Bhushan Kapur

Pre-conceptional Vitamin/Folic Acid Supplementation 2007: The Use of Folic Acid in Combination With a Multivitamin Supplement for the Prevention of Neural Tube Defects and Other Congenital Anomalies

OBJECTIVE To provide information regarding the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies, so that physicians, midwives, nurses, and other health care workers can assist in the education of women in the pre-conception phase of their health care. OPTION: Supplementation with folic acid and vitamins is problematic, since 50% of pregnancies are unplanned, and womens health status may not be optimal when they conceive. OUTCOMES Folic acid in combination with a multivitamin supplement has been associated with a decrease in specific birth defects. EVIDENCE Medline, PubMed, and Cochrane Database were searched for relevant English language articles published between 1985 and 2007. The previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of November 1993 and statements from the American College of Obstetrics and Gynecology and Canadian College of Medical Geneticists were also reviewed in developing this clinical practice guideline. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Promoting the use of folic acid and a multivitamin supplement among women of reproductive age will reduce the incidence of birth defects. The costs are those of daily vitamin supplementation and eating a healthy diet. RECOMMENDATIONS 1. Women in the reproductive age group should be advised about the benefits of folic acid in addition to a multivitamin supplement during wellness visits (birth control renewal, Pap testing, yearly examination) especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy diet, as recommended in Eating Well With Canadas Food Guide (Health Canada). Foods containing excellent to good sources of folic acid are fortified grains, spinach, lentils, chick peas, asparagus, broccoli, peas, Brussels sprouts, corn, and oranges. However, it is unlikely that diet alone can provide levels similar to folate-multivitamin supplementation. (III-A) 3. Women taking a multivitamin containing folic acid should be advised not to take more than one daily dose of vitamin supplement, as indicated on the product label. (II-2-A) 4. Folic acid and multivitamin supplements should be widely available without financial or other barriers for women planning pregnancy to ensure the extra level of supplementation. (III-B) 5. Folic acid 5 mg supplementation will not mask vitamin B12 deficiency (pernicious anemia), and investigations (examination or laboratory) are not required prior to initiating supplementation. (II-2-A) 6. The recommended strategy to prevent recurrence of a congenital anomaly (anencephaly, myelomeningocele, meningocele, oral facial cleft, structural heart disease, limb defect, urinary tract anomaly, hydrocephalus) that has been reported to have a decreased incidence following preconception / first trimester folic acid +/- multivitamin oral supplementation is planned pregnancy +/- supplementation compliance. A folate-supplemented diet with additional daily supplementation of multivitamins with 5 mg folic acid should begin at least three months before conception and continue until 10 to 12 weeks post conception. From 12 weeks post-conception and continuing throughout pregnancy and the postpartum period (4-6 weeks or as long as breastfeeding continues), supplementation should consist of a multivitamin with folic acid (0.4-1.0 mg). (I-A) 7. The recommended strategy(ies) for primary prevention or to decrease the incidence of fetal congenital anomalies will include a number of options or treatment approaches depending on patient age, ethnicity, compliance, and genetic congenital anomaly risk status. OPTION A: Patients with no personal health risks, planned pregnancy, and good compliance require a good diet of folate-rich foods and daily supplementation with a multivitamin with folic acid (0.4-1.0 mg) for at least two to three months before conception and throughout pregnancy and the postpartum period (4-6 weeks and as long as breastfeeding continues). (II-2-A) OPTION B: Patients with health risks, including epilepsy, insulin dependent diabetes, obesity with BMI >35 kg/m2, family history of neural tube defect, belonging to a high-risk ethnic group (e.g., Sikh) require increased dietary intake of folate-rich foods and daily supplementation, with multivitamins with 5 mg folic acid, beginning at least three months before conception and continuing until 10 to 12 weeks post conception. From 12 weeks post-conception and continuing throughout pregnancy and the postpartum period (4-6 weeks or as long as breastfeeding continues), supplementation should consist of a multivitamin with folic acid (0.4-1.0 mg). (II-2-A) OPTION C: Patients who have a history of poor compliance with medications and additional lifestyle issues of variable diet, no consistent birth control, and possible teratogenic substance use (alcohol, tobacco, recreational non-prescription drugs) require counselling about the prevention of birth defects and health problems with folic acid and multivitamin supplementation. The higher dose folic acid strategy (5 mg) with multivitamin should be used, as it may obtain a more adequate serum red blood cell folate level with irregular vitamin / folic acid intake but with a minimal additional health risk. (III-B) 8. The Canadian Federal Government could consider an evaluation process for the benefit/risk of increasing the level of national folic acid flour fortification to 300 mg/100 g (present level 140 mg/100 g). (III-B) 9. The Canadian Federal Government could consider an evaluation process for the benefit/risk of additional flour fortification with multivitamins other than folic acid. (III-B) 10. The Society of Obstetricians and Gynaecologists of Canada will explore the possibility of a Canadian Consensus conference on the use of folic acid and multivitamins for the primary prevention of specific congenital anomalies. The conference would include Health Canada/Congenital Anomalies Surveillance, Canadian College of Medical Geneticists, Canadian Paediatric Society, Motherisk, and pharmaceutical industry representatives. VALIDATION This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used. SPONSOR The Society of Obstetricians and Gynaecologists of Canada.

Population baseline of meconium fatty acid ethyl esters among infants of nondrinking women in Jerusalem and Toronto.

The detection of fatty acid ethyl esters (FAEE) in meconium may provide an objective estimate of prenatal alcohol exposure independent of maternal history. The authors report the results of the first population-based study conducted to investigate basal FAEE levels in the meconium of neonates not exposed to alcohol. Two hundred seven nondrinking women and their neonates were recruited from Toronto and Jerusalem. FAEE were extracted from meconium by solid-phase extraction and analyzed by GC/FID. Similar procedures were conducted in six neonates born to confirmed heavy drinkers. Low levels of meconium FAEE were detected from both cohorts (mean, 1.37 nmol/g vs. 2.08 nmol/g, Toronto vs. Jerusalem). Ethyl stearate, oleate, and linoleate were below the limit of detection in >80% of all samples, whereas ethyl laurate and palmitate were detected in >50% of the samples. Ethyl myristate was the FAEE most commonly detected (>80%). All six meconium samples with confirmed maternal drinking histories tested positive for FAEE at significantly higher levels (mean, 11.08 nmol/g). The use of 2 nmol total FAEE/g meconium as the positive cutoff, when lauric and myristic acid ethyl esters were excluded, yielded the greatest sensitivity (100%) and specificity (98.4%). The authors conclude that certain FAEE are present at measurable levels in the meconium of neonates not exposed to maternal drinking, and correction is needed to allow high specificity.

Methadone: a review of drug-drug and pathophysiological interactions

Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1 -acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone’s fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

Pharmacogenetics of chronic pain management

OBJECTIVE The experience of chronic pain is one of the commonest reasons individuals seek medical attention, making the management of chronic pain a major issue in clinical practice. Drug metabolism and responses are affected by many factors, with genetic variations offering only a partial explanation of an individuals response. There is a paucity of evidence for the benefits of pharmacogenetic testing in the context of pain management. DESIGN AND METHODS We reviewed the literature between 2000 and 2013, and references cited therein, using various keywords related to pain management, pharmacology and pharmacogenetics. RESULTS Opioids continue to be the mainstay of chronic pain management. Several non-opioid based therapies, such as treatment with cannabinoids, gene therapy and epigenetic-based approaches are now available for these patients. Adjuvant therapies with antidepressants, benzodiazepines or anticonvulsants can also be useful in managing pain. Currently, laboratory monitoring of pain management patients, if performed, is largely through urine drug measurements. CONCLUSIONS Drug half-life calculations can be used as functional markers of the cumulative effect of pharmacogenetics and drug-drug interactions. Assessment of half-life and therapeutic effects may be more useful than genetic testing in preventing adverse drug reactions to pain medications, while ensuring effective analgesia. Definitive, mass spectrometry-based methods, capable of measuring parent drug and metabolite levels, are the most useful assays for this purpose. Urine drug measurements do not necessarily correlate with serum drug concentrations or therapeutic effects. Therefore, they are limited in their use in monitoring efficacy and toxicity.

Folate fortification and supplementation--are we there yet?

BACKGROUND Folic acid fortification of flour has significantly decreased the incidence of neural tube defects (NTDs). We aimed at examining whether Ontario women of child-bearing age exhibit protective levels of RBC folate. METHODS We reviewed laboratory databases on RBC folic acid from pre and post fortification years. The data included age, gender, RBC folate, hemoglobin, mean cell volume and pregnancy test. We examined a sub-set of females at ages 14-45 years who were non-anemic and normocytic. Complete protection against NTD was defined as RBC folate concentration above 900 nmol/L. RESULTS In 2006, 40% of the women of child-bearing age and 36% of pregnant women, exhibited RBC folate levels below 900 nmol/L, rendering them sub-optimally protected against NTD. CONCLUSION A considerable proportion of pregnant women is still at risk of having a baby with NTD. This should be remedied by increasing the mandatory concentrations of folic acid required in flour, complemented by public education and increasing the folic acid in prenatal supplements.

Folic Acid Transport to the Human Fetus Is Decreased in Pregnancies with Chronic Alcohol Exposure

Background During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. Methodology/Principal Findings Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal∶maternal serum folate ratio was ≤1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15±19.89 vs 45.91±20.73, p = 0.04). Conclusions/Significance Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders.

False-positive meconium test results for fatty acid ethyl esters secondary to delayed sample collection.

BACKGROUND Meconium analysis for fatty acid ethyl esters (FAEEs) is a validated method for identifying heavy prenatal ethanol (EtOH) exposure. This study investigated whether delayed sample collection can result in false-positive test results for FAEEs because of collection of samples potentially contaminated with postnatally produced stool. METHODS Serial excretions were prospectively collected from neonates born to nondrinking mothers to capture the transition from meconium to postnatal stool. These were analyzed for FAEEs using headspace-solid phase microextraction and gas chromatography-mass spectrometry. Experiments involving incubation of samples with glucose or EtOH were performed to explore a potential mechanism of FAEE elevation. RESULTS A total of 136 samples were collected from 30 neonates during their first few days of life (median of 4 samples/baby over a mean period of 68.5 hours postpartum). Although the first-collected meconium sample tested negative for FAEEs in all babies, later samples tested above the 2 nmol/g positive cutoff in 19 of 30 babies. Median time to appearance of FAEE-positive samples was 59.2 hours postpartum. In vitro experiments demonstrated that FAEE levels can be further increased in late samples (likely containing postnatal stool) after incubation with glucose, and that FAEEs are readily formed in meconium in the presence of EtOH. CONCLUSIONS Collection of samples excreted later in the postpartum period can lead to false-positive test results for FAEEs, which could be because of contamination with dietary components of postnatally produced stool and EtOH-producing microorganisms. Clinically, it is critical to collect the earliest possible excretion for determination of FAEEs to ensure that the FAEE content is representative of in utero EtOH exposure.

Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age

BACKGROUND Synthetic folic acid (0.4-1.0 mg) consumed during the periconceptional period has been shown to reduce the risk of neural tube defects. Women with poor supplement adherence or a previous pregnancy affected by a neural tube defect may need to take higher doses of folic acid (4-5 mg). However, there are limited data on the pharmacokinetics of higher folic acid doses. OBJECTIVE Our aim was to compare steady state folate concentrations in women of childbearing age who took 5 or 1.1 mg folic acid daily for 30 wk. DESIGN Forty nonpregnant women aged between 18 and 45 y, who did not take folic acid supplements, were enrolled in the study. Subjects were randomly assigned to take either 5 or 1.1 mg folic acid daily for 30 wk. Plasma and red blood cell (RBC) folate concentrations were measured at baseline and at weeks 2, 4, 6, 12, and 30. RESULTS There was no significant difference in baseline RBC folate concentrations between the 2 groups (1121 +/- 410 and 1035 +/- 273 nmol/L for the 5- and 1.1-mg folic acid groups, respectively). Significant differences in RBC folate were detected between groups at weeks 4, 6, 12, and 30. RBC folate concentrations by week 30 were 2339 +/- 782 and 1625 +/- 339 nmol/L for the 5- and 1.1-mg folic acid groups, respectively. CONCLUSION The use of 5 mg folic acid among women of childbearing age produced higher blood folate concentrations, with a faster rate of folate accumulation, compared with 1.1 mg folic acid.

Enzymes and circulating proteins as markers of alcohol abuse

The identification of alcohol abuse is an important social and clinical objective for which various biochemical procedures have been utilized, serum enzymes and circulating proteins being predominant. Tests are required to detect alcohol abuse as screening procedures in the general population as well as for the specific diagnosis of those presenting as hospital inpatients or outpatients, especially when liver disease is present or suspected. The amino-transferases are of limited value, although the mitochondrial isoenzyme of aspartate amino-transferase has been strongly advocated and is quite useful in detecting alcoholics among patients with liver disease. Gammaglutamyl transferase, by contrast, is raised in all forms of liver disease but can identify 30-50% of those consuming excessive amounts of alcohol before organic damage becomes manifest. Serum carbohydrate-deficient transferrin (CDT) is raised in many alcohol abusers without and most with liver damage, but is rarely elevated in other forms of liver disease. Haemoglobin-associated acetaldehyde, the newest biochemical index to be evaluated in alcoholics, is one of several adducts formed by the reaction of acetaldehyde with various proteins, and antibodies to these adducts may contribute, at least in part, to immunological tissue damage provoked by chronic excessive consumption of alcohol. Its assay is technically complex and it appears to be present in higher concentrations in heavy drinkers than in those who fulfill the criteria of addictive alcohol abuse. Many other markers have been introduced in the last decade but the search for a reliable index continues. CDT comes closest at the present time to matching the desired specificity, although it is of limited value in screening unselected non-hospitalized subjects.

Alcohol and Breast Feeding: Calculation of Time to Zero Level in Milk

Objective: To create a nomogram that will guide lactating women who drink socially on how to avoid neonatal exposure to ethanol through breast milk. Design: Pharmacokinetic modeling of ethanol elimination from milk based on reference values. Calculation of the time to zero alcohol in breast milk for a range of doses and body weights. Results: The elimination of alcohol and time-to-zero levels in breast milk are described in a nomogram as a function of the amount of alcohol consumed and the body weight of the woman. Conclusions: Careful planning of a breast feeding schedule, by storing milk before drinking and/or waiting for complete alcohol elimination from the breast milk, can ensure women that their babies are not exposed to any alcohol.