Folate, vitamin B12 and homocysteine status in an Italian blood donor population.

BACKGROUND AND AIMS: The relevance of folate, other B-vitamins and homocysteine (Hcy) for the occurrence or prevention of several diseases has induced growing interest. Unfortunately, little evidence is available regarding B-vitamin concentrations in Italy. This study evaluated in a region of middle-southern Italy, folate, vitamin B12 and Hcy concentrations and the prevalence of their ideal blood levels. The main determinants of B-vitamins and Hcy were also considered. METHODS AND RESULTS: Male and female blood donors (n=240), aged 18-66 years and living in Molise region (Italy), were enrolled in the study. They completed a brief questionnaire concerning fruit and vegetables intake, physical activity and smoking; serum and red blood cell (RBC) folate and serum vitamin B12 were measured by an immunoassay on an automated analyzer. Total Hcy was measured by high performance liquid chromatography (HPLC). Geometric means of serum folate, RBC folate and serum vitamin B12 were 10.8nmoll(-1), 426.0nmoll(-1) and 245.0pmoll(-1), respectively. Only 22.5%, 24.2% and 16.3% of blood donors showed an adequate level of serum folate, RBC folate or serum vitamin B12 respectively. When a cut-off of RBC folate ≥906nmoll(-1) was used no women of childbearing age had adequate levels. A geometric mean of 14.0µmoll(-1) was found for total Hcy, with an ideal concentration in 12.1% of subjects. Folate concentration was higher in women and non-smokers and in subjects with higher consumption of fruit and vegetable. CONCLUSION: This study shows a low-moderate B-vitamins status in middle-southern Italy, associated with an inadequate fruit and vegetable consumption. A public health strategy should be undertaken to encourage a B-vitamin-rich diet with the addition of vitamin supplements or vitamin fortified foods in population subgroups with special needs.

[Accessibility and quality to health social services in Italy for the patients with rare diseases: the opinion of associations]. / Accessibilità e qualita dei servizi socio-sanitari italiani per i pazienti con malattie rare: il parere delle associazioni.

This paper concerns the first phase of a study about the perception of social and health needs of people with rare diseases. The study was performed by the National Center for Rare Diseases at the Italian National Institute of Health (Istituto Superiore di Sanità - ISS). The project wants to be an example of collaboration between the research and the association worlds. Responsible of Associations of Patients and their relatives were asked their opinion about the accessibility and quality of important features of health and social services (accessibility and quality of diagnostic, pharmacological, psychological and rehabilitative interventions, social support, school and vocational training, information that was given to relatives). An ad hoc questionnaire was developed through focus groups. The questionnaire was completed by 108 associations (26,5% of the associations thar are recorded in the ISS database). Average scores showed satisfaction only for some variables and a negative gradient north-south was observed. The most frequent complaints were about information, quality of school and job training services and availability of psychological support. The study showed an high level of dissatisfaction with availability, quality and integration health and social services.

[Periconceptional supplementation with folic acid for the primary prevention of congenital malformations]. / La supplementazione con acido folico nel periodo periconcezionale: un intervento di prevenzione primaria delle malformazioni congenite.

Most international trials support the recommendation that all women planning or at risk of pregnancy take a daily multivitamin supplement containing folic acid, beginning one month before conception and continuing through the first trimester for primary prevention of neural tube defects and other congenital malformations. Recently an intervention project started also in Italy, in order to support and maintain the periconceptional supplementation and to evaluate the efficacy of a national preventive campaign on parents' behaviour.

Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype.

We report two patients with clinical and radiological findings of achondroplasia, who had the most common FGFR3 mutation occurring in thanatophoric dysplasia type I and hypochondroplasia, respectively. Thanatophoric dysplasia is usually a lethal condition, but the patient carrying this mutation is alive and presents a medical history similar to that of patients with achondroplasia. The events leading to such a discrepancy between genotype and phenotype are unclear. These rare cases may influence an appropriate medical and genetic counseling.

Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study.

OBJECTIVE: Because there are no studies available on the safety of venlafaxine during pregnancy, the authors' goal in this study was to determine whether venlafaxine increases the risk for major malformations. METHOD: Data on 150 women exposed to venlafaxine during pregnancy in seven pregnancy counseling centers were compared with data from studies of pregnant women who 1) received selective serotonin reuptake inhibitor antidepressants (SSRIs) (N=150) and 2) who received nonteratogenic drugs (N=150). RESULTS: Among the 150 women who were exposed to venlafaxine during pregnancy, 125 had live births, 18 had spontaneous abortions, and seven had therapeutic abortions; two of the babies had major malformations. There were no significant differences between these women and the two comparison groups on any of the measures analyzed. CONCLUSIONS: These results suggest that the use of venlafaxine during pregnancy does not increase the rates of major malformations above the baseline rate of 1%-3%.

Prospective, controlled, multicentre study of loperamide in pregnancy.

BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies. OBJECTIVES: To determine whether loperamide use in pregnancy is associated with an increased risk of major malformations. The secondary end points were rates of minor malformations, spontaneous and therapeutic abortions, and premature births, and mean birth weights. PATIENTS AND METHODS: Women counselled by five teratogen information centres on the safety and risk of loperamide in pregnancy were followed after delivery and compared with a similar group of women matched for age, smoking, alcohol and other exposures. RESULTS: One hundred and five follow-ups were completed; 89 of the women were exposed to loperamide in the first trimester of pregnancy. There were no statistically significant differences between the study group and the control group in any of the end points that were analyzed. However, of women who took loperamide throughout their pregnancy, 21 of 105 had babies who were 200 g smaller than babies in the control group. CONCLUSIONS: The results of this study suggest that the use of loperamide during pregnancy is not associated with an increased risk of major malformations.

The C677T mutation of the 5,10-methylenetetrahydrofolate reductase gene is a moderate risk factor for spina bifida in Italy.

OBJECTIVE: To estimate the risk for spina bifida associated with the common mutation C677T of the MTHFR gene in a country with a relatively low prevalence of NTDs. DESIGN: Case-control study. CASES: 203 living patients affected with spina bifida (173 myelomeningocele and 30 lipomeningocele); controls: 583 subjects (306 young adults and 277 unselected newborns) from northern and central-southern Italy. CASES: three spina bifida centres; young adult controls: DNA banks; newborn controls: regional neonatal screening centres. MAIN OUTCOME MEASURES: Prevalence of the C677T genotypes in cases and controls by place of birth; odds ratios for spina bifida and estimated attributable fraction. RESULTS: The prevalence of T/T, T/C, and C/C genotype was 16.6%, 53.7%, and 29.7% in controls and 25.6%, 43.8%, and 30.6% in cases, respectively. We found no differences between type of defect or place of birth. The odds ratio for spina bifida associated with the T/T genotype v C/C plus T/C was 1.73 (95% CI 1.15, 2.59) and the corresponding attributable fraction was 10.8%. No increased risk was found for heterozygous patients (OR=0.79, 95% CI 0.53-1.18). CONCLUSION: This study, as well as the meta-analysis we updated, shows that homozygosity for the MTHFR C677T mutation is a moderate risk factor in Europe, and even in Italy where there is a relatively low prevalence of spina bifida. The estimated attributable fraction associated with this risk factor explains only a small proportion of cases preventable by periconceptional folic acid supplementation. Thus, other genes involved in folate-homocysteine metabolism, their interaction, and the interaction between genetic and environmental factors should be investigated further.

Exploring gene-gene interactions in the etiology of neural tube defects.

The role of susceptibility genes in the etiology of birth defects is unclear, but may involve in some cases multiple alleles at multiple loci. We suggest a simple epidemiologic approach to explore gene-gene interactions, and use it to reevaluate data from a recent case-control study on the possible association of neural tube defects (NTDs) with specific mutations of two genes, 5,10-methylene-tetrahydrofolate reductase (MTHFR) and cystathionine-beta synthase (CBS). We found that, compared with the common genotype, homozygosity for the MTHFR mutation alone was associated with a two-fold increased risk for NTDs, while homozygosity for the CBS mutation alone was not a risk factor. However, homozygous individuals for the mutations at both loci had a five-fold greater risk for NTDs than those with the reference genotype. Though the original study was too small to detect statistically significant differences among most of the risk estimates, these results, if confirmed by independent and larger studies, suggest that gene-gene interaction may play a role in modulating the susceptibility to NTDs in a proportion of affected individuals. This approach, moreover, could be a valuable adjunct to the study of gene gene interactions in the etiology of human disease.

Cisapride use during human pregnancy: a prospective, controlled multicenter study.

The objective of this prospective multicenter study was to determine whether cisapride is associated with increased risk of malformations, spontaneous abortions, or decreased birthweight when used during pregnancy. Cases were paired for age, smoking, and alcohol consumption with controls exposed to nonteratogens, as well as with disease-paired controls. One hundred and twenty-nine pregnant women were exposed to cisapride during pregnancy, including 88 during the period of fetal organogenesis. There were no differences in maternal history, birthweight, gestational age at delivery, and rates of livebirths, spontaneous or therapeutic abortions, fetal distress, and major or minor malformations among groups. It is concluded that exposure to cisapride during pregnancy is not associated with a major increased risk of malformations or spontaneous abortions or with decreased birthweight.

Randomised controlled trial assessing the effectiveness of a booklet on the duration of breast feeding.

OBJECTIVE: To test the efficacy of an information booklet to increase the duration of breast feeding. RESEARCH DESIGN: Randomised design, stratifying by maternal residence and working activity. Two hundred women were recruited, 103 received the booklet and verbal counselling and 97 verbal counselling only. POPULATION: Infants observed from 15 September 1993 to 15 June 1994 in the well baby outpatient clinic of the Paediatric Institute of the Catholic University of Rome, Italy. MAIN RESULTS: No statistically significant difference was found between the two groups in the prevalence of exclusive or complementary breast feeding at 6 months of age: 48.5% and 59.2% in the intervention group, 43.7% and 51.5% in the control group. The median duration of exclusive or complementary breast feeding was 24 and 27 weeks in the treated group, 22 and 25 in the control group. CONCLUSIONS: The information booklet alone does not seem to increase the duration and the prevalence of breast feeding at 6 months of age. The use of written material with a more individualised support and more extensive use of randomised clinical trials in the evaluation of health promoting programmes is recommended.

Opitz C trigonocephaly syndrome and midline brain anomalies.

We describe a child with trigonocephaly, strabismus, upslanting palpebral fissures, nasal bridge hypoplasia, hypertrophic alveolar ridges and large gingivo-labial frenula, short neck, hip "dysplasia," equinovarus deformities, cryptorchidism, atrial septal defect ostium secundum, and severe mental retardation, findings consistent with C syndrome. The patient also had a Dandy-Walker malformation, complete callosal agenesis, and occipital meningocele. These structural defects are independent of the premature closure of the metopic suture, and confirm that midline brain anomalies are part of C syndrome. The hypothesis that the basic developmental defect in this syndrome primarily affects the midline field is supported by the concomitance of other anomalies, such as conotruncal heart defects, omphalocele, and genital anomalies.

Chorionic villus sampling and transverse digital deficiencies: evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies.

Several but not all studies indicate that chorionic villus sampling (CVS) is associated with an increased risk for transverse limb deficiencies, including digital deficiencies. It has been suggested that variations in results regarding the transverse digital deficiencies (TDDs) may be due to the use of different classification criteria. We present the combined analysis of two case-control studies, the U.S. Multistate CVS (US) study and the Italian Multicentric Birth Defects (IP-IMC) study, using two different definitions of TDDs. We compared the frequency of CVS exposure in control infants with that among those infants with any number of affected digits (any TDD), and those with all five digits of at least one limb affected (extensive TDDs). The estimated relative risk (RR) for any TDD following CVS was 10.6 (IPIMC) and 6.6 (US). For the extensive TDDs, the RR was 30.5 (IPIMC) and 10.7 (US). In both studies, extensive TDDs were less than 25% of all TDDs. Compared to all TDDs, extensive TDDs were more likely to occur after CVS performed earlier in the first trimester (before 10-11 weeks' gestation). These findings suggest a relationship between the timing of CVS and the severity of TDDs; indicate that using a restrictive definition of TDDs (all five digits affected) may limit the ability to evaluate the association between CVS and TDDs in populations in whom CVS is usually performed at or after 10 weeks' gestation; and highlight the necessity to consider gestational age in any evaluation of the relative risk for limb deficiencies associated with CVS.

Antioxidant vitamins and immunodeficiency.

On the plasma of 20 children from 1 to 6 years old with HIV infection, the following analyses were carried out: vitamin assays (vitamin E and beta-carotene), hematochemical assays, and immunoassays. From the body of our results it emerged that in the seropositive children considered, in addition to the already well-known alterations of the hematic and immune situation, there is a state of hypovitaminosis involving the most important antioxidant vitamins.

Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.

The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congénitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area.

Social and geographical inequalities in prenatal care in Italy.

The purpose of this study was to find out possible differences in prenatal diagnosis (PD) by amniocentesis or chorionic villus sampling and ultrasound examination before 16 weeks' gestation (early ultrasound examination, EUE), according to area of residence and level of education of the mothers. Data come from a multicentre study in Italy involving 43 maternity hospitals (Mercurio project) and were collected through structured interviews a few days after delivery. Study subjects were 1541 mothers of single non-malformed infants born between April 1992 and March 1994. Overall, the incidence of PD and EUE was 5.8 and 80 per cent, respectively. After adjustment for maternal age and other possible confounders, the odds ratios for PD were 2.19 (95 per cent confidence interval (CI) = 1.26-3.81) when women residing in the northern regions were compared with those residing in the southern regions, and 2.06 (95 per cent CI = 1.12-3.79) and 4.08 (95 per cent CI = 1.97-8.42) when women with medium and high levels of education were compared with those with low level. For EUE, the odds ratios were 1.77 (95 per cent CI = 1.32-2.36) and 2.88 (95 per cent CI = 1.56-5.29) when comparing women with medium and high levels of education with those with low level. No relationship was found between area of residence and EUE. These geographical and social inequalities in prenatal care in Italy should be taken into account for the organization, delivery, and evaluation of pregnancy services in the coming years.

International study of sex ratio and twinning of neural tube defects.

The goal of this study, based on information collected from eight congenital malformation registry programs around the world, was to analyze sex and twinning of affected infants and fetuses, according to type of neural tube defect (NTD) and other variables. The type of defect and its location, whether it occurred in isolated form or was associated with other malformations, population from which data were retrieved, vital status of the infant, and gestational age of the fetus/infant were considered. The material included 3,416 infants and 168 selectively aborted fetuses with anencephaly, 4,830 infants and 76 fetuses with spina bifida, and 1,022 infants and 19 fetuses with encephalocele. Less than 20% of infants with anencephaly or spina bifida and more than one-third of infants with encephalocele had associated malformations. A female excess was found among all infants with NTD but a male excess in fetuses delivered spontaneously before week 20, indicating selective male late fetal deaths. Sex ratio varied by type of NTD, vital status at birth, presence of associated malformations, and year of birth, with an increasing sex ratio for anencephaly during the 1960s and 1970s. Twinning was positively associated with NTD but the extent of this association varied with NTD type and program, while the distribution by sex type of pair of twin appeared to be similar to that of all births. Twins concordant for anencephaly or encephalocele were mainly found when the defect occurred as part of a syndrome, and only in like-sexed pairs. Twins concordant for spina bifida had the isolated form of the defect and 5 of 6 pairs were like-sexed.(ABSTRACT TRUNCATED AT 250 WORDS)

Chorionic villus sampling and transverse limb deficiencies: maternal age is not a confounder.

Advanced maternal age is a frequent indication for performing chorionic villus sampling (CVS) and it might be a confounder of the association between transverse limb deficiencies (TLD) and early CVS. We have first analyzed the maternal age-specific rates of TLD in the population monitored by the Italian Multicentric Birth Registry; then we updated a case control study controlling for maternal age. The rate of all limb deficiencies (LD) was 5.9 per 10,000 births. No trend for an excess risk for TLD or other LD with advancing maternal age was found. The relative risk for women 35 years of age and older vs. those under 35 was 0.92 (95% CI, 0.72-1.19) for any LD and 0.99 (95% CI, 0.71-1.39) for TLD. In the case control study, 11 mothers of case patients with a TLD had been exposed to CVS out of a total of 206 (5.3%), compared to 54 mothers of control patients with defects other than TLD out of a total of 12,140 (0.4%). The risk estimate for TLD associated with CVS was high in the overall analysis (OR, 12.63) and did not decrease after stratification, both in the overall sample (Mantel-Haenszel OR, 14.01) and in each gestational age stratum. Thus, advanced maternal age does not explain the association between CVS and TLD found in this study and it is unlikely to explain that observed in the several other positive studies. We recommend that any study addressing the relationship between CVS and LD should include a careful evaluation of the type of LD and the timing of CVS, and present the results for specific gestational age periods.