Vitamin D in pregnancy: Where we are and where we should go.

Vitamin D deficiency has been widely reported among pregnant women and infants around the world. Women with low sun exposure, high BMI, low vitamin D intakes and socioeconomic disadvantage with poor quality diets are at greatest risk of vitamin D deficiency, leading to very low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in their offspring and an increased risk of nutritional rickets. Many observational studies, supported by compelling in vitro and in vivo data, have generated evidence suggesting that low vitamin D status in pregnancy may also contribute to the risk of adverse perinatal outcomes including hypertensive disorders (e.g., preeclampsia), fetal growth restriction, and preterm birth. However, the few large randomized controlled trials (RCTs) conducted to date have generated conflicting evidence for a role of vitamin D supplementation in improving perinatal outcomes. Vitamin D supplementation policies during pregnancy and implementation of policies vary within and between jurisdictions. Regulatory authorities have cited insufficient evidence to establish pregnancy-specific targets for serum 25(OH)D concentrations or prenatal vitamin D intake that effectively reduce the risks of adverse perinatal and infant outcomes. This paper arises from a Debate on Vitamin D Requirements during Pregnancy, held at the 22nd Vitamin D Workshop, 2019. From varied perspectives, our objectives were to evaluate the evidence for: vitamin D metabolism in pregnancy and the prevalence of gestational vitamin D deficiency worldwide; the translation of laboratory research findings to clinical studies on the role of vitamin D in perinatal health; the challenges of designing and conducting clinical trials to establish prenatal vitamin D requirements; and results to date of major large RCTs of prenatal vitamin D supplementation. Lastly, we explored potential next steps towards generating robust clinical data in this field to address both public health protection and patient care.

Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials.

Maternal-child health benefits of optimizing vitamin D status during pregnancy may include a reduced risk of pre-eclampsia, improved fetal growth and beneficial effects on infant immune function. These hypotheses require evaluation by randomized controlled antenatal vitamin D supplementation trials using doses that are high enough to elevate serum 25-hydroxyvitamin D concentrations into the range believed to be associated with improved health outcomes. Such doses may be considerably higher than the current recommended dietary allowance (600 IU day(-1)) or standard prenatal supplement dose (400 IU day(-1)), and may even be higher than the tolerable upper intake level (4000 IU day(-1)) advised by the Institute of Medicine (2010). A critical review of the published literature yielded limited data regarding the safety of antenatal vitamin D regimens. There have been no published reports of the teratogenic effects of vitamin D on humans. Some animal studies have suggested the potential for dose-dependent fetal toxicities (for example, growth impairment, skeletal malformations and cardiovascular anomalies), but the relevance of these observations to humans is unknown. Antenatal vitamin D supplementation trials should incorporate a range of methods for objectively establishing maternal and fetal safety, and aim to identify the lowest doses of vitamin D required to achieve target outcomes.

Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh.

AIM: Acute lower respiratory tract infection (ALRI) is the most important global cause of childhood death. Micronutrient deficiencies may increase the risk of ALRI. A case-control study was conducted to assess the association between vitamin D status and ALRI in rural Bangladesh. METHODS: Children aged 1-18 months hospitalized with ALRI (cases) were individually matched to controls on age, sex, and village (N = 25 pairs). The mean serum 25-hydroxyvitamin D concentration [25(OH)D] in cases and controls was compared using paired t-test. The unadjusted and adjusted odds of ALRI were assessed by multivariate conditional logistic regression. RESULTS: Mean [25(OH)D] was significantly lower among ALRI cases than controls (29.1 nmol/L vs. 39.1 nmol/L; p = 0.015). The unadjusted odds of ALRI was halved for each 10 nmol/L increase in [25(OH)D] (OR 0.53, 95% CI 0.30-0.96). Adjustment for confounders increased the magnitude of the association. CONCLUSION: Vitamin D status was associated with early childhood ALRI in a matched case-control study in rural Bangladesh. Randomized trials may establish whether interventions to improve vitamin D status can reduce the burden of ALRI in early childhood.

Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood.

The association between vitamin D status and susceptibility to acute lower respiratory tract infection (ALRI) was studied in young Canadian children. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured in patients aged 1-25 months admitted to hospital with uncomplicated ALRI (primarily viral bronchiolitis) as well as in healthy, similarly aged patients without a history of hospitalization for ALRI (controls). Serum 25(OH)D concentrations were similar among cases and controls (77.0 versus 77.2 nmol l(-1); P=0.960), and there was no case-control difference in the prevalence of vitamin D insufficiency using two thresholds (<40 nmol l(-1): 4.7 versus 1.5%, P=0.365; <80 nmol l(-1): 51.6 versus 56.9%, P=0.598). Vitamin D status was not associated with the risk of hospitalization for ALRI in this population.

Posttreatment follow-up of Helicobacter pylori infection using a stool antigen immunoassay.

The Helicobacter pylori stool antigen enzyme immunoassay (HpSA) was evaluated during posttreatment follow-up of patients in a country with a very high prevalence of H. pylori infection. From among 273 dyspeptic individuals (18 to 55 years) initially recruited from a shantytown in Lima, Peru, 238 participants who met the inclusion criteria and were suspected to be H. pylori positive based on (14)C urea breath test (UBT) results underwent endoscopy. Participants with endoscopy-proven infections received standard eradication therapy and were monitored by UBT and HpSA at 1 month following treatment and at 3-month intervals for 9 months posttreatment. A second endoscopy was performed if UBT results showed evidence of treatment failure or H. pylori recurrence. Biopsy results were considered the "gold standard" in all analyses. Among patients who underwent endoscopy, HpSA had a pretreatment sensitivity of 93%. Two-hundred thirty patients completed the treatment regimen, of whom 201 (93%) were considered to have had successful treatment outcomes based on a negative follow-up UBT. Thirty-two patients with UBT-defined treatment failures or H. pylori recurrences at any point during the 9-month follow-up underwent a second endoscopy. In the posttreatment setting, HpSA had an overall sensitivity of 73% and a specificity of 67%. Agreement between UBT and HpSA diminished throughout the follow-up. Among 14 participants in whom HpSA remained positive at 1 month following treatment despite UBT evidence of treatment success, 12 (86%) became HpSA negative within 3 months posttreatment. Although this study confirmed the validity of the HpSA in the initial assessment of dyspeptic patients, the test demonstrated a reduced overall accuracy in the detection of treatment failures and H. pylori recurrences during 9 months of posttreatment follow-up. Furthermore, in some patients it may take up to 3 months after successful eradication for antigen shedding to diminish to levels within the negative HpSA range.

Alternatives to Sulfasalazine: A Meta-analysis of 5-ASA in the Treatment of Ulcerative Colitis.

SUMMARY: : The purpose of this study was to assess the efficacy and safety of the newer release formulations of 5-aminosalicylic acid (5-ASA) compared with placebo or sulfasalazine (SASP) for the treatment of active disease and the maintenance of remission in ulcerative colitis. A computer-assisted literature search for relevant studies (1981-1996) was performed using MEDLINE, BIOS, and Science Citation Index, followed by a manual search of reference lists from previously retrieved articles, review articles, symposia proceedings, and abstracts from major gastrointestinal conferences. Studies were accepted for analysis if they were randomized, double-blinded, and controlled clinical trials of parallel design, with treatment durations of a minimum of 4 weeks for the treatment of active disease (19 studies), and a minimum of 6 months for maintenance therapy (16 studies). Based on an intention-to-treat principle, the outcomes of interest in the treatment of active disease were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, or endoscopic improvement. For maintenance therapy, the primary measured outcome was the failure to maintain clinical or endoscopic remission. In active disease, 5-ASA was superior to placebo with regard to all measured outcome variables. For the failure to induce global/clinical improvement or remission, the pooled odds ratio was 0.39 [95% confidence interval (CI), 0.29-0.52]. A dose-response trend for 5-ASA was also observed. When 5-ASA was compared with SASP in active disease, the pooled odds ratio was 0.87 (CI, 0.63-1.20) for the failure to induce global/clinical improvement or remission, and 0.66 (CI, 0.42-1.04) for the failure to induce endoscopic improvement. In maintenance therapy, the pooled odds ratio for the failure to maintain clinical or endoscopic remission (withdrawals and relapses) for 5-ASA versus placebo was 0.48 (CI, 0.35-0.65) and versus SASP, 1.29 (CI, 1.06-1.57) at 6 months and 1.15 (0.89-1.50) at 12 months. SASP was not as well tolerated as 5-ASA in active disease despite their relatively similar tolerabilities in maintenance therapy. The newer 5-ASA preparations were superior to placebo for both active disease and maintenance of remission. In a patient population selected for tolerance to SASP, there is insufficient evidence to confirm their benefit over SASP for either active or maintenance therapy.

Molecular basis of human carbonic anhydrase II deficiency.

Deficiency of carbonic anhydrase II (carbonate hydro-lyase, EC 4.2.1.1) is the primary defect in the syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. In this report we describe the molecular basis for carbonic anhydrase II deficiency in the American family in which the association of carbonic anhydrase II deficiency with this syndrome was first recognized. The three affected siblings from this family are compound heterozygotes, each having inherited two different mutations in the structural gene for carbonic anhydrase II. The paternal mutation is a splice acceptor site mutation at the 3' end of intron 5. The maternal mutation is a missense mutation in exon 3 that substitutes a tyrosine for histidine-107. We show that the mutant enzyme expressed in bacteria from the cDNA containing the His-107----Tyr mutation has detectable, though greatly reduced, activity. We suggest that residual activity of the His-107----Tyr mutant enzyme may explain the absence of mental retardation and the relatively mild phenotype of carbonic anhydrase II deficiency in affected members of this family.

A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries.

Clinical manifestations in patients with carbonic anhydrase (CA) II deficiency include osteopetrosis, renal tubular acidosis, and cerebral calcification. Of the 39 reported cases of the carbonic anhydrase II deficiency syndrome, 72% were patients from North African and Middle Eastern countries, most, if not all, of whom were of Arabic descent. We have analyzed DNAs from members of six unrelated Arabic kindreds and found five to be homozygous and one heterozygous for a novel splice junction (donor site) mutation at the 5' end of intron 2. These findings suggest that a common "Arabic" mutation may be the predominant cause of CA II deficiency in this region. The mutation introduces a new Sau3A1 restriction site which allows polymerase chain reaction (PCR)-based diagnosis of this mutation that should be useful in diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of the patients with the Arabic mutation from those of the American and Belgian patients with the His 107-->Tyr mutation.

Safety and efficacy of a broad-spectrum sunscreen in patients with discoid or subacute cutaneous lupus erythematosus.

An eight-week, open-label study was conducted to test the efficacy, safety, and cosmetic acceptability of a broad-spectrum sunscreen in patients with discoid lupus erythematosus or subacute cutaneous lupus erythematosus. The sunscreen combined the ultraviolet A absorber avobenzone (Parsol 1789, Givaudan Corp) and the ultraviolet B absorber padimate O and had a sun protection factor greater than fifteen. The overall clinical disease severity decreased from 2.7 (four point scale) at baseline to 1.7 after eight weeks (p = 0.005). Cutaneous signs and symptoms, including hyperpigmentation, papules, scaling, and erythema, were significantly less severe at the end of the study. The level of protection provided by the sunscreen was good to excellent in 54 percent of patients, and was judged to be superior or far superior to previously used sun protection factor-fifteen sunscreens in 77 percent of patients. Most patients found the sunscreen highly acceptable with respect to its cosmetic properties.

Rothmund-Thomson syndrome: a case report.

We present a 4-year-old girl with poikiloderma, radial aplasia, short stature, facial dysmorphism, and sparse hair. We believe these findings to be consistent with a diagnosis of Rothmund-Thomson syndrome.

Annular atrophic connective tissue panniculitis of the ankles.

A case of annular lipoatrophy of the ankles in a 4-year-old girl is presented. Histologically a lobular lymphohistiocytic panniculitis with masses of foam cells was present. This pattern resembles that seen in atrophic connective tissue panniculitis. The patient responded to treatment with prednisone and dapsone and now has residual lipoatrophy.

Cutaneous reactions to drugs used for rheumatologic disorders.

Cutaneous reactions to medications probably represent the most common manifestation of drug reactions. The diversity of cutaneous eruptions produced by drugs provide a challenge in searching for the mechanisms producing the reaction. Many eruptions are due to a form of allergic hypersensitivity, while others may be idiosyncratic, due to a metabolic abnormality, or represent a cumulative phenomenon. This article discusses the diagnosis of drug-induced cutaneous reactions by reviewing specific drugs commonly used in rheumatologic therapy.

Possible ultraviolet A-induced lentigines: a side effect of chronic tanning salon usage.

A patient who developed lentigines after prolonged ultraviolet A (UVA) exposure in a tanning booth is described. The patient had no exposure to psoralens or furocoumarins. Histologic examination of a representative lentigo revealed melanocytic hyperplasia and cytologic atypia. Increased nevocytic activity with histologic dysplasia was present in several junctional nevi excised during the period of UVA exposure. Several studies have revealed significant effects of UVA on melanocytes. Patients should be cautioned to avoid tanning bed use in view of these potentially deleterious effects.

Sporadic dysplastic nevus syndrome in a tyrosinase-positive oculocutaneous albino.

A case of dysplastic nevus syndrome in a 41-year-old tyrosinase-positive oculocutaneous albino man is presented. Clinically the patient exhibited multiple amelanotic lesions; histologic examination provided the diagnosis of dysplastic nevus syndrome. Fontana-Masson silver staining revealed the presence of melanin in the nevus cells. Hair bulbs incubated in tyrosine buffer produced melanin. This is the second reported case of dysplastic nevus syndrome in an oculocutaneous albino and the first case of dysplastic nevus syndrome in a tyrosinase-positive albino of which we are aware.