Corticosteroid use during pregnancy and risk of orofacial clefts

Background

The association between the risk of orofacial clefts in infants and the use of corticosteroids during pregnancy is unclear from the available evidence. We conducted a nationwide cohort study of all live births in Denmark over a 12-year period.

Methods

We collected data on all live births in Denmark from Jan. 1, 1996, to Sept. 30, 2008. We included live births for which information was available from nationwide health registries on the use of corticosteroids during pregnancy, the diagnosis of an orofacial cleft and possible confounders.

Results

There were 832 636 live births during the study period. Exposure to corticosteroids during the first trimester occurred in 51 973 of the pregnancies. A total of 1232 isolated orofacial clefts (i.e., cleft lip, cleft palate, or cleft lip and cleft palate) were diagnosed within the first year of life, including 84 instances in which the infant had been exposed to corticosteroids during the first trimester of pregnancy. We did not identify any statistically significant increased risk of orofacial clefts associated with the use of corticosteroids: cleft lip with or without cleft palate, prevalence odds ratio (OR) 1.05 (95% confidence interval [CI] 0.80–1.38]; cleft palate alone, prevalence OR 1.23 (95% CI 0.83–1.82). Odds ratios for risk of orofacial clefts by method of delivery (i.e., oral, inhalant, nasal spray, or dermatologic and other topicals) were consistent with the overall results of the study and did not display significant heterogeneity, although the OR for cleft lip with or without cleft palate associated with the use of dermatologic corticosteroids was 1.45 (95% CI 1.03–2.05).

Interpretation

Our results add to the safety information on a class of drugs commonly used during pregnancy. Our study did not show an increased risk of orofacial clefts with the use of corticosteroids during pregnancy. Indepth investigation of the pattern of association between orofacial clefts and the use of dermatologic corticosteroids during pregnancy indicated that this result did not signify a causal connection and likely arose from multiple statistical comparisons.The anti-inflammatory and immuno-suppressive properties of corticosteroids in pharmacotherapeutic doses has a wide range of clinical uses, such as for the treatment of asthma, atopic dermatitis and other allergic conditions, autoimmune diseases and cancer. However, caution is warranted for the use of corticosteroid medications during pregnancy. Corticosteroid use during pregnancy has been associated with orofacial clefts in animals, and similar risks in humans are suspected.^1,2 The available epidemiologic evidence favours an association, but many of the studies that have been done have been limited by recall bias and a lack of statistical power. The association between risk of orofacial clefts and the use of corticosteroids during pregnancy remains unclear.^3–10We conducted a nationwide cohort study in Denmark with independent and prospective determination of corticosteroid use during pregnancy and the diagnosis of orofacial clefts. Our study comprised all live births from January 1996 to September 2008.     

Prolonged corticosteroid treatment exerts transient inhibitory effect on prostaglandin E2 release from rabbits' eyes

In humans, the retina and choroid (the photoreceptor and its vascular layers, respectively), are affected by an immunogenic inflammatory reaction--uveitis, associated with excessive levels of prostaglandin E2 (PGE2), and treated for prolonged periods with corticosteroids, known for their inhibitory effect on prostaglandins (PGs) production. In order to assess whether this drug retains its inhibitory effect during chronic use, we investigated the effect of long-term systemic administration of corticosteroids on PGE2 release by the choroid and retina of rabbits' eyes. We used eyes traumatized by laser irradiation, in which the inflammatory reaction is associated with an enhanced PGE2 in vitro release by the choroid-retina throughout a 2-week period; levels peaked on days 1 and 7 to values 2.2- and 5.5-fold, respectively, greater than baseline. Systemic corticosteroid administration to laser-exposed rabbits curtailed the excessive PGE2 release during the first post-laser week; later the amounts released progressively increased to levels 5.5-fold higher than baseline (day 14), whereas in the corresponding untreated laser group, levels were significantly lower. PGE2 tissue content on days 7 and 14 in steroid-treated and untreated laser groups were similarly elevated. We conclude that during prolonged systemic corticosteroids treatment the steroidal inhibitory effect on enhanced PGE2 formation by the retina-choroid of laser injured eyes is transient; it is evident during the early phase following drug administration, whereas later excessive PGE2 release is resumed.     

US News

To document the persistence of perioral dermatitis at dermatology clinics at University Hospital, Saskatoon, we reviewed the charts of all patients with the condition seen between January 1983 and March 1985. Patients with rosacea referred to the clinics during the same period were used as a comparison group. A total of 80 patients with perioral dermatitis and 117 patients with rosacea were seen during the study period; most were female. Those with perioral dermatitis were significantly younger and had a significantly shorter mean duration of the eruption before presentation than those with rosacea (p less than 0.001). The distribution of the lesions was different in the two groups. Sixty-eight (85%) of the patients with perioral dermatitis and 45 (38%) of those with rosacea had used topical corticosteroids, a postulated risk factor for perioral dermatitis; the use of potent topical corticosteroids was frequent in both groups. Despite continuing medical education on the dangers of chronic use of these agents for eruptions on the face, physicians continue to prescribe them.     

RENAL VASCULAR HYPERTENSION

The use of corticosteroids systemically in dermatology has benefited patients with pemphigus and systemic lupus erythematosus in that they now have a better chance to carry on a productive life. These hormones, used cautiously, can alleviate some of the tremendous suffering during the explosive exacerbations and acute crises of atopic and neurodermatitis. Corticosteroids are useful in the widespread and acute contact dermatitis and drug eruptions; they are contraindicated in the treatment of ordinary psoriasis.Every attempt should be made by history-taking, clinical examination and necessary laboratory studies to reach an accurate diagnosis before corticosteroids are used. If use of them is indicated, then total patient care is required to avoid complications, and a very careful follow-up is mandatory.     

Effects of systemic versus local administration of corticosteroids on mucosal tolerance

Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperactivity in animal models of asthma. Whereas systemic administration of dexamethasone during the delivery of respiratory Ag has been suggested to prevent the development of mucosal tolerance, the effects of local administration of corticosteroids, first-line treatment for patients with bronchial asthma, on mucosal tolerance remain unknown. To analyze the effects of systemic versus local administration of different types of corticosteroids on the development of mucosal tolerance, mice were exposed to respiratory allergen to induce mucosal tolerance with or without systemic or intranasal application of different doses of dexamethasone or prednisolone. After the induction of mucosal tolerance, proliferation of T cells was inhibited in tolerized mice, whereas systemic applications of corticosteroids restored T cell proliferation and secretion of Th2 cytokines. In contrast, inhaled corticosteroids showed no effect on both T cell proliferation and cytokine secretion. In addition, mice systemically treated with corticosteroids showed an increased airway hyperactivity with a significant lung inflammation, but also an increased T effector cells/regulatory T cells ratio in the second lymphoid organs when compared with mice that receive corticosteroids by inhalation. These results demonstrate that local administration of corticosteroids has no effect on the development of immune tolerance in contrast to systemically applied corticosteroids. Furthermore, although different concentrations of corticosteroids are administered to patients, our results demonstrated that the route of administration rather than the doses affects the effect of corticosteroids on respiratory tolerance induction. Considering the broad application of corticosteroids in patients with allergic disease and asthma, the route of administration of steroid substances seems crucial in terms of treatment and potential side effects. These findings may help elucidate the apparently contradicting results of corticosteroid treatment in allergic diseases.     

Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis

Objective To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock.Data sources Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group''s trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS.Review method Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them. We obtained some missing data from authors of trials and assessed methodological quality of trials.Results 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (≥ 5 days) with low dose (≤ 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects.Conclusions For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.     

Inflammatory Bowel Disease and Risk of Adverse Pregnancy Outcomes

Background and Objectives

Existing data on pregnancy complications in inflammatory bowel disease (IBD) are inconsistent. To address these inconsistencies, we investigated potential associations between IBD, IBD-related medication use during pregnancy, and pregnancy loss, pre-eclampsia, preterm delivery, Apgar score, and congenital abnormalities.

Methods

We conducted a cohort study in >85,000 Danish National Birth Cohort women who were pregnant in the period 1996-2002 and had information on IBD, IBD-related medication use (systemic or local corticosteroids, 5-aminosalicylates), pregnancy outcomes and potential confounders. We evaluated associations between IBD and adverse pregnancy/birth outcomes using Cox regression and log-linear binomial regression.

Results

IBD was strongly and significantly associated with severe pre-eclampsia, preterm premature rupture of membranes and medically indicated preterm delivery in women using systemic corticosteroids during pregnancy (hazard ratios [HRs] >7). IBD was also associated with premature preterm rupture of membranes in women using local corticosteroid medications (HR 3.30, 95% confidence interval [CI] 1.33-8.20) and with medically indicated preterm delivery (HR 1.91, 95% CI 0.99-3.68) in non-medicated women. Furthermore, IBD was associated with low 5-minute Apgar score in term infants (risk ratio [RR] 2.19, 95% CI 1.03-4.66). Finally, Crohn’s disease (but not ulcerative colitis) was associated with major congenital abnormalities in the offspring (RR 1.85, 95% CI 1.06-3.21). No child with a congenital abnormality born to a woman with IBD was exposed to systemic corticosteroids in utero.

Conclusion

Women with IBD are at increased risk of severe pre-eclampsia, medically indicated preterm delivery, preterm premature rupture of membranes, and delivering infants with low Apgar score and major congenital malformations. These associations are only partly explained by severe disease as reflected by systemic corticosteroid use.     

Corticosteroids and Pediatric Septic Shock Outcomes: A Risk Stratified Analysis

Background

The potential benefits of corticosteroids for septic shock may depend on initial mortality risk.

Objective

We determined associations between corticosteroids and outcomes in children with septic shock who were stratified by initial mortality risk.

Methods

We conducted a retrospective analysis of an ongoing, multi-center pediatric septic shock clinical and biological database. Using a validated biomarker-based stratification tool (PERSEVERE), 496 subjects were stratified into three initial mortality risk strata (low, intermediate, and high). Subjects receiving corticosteroids during the initial 7 days of admission (n = 252) were compared to subjects who did not receive corticosteroids (n = 244). Logistic regression was used to model the effects of corticosteroids on 28-day mortality and complicated course, defined as death within 28 days or persistence of two or more organ failures at 7 days.

Results

Subjects who received corticosteroids had greater organ failure burden, higher illness severity, higher mortality, and a greater requirement for vasoactive medications, compared to subjects who did not receive corticosteroids. PERSEVERE-based mortality risk did not differ between the two groups. For the entire cohort, corticosteroids were associated with increased risk of mortality (OR 2.3, 95% CI 1.3–4.0, p = 0.004) and a complicated course (OR 1.7, 95% CI 1.1–2.5, p = 0.012). Within each PERSEVERE-based stratum, corticosteroid administration was not associated with improved outcomes. Similarly, corticosteroid administration was not associated with improved outcomes among patients with no comorbidities, nor in groups of patients stratified by PRISM.

Conclusions

Risk stratified analysis failed to demonstrate any benefit from corticosteroids in this pediatric septic shock cohort.     

Recovery of Adrenocortical Function during Long-term Treatment with Corticosteroids

The recovery of adrenocortical function during very slow withdrawal of corticosteroids was studied in a homogeneous group of patients suffering from sarcoidosis. All patients had been treated with gradually decreasing doses of prednisone for at least two years. The initial dose had been 40 mg. daily in all cases. Determination of the cortisol production rate and of plasma fluorogenic corticosteroids was done under basal conditions and after tetracosactrin stimulation. There was good correlation between cortisol production rate and plasma fluorogenic corticosteroids throughout all the tests. Cortisol production rate and plasma fluorogenic corticosteroids started to rise when the dosage of prednisone was lowered to 7·5 mg. daily and reached normal values when the dosage was reduced to 2·5 mg. The response to tetracosactrin began to increase at the same dosage level, but was not normal at 2·5 mg., or when prednisone treatment was stopped. At a dosage level of 7·5 mg. of prednisone plasma fluorogenic corticosteroids already showed a nyctohemeral rhythm.It may be calculated that even very low dosages of prednisone given during the last stage of a treatment schedule enhance total corticosteroid activity beyond the normal level, which would account for their therapeutic value.     

Azathioprine in Treatment of Bullous Pemphigoid

Azathioprine was given to 11 patients with pemphigoid who had been on long-term maintenance therapy with prednisone or prednisolone. In nine of these prednisone therapy was withdrawn and all were maintained symptom-free on azathioprine alone, while in two the dose of prednisone was considerably reduced. One patient who had never received corticosteroids was controlled by azathioprine alone during the initial acute phase of the illness. Since azathioprine acts slowly, it is recommended that corticosteroids should be used together with azathioprine during the acute stage. Thus azathioprine is valuable in long-term management of pemphigoid, particularly in patients showing corticosteroid toxicity or in whom the minimum maintenance dose is dangerously high.     

Growth factors in idiopathic pulmonary fibrosis: relative roles

Treatment of idiopathic pulmonary fibrosis patients has evolved very slowly; the fundamental approach of corticosteroids alone or in combination with other immunosuppressive agents has had little impact on long-term survival. The continued use of corticosteroids is justified because of the lack of a more effective alternative. Current research indicates that the mechanisms driving idiopathic pulmonary fibrosis reflect abnormal, dysregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of profibrogenic growth factors. An understanding of the roles of these growth factors, and the way in which they modulate events at cellular level, could lead to more targeted therapeutic strategies, improving patients' quality of life and survival.     

Adenovirus-specific T-lymphocyte efficacy in the presence of methylprednisolone: An in vitro study

Virus-specific T-cell (VST) infusion becomes a promising alternative treatment for refractory viral infections after hematopoietic stem cell transplantation (HSCT). However, VSTs are often infused during an immunosuppressive treatment course, especially corticosteroids, which are a first-line curative treatment of graft-versus-host disease (GVHD). We were interested in whether corticosteroids could affect adenovirus (ADV)-VST functions. After interferon (IFN)-γ based immunomagnetic selection, ADV-VSTs were in vitro expanded according to three different culture conditions: without methylprednisolone (MP; n?=?7), with a final concentration of MP 1?µg/mL (n?=?7) or MP 2?µg/mL (n?=?7) during 28?±?11 days. Efficacy and alloreactivity of expanded ADV-VSTs was controlled in vitro. MP transitorily inhibited ADV-VST early expansion. No impairment of specific IFN-γ secretion capacity and cytotoxicity of ADV-VSTs was observed in the presence of MP. However, specific proliferation and alloreactivity of ADV-VSTs were decreased in the presence of MP. Altogether, these results and the preliminary encouraging clinical experiences of co-administration of MP 1?mg/kg and ADV-VSTs will contribute to safe and efficient use of anti-viral immunotherapy.     

Inhaled corticosteroids for abnormal pulmonary function in children with a history of Chronic Lung Disease of Infancy: study protocol [ISRCTN55153521]

Background

There is considerable evidence from the literature that children with chronic lung disease of infancy (CLD) have abnormal pulmonary function in childhood and this could have an impact on their life quality and overall health. There are similarities between CLD and asthma, and corticosteroids are the mainstay treatment for asthma. Many physicians use inhaled corticosteroids in children with CLD with no evidence. Therefore we wish to conduct a randomized double-blinded placebo controlled trial to test for the role of inhaled corticosteroids in children aged from3 to 9 years with a history of CLD. Our primary hypothesis will be that inhaled corticosteroids are beneficial in children with CLD.

Methods

Our primary hypothesis is that using inhaled steroids; Beclomethasone Dipropionate (QVAR) 100 mcg 2 puffs 2 times a day for 6 weeks will improve the respiratory system resistance and the quality of life in children with CLD.

Discussion

We propose that Beclomethasone Dipropionate (QVAR) will affect the pulmonary function after 6 weeks of treatment. In summary we think that our study will highlight knowledge on whether the use of inhaled steroids is clinically effective for CLD.     

Growth factors in idiopathic pulmonary fibrosis: relative roles

Treatment of idiopathic pulmonary fibrosis patients has evolved very slowly; the fundamental approach of corticosteroids alone or in combination with other immunosuppressive agents has had little impact on long-term survival. The continued use of corticosteroids is justified because of the lack of a more effective alternative. Current research indicates that the mechanisms driving idiopathic pulmonary fibrosis reflect abnormal, dysregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of profibrogenic growth factors. An understanding of the roles of these growth factors, and the way in which they modulate events at cellular level, could lead to more targeted therapeutic strategies, improving patients' quality of life and survival.     

Risk factors for asthma and allergy associated with urban migration: background and methodology of a cross-sectional study in Afro-Ecuadorian school children in Northeastern Ecuador (Esmeraldas-SCAALA Study)

Background

This study examined the attitudes and actions of 3415 physician-recruited adults aged ≥ 16 years with asthma in eleven countries who were prescribed regular maintenance therapy with inhaled corticosteroids or inhaled corticosteroids plus long-acting β₂-agonists.

Methods

Structured interviews were conducted to assess medication use, asthma control, and patients' ability to recognise and self-manage worsening asthma.

Results

Despite being prescribed regular maintenance therapy, 74% of patients used short-acting β₂-agonists daily and 51% were classified by the Asthma Control Questionnaire as having uncontrolled asthma. Even patients with well-controlled asthma reported an average of 6 worsenings/year. The mean period from the onset to the peak symptoms of a worsening was 5.1 days. Although most patients recognised the early signs of worsenings, the most common response was to increase short-acting β₂-agonist use; inhaled corticosteroids were increased to a lesser extent at the peak of a worsening.

Conclusion

Previous studies of this nature have also reported considerable patient morbidity, but in those studies approximately three-quarters of patients were not receiving regular maintenance therapy and not all had a physician-confirmed diagnosis of asthma. This study shows that patients with asthma receiving regular maintenance therapy still have high levels of inadequately controlled asthma. The study also shows that patients recognise deteriorating asthma control and adjust their medication during episodes of worsening. However, they often adjust treatment in an inappropriate manner, which represents a window of missed opportunity.     

Vasoactive intestinal peptide inhibits TNF-α-induced apoptotic events in acinar cells from nonobese diabetic mice submandibular glands

Introduction

In systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents.

Methods

Data on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS).

Results

A total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose ≥ 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties.

Conclusions

Despite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.     

The quantitative measurement of steroids secreted by isolated adrenals from sodium depleted rats

A simple, rapid and reproducible method has been developed to quantitate the principal corticosteroids secreted by isolated adrenals from sodium-depleted rats. Isooctane is used to preferentially extract DOC from the other major adrenal corticosteroids, circumventing the need for extensive and laborious paper or thin layer chromatography prior to derivatization and analysis. The technique combines the use of established fluorescence and gas-liquid chromatographic analysis and is applicable to a variety of biological samples from rats (or mice) in studies of the effects of physiological or pharmacological factors on corticosteroid secretion. Examples of the routine application of this technique are provided.     

Effects of Treatment on the Mortality Rate in Septicaemia

The results of treatment have been analysed in 173 patients with septicaemia during 1962–8. Between 1962 and 1965 various antibiotics were used, and shock was treated with vasopressor agents. Between 1966 and 1968 kanamycin was given initially, and shock was treated with corticosteroids and with intravenous fluid therapy monitored with a central venous pressure manometer.The mortality rate in 1966–8 fell to half that of the earlier period in patients with Gram-negative infections, and in those with shock. The reduced mortality in the latter was clearly associated with the use of a central venous manometer to control intravenous fluid therapy, though whether the reduction resulted from specific improvement in intravenous therapy or from the necessary closer observation of the patient is not clear. Staphylococcal septicaemia was common during both periods, and its mortality rate did not fall; hence methicillin together with kanamycin is now given initially in all cases.     

A non‐invasive stress assay based upon measurement of free cortisol released into the water by rainbow trout

A procedure previously used for sex steroids was adapted to extract free cortisol and cortisone from water samples taken from rainbow trout Oncorhynchus mykiss tanks. Both corticosteroids could be readily detected by radioimmunoassay (RIA), with cortisol being predominant. All stages of the sampling, extraction and RIA procedure were validated for cortisol. An intermittent problem with poor replication was traced to the use of diethyl ether during the extraction procedure, and was overcome by the use of ethyl acetate. Other modifications were also introduced to speed up the procedure. The concentration and time course of release of both corticosteroids were shown to be related to the degree of stress that the fish had been subjected to. It was confirmed that cortisol concentrations in water and estimated cortisol release rates increased in response to handling stress, and that both were correlated with plasma cortisol concentrations. The potential for using water cortisol concentration and release rates to assess the primary stress response of fishes as a non‐invasive alternative to blood sampling is discussed.