Association between the thrombophilic polymorphisms MTHFR C677T, Factor V Leiden, and prothrombin G20210A and recurrent miscarriage in Brazilian women.

Some cases of recurrent first trimester miscarriage have a thrombotic etiology. The aim of this study was to investigate the prevalence of the most common thrombophilic mutations - factor V (FV) Leiden G1691A (FVL), prothrombin (FII) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T - in women with recurrent miscarriages. In this case-control study, we included 137 women with two or more consecutive first-trimester miscarriages (£12 weeks of gestation) and 100 healthy women with no history of pregnancy loss, and with at least one living child. DNA was extracted from the patient samples, and the relevant genes (FVL, FII, and MTHFR) were amplified by PCR, followed by restriction fragment length polymorphism, to assess the polymorphisms in these genes. The allelic frequencies of polymorphisms were not significantly different between the case and control groups. Polymorphisms in the MTHFR, FVL, and FII genes were not associated with recurrent miscarriage during the first trimester of pregnancy in Brazilian women (P = 0.479; P = 0.491 and P = 0.107, respectively). However, the etiologic identification of genetic factors is important for genetic counseling.

p53 signaling pathway polymorphisms associated to recurrent pregnancy loss.

The p53 protein is known for performing essential functions in the maintenance of genomic stability in somatic cells and prevention of tumor formation. Studies of the p53 signaling pathway have suggested associations between some polymorphisms and infertility, post-in vitro fertilization implantation failure and recurrent abortions. The TP53 Pro72Arg polymorphism has been implicated as a risk factor for recurrent pregnancy loss (RPL); however, the association is controversial. In this study, our objective was to evaluate selected polymorphisms in genes of the p53 signalling pathway [TP53 c.215G>C (Pro72Arg), MDM2 c.14+309T>G (SNP309) and LIF c.1414T>G in the region 3' UTR] and determine their effect as risk factors for RPL. In a case-control study, we investigated 120 women with two or more pregnancy losses and 143 fertile control women reporting at least two live births and no history of pregnancy loss. When analyzed separately, the allele and genotype distributions of the polymorphisms in the two groups were not different. However, in a multivariate analysis adjusted for alcohol consumption, smoking, ethnicity, and number of pregnancies, the interaction between the genotypes TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) showed to be associated to RPL, increasing the risk for this condition (OR = 2.58, 95% CI: 1.31-5.07, p = 0.006). In conclusion, our study indicates that the combination of TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) genotypes may be a risk factor for RPL.

Severe fetal hydrocephalus with and without neural tube defect: a comparative study.

OBJECTIVE: To describe the main perinatal and 1-year outcomes in babies with a prenatal ultrasonographic diagnosis of severe hydrocephalus according to the presence or absence of a neural tube defect (NTD) in a country where abortion is illegal. METHOD: The study population consisted of cases referred to and delivered at Hospital de Clínicas de Porto Alegre, diagnosed between January 1993 and December 2001. The diagnosis of severe hydrocephalus was based on a lateral ventricular atrium diameter > or =15 mm in at least one hemisphere. RESULTS: Sixty cases were ascertained: 28 with NTD (group 1) and 32 without NTD (group 2). The groups were similar in terms of maternal and child variables at birth and hospitalization days during the 1st year of life. The mortality (including intrauterine deaths and deaths of babies with malformations incompatible with life that characterize a very poor prognosis) until 1 year of age was 36% in group 1 and 59% in group 2 (p = 0.077). The rate of cardiac malformations was higher in the group without NTD (p = 0.015). The length of hospital stay after birth (1st admission) was significantly higher in the group with NTD (p = 0.007). CONCLUSIONS: The morbidity was higher in the group with NTD, possibly due to the higher number of surgical interventions in the central nervous system. However, the mortality was higher in the group without NTD, possibly due to the presence of other associated malformations, especially congenital heart disease. Further studies should focus on neurological function and quality of life of the children and their families at the end of the 1st year and after 2 or 6 years of age.

Assessment of fetal risk associated with exposure to cancer chemotherapy during pregnancy: a multicenter study

The objective of the present study was to evaluate and quantify fetal risks involved in the administration of cancer chemotherapy during gestation, as well as to assess the long-term effects on the exposed children. In this retrospective, cohort study, we reviewed the records of women aged 15 to 45 years with a diagnosis of malignancy or benign tumors with malignant behavior at three reference services in the State of Rio Grande do Sul, Brazil, from 1990 to 1997. All patients with a diagnosis of pregnancy at any time during the course of the disease were selected, regardless of whether or not they received specific medication. Fetal outcomes of 14 pregnancies with chemotherapy exposure were compared to that of 15 control pregnancies in which these drugs were not used. Long-term follow-up of the exposed children was carried out. Fisher's exact test was used to compare the groups. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. We found an increased rate of prematurity (6/8 vs 2/10; RR: 3.75; CI: 1.02-13.8; P = 0.03) in the exposed group. There was a trend to an increased fetal death rate (4/12 vs 0/10; P = 0.07) in the group exposed to chemotherapy. No malformations were detected in any child, which can be related to our small sample size as well as to the fact that most exposures occurred after the first trimester of pregnancy. Other larger, controlled studies are needed to establish the actual risk related to cancer chemotherapy during pregnancy

Assessment of fetal risk associated with exposure to cancer chemotherapy during pregnancy: a multicenter study.

The objective of the present study was to evaluate and quantify fetal risks involved in the administration of cancer chemotherapy during gestation, as well as to assess the long-term effects on the exposed children. In this retrospective, cohort study, we reviewed the records of women aged 15 to 45 years with a diagnosis of malignancy or benign tumors with malignant behavior at three reference services in the State of Rio Grande do Sul, Brazil, from 1990 to 1997. All patients with a diagnosis of pregnancy at any time during the course of the disease were selected, regardless of whether or not they received specific medication. Fetal outcomes of 14 pregnancies with chemotherapy exposure were compared to that of 15 control pregnancies in which these drugs were not used. Long-term follow-up of the exposed children was carried out. Fisher's exact test was used to compare the groups. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. We found an increased rate of prematurity (6/8 vs 2/10; RR: 3.75; CI: 1.02-13.8; P = 0.03) in the exposed group. There was a trend to an increased fetal death rate (4/12 vs 0/10; P = 0.07) in the group exposed to chemotherapy. No malformations were detected in any child, which can be related to our small sample size as well as to the fact that most exposures occurred after the first trimester of pregnancy. Other larger, controlled studies are needed to establish the actual risk related to cancer chemotherapy during pregnancy.

[Organic aciduria: diagnosis in high-risk Brazilian patients] / Acidúrias orgânicas: diagnóstico em pacientes de alto risco no Brasil.

OBJECTIVE: To determine the prevalence of organic acidurias in high-risk Brazilian patients. METHODS: Laboratory techniques for the detection and quantification of organic acids by gas chromatography/mass spectrometry were implemented in Porto Alegre, Brazil. We investigated 1,480 patients suspected of organic aciduria between January 1994 and June 2000. RESULTS: Seventy three (4.9%) cases of organic acidemias (acidurias) were diagnosed among the tested individuals. In most of these patients, prompt therapy resulted in rapid symptom improvement; these results are completely different from our previous cases diagnosed in other laboratories in Europe and the United States, where several patients died before any measures could be taken. CONCLUSIONS: These results demonstrate the importance of diagnosing organic acidurias in loco even in developing countries, in spite of the extra costs involved.

[Application of a clinical and laboratory protocol for the investigation of inborn errors of metabolism among critically ill children] / Aplicação de um protocolo clínico-laboratorial para identificação de erros inatos do metabolismo em crianças gravemente enfermas.

OBJECTIVE: The aim of this work was to evaluate a protocol for investigation of Inborn Errors of Metabolism (IEM) in children who are acutely ill.METHODS: Forty six children with clinical suspicion of a metabolic disorder were studied during 2 years. They were selected through request for investigation of IEM from Pediatrics or Neonatal Intensive Care Units located in the metropolitan area of Porto Alegre. Criteria for inclusion were presence of one or more of the following clinical alterations, without defined etiology: Metabolic acidosis, electrolyte disturbances, hypoglycemia, seizures, lethargy, liver disfunction, family history suggestive of IEM. The protocol included clinical evaluation, compulsory tests (performed in all patients) and optional tests (performed selectively according to the results from the first tests or through specific clinical hypothesis).RESULTS: Six cases of IEM were identified: galactosemia, non-ketotic hyperglycinaemia, propionic acidemia, isovaleric acidemia, 3-hydroxy-3-methylglutaric acidemia and deficiency of 3-ketothiolase deficiency.CONCLUSIONS: The frequency of organic acidurias in this group was 4/46 (8.7%), which justifies the inclusion of organic acids analysis among the first line exams in acutely and severely ill children with undefined etiology. The relatively high frequency of IEM (6/46 or 13%), which is comparable to the ones observed in other studies within high risk groups, indicates that the protocol suggested is efficient and justifies the systematic investigation of IEM in not explained critically ill children.

[Alpha-fetoprotein: normal values in amniotic fluid between 14 and 21 weeks]. / Alfafetoproteína: valores normais no líquido amniótico entre 14 e 21 semanas.

BACKGROUND: To define the normal values of amniotic fluid alphafetoprotein in pregnant women, whose gestational ages range from 14 to 21 weeks, in the Hospital de Clínicas de Porto Alegre. MATERIAL AND METHOD: One hundred thirty seven women with indication for amniocentesis were studied. The alphafetoprotein was measured in all samples using enzyme immunoassay. One hundred and nine normal pregnancies were selected. All of these fetuses had normal karyotype and had no malformation. They were not twins and their amniotic fluid samples were not bloody. These samples were divided by their gestational ages. Then the medians of the alphafetoprotein values and their multiples were calculated. RESULTS: The medians of alphafetoprotein (KUI/ml) for each gestational age were as follows: 14 weeks: 16.32; 15 weeks: 14.36; 16 weeks: 13.43; 17 weeks: 10.93; 18 weeks: 8.22; 19 weeks: 7.35; 20 weeks: 5.62; 21 weeks: 4.47. CONCLUSION: The establishment of alphafetoprotein normal values in our service allows us to use this assay for patients at risk of neural tube defects. It also makes possible to analyze samples sent for cytogenetic or metabolic studies, in order to identify elevated levels of alphafetoprotein, so that these fetuses could have a more detailed sonography study to look for malformations.

Alfafetoproteína: valores normais no líquido amniótico entre 14 e 21 semanas / Alphafetoproteín: amniotic fluid normal values between 14 and 21 weeks

Objetivo. Definir uma curva de normalidade dos valores de alfafetoproteína (AFP) no líquido amniótico em gestantes entre 14 e 21 semanas de gravidez no Hospital de Clínicas de Porto Alegre. Materiais e Métodos. Nas 137 mulheres que procuraram o diagnóstico pré-natal e tiveram indicaçao de coleta de líquido amniótico. A alfafetroproteína foi dosada em todas as amostras por enzima imunoensaio. Foram selecionadas 109 gestaçoes normais (sem malformaçoes, cariótipo normal, nao-gemelares) e cujas amostras de líquido amniótico nao eram sanguinolentas. Essas foram divididas quanto à idade gestacional e tiveram calculadas as medianas dos valores de AFP e seus múltiplos. Resultados. As medianas da alfafetoproteína (KUI/ml) para cada idade gestacional foram as seguintes: 14 semanas: 16,32; 15 semanas: 14,36; 16 semanas: 13,43; 17 semanas: 10,93; 18 semanas: 8,22; 19 semanas: 7,35; 20 semanas: 5,62; 21 semanas: 4,47. Conclusao. O estabelecimento de uma curva normal de AFP em nosso serviço permite a utilizaçao deste exame para pacientes em risco de defeitos de fechamento de tubo neural. Permite também que sejam analisadas amostras enviadas para estudos citogenéticos ou metabólicos de maneira a identificar fetos com níveis elevados de AFP que necessitarao de estudos ultrasonográficos mais detalhados pela possibilidade de defeitos morfológicos.

[Management of a case of maple syrup urine disease--the use of gluco-insulinotherapy]. / Uma experiência terapêutica no manejo da doença da urina do xarope do bordo.

We report here the treatment and poor outcome of a case of Maple Syrup Urine Disease with late diagnosis and retrieval (2 and 5 months, respectively). As the proband had quite high levels of plasmatic leucine (1956 micromol/L for a normal upper limit of 77), we started immediately with a gluco-insulin therapy to produce anabolism in the infant. When leucine has fallen to 275.3 micromol/L, we instituted feeding with branched chain amino acid-free protein and high energy from carbohydrates. After reviewing briefly the clinical, biochemical and therapeutic aspects of this disorder, we comment on the great difficulties of making early diagnosis and of obtaining the specific dietetic formulas to Maple Syrup Urine Disease, in Brazil.

Biochemical investigation of a Brazilian patient with a defect in mitochondrial acetoacetylcoenzyme-A thiolase.

A case report of 3-ketothiolase deficiency due to a defect of mitochondrial acetoacetyl-CoA thiolase protein in a Brazilian boy and its biochemical investigation is presented. The child had moderate generalized hypotonia, EEG alterations and crises of metabolic acidosis following infections. Hypotonia and EEG abnormalities disappeared with a low protein diet, and physical and mental development are normal. Urinary organic acid excretion was typical of 3-ketothiolase deficiency, showing consistently high levels of 2-methyl-3-hydroxybutyric acid and tiglylglycine. Activation of acetoacetyl-CoA thiolase activity by potassium (K) ion in cultured fibroblasts was not observed, demonstrating the lack of activity of mitochondrial acetoacetyl-CoA thiolase. In addition, the signal for the mitochondrial acetoacetyl-CoA thiolase protein was undetectable in the immunoblot analysis. In the pulse-chase experiments, the signal for mitochondrial acetoacetyl-CoA thiolase was detected after a 1-h pulse but not after a 24-h chase. These results indicate that the deficiency was caused by an unstable mitochondrial acetoacetyl-CoA thiolase protein.