Vitamin D in pregnancy: understanding immune effects in the decidua

Epidemiology has linked preeclampsia (PET) to vitamin D deficiency. To date, studies have focused upon serum 25-hydroxyvitamin D3 (25(0H. )D3) alone as the marker of vitamin D status.~We provide strong evidence comprehensive analysis of vitamin D metabolites in pregnancy is highly informative, particularly within the context of PET. Uniquely, analysis of maternal urinary metabolites provides a novel insight into vitamin D and the kidney, with lower 25(0H)D3 and 24,25(0H)2D3 excretion early indicators of a predisposition towards PET. Since vitamin D is a potent regulator of immune function, and the decidua appears a key extra-renal site for vitamin D metabolism, we investigated effects of 1 ,25(0H)2D3 upon decidual uterine natural killer cells and macrophages. We show both express a functional vitamin-D system and demonstrate differential sensitivity to 1 ,25(0H)2D3 compared to their peripheral counterparts. To understand the functional impact of vitamin D, whole transcriptomic analysis of 1,25(0H)2D3-mediated effects upon uNK and macrophages was performed. We show the actions of vitamin D extend far beyond simple immuno-regulation, targeting major cellular functions including migration, adhesion and apoptosis. In particular, our data support effects highly relevant to decidualisation. We anticipate these findings to be highly relevant within the context of vitamin D deficiency, mal placentation and PET

Serum and urine vitamin D metabolite analysis in early preeclampsia

Vitamin D-deficiency is common in pregnant women, and may contribute to adverse events in pregnancy such as preeclampsia (PET). To date, studies of vitamin D and PET have focused primarily on serum concentrations vitamin D, 25-hydroxyvitamin D3 (25(OH)D3) later in pregnancy. The aim here was to determine whether a more comprehensive analysis of vitamin D metabolites earlier in pregnancy could provide predictors of PET. Using samples from the SCOPE pregnancy cohort, multiple vitamin D metabolites were quantified by liquid chromatography-tandem mass spectrometry in paired serum and urine prior to the onset of PET symptoms. Samples from 50 women at pregnancy week 15 were analysed, with 25 (50%) developing PET by the end of the pregnancy and 25 continuing with uncomplicated pregnancy. Paired serum and urine from non-pregnant women (n=9) of reproductive age were also used as a control. Serum concentrations of 25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 were measured and showed no significant difference between women with uncomplicated pregnancies and those developing PET. As previously reported, serum 1,25(OH)2D3 was higher in all pregnant women (in the second trimester), but serum 25(OH)D2 was also higher compared to non-pregnant women. In urine, 25(OH)D3 and 24,25(OH)2D3 were quantifiable, with both metabolites demonstrating significantly lower (p&lt;0.05) concentrations of both of these metabolites in those destined to develop PET. These data indicate that analysis of urinary metabolites provides an additional insight into vitamin D and the kidney, with lower urinary 25(OH)D3, and 24,25(OH)2D3 excretion being an early indicator of a predisposition towards developing PET.</p

Management of obstetric postpartum hemorrhage: a national service evaluation of current practice in the UK

BACKGROUND: Postpartum hemorrhage (PPH) continues to be one of the major causes of maternal mortality and morbidity in obstetrics. Variations in practice often lead to adverse maternity outcomes following PPH. Our objective was to assess the current practice in managing PPH in the UK. METHODS: We performed a national multicenter prospective service evaluation study over one calendar month and compared the current performance to national standards for managing PPH. We used a standardized data collection tool and collected data on patients’ demographics, incidence of PPH, estimated blood loss (EBL), prophylactic and treatment measures, onset of labor, and mode of delivery. RESULTS: We collected data from 98 obstetric units, including 3663 cases of primary PPH. Fifty percent of cases were minor PPH (EBL 500–1000 mL, n=1900/3613, 52.6%) and the remaining were moderate PPH (EBL >1000 to <2000 mL, n=1424/3613, 39.4%) and severe PPH (EBL >2000 mL, n=289/3613, 8%). The majority of women received active management of the third stage of labor (3504/3613, 97%) most commonly with Syntometrine intramuscular (1479/3613, 40.9%). More than half required one additional uterotonic agent (2364/3613, 65.4%) most commonly with Syntocinon intravenous infusion (1155/2364, 48.8%). There was a poor involvement of consultant obstetricians and anesthetists in managing PPH cases, which was more prevalent when managing major PPH (p=0.0001). CONCLUSION: There are still variations in managing PPH in the UK against national guidelines. More senior doctor involvement and regular service evaluation are needed to improve maternal outcomes following PPH

Vitamin D, the placenta and early pregnancy:effects on trophoblast function

Pregnancy is associated with significant changes in vitamin D metabolism, notably increased maternal serum levels of active vitamin D, 1,25-dihydroxyvitamin (1,25(OH)2D). This appears to be due primarily to increased renal activity of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) that catalyzes synthesis of 1,25(OH)2D, but CYP27B1 expression is also prominent in both the maternal decidua and fetal trophoblast components of the placenta. The precise function of placental synthesis of 1,25(OH)2D remains unclear, but is likely to involve localised tissue-specific responses with both decidua and trophoblast also expressing the vitamin D receptor (VDR) for 1,25(OH)2D. We have previously described immunomodulatory responses to 1,25(OH)2D by diverse populations of VDR-expressing cells within the decidua. The aim of the current review is to detail the role of vitamin D in pregnancy from a trophoblast perspective, with particular emphasis on the potential role of 1,25(OH)2D as a regulator of trophoblast invasion in early pregnancy. Vitamin D-deficiency is common in pregnant women, and a wide range of studies have linked low vitamin D status to adverse events in pregnancy. To date most of these studies have focused on adverse events later in pregnancy, but the current review will explore the potential impact of vitamin D on early pregnancy, and how this may influence implantation and miscarriage

International Comparison in Opiate Prescribing for New Users in Primary Care using Electronic Medical Record Data

Introduction The opioid epidemic in North America has, in part, been attributed to an increase in opiate use for non-cancer pain and the prescription of more potent molecules. In contrast, the United Kingdom appears unaffected by this crisis, possibly because of differences in primary care prescribing, or health system policies. Objective To determine if there are differences in opiate prescribing for new users in primary care in the United Kingdom, United States, and Canada. Approach Electronic health record data from Quebec, Canada (MOXXI), the United States (Partners Health Care, Boston MA), and the United Kingdom (CPRD random sample of 600,000) were used to identify new users of opiates (no prior prescription in 2 years), at least 18 years old between 2006-2016. Cancer patients were excluded after harmonizing equivalent READ and ICD9/10 codes. Generic drug names in each jurisdiction were mapped to the WHO ATC classification, and characterized using morphine milligram equivalents (MME). Results Overall 655,877 new users were identified, of whom 78% of 58,286 (U.S.), 88% of 6,251 (Canada), and 96% of 600,000 (UK) were non-cancer patients. Mean age of new users was 49 (SD 16) in the US, 57 (SD 16) in Canada, and 52 (SD 19) in the UK. 57.6% (UK) to 67.3% (US) of new users were women. In the UK, 86.5% of patients were started on codeine (MME:0.15), compared to 43.9% in Canada and 8.5% in the U.S. In the U.S 65.0\% were started on oxycodone (MME:1.5), and 10.9% on hydrocodone (MME:1). In Canada, tramadol (18.2%; MME: 0.1) followed by oxycodone (13.2%) were the next most commonly prescribed drugs. Conclusion/Implications Substantial differences in opioid prescribing practices for non-cancer pain were observed between the UK and Canadian and United States sites. The predilection to start patients on more potent opiates in North America may be a contributing cause to the opiate epidemic

Trophoblast uptake of DBP regulates intracellular actin and promotes matrix invasion

Early pregnancy is characterised by elevated circulating levels of vitamin D binding protein (DBP). The impact of this on maternal and fetal health is unclear but DBP is present in the placenta, and DBP gene variants have been linked to malplacentation disorders such as preeclampsia. The functional role of DBP in the placenta was investigated using trophoblastic JEG3, BeWo and HTR8 cells. All three cell lines showed intracellular DBP with increased expression and nuclear localisation of DBP in cells treated with the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D). When cultured in the serum of mice lacking DBP (DBP-/-), JEG3 cells showed no intracellular DBP indicating uptake of exogenous DBP. Inhibition of the membrane receptor for DBP, megalin, also suppressed intracellular DBP. Elimination of intracellular DBP with DBP-/- serum or megalin inhibitor suppressed matrix invasion by trophoblast cells and was associated with increased nuclear accumulation of G-actin. Conversely, treatment with 1,25D enhanced matrix invasion. This was independent of the nuclear vitamin D receptor but was associated with enhanced ERK phosphorylation, and inhibition of ERK kinase suppressed trophoblast matrix invasion. When cultured with serum from pregnant women, trophoblast matrix invasion correlated with DBP concentration, and DBP was lower in first-trimester serum from women who later developed preeclampsia. These data show that the trophoblast matrix invasion involves uptake of serum DBP and associated intracellular actin-binding and homeostasis. DBP is a potential marker of placentation disorders such as preeclampsia and may also provide a therapeutic option for improved placenta and pregnancy health

The international generalisability of evidence for health policy: a cross country comparison of medication adherence following policy change

Copayments for prescriptions may increase morbidity and mortality via reductions in adherence to medications. Relevant data can inform policy to minimise such unintended effects. We explored the generalisability of evidence for copayments by comparing two international copayment polices, one in Massachusetts and one in Ireland, to assess whether effects on medication adherence were comparable. We used national prescription data for public health insurance programmes in Ireland and Medicaid data in the U.S. New users of oral anti-hypertensive, anti-hyperlipidaemic and diabetic drugs were included (total n = 14,259 in U.S. and n = 43,843 in Ireland). We examined changes in adherence in intervention and comparator groups in each setting using segmented linear regression with generalised estimating equations. In Massachusetts, a gradual decrease in adherence to anti-hypertensive medications of −1% per month following the policy occurred. In contrast, the response in Ireland was confined to a −2.9% decrease in adherence immediately following the policy, with no further decrease over the 8 month follow-up. Reductions in adherence to oral diabetes drugs were larger in the U.S. group in comparison to the Irish group. No difference in adherence changes between the two settings for anti-hyperlipidaemic drugs occurred. Evidence on cost-sharing for prescription medicines is not ‘one size fits all’. Time since policy implementation and structural differences between health systems may influence the differential impact of copayment policies in international settings