Thalidomide and its metabolite 5-hydroxythalidomide induce teratogenicity via the cereblon neosubstrate PLZF.

Thalidomide causes teratogenic effects by inducing protein degradation via cereblon (CRBN)-containing ubiquitin ligase and modification of its substrate specificity. Human P450 cytochromes convert thalidomide into two monohydroxylated metabolites that are considered to contribute to thalidomide effects, through mechanisms that remain unclear. Here, we report that promyelocytic leukaemia zinc finger (PLZF)/ZBTB16 is a CRBN target protein whose degradation is involved in thalidomide- and 5-hydroxythalidomide-induced teratogenicity. Using a human transcription factor protein array produced in a wheat cell-free protein synthesis system, PLZF was identified as a thalidomide-dependent CRBN substrate. PLZF is degraded by the ubiquitin ligase CRL4CRBN in complex with thalidomide, its derivatives or 5-hydroxythalidomide in a manner dependent on the conserved first and third zinc finger domains of PLZF. Surprisingly, thalidomide and 5-hydroxythalidomide confer distinctly different substrate specificities to mouse and chicken CRBN, and both compounds cause teratogenic phenotypes in chicken embryos. Consistently, knockdown of Plzf induces short bone formation in chicken limbs. Most importantly, degradation of PLZF protein, but not of the known thalidomide-dependent CRBN substrate SALL4, was induced by thalidomide or 5-hydroxythalidomide treatment in chicken embryos. Furthermore, PLZF overexpression partially rescued the thalidomide-induced phenotypes. Our findings implicate PLZF as an important thalidomide-induced CRBN neosubstrate involved in thalidomide teratogenicity.

Undetected, natural conception pregnancies in luteal phase stimulations-case series and review of literature.

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.

The good, the bad and the ugly of luteal phase stimulations.

An early follicular phase start of ovarian stimulation in assisted reproductive technology (ART) is only required if a fresh embryo transfer is planned. A shift from fresh to frozen embryo transfers has recently characterized ART treatments and, combined with the trend towards treatment individualization and simplification, facilitated random-start stimulation. Luteal phase stimulation, started between ovulation and the next menses, has gained momentum and the good, the bad and the ugly sides have become obvious with the increasing number performed. Unprotected intercourse during the follicular phase or around ovulation can result in an unknown and undetectable conception at the time of starting stimulation. Aside from the theoretical implications for embryo development from exposure to stimulation medication, embryo-derived human chorionic gonadotrophin may cause ovarian hyperstimulation syndrome. The duration of stimulation and consumption of gonadotrophin appear to be longer and higher than in the early follicular phase start approach, although the number of retrieved/mature oocytes is comparable or, in some instances, higher. On the other hand, elevated progesterone concentrations during the luteal phase may prevent premature ovulation and, in theory, might replace pituitary suppression using gonadotrophin-releasing hormone antagonists or exogeneous progestins. Furthermore, the flexibility in stimulation timing will meet the needs of patients with time constraints.

Glucagon-like peptide-1 receptor agonist use in pregnancy: a review.

Glucagon-like peptide-1 receptor agonists are peptide analogues that are used to treat type 2 diabetes mellitus and obesity. The first medication in this class, exenatide, was approved in 2005, and these medications, specifically semaglutide, have become more popular in recent years due to their pronounced effects on glycemic control, weight reduction, and cardiovascular health. Due to successful weight loss from these medications, many women previously diagnosed with oligomenorrhea and unable to conceive have experienced unplanned pregnancies while taking the medications. However, there are currently little data for clinicians to use in counseling patients in cases of accidental periconceptional exposure. In some studies examining small animals exposed to glucagon-like peptide-1 receptor agonists in pregnancy, there has been evidence of adverse outcomes in the offspring, including decreased fetal growth, skeletal and visceral anomalies, and embryonic death. Although there are no prospective studies in humans, case reports, cohort studies, and population-based studies have not shown a pattern of congenital anomalies in infants. A recent large, observational, population-based cohort study examined 938 pregnancies affected by type 2 diabetes mellitus and compared outcomes from periconceptional exposure to glucagon-like peptide-1 receptor agonists and insulin. The authors concluded there was not a significantly increased risk of major congenital malformations in patients taking glucagon-like peptide-1 receptor agonists, although there was no information on maternal glycemic control or diabetic fetopathy. As diabetic embryopathy is directly related to the degree of maternal hyperglycemia and not the diagnosis of diabetes itself, it is not possible to make this conclusion without this information. Furthermore, there is little evidence available regarding fetal growth restriction, embryonic or fetal death, or other potential complications. At this time, patients should be counseled there is not enough evidence to predict any adverse effects, or the lack thereof, of periconceptional exposure of glucagon-like peptide-1 receptor agonists during pregnancy. We recommend that all patients use contraception to prevent unintended pregnancy while taking glucagon-like peptide-1 receptor agonists.

Antiretroviral Therapy in Pregnancy: A 2023 Review of the Literature.

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. 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.

Thalidomide for the Management of Gastrointestinal Bleeding in a Palliative Care Setting.

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.

Neurotoxic effects of carbamazepine on the mosquitofish Gambusia affinis.

In 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.

Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury.

BACKGROUND: Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs. METHODS: TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions. RESULTS: TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice. CONCLUSION: TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component.

Placental disposition of cannabidiol: An ex vivo perfusion study.

OBJECTIVE: In the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small-molecule, highly lipid-soluble drug, CBD is likely to be distributed into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short-term placental effects, we conducted an ex vivo perfusion study in human placentas. METHODS: Placentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD-containing medium (250 ng/mL, .796 µmol·L-1 ; representative of a low therapeutic concentration; n = 8). CBD concentrations were determined at 180 min in the medium and placental tissue using liquid chromatography-tandem mass spectrometry. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 µmol·L-1 ; high therapeutic concentration; n = 8) and in those exposed to the vehicle. RESULTS: CBD was sequestered in the placental tissue, exhibiting significant variability across samples (median = 5342 ng/g tissue, range = 1066-9351 ng/g tissue). CBD concentrations in the fetal compartment were one fifth of those measured in the maternal compartment (median = 59 ng/mL, range = 48-72 ng/mL vs. 280 = ng/mL, range = 159-388 ng/mL, respectively; p < .01). Placental gene expression was not significantly altered by CBD. SIGNIFICANCE: The placenta acts as a depot compartment for CBD, slowing down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD.

Birth outcomes in pregnant women with epilepsy: A Nationwide multicenter study from Türkiye.

OBJECTIVE: The present study was aimed at investigating the effects of anti-seizure medications (ASMs), patient demographic characteristics, and the seizure type and frequency on the development of congenital malformations (CMs) in the infants of pregnant women with epilepsy (PWWE). METHODS: PWWE followed up at the neurology outpatient clinic of 21 centers between 2014 and 2019 were included in this prospective study. The follow-up of PWWE was conducted using structured, general pregnant follow-up forms prepared by the Pregnancy and Epilepsy Study Committee. The newborns were examined by a neonatologist after delivery and at 1 and 3 months postpartum. RESULTS: Of the infants of 759 PWWE, 7.2% had CMs, with 5.6% having major CMs. Polytherapy, monotherapy, and no medications were received by 168 (22.1%), 548 (72.2 %), and 43 (5.7 %) patients, respectively. CMs were detected at an incidence of 2.3% in infants of PWWE who did not receive medication, 5.7% in infants of PWWE who received monotherapy, and 13.7% in infants of PWWE who received polytherapy. The risk of malformation was 2.31-fold (95% confidence interval (CI): 1.48-4.61, p < .001) higher in infants of PWWE who received polytherapy. Levetiracetam was the most frequently used seizure medication as monotherapy, with the highest incidence of CMs occurring with valproic acid (VPA) use (8.5%) and the lowest with lamotrigine use (2.1%). The incidence of CMs was 5% at a carbamazepine dose <700 mg, 10% at a carbamazepine dose ≥700 mg, 5.5% at a VPA dose <750 mg, and 14.8% at a VPA dose ≥750 mg. Thus the risk of malformation increased 2.33 times (p = .041) in infants of PWWE receiving high-dose ASMs. SIGNIFICANCE: Birth outcomes of PWWE receiving and not receiving ASMs were evaluated. The risk of CMs occurrence was higher, particularly in infants of PWWE using VPA and receiving polytherapy. The incidence of CMs was found to be lower in infants of PWWE receiving lamotrigine.

Risk of fetal or neonatal death or neonatal intensive care unit admission associated with gadolinium magnetic resonance imaging exposure during pregnancy.

BACKGROUND: Concerns have been raised about prenatal exposure to magnetic resonance imaging with gadolinium-based contrast agents because of nonclinical findings of gadolinium retention in fetal tissue and 1 population-based study reporting an association with adverse pregnancy outcomes. OBJECTIVE: This study aimed to evaluate the association between prenatal magnetic resonance imaging exposure with and without gadolinium-based contrast agents and fetal and neonatal death and neonatal intensive care unit admission. STUDY DESIGN: We constructed a retrospective cohort of >11 million Medicaid-covered pregnancies between 1999 and 2014 to evaluate the association between prenatal magnetic resonance imaging exposure with and without gadolinium-based contrast agents and fetal and neonatal death (primary endpoint) and neonatal intensive care unit admissions (secondary endpoint). Medicaid claims data were linked to medical records, Florida birth and fetal death records, and the National Death Index to validate the outcomes and gestational age estimates. Pregnancies with multiples, concurrent cancer, teratogenic drug exposure, magnetic resonance imaging focused on fetal or pelvic evaluation, undetermined gadolinium-based contrast agent use, or those preceded by or contemporaneous with congenital anomaly diagnoses were excluded. We adjusted for potential confounders with standardized mortality ratio weighting using propensity scores. RESULTS: Among 5991 qualifying pregnancies, we found 11 fetal or neonatal deaths in the gadolinium-based contrast agent magnetic resonance imaging group (1.4%) and 73 in the non-gadolinium-based contrast agent magnetic resonance imaging group (1.4%) with an adjusted relative risk of 0.73 (95% confidence interval, 0.34-1.55); the neonatal intensive care unit admission adjusted relative risk was 1.03 (0.76-1.39). Sensitivity analyses investigating the timing of magnetic resonance imaging or repeat magnetic resonance imaging exposure during pregnancy and simulating the impact of exposure misclassification corroborated these results. CONCLUSION: This study addressed the safety concerns related to prenatal exposure to gadolinium-based contrast agents used in magnetic resonance imaging and the risk thereof on fetal and neonatal death or the need for neonatal intensive care unit admission. Although the results on fatal or severe acute effects are reassuring, the impact on subacute outcomes was not evaluated.

Pharmacoethics and pregnancy: Overcoming the therapeutic orphan stigma.

There is paucity of evidence to support clinical decision making and counselling related to medication use in pregnancy. Despite multiple efforts from legislative bodies and advocacy groups, the inclusion of pregnant women in clinical drug trials assessing efficacy and safety remains scarce. Pregnancy can be complicated by multiple comorbidities that require pharmacological intervention; these interventions primarily target the pregnant woman but also sometimes have secondary effects for the foetus. The US Food and Drug Administration has issued multiple guidance documents on incorporating pregnant women in clinical trials to aid pharmaceutical companies in designing a protocol to ensure safety and adherence to ethical standards. Advances in paediatric pharmacology studies provide lessons for researchers on the best practice of designing clinical trials with inclusion of patients from special populations. In this review, we present the status of pregnant women in clinical trials, highlighting the ethical stigma and possible future directives.

Reproductive Toxicity and Teratogenicity of Fluorene-9-bisphenol on Chinese Medaka (Oryzias sinensis): A Study from Laboratory to Field.

Fluorene-9-bisphenol (BHPF), a bisphenol A (BPA) substitute, has been increasingly used as a material in syntheses of polymers that are widely used in road markings, artificial tracks, coating floors, building paints, etc., increasing the likelihood of BHPF contamination in the aquatic environment due to its release from the products. However, to date, it is unknown whether it may have actual impacts on fish in real environments. In this study, a 105-day exposure experiment of BHPF at various concentrations (0.01, 0.1, 1, and 10 µg/L) on Chinese medaka (Oryzias sinensis) was performed under laboratory conditions and found decreased fecundity, such as lower egg qualities and quantities, retarded oogenesis, and atretic follicles in the fish and deformed eyes and bodies in its F1 generation. Toxico-transcriptome analyses showed that estrogen-responsive genes were significantly suppressed by BHPF, indicating that antagonist properties of BHPF on estrogen receptors might be causes for the decreased fecundity. Field investigations (Beijing) demonstrated that BHPF was detectable in 60% surface waters, with a mean concentration of 10.49 ± 6.33 ng/L, by gas chromatography-mass spectrometry, and similar effects in wild Chinese medaka were also observed, some of which the parameters were found to be obviously correlated with the BHPF levels in corresponding waters.

Trends in antiseizure medications utilization among women of childbearing age with epilepsy in Poland between 2015 and 2019.

PURPOSE: To determine trends in the use of antiseizure medications (ASMs) among women of childbearing age (WOCA) and girls aged 12-14 years with epilepsy between 2015 and 2019 in Poland. METHODS: The study used data from the Pex database, which captures information on prescriptions dispensed from 85% of community pharmacies in Poland. The prescriptions issued by neurologists who provide epilepsy care in Poland were studied. Six of the most commonly prescribed ASMs were analyzed: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate. RESULTS: The use of valproate and carbamazepine decreased in all age groups. Among the newer ASMs, the use of lamotrigine, levetiracetam, and topiramate increased and oxcarbazepine decreased significantly in WOCA. The only subgroup with statistically significant changes in all ASMs prescriptions were women aged 19-34 years. For girls aged 12-14 years, significant changes were found only for valproate and carbamazepine. In the last year of observation (2019) valproate and lamotrigine accounted for two-thirds of ASMs units prescribed to WOCA. Valproate accounted for half of the prescribed drug units in girls aged 12-14 years. The lowest rates of VPA prescriptions were found in women aged 19-34 years. CONCLUSIONS: There is a change in prescribing habits in WOCA with epilepsy in Poland with trends toward using less teratogenic ASMs. However, many WOCAs are treated with valproate and topiramate despite their known teratogenicity risk. Valproate is still the most commonly prescribed ASM in WOCA and girls aged 12-14 years. Educational interventions for healthcare professionals are needed to improve prescribing practices in WOCA with epilepsy in Poland.

Evaluating awareness, knowledge and practice of healthcare professionals following implementation of a revised pregnancy prevention programme for isotretinoin in Ireland: A multi-stakeholder cross-sectional study.

PURPOSE: In 2018, following an EU-wide safety review, a revised pregnancy prevention programme (PPP) was introduced for isotretinoin (Roaccutane®). This study aimed to examine awareness, knowledge, and experience implementing the revised isotretinoin PPP in clinical practice across three healthcare professional (HCP) groups in Ireland. METHODS: A cross-sectional study using anonymous online surveys among general practitioners (GPs), community pharmacists, and specialist consultants was undertaken. Descriptive analyses are presented. RESULTS: Across all HCP groups there was high (≥87%) awareness that oral isotretinoin is contraindicated in women of childbearing potential (WCBP) unless the conditions of the PPP are fulfilled, but varying awareness among GPs (54.9%) and community pharmacists (45.9%) that exposure during pregnancy can cause both severe fetal malformations and spontaneous abortions. Implementation of the PPP in clinical practice varied across HCP groups. When initiating isotretinoin in WCBP, 66.7% of specialists and 40.8% of GPs indicated they had considered alternative treatment options, and 71.4% of specialists and 31.6% of GPs reported they first requested a pregnancy test. There was limited provision of the patient reminder card to WCBP, where 26.1% of community pharmacists provide this at each dispensing, while 47.6% of specialists and 11.8% of GPs ensured WCBP had a copy of the card when initiating treatment. Across all HCP groups, there was high (≥81.6%) awareness of the need for urgent consultation and immediate cessation of isotretinoin in the event of an unplanned or suspected pregnancy. CONCLUSIONS: Reinforcement of the provision and utilisation of the isotretinoin patient reminder card may be required, and further targeted education on specific elements of the PPP should be considered for GPs and community pharmacists.

Assessment of the scope, completeness, and consistency of various drug information resources related to COVID-19 medications in pregnancy and lactation.

BACKGROUND: Drug use in pregnancy and lactation is challenging. It becomes more challenging in pregnant and lactating women with certain critical clinical conditions such as COVID-19, because of inconsistent drug safety data. Therefore, we aimed to evaluate the various drug information resources for the scope, completeness, and consistency of the information related to COVID-19 medications in pregnancy and lactation. METHODS: Data related to COVID-19 medications from various drug information resources such as text references, subscription databases, and free online tools were used for the comparison. The congregated data were analyzed for scope, completeness, and consistency. RESULTS: Scope scores were highest for Portable Electronic Physician Information Database (PEPID), Up-to-date, and drugs.com compared to other resources. The overall completeness scores were higher for Micromedex and drugs.com (p < 0.05 compared to all other resources). The inter-reliability analysis for overall components by Fleiss kappa among all the resources was found to be 'slight' (k < 0.20, p < 0.0001). The information related to the older drugs in most of the resources, provides in-depth details on various components such as pregnancy safety, clinical data related to lactation, the effect of the drug distribution into breast milk, reproductive potential/infertility risk and the pregnancy category/recommendations. However, the information related to these components for newer drugs was superficial and incomplete, with insufficient data and inconclusive evidence, which is a statistically significant observation. The strength of observer agreement for the various COVID-19 medications ranged from poor to fair and moderate for the various recommendation categories studied. CONCLUSION: This study reports discrepancies in the information related to pregnancy, lactation, drug level, reproductive risk, and pregnancy recommendations among the resources directing to refer to more than one resource for information about the safe and quality use of medications in this special population.The present study also emphasizes the need for development of comprehensive, evidence-based, and precise information guide that can promote safe and effective drug use in this special population.

Toxicological effects of the Morinda citrifolia L. fruit extract on maternal reproduction and fetal development in rats.

Morinda citrifolia L., also known as Noni, is widely used plant in folk medicine for various therapeutic purposes. However, reports on its effects during pregnancy are limited. Therefore, the objective of this study was to evaluate the effects of the M. citrifolia fruit extract on maternal performance and fetal development during pregnancy in rats. Pregnant Wistar rats (n = 12/group) were treated from gestational days (GD) 0-21 with water (control group) or the aqueous extract of M. citrifolia fruit at doses of 200, 400, or 750 mg/kg, orally. During pregnancy, clinical signs of toxicity, maternal weight, feed intake, and water consumption were noted. On GD 21, the rats were anesthetized and blood was collected to evaluate various biochemical parameters. During laparotomy, reproductive performance parameters were recorded, and fetuses were weighed and the anomalies analyzed. Reduced placental efficiency and fetal growth restriction were observed in the group treated with 400 mg/kg of M. citrifolia extract. The highest dose (750 mg/kg) augmented aspartate aminotransferase concentration and preimplantation losses, while reducing the number of live fetuses. Furthermore, both doses (400 and 750 mg/kg) of the plant extract caused fetal anomalies. In conclusion, consumption of high doses of the M. citrifolia aqueous extrac during pregnancy leads to maternal hepatotoxicity, anti-implantation effects, intrauterine growth restriction and fetal abnormalities, indicating that the plant fruit extract can be harmful to both the mother and the fetus.

Developmental Toxicity Studies: The Path towards Humanized 3D Stem Cell-Based Models.

Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification.

Cyclophilin A as a Pro-Inflammatory Factor Exhibits Embryotoxic and Teratogenic Effects during Fetal Organogenesis.

The precise balance of Th1, Th2, and Th17 cytokines is a key factor in successful pregnancy and normal embryonic development. However, to date, not all humoral factors that regulate and influence physiological pregnancy have been completely studied. Our data here pointed out cyclophilin A (CypA) as the adverse pro-inflammatory factor negatively affecting fetal development and associated with pregnancy complications. In different mouse models in vivo, we demonstrated dramatic embryotoxicity and teratogenicity of increased CypA levels during pregnancy. Using generated transgenic models, we showed that CypA overexpression in fetal tissues induced the death of all transgenic fetuses and complete miscarriage. Administration of recombinant human CypA in a high dose to pregnant females during fetal organogenesis (6.5-11.5 dpc) exhibited teratogenic effects, causing severe defects in the brain and bone development that could lead to malformations and postnatal behavioral and cognitive disorders in the offspring. Embryotoxic and teratogenic effects could be mediated by CypA-induced up-regulation of M1 macrophage polarization via activation of the STAT1/3 signaling pathways. Here, we propose secreted CypA as a novel marker of complicated pregnancy and a therapeutic target for the correction of pregnancy complications.

[Psychopharmacotherapy during pregnancy and breastfeeding-Part I: focus on pregnancy : Support options by using therapeutic drug monitoring]. / Psychopharmakotherapie in Schwangerschaft und Stillzeit ­ Teil I: Schwerpunkt Schwangerschaft : Möglichkeiten der Unterstützung durch therapeutisches Drug-Monitoring.

The medicinal treatment of mental disorders during pregnancy and lactation requires special knowledge about possible effects of the psychopharmacotherapy on the intrauterine exposure of the embryo/fetus. Therefore, the first part of this 2­part article focuses on the use of psychotropic drugs during pregnancy. In the second part, the use of psychotropic drugs during breastfeeding is addressed. Possible substance-specific risks as a consequence of the administration have to be assessed compared to the natural risk of pregnancy complications, birth complications and neonatal complications associated with the appropriate (untreated) mental disease. Pharmacokinetic changes during pregnancy require a special focus on the safety of drug treatment and treatment efficacy. Currently, neither the European Medicines Agency (EMA) nor the U. S. Food and Drug Administration (FDA) has approved any psychotropic drug for use during pregnancy or breastfeeding. A more detailed consideration of the risk profiles of all psychotropic drugs, prescribed off-label during this time, is important. Antidepressants, antipsychotics, and mood stabilizers are the main drugs used, despite their lack of approval. This first part of our 2­part article provides an overview of the most frequently used substance groups during pregnancy and their special characteristics. Therapeutic drug monitoring (TDM) is presented as a clinical tool that can provide a supportive contribution to treatment safety and effectiveness during pregnancy and later also during breastfeeding, not only because of the changing pharmacokinetics. In this context, the measurement of concentrations of the active substance allows a better quantification of the intrauterine and postpartum exposure risk. Despite all clinical support possibilities, each therapeutic decision for the administration of a psychotropic drug remains an individual case decision. For those involved in the treatment, this means a careful balancing of the possible consequences of non-treatment and the possible sequelae of the use of psychopharmacotherapy.