Ilan Matok

Folate intake and the risk of colorectal cancer: A systematic review and meta-analysis

INTRODUCTIONnFolic acid fortification and supplementation to prevent neural tube defects has led to concerns regarding increased risk of colorectal cancer. The results of existing studies have been inconclusive. The purpose was to examine the relationship between level of folate intake and the incidence of colorectal cancer.nnnMETHODSnA systematic review and meta analysis were conducted. MEDLINE, Embase, and SCOPUS were searched from inception to October 2009 with the following search terms folic acid, folate, colorectal cancer, colon neoplasms, rectal neoplasms. Observational studies in adult populations were included that defined levels of folate intake and incidence of colorectal cancer.nnnRESULTnOut of 6427 references, 27 studies met our inclusion criteria. The summary risk estimate for case control studies comparing high versus low total folate intake was 0.85 (CI 95% 0.74-0.99) with no significant heterogeneity among studies. Similarly, for cohort studies, the resulting summary risk estimate for high versus low dietary folate intake was 0.92 (CI 95% 0.81-1.05) with no significant heterogeneity. However, defining what represents a higher intake of folic acid is difficult as there is variability in the upper limit of folic acid intake used in the studies.nnnDISCUSSIONnThese results suggest that higher folate intake levels offer a reduction in one of the perceived risks associated with developing colorectal cancer. These data can serve to help reassure women planning a pregnancy to increase folic intake during the preconception period to levels sufficient to prevent neural tube defects.

Terlipressin as rescue therapy for intractable hypotension due to septic shock in children.

Intractable hypotension due to septic shock is associated with high mortality rates in critically ill children worldwide. The use of terlipressin (triglycyl-lysine-vasopressin), an analog of vasopressin with a longer duration of action, recently emerged as a treatment of hypotension not responsive to vasopressors and inotropes. This was a retrospective study set in an 18-bed pediatric critical care department in a tertiary care children’s hospital. We reviewed the files of all children with septic shock who were treated with terlipressin between January 2003 and February 2004. Fourteen children (mean age, 5.6 years; range, 4 days to 17.7 years) were treated with terlipressin in 16 septic shock episodes. Significant improvements in respiratory and hemodynamic indices were noted shortly after treatment. Mean arterial blood pressure increased significantly from 54 ± 3 to 72 ± 5 mmHg 10 min after terlipressin administration (P = 0.001). Heart rate decreased from 153.0 ± 6.5 beats/min to 138.0 ± 7.5 beats/min 12 h after treatment onset (P = 0.003). Epinephrine infusion was decreased or stopped in eight patients after terlipressin administration. Urine output increased from 1.6 ± 0.5 mL/kg/h to 4.3 ± 1.2 mL/kg/h 1 h after treatment onset (P = 0.011). PaO2 increased from 95.1 ± 12.3 mmHg to 110.1 ± 20.5 mmHg, and the oxygenation index decreased from 10.2 ± 2.2 to 9.2 ± 1.7. Terlipressin treatment of hypotension due to septic shock was successful in eight out of 16 episodes. Six of the 14 patients with poor prognosis for survival recovered. We conclude that terlipressin improves hemodynamic indices and renal function in critically ill children. Terlipressin should be considered as a rescue therapy in intractable shock not responsive to catecholamines in children.

Beneficial effects of terlipressin in prolonged pediatric cardiopulmonary resuscitation: a case series.

Objective:Arginine vasopressin was found in experimental and clinical studies to have a beneficial effect in cardiopulmonary resuscitation. The American Heart Association 2000 guidelines recommended its use for adult ventricular fibrillation arrest, and the American Heart Association 2005 guidelines noted that it may replace the first or second epinephrine dose. There is little reported experience with arginine vasopressin in cardiopulmonary resuscitation of children. Terlipressin, a long-acting analog of arginine vasopressin, has recently emerged as a treatment for vasodilatory shock in both adults and in children, but evidence of its effectiveness in the pediatric setting is sparse. The objective of this retrospective study is to describe our experience in adding terlipressin to the conventional protocol in children with cardiac arrest. Design:Retrospective case series study. Setting:An 18-bed pediatric critical care department at a university-affiliated tertiary care childrens hospital. Patients:Seven pediatric patients with asystole, aged 2 months to 5 yrs, who experienced eight episodes of refractory cardiac arrest and did not respond to conventional therapy. Interventions:Addition of terlipressin to epinephrine during cardiopulmonary resuscitation of children. Measurements and Main Results:Return of spontaneous circulation was monitored and achieved in six out of eight episodes of cardiac arrest. One patient died 12 hrs after return of spontaneous circulation, and four patients survived to discharge with no neurologic sequelae. Conclusions:The combination of terlipressin to epinephrine during cardiopulmonary resuscitation may have a beneficial effect in children with cardiac arrest. More studies on this drugs safety and efficacy in this setting are mandated.

Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock.

Objective To report the successful use of terlipressin in an 8-day-old infant for treatment of intractable hypotension caused by septic shock. Design Descriptive case report. Setting An 18-bed pediatric intensive care unit at a tertiary care children’s hospital. Patient An 8-day-old child with intractable hypotension due to septic shock after heart surgery. Interventions General supportive intensive care including mechanical ventilatory support, volume replacement, and inotropic support with dopamine 20 &mgr;g·kg−1·min−1, milrinone 0.75 &mgr;g·kg−1·min−1, and epinephrine 0.8 &mgr;g·kg−1·min−1. Measurements and Main Results Terlipressin (7 &mgr;g/kg per dose twice daily) was added as rescue therapy because of profound intractable hypotension. Shortly after the beginning of treatment, blood pressure and perfusion dramatically improved. Conclusions There is circumstantial evidence that the administration of terlipressin caused the increase in blood pressure. We suggest that terlipressin should be considered as rescue therapy when high-dose catecholamine therapy does not result in sufficient perfusion pressure. Further investigation is needed to prove terlipressin’s effectiveness and safety in infants and children.

Recombinant activated factor VII for life-threatening pulmonary hemorrhage after pediatric cardiac surgery.

Objective To report intractable life-threatening pulmonary hemorrhage after cardiac surgery in an infant who was treated successfully with recombinant activated factor VII (rFVIIa). Design Descriptive case report. Setting An 18-bed pediatric intensive care unit at a tertiary-care children’s hospital. Patient A 10-wk-old child with acute life-threatening pulmonary hemorrhage after cardiac surgery. Interventions General supportive intensive care. Measurements and Main Results Care included mechanical ventilatory support, inotropic support, and concurrent treatment with blood products (packed cells, platelet concentrates, and plasma-derived products), as well as aprotinin and desmopressin to improve hemostasis. The addition of rFVIIa resulted in complete resolution of the hemorrhage. Conclusions rFVIIa should be considered as a possible novel therapeutic approach to be used as rescue therapy for patients presenting with massive life-threatening hemorrhage progressing into hemorrhagic shock. Further controlled trials to elucidate the safety of this treatment are warranted.

A systematic review of the fetal safety of interferon alpha

BACKGROUNDnInterferon alpha (IFN) is an effective treatment for a variety of conditions including essential thrombocythemia (ET), chronic myelocytic leukemia, Hepatitis B and C. Because these conditions also occur in women of childbearing age who may become pregnant, information regarding the safety of this medication in pregnancy is essential. This systematic review attempts to summarize all published data on outcome of pregnancies exposed to IFN alpha, trying to differentiate between disease effect and drug effect.nnnMETHODSnReports on the use of IFN alpha in human pregnancy and reports on essential thrombocythemia (ET) without use of any medication in pregnancy were identified by a systematic search of the medical literature. We were able to locate only case reports of IFN alpha exposure in pregnancy, of whom 40 out of 63 were diagnosed with ET. We also collected randomly 71 cases (more cases were available in the literature) that were diagnosed with ET due to different etiologies, but who had not received any medication in pregnancy.nnnRESULTSnAmong the 63 IFN alpha exposures in pregnancy, the mean maternal age was 30±6 years and the mean full term babies weight was 3096±463 g. Mean gestational age at delivery was 37±3 weeks. There were 55 single and 4 twin pregnancies. No cases of major malformations or stillbirths were reported. There was one case of spontaneous abortion and 13 preterm deliveries (20% of all exposed cases). Among the 71 cases with untreated ET in pregnancy of different etiologies, 46 (65%) had early (within the first 12 weeks of pregnancy) or late (13-20 weeks of gestation) pregnancy loss. There were also 3 cases (4%) of stillbirth and 4 cases (5.6%) of preterm delivery. Only 18 women (25%) delivered healthy term babies.nnnCONCLUSIONSnThe results of our systematic review suggest that IFN-α does not significantly increase the risk of major malformation, miscarriage, stillbirth or preterm delivery above general population rates. It is also possible that IFN-α may have a protective effect against pregnancy loss in cases of ET.

Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis

Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms “folic acid,” “folate,” “colorectal cancer,” “methylenetetrahydrofolate reductase,” “MTHFR.” Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95–1.10) and for 677TT versus CC was 0.88 (95% CI 0.80–0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56–0.89) and the 677TT genotype 0.63 (95% CI 0.41–0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes.

Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTn* Previous studies have suggested a tendency of antifolate drugs to be associated with higher rates of neural tube defects.nnnWHAT THIS STUDY ADDSn* This study makes use of the data on abortuses, which is missed in many other studies. In this case, the abortion data were critical. * The study documents that clinicians should avoid, as much as possible, the use of folic acid antagonists during the first trimester of pregnancy, when embryogenesis takes place.nnnAIMnTo investigate the safety of folic acid antagonists during the first trimester of pregnancy in a large cohort.nnnMETHODSnComputerized databases for medications dispensed from 1998 to 2007 to women registered in Clalit HMO, Israel southern district, was linked with maternal and infant hospitalization records, and to therapeutics abortions data. The risk for adverse pregnancy outcomes of folic acid antagonists exposure was assessed by adjusting for known confounders.nnnRESULTSnEighty-four thousand, eight hundred and twenty-three infants were born and 998 therapeutic abortions took place; 571 fetuses and infants were exposed to one or more folic acid antagonists in the first trimester of pregnancy. Exposure was associated with an overall increased risk of congenital malformations [odds ratio (OR) 2.43, 95% confidence interval (CI) 1.92, 3.08], due mainly to increased risk for neural tube (adjusted OR 6.5, 95% CI 4.34, 9.15) and cardiovascular defects (OR 1.76, CI 1.05, 2.95).nnnCONCLUSIONnFirst-trimester exposure to folic acid antagonists is associated with increased risk of congenital malformations.

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.

Background: Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers (PMs), individuals who have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia. Objective: The aim was to study the relationship between CYP2D6 genotype and codeine analgesia among women recovering from c-section. Methods: Forty-five mothers prescribed codeine provided a blood sample for CYP2D6 genotyping and recorded their pain level 4 times a day for 3 days immediately after a c-section. Codeine was used on an as-needed basis; doses and times were recorded. The relationship between CYP2D6 genotype, pain scores, need for codeine, and adverse events was studied. Theoretical morphine dose, based on CYP2D6 genotype, was estimated. Results: Women at the genotypic extremes reported codeine effects consistent with their genotype: the 2 PMs of codeine reported no analgesia as a result of taking codeine, whereas 2 of the 3 UMs reported immediate pain relief from codeine but stopped taking it due to dizziness and constipation. Much larger numbers are needed to study similar correlations among extensive and intermediate metabolizers. Conclusions: In this pilot study, the extreme CYP2D6 genotypes (PMs and UMs) seemed to predict pain response and adverse events. Larger sample sizes are needed to correlate the range of genotypes with pain response.

Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy.

Objective. Nonsteroidal antiinflammatory drugs (NSAID) are among the most common medicines used by pregnant women. Published data are controversial regarding fetal safety following intrauterine exposure to NSAID. We investigated exposure to NSAID in the first trimester in a large cohort of infants and fetuses. Methods. A computerized database of medications dispensed from 1998 to 2009 to all women registered in the “Clalit” health maintenance organization in Southern Israel was linked with 2 computerized databases containing maternal and infant hospitalization records. Pregnancy terminations for medical reasons were analyzed. The following confounders were controlled for: parity, maternal age, ethnicity, maternal pregestational diabetes, maternal inflammatory disease, and year of birth or pregnancy termination. First trimester exposure to nonselective cyclooxygenase (COX) inhibitors and to selective COX-2 inhibitors as groups and to individual drugs was analyzed. Results. There were 110,783 pregnancies during the study period: 109,544 singleton births and 1239 pregnancy terminations for medical reasons. In total, 5267 mothers were exposed to NSAID during the first trimester of pregnancy: 5153 to nonselective COX inhibitors and 114 to COX-2 selective inhibitors. Exposure to NSAID in the first trimester, as groups (nonselective COX and selective COX-2 inhibitors) and as individual drugs, was not associated with an increased risk of major congenital malformations in general (adjusted OR 1.07, 95% CI 0.96−1.21 for nonselective; and adjusted OR 1.40, 95% CI 0.70−2.78, for selective COX-2 inhibitors), although an increased risk for musculoskeletal malformations was found following exposure to COX-2 selective inhibitors (adjusted OR 3.39, 95% CI 1.37−8.34). Conclusion. Intrauterine exposure to NSAID was not associated with increased risk for major congenital malformations. Further studies are needed to assess the risk for malformations after exposure to COX-2 selective inhibitors.