BackgroundSafe use of medications during pregnancy requires a comprehensive understanding of risk-benefit profiles for individual treatments. Pharmacists are supported in this aspect by clinical information agencies (e.g. MotherSafe, a telephone-based teratogen information service) and reference texts. To what extent and for what reasons Australian pharmacists utilise these services/resources are yet unknown. Further, debate on replacement of conventionally defined medication safety in pregnancy categories (A, B1-3, C, D, X) by narratively stated safety evidence may affect pharmacists’ routine practice. This study aimed to gauge pharmacists’ experiences and resource needs in undertaking support roles regarding gestational drug use.MethodsSemi-structured interviews (audio-recorded or documented using field notes) were performed with community pharmacists in Australia and transcribed verbatim. Inductive thematic analysis was conducted using the NVivo software (Version 11, QSR International).ResultsData saturation was achieved with 24 interviews. Qualitative data yielded 5 emergent themes: barriers to effective counselling, patient trust, risk perception, role definition and practice support needs. Overall, participants relied on pregnancy categories, were risk averse and cautious in offering advice. Currently available data for unclassified and category B therapeutic agents (limited human data) were deemed inadequate. Reluctance to use the proposed narrative system was also expressed.DiscussionThis study highlights key barriers in the provision of maternal care by pharmacists and the potential tension present if the existing category system is replaced by a narrative one. These need to be addressed through training and development of practice support resources to enhance pharmacists’ skills in evidence-based risk estimation and communication.
Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.
This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.
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