Janus kinase-signal transducer and activator of transcription signaling pathway in the ocular cells of rat fetuses exposed to maternal saturated fat ingestion.

OBJECTIVE: The aim of this study was to analyze possible alterations (morphological and inflammatory) in the ocular cells of fetuses from mothers with insulin resistance exposed to saturated fatty acids through the period of pregnancy. METHODS: Wistar female rats were induced to develop insulin resistance before pregnancy. Fetuses' skulls were collected on the 20th day of intrauterine life. The rats were separated on the first day of management into two groups according to the diet applied: control group (C): diet containing soybean oil as a source of fat; and saturated fatty acid group (S): diet containing butter as a source of fat. RESULTS: Histological and immunohistochemical analyses have been conducted. The immunohistochemical analyses of interleukin 6, suppressor of cytokine signaling, 3 and signal transducer and activator of transcription 3 did not demonstrate alterations in the expression of proteins in the fetuses of mothers fed with a saturated fatty diet. Moreover, no histopathological changes were noticed between groups. CONCLUSION: The saturated fatty diet does not induce tissue changes or activate the Janus kinase/signal transducer and activator of transcription signaling pathway during eye development in the fetuses of mothers with insulin resistance.

Anesthetic recommendations for maternal and fetal safety in nonobstetric surgery: a balancing act.

PURPOSE OF REVIEW: Nonobstetric surgery during pregnancy is associated with maternal and fetal risks. Several physiologic changes create unique challenges for anesthesiologists. This review highlights physiologic changes of pregnancy and presents clinical recommendations based on recent literature to guide anesthetic management for the pregnant patient undergoing nonobstetric surgery. RECENT FINDINGS: Nearly every anesthetic technique has been safely used in pregnant patients. Although it is difficult to eliminate confounding factors, exposure to anesthetics could endanger fetal brain development. Perioperative fetal monitoring decisions require an obstetric consult based on anticipated maternal and fetal concerns. Given the limitations of fasting guidelines, bedside gastric ultrasound is useful in assessing aspiration risk in pregnant patients. Although there is concern about appropriateness of sugammadex for neuromuscular blockade reversal due its binding to progesterone, preliminary literature supports its safety. SUMMARY: These recommendations will equip anesthesiologists to provide safe care for the pregnant patient and fetus undergoing nonobstetric surgery.

α-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism.

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes developmental and reproductive disorders in pups due to the attenuated luteinizing hormone (LH) production during the perinatal stage; however, the administration of α-lipoic acid (LA) to TCDD-exposed pregnant rats reversed the attenuated LH production. Therefore, reproductive disorders in pups are expected to be ameliorated with LA supplementation. To address this issue, pregnant rats orally received low dose TCDD at gestational day 15 (GD15) and proceeded to parturition. The control received a corn oil vehicle. To examine the preventive effects of LA, supplementation with LA was provided until postnatal day 21. In this study, we demonstrated that maternal administration of LA restored the sexually dimorphic behavior of male and female offspring. TCDD-induced LA insufficiency is likely a direct cause of TCDD reproductive toxicity. In the analysis to clarify the mechanism of the decrease in LA, we found evidence suggesting that TCDD inhibits the synthesis and increases the utilization of S-adenosylmethionine (SAM), a cofactor for LA synthesis, resulting in a decrease in the SAM level. Furthermore, folate metabolism, which is involved in SAM synthesis, is disrupted by TCDD, which may adversely affect infant growth. Maternal supplementation of LA restored SAM to its original level in the fetal hypothalamus; in turn, SAM ameliorated abnormal folate consumption and suppressed aryl hydrocarbon receptor activation induced by TCDD. The study demonstrates that the application of LA could prevent and recover next-generation dioxin reproductive toxicity, which provides the potential to establish effective protective measures against dioxin toxicity.

Amelioration potential of Moringa oleifera extracts against sodium arsenate induced embryotoxicity and genotoxicity in mouse (Mus musculus) / Potencial de melhoria de extratos de Moringa oleifera contra embriotoxicidade e genotoxicidade induzida por arseniato de sódio em camundongos (Mus musculus)

Previous studies have suggested that arsenic crosses the placenta and affects the fetus development. The study under consideration aims to show comparative ameliorative effect of Moringa oleifera leaf and flower extracts against sodium arsenate induced fetus toxicity of mice. Pregnant mice (N=44) were kept in lab and divided into eleven group from (A to K) and were orally administered the doses 6 mg/kg, 12 mg/kg for sodium arsenate, 150 mg/kg and 300 mg/kg for Moringa oleifera leaf extracts (MOLE) and 150 mg/kg and 300 mg/kg for Moringa oleifera flower extracts (MOFE) comparing with control. The investigation revealed evident reduction in the fetuses weight, hind limb, fore limb, tail and snout length, crown rump and head circumferences well as malformations in tail, feet, arms, legs, skin and eyes in the negative control group (only administered with sodium arsenate). Co-administration of sodium arsenate with MOLE and MOFE ameliorate the reversed effect of sodium arsenate on the shape, length, body weight and DNA damage of fetus significantly at 95% confidence interval. However, Moringa oleifera leaf extract showed more significant results in comparison to Moringa oleifera flower extract. Hence concluded that Moringa oleifera leaf extract ameliorated the embryo toxic effects of sodium arsenate and can be used against environmental teratogens.

Estudos anteriores sugeriram que o arsênio atravessa a placenta e afeta o desenvolvimento do feto. O estudo em consideração visa mostrar o efeito melhorador comparativo de extratos de folhas e flores de Moringa oleifera contra a toxicidade fetal induzida por arseniato de sódio em camundongos. Camundongos grávidas (N = 44) foram mantidos em laboratório e divididos em 11 grupos (de A a K) e foram administrados por via oral nas doses de 6 mg/kg, 12 mg/kg para arseniato de sódio, 150 mg/kg e 300 mg/kg para extratos de folhas de Moringa oleifera (MOLE) e 150 mg/kg e 300 mg/kg para extratos de flores de Moringa oleifera (MOFE) em comparação com o controle. A investigação revelou redução evidente no peso do feto, membro posterior, membro anterior, comprimento da cauda e focinho, coroa, nádega e circunferência da cabeça, bem como malformações na cauda, pés, braços, pernas, pele e olhos no grupo de controle negativo (apenas administrado com arseniato de sódio). A coadministração de arseniato de sódio com MOLE e MOFE melhora significativamente o efeito reverso do arseniato de sódio na forma, comprimento, peso corporal e dano ao DNA do feto, com intervalo de confiança de 95%. No entanto, o extrato da folha da Moringa oleifera apresentou resultados mais significativos em comparação ao extrato da flor da Moringa oleifera. Portanto, concluiu que o extrato da folha de Moringa oleifera melhorou os efeitos tóxicos do arseniato de sódio para o embrião e pode ser usado contra teratógenos ambientais.

Duration of Exposure to General Endotracheal Anesthesia during Cesarean Deliveries at Term and Perinatal Complications.

OBJECTIVE: To examine whether the duration of time from initiation of general endotracheal anesthesia (GETA) to delivery for cesarean deliveries (CDs) performed is related to perinatal outcomes. STUDY DESIGN: This is a retrospective study of patients with singleton nonanomalous gestations undergoing CD ≥37 weeks of gestation under GETA with reassuring fetal status at a single tertiary care center from 2000 to 2016. Duration from GETA initiation until delivery was calculated as the time interval from GETA induction to delivery (I-D), categorized into tertiles. Outcomes for those in the tertile with the shortest I-D were compared with those in the other two tertiles. The primary perinatal outcome was a composite of complications (continuous positive airway pressure or high-flow nasal cannula for ≥2 consecutive hours, inspired oxygen ≥30% for ≥4 consecutive hours, mechanical ventilation, stillbirth, or neonatal death ≤72 hours after birth). Secondary outcomes were 5-minute Apgar score <7 and a composite of maternal morbidity (bladder injury, bowel injury, and extension of hysterotomy). Bivariable and multivariable analyses were used to compare outcomes. RESULTS: Two hundred eighteen maternal-perinatal dyads were analyzed. They were dichotomized based on I-D ≤4 minutes (those in the tertile with the shortest duration) or >4 minutes. Women with I-D >4 minutes were more likely to have prior abdominal surgery and less likely to have labored prior to CD. I-D >4 minutes was associated with significantly increased frequency of the primary perinatal outcome. This persisted after multivariable adjustment. In bivariable analysis, 5-minute Apgar <7 was more common in the group with I-D >4 minutes, but this did not persist in multivariable analysis. Frequency of maternal morbidity did not differ. CONCLUSION: When CD is performed at term using GETA without evidence of nonreassuring fetal status prior to delivery, I-D interval >4 minutes is associated with increased frequency of perinatal complications. KEY POINTS: · Cesarean delivery under general anesthesia is associated with increased perinatal complications.. · Perinatal complications are increased with increasing duration of exposure to general anesthetics.. · Maternal complications were not increased with shorter duration of exposure to general anesthesia..

Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5'-nucleotidase/CD73 in the Rat Fetal Brain.

Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for the completion of organ maturation in the fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment. Purinergic signaling is involved in neurodevelopment and controlled by ectonucleotidases, among which in the brain the most abundant are ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5'-nucleotidase (e5'NT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, processes integral to brain development. Upregulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5 mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment was confirmed in both sexes, although showing a slight bias in males. Due to the involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of these observed changes in the adverse effects of antenatal DEX treatment.

Polystyrene microplastics disturb maternal-fetal immune balance and cause reproductive toxicity in pregnant mice.

Microplastics (MPs), which are emerging as a new type of environmental pollutants, have raised great concerns regarding their threats to human health. A successful pregnancy depends on the sophisticated regulation of the maternal-fetal immune balance, but the risks of polystyrene MP (PS-MP) exposure in early pregnancy remain unclear. In this study, we exposed the C57BL/6-mated BALB/c mice to PS-MP particles and used the flow cytometry to explore threats towards the immune system. Herein, the allogeneic mating murine model showed an elevated embryo resorption rate with a 10 µm PS-MP particle exposure during the peri-implantation period. Both the number and diameter of uterine arterioles decreased, which might reduce the uterine blood supply. Moreover, the percentage of decidual natural killer cells was reduced, whereas the helper T cells in the placenta increased. In addition, the M1/M2 ratio in macrophages reversed significantly to a dominant M2-subtype. Lastly, the cytokine secretion shifted towards an immunosuppressive state. Overall, our results demonstrated that PS-MPs have the potential to cause adverse effects on pregnancy outcomes via immune disturbance, providing new insights into the study of reproductive toxicity of MP particles in the human body.

Benzo[a]pyrene impairs the migratory pattern of human gonadotropin-releasing-hormone-secreting neuroblasts.

Benzo[a]pyrene (BaP) is a widespread pollutant that can act as an endocrine disrupting compound (EDC) and interferes with reproductive function. The central regulatory network of the reproductive system is mediated by gonadotropin-releasing hormone (GnRH) neurons, which originate in the olfactory placode and, during ontogenesis, migrate into the hypothalamus. Given the importance of the migratory process for GnRH neuron maturation, we investigated the effect of BaP (10 µM for 24 h) on GnRH neuroblasts isolated from the human fetal olfactory epithelium (FNCB4). BaP exposure significantly reduced the mRNA level of genes implicated in FNCB4 cell migration and affected their migratory ability. Our findings demonstrate that BaP may interfere with the central neuronal network controlling human reproduction affecting GnRH neuron maturation.

Clastogenic effects of cigarette smoke and urethane and their modulation by olive oil, curcumin and carotenoids in adult mice and foetuses.

In spite of the overwhelming epidemiological evidence for cigarette smoke (CS) carcinogenicity, less attention has been paid to the effects of CS as a complex mixture. As assessed in a series of experiments in murine models, the whole-body exposure to mainstream CS induced significant increases of micronucleated cells in the respiratory tract, bone marrow and peripheral blood of adult mice as well as in the liver and peripheral blood of foetuses whose mothers had been exposed throughout pregnancy. Urethane was potently clastogenic in the same cells when injected intraperitoneally. The daily administration of extra-virgin olive oil by gavage produced evident and consistent protective effects in all monitored experimental systems. In contrast, sunflower oil exhibited some adverse effects. Curcumin did not produce any significant effect in the bone marrow of both CS-exposed adults and foetuses but it elicited a dose-dependent protective effect traceable in blood erythrocytes. However, the higher curcumin dose further increased the frequency of micronucleated pulmonary alveolar macrophages. The apparent protective effects produced by lycopene and by a carotenoid mix were overwhelmed by those produced by olive oil, and lycopene even exhibited a worsening effect on the frequency of micronucleated erythroblasts in the bone marrow of urethane-treated adult mice.

Doxorubicin-Induced Fetal Mesangial Cell Death Occurs Independently of TRPC6 Channel Upregulation but Involves Mitochondrial Generation of Reactive Oxygen Species.

Doxorubicin (DOX), a category D pregnancy drug, is a chemotherapeutic agent that has been shown in animal studies to induce fetal toxicity, including renal abnormalities. Upregulation of the transient receptor potential cation (TRPC) 6 channel is involved in DOX-induced podocyte apoptosis. We have previously reported that TRPC6-mediated Ca2+ signaling promotes neonatal glomerular mesangial cell (GMC) death. However, it is unknown whether DOX alters mesangial TRPC expression or viability in the fetus. In this study, cell growth was tracked in control and DOX-treated primary GMCs derived from fetal pigs. Live-cell imaging demonstrated that exposure to DOX inhibited the proliferation of fetal pig GMCs and induced cell death. DOX did not alter the TRPC3 expression levels. By contrast, TRPC6 protein expression in the cells was markedly reduced by DOX. DOX treatment also attenuated the TRPC6-mediated intracellular Ca2+ elevation. DOX stimulated mitochondrial reactive oxygen species (mtROS) generation and mitophagy by the GMCs. The DOX-induced mtROS generation and apoptosis were reversed by the mitochondria-targeted antioxidant mitoquinone. These data suggest that DOX-induced fetal pig GMC apoptosis is independent of TRPC6 channel upregulation but requires mtROS production. The mtROS-dependent GMC death may contribute to DOX-induced fetal nephrotoxicity when administered prenatally.

A Novel Calcium-Dependent Protein Kinase 1 Inhibitor Potently Prevents Toxoplasma gondii Transmission to Foetuses in Mouse.

Treatments currently used to prevent congenital toxoplasmosis are non-specific of Toxoplasma gondii and have grievous side effects. To develop a more specific and less toxic drug, we have designed SP230, an imidazo[1,2-b]pyridazine salt targeting the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) and active against acute toxoplasmosis in mice. Efficiency of SP230 to inhibit foetal transmission of the parasite was evaluated in a mouse model of congenital toxoplasmosis. Swiss mice were infected at mid-pregnancy with tachyzoites or cysts of the ME49 strain of T. gondii by intraperitoneal and oral route, respectively, and treated with SP230 at 50 mg/kg for 5 days by the same routes. Parasite burden in organs of dams and in foetuses was measured by quantitative PCR. Intraperitoneal administration of SP230 drastically reduced the number of parasites (more than 97% of reduction) in the brain and lungs of dams, and led to a reduction of 66% of parasite burden in foetuses. Oral administration of SP230 was particularly efficient with 97% of reduction of parasite burdens in foetuses. SP230 did not impact number and weight of offspring in our conditions. This inhibitor of TgCDPK1 is a promising candidate for the development of alternative therapeutics to treat infected pregnant women.

Prenatal Exposure to BPA: The Effects on Hepatic Lipid Metabolism in Male and Female Rat Fetuses.

Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has been observed. All these effects are dependent on sex, being observable only in female rat fetuses. In conclusion, this work demonstrates that maternal exposure to BPA compromises hepatic lipid metabolism in female offspring, and it also reveals the perspective impact of BPA on human health at doses currently considered safe.

Histone deacetylase 9 deficiency exaggerates uterine M2 macrophage polarization.

The maternal-foetal interface is an immune-privileged site where the semi-allogeneic embryo is protected from attacks by the maternal immune system. Uterine macrophages are key players in establishing and maintaining pregnancy, and the dysregulation of the M1-M2 subpopulation balance causes abortion. We separated two distinct mouse uterine macrophage subpopulations during early pregnancy, CD45+ F4/80+ CD206- M1-like (M1) and CD45+ F4/80+ CD206+ M2-like (M2) cells. The M1 preponderance was significantly exaggerated at 6 hours after lipopolysaccharide (LPS) treatment, and adoptive transfer of M2 macrophages partially rescued LPS-induced abortion. RNA sequencing analysis of mouse uterine M2 versus M1 revealed 1837 differentially expressed genes (DEGs), among which 629 was up-regulated and 1208 was down-regulated. Histone deacetylase 9 (Hdac9) was one of the DEGs and validated to be significantly up-regulated in uterine M2 as compared with M1. Remarkably, this differential expression profile between M1 and M2 was also evident in primary splenic macrophages and in vitro polarized murine peritoneal, bone marrow-derived and RAW 264.7 macrophages. In Hdac9/HDAC9 knockout RAW 264.7 and human THP-1-derived macrophages, the expression of M1 differentiation markers was unchanged or decreased whereas M2 markers were increased compared with the wild-type cells, and these effects were unrelated to compromised proliferation. Furthermore, Hdac9/HDAC9 ablation significantly enhanced the phagocytosis of fluorescent microspheres in M2 Raw 264.7 cells yet decreased the capacity of THP-1-derived M1 macrophages. The above results demonstrate that Hdac9/HDAC9 deficiency exaggerates M2 macrophage polarization in mouse and human macrophages, which may provide clues for our understanding of the epigenetic regulation on macrophage M1/M2 polarization in maternal-foetal tolerance.

Trichostatin A mitigates radiation-induced teratogenesis in C57Bl/6 mice.

Radiation exposure in utero is known to lead to serious concerns to both the mother and children, including developmental anomalies in the children. In the recent past, trichostatin A, an HDAC (histone deacetylase) inhibitor and epigenetic modifier, has been shown to mitigate radiation-induced anomalies in the male reproductive system of C57BL/6 mice. Therefore, the current study was undertaken to evaluate the mitigating effects of trichostatin A (TSA) against radiation-induced developmental anomalies in mice. Foetuses of in utero whole-body gamma-irradiated mice during the active organogenesis period were examined for developmental anomalies at 8.5 and 18.5 days of gestation. In utero radiation exposure caused developmental anomalies like microcephaly, microphthalmia, gastroschisis and kinky tail besides prenatal mortality. TSA administration post-irradiation was observed to reduce 50% of prenatal mortality at E18.5 by reducing congenital and developmental anomalies. Observation of such results could be corroborated with the HDAC inhibitory potential of TSA knowing that developmental anomalies may have epigenetic origin. TSA, therefore, can be considered as a potential radiomitigator.

Novel agents for the treatment of lymphomas during pregnancy: A comprehensive literature review.

Lymphoproliferative diseases occurring during pregnancy present unique diagnostic and therapeutic challenges aiming to achieve maternal cure without impairing fetal health, growth, and survival. These goals are further complicated by the fast-paced emergence of novel therapies and their introduction as standard of care, even in newly diagnosed patients. Due to the rarity of hematological malignancies in pregnancy and the exclusion of pregnancy in almost all clinical trials, available data on the fetal effects of novel drugs are limited to animal models and case reports. The current review addresses the entire multidisciplinary team involved in treating pregnant patients with lymphoproliferative diseases. We describe novel agents according to their mechanism of action, and summarize our knowledge of their effects during the gestational period, particularly those associated with fetotoxicity. Therapeutic dilemmas associated with the employment of these new agents are also discussed.

ß-estradiol promotes the growth of primary human fetal spermatogonial stem cells via the induction of stem cell factor in Sertoli cells.

BACKGROUND: Mammalian spermatogenesis is responsible for male fertility and is supported by the self-renewal and differentiation of spermatogonial stem cells (SSCs). Sertoli cells provide a supportive microenvironment for SSCs, in part by the production of stem cell factor (SCF), which is a potent regulator of spermatogonia proliferation and survival. METHODS: We investigated the novel role of ß-estradiol in modulating the proliferation and apoptosis of fetal SSCs via the regulation of SCF secretion in Sertoli cells isolated from human fetal testes. The proliferation of SSCs in the co-culture system was determined by colony formation and BrdU incorporation assays. TUNEL assay was used to measure SSC apoptosis in co-culture in response to treatment with control, ß-estradiol, or the combination of ß-estradiol and the estrogen receptor inhibitor ICI 182780. RESULTS: In the system with purified human fetal Sertoli cells (MIS+/c-Kit-/AP-), ß-estradiol upregulated the production of SCF in a dose- and time-dependent manner. In the co-culture system of primary human fetal SSCs (c-Kit+/SSEA-4+/Oct-4+/AP+) and Sertoli cells (MIS+), ß-estradiol markedly increased the proliferation of SSCs. Moreover, SSC apoptosis was significantly inhibited by ß-estradiol and was completely reversed by the combination of ß-estradiol and ICI 182780. CONCLUSION: Here we report, for the first time, that ß-estradiol can induce the increase of SCF expression in human fetal Sertoli cells and regulates the growth and survival of human fetal SSCs. These novel findings provide new perspectives on the current understanding of the role of estrogen in human spermatogenesis.

Trastuzumab administration during pregnancy: an update.

BACKGROUND: Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. METHODS: Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words "breast", "cancer", "trastuzumab" and "pregnancy". This study was performed in accordance with the PRISMA guidelines. RESULTS: A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. CONCLUSIONS: Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.

Human-relevant concentrations of the antifungal drug clotrimazole disrupt maternal and fetal steroid hormone profiles in rats.

Clotrimazole is a non-prescription and broad-spectrum antifungal drug sold under brand names such as Canesten® and Lotrimin®. It is used to treat different types of fungal infections, from oral thrush to athlete's foot and vaginal mycosis. The level of exposure to clotrimazole is uncertain, as the exact usage amongst self-medicating patients is unclear. Recent studies have raised potential concern about the unsupervised use of clotrimazole during pregnancy, especially since it is a potent inhibitor of CYP enzymes of the steroidogenesis pathway. To address some of these concerns, we have assessed the effects of intrauterine exposure to clotrimazole on developing rat fetuses. By exposing pregnant rats to clotrimazole 25 or 75 mg/kg bw/day during gestation days 7-21, we obtained internal fetal concentrations close to those observed in humans. These in vivo data are in strong agreement with our physiologically-based pharmacokinetic (PBK)-modelled levels. At these doses, we observed no obvious morphological changes to the reproductive system, nor shorter male anogenital distance; a well-established morphometric marker for anti-androgenic effects in male offspring. However, steroid hormone profiles were significantly affected in both maternal and fetal plasma, in particular pronounced suppression of estrogens was seen. In fetal testes, marked up-concentration of hydroxyprogesterone was observed, which indicates a specific action on steroidogenesis. Since systemic clotrimazole is rapidly metabolized in humans, relevant exposure levels may not in itself cause adverse changes to the reproductive systems. Its capacity to significantly alter steroid hormone concentrations, however, suggests that clotrimazole should be used with caution during pregnancy.

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.

BACKGROUND: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning. METHODS: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses. RESULTS: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine. CONCLUSION: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed. PROSPERO REGISTRATION NUMBER: CRD42018115194.