Multiple Sclerosis and Motherhood Choice: an Observational Study in Portuguese Women Patients

INTRODUCTION. Multiple sclerosis (MS) is a disabling disease occurring mainly in women of childbearing age. MS may interfere with family planning and motherhood decision. AIM. To study the influence of MS diagnosis and course of the disease on motherhood decision. PATIENTS AND METHODS. The cohort of 35 to 45-year-old female patients diagnosed with MS for at least ten years was selected from six Portuguese MS centers. A structured questionnaire was applied to all patients in consecutive consultation days. Clinical records were reviewed to characterize and collect information about the disease and pregnancies. RESULTS. One hundred women were included; mean age at MS diagnosis was 26.3 ± 5.0 years; 90% of the participants presented with a relapsing-remitting MS; 57% had no pregnancies after the diagnosis. MS type and number of relapses were not significantly different between women with or without pregnancies after the diagnosis (p = 0.39 and p = 0.50, respectively). Seventy-seven percent of the patients did not have the intended number of pregnancies. Main reasons given were fear of future disability and the possibility of having relapses. Forty-three women considered that pregnancy might worsen MS. CONCLUSION. In our population, motherhood choice was unrelated to the MS type and the number of relapses. However, a relevant number of women had fewer pregnancies than those intended before MS diagnosis and believed that pregnancy could worsen the disease. An effort to better inform the patients should be made to minimize the impact of MS diagnosis on motherhood decision.

Differences in Nevirapine Biotransformation as a Factor for its Sex-Dependent Dimorphic Profile of Adverse Drug Reactions

OBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex-related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy-nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy-nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of nevirapine toxicity.

EULAR Recommendations for Women's Health and the Management of Family Planning, Assisted Reproduction, Pregnancy and Menopause in Patients with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Magnetic Resonance Imaging and Gynecological Devices

Background: Performing magnetic resonance imaging (MRI) on women with gynecological devices is a completely accepted practice. The goal of our review is to assess how safe it is to perform MRI on women using contraceptive implants or devices. Study Design: Literature review, searching in PubMed-Medline/Ovid for the following keywords: magnetic resonance imaging, intrauterine devices, Implanon® and Essure®. Results: Though plastic devices do not represent a contraindication to the use of the technique, those including metallic components have been submitted to several tests, after which they were classified as MR Conditional (devices presenting no risks in MR-specific environments) by the Food and Drug Administration. Thus, the use of MRI can be safely advised to women with this type of device as long as the magnetic resonance equipment is ≤3.0 T. Conclusions: Presently, there is no scientific evidence that contraindicates performing MRI on women with any kind of gynecological device. Therefore, this procedure is safe as long as it is performed under previously tested conditions.

Drug Provocation Tests to Betalactam Antibiotics: Experience in a Paediatric Setting

Background: Few studies have been performed in children withs uspected betalactam allergy.We aimed to assess the role of the drug provocation test(DPT)with betalactams in a paediatric setting and to study the association between allergy to betalactam antibiotics and other allergic diseases. Methods:We included all the patients under 15 years old who were consecutively referred to the Immunoallergy Department, Dona Estefânia Hospital,Portugal(January 2002 to April 2008)for a compatible history of allergic reaction to betalactam. All were submitted to a DPT.Children were proposed to performs kintests(ST)to betalactam antibiotics followed by DPT. If they decline ST,a DPT with the culprit drug was performed. Results: We studied 161 children,60%were boys,with a median age of 5years old at the time of the DPT.Thirty-three patients(20.5%)had an immediate reaction and 33(20.5%)a non-immediate reaction. These verity of there porte dreactions was low in most cases. Skin tests to betalactams were performed in 47 children and were positive in 8.DPT was positive inonlyone(3.4%)of the patients skin tested and in 11(13.4%)of those not skin tested. These verity of the DPT reaction was low.Asthma and food allergy were associated with a positive DPT in the later group. Conclusions: DPT seems a safe procedure even in the absence of ST in non-severe cases. This could be a practical optionin infants and pre-school children,where ST are painful and difficult to perform.Additional caution should be taken in children with asthma and food allergy.

Sirolimus-Induced Drug Fever in a Renal Transplant Patient: a Case Report

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

Clinical and Pathological Findings in Women with Fabry Disease

Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease.

In Situ Breakage of Implanon® - Two Cases of a Rare Occurrence

BACKGROUND: In situ breakage of Implanon® is a rare occurrence with unknown clinical significance. Authors report two different cases of broken Implanon® of women attended at our Family Planning Clinic. DISCUSSION: In situ implants may spontaneously and asymptomatically break, although some uncertainty relies on whether that situation has a real impact on the contraceptive effectiveness or on bleeding patterns. Even more, it can be argued if, as a result of an occurrence of that nature, the implant shall or shall not be removed before the envisaged 3-year period of effectiveness. CONCLUSION: Currently, the clinical significance of implant breakage remains unknown. The decision to remove a broken or bent implant should be based on clinical judgements considering patients' wishes.

Factor V Leiden and Prothrombin G20210A in Portuguese Women with Recurrent Miscarriage: Is it Worthwhile to Investigate?

OBJECTIVE: To compare the prevalence of factor V Leiden (FVL) and prothrombin (PT) G20210A mutations in Portuguese women with unexplained recurrent miscarriage (RM) and a control group of parous women. MATERIALS AND METHODS: FVL and PT G20210A analysis were carried out in 100 women with three or more consecutive miscarriages and 100 controls with no history of pregnancy losses. Secondary analysis was made regarding gestational age at miscarriage (embryonic and fetal losses). RESULTS: Overall, the prevalence of FVL and PT G20210A was similar in women with RM (5 and 3%) compared with controls (5 and 1%) OR 1.36 (CI 95% 0.45-4.08). In RM embryonic subgroup, PT G20210A was observed in 1.3% of women and FVL prevalence (2.6%) was inclusively lesser than that of controls. Both polymorphisms were more prevalent in women with fetal losses than in controls, although statistical significance was not reached due to the small size of the >10 weeks' subgroup. CONCLUSION: These data indicate that neither FVL nor PT G20210A is associated with RM prior to 10 weeks of gestation. Therefore, its screening is not indicated as an initial approach in Portuguese women with embryonic RM and negative personal thromboembolic history.

Carotid Intima-Media Thickness and Carotid Plaques Improves Prediction of Obstructive Angiographic Coronary Artery Disease in Women

Does carotid intima-media thickness (cIMT), a surrogate marker of cardiovascular events, have predictive incremental value over established risk factors for stable coronary artery disease (CAD)? Prospective study of 300 patients, with suspected stable CAD, admitted for an elective coronary angiography and carotid ultrasound. The CAD patients had a higher cIMT, which showed a modest predictive accuracy for CAD (area under the receiver-operating characteristic curve 0.638, 95% confidence interval 0.576-0.701, P < .001). The cIMT was an independent predictor of CAD, together with age, gender, and diabetes. C-statistic for CAD prediction by traditional risk factors was not significantly different from a model that included cIMT, carotid plaque presence, or both. However, in women, it was significantly increased by the addition of cIMT or carotid plaque presence. Although cIMT cannot be used as a sole indicator of CAD, it should be considered in the panel of investigations that is requested, particularly in women who are candidates for coronary angiography.

Cortisol and Anxiety Response to a Relaxing Intervention on Pregnant Women Awaiting Amniocentesis

Background: Stress and anxiety during pregnancy have been associated with premature and low birth weight babies, presumably through fetus over exposion to glucocorticoids. Antenatal stress also seems to have long-term effects upon infant development and adult health. However, medication for stress may carry risks to the expectant mother, therefore the efficacy of nonpharmacological interventions should be investigated. Methods: Pregnant women (n = 154) awaiting amniocentesis, were randomly assigned in the morning and the afternoon to three groups for 30 min: (1) listening to relaxing music, (2) sitting and reading magazines, and (3) sitting in the waiting-room. Before and after that period, they completed the Spielberger’s State and Trait anxiety inventory and provided blood samples for cortisol. The groups were then compared regarding change in cortisol levels and anxiety. Results: Maternal cortisol and state anxiety were correlated (r = 0.25, p = 0.04) in the afternoon, but not in the morning. The larger decreases in cortisol occurred in the music group ( 61.8 nmol/L, ANOVA: p = 0.01), followed by magazine, being differences among groups more pronounced in the morning. Women in the music group also exhibited the greater decreases in state anxiety ( p < 0.001). Younger mothers with less gestational age were on average the most anxious, and also the ones with greater decreases in cortisol and anxiety levels after relaxation. Conclusion: A relaxing intervention as short as 30 min, especially listening to music, decreases plasma cortisol and self-reported state anxiety score. Pregnant women might benefit from the routine practice of relaxation in the imminence of clinical stressful events.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Genomic Signatures and Antiviral Drug Susceptibility Profile of A(H1N1)pdm09

Background: Genetic changes in influenza surface and internal genes can alter viral fitness and virulence. Mutation trend analysis and antiviral drug susceptibility profiling of A(H1N1)pdm09 viruses is essential for risk assessment of emergent strains and disease management. Objective: To profile genomic signatures and antiviral drug resistance of A(H1N1)pdm09 viruses and to discuss the potential role of mutated residues in human host adaptation and virulence. Study design: A(H1N1)pdm09 viruses circulating in Portugal during pandemic and post-pandemic periods and 2009/2010 season. Viruses were isolated in MDCK-SIAT1 cell culture and subjected to mutation analysis of surface and internal proteins, and to antiviral drug susceptibility profiling. Results: The A(H1N1)pdm09 strains circulating during the epidemic period in Portugal were resistant to amantadine. The majority of the strains were found to be susceptible to oseltamivir and zanamivir, with five outliers to neuraminidase inhibitors (NAIs) identified. Specific mutation patterns were detected within the functional domains of internal proteins PB2, PB1, PA, NP, NS1, M1 and NS2/NEP, which were common to all isolates and also some cluster-specific. Discussion: Modification of viral genome transcription, replication and apoptosis kinetics, changes in antigenicity and antiviral drug susceptibility are known determinants of virulence. We report several point mutations with putative roles in viral fitness and virulence, and discuss their potential to result in more virulent phenotypes. Monitoring of specific mutations and genetic patterns in influenza viral genes is essential for risk assessing emergent strains, disease epidemiology and public health implications.