Folinic Acid Supplementation Research Articles

Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia.

Intellectual disability (ID) is a lifelong, debilitating condition affecting 2% to 3% Canadians (1). It is defined by deficits in cognitive functioning (IQ 2 developmental domains, eg, fine/gross motor skills, speech and interaction) (2,3). In Canada, approximately 7600 to 11,500 children are born with GDD annually (1). In the present commentary, the term ID will be used to refer to ID/GDD.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit. We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001]. The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.

Reversal of respiratory failure in both neonatal and late onset isolated remethylation disorders.

Respiratory failure is a well-documented potential presentation of inherited isolated remethylation disorders (IRDs). It appears to be a combination of both central and peripheral neuropathy and has previously often been considered to herald an irreversible neurological decline. We present three patients, one with methionine synthase (cblG) and two with methyltetrahydrofolate reductase deficiency (MTHFR). One patient with MTHFR presented in infancy, and other patients in later childhood. All three patients required intubation for respiratory failure but in all three, this was totally reversed by the initiation of medical therapy. This consisted of betaine and folinic acid supplementation in all three, methionine in two and cobalamin supplementation in two. The rate of respiratory improvement was variable, though two of the cases were successful extubated within a week of commencement of medical therapy. We document their subsequent clinical, biochemical and electrophysiological progress and review the potential pathological mechanisms underlying respiratory failure in these disorders.

Fish oil in comparison to folinic acid for protection against adverse effects of methotrexate chemotherapy on bone

Methotrexate (MTX) chemotherapy is known to cause bone loss which lacks specific preventative treatments, although clinically folinic acid is often used to reduce MTX toxicity in soft tissues. This study investigated damaging effects of MTX injections (0.75 mg/kg/day for 5 days) in rats and potential protective benefits of fish oil (0.25, 0.5, or 0.75 ml/100 g/day) in comparison to folinic acid (0.75 mg/kg) in the tibial metaphysis. MTX treatment significantly reduced height of primary spongiosa and volume of trabecular bone while reducing density of osteoblasts. Consistently, MTX reduced osteogenic differentiation but increased adipogenesis of bone marrow stromal cells, accompanied by lower mRNA expression of osteogenic transcription factors Runx2 and Osx, but an up-regulation of adipogenesis-related genes FABP4 and PPAR-γ. MTX also increased osteoclast density, bone marrow osteoclast formation, and mRNA expression of proinflammatory cytokines IL-1, IL-6, TNF-α, and RANKL/OPG ratio in bone. Fish oil (0.5 or 0.75 ml/100 g) or folinic acid supplementation preserved bone volume, osteoblast density, and osteogenic differentiation, and suppressed MTX-induced cytokine expression, osteoclastogenesis, and adipogenesis. Thus, fish oil at 0.5 ml/100 g or above is as effective as folinic acid in counteracting MTX-induced bone damage, conserving bone formation, suppressing resorption and marrow adiposity, suggesting its therapeutic potential in preventing bone loss during MTX chemotherapy.

Acute leukoencephalopathy due to pyrimethamine. An insight into methotrexate neurotoxicity?

A unique case of pyrimethamine-related stroke-like leukoencephalopathy is described. The imputability of the drug is discussed as well as the similarities with the well-known methotrexate neurotoxicity. Owing to the same mode of action of both drugs by inhibition of the enzyme dihydrofolate reductase, this case is highly suggestive of the pathogenetic role of methylation pathway blockade on myelin synthesis resulting in delayed demyelination. This complication could be avoided by a concurrent folinic acid supplementation.

PP4.6 – 1784 S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation

PP4.6 – 1784 S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly). Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Short-term folinic acid supplementation improves vascular reactivity in HIV-infected individuals: A randomized trial

ObjectiveHIV-infected individuals present a cluster of conditions that activate or injure the vascular endothelium. The administration of folates may exert beneficial effects on endothelial function in different populations at risk for cardiovascular disease. The aim of this study was to determine the effects of 4 wk of folinic acid supplementation on forearm vascular responses during reactive hyperemia in HIV-infected patients under highly active antiretroviral therapy. MethodsThis was a prospective, randomized, double-blind, placebo-controlled trial to compare the effects of 4 wk of daily ingestion of 5 mg of folinic acid (n = 15) or placebo (n = 15). Participants had to have been on antiretroviral therapy (ART) for at least 6 mo before enrollment, with undetectable viral load, and CD4 cell count >200 cells/mm3. Vascular function was evaluated with venous occlusion plethysmography at baseline and after 4 wk, for the determination of brachial artery reactive hyperemia, and after isosorbide dinitrate administration. ResultsThe groups were comparable. The mean age of patients was 45 y; there were eight women in each group. There was no difference regarding ART regimen. The supplementation of folinic acid produced a significant improvement in reactive hyperemia (from 14.9 to 21.2 mL•min•100 mL). The same was not observed in placebo group (from 15.3 to 14.6 mL•min•100 mL; group P, 0.017; time P < 0.001; interaction P < 0.001). Endothelium-independent responses remained unchanged. ConclusionsShort-term folinic acid supplementation improved vascular reactivity in HIV-infected individuals enrolled in the studied. As folate supplementation is safe and relatively inexpensive, long-term clinical trials should be conducted.

Mutation at the folate receptor 4 locus modulates gene expression profiles in the mouse uterus in response to periconceptional folate supplementation

Periconceptional supplementation of folic acid to the diet of women is considered a great success for a public health intervention. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has led to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental — for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize the response to a periconceptional regimen of supplementation with folinic acid, we performed gene expression profiling experiments on uterus tissue of pregnant mice with either wildtype alleles or targeted disruption at the folate receptor 4 locus. We observed that, depending on the genetic background, folinic acid supplementation affects expression of genes that contribute to lipid metabolism, protein synthesis, mitochondrial function, cell cycle, and cell activation. The extent of the response is strongly modulated by the genetic background. Finally, we provide evidence that folinic acid supplementation in the mutant paradigm affects histone methylation status, a potential mechanism of gene regulation in this model.

S‐adenosylmethionine and S‐adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.

Folinic Acid Supplementation in Higher Doses is Associated with Graft Rejection in Pediatric Hematopoietic Stem Cell Transplantation

Folinic acid is widely used in hematopoietic stem cell transplantation (SCT), mainly to reverse antifolate effects of such drugs as methotrexate and cotrimoxazole but also empirically to reduce toxicity and support hematopoietic recovery. However, concerns have been raised in oncohematology about reduced curative rates associated with folinic acid administration. The clinical impact of folinic acid with regard to graft-versus-host disease (GVHD), relapse, and rejection in pediatric SCT is largely undetermined. In this single-center retrospective study we investigated folinic acid administration in 87 children undergoing SCT between 2007 and 2010. Data on folinic acid dosage and duration were analyzed along with SCT parameters using univariate and multivariate statistics. Folinic acid treatment was not correlated with relapse or GVHD grades ≥ II. However, significantly higher folinic acid doses until day +21 post-SCT had been administered to patients rejecting their grafts (P < .005). In a subanalysis of nonmalignant disease and reduced-intensity conditioning (RIC) SCTs, higher total folinic acid doses were found to be associated with rejection (P = .015 and P = .026). Multivariate analysis identified RIC (odds ratio, 19.9; P < .01) and an early total folinic acid dose of >185 mg/m2 (odds ratio, 11.4; P = .03) as risk factors for graft rejection. Late folinic acid treatment had no impact on relapse, GVHD, and rejection. To conclude, administration of folinic acid in pediatric SCT seems safe in terms of relapse and GVHD. However, it should be carried out with caution, especially in patients with nonmalignant conditions and those receiving RIC to avoid graft rejection.

Clinico-Pathologic Characteristics of Patients Experiencing Severe Pyrimethamine Poisoning

Abstract 5162Pyrimethamine (Pyr) is a folate antagonist with a variety of indications. We report on the inadvertent poisoning of patients with Pyr who underwent bone marrow (BM) biopsy. There were 17 patients (median age 54); the most common presentation was gastrointestinal bleeding and pancytopenia. In January, 2012, hundreds of patients suffering from cardiac conditions were inadvertently poisoned with high dose Pyr at Punjab Institute for Cardiology in Lahore, Pakistan. There were more than 130 fatalities. A batch of isosorbide mononitrate tablets (Isotab, 20 mg) was contaminated with Pyr 50 mg. Patients estimated to have received contaminated drug for 14–21 days (cumulative dosage 2–3 grams). Patients presented with gastrointestinal bleeding, epistaxis, gum bleeding and subconjuntival ecchymosis, 5 with skin darkening, 1 with abdominal pain and vomiting, 4 had infectious complications (2 pneumonias, 2 febrile neutropenias); 1 died due to underlying cardiac disease.Laboratory analysis demonstrated (mean blood counts at admission): haemoglobin 113 g/L (61–154), white blood cells 2. 55 × 109/L (0. 7–7. 6), platelets 33 × 109/L(4–128). Clinical data provided by Jinnah and Services Hospital, Lahore, Pakistan. BM aspirates reviewed in haematology laboratory, Royal Free Hospital, London. BM samples taken in Pakistan before starting FA, within 2 weeks of stopping Pyr (stained with Romanowsky stain). Blood film, nor data on mean corpuscular volume (MCV) nor BM trephine available. All 17 had normal or hypercellular BM with severe megaloblastosis. Mean myeloid-erythroid ratio 4:1 (14. 7:1–1. 6:1). Severe megaloblastic change, giant metamyelocytes and abnormally lobulated mature granulocytes, 13 of 17 samples were left-shifted, with mild to moderate toxic change in 9. Erythroid lineage was not assessed in 5 due to quality of samples, 13 with marked nuclear:cytoplasmic dysynchrony and moderately severe dysplastic changes: ragged cytoplasm in 13, cytoplasmic bridging in 6, binucleate forms in 6, poor haemoglobinization in 3. Thrombopoiesis adequately assessed in 7, megaloblastic megakaryocytes in 2. High macrophage activity in 1 normocellular BM. Eosinophil count >5% in 6 cases.Following recognition of the cause, count recovery was prompt following discontinuation of Pyr and admistration of folinic acid (FA), Mean time to recovery of blood counts after FA 3. 89 days (2–5), and in 6 patients returned to normal before FA supplementation. FA started approximately 7 days after BM biopsy (mean time: 6, 5 days (5–10)). Mean duration of admission 10 days (3–28), 14 needed transfusion of blood components.Notable wide varietry of presentations, symptoms, depth of cytopenias and time to recovery. Part of this may be due to total dose, individual compliance with medication and pre-existing folate stores. In our series absolute dose of Pyr caused megaloblastosis, in patient group not known to be at risk of folate depletion. BM failure and megaloblastosis in absence of identifiable cause should prompt consideration of folate antagonists poisoning. Pyr can cause BM toxicity even as sole agent, independent of co-administration of other folate antagonists. Pyr poisoning, should be suspected in patients with unexplained cytopenias with megaloblastosis. FA therapy results in rapid improvement and should be offered to all patients, initially via the intravenous route. Disclosures:No relevant conflicts of interest to declare.

Prevention of Bone Growth Defects, Increased Bone Resorption and Marrow Adiposity with Folinic Acid in Rats Receiving Long-Term Methotrexate

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.

Adult-Onset Cerebral Folate Deficiency

To report new manifestations of cerebral folate deficiency, a rare metabolic autoimmune syndrome,in an adult. Case report. University teaching hospital. A 58-year-old woman with progressive memory loss and myoclonus presented for medical attention. Results of cerebral spinal fluid analysis showed low levels of tetrahydrobiopterin and 5-methyltetrahydrofolate. The patient's serum folate level was normal. Serum contained folate receptor 1 blocking and binding antibodies. The patient was treated successfully with folinic acid supplementation, and after 6 months of treatment,clinical symptoms had resolved. To our knowledge, we report the first case of adult-onset cerebral folate deficiency. Furthermore, this condition could represent a treatable form of early-onset dementia.

Novel effects of folinic acid supplementation in embryonic zebrafish, danio rerio

Although periconceptional folate supplementation has lead to a decrease in the incidence of neural tube defects (Rosano et al., 1999), studies suggest that there is also a relationship with the increased incidence of autism spectrum disorders (Beard et al., 2011). The purpose of the current study was to examine the effect of folinic acid (FA) on embryonic development. Adult zebrafish, Danio rerio, were maintained using standard procedures and breed in house. After light onset, embryos were sorted into either FA (10 mM for 24 hrs) or Control. Assessments (time to hatch, gross morphology, startle response (SR), and development of swim behavior (ST)) were made at 2, 3, and 5 DPF. FA was found to alter the timing of development, with an increase in the percentage hatched prematurely to 2 DPF. Embryos were also found to be smaller at 3 DPF (M = 3.22, SD = 0.26) than the control (M = 3.37, SD = 0.19). However, by 5 DPF the FA group had larger overall body size (FA: M = 3.67, SD = 0.17 Control: M = 3.46, SD = 0.20). While both SR and ST behaviors were similar at 3 DPF, at 5 DPF the FA had lower swim time (higher anxiety). The obtained results indicate that FA exposure had an effect on both anatomical developmental and locomotor behavior. Embryos exposed to FA hatched approximately 24 hours before the control group and showed higher level of anxiety in both the startle response and swim behavior.

Folinic Acid Supplementation in Rett Syndrome Patients Does Not Influence the Course of the Disease: A Randomized Study

Rett syndrome is a neurodevelopmental disorder in girls, related to mutations in MECP2 gene. It has been postulated that low 5-methyltetrahydrofolate (5-MTHF) levels are present in cerebrospinal fluid. Folinic acid demonstrated clinical improvement. However, because studies have produced conflicting results, we performed a randomized, double-blind crossover, long-term, follow-up study on folinic acid. Eight Rett syndrome patients received both folinic acid and placebo, for 1 year each. Measurements included plasma folate, 5-MTHF, and clinical outcome scores like Rett Syndrome Motor Behavioral Assessment, Hand Apraxia Scale, and the parental Overall Well-Being Index. In 2 patients, low 5-MTHF levels were present. Folinic acid supplementation increased cerebrospinal fluid 5-MTHF levels, but with no objective evidence of clinical improvement. The Overall Well-Being Index showed a significant difference in favor of folinic acid, not confirmed objectively. In our double-blind randomized study, folinic acid supplementation resulted in increased 5-MTHF levels, but with no objective signs of clinical improvement.

Novel effects of folinic acid and folate supplementation on locomotor development in embryonic Zebrafish, Danio rerio

Novel effects of folinic acid and folate supplementation on locomotor development in embryonic Zebrafish, Danio rerio

1FC4.6 A randomized study of folinic acid supplementation in Rett patients: no effects on the course of the disease

1FC4.6 A randomized study of folinic acid supplementation in Rett patients: no effects on the course of the disease

The effect of folinic acid supplementation on homocysteine concentrations in newborns

The incidence of cerebrovascular accidents (CVA) occurring perinatally is relatively high and aspects of the multifactorial pathophysiology remain unclear. Elevated homocysteine concentrations have been shown to be associated with an increased risk for CVA in children and even in newborns. We studied the possible homocysteine lowering effect of folinic acid in newborns. We included 37 newborns in our prospective randomized folinic acid (given as 5-formyltetrahydrofolate) intervention study from patients admitted to our neonatal intensive care unit (18 controls, 19 intervention group). We measured total homocysteine (tHcy) and plasma folate concentrations at three time points (baseline, 1 and 2 weeks after intervention). The intervention group was treated with folinic acid (70 μg/kg/day) for 2 weeks. We calculated median concentrations (25th and 75th percentiles). Median tHcy concentrations at the three time points did not differ from each other in the control group nor in the intervention group. We also could not observe different tHcy concentrations between both groups. Plasma folate concentrations increased in the intervention group (mean increase 167% (95% confidence interval (CI) -291, 625)) compared with control group (mean increase -12% (95% CI -132, 108)), P for treatment effect: 0.03. We could not demonstrate a homocysteine lowering effect of folinic acid administration in newborns. This indicates that one carbon metabolism in newborns differs form adults. Cobalamin might be a better strategy to lower tHcy concentrations in newborns.

Congenital toxoplasmosis—a report on the Danish neonatal screening programme 1999–2007

This paper reports on the national neonatal screening programme for congenital toxoplasmosis (CT) in Denmark conducted from 1999 to 2007, including background, basis for initiation of screening, methods, results, and finally reasons for the discontinuation of the screening. A nationwide screening was conducted at Statens Serum Institut, including >98% newborns, and using filter paper eluates (Guthrie card, PKU card) obtained from newborns 5-10days old. These were analysed for Toxoplasma gondii-specific antibodies (IgM), and if positive, then IgM (ISAGA). Confirmatory serology was performed on children and their mothers (IgM, IgG, IgA, dye test) where infection was suspected, and children with suspected or confirmed CT initiated a 3-month treatment regimen with pyrimethamine, sulfadiazine and folinic acid supplements. Selective cohorts were followed with regard to developmental and clinical outcome. A total of 100 children were diagnosed with CT in the screening period, and only 2 cases were detected outside of the screening programme. CT prevalence was 1.6 per 10,000 live-born infants. Follow-up studies showed new retinochoroidal lesions in affected children despite treatment. Screening was terminated August 2007, after it became apparent that no benefit of treatment could be shown. CT was evaluated using a Danish adaptation of the Uniform Screening Panel (ACMG), showing CT as an unlikely candidate for screening today. Whereas results might be comparable with other low-endemic countries with similar strains of T. gondii, neonatal screening and treatment might offer different results in regions with either high prevalence or different strains of T. gondii.