The Incidence and Prevention of Folate Deficiency in a Pregnant Clinic Population

Non-anemic women attending a public antenatal clinic were given, daily, a multivitamin tablet containing 78 mg. of elemental iron. The follow-up studies included an analysis of their diets. A total of 311 patients were included, of which one group received a supplement of 0.5 mg. folic acid and 0.005 mg. vitamin B₁₂. The incidence of megaloblastic bone marrow change in the unsupplemented group was 26% and of low blood folates approximately 50%. The incidence of megaloblastic changes was sharply reduced in the supplemented group and the blood folates were elevated to supranormal levels, indicating that the dose of folic acid used may have been above the minimal requirement. Formiminoglutamic acid (FIGLU) excretion could not be correlated with other parameters of folate deficiency. Neutrophil lobe counts did not relate to megaloblastic changes or low folate levels unless there was more than 5% hypersegmentation. The dietary intake was suboptimal in total calories, iron and food folate.     

Nutritional Anemia and Megaloblastosis in Pregnancy

Macrogranulocytic and/or erythroid megaloblastic bone marrow changes which could not be accurately predicted from the hematologic findings in the blood were present in 25% of 305 mildly to moderately anemic pregnant women attending a public antepartum clinic in Montreal. Iron deficiency was the primary cause of anemia in most instances. Serum folate activity of less than 4.1 ng./ml. and/or serum vitamin B₁₂ levels of less than 100 pg./ml. were present in 90% of the 77 patients having these bone marrow changes, whereas approximately one-third of 228 patients with normoblastic marrow had these low values. Red cell folate did not correlate as well as serum folate activity with bone marrow changes. After treatment with oral folic acid in the range of 0.2 mg. to 0.8 mg., daily, for seven to 14 days, the megaloblastic and macrogranulocytic changes in patients with low serum folate activity and normal serum vitamin B₁₂ values disappeared in 15 of 21 patients. Of five women having both low folate and vitamin B₁₂ values, three failed to respond and two showed only partial improvement after 0.4 mg. of folic acid daily, per os, for 10 days. The average diet of these anemic women was suboptimal in folate and in iron.     

Evaluation of a Single Dose of Ferric Carboxymaltose in Fatigued,Iron-Deficient Women – PREFER a Randomized,Placebo-Controlled Study

Background

Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue.

Methods

Fatigued women (Piper Fatigue Scale [PFS] score ≥5) with iron deficiency (ferritin <50 µg/L and transferrin saturation <20%, or ferritin <15 µg/L) and normal or borderline hemoglobin (≥115 g/L) were enrolled in 21 sites in Austria, Germany, Sweden and Switzerland, blinded to the study drug and randomized (computer-generated randomization sequence) to a single FCM (1000 mg iron) or saline (placebo) infusion. Primary endpoint was the proportion of patients with reduced fatigue (≥1 point decrease in PFS score from baseline to Day 56).

Results

The full analysis included 290 women (FCM 144, placebo 146). Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68, 95%CI 1.05–2.70; p = 0.03). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients (p<0.001). At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM. ‘Power of attention’ improved better in FCM-treated patients with ferritin <15 µg/L. Treatment-emergent adverse events (placebo 114, FCM 209; most frequently headache, nasopharyngitis, pyrexia and nausea) were mainly mild or moderate.

Conclusion

A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women’s health, and a normal iron status should be maintained independent of hemoglobin levels.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01110356","term_id":"NCT01110356"}}NCT01110356     

Screening for Abnormal Haemoglobins: A Pilot Study

A pilot study has been made of the implication of screening for abnormal haemoglobins in immigrant schoolchildren. An abnormality was detected by capillary blood haemoglobin electrophoresis in 8·4% of 6,835 children and a haemoglobinopathy outpatient clinic had to be established to deal with the heavy work load which resulted. The clinic was also used to determine the value of investigating the remaining members of the family once an abnormality had been detected in one child.Healthy siblings with normal haemoglobin electrophoretic patterns and normal iron and folate levels were studied to determine a normal range for haemoglobin in relation to age for adequately nourished immigrant children. The lower limit of the normal range was close to the mean value minus 1½ S.D.; by using this definition 10·3% of 280 children were subsequently found to be anaemic.Population screening of this type is desirable, but further pilot studies of patient education, genetic counselling, organization of specimen collection, data processing, and follow-up health care facilities are required before screening is extended more widely in the United Kingdom.     

Preliminary Evaluation of Four Oral Contraceptives Containing only Progestogens

One hundred and seventy-five women took part in a comparative clinical trial of four progestogen-only oral contraceptives and were followed for either a year or until treatment was discontinued. Megestrol acetate 0·25 mg. was found to be a very ineffective contraceptive, 21 out of 43 women becoming pregnant. One, three, and four pregnancies occurred during treatment with norethisterone acetate 0·3 mg., norgestrel 0·05 mg., and chlormadinone 0·5 mg., respectively, corresponding to pregnancy rates of 4, 9, and 12 per 100 woman-years of use.All three effective progestogens were very much less acceptable than modern low-dose combined oral contraceptives. Discontinuation of treatment for medical reasons (particularly menstrual disturbances) during the course of only one year affected 24% receiving norethisterone acetate, 38% receiving norgestrel, and 46% receiving chlormadinone.     

Ten-year haematological follow-up: Mortality and haematological changes

In a 10-year follow-up study of 543 men and 180 women seen in a community survey in 1958 mortality was examined in relation to the 1958 haematological data, and 91% of the survivors were re-examined. Analyses based on the 1958 haemoglobin and packed cell volume estimations suggested that those with values near the mean may subsequently have lower death rates. Higher death rates occurred in those having low serum iron levels. Comparisons of haemoglobin concentrations and of packed cell volumes in 1958 and 1968 show correlation coefficients (r) between 0·30 and 0·60 in various subgroups.     

Additive antianginal effect of verapamil in patients receiving propranolol

Ten men with stable angina pectoris not fully relieved by optimal doses of propranolol (mean 218 mg daily) were given a single oral dose of 120 mg verapamil or a placebo on alternate mornings; the order of treatment was double blind. Patients had trained in a protocol that precipitated angina after three to six minutes of exercise on a bicycle ergometer. On test days, and with continued propranolol treatment, bicycle exercise was performed just before the administration of verapamil or placebo and hourly thereafter for eight hours. Mean exercise tolerance was 118 seconds greater one hour after verapamil than one hour after placebo (p <0·001), and a significant though somewhat diminished difference of 66 seconds was still present at six hours (p <0·01). Verapamil lowered resting systolic blood pressure by 12 mm Hg (p <0·01) without changing heart rate. None of the 10 patients showed adverse effects from the verapamil-propranolol combination.The results of this study suggest that verapamil is a highly effective antianginal supplement to propranolol.     

Weight loss in obese subjects on a restricted diet given BRL 26830A,a new atypical β adrenoceptor agonist

A double blind placebo controlled study was carried out in 40 subjects newly referred for treatment for obesity to determine the effects of the new thermogenic β adrenoceptor agonist BRL 26830A. The subjects were randomised to receive either BRL 26830A, 200 mg daily for two weeks then 400 mg daily, or placebo for 18 weeks, and all were instructed to follow a 3·35 MJ diet that was low in fat and high in fibre. Weight loss was 15·4 (SD 6·6) kg in subjects given BRL 26830A compared with 10·0 (5·9) kg in those given placebo (p=0·02). The relative weight loss was 0·93 (0·39)% a week with BRL 26830A and 0·61 (0·38)% with placebo (p=0·02). Urinary excretion of nitrogen was similar in both groups, whereas measurements of skinfold thickness indicated a 4·1 kg difference in the amount of fat lost, suggesting that weight loss with BRL 26830A was mainly from adipose and not lean tissue. BRL 26830A had no effect on resting pulse rate or pressor effects on either diastolic or systolic blood pressure. No significant differences were found between the two groups in serum cholesterol concentration, percentage of high density lipoprotein cholesterol, plasma concentrations of glucose and insulin, the ratio of glucose to insulin, serum concentrations of triiodothyronine and thyroxine, and creatinine clearance. Short term administration of BRL 26830A to six subjects who had taken the drug for 18 weeks showed that the expenditure of energy increased by 11·6% during the second hour after administration, which suggests that BRL 26830A may enhance weight loss thermogenically.BRL 26830A may be a useful drug in the treatment of obesity.     

Folic Acid in Folate-deficient Patients with Epilepsy

A double-blind trial using folic acid 15 mg. daily and identical placebo was carried out in 51 epileptic patients having a serum folate level below 3·6 ng./ml. Treatment was for a minimum of six months and in 41 patients was for more than one year. There were no significant changes in the frequency of seizures, behaviour, and personality, or in a number of cognitive functions.     

Serum and Urinary Folate in Liver Disease

During the active phase of viral hepatitis urinary folate loss was found to be 8·0 to 48·3 (mean 31·1) μg./day, compared with a normal urinary folate excretion of 0·1 to 18·0 (mean 9·5) μg./day. In cirrhosis and cardiac failure with congestive hepatomegaly the corresponding values were 25·8 to 55·0 (mean 35·7) μg./day and 2·5 to 61·6 (mean 26·9) μg./day, respectively. Urinary folate loss may be a significant factor in the aetiology of folate deficiency of chronic liver disease, particularly when dietary intake is poor.After prolonged dialysis in Visking casing urinary folate was almost totally dialysable, but an appreciable fraction of serum folate was not, even after 72 hours. The dialysable (free) folate fraction of serum and urine disappeared maximally during the first six hours'' dialysis, and was virtually cleared after 24 hours'' dialysis; clearance curves in normal individuals and in liver disease were comparable. The non-dialysable serum folate fraction was of similar magnitude in all subjects studied, in spite of marked variation in total folate, and probably represented protein-bound folate.     

Anaemia of pregnancy: the changing postwar pattern.

A popluation survey covering over a quarter of a century has shown clearly the improvement in haemoglobin levels in women attending antenatal clinics at the Glasgow Royal Maternity Hospital. Various influences have helped to bring this about, foremost among these being routine early prophylaxis with combined iron and folate supplements. Indeed, a time-space relationship between changes in prophylactic therapy, rates of improvement, and the incidence of megaloblastic anaemia can be shown. The women at risk are still essentially the same except for a new group of young, unmarried girls, who must be watched. In our view the withdrawal of routine prophylactic therapy in pregnancy would be retrograde step.     

Prophylactic iron supplementation in pregnant women in Norway

In the present study 67 non-anaemic women were randomly allocated to either 100 mg or 15 mg iron daily at about the 10. week of pregnancy. At about week 18, 30 and 36 of pregnancy, as well as 6 weeks after delivery, hemoglobin and the serum concentrations of ferritin, vitamin B12, folates, Zn, Cu and Se were monitored. Dietary allowances of other minerals and vitamins are also increased in pregnancy, and the 15 mg iron tablet was enriched with Zn (10 mg), Cu (2 mg), Se (50 microg), vitamin B12 (3 microg), and folate (0.1 mg). Neither ferritin, nor Cu, Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy. Ferritin and Zn appeared to decrease approximately parallel to the hemodilution, whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy. Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate (around 15 micromol/L) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation, whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily. Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin. It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy.     

Metabolic Effects of Oestrogen Treatment in Patients with Carcinoma of Prostate: A Comparison of Stilboestrol and Conjugated Equine Oestrogens

Serum cholesterol and triglyceride levels were estimated and oral glucose tolerance tests performed on 16 patients with carcinoma of the prostate before treatment and while receiving stilboestrol in doses of 1 mg, 7·5 mg, and 15 mg daily and conjugated equine oestrogens (Premarin) 15 mg daily. Serum triglyceride levels were greater than 170 mg/100 ml in nearly all the patients while receiving Premarin or stilboestrol 7·5 mg and 15 mg daily. In six out of 10 patients who were given stilboestrol 1 mg daily the serum triglycerides remained within the normal range. No significant effects on serum cholesterol levels or glucose tolerance tests were observed with the various oestrogen regimens. The results support previous suggestions that a daily dose of 1 mg of stilboestrol should be regularly used in the treatment of carcinoma of the prostate.     

Double-blind Evaluation of Verapamil,Propranolol, and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels—namely, 80 mg thrice daily and 120 mg thrice daily—propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0·01) and in the prolongation of exercise test (P < 0·05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0·01).     

Folate Status Throughout Pregnancy and in Postpartum Period

The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum. In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery, at which time over half were in the deficient range. There appears to be a delay before this test reflects the current folate status when this changes rapidly. In those receiving iron plus 330 μg. of folic acid a day the results at this time were close to those at the beginning of pregnancy. Subnormal whole blood folate, red cell folate, and serum folate values occurred close to term in patients receiving iron alone, but were not found in those also receiving folic acid. Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy.The observations are consistent with the previous suggestion that 300 μg. of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium.     

A Randomized Controlled Trial of the Efficacy and Safety of CCX282-B,an Orally-Administered Blocker of Chemokine Receptor CCR9, for Patients with Crohn’s Disease

CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00306215","term_id":"NCT00306215"}}NCT00306215.     

Impact of Chronodisruption during Primate Pregnancy on the Maternal and Newborn Temperature Rhythms

Disruption of the maternal environment during pregnancy is a key contributor to offspring diseases that develop in adult life. To explore the impact of chronodisruption during pregnancy in primates, we exposed pregnant capuchin monkeys to constant light (eliminating the maternal melatonin rhythm) from the last third of gestation to term. Maternal temperature and activity circadian rhythms were assessed as well as the newborn temperature rhythm. Additionally we studied the effect of daily maternal melatonin replacement during pregnancy on these rhythms. Ten pregnant capuchin monkeys were exposed to constant light from 60% of gestation to term. Five received a daily oral dose of melatonin (250 µg kg/body weight) at 1800 h (LL+Mel) and the other five a placebo (LL). Six additional pregnant females were maintained in a 14∶10 light:dark cycles and their newborns were used as controls (LD). Rhythms were recorded 96 h before delivery in the mother and at 4–6 days of age in the newborn. Exposure to constant light had no effect on the maternal body temperature rhythm however it delayed the acrophase of the activity rhythm. Neither rhythm was affected by melatonin replacement. In contrast, maternal exposure to constant light affected the newborn body temperature rhythm. This rhythm was entrained in control newborns whereas LL newborns showed a random distribution of the acrophases over 24-h. In addition, mean temperature was decreased (34.0±0.6 vs 36.1±0.2°C, in LL and control, respectively P<0.05). Maternal melatonin replacement during pregnancy re-synchronized the acrophases and restored mean temperature to the values in control newborns. Our findings demonstrate that prenatal melatonin is a Zeitgeber for the newborn temperature rhythm and supports normal body temperature maintenance. Altogether these prenatal melatonin effects highlight the physiological importance of the maternal melatonin rhythm during pregnancy for the newborn primate.     

Thalassaemia,iron, and pregnancy.

Haematological values of 35 pregnant women with beta-thalassaemia trait were followed during pregnancy. The discriminant function, calculated from haematological indices, was of no value in diagnosing beta-thalassaemia trait during pregnancy. Initially patients were given iron supplements only if the serum iron and total iron binding capacity levels indicated iron deficiency, but bone marrow biopsies performed in the first 22 patients at 32 weeks indicated deficient iron stores. These patients were therefore given iron irrespective of their serum iron level. All subsequent patients with beta-thalassaemia were also put on iron routinely at booking. Retrospectively the patients were divided into two groups. Patients in group 1 (18 patients) had received iron for less than 12 weeks, and their haemoglobin levels fell significantly during pregnancy (P less than 0-001). Haemoglobin levels in 16 patients who had received iron for more than 12 weeks (group 2), however, did not fall significantly during pregnancy (P less than 0-6). It is suggested (contrary to common practice) that patients with beta-thalassaemia trait should be given iron supplements during pregnancy. Serum folate and vitamin B12 levels did not change significantly in these patients and there was no increase in the incidence of maternal or fetal complications.