Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

Multi­organ assessment via a 9.4­Tesla MRS evaluation of metabolites during the embryonic development of cleft palate induced by dexamethasone.

The aim of the present study was to determine the association between maternal metabolism and development of the fetal palate, and to suggest a potential non­invasive prenatal diagnostic method for fetal cleft palate (CP). Dexamethasone (DXM) was used to create a CP mouse model. A 9.4­Tesla (T) magnetic resonance spectroscopy (MRS) imager was used to measure an array of metabolites in the maternal serum, placental tissue, amniotic fluid and fetal palates. Multivariate statistical analysis was performed using SIMCA­P 14.1 software. Following DXM treatment, variations were detected in multiple metabolites in the female mice and their fetuses based on 9.4T MRS. It was indicated that in the experimental group during CP formation, leucine, valine, creatine, acetate and citrate levels in the palatal tissue were lower, whereas lactate, alanine, proline/inositol and glutamate­containing metabolite levels were higher, compared with the levels in the control group. In placental tissue and amniotic fluid, succinate and choline levels were lower in the experimental group. The relative concentrations of cholesterol and lipids in palatal tissues from mice treated with DXM were higher compared with the concentrations in tissues from mice in the control group, with the exception of (CH2)n lipids. In the placental tissue, the alteration in cholesterol level exhibited the opposite trend. Lipid levels for the different lipid forms varied and most of them were unsaturated lipids.

An Assessment of Mutagenic Effect of 3, 3', 4, 4', 5 Pentachlorobiphenyl (PCB126) in Muta Mouse Fetuses.

PCBs are persistent environmental agents that induce multiple impairments in living beings. In this study we used a transgenic mouse model (Muta(TM) Mouse), carrying bacterial lacZ genes for mutation assays and for assessment of the genotoxic effect of PCB126 on fetal mice. Mothers of experimental groups were subjected to a single oral dose of PCB126 (125, 250 and 500 microg/kg) on the 10th day of pregnancy, respectively. Fetuses were autopsied on the 18th day of gestation. Cleft palate was observed in 2 out of 11 fetuses from 3 litters in 500 microg/kg treated group. Other external malformations were not observed. The DNA mutation frequencies (MF) of fetuses in each group were 1.15 +/- 0.24 x 10(-5), 0.90 +/- 0.20 x 10(-5) and 1.08 +/- 0.24 x 10(-5) in fetuses of 125, 250 and 500 microg/kg treated groups, respectively. The MF of controls was 0.81 +/- 0.22 x 10(-5). There were no significant differences among the groups. However, the MF of each treated group was a little highter than that of control group. Possible relationships between PCB and its mutagenic effects in the offspring of mice are discussed.

Assessment of the developmental toxicity, metabolism, and placental transfer of Di-n-butyl phthalate administered to pregnant rats.

The developmental toxicity and placental transfer of di-n-butyl phthalate (DBP) were evaluated in Sprague-Dawley rats given a single oral dose of DBP on Gestational Day 14. In the developmental toxicity study, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg and were necropsied on GD21. Increased incidence of resorptions and reduced fetal body weight were observed at 1.5 and 2 g/kg. Higher incidences of skeletal variations were found at doses > or = at 1 g/kg. No embryotoxic or teratogenic effects were observed at a dose of 0.5 g/kg. In the placental transfer study, dams were dosed with 0.5 or 1.5 g [14C]DBP/kg. Maternal and embryonic tissues were collected at intervals from 0.5 to 48 h. Embryonic tissues accounted for less than 0.12-0.15% of the administered dose. Levels of radiocarbon in placenta and embryo were one-third or less of those in maternal plasma. No accumulation of radioactivity was observed in the maternal or embryonic tissues. From HPLC analyses, it was shown that unchanged DBP and its metabolites mono-n-butyl phthalate (MBP) and MBP glucuronide were rapidly transferred to the embryonic tissues, where their levels were constantly lower than those in maternal plasma. MBP accounted for most of the radioactivity recovered in maternal plasma, placenta, and embryo. Unchanged DBP was found only in small amounts. These findings support the hypothesis that MBP, a potent teratogen, largely contributes to the embryotoxic effects of DBP.

Tree-structured logistic models for over-dispersed binomial data with application to modeling developmental effects.

This article proposes tree-structured logistic regression modeling for over-dispersed binomial data. Recursive partitioning is performed using a combination of statistical tests and residual analysis. The splitting criterion in cross-validation is based on the deviance function. A nested grid algorithm to estimate the bootstrap parameters is developed. The regression tree procedure provides a new approach for exploring in detail the relationship between the binomial response and explanatory variables. The proposed procedure is used to model the relationship between the incidence of malformation and dose and fetal weight using data from a developmental experiment conducted at the National Center for Toxicological Research. A conditional Gaussian chain model is used to account for the effect of fetal weight by dose.

Teratogenic potency of 2,3,4,7,8-pentachlorodibenzofuran and of three mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans in mice. Problems with risk assessment using TCDD toxic-equivalency factors.

The potency of 2,3,4,7,8-pentachlorodibenzofuran (P5CDF) and of three defined 2,3,7,8-TCDD-free mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs) to induce cleft palates in NMRI mice was studied. The data were compared with a dose-response curve for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The slope of the dose-response curve for P5CDF was the same as for TCDD. However, application of the International-TCDD-Toxic-Equivalency (I-TE) factor (NATO/CCMS 1988) of 0.5 overestimated the potency of the pentachlorinated congener about 2.5-fold under these experimental conditions, suggesting 0.2 as a TE factor. When assessing the cleft palate frequency on the basis of I-TEs and the weight of the substances, the potencies of the two PCDF mixtures studied were also clearly overestimated. This result was not substantially changed when using the TE factor of 0.2 for P5CDF. For the PCDD mixture studied, the cleft palate-inducing potency found largely agreed with the prediction when applying the I-TE factors. According to our data, the use of TE factors as calculated by the UBA/BGA (1985) or the NATO/CCMS (1988) are both conservative when attempting to assess the cleft palate incidence induced by PCDF mixtures in mice.

Biologic basis for a risk assessment model for cleft palate.

A biologic model for palatogenesis is presented, intended as a basis for risk assessment. It comprises a sequence of developmental stages: growth and migration of neural crest cells, downward growth of palatal buds, elevation of palatal shelves, and differentiation of the epithelium followed by shelf fusion. Several events representing these stages and amenable to mathematical translation may be measurable in the form of biomarkers such as DNA and protein synthesis, phospholipid metabolism, and signal transducing systems. Interrupting components of the model will result in cleft palate. Teratogens with known mechanisms of action are compared with the model. The quantitative risk of cleft palate is conceived as a sequence of mathematical probabilities that any stage of the model runs an abnormal course. Stage-specific probabilities are determined by a chemical's potency and dose, and by duration of exposure and gestational age. Species or strain sensitivity may be expressed as quantitative differences in model parameters. Although the model is designed for cleft palate, the risk model may also estimate a multiple response risk to the same exposures.