in mice.

OBJECTIVES: The anticonvulsant valproic acid (VPA) has a known teratogenic effect capable of inducing major congenital malformations and developmental disorders. A comparative teratogenicity study of VPA and its analog valnoctamide (VCD), which is a new generation candidate antiepileptic drug, was carried out using Swiss Vancouver (SWV) mice. METHODS: Pregnant SWV dams were treated with either a single intraperitoneal injection of VPA (1.8 and 2.7 mmol/kg), VCD (1.8 and 2.7 mmol/kg), or vehicle on E8:12 (gestational day:hour). The numbers of implantation and resorption, viable and dead fetuses, and the presence of gross fetal visceral and skeletal abnormalities were determined (E18). Real-time Polymerase chain reaction (RT-PCR) arrays were used to analyze the expression of 84 genes related to the processes of neurogenesis and neural stem cell differentiation. RESULTS: Significant decreases in pregnancy weight gain and the number of live fetuses were observed when VPA was administered at the high dose, whereas the percentage of exencephalic fetuses was significantly increased in VPA treated compared with an equivalent VCD dosage group. There was a dose-related increase in visceral defects in the VPA-exposed fetuses. Missing skull bones and fused vertebrae in fetuses occurred at the high dose of VPA. Three genes (Mtap2, Bmp8b, and Stat3) were significantly upregulated and one (Heyl) was downregulated in samples from VPA-treated dams. CONCLUSIONS: The study demonstrates that the teratogenicity of VPA was significantly greater than that of an equimolar dose of VCD. Four genes (Mtap2, Bmp8b, Stat3, and Heyl) represent candidate target genes for the underlying teratogenic mechanism responsible for VPA-induced malformations.

Pesticides as the drivers of neuropsychotic diseases, cancers, and teratogenicity among agro-workers as well as general public.

The need to maximize agricultural productivity has made pesticides an indispensable part of current times. Farmers are unaware of the lurking consequences of the pesticide exposure, which endanger their health. It also puts the unsuspecting consumers in peril. The pesticides (from organophosphates, organochlorine, and carbamate class) disrupt the immune and hormonal signaling, causing recurrent inflammation, which leads to a wide array pathologies, including teratogenicity. Numerous farmers have fallen victim to neural disorders-driven suicides and lungs, prostate/breast cancer-caused untimely deaths. Green revolution which significantly escalated agricultural productivity is backfiring now. It is high time that environmental and agricultural authorities act to restrain the excessive usage of the detrimental chemicals and educate farmers regarding the crisis. This review discusses the biological mechanisms of pesticide-driven pathogenesis (such as the activation or inhibition of caspase, serine protease, acetylcholinesterase) and presents the pesticide-exposure-caused health deterioration in USA, India, and Africa. This holistic and critical review should be an eye-opener for general public, and a guide for researchers.

Non-toxic and non teratogenic extract of Thuja orientalis L. inhibited angiogenesis in zebra fish and suppressed the growth of human lung cancer cell line.

Lung cancer is a malignant tumour with minimal survival rate and the current treatments are not showing complete remission of tumour and have many side effects. Thus a natural herbal medicine with good anti-cancer properties is highly demanded. Thuja orientalis L. is a traditionally used medicine to cure cough, bronchitis, excessive menstruation, asthma, skin infection and premature baldness. In addition, recent studies have revealed that it has anti-proliferative and anti-cancer activity. Angiogenesis is the main reason for the propagation and metastasis of cancers. We therefore intended to study the effects of the leaf extract of Thuja orientalis L. on angiogenesis as well as lung cancer cell growth. We have tested the anti-angiogenesis efficiency by alkaline phosphatase assay and also analysed the in vivo toxicity and teratogenic effects of various concentration of Thuja orientalis L. extract by establishing an in vivo zebra fish (Danio rerio), a promising model for cancer research which share genetic structure similarity to that of human beings. Also we demonstrated an anti-cancer effect of leaf extract from Thuja orientalis L. on human lung cancer cell line (A549) by MTT and trypan blue assay. The results revealed that the Thuja orientalis L. extract is efficient in repressing lung tumour cell growth significantly (p ≤ 0.01) in all treatments (2.4 mg/ml to 0.3 mg/ml) except 0.15 mg/ml compared to the control. The in vivo toxicity assay has proven that it is non-toxic at concentrations 0.6 mg/ml, 0.3 mg/ml and 0.15 mg/ml in zebrafish. The teratogenic assays revealed the therapeutic index (TI) as 0.808 with 0.7029 mg/ml as LC50 concentration at 24 h which is within the desirable value (below 1) for drug administration. Noticeable inhibition of angiogenesis also was observed in treatment with 2.4 mg/ml to 0.3 mg/ml. Overall we found that Thuja orientalis L. plant leaf extract exhibits better anti-cancer properties as we have validated by in vitro and in vivo analysis.

Is post exposure prevention of teratogenic damage possible: Studies on diabetes, valproic acid, alcohol and anti folates in pregnancy: Animal studies with reflection to human.

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.

The safe use of Doliocarpus dentatus in the gestational period: Absence of changes in maternal reproductive performance, embryo-fetal development and DNA integrity.

ETHNOPHARMACOLOGICAL RELEVANCE: Doliocarpus dentatus (Dilleniaceae) is commonly used in Brazil for the treatment of inflammatory process pain and urinary retention. Previous studies of our group have demonstrated the anti-inflammatory and antimycobacterial action of the ethanolic extract of Doliocarpus dentatus (EEDd) as well as the safety of its use. AIM OF THE STUDY: we investigated the effects of EEDd on reproductive performance, fetal development and DNA integrity in pregnant female Swiss mice. MATERIAL AND METHODS: thirty female Swiss mice were divided into three experimental groups (n = 10): control group treated with 1% tween-80 and EEDd1 and EEDd2 groups treated with EEDd at doses of 100 and 1000 mg/kg, respectively. The treatment occurred by oral gavage throughout the gestational period. At the end of pregnancy, parameters related to reproductive performance, embryofoetal development and DNA integrity was evaluated. RESULTS: both doses of the extract tested did not alter the reproductive parameters, did not present significant differences in the embryofetal development when compared to the control group and also did not induce the formation of micronuclei. CONCLUSION: the EEDd do not alter the reproductive parameters, embryofetal development and DNA integrity, ensuring its safe use during pregnancy.

Evaluation of embryotoxic and teratogenic effects of the oil extracted from Caryocar brasiliense Cambess pulp in rats.

The objective of this study was to evaluate the maternal, embryotoxic and teratogenic effects of Caryocar brasiliense pulp oil (OPCB), oil widely used in Brazilian cuisine and traditional medicine. Pregnant Wistar female rats were used in this study for three treatment groups (250, 500 and 1000 mg/kg/day) and a control group. The OPCB was administered orally throughout the period of organogenesis of females (6th until the 15th day of gestation). The pregnant females were gross necropsied on d20, followed by maternal and fetus examination, to evaluate the teratogenicity, reproductive and developmental performance of OPCB. The results showed there was no significant statistical difference in the ponderal evolution of the pregnant females, as well as in the behavioral, hematological, biochemical or histopathological data, indicating the absence of maternal toxicity of the oil. The mean number of corpora lutea, implantation and resorption sites, as well as all calculated reproductive rates, also remained statistically similar between the groups, indicating low embryotoxic effects of the tested plant specie. In fetal examination, external anomalies and skeletal abnormalities were observed in all treated and control groups. The NOAEL for maternal toxicity and embryo/fetal development for the OPCB administered by gavage, was 1000 mg/kg/bw/day.

Fetal Valproate Syndrome - Still a Problem Today!

Introduction Fetal exposition to valproate can lead to a cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. Case Report In this report we describe 2 cases of fetal valproate syndrome. In the first case, the gravida had a valproate medication before and during pregnancy with additional folic acid. She delivered a male premature infant at 25+2 weeks of gestation due to preterm labor and rupture of the membranes. Physical examination showed even in the premature infant typical signs of fetal valproate syndrome with trigonocephaly, epicanthal folds, broad root of the nose, low-set ears, thin upper lip and anteverted nares. In the second case, the gravida was under antiepileptic therapy with valproate and lamotrigine before and during pregnancy without any prophylaxis with folic acid. Sonographic examination during pregnancy diagnosed a spina bifida, Chiari II malformation and clubfeet. A female newborn was delivered at 39+4 weeks of gestation. Besides the prenatally detected anomalies, facial dysmorphism including microcephaly, low-set ears, thin upper lip and shallow philtrum were seen after birth. Conclusion Valproate, a widely used anticonvulsant medication, is known for its teratogenic effects. The risk of congenital anomalies is even higher in combination with other antiepileptic drugs. Therefore, the avoidance of valproate or at least supplementation with a high dose prophylactic folic acid before and during pregnancy is highly recommended for women with epilepsy.

Developmental toxicity evaluation of Pimenta pseudocaryophyllus (Gomes) Landrum, (E)-methyl isoeugenol chemotype, in Wistar rats.

BACKGROUND: Pimenta pseudocaryophyllus (Gomes) Landrum (Myrtaceae) has been traditionally used in Brazilian folk medicine. Studies have established the botanical characterization, phytochemistry profile, and pharmacological potential of this species, including antibiotic, anxiolytic, antidepressant, antioxidant, antinociceptive, and anti-inflammatory properties. Despite its widespread use, no previous study has been conducted regarding its toxicological profile, especially during pregnancy. Thus, this study investigated the developmental toxicity of the dry leaf extract of the P. pseudocaryophyllus, (E)-methyl isoeugenol chemotype, in rats. METHODS: First, the dry leaf extract was prepared by a spray-drying technique. Then, pregnant Wistar rats were orally treated with dry extract at doses of 0, 2000, 2500, or 3000 mg/kg from gestational day 6 through 15 (organogenesis period). On gestational day 21, the rats underwent cesarean sections and the reproductive outcomes and biochemistry parameters related to hepatic and renal markers were evaluated. Additionally, the fetuses were examined for external and skeletal variations and malformations. RESULTS: The spray-drying technique preserved the phytocomplex components and showed a satisfactory yield. No relevant differences were seen in the food consumption, reproductive performances, and hepatic and renal biochemical parameters between groups. However, there was a decrease in body weight gain of the dams during the organogenesis period and an increase of minor skeletal variations in the offspring (increased fetal incidences only of delayed ossification of the metacarpals, metatarsals, phalanges, sternebra, and rudimentary ribs) treated with the dry extract. CONCLUSION: The extract of P. pseudocaryophyllus, (E)-methyl isoeugenol chemotype, showed low maternal toxicity and induced minor skeletal variations in the offspring. Birth Defects Research 109:1292-1300, 2017. © 2017 Wiley Periodicals, Inc.

Fetopathies associated with exposure to angiotensin converting enzyme inhibitor from Tropaeolum majus L.

The prevalence of the use of herbal medicines is on the rise across the world, especially amongst pregnant women. A fact that draws attention is that many species commonly used by pregnant women, including the Tropaeolum majus L. (Tropaeolaceae), also present inhibitory activity on the angiotensin-converting enzyme (ACE). Herein, we have investigated the effects of T. majus extract (HETM) on fetal development, evaluating its relationship with possible ACE inhibitory activity. Pregnant Wistar rats were treated with different HETM doses (3, 30 and 300 mg/kg/day) from gestational days 8-20. Rats were sacrificed on the day 20 of pregnancy and the following parameters were evaluated: clinical symptoms of maternal toxicity; maternal body weight; feed and water intake; maternal liver, kidney, and ovary weights, maternal ACE activity and aldosterone levels, live fetuses mean; dead fetuses percentage, fetus weight, and fetal malformation. All pregnant rats treated with high HETM doses showed significant reduction in plasma ACE activity accompanied by a decrease in serum aldosterone levels. Moreover, significant changes in fetal development were observed, including growth retardation and renal damage after 20 days of gestation. Thus, data presented demonstrate the significant effects of the use of HETM on fetal development during pregnancy.

Fetal Valproate Syndrome.

BACKGROUND: There have been several reports of congenital malformations in the offspring of mothers who took valproic acid (VPA) during pregnancy as a treatment for epilepsy. METHODS: Herein, we describe four cases with typically similar facial features of fetal valproate syndrome accompanied to minor skeletal abnormalities. RESULTS: The first case was a 16-month-old girl, presenting with facial dysmorphism, and finger abnormalities. Her mother took VPA (1500 mg/d) up to the 10th gestational week and at a dosage of 1000 mg/d through the pregnancy. The second patient was 5-year-old boy with speech disability, bilateral cryptorchidism, facial dysmorphism, and finger abnormalities whose mother took VPA (1000 mg/d) through pregnancy. The third 19-month-old patient was the brother of the second patient who had facial dysmorphism, bilateral cryptorchidism, and finger abnormalities. His mother also took VPA (1000 mg/d) through pregnancy. The fourth 3-year and 6 month-old boy with minor facial dysmorphism and sternum deformity was exposed to VPA (500 mg/d) in utero. CONCLUSION: In conclusion, there is a recognizable spectrum of abnormalities in some infants exposed to VPA without dose-depence and the common facial dysmorphic features and minor skeletal abnormalities that may occur within the both low and high dose VPA use.