Early pregnancy exposure to beta-cypermethrin compromises endometrial decidualisation in mice via downregulation of cyclin D3, CDK4/6, and p21.

Beta-cypermethrin (ß-CYP) is a highly effective broad-spectrum insecticide that can potentially affect female reproduction. However, little is known about the effect of ß-CYP on uterine decidualisation, which is a vital process by which the uterus provides a suitable microenvironment for pregnancy maintenance. Therefore, we focused on the effect and mechanism of ß-CYP on endometrial decidualisation during early pregnancy in mice. The results indicated that the expression levels of HOXA10, BMP2, and IGFBP1 was significantly downregulated in the decidual tissue and primary endometrial stromal cells of pregnant and pseudopregnant mice following ß-CYP treatment. Serum E2 concentration was significantly increased, whereas P4 concentration and oestrogen receptor (ERα) and progesterone receptor (PRA) expression were significantly downregulated following ß-CYP exposure. The number of polyploid decidual cells was lower in the ß-CYP-treated group. Furthermore, ß-CYP significantly downregulated the protein expression levels of CDK4 and CDK6, and the mRNA expression levels of cyclin D3 and p21. The number of foetuses per female in the first litter was markedly reduced following exposure to ß-CYP. In summary, early pregnancy exposure to ß-CYP may result in defective endometrial decidualisation via compromised proliferation of uterine stromal cells and reduced expressions of cyclin D3, CDK4/6, and p21 in mice.

Fetal proximal and distal limb anomalies following exposure to mycophenolate mofetil during pregnancy: A case report and review of the literature.

BACKGROUND: Mycophenolate mofetil (MMF) is currently used in a wide spectrum of autoimmune diseases and has been rendered very effective in the management of systemic lupus erythematosus and lupus nephritis. MMF is known to be teratogenic (FDA category D) and therefore, women in childbearing period receiving MMF should be counselled to use effective contraceptive methods to avoid an unplanned pregnancy. CASE: A 22-year-old lady accidentally discovered to be pregnant while using MMF as a treatment of lupus nephritis which was replaced later on by azathioprine. After maternal and fetal evaluation, maternal lupus flare was confirmed and multiple fetal skeletal deformities associated with intrauterine growth restriction (IUGR) were diagnosed by 4-dimensional ultrasound. Termination of pregnancy was decided after shared decision making. CONCLUSION: Women in childbearing period should be advised to postpone pregnancy for at least six weeks after stoppage of MMF therapy because of its potential teratogenic effects during pregnancy.

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.

Consequences of Perinatal Cannabis Exposure.

Cannabis exposure during the perinatal period results in varied and significant consequences in affected offspring. The prevalence of detrimental outcomes of perinatal cannabis exposure is likely to increase in tandem with the broadening of legalization and acceptance of the drug. As such, it is crucial to highlight the immediate and protracted consequences of cannabis exposure on pre- and postnatal development. Here, we identify lasting changes in neurons' learning flexibility (synaptic plasticity) and epigenetic misregulation in animal models of perinatal cannabinoid exposure (using synthetic cannabinoids or active components of the cannabis plant), in addition to significant alterations in social behavior and executive functions. These findings are supported by epidemiological data indicating similar behavioral outcomes throughout life in human offspring exposed to cannabis during pregnancy. Further, we indicate important lingering questions regarding accurate modeling of perinatal cannabis exposure as well as the need for sex- and age-dependent outcome measures in future studies.

Effects of quercetin on Aroclor 1254-induced expression of CYP450 and cytokines in pregnant rats.

The present study aimed to investigate the protective effect of quercetin on polychlorinated biphenyls (PCB)-induced liver and embryo damage in pregnant Sprague-Dawley rats. Pregnant rats were divided into five groups, and then were orally gavaged daily with peanut oil (vehicle) or a commercial PCB mixture (Aroclor 1254) - with or without co-treatment with 75, 150, or 300 mg/kg quercetin - on gestation days (GD) 4-7. At GD 9, all rats were euthanized, and their blood, liver, and uterus were collected. Expressions of CYP450 mRNA and protein in liver, cytokines (IFNγ, IL-2, IL-4, and IL-6) and IFNγ/IL-4 ratios in liver and sera, liver morphology, and the status of implanted embryos were analyzed. The results showed Aroclor 1254 treatment alone caused hepatic cord damage (i.e. cell disorganization, swelling, decreased cytoplasm, vacuolization), and that quercetin co-treatment appeared to mitigate this damage. Similarly, levels of CYP1A1 and CYP2B1 mRNA in livers of Aroclor 1254-only-treated rats were significantly higher than those in rats co-treated with quercetin. Hepatic and sera levels of IFNγ, IL-2, IL-6, and IFNγ/IL-4 ratios, and the ratio of delayed-development embryos, all increased in Aroclor 1254-treated rats, but were relatively decreased as a result of quercetin co-treatments. IL-4 levels were decreased by Aroclor 1254 and tended to increase back to normal when quercetin was used. The results indicated that quercetin imparted a protective effect against Aroclor 1254-induced toxicity in pregnant rats, in part, by modulating levels of important pro-inflammatory cytokines and reducing induced CYP1A1 and CYP2B1 expression.

Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep.

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury.

BACKGROUND: Preterm newborns are at high risk of developing neurodevelopmental deficits caused by neuroinflammation leading to perinatal brain injury. Human Wharton's jelly mesenchymal stem cells (hWJ-MSC) derived from the umbilical cord have been suggested to reduce neuroinflammation, in part through the release of extracellular vesicle-like exosomes. Here, we studied whether exosomes derived from hWJ-MSC have anti-inflammatory effects on microglia-mediated neuroinflammation in perinatal brain injury. METHODS: Using ultracentrifugation, we isolated exosomes from hWJ-MSC culture supernatants. In an in vitro model of neuroinflammation, we stimulated immortalized BV-2 microglia and primary mixed glial cells with lipopolysaccharide (LPS) in the presence or absence of exosomes. In vivo, we introduced brain damage in 3-day-old rat pups and treated them intranasally with hWJ-MSC-derived exosomes. RESULTS: hWJ-MSC-derived exosomes dampened the LPS-induced expression of inflammation-related genes by BV-2 microglia and primary mixed glial cells. The secretion of pro-inflammatory cytokines by LPS-stimulated primary mixed glial was inhibited by exosomes as well. Exosomes interfered within the Toll-like receptor 4 signaling of BV-2 microglia, as they prevented the degradation of the NFκB inhibitor IκBα and the phosphorylation of molecules of the mitogen-activated protein kinase family in response to LPS stimulation. Finally, intranasally administered exosomes reached the brain and reduced microglia-mediated neuroinflammation in rats with perinatal brain injury. CONCLUSIONS: Our data suggest that the administration of hWJ-MSC-derived exosomes represents a promising therapy to prevent and treat perinatal brain injury.

Prenatal exposure to pyrrolizidine alkaloids induced hepatotoxicity and pulmonary injury in fetal rats.

Hepatic and pulmonary toxicity in fetal rats induced by pyrrolizidine alkaloids (PAs) was investigated. Retrorsine (RTS) or monocrotaline (MCT) was intragastrically administered during pregnancy. The reduction of body and tail lengths was consistent with body weight loss in PA-exposed fetuses, and pathological lesions in liver and lung were observed only in fetuses. Both PAs reduced fetal serum transaminase activities. The GSH/GSSG ratio, GSH peroxidase and superoxide dismutase activities also decreased but glutathione S-transferase activity increased in fetal lung, especially for MCT. The pyrrole-protein adducts in fetal liver and lung could be detected, and those adducts in RTS fetal lungs were about 65% of those in MCT group. In conclusion, prenatal PAs exposure induced fetal hepatic and pulmonary toxicities through the generation of pyrrole metabolites and oxidative injury. The difference on fetal pulmonary redox homeostasis between two PAs groups might be associated with the content of PAs migrated to fetal lungs.

Severe neurologic and hepatic toxicity in a newborn prenatally exposed to methamphetamine. A case report.

OBJECTIVE: In the recent years the increase of methamphetamines (MTA) abusers women has become an emerging problem. Very little data has been published regarding the effects of prenatal MTA exposure. We describe a case of MTA related toxicity in a term newborn which have early onset of neonatal encephalopathy and liver failure. CASE REPORT: A term infant born to a MTA abuser mother developed seizures and severe neurological symptoms shortly after birth. Methamphetamine was detected both in maternal and in neonatal urine. The laboratoristic tests revealed severe hepatic insufficiency, coagulopathy and thrombocytopenia. Due to neonatal encephalopathy the newborn underwent hypothermia. Phenobarbital, fresh frozen plasma, platelet transfusions and vitamin K were administered. Cranial ultrasonography and magnetic resonance imaging (MRI) showed diffuse white matter damage and two ischemic-hemorrhagic cerebral lesions. Gradually the clinical conditions improved, at 1 month MRI showed a stabilization of cerebral lesions with residual diffuse leukomalacia. Physiotherapy and neurological follow up is ongoing to evaluate the long term effects. CONCLUSIONS: although infrequent, MTA-related toxicity should be suspected in infants with neurologic and hepatic symptoms. Further studies are warranted to confirm our findings in order to identify newborns at high risk of acute MTA toxicity in time to provide them the appropriate support.

Micronuclei Induction in Amniotic Fluid Cells from Cyclophosphamide Treated Rats.

The aim of the study was to determine if amniotic fluid cells of rats can be used to provide evidence of genotoxicity. In order to do that micronuclei formation was induced in rats during pregnancy after treatment with cyclophosphamide (CP), at different CP doses. On gestational day 19, we collected the amniotic fluid and determined the frequency of micronucleated cells (MNCs) from the offspring. Samples were centrifuged and placed on clean slides. The smears were observed with an epifluorescence microscope. The number of MNCs in 2000 cells per pregnant rat was counted. The fetus weight and size were recorded and provided evidence of DNA damage caused by CP administration to their mothers. A significantly greater number of MNCs was observed only for the medium CP dose (P<0.01) and the high CP dose (P<0.02) groups versus the negative control group. Birth defects produced by the administration of the CP were evident in the CP-treated groups. This study showed an alternative method to determine if compounds administrated to pregnant rat cause damage to the genetic material of their offspring. Using micronuclei testing of amniotic fluid cells enables us to determine in one test the genotoxicity and the teratogenic potential of a compound.

High Prenatal Exposure to Bisphenol A Reduces Anogenital Distance in Healthy Male Newborns.

OBJECTIVE: To estimate the relationship between cord blood bisphenol A (BPA) levels and anogenital measurements in healthy newborns. METHODS: Pregnancy and birth history, together with body mass and length data, anogenital measurements, penile measurements and cord blood samples were obtained from healthy newborns. Cord blood concentration of BPA was analyzed by sandwich enzyme-linked immunosorbent assays kit. RESULTS: Among 130 healthy newborns (72 boys, 58 girls), mean anopenile distance was 45.2±6 mm and anoscrotal distance was 21.9±5.4 mm in boys; mean anoclitoral distance was 33.8±6.6 mm and mean anofourchette distance was 12.2±4.9 mm in girls. Mean cord blood BPA level was 4.75±2.18 ng/mL. 90th percentile value for cord blood BPA was 8.26 ng/mL and the analysis showed a statistically significant correlation between anoscrotal distance and cord blood BPA levels above the 90th percentile (p=0.047) in boys. The changes in anogenital distance in girls were not statistically significant. CONCLUSION: We showed a significant association between high cord blood BPA levels and shortened anoscrotal distance in male newborns. However, this result should be interpreted with caution since there were no significant external genital abnormalities in our study group.

Fetal liver injury ameliorated by migration inhibitory factor inhibition in a rat model of acute pancreatitis in pregnancy.

AIM: This study was designed to investigate and assess fetal liver injury in a rat model of acute pancreatitis in pregnancy (APIP) as well as its possible mechanisms and potential therapeutic targets. METHODS: The APIP model was induced by sodium taurocholate in Sprague-Dawley rats during the third trimester. ISO-1, a macrophage migration inhibitory factor (MIF) antagonist, was given before the induction of APIP. In addition, sham-operated rats at later gestation were set as controls. Histological changes in the fetal liver and maternal pancreas were assessed. Amylase and lipase activity as well as the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were examined. The expression of MIF in fetal liver was determined by immunochemistry and the expression of NF-κB, IκBα, high mobility group box-1 protein (HMGB1), TNF-α, and IL-1ß in fetal liver was determined by Western blot analysis. Ultrastructures of hepatic cells in fetal rats were observed under transmission electron microscopy. RESULTS: ISO-1 ameliorated the following: (i) pathological injuries in maternal pancreas and fetal liver; (ii) levels of TNF-α and IL-1ß in maternal serum; and (iii) levels of MIF, myeloperoxidase, NF-κB, HMGB1, TNF-α, and IL-1ß in fetal liver. CONCLUSION: Pathological damage and an inflammatory response in fetal liver were induced by APIP, and MIF inhibition ameliorated fetal liver injury by inhibiting the inflammatory cascade.

High-risk behaviours for the fœtus in pregnant women: The medicolegal and judicial aspects.

Pregnancy is a period of psychological change which may lead to difficulties of adaptation and psychological suffering and give rise to high-risk behaviours for the fœtus in pregnant women. These risk behaviours, which are defined by certain authors as a form of "maltreatment" of the fœtus, usually spring from the psychological distress of the pregnant woman but are not recognised as a specific medical disorder. We illustrate the difficulties encountered in the identification of, and the specific intervention in, these situations through the clinical case of a pregnant drugs-dependent patient subjected to several stress factors who, in addition to consuming substances, developed high-risk behaviours for herself and her pregnancy: self-endangerment under the influence of substances, falls or refusals of treatment. In our first part, we discuss the medicolegal possibilities afforded by French law to protect the fœtus in the event of the future mother's high-risk behaviours. In our second part, we discuss the successive evolutions of the legal status of the fœtus and pregnancy, and their consequences for medical practice and the clinical situations concerned. The lack of an answer concerning the designation of these behaviours, as either medical, legal or social acts, will prompt perinatal practitioners to a certain medicolegal prudence.

Triclosan/triclocarban levels in maternal and umbilical blood samples and their association with fetal malformation.

Triclosan (TCS) and triclocarban (TCC) are widely used as antimicrobial compounds in consumer products. TCS and TCC are frequently found in waste water and sewage. In this study, we investigate the potential impact of exposure to triclosan (TCS) and triclocarban (TCC) on fetal abnormalities. We measured TCS and TCC levels in maternal and umbilical cord blood samples from 39 pregnant women diagnosed with fetal or post-birth abnormalities at Beijing Obstetrics and Gynecology Hospital. 52 pregnant women who gave birth to healthy neonates during the same period of time were included as controls. Applying ultra-performance liquid chromatography-tandem mass spectrometry, TCS and TCC concentrations were measured in maternal and fetal sera. Significantly increased levels of TCS were detected in maternal sera from mothers with abnormal births. Similar levels of TCS or TCC were found in maternal and cord sera in control group. The concentrations of TCS or TCC in maternal sera correlated with those in umbilical cord sera (r=0.649, P<0.01). These observations suggest that maternal blood test could be a useful assay for detecting fetal exposure to TCS and TCC, and high exposure to TCS may be potentially associated with increased risk for fetal malformations.

Real-time measurement of blood pressure with Nexfin in a patient with thalidomide-related phocomelia.

We report the novel application of photoplethysmographic technology with the Nexfin HD monitor for real-time measurement of blood pressure (BP) in a patient with tetraamelia. The patient was a 58-year-old man with tetraamelia secondary to thalidomide exposure in utero, who presented for surgical excision of a maxillary schwannoma. Because difficulty of cuff use on rudimentary limbs and failure to gain invasive arterial access due to abnormalities of limb vasculature, this population is known to pose some unique challenges for BP measurement. Nexfin may offer an alternative noninvasive method to detect BP in patients with phocomelia during the perioperative period.

Clinical and non-clinical safety of artemisinin derivatives in pregnancy.

Malaria in pregnancy is a clinically wasting infectious disease, where drug therapy has to be promptly initiated. Currently, the treatment of this infection depends on the use of artemisinin derivatives. The World Health Organization does not recommend the use of these drugs in the first trimester of pregnancy due to non-clinical findings that have shown embryolethality and teratogenic effects. Nevertheless, until now, this toxicity has not been proved in humans. Artemisinin derivatives mechanisms of embryotoxicity are related to depletion of circulating embryonic primitive erythroblasts. Species differences in this sensitive period for toxicity and the presence of malaria infection, which could reduce drug distribution to the fetus, are significant to the risk assessment of artemisinin derivatives treatment to pregnant women. In this review we aimed to assess the results of non-clinical and clinical studies with artemisinin derivatives, their mechanisms of embryotoxicity and discuss the safety of their use during pregnancy.

Craniosynostosis Following Fetal Methotrexate Exposure.

Methotrexate (MTX) is an antimetabolite, folic acid antagonist that inhibits purine nucleotide production, DNA synthesis, and cellular proliferation. Despite widespread therapeutic uses, MTX remains a potent teratogen. Methotrexate embryopathy encompasses multiorgan system dysfunction, including intrauterine growth restriction as well as cardiac, craniofacial, renal, genital, and skeletal abnormalities. Effects of MTX exposure on fetal development continue to be described. This series of 4 patients with MTX-associated craniosynostosis represents the largest published association between prenatal MTX exposure and premature cranial suture closure.

Sequential Amniotic Fluid Thyroid Hormone Changes Correlate with Goiter Shrinkage following in utero Thyroxine Therapy.

Several isolated reports of fetal goiter treatment have shown limited generalizability of approaches and provide no real guidance for optimal timing, dosages, and treatment strategies. Graves' disease accounts for >60% of these cases. Maternal treatments of hyperthyroidism include antithyroid medications such as methimazole and more commonly propylthiouracil (PTU). Here, our management of a patient with a fetal thyroid goiter from maternal exposure to PTU diagnosed at 23.6 weeks' gestation and the management of other cases allow us propose a general strategy for treatment. Intrauterine therapy with 200 and then 400 µg of levothyroxine (3 weeks apart) showed an 85% reduction in fetal thyroid goiter volume. We collected amniotic fluid samples at the time of treatments and assayed thyroid hormones and associated antibodies which closely reflected the changes in thyroid goiter mass volume. Our observations suggest a weekly or biweekly therapeutic intervention schedule. Utilizing both goiter size as well as a novel approach in using amniotic fluid hormone levels to monitor therapy efficacy might improve the quality of treatments. Only with a standardized approach and collection of amniotic fluid thyroid panels do we have the opportunity to develop the database required to determine the number and timing of treatments needed.

Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy.

OBJECTIVE: Antipsychotic medications are used by increasing numbers of women of reproductive age. The safety of these medications during pregnancy has not been well described. We undertook a systematic review and meta-analysis of the adverse obstetric and neonatal outcomes associated with exposure to antipsychotics during pregnancy. DATA SOURCES: PubMed, Reprotox, and ClinicalTrials.gov were searched to identify potential studies for inclusion. METHODS OF STUDY SELECTION: Case-control or cohort studies estimating adverse birth outcomes associated with antipsychotic exposure during pregnancy were included. Pooled odds ratios (ORs) were used for dichotomous outcomes and weighted mean differences were used for neonatal birth weight and gestational age. Thirteen cohort studies, including 6,289 antipsychotic-exposed and 1,618,039 unexposed pregnancies, were included. TABULATION, INTEGRATION, AND RESULTS: Antipsychotic exposure was associated with an increased risk of major malformations (absolute risk difference [ARD] 0.03, 95% confidence interval [CI] 0.00-0.05, P=.04, Z=2.06), heart defects (ARD 0.01, 95% CI 0.00-0.01, P<.001, Z=3.44), preterm delivery (ARD 0.05, 95% CI 0.03-0.08, P<.001, Z=4.10), small-for-gestational-age births (ARD 0.05, 95% CI 0.02-0.09, P=.006, Z=2.74), elective termination (ARD 0.09, 95% CI 0.05-0.13, P<.001, Z=4.69), and decreased birth weight (weighted mean difference -57.89 g, 95% CI -103.69 to -12.10 g, P=.01). There was no significant difference in the risk of major malformations (test for subgroup differences: χ²=0.07, degrees of freedom=1, P=.79) between typical (OR 1.55, 95% CI 1.21-1.99, P=.006) and atypical (OR 1.39, 95% CI 0.66-2.93, P=.38) antipsychotic medications. Antipsychotic exposure was not associated with risk of large-for-gestational-age births, stillbirth, and spontaneous abortion. Although antipsychotic exposure during pregnancy was associated with increased risk of adverse obstetric and neonatal outcomes, this association does not necessarily imply causation. This analysis was limited by the small number of included studies and limited adjustment in studies for possible confounders. CONCLUSION: Women requiring antipsychotic treatment during pregnancy appear at higher risk of adverse birth outcomes, regardless of causation, and may benefit from close monitoring and minimization of other potential risk factors during pregnancy.