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Interventions for pain with intrauterine device insertion.
Lopez, LM, Bernholc, A, Zeng, Y, Allen, RH, Bartz, D, O'Brien, PA, Hubacher, D
The Cochrane database of systematic reviews. 2015;(7):CD007373
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Abstract
BACKGROUND Fear of pain during insertion of intrauterine contraception (IUC) is a barrier to use of this method. IUC includes copper-containing intrauterine devices and levonorgestrel-releasing intrauterine systems. Interventions for pain control during IUC insertion include non-steroidal anti-inflammatory drugs (NSAIDs), local cervical anesthetics, and cervical ripening agents such as misoprostol. OBJECTIVES To review randomized controlled trials (RCTs) of interventions for reducing IUC insertion-related pain SEARCH METHODS We searched for trials in CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov, and ICTRP. The most recent search was 22 June 2015. We examined reference lists of pertinent articles. For the initial review, we wrote to investigators to find other published or unpublished trials. SELECTION CRITERIA We included RCTs that evaluated an intervention for preventing IUC insertion-related pain. The comparison could have been a placebo, no intervention, or another active intervention. The primary outcomes were self-reported pain at tenaculum placement, during IUC insertion, and after IUC insertion (up to six hours). DATA COLLECTION AND ANALYSIS Two authors extracted data from eligible trials. For dichotomous variables, we calculated the Mantel-Haenszel odds ratio (OR) with 95% confidence interval (CI). For continuous variables, we computed the mean difference (MD) with 95% CI. In meta-analysis of trials with different measurement scales, we used the standardized mean difference (SMD). MAIN RESULTS We included 33 trials with 5710 participants total; 29 were published from 2010 to 2015. Studies examined lidocaine, misoprostol, NSAIDs, and other interventions. Here we synthesize results from trials with sufficient outcome data and moderate- or high-quality evidence.For lidocaine, meta-analysis showed topical 2% gel had no effect on pain at tenaculum placement (two trials) or on pain during IUC insertion (three trials). Other formulations were effective compared with placebo in individual trials. Mean score for IUC-insertion pain was lower with lidocaine and prilocaine cream (MD -1.96, 95% CI -3.00 to -0.92). Among nulliparous women, topical 4% formulation showed lower scores for IUC-insertion pain assessed within 10 minutes (MD -15.90, 95% CI -22.77 to -9.03) and at 30 minutes later (MD -11.10, 95% CI -19.05 to -3.15). Among parous women, IUC-insertion pain was lower with 10% spray (median 1.00 versus 3.00). Compared with no intervention, pain at tenaculum placement was lower with 1% paracervical block (median 12 versus 28).For misoprostol, meta-analysis showed a higher mean score for IUC insertion compared with placebo (SMD 0.27, 95% CI 0.07 to 0.46; four studies). In meta-analysis, cramping was more likely with misoprostol (OR 2.64, 95% CI 1.46 to 4.76; four studies). A trial with nulliparous women found a higher score for IUC-insertion pain with misoprostol (median 46 versus 34). Pain before leaving the clinic was higher for misoprostol in two trials with nulliparous women (MD 7.60, 95% CI 6.48 to 8.72; medians 35.5 versus 20.5). In one trial with nulliparous women, moderate or severe pain at IUC insertion was less likely with misoprostol (OR 0.30, 95% CI 0.16 to 0.55). In the same trial, the misoprostol group was more likely to rate the experience favorably. Within two trials of misoprostol plus diclofenac, shivering, headache, or abdominal pain were more likely with misoprostol. Participants had no vaginal delivery. One trial showed the misoprostol group less likely to choose or recommend the treatment.Among multiparous women, mean score for IUC-insertion pain was lower for tramadol 50 mg versus naproxen 550 mg (MD -0.63, 95% CI -0.94 to -0.32) and for naproxen versus placebo (MD -1.94, 95% CI -2.35 to -1.53). The naproxen group was less likely than the placebo group to report the insertion experience as unpleasant and not want the medication in the future. An older trial showed repeated doses of naproxen 300 mg led to lower pain scores at one hour (MD -1.04, 95% CI -1.67 to -0.41) and two hours (MD -0.98, 95% CI -1.64 to -0.32) after insertion. Most women were nulliparous and also had lidocaine paracervical block. AUTHORS' CONCLUSIONS Nearly all trials used modern IUC. Most effectiveness evidence was of moderate quality, having come from single trials. Lidocaine 2% gel, misoprostol, and most NSAIDs did not help reduce pain. Some lidocaine formulations, tramadol, and naproxen had some effect on reducing IUC insertion-related pain in specific groups. The ineffective interventions do not need further research.
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Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites.
Davenport, C, Yan, J, Taesuwan, S, Shields, K, West, AA, Jiang, X, Perry, CA, Malysheva, OV, Stabler, SP, Allen, RH, et al
The Journal of nutritional biochemistry. 2015;(9):903-11
Abstract
Demand for the vital nutrient choline is high during lactation; however, few studies have examined choline metabolism and requirements in this reproductive state. The present study sought to discern the effects of lactation and varied choline intake on maternal biomarkers of choline metabolism and breast milk choline content. Lactating (n=28) and control (n=21) women were randomized to 480 or 930 mg choline/day for 10-12 weeks as part of a controlled feeding study. During the last 4-6 weeks, 20% of the total choline intake was provided as an isotopically labeled choline tracer (methyl-d9-choline). Blood, urine and breast milk samples were collected for choline metabolite quantification, enrichment measurements, and gene expression analysis of choline metabolic genes. Lactating (vs. control) women exhibited higher (P < .001) plasma choline concentrations but lower (P ≤ .002) urinary excretion of choline metabolites, decreased use of choline as a methyl donor (e.g., lower enrichment of d6-dimethylglycine, P ≤ .08) and lower (P ≤ .02) leukocyte expression of most choline-metabolizing genes. A higher choline intake during lactation differentially influenced breast milk d9- vs. d3-choline metabolite enrichment. Increases (P ≤ .03) were detected among the d3-metabolites, which are generated endogenously via the hepatic phosphatidylethanolamine N-methyltransferase (PEMT), but not among the d9-metabolites generated from intact exogenous choline. These data suggest that lactation induces metabolic adaptations that increase the supply of intact choline to the mammary epithelium, and that extra maternal choline enhances breast milk choline content by increasing supply of PEMT-derived choline metabolites. This trial was registered at clinicaltrials.gov as NCT01127022.
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Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women.
Yan, J, Jiang, X, West, AA, Perry, CA, Malysheva, OV, Brenna, JT, Stabler, SP, Allen, RH, Gregory, JF, Caudill, MA
The American journal of clinical nutrition. 2013;(6):1459-67
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Abstract
BACKGROUND Although biomarkers of choline metabolism are altered by pregnancy, little is known about the influence of human pregnancy on the dynamics of choline-related metabolic processes. OBJECTIVE This study used stable isotope methodology to examine the effects of pregnancy on choline partitioning and the metabolic activity of choline-related pathways. DESIGN Healthy third-trimester pregnant (n = 26; initially week 27 of gestation) and nonpregnant (n = 21) women consumed 22% of their total choline intake (480 or 930 mg/d) as methyl-d9-choline for the final 6 wk of a 12-wk feeding study. RESULTS Plasma d9-betaine:d9-phosphatidylcholine (PC) was lower (P ≤ 0.04) in pregnant than in nonpregnant women, suggesting greater partitioning of choline into the cytidine diphosphate-choline (CDP-choline) PC biosynthetic pathway relative to betaine synthesis during pregnancy. Pregnant women also used more choline-derived methyl groups for PC synthesis via phosphatidylethanolamine N-methyltransferase (PEMT) as indicated by comparable increases in PEMT-PC enrichment in pregnant and nonpregnant women despite unequal (pregnant > nonpregnant; P < 0.001) PC pool sizes. Pregnancy enhanced the hydrolysis of PEMT-PC to free choline as shown by greater (P < 0.001) plasma d3-choline:d3-PC. Notably, d3-PC enrichment increased (P ≤ 0.011) incrementally from maternal to placental to fetal compartments, signifying the selective transfer of PEMT-PC to the fetus. CONCLUSIONS The enhanced use of choline for PC production via both the CDP-choline and PEMT pathways shows the substantial demand for choline during late pregnancy. Selective partitioning of PEMT-PC to the fetal compartment may imply a unique requirement of PEMT-PC by the developing fetus.
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Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans.
Yan, J, Jiang, X, West, AA, Perry, CA, Malysheva, OV, Devapatla, S, Pressman, E, Vermeylen, F, Stabler, SP, Allen, RH, et al
The American journal of clinical nutrition. 2012;(5):1060-71
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Abstract
BACKGROUND In 1998 choline Adequate Intakes of 425 and 450 mg/d were established for nonpregnant and pregnant women, respectively. However, to our knowledge, no dose-response studies have been conducted to evaluate the effects of pregnancy or maternal choline intake on biomarkers of choline metabolism. OBJECTIVE We sought to quantify the effects of pregnancy and maternal choline intake on maternal and fetal indicators of choline metabolism. DESIGN Healthy pregnant (n = 26; 27 wk gestation) and nonpregnant (n = 21) women were randomly assigned to receive 480 or 930 mg choline/d for 12 wk. Fasting blood samples and placental tissue and umbilical cord venous blood were collected and analyzed for choline and its metabolites. RESULTS Regardless of the choline intake, pregnant women had higher circulating concentrations of choline (30%; P < 0.001) but lower concentrations of betaine, dimethylglycine, sarcosine, and methionine (13-55%; P < 0.001). Obligatory losses of urinary choline and betaine in pregnant women were ∼2-4 times as high (P ≤ 0.02) as those in nonpregnant women. A higher choline intake yielded higher concentrations of choline, betaine, dimethylglycine, and sarcosine (12-46%; P ≤ 0.08) in both pregnant and nonpregnant women without affecting urinary choline excretion. The higher maternal choline intake also led to a doubling of dimethylglycine in cord plasma (P = 0.002). CONCLUSION These data suggest that an increment of 25 mg choline/d to meet the demands of pregnancy is insufficient and show that a higher maternal choline intake increases the use of choline as a methyl donor in both maternal and fetal compartments. This trial was registered at clinicaltrials.gov as NCT01127022.
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MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline.
Yan, J, Wang, W, Gregory, JF, Malysheva, O, Brenna, JT, Stabler, SP, Allen, RH, Caudill, MA
The American journal of clinical nutrition. 2011;(2):348-55
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BACKGROUND Homozygosity for the variant 677T allele in the methylenetetrahydrofolate reductase (MTHFR) gene increases the requirement for folate and may alter the metabolic use of choline. The choline adequate intake is 550 mg/d for men, although the metabolic consequences of consuming extra choline are unclear. OBJECTIVE Deuterium-labeled choline (d9-choline) as tracer was used to determine the differential effects of the MTHFR C677T genotype and the effect of various choline intakes on the isotopic enrichment of choline derivatives in folate-compromised men. DESIGN Mexican American men with the MTHFR 677CC or 677TT genotype consumed a diet providing 300 mg choline/d plus supplemental choline chloride for total choline intakes of 550 (n = 11; 4 with 677CC and 7 with 677TT) or 1100 (n = 12; 4 with 677CC and 8 with 677TT) mg/d for 12 wk. During the last 3 wk, 15% of the total choline intake was provided as d9-choline. RESULTS Low but measurable enrichments of the choline metabolites were achieved, including that of d3-phosphatidylcholine (d3-PtdCho)--a metabolite produced in the de novo pathway via choline-derived methyl groups. Men with the MTHFR 677TT genotype had a higher urinary enrichment ratio of betaine to choline (P = 0.041), a higher urinary enrichment of sarcosine (P = 0.041), and a greater plasma enrichment ratio of d9-betaine to d9-PtdCho with the 1100 mg choline/d intake (P = 0.033). CONCLUSION These data show for the first time in humans that choline itself is a source of methyl groups for de novo PtdCho biosynthesis and indicate that the MTHFR 677TT genotype favors the use of choline as a methyl donor.
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Sex and menopausal status influence human dietary requirements for the nutrient choline.
Fischer, LM, daCosta, KA, Kwock, L, Stewart, PW, Lu, TS, Stabler, SP, Allen, RH, Zeisel, SH
The American journal of clinical nutrition. 2007;85(5):1275-85
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Plain language summary
Choline is used to form cell membranes, and it is a precursor for the neurotransmitter acetylcholine. Other than from the diet, choline can also be derived from the de novo biosynthesis of phosphatidylcholine. The current Adequate Intake for choline is considered sufficient to prevent deficiency, however an Estimated Average Requirement cannot be generated due to lack of availability of adequate human data. The aim of this study was to evaluate the dietary choline requirement in healthy men and women (pre- and postmenopausal), and to identify the clinical and metabolic sequelae of choline deficiency. Fifty-seven adult participants (26 healthy men, 16 premenopausal women and 15 postmenopausal women) were recruited for the study. A randomised double-blind protocol was followed to assign participants in one of the 2 arms; folate only (100 DFE) vs a dietary supplement of 400μg folic acid/d (768 DFE). Results show that independent of folate status, most men and postmenopausal women developed liver or muscle dysfunction when fed a low-choline diet, whereas premenopausal women were more resistant to developing such organ dysfunction. AP activity increased in all subjects in response to the low-choline diet regardless of whether they manifested organ dysfunction. Liver and muscle dysfunction occurred in response to a low-choline diet in both men and women. The current AI for choline was not be sufficient for some of the participants who became depleted despite this level of intake.
Abstract
BACKGROUND Although humans require dietary choline for methyl donation, membrane function, and neurotransmission, choline can also be derived from the de novo synthesis of phosphatidylcholine, which is up-regulated by estrogen. A recommended Adequate Intake (AI) exists for choline; however, an Estimated Average Requirement has not been set because of a lack of sufficient human data. OBJECTIVE The objective of the study was to evaluate the dietary requirements for choline in healthy men and women and to investigate the clinical sequelae of choline deficiency. DESIGN Fifty-seven adult subjects (26 men, 16 premenopausal women, 15 postmenopausal women) were fed a diet containing 550 mg choline x 70 kg(-1) x d(-1) for 10 d followed by <50 mg choline x 70 kg(-1) x d(-1) with or without a folic acid supplement (400 microg/d per randomization) for up to 42 d. Subjects who developed organ dysfunction during this diet had normal organ function restored after incremental amounts of choline were added back to the diet. Blood and urine were monitored for signs of toxicity and metabolite concentrations, and liver fat was assessed by using magnetic resonance imaging. RESULTS When deprived of dietary choline, 77% of men and 80% of postmenopausal women developed fatty liver or muscle damage, whereas only 44% of premenopausal women developed such signs of organ dysfunction. Moreover, 6 men developed these signs while consuming 550 mg choline x 70 kg(-1) x d(-1), the AI for choline. Folic acid supplementation did not alter the subjects' response. CONCLUSION Subject characteristics (eg, menopausal status) modulated the dietary requirement for choline, and a daily intake at the current AI was not sufficient to prevent organ dysfunction in 19 of the subjects.
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The role of family planning in poverty reduction.
Allen, RH
Obstetrics and gynecology. 2007;(5):999-1002
Abstract
Family planning plays a pivotal role in population growth, poverty reduction, and human development. Evidence from the United Nations and other governmental and nongovernmental organizations supports this conclusion. Failure to sustain family planning programs, both domestically and abroad, will lead to increased population growth and poorer health worldwide, especially among the poor. However, robust family planning services have a range of benefits, including maternal and infant survival, nutrition, educational attainment, the status of girls and women at home and in society, human immunodeficiency virus (HIV) prevention, and environmental conservation efforts. Family planning is a prerequisite for achievement of the United Nations' Millennium Development Goals and for realizing the human right of reproductive choice. Despite this well-documented need, the U.S. contribution to global family planning has declined in recent years.
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High- but not low-dose folic acid improves endothelial function in coronary artery disease.
Moat, SJ, Madhavan, A, Taylor, SY, Payne, N, Allen, RH, Stabler, SP, Goodfellow, J, McDowell, IF, Lewis, MJ, Lang, D
European journal of clinical investigation. 2006;(12):850-9
Abstract
BACKGROUND While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated. MATERIALS AND METHODS Eighty-four patients with CAD received either 400 microg FA or 5 mg placebo daily for a 6-week treatment period. A further 44 patients with CAD received either 100 mg kg(-1) day(-1) of betaine or placebo for a 6-week treatment period. Flow-mediated dilatation (FMD), a measure of endothelial function, was assessed before and after the 6-week periods. Isometric tension and Western blotting were used to investigate the effect of FA on endothelial function and endothelial nitric oxide synthase (eNOS) dimerization in isolated rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC), respectively. RESULTS Both 400 micro g day(-1) and 5 mg day(-1) FA significantly increased plasma folate and decreased plasma Hcy. The FMD improved significantly after 6 weeks' treatment of 5 mg day(-1) FA but did not correlate with the reduction in Hcy. There was no change in FMD in either the 400 micro g FA or placebo group. In a subgroup analysis of 11 patients in the betaine group, despite a reduced Hcy, a significant impairment in FMD was observed. In the in vitro studies FA, but not betaine, reversed methionine-induced endothelial dysfunction. Moreover, the FA promoted eNOS dimerization in cultured PAEC. CONCLUSIONS These data suggest that FA dose-dependently improves endothelial function in CAD via a mechanism independently of Hcy lowering. It may involve promotion of eNOS dimerization.
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Elevated serum S-adenosylhomocysteine in cobalamin-deficient elderly and response to treatment.
Stabler, SP, Allen, RH, Dolce, ET, Johnson, MA
The American journal of clinical nutrition. 2006;(6):1422-9
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Abstract
BACKGROUND S-Adenosylmethionine (SAM)-dependent methylation reactions produce S-adenosylhomocysteine (SAH), the precursor of homocysteine, which has been associated with adverse events when it is elevated. OBJECTIVE We studied a cohort of elderly with a high prevalence of cobalamin deficiency to determine whether SAH, SAM, or their ratio was abnormal; whether they correlated with other markers of vitamin deficiency; and whether they changed with cobalamin therapy. DESIGN A convenience sample of elderly attending nutrition centers was enrolled for baseline demographic, biochemical, and nutritional assessments. Methylmalonic acid (MMA), total homocysteine, and other metabolites were measured by using gas chromatography-mass spectrometry. Serum SAM and SAH were measured by using stable-isotope-dilution liquid chromatography-mass spectrometry. Subjects found to have elevated serum MMA were treated with oral cyanocobalamin tablets (1000 microg/d) for 3 mo. Subjects with normal MMA were randomly assigned to 1 of 3 dosage groups: 0, 25, or 100 microg cyanocobalamin/d. RESULTS The 149 elderly subjects had a mean age of 76.3 y; 81% were female, and 30% were African American. Serum MMA concentrations were elevated in 30% and SAH concentrations were elevated in 64% of the cohort. Those with elevated MMA concentrations had higher SAH and SAM concentrations. High-dose oral cobalamin lowered SAH, MMA, and total homocysteine concentrations significantly, although subjects with creatinine concentrations >109 umol/L had higher posttreatment SAH than did those with lower creatinine. CONCLUSIONS Elevated serum SAH concentrations are common in elderly and are strongly influenced by both renal status and cobalamin deficiency. These elevated concentrations can be lowered with high-dose oral cobalamin therapy.
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Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults.
Rajan, S, Wallace, JI, Brodkin, KI, Beresford, SA, Allen, RH, Stabler, SP
Journal of the American Geriatrics Society. 2002;(11):1789-95
Abstract
OBJECTIVES Because the effects of lower-dose oral cobalamin (Cbl) supplements on older people with cobalamin deficiency are not known, we determined whether oral Cbl supplements at three different dose levels would normalize elevated serum methylmalonic acid (MMA) and total homocysteine (tHcy) concentrations. DESIGN Sequential nonrandomized intervention study of three dose levels. SETTINGS Two university-based senior care clinics. PARTICIPANTS Twenty-three older adults (aged ≥65) with serum Cbl levels of 221 pmol/L (300 pg/mL) or lower and serum MMA greater than 271 nmol/L who had been enrolled in a previous screening study for Cbl deficiency (mean age 79 +/- 9; 17 male, 6 female; 17 white, 6 other). INTERVENTION Sequential daily treatment with 25 microg oral cobalamin, followed by 100 microg and 1,000 microg cobalamin each for a 6-week period. MEASUREMENTS Serum MMA, tHcy, and other metabolites at baseline and after each 6-week dosing interval. RESULTS Treatment with 25 microg and 100 microg lowered but did not normalize MMA levels in most subjects. A dose of 1,000 microg/day proved to be the most effective in lowering MMA levels to within normal limits. Serum tHcy was normalized in six of 11 subjects who had elevated tHcy pretreatment with oral Cbl alone and in one subject in combination with a multivitamin. CONCLUSIONS Most Cbl-deficient older people require more than 100 microg of oral Cbl to normalize serum MMA, which is a larger dose than is available in most standard multivitamins and Cbl supplements.