Patricia Nguyen

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.

Colchicine poisoning: the dark side of an ancient drug

Introduction. Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. Methods. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included “colchicine” and “poisoning” or “overdose” or “toxicity” or “intoxication.” Toxicokinetics. Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. Therapeutic and toxic doses. The usual adult oral doses for FMF is 1.2–2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5–0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7–26 mg. Drug interactions. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Mechanisms of toxicity. Colchicines toxicity is an extension of its mechanism of action – binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. Reproductive toxicology and lactation. Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Clinical features. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10–24 h after ingestion – gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion – multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. Diagnosis. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Management. Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Conclusion. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.

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.

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.

Managing nausea and vomiting of pregnancy with pharmacological and nonpharmacological treatments.

Patients with congenital heart disease who wish to become pregnant offer a challenge to obstetricians, cardiologists and anesthetists. Although no large randomized trials exist to support the management of this emerging population, small prospective and retrospective studies provide valuable data on the likely success of pregnancy and the risks involved. Recently, there is emerging consensus on the management of this specialized group of patients, and this article aims to provide the practitioner with an overview of patient needs and the issues to be addressed. All patients with congenital heart disease wishing to consider pregnancy should be referred for specialist assessment prior to conception. Maternal risk, fetal risk and recurrence risk in the fetus should all be addressed. Most women with congenital heart disease can undergo pregnancy without significant risk. However, for some women the risk of maternal death is high, including those with: severe aortic stenosis, impaired left ventricular function, pulmonary hypertension and Marfan syndrome with dilated aortic root. All patients should be offered a detailed 20-week fetal cardiac scan and, in certain cases, prepregnancy genetic counseling. Most patients can deliver vaginally, with cesarean section reserved for obstetric indications or patients in whom straining at delivery could be potentially fatal (i.e., those with Marfan syndrome, aortic aneurysm, severe fixed left heart obstruction, or the acutely unwell mother). Antibiotic prophylaxis should be given routinely in labor to all patients in whom dental prophylaxis is indicated.Nausea and vomiting of pregnancy (NVP) affects approximately 80% of pregnant women; however, this condition is not always addressed, let alone treated appropriately. NVP can be physically debilitating and can also interfere with the socioeconomic aspects of a womans life. Some women and healthcare providers are unaware of the various NVP treatments and means of management. Lack of treatment may result from misinformation or misperception regarding NVP treatments and its safety during pregnancy. However, several studies have shown that there are effective pharmacological options that do not cause adverse effects in the mother or her unborn baby. The potential consequences of untreated NVP include substantial maternal weight loss, dehydration, hospitalization, low birthweight and depression. The following review provides a detailed description of NVP and how it can adversely affect a womans life, as well as evidence-based information on treatment strategies.

Predictors of Prenatal Multivitamin Adherence in Pregnant Women

There is no study available that has investigated determinants of prenatal multivitamin adherence among pregnant women, based on gastrointestinal (GI) adverse events. The objective of this study was to identify determinants predicting adherence to prenatal multivitamins in pregnant women who were randomized to take 2 different supplements. The authors recruited and interviewed 70 women on the importance of various factors that may have affected adherence to previous and assigned multivitamins. The different factors included GI symptoms and swallowing difficulty. The authors used a 5‐point scale to measure degree of importance. The highest scoring factors for not taking or discontinuing any previous multivitamins were fear of or experience of nausea, vomiting, and gagging. For women who never took the assigned prenatal multivitamins, the highest scoring factors contributing to that decision were fear of nausea, fear of vomiting, and health care provider advice. For women who started taking the assigned supplements, the most important factors affecting adherence were dosing regimen, health care provider advice, and mode of product distribution. Adherence to assigned prenatal multivitamins significantly correlated only with the importance of constipation in deciding to discontinue any previous multivitamins. It is concluded that predictors of adherence to recommended prenatal multivitamins during pregnancy are rooted in womens prior experiences with multivitamin use.

Pregnancy-induced changes in the long-term pharmacokinetics of 1.1 mg vs. 5 mg folic acid: A randomized clinical trial

The objective of this randomized clinical trial was to compare steady‐state gestational RBC and plasma folate concentrations in pregnant women supplementing daily with 1.1 mg (regular dose) vs. 5 mg (high dose) folic acid. Thirty‐seven pregnant women, who were not previously taking folic acid, were enrolled in this open‐label, 2‐arm, randomized clinical trial after informed consent. Participants were randomly assigned either 1.1 or 5 mg of folic acid‐containing prenatals until gestational age (g.a.) 30 weeks. Plasma and RBC folate concentrations were measured at baseline, g.a.6 weeks, g.a.12 weeks, and g.a.30 weeks using a chemiluminescent immunoassay. Results showed sustained significant increase in RBC folate in the 5 mg group between g.a.6 weeks and g.a.30 weeks (P < 0.001), and between g.a.12 weeks and g.a.30 weeks (P < 0.01), whereas a significant increase in RBC folate concentrations was observed in the 1.1 mg group only between g.a.12 weeks to g.a.30 weeks (P < 0.05). Plasma folate increased in both groups from baseline to g.a.6 weeks, and then decreased between g.a.6 weeks and g.a.30 weeks, but this was not statistically significant. Plasma concentrations at g.a.30 weeks in both groups were comparable to their respective baseline concentrations. Thus, physiological changes in pregnancy alter long‐term folate pharmacokinetics. Despite supplementation over an extended period of time, steady‐state does not seem to be achieved in either dose group within our study.