A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes.

The evidence to date regarding corticosteroid exposure in pregnancy and select pregnancy and birth outcomes is limited and inconsistent. The authors provide a narrative review of published literature summarizing the findings for oral clefts, preterm birth, birth weight, preeclampsia, and gestational diabetes mellitus. Whenever possible, the results are limited to oral or systemic administration with a further focus on use in autoimmune disease. Although previous studies of corticosteroid exposure in pregnancy reported an increased risk of oral clefts in the offspring, more recent studies have not replicated these findings.

Maternal exposure to traffic-related air pollution and birth defects in Massachusetts.

Exposures to particulate matter with diameter of 2.5µm or less (PM2.5) may influence risk of birth defects. We estimated associations between maternal exposure to prenatal traffic-related air pollution and risk of cardiac, orofacial, and neural tube defects among Massachusetts births conceived 2001 through 2008. Our analyses included 2729 cardiac, 255 neural tube, and 729 orofacial defects. We used satellite remote sensing, meteorological and land use data to assess PM2.5 and traffic-related exposures (distance to roads and traffic density) at geocoded birth addresses. We calculated adjusted odds ratios (OR) and confidence intervals (CI) using logistic regression models. Generalized additive models were used to assess spatial patterns of birth defect risk. There were positive but non-significant associations for a 10µg/m(3) increase in PM2.5 and perimembranous ventricular septal defects (OR=1.34, 95% CI: 0.98, 1.83), patent foramen ovale (OR=1.19, 95% CI: 0.92, 1.54) and patent ductus arteriosus (OR=1.20, 95% CI: 0.95, 1.62). There was a non-significant inverse association between PM2.5 and cleft lip with or without palate (OR=0.76, 95% CI: 0.50, 1.10), cleft palate only (OR=0.89, 95% CI: 0.54, 1.46) and neural tube defects (OR=0.77, 95% CI: 0.46, 1.05). Results for traffic related exposure were similar. Only ostium secundum atrial septal defects displayed significant spatial variation after accounting for known risk factors.

Transcriptional responses, metabolic activity and mouthpart deformities in natural populations of Chironomus riparius larvae exposed to environmental pollutants.

Biomarkers are an important tool in laboratory assays that link exposure or effect of specific toxicants to key molecular and cellular events, but they have not been widely used in invertebrate populations exposed to complex mixtures of environmental contaminants in their natural habitats. The present study focused on a battery of biomarkers and their comparative analysis in natural populations of the benthic larvae of Chironomus riparius (Diptera), sampled in three differentially polluted rivers (the Con, Sar, and Louro in Galicia, Spain). In our study, some parameters were identified, such as hsp70 gene activity, GST enzymatic activity, total glycogen content and mouthpart deformities, which showed significant differences among populations from the three rivers that differed in the levels and types of sedimentary contaminants analyzed (metals, organic-chlorine pesticides, alkylphenols, pharmaceutical, and personal care products). In contrast to these sensitive biomarkers, other parameters showed no significant differences (hsc70 gene, EcR gene, P450 gene, RNA:DNA ratio, total protein content), and were stable even when comparing field and nonexposed laboratory populations. The hsp70 gene seems to be particularly sensitive to conditions of pollutant exposure, while its constitutive counterpart hsc70 showed invariable expression, suggesting that the hsc70/hsp70 ratio may be a potential indicator of polluted environments. Although further studies are required to understand the correlation between molecular responses and the ecological effects of pollutants on natural populations, the results provide new data about the biological responses to multiple-stressor environments. This field study adds new molecular endpoints, including gene expression, as suitable tools that, complementing other ecotoxicological parameters, may help to improve the methodologies of freshwater monitoring under the increasing burden of xenobiotics.

Stage-dependent toxicity of bisphenol a on Rhinella arenarum (anura, bufonidae) embryos and larvae.

The acute and chronic toxicity of bisphenol A (BPA) was evaluated on the common South American toad Rhinella arenarum embryos and larvae by means of continuous and pulse exposure treatments. Embryos were treated continuously from early blastula (S.4) up to complete operculum (S.25), during early larval stages and by means of 24 h pulse exposures of BPA in concentrations ranging between 1.25 and 40 mg L(-1) , in order to evaluate the susceptibility to this compound in different developmental stages. For lethal effects, S.25 was the most sensitive and gastrula was the most resistant to BPA. The Teratogenic Index for neurula, the most sensitive embryonic stage for sublethal effects was 4.7. The main morphological alterations during early stages were: delayed or arrested development, reduced body size, persistent yolk plug, microcephaly, axial/tail flexures, edemas, blisters, waving fin, underdeveloped gills, mouth malformations, and cellular dissociation. BPA caused a remarkable narcotic effect from gill circulation stage (S.20) onwards in all the organisms exposed after 3 h of treatment with 10 mg L(-1) BPA. After recovering, the embryos exhibited scarce response to stimuli, erratic or circular swimming, and spasmodic contractions from 5 mg L(-1) onwards. Our results highlight the lethal and sublethal effectsof BPA on R. arenarum embryos and larvae, in the last case both at structural and functional levels.

Antiepileptic drugs (AEDs) during pregnancy and risk of congenital jaw and oral malformation.

In the United States, an estimate of 1.3 million women suffering from epilepsy are in their childbearing age. Potential teratogenicity of antiepileptic drugs (AEDs) is of concern to these women considering pregnancy because discontinuing pharmacotherapy during pregnancy may not be advised due to the risk of seizures that may be dangerous to the mother as well as the fetus. Using a Relational Online Analytical Processing (ROLAP) software licensed by Simultek, we searched for medications reported for congenital jaw and oral cavity malformation on the FDA Adverse Event Reporting System (AERS), a voluntary adverse event reporting program that contains over 55 million adverse event reports of medical products in the United.States. Our results indicate that various forms of valproic acid, and more importantly, newer generation antiepileptic agents including lamotrigine, topiramate, and gabapentin show signals for either congenital jaw or oral malformation. Although teratogenic potential of valproic acid has long been confirmed, information on teratogenicity of the newer generation antiepileptic drugs is relatively scarce and inconclusive. Early safety signals on the teratogenic potential of AEDs detected in this study are crude statistics that do not establish causation nor exclude confounding. The results require validation and further investigation via properly controlled epidemiological studies.

Effects of inbreeding on mouthpart deformities of Chironomus riparius under sublethal pesticide exposure.

Mouthpart deformities in chironomids have been reported to indicate adverse effects of environmental pollutants. The authors assessed rates of mouthpart deformities in tributyltin-exposed, inbred, and outcrossed Chironomus riparius larvae over multiple generations. The authors found that the occurrence of mouthpart deformities was significantly correlated with inbreeding, whereas no correlation was found with the tributyltin exposure. The present study confirms the strong effect of high inbreeding rates on developmental deformities in chironomids.

Induction of mouthpart deformities in chironomid larvae exposed to contaminated sediments.

The aim of the present study was to improve the cause-effect relationship between toxicant exposure and chironomid mouthpart deformities, by linking induction of mouthpart deformities to contaminated field sediments, metal mixtures and a mutagenic polycyclic aromatic compound metabolite (acridone). Mouthpart deformities in Chironomus riparius larvae were induced by both the heavy metal mixture and by acridone. A clear correlation between metal concentrations in the sediment and deformities incidence was only observed when the contaminated field sediments were left out of the analysis, probably because these natural sediments contained other toxic compounds, which could be responsible for a higher incidence of deformities than predicted by the measured metal concentrations only. The present study clearly improved the cause-effect relationship between toxicant exposure and the induction of mouthpart deformities. It is concluded that the incidence of mouthpart deformities may better reflect the potential toxicity of contaminated sediments than chemical analysis.

Chironomid mouthpart deformities as indicator of environmental quality: a case study in Lake Trasimeno (Italy).

The aim of the present study was to monitor mouthpart deformities of Chironomus plumosus (Insecta-Diptera) in Lake Trasimeno (2000-2010) in relation with sediment contamination by heavy metals, which is one of the main causes of deformity induction. In Lake Trasimeno, concentrations of heavy metals in the investigated littoral zone were low, in comparison with those of the central area. By contrast, the incidence of deformities was much higher in the littoral station (2006-2009) than in the central area. In the littoral zone, the deformities progressively decreased and by 2010 reached values similar to those observed in the central area (2000-2002, 2010). This decrease was mainly due to the reduction of severe deformities, thus indicating an environmental quality recovery of this littoral sector. Chemical analysis revealed that the higher incidence of deformities in the littoral zone was not caused by heavy metal contamination, unless they may have contributed to a joint action with other toxicants. The present study on Lake Trasimeno provided additional evidence that chironomid mouthpart deformities can be used in biomonitoring programs to evaluate sediment contamination by toxicants. Since mouthpart deformities may also be induced by compounds not included in routine chemical analyses, they may better reflect sediment quality than chemical analysis alone.

Taxonomic and nontaxonomic responses to ecological changes in an urban lowland stream through the use of Chironomidae (Diptera) larvae.

Biotic descriptors--both taxonomic (diversity indices, species richness, and indicator species) and nontaxonomic (biomass, oxygen consumption/production, and anatomical deformities)--are useful tools for measuring a stream's ecological condition. Nontaxonomic parameters detect critical effects not reflected taxonomically. We analyzed changes in Chironomidae populations as taxonomic parameters and mentum deformities as a nontaxonomic parameter for evaluating a South-American-plains stream (Argentina). We performed samplings seasonally (March, June, September, and December; 2005) and physical and chemical measurements at three sampling sites of the stream (DC1 at river source, through DC3 downstream). The specimens collected in sediment and vegetation were analyzed to investigate mouth deformities in Chironomidae larvae. We identified a total of 9 taxa from Chironomidae and Orthocladiinae subfamilies. Shannon's diversity index for Chironomidae decreased from 1.6 bits ind⁻¹ (DC1) to 0.3 bits ind⁻¹ (DC3). The total density of the Chironomidae exhibited a great increase in abundance at site DC3, especially that of Chironomus calligraphus. Chironomidae taxonomic composition also changed among the three sites despite their spatial proximity: C. calligraphus, Goeldichironomus holoprasinus, Parachironomus longistilus, and Polypedilum were present at all three; Corynoneura and Paratanytarsu at DC1 only; Cricotopus at DC1 and DC3; Apedilum elachistus notably at DC2 and DC3; and Parametriocnemus only at DC2. C. calligraphus individuals from DC1 showed no mentum deformities; only 2 from DC2 exhibited mouth-structure alterations; while specimens from DC3 presented the most abnormalities, especially during autumn and late winter. Type-II deformities (supernumerary teeth and gaps) were the most common. Anatomical deformities are sublethal effects representing an early alert to chemically caused environmental degradation. Mentum deformities in benthic-Chironomidae larvae constitute an effective biological-surveillance tool for detecting adverse conditions in sediments and evaluating sediment-quality-criteria compliance. Taxonomic (community composition) and nontaxonomic (condition of larval mouth parts) descriptors, used together, can indicate a stream's ecological state.

Diversity of larvae of littoral Chironomidae (Diptera: Insecta) and their role as bioindicators in urban reservoirs of different trophic levels.

The Chironomidae (Diptera: Insecta) have a high species richness, with species adapted to live under widely different environmental conditions. The study of the taxonomic composition of chironomid larvae and the percentage of occurrence of deformities in mouthparts, mainly in the mentum, are used in biomonitoring programmes in order to obtain information on the levels of organic and chemical pollution of aquatic ecosystems. The objective of this study was to evaluate the abundance of chironomid larvae and to quantify the occurrence of mentum deformities in the specimens collected in three urban reservoirs with different trophic levels. The reservoirs are located in the hydrographic basin of the Paraopeba River, an affluent of the São Francisco River basin (Minas Gerais State, southeastern Brazil). The Serra Azul Reservoir is oligotrophic, the Vargem das Flores Reservoir is mesotrophic, and the Ibirité Reservoir is eutrophic. Along the littoral zone of each reservoir, 30 samples were collected during each sampling campaign. Sampling was carried out every three months for one year, with two sampling campaigns during the wet season and two during the dry season in 2008. Physical and chemical parameters measured in the water column included the water depth, Secchi depth, air and water temperature, electrical conductivity, total dissolved solids, redox potential, dissolved oxygen, pH, turbidity, Total-N, Total-P, P-ortho, and chlorophyll-a. The chironomid larvae were identified to the genus level. The structure of the chironomid assemblages was evaluated based on taxonomic richness (24 genera), density, equitability, and diversity. The potential indicator taxa for each reservoir were established through an Indicator Species Analysis. The values for taxonomic richness (20 taxa), equitability (0.737), and Shannon-Wiener diversity (2.215) were highest in the Serra Azul Reservoir. Fissimentum was the indicator taxon in Serra Azul, the oligotrophic reservoir; whereas Pelomus was the indicator taxon in Vargem das Flores, and Chironomus in Ibirité. The highest percentage of mentum deformities was found during the dry season in Serra Azul (6.9%), while the lowest percentage was found during the wet season in Vargem das Flores (0.8%). The results of this study evidenced significant differences in the taxonomic composition, richness, equitability, and diversity of the chironomid assemblages in these three reservoirs of different trophic levels.

Teratogenic effects of antiepileptic drugs.

Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure.

Assessing toxicity of the insecticide thiacloprid on Chironomus riparius (Insecta: Diptera) using multiple end points.

Since data documentation on neonicotinic toxicity to nontarget organisms should be enhanced, we investigate the effects of thiacloprid, a novel neonicotinoid insecticide, on the sediment-dwelling nontarget insect Chironomus riparius. Further, we wanted to validate the sensitivity of end points on different biological levels and obtain the greatest amount of information regarding the effects of this compound by using a battery of several end points such as larval mortality, behavior, body weight gain, emergence rate, time of development, gender ratio, Hsp70 stress protein level, and larval mouthpart deformities after exposure at a concentration range of 0.1 to 1000 microg/L thiacloprid. C. riparius was impacted starting at concentrations of 0.5 microg/L, a concentration that can be considered environmentally relevant. Larval mortality, behavior, emergence, and Hsp70 protein level were sensitive indicators for the toxic effect of thiacloprid, whereas gender ratio and mouthpart morphology were not affected. In our case life-cycle end points like survival rate (LC(50): 1.57 microg/L) and emergence rate (EC(50): 0.54 microg/L) proved to be more sensitive than tested physiological end points for the neurotoxic insecticide.

Histaminergic activity in a rodent model of Parkinson's disease.

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson's disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 microg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites L: -3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H(1); cimetidine, H(2); thioperamide, H(3) agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H(3) antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.

Exposure to coal combustion residues during metamorphosis elevates corticosterone content and adversely affects oral morphology, growth, and development in Rana sphenocephala.

Coal combustion residues (CCRs) are documented to negatively impact oral morphology, growth, and development in larval amphibians. It is currently unclear what physiological mechanisms may mediate these effects. Corticosterone, a glucocorticoid hormone, is a likely mediator because when administered exogenously it, like CCRs, also negatively influences oral morphology, growth, and development in larval amphibians. In an attempt to identify if corticosterone mediates these effects, we raised larval Southern Leopard Frogs, Rana sphenocephala, on either sand or CCR substrate and documented effects of sediment type on whole body corticosterone, oral morphology, and time to and mass at key metamorphic stages. Coal combustion residue treated tadpoles contained significantly more corticosterone than controls throughout metamorphosis. However, significantly more oral abnormalities occurred early in metamorphosis when differences in corticosterone levels between treatments were minimal. Overall, CCR-treated tadpoles took significantly more time to transition between key stages and gained less mass between stages than controls, but these differences between treatments decreased during later stages when corticosterone differences between treatments were greatest. Our results suggest endogenous increase in corticosterone content and its influence on oral morphology, growth and development is more complex than previously thought.

Characterization of heat shock protein 40 and 90 in Chironomus riparius larvae: effects of di(2-ethylhexyl) phthalate exposure on gene expressions and mouthpart deformities.

Di(2-ethylhexyl) phthalate (DEHP) is a widely distributed phthalate that organisms are frequently exposed to due to its wide range of commercial and manufacturing uses as a plasticizer. Indeed, DEHP is often found in freshwater systems that receive domestic waste water discharges. Therefore, we evaluated the effects of DEHP on the mRNA levels of heat shock protein (HSP) 40 and 90 in chironomids. In addition, we evaluated the effects of exposure to DEHP on the induction of morphological deformities in chironomids. To accomplish this, partial sequences of HSP 40 and 90 from Chironomus riparius larvae were amplified and sequenced. The inferred amino acid sequences were then aligned with those of other insect HSP 40 and 90 genes. The results of this alignment revealed that there was a high degree of similarity among the homologues. In addition, the HSP 40 and 90 mRNA expressions were significantly upregulated in response to short and long-term exposure to DEHP at concentrations of 1, 10, and 30 microgL(-1). Furthermore, the occurrence of mouthpart deformities was significantly higher in chironomids that were treated with DEHP (12-20%) than in controls (3-5%). Taken together, these results indicate that HSP 40 and 90 play important roles in the physiological changes related to metabolism and cell protection that occur in C. riparius larvae that have been exposed to DEHP.

Using corticosteroids during pregnancy. Are topical, inhaled, or systemic agents associated with risk?

QUESTION: I am concerned about use of corticosteroids during pregnancy. Some of my women patients of reproductive age are using topical, inhaled, or oral preparations, and I am not sure what to advise. ANSWER: Both topical and systemic corticosteroids are used for a variety of autoimmune and inflammatory conditions. Results of first-trimester studies were inconclusive and underpowered. Recent meta-analyses suggest a small but significant association between use of systemic corticosteroids during the first trimester and oral clefts. This is consistent with results of animal studies. No similar evidence exists for topical or inhaled corticosteroids, probably because of much lower systemic exposure.

Effects of exposure to a combination of zinc- and lead-spiked sediments on mouthpart development and growth in Chironomus tentans.

Exposures to either zinc or lead in contaminated sediments have been shown to induce characteristic deformities in larval chironomids. This study examined the effects of exposure to lead and zinc in combination on Chironomus tentans larvae. Proportions of mouthpart deformities in populations of larvae reared in sediments containing nominal combinations of lead and zinc were tested for additive, synergistic, and antagonistic interactions using logistic regression. Metal body burdens, body size measurements, and survival were used to evaluate toxicity and developmental impacts. Results demonstrate zinc and lead mixtures produce fewer deformities than the individual metal, so their interaction may be characterized as antagonistic. However, exposure to the metal mixtures also caused delayed development and failure to hatch. The apparent decline in deformities may be an artifact of higher mortalities or developmental effects. This research provides better understanding of some of the problems and considerations for use of chironomid population deformity proportions in bioassessments for sediment metal contamination.

Methanol exposure during gastrulation causes holoprosencephaly, facial dysgenesis, and cervical vertebral malformations in C57BL/6J mice.

BACKGROUND: Exposure of pregnant outbred CD-1 mice to methanol during the period of gastrulation results in exencephaly, cleft palate, and cervical vertebra malformations [Rogers and Mole, Teratology 55: 364, 1997], while inbred C57BL/6J mice are sensitive to the teratogenicity of ethanol. C57BL/6J fetuses exhibit the holoprosencephaly spectrum of malformations after maternal exposure to ethanol during gastrulation, but the sensitivity of C57BL/6J mice to methanol-induced teratogenesis has not been previously described. METHODS: Pregnant C57BL/6J mice were administered two i.p. injections totaling 3.4 or 4.9 g/kg methanol or distilled water four hrs apart on gestation day 'GD' 7. On GD 17, litters were examined for numbers of live, dead and resorbed conceptuses, fetuses were weighed as a litter and examined externally, and all fetuses were double stained for skeletal analysis. RESULTS: No maternal intoxication was apparent, but the high dosage level caused a transient deficit in maternal weight gain. The number of live fetuses per litter was reduced at both dosages of methanol, and fetal weight was lower in the high dosage group. Craniofacial defects were observed in 55.8% of fetuses in the low dosage group and 91.0% of fetuses in the high dosage group, including micro/anophthalmia, holoprosencephaly, facial clefts and gross facial angenesis. Skeletal malformations, particularly of the cervical vertebrae, were observed at both dosages of methanol, and were similar to those previously reported in the CD-1 mouse following methanol exposure. CONCLUSIONS: The types of craniofacial malformations induced in the C57BL/6J mouse by methanol indicate that methanol and ethanol have common targets and may have common modes of action.