Quantifying Proximal Collecting Tubule Deficiency in Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Fetopathy.

INTRODUCTION: Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers (AAs) are used for several indications, with cessation recommended in pregnancy due to toxic effects. AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs). Our study aimed to quantify the reduction of PCTs in fetuses and infants with prenatal exposure to AAs. MATERIALS AND METHODS: We identified 5 fetal AA exposure cases that underwent autopsy at our institution between 2011 and 2018 and compared with 5 gestational age-matched controls. Immunohistochemistry with CD10 and epithelial membrane antigen (EMA) was utilized. RESULTS: CD10 and EMA identified a median PCT density of 19.0% ± 12.3% in AA fetopathy patients, significantly less than controls (52.8% ± 4.4%; p < 0.0001). One case with in utero cessation had a PCT density of 34.2% ± 0.2%. Among other AA fetopathy findings, 1 case demonstrated unilateral renal vein thrombosis and 4 had hypocalvaria. CONCLUSIONS: We have quantified the reduction in AA fetopathy PCT density, and demonstrated in utero cessation may recover PCT differentiation. Future studies may benefit from calculating PCT percentage as a potential biomarker to correlate with post-natal renal function and maternal factors including medication type, dosage, duration, and time from medication cessation.

In Vivo Assessment of Drug-Induced Hepatotoxicity Using Xenopus Embryos.

Failure to predict drug-induced toxicity reactions is a major problem contributing to a high attrition rate and tremendous cost in drug development. Drug screening in X. laevis embryos is high-throughput relative to screening in rodents, potentially making them ideal for this use. Xenopus embryos have been used as a toxicity model in the frog embryo teratogenesis assay on Xenopus (FETAX) for the early stages of drug safety evaluation. We previously developed compound-screening methods using Xenopus embryos and believe they could be used for in vitro drug-induced toxicity safety assessment before expensive preclinical trials in mammals. Specifically, Xenopus embryos could help predict drug-induced hepatotoxicity and consequently aid lead candidate prioritization. Here we present methods, which we have modified for use on Xenopus embryos, to help measure the potential for a drug to induce liver toxicity. One such method examines the release of the liver-specific microRNA (miRNA) miR-122 from the liver into the vasculature as a result of hepatocellular damage, which could be due to drug-induced acute liver injury. Paracetamol, a known hepatotoxin at high doses, can be used as a positive control. We previously showed that some of the phenotypes of mammalian paracetamol overdose are reflected in Xenopus embryos. Consequently, we have also included here a method that measures the concentration of free glutathione (GSH), which is an indicator of paracetamol-induced liver injury. These methods can be used as part of a panel of protocols to help predict the hepatoxicity of a drug at an early stage in drug development.

Genetic/idiopathic generalized epilepsies: Not so good as that!

Genetic or idiopathic generalized epilepsies (IGEs) account for 15-20% of all epilepsies. These syndromes have always been considered as good prognosis forms of epilepsy over time; however, for some patients, there is a need to maintain antiseizure drugs (ASD) for a long-time. Drug resistance is not uncommon (7-15%). Lifestyle remains essential and is an integral part of the treatment. Comorbidities such as obstructive sleep apnea syndrome must be considered and treated. A highly underestimated condition is the risk of sudden unexpected death in epilepsy (SUDEP). Very few data are available about the prevalence of SUDEP in IGE, but patients with generalized tonic-clonic seizures (GTCS) are exposed to this risk. IGEs are also characterized by a specific pharmalogical sensisitivity but may be aggravated by ASDs. Historically, the treatment of IGEs has relied mostly on valproate but this drug should be avoided in women of childbearing potential. Women with IGE not treated with valproate are more likely to have unsatisfactory seizure control. Female gender appears now as a new risk factor for drug-resistance. Finally, aside from the typical forms, there are epilepsies that fulfill most of the criteria of IGE, but that have an unusual history with GTCS, absences, falls, and drug resistance. Patients do not have psychomotor regression, brain magnetic resonance imaging is normal. EEG shows generalized fast rhythms during NREM sleep. These patients with refractory generalized epilepsy with sleep-related fast activities do not belong to a well-established syndromic category. These cases are considered "intermediary" between IGE and epileptic encephalopathies.

Prevalence of epilepsy in Saudi pregnant women and possible effects of anti-epileptic drugs on pregnancy outcomes.

OBJECTIVE: To determine the prevalence of epilepsy in Saudi pregnant women and estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities. It also aimed to report the teratogenic effects of anti-epileptic drugs as observed in neonates. METHODS: This prospective study was conducted at King Fahd University Hospital from June 2018 to July 2019. Sixty-eight pregnant women diagnosed with epilepsy were included in this study. Seizure types and their frequencies were recorded along with anti-epileptic drug therapies and their association with fetal/neonatal malformations RESULTS: Out of 68 epileptic pregnant females, 30 (44.1%) experienced focal seizures and 38 (55.9%) experienced generalized seizures. Thirty-nine (57.3%) received monotherapy, 21 (30.9%) received polytherapy and 8 (11.8%) did not take antiepileptic drugs during pregnancy. Thirty-six (52.9%) patients experienced no change in seizure frequency during pregnancy, 19 (27.9%) experienced increase in seizure frequency and 13 (19.1%) showed decreased seizure frequency. The pregnancy outcomes analysis showed 2 (2.9%) intrauterine fetal deaths, whereas 4 (4.9%) neonates showed facial and/or organ malformations. CONCLUSION: The frequency of seizures was found to increase in only 27.9% of the pregnant women in the sample. Malformation and mortality rates were higher in fetuses/neonates of patients with generalized seizures. It was observed that for the patient group using monotherapy, the rate of healthy babies was higher than that of the group using polytherapy.

Assessment of Gross Fetal Malformations: The Modernized Wilson Technique and Skeletal Staining.

Teratology is the study of anatomical and physiological abnormalities, commonly known as birth defects. If an embryo is exposed to a harmful substance, or teratogen, during the critical period of development, an ensuing malformation may occur. These malformations and their associated mechanisms are studied and analyzed in laboratory animals in order to prevent them from occurring in humans. Rodents such as rats and mice have commonly been used in such studies because of their similarity to humans. In 1959, James G. Wilson designed, developed, and tested a protocol on how to observe and analyze structural malformations in rodent fetuses, which included: external examination, skeletal evaluation, soft tissue analysis, and data collection/analysis. For standardization purposes, i.e., to normalize findings from one lab to another, it is important that this protocol be followed with precision. Although many years have passed since Wilson initially created this protocol, it is still widely used to this day, and only minor changes have been made to his instructions such as the chemical reagents used in the experiments and methods of analysis of the experimental data. Such testing has resulted in major advances in the dissemination of teratology information, including the identification of an increasing number of teratogens and the understanding of the pathogenesis of birth defects. While mechanistically birth defect prevention will include the understanding of individual genomes and pharmacogenomics, overall, morphological assessment will still be required as an integral part of birth defects research. As the interaction between teratogenic and genetic factors is better understood, it is anticipated that the incidence of most types of defects will substantially be reduced.

Learning the effects of psychotropic drugs during pregnancy using real-world safety data: a paradigm shift toward modern pharmacovigilance.

The growing evidence on psychotropic drug safety in pregnancy has been possible thanks to the increasing availability of real-world data, i.e. data not collected in conventional randomised controlled trials. Use of these data is a key to establish psychotropic drug effects on foetal, child, and maternal health. Despite the inherent limitations and pitfalls of observational data, these can still be informative after a critical appraisal of the collective body of evidence has been done. By valuing real-world safety data, and making these a larger part of the regulatory decision-making process, we move toward a modern pregnancy pharmacovigilance. The recent uptake of real-world safety data by health authorities has set the basis for an important paradigm shift, which is integrating such data into drug labelling. The recent safety assessment of sodium valproate in pregnant and childbearing women is probably one of the first examples of modern pregnancy pharmacovigilance.

Use of Nimesulide During Early Pregnancy and the Risk of Congenital Malformations: A Population-Based Study from Italy.

INTRODUCTION: Nimesulide is the most prescribed non-steroidal anti-inflammatory drug in Italy, and it is currently marketed in about 50 countries worldwide. The association between the use of nimesulide in early pregnancy and the risk of birth defects was investigated in a large cohort of pregnant women from Italy. METHODS: Data were from the healthcare utilization databases of the Italian region of Lombardy. The cohort of 353,081 newborns occurring in Lombardy during the period 2005-2010 was investigated. Exposure to nimesulide during the first trimester of pregnancy, and congenital malformations detected at presentation and within 90 days after birth (outcome), were investigated. Exposure-outcome association was measured by the ratio between the prevalence of congenital malformations among users and non-users of nimesulide. Propensity score stratification was used to control for potential confounders, including maternal medical comorbidities, concomitant medications and sociodemographic characteristics. RESULTS: The 627 (0.18%) women who filled prescriptions for nimesulide in the first trimester of pregnancy had a 2.6-fold risk of having children with congenital urinary tract anomalies compared to those who did not (adjusted prevalence ratio 2.6; 95% CI 1.2-5.7). Weaker and non-significant evidence for congenital malformations as a whole was found (adjusted prevalence ratio 1.2, 95% CI 0.9-1.6). CONCLUSION: Our study suggests that the use of nimesulide in early pregnancy may result in a greater risk of having births with congenital urinary tract anomalies. FUNDING: This study was funded by grants from the Italian Ministry of the Education, University and Research ('Fondo d'Ateneo per la Ricerca' portion, year 2015).

Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome.

Fetuses exposed to warfarin during pregnancy are at an increased risk of developing an embryopathy known as fetal warfarin syndrome or warfarin embryopathy. The most consistent anomalies are nasal hypoplasia and stippling of vertebrae or bony epiphyses. Management of pregnant patients on anticoagulation is challenging. Current guidelines suggest the use of warfarin if the therapeutic dose is ≤5 mg/day. We report the case of a newborn with signs of warfarin embryopathy born from a mother anticoagulated with warfarin due to mechanical mitral and aortic heart valves. Warfarin was required at the dose of 5 mg/day and was withheld without medical advice between weeks 8 and 10 with no other anticoagulation. The newborn presented with skeletal abnormalities and a ventricular septal defect that have not required specific treatment during the first year of life. Low-dose warfarin is associated with a lower risk of warfarin-related fetopathy but the risk of embryopathy seems unchanged.

Embriopatía por isotretinoína: Una entidad que puede evitarse / Isotretinoin embryopathy: An entity that can be avoided

La isotretinoína es el medicamento más efectivo en el tratamiento del acné noduloquístico recalcitrante grave. Sin embargo, el tratamiento con este fármaco se encuentra asociado con efectos adversos, y el más grave es la teratogénesis. Se ha estimado que 40% de los embarazos expuestos a isotretinoína presenta un aborto espontáneo y 35% desarrolla embriopatía. Se presenta el caso de un recién nacido con antecedente de exposición prenatal a isotretinoína, una entidad clínica que puede evitarse, con graves defectos congénitos en el sistema nervioso central e importantes dismorfias faciales, con evolución clínica desfavorable.

Isotretinoin is the most effective drug in the treatment of severe recalcitrant nodulocystic acne. However, treatment with this drug is associated with adverse effects, the most severe being teratogenesis. It has been estimated that 40% of pregnancies exposed to isotretinoin present spontaneous abortion and 35% develop embryopathy. We present the case of a newborn with a history of prenatal exposure to isotretinoin, a clinical entity that can be avoided, with severe congenital defects in the central nervous system and important facial dysmorphisms, with unfavorable clinical course.

[Isotretinoin embryopathy: An entity that can be avoided]. / Embriopatía por isotretinoína: Una entidad que puede evitarse.

Isotretinoin is the most effective drug in the treatment of severe recalcitrant nodulocystic acne. However, treatment with this drug is associated with adverse effects, the most severe being teratogenesis. It has been estimated that 40% of pregnancies exposed to isotretinoin present spontaneous abortion and 35% develop embryopathy. We present the case of a newborn with a history of prenatal exposure to isotretinoin, a clinical entity that can be avoided, with severe congenital defects in the central nervous system and important facial dysmorphisms, with unfavorable clinical course.

La isotretinoína es el medicamento más efectivo en el tratamiento del acné noduloquístico recalcitrante grave. Sin embargo, el tratamiento con este fármaco se encuentra asociado con efectos adversos, y el más grave es la teratogénesis. Se ha estimado que 40% de los embarazos expuestos a isotretinoína presenta un aborto espontáneo y 35% desarrolla embriopatía. Se presenta el caso de un recién nacido con antecedente de exposición prenatal a isotretinoína, una entidad clínica que puede evitarse, con graves defectos congénitos en el sistema nervioso central e importantes dismorfias faciales, con evolución clínica desfavorable.

Fetal valproate syndrome: the Irish experience.

INTRODUCTION: Fetal valproate syndrome was first described in 1984. Valproic acid crosses the placenta and can potentially lead to major congenital malformation, dysmorphism and neurodevelopmental disorder. METHODS: A retrospective study of 29 cases of FVS diagnosed by geneticists from 1995 to 2016. The cases were diagnosed based on criteria of fetal anticonvulsant syndrome. RESULTS: A total of 29 cases reported in the last 21 years. Features commonly described are prominent metopic ridge, midface hypoplasia, epicanthic folds, micrognathia and broad and flat nasal bridge. Four (13.7%) had cleft palate, three (10%) had neural tube defect, four (13.7%) with cardiac malformation, 15 (52%) experienced developmental delay including six (40%) with speech delay, 11 (38%) with limb defects, four (13.7%) reported with neurodevelopmental disorder and two (7%) had hypospadias. CONCLUSION: FVS is still seen in the Irish population even though the teratogenicity of the VPA has been known for over 32 years. It is very important to create public and professional awareness to prevent FVS whenever possible.

Categorization of fetal external findings in developmental toxicology studies by the Terminology Committee of the Japanese Teratology Society.

Categorization of fetal external findings in common laboratory animals, intended to make the agreement at Berlin Workshop in 2014 more practical, was proposed by the Terminology Committee of the Japanese Teratology Society at the Workshop in the 55th Japanese Teratology Society Annual Meeting in 2015. In the Workshop, 73 external findings, which had been categorized as "Gray zone" anomalies but not as "Malformation" or "Variation" in the 2014 Berlin Workshop, were discussed and classified as Malformation, "Non-structural abnormality," Variation, and "Not applicable." The proposal was based on the results of a survey conducted in 2014, where 20 facilities (including pharmaceutical, chemical, and pesticide companies and contract laboratories) and 2 selected expert teratologists in Japan were asked for their opinions on the categorization of these findings. Based on the discussion, Japanese Teratology Society members have agreed that 42 out of the 73 findings can be classified as Malformations (38), Non-structural abnormalities (3), Malformations/Non-structural abnormalities (1), and Variations (0), while the remaining 31 findings were recommended to be categorized as Not applicable for fetuses. The details of the classification are shown on the website of the Japanese Teratology Society (http://www.umin.ac.jp/cadb/External.pdf).

Primary Prevention of Congenital Anomalies: Special Focus on Environmental Chemicals and other Toxicants, Maternal Health and Health Services and Infectious Diseases.

Congenital anomalies (CA) represent an important fraction of rare diseases, due to the critical role of non-genetic factors in their pathogenesis. CA are the main group of rare diseases in which primary prevention measures will have a beneficial impact. Indeed, since 2013 the European Union has endorsed a body of evidence-based recommendations for CA primary prevention; the recommendations aim at facilitating the inclusion of primary prevention actions the National Rare Disease Plans of EU Member States and encompass different public health fields, from environment through to maternal diseases and lifestyles.The chapter overviews and discusses the assessment of main risk factors for CA, such as environmental toxicants, maternal health and lifestyles and infections, with a special attention to issues that are emerging or need more knowledge.Overall, the availability of CA registries is important for estimating the health burden of CA, identifying possible hotspots, assessing the impact of interventions and addressing further, fit-to-purpose research.The integration of relevant public health actions that are already in place (e.g., control of noxious chemicals, vaccination programmes, public health services addressing chronic maternal conditions) can increase the affordability and sustainability of CA primary prevention. In developing countries with less primary prevention in place and limited overall resources, a first recognition phase may be pivotal in order to identify priority targets. In the meanwhile, policy makers should be made aware that primary prevention of RD supports publicly endorsed societal values like the knowledge-based promotion of health, empowerment, equity and social inclusiveness.

The effects of microduplication 1q21.1 and in-utero isotretinoin exposure.

The impact of in-utero isotretinoin exposure has been widely reported, with many affected pregnancies failing to reach term.1 2 Due to the low numbers of in-utero isotretinoin exposed pregnancies, the interactions between this drug and rare genetic defects such as microduplication 1q21.1 are unclear, particularly how they might manifest phenotypically. We present this case of in-utero isotretinoin exposure occurring in a child with microduplication 1q21.1. The child was born with congenital abnormalities which did not fit into a single syndrome. Regrettably in-utero exposure to isotretinoin continues to occur. We hope this case will trigger further discussion on the dangers of dispensing Isotretinoin without ensuring stringent pregnancy testing and its potential interaction with genetic abnormalities, in particular with microduplication 1q21.1.

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.

Birth defects after use of antithyroid drugs in early pregnancy: a Swedish nationwide study.

OBJECTIVE: Antithyroid drugs (ATDs) may have teratogenic effects, but more evidence is needed on the risk and types of birth defects after the use of methimazole (MMI) and propylthiouracil (PTU). This study aimed to evaluate the association between the use of ATDs in early pregnancy and birth defects. DESIGN: Swedish nationwide register-based cohort study. METHODS: The study included 684 340 children live-born in Sweden from 2006 to 2012. Exposure groups defined by maternal ATD use in early pregnancy were MMI (n = 162); PTU (n = 218); MMI and PTU (n = 66); ATD before or after, but not in pregnancy (n = 1551) and non-exposed (never ATD (n = 682 343)). Outcome was cumulative incidence of birth defects diagnosed before two years of age. RESULTS: The cumulative incidence of birth defects was not significantly different in children exposed to MMI (6.8%, P = 0.6) or PTU (6.4%, P = 0.4) vs non-exposed (8.0%). For subtypes of birth defects, MMI was associated with an increased incidence of septal heart defects (P = 0.02). PTU was associated with ear (P = 0.005) and obstructive urinary system malformations (P = 0.006). A case of choanal atresia was observed after exposure to both MMI and PTU. The incidence of birth defects in children born to mothers who received ATD before or after, but not in pregnancy, was 8.8% and not significantly different from non-exposed (P = 0.3), MMI exposed (P = 0.4) or PTU exposed (P = 0.2). CONCLUSIONS: MMI and PTU were associated with subtypes of birth defects previously reported, but the frequency of ATD exposure in early pregnancy was low and severe malformations described in the MMI embryopathy were rarely observed.

The Molecular Mechanisms of Thalidomide Teratogenicity and Implications for Modern Medicine.

Thalidomide is a teratogen that affects many organs but primarily induces limb truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led to misinterpretations of animal tests and to the fatal assumption that the drug was safe for pregnant women to use against morning sickness. The result was one of the biggest scandals in medical history: 10.000 and more infants with birth defects in Europe. Nonetheless, thalidomide still has its place in modern medicine as it has strong therapeutic potential: it has been approved by the FDA for multiple myeloma and erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and antiangiogenic activities are considered in many other refractory diseases. The aim is to develop derivatives that are not teratogenic but maintain the therapeutic potential. This requires detailed knowledge about the underlying molecular mechanisms. Much progress has been made in deciphering the teratogenic mechanisms in the last decade. Here, we summarize these mechanisms, explain thalidomide resistance of rodents, and discuss possible mechanisms that could explain why the drug primarily targets the developing limb in the embryo. We also summarize the most important therapeutic mechanisms. Finally, we discuss which therapeutic and teratogenic mechanisms do and do not overlap, and if there is a chance for the development of non-teratogenic thalidomide derivatives with therapeutic potential.