Ferenc Bánhidy

Folate Deficiency and Folic Acid Supplementation: The Prevention of Neural-Tube Defects and Congenital Heart Defects

Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin’s statement: “An ounce of prevention is better than a pound of care”.

Vitamin D and Pre-Eclampsia: Original Data, Systematic Review and Meta-Analysis

Background/Aims: Vitamin D may protect from pre-eclampsia through influences on immune modulation and vascular function. To evaluate the role of vitamin D in the development of pre-eclampsia, we conducted a systematic review and meta-analysis including novel data from 2 large-scale epidemiological studies. Methods: PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for prospective observational studies of association between vitamin D supplementation or status (measured by maternal 25-hydroxyvitamin D, 25(OH)D) with a subsequent risk of pre-eclampsia, or randomised controlled trials using vitamin D supplementation to prevent pre-eclampsia. The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) and the Avon Longitudinal Study of Parents and Children (ALSPAC) were included in meta-analyses with published studies. Results: Mothers receiving vitamin D supplementation earlier in pregnancy had lower odds of pre-eclampsia [pooled odds ratios (OR) 0.81 and 95% confidence interval (CI) 0.75-0.87, p = 2.4 × 10-8, 2 studies] in the meta-analysis of published studies with HCCSCA. The meta-analysis of published studies with ALSPAC suggested an association between higher serum 25(OH)D levels and a reduced risk of pre-eclampsia (pooled OR 0.52 and 95% CI 0.30-0.89, p = 0.02, 6 studies). Randomised trials of supplementation were suggestive of protective association (pooled OR 0.66 and 95% CI 0.52-0.83, p = 0.001, 4 studies). Conclusions: This study suggests that low maternal serum 25(OH)D concentrations increase pre-eclampsia risk and that vitamin D supplementation lowers this risk. The quality of evidence is insufficient to determine a causal association, which highlights the need for adequately powered clinical trials.

Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study.

OBJECTIVE Periconceptional folic acid or multivitamin supplementation is recommended for prospective pregnant women to prevent neural-tube defects. The question is whether it is worth continuing these supplementations after the first trimester of pregnancy or not. Thus the possible fetal growth promoting and/or preterm birth reducing effect of vitamin supplements in the second and mainly in the third trimester was studied. STUDY DESIGN Comparison of birth outcomes of singletons born to primiparous pregnant women with prospectively and medically recorded vitamin supplement in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996 contained 6293, 169, and 311 primiparae with folic acid alone, multivitamins and folic acid+multivitamin supplementation, respectively, and their data were compared to the data of 7319 pregnant women without folic acid and folic acid-containing multivitamin supplementation as reference. RESULTS Mean gestational age was 0.3 week longer and mean birth weight was by 37 g higher in the group of folic acid alone, than in the reference group (39.2 weeks; 3216 g). The rate of preterm births (7.6%) was significantly lower compared with the reference sample (11.8%), but the rate of low birth weight newborns did not show significant reduction. Folic acid alone in the third trimester associated with 0.6 week longer gestational age and a more significant reduction in the rate of preterm births (4.8%). CONCLUSIONS Minor increase in mean birth weight after high dose of folic acid supplementation during pregnancy would not be expected to result in too large babies; however, the significant reduction in the rate of preterm births may have great public health benefit.

Iron deficiency anemia: Pregnancy outcomes with or without iron supplementation

OBJECTIVE To estimate the efficacy of iron supplementation in anemic pregnant women on the basis of occurrence of pregnancy complications and birth outcomes. METHODS Comparison of the occurrence of medically recorded pregnancy complications and birth outcomes in pregnant women affected with medically recorded iron deficiency anemia and iron supplementation who had malformed fetuses/newborns (cases) and who delivered healthy babies (controls) in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS Of 22,843 cases with congenital abnormalities, 3242 (14.2%), while of 38,151 controls, 6358 (16.7%) had mothers with anemia. There was no higher rate of preterm births and low birth weight in the newborns of anemic pregnant women supplemented by iron. However, anemic pregnant women without iron treatment had a significantly shorter gestational age at delivery with a somewhat higher rate of preterm births but these adverse birth outcomes were prevented with iron supplementation. The rate of total and some congenital abnormalities was lower than expected and explained mainly by the healthier lifestyle and folic acid supplements. The secondary findings of the study showed a higher risk of constipation-related hemorrhoids and hypotension in anemic pregnant women with iron supplementation. CONCLUSION A higher rate of preterm birth was found in anemic pregnant women without iron treatment but this adverse birth outcome was prevented with iron supplementation. There was no higher rate of congenital abnormalities in the offspring of anemic pregnant women supplemented with iron and/or folic acid supplements.

Prevention of neural-tube defects with periconceptional folic acid, methylfolate, or multivitamins?

Background/Aims: To review the main results of intervention trials which showed the efficacy of periconceptional folic acid-containing multivitamin and folic acid supplementation in the prevention of neural-tube defects (NTD). Methods and Results: The main findings of 5 intervention trials are known: (i) the efficacy of a multivitamin containing 0.36 mg folic acid in a UK nonrandomized controlled trial resulted in an 83–91% reduction in NTD recurrence, while the results of the Hungarian (ii) randomized controlled trial and (iii) cohort-controlled trial using a multivitamin containing 0.8 mg folic acid showed 93 and 89% reductions in the first occurrence of NTD, respectively. On the other hand, (iv) another multicenter randomized controlled trial proved a 71% efficacy of 4 mg folic acid in the reduction of recurrent NTD, while (v) a public health-oriented Chinese-US trial showed a 41–79% reduction in the first occurrence of NTD depending on the incidence of NTD. Conclusions: Translational application of these findings could result in a breakthrough in the primary prevention of NTD, but so far this is not widely applied in practice. The benefits and drawbacks of 4 main possible uses of periconceptional folic acid/multivitamin supplementation, i.e. (i) dietary intake, (ii) periconceptional supplementation, (iii) flour fortification, and (iv) the recent attempt for the use of combination of oral contraceptives with 6S-5-methytetrahydrofolate (methylfolate), are discussed. Obviously, prevention of NTD is much better than the frequent elective termination of pregnancies after prenatal diagnosis of NTD fetuses.

Pregnancy complications and birth outcomes of pregnant women with urinary tract infections and related drug treatments

Maternal urinary tract infections in pregnancy showed an association with a higher rate of preterm birth in previous studies. The aim of this study was to check this relationship, and in addition to evaluate the efficacy of recent medical treatments. The population-based large control (without any defects) data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities was evaluated. Of 38,151 newborn infants, 2188 (5.7%) had mothers with urinary tract infections during pregnancy, and 90% of these maternal diseases were prospectively and medically recorded. The prevalence of pre-eclampsia and polyhydramnios showed an association with urinary tract infections during pregnancy. Pregnant women with urinary tract infections in pregnancy had a somewhat shorter gestational age (0.1 week) and a higher proportion of preterm births (10.4% vs 9.1%). These differences were correlated with the severity of urinary tract infections. However, the preterm-inducing effect of maternal urinary tract infections is preventable by some antimicrobial drugs such as ampicillin, cefalexin and cotrimoxazole. In conclusion, maternal urinary tract infections during pregnancy increase pre-eclampsia and polyhydramnios, and in addition the rate of preterm birth; however, the latter is preventable by appropriate drug treatments.

Pregnancy complications and delivery outcomes of pregnant women with influenza

Objectives. In a previous study, we showed that maternal influenza in pregnancy gives rise to an increase in some congenital abnormality groups. The aim of this study was to ascertain the relationship between influenza during pregnancy and pregnancy complications, and in addition, delivery outcomes particularly preterm birth and low birth weight in newborns. Methods. The population-based large control (without any defects) data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities, in which pregnancy complications, gestational age and birth weight are medically recorded, was evaluated. Results. Of 38 151 newborn infants, 1838 (4.8%) had mothers with influenza during pregnancy. The prevalence of pregnancy complications showed no difference between mothers with or without influenza during the study pregnancy. Mothers with influenza in pregnancy had a somewhat higher gestational age (0.1 week) and a lower proportion of preterm births (8.0% vs. 9.2%). These findings were reflected in the mean birth weight (+37 g) and lower proportion of low birth weight newborns (4.7% vs. 5.1%); these differences were explained by confounders. Conclusion. Maternal influenza during pregnancy does not increase the prevalence of pregnancy complications and unsuccessful delivery outcomes.

Population-based case-control study of the common cold during pregnancy and congenital abnormalities

The common cold is the most frequent maternal disease during pregnancy. The possible association between different congenital abnormalities and the common cold in pregnant women was evaluated in the data set of the Hungarian Case–Control Surveillance of Congenital Abnormalities between 1980 and 1996. Of 22,843 cases with congenital abnormalities, 3,827 (16.8%) had mothers with the common cold, while of 38,151 population controls without congenital abnormalities, 5,475 (14.4%) (adjusted prevalence odds ratio: POR: 1.26 with 95% CI: 1.20–1.32). Of 834 malformed controls with Down syndrome, 114 (17.3%) had mothers with the common cold (POR: 0.96 with 95% CI: 0.80–1.16). Nearly half of mothers with the common cold had secondary complications with antifever therapy. The comparison of cases with 25 congenital abnormalities and population control mothers with medically recorded common cold during the second and third months of gestation showed that five congenital abnormality groups: congenital hydrocephaly (3.6, 1.3–9.7), cleft lip±palate (2.3, 1.5–3.6), posterior cleft palate (2.3, 1.2–4.1), limb deficiencies (2.2, 1.1–4.1) and multiple CAs (2.0, 1.4–2.9) had adjusted POR 2 or more. The comparison of cases with different congenital abnormalities and malformed controls (including offspring with Down syndrome) as referent, indicated a higher prevalence of the common cold during the second and third month of gestation only in the mothers of cases with cleft lip±palate (adjusted POR: 1.7 with 95% CI: 1.2–2.5), however, congenital hydrocephaly, neural-tube defects and multiple CAs had also mothers with a somewhat higher occurrence of the common cold. The possible association between the common cold during early pregnancy and the above mentioned congenital abnormalities may be connected mainly with the indirect effect of secondary complications of maternal common cold, particularly high fever because antifever drugs were able to prevent the possible teratogenic effect of the common cold.

The effects of Remifemin® on subjective symptoms of menopause

The authors studied the changes in subjective symptoms of menopause in 2016 Hungarian women who had been treated with an isopropanol extract ofCimicifuga racemosa (black cohosh). The inclusion criteria were age (40–65 y). Kupperman index (20), and refusal or contraindication for estrogen therapy. The severity of the symptoms was evaluated at the start of the study and at the end of 4, 8, and 12 weeks of treatment. The average decrease in Kupperman index after 12 weeks of therapy was 17.64 points (P< .001). Based on the weighted symptom scores, the most favorable changes were found in hot flashes (−6.31 points), sweating (−2.86 points), insomnia (−2.27 points), and anxiety (−2.00 points) (P< .001 in each case). The isopropanol extract ofC racemosa was found to be effective in the alleviation of menopausal symptoms.

Congenital abnormalities in the offspring of pregnant women with type 1, type 2 and gestational diabetes mellitus: A population-based case-control study

To estimate the risk of structural birth defects (i.e. congenital abnormalities [CA]) in the offspring of pregnant women with type 1 (DM‐1), type 2 (DM‐2) and gestational diabetes mellitus (GDM) and to check the efficacy of recent specific care of diabetic pregnant women in the reduction of DM‐related CA. Comparison was made of the occurrence of medically recorded types of diabetes mellitus in pregnant women who had malformed fetuses/newborns (cases) and who delivered healthy babies (controls) in the population‐based Hungarian Case‐Control Surveillance System of Congenital Abnormalities, 1980–1996. In the case group, which included 22 843 offspring, there were 79 (0.35%) pregnant women with DM‐1, 77 (0.34%) pregnant women with DM‐2 and 120 (0.53%) pregnant women with GDM. The control group comprised 38 151 newborns, and 88 (0.23%), 141 (0.37%) and 229 (0.60%) pregnant women with DM‐1, DM‐2 and GDM, respectively. The total rate of cases with CA was higher only in the DM‐1 group (adjusted OR with 95% CI: 1.5, 1.1–2.0) and within four specific types/groups: isolated renal a/dysgenesis, obstructive CA of the urinary tract, cardiovascular CA and multiple CA; namely, caudal dysplasia sequence. The risk of total CA was lower in the present study compared to the risk in previous studies and the DM‐1‐related spectrum of CA was also different. There was no higher risk of total CA in the offspring of pregnant women with DM‐2 and GDM. The certain part of maternal teratogenic effect of DM‐1 is preventable with appropriate periconceptional and prenatal care of diabetic women.