Eva Bermejo

Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase ( MTHFR ): findings from over 7000 newborns from 16 areas world wide

Since its biochemical characterisation in 19911 and its genetic identification in 1995,2 677C>T allele (T allele) of the 5,10 methylenetetrahydrofolate reductase ( MTHFR ) gene has been a focus of increasing interest from researchers world wide. The expanding spectrum of common conditions linked with the 677C>T allele now includes certain adverse birth outcomes (including birth defects), pregnancy complications, cancers, adult cardiovascular diseases, and psychiatric disorders.3–8 Although several of these associations remain unconfirmed or controversial,4 their scope is such that it becomes of interest to explore the geographical and ethnic distribution of the allele and associated genotypes.9 Accurate information on such distribution can contribute to studies of gene-disease associations (by providing reference population data) and population genetics (by highlighting geographical and ethnic variations suggestive of evolutionary pressures),10 as well as help to evaluate health impact (by allowing estimates of population attributable fraction). Current population data, however, show gaps and even for some ethnic groups or large geographical areas (for example, China) few data are available.3 Our aim was to supplement the available data by collecting a large and diverse sample of newborns from different geographical areas and ethnic groups, and to examine international variations in the distribution of the 677C>T allele. We present findings relating to more than 7000 newborns from 16 areas around the world. The study was conducted under the auspices of the International Clearinghouse for Birth Defect Monitoring Systems (ICBDMS) and was coordinated through its head office, the International Center on Birth Defects (ICBD). ### Sample selection Participating programmes, in consultation with the coordinating group, identified a population sampling approach that would be simple yet minimise sampling bias with respect to the MTHFR genotype. We made an explicit attempt to sample systematically the newborn population. Details of each programme’s approach are listed below, and further …

Gastroschisis and associated defects: An international study†

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non‐isolated cases. Case‐by‐case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non‐isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio‐vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb‐body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non‐syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non‐isolated cases and a thorough case‐by‐case review.

Pre‐gestational maternal body mass index predicts an increased risk of congenital malformations in infants of mothers with gestational diabetes

Aims  The aim of the present study was to identify characteristics in women diagnosed with gestational diabetes mellitus (GDM) that could be predictive of congenital malformations in their infants.

Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes : Is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with down syndrome?

This study was aimed at analyzing the effect of mutations in three non‐synonymous SNP genes (677C > T and 1298A > C of the methylenetetrahydrofolate reductase (MTHFR) gene, and 66A > G in the MTRR gene) on total plasmatic homocysteine (Hcy), in 91 mothers of Down syndrome (DS) infants and 90 control mothers. The comparison of both groups of mothers is a new way to determine if those mutations and their interactions increase the risk for DS. Material came from the case‐control network of the Spanish Collaborative Study of Congenital Malformations (ECEMC).

Epidemiological analysis of rare polydactylies

This work includes all cases with extra digits (polydactyly) registered from a birth sample of over four million births aggregated from two comparable birth series: the Latin-American Collaborative Study of Congenital Malformations: ECLAMC (3,128,957 live and still births from the 1967 to 1993 period), and the Spanish Collaborative Study of Congenital Malformations: ECEMC (1,093,865 livebirths from April 1976 to September 1993, and 7,271 stillbirths from January 1980 to September 1993). All but 2 of 6,912 registered polydactyly cases fit well into one of the following 11 preestablished polydactyly types (observed number of cases in parentheses): Postaxial hexadactyly (5,345), Preaxial-I hexadactyly (1,018), Seven or more digits (57), synpolydactyly (15), crossed polydactyly (45), 1st digit triphalangism (33), 2nd digit duplication (39), 3rd digit duplication (18), 4th digit duplication (22), Haas polysyndactyly (3), and high degree of duplication (4). The birth prevalence rates observed in both series were similar except for postaxial polydactyly, which was more frequent in the ECLAMC (150.2/100,000) than in the ECEMC (67.4/100,000), as expected due to the higher African Black ethnic extraction of the South-American than of the Spanish populations. This similar frequency for the rare polydactylies (5.4 per 100,000 in South America and 5.7 in Spain), and for each one of the 9 categories, suggests that the values reported here are valid for most populations. The rare polydactylies are frequently syndromal: one third of them (77/236) were found in association with other congenital anomalies, 11.0% (26/236) in MCA cases and 21.6% (51/236) in recognized syndromes.

Preferential associations between oral clefts and other major congenital anomalies

Objectives: To identify preferential associations between oral clefts (CL  =  cleft lip only, CLP  =  cleft lip with cleft palate, CP  =  cleft palate) and nonoral cleft anomalies, to interpret them on clinical grounds, and, based on the patterns of associated defects, to establish whether CL and CLP are different conditions. Design And Settings: Included were 1416 cleft cases (CL  =  131, CLP  =  565, CP  =  720), among 8304 live- and stillborn infants with multiple congenital anomalies, from 6,559,028 births reported to the International Clearinghouse for Birth Defects Surveillance and Research by 15 registries between 1994 and 2004. Rates of associated anomalies were established, and multinomial logistic regressions applied to identify significant associations. Results: Positive associations with clefts were observed for only a few defects, among which anencephaly, encephaloceles, club feet, and ear anomalies were the most outstanding. Anomalies negatively associated with clefts included congenital heart defects, VATER complex (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia), and spina bifida. Conclusion: The strong association between all types of clefts and anencephaly seems to be attributable to cases with disruptions; the association between CP and club feet seems to be attributable to conditions with fetal akinesia. Some negative associations may depend on methodologic factors, while others, such as clefts with VATER components or clefts with spina bifida, may depend on biological factors. The different patterns of defects associated with CL and CLP, indicating different underlying mechanisms, suggest that CL and CLP reflect more than just variable degrees of severity, and that distinct pathways might be involved.

Does single umbilical artery (SUA) predict any type of congenital defect? Clinical-epidemiological analysis of a large consecutive series of malformed infants.

Most studies associating different types of malformations with the presence of a single umbilical artery (SUA) are based on small and selected series. Here, we present the results of a study aimed at identifying the most frequent, and the most specific anomalies related to SUA. We analyzed 19,909 consecutive newborn infants with congenital malformations, from the Spanish Collaborative Study of Congenital Malformations (ECEMC). To estimate the specificity of the relationship of different congenital defects with SUA, we calculated their relative frequencies (RF) by dividing their frequency in infants with SUA by the corresponding frequency in newborn infants without SUA. Using the different levels of the ECEMC coding system, we calculated the RFs in three steps: (a) a group of individual congenital defects, (b) different groups of malformed infants, and (c) each individual malformation by its clinical presentation in some of the studied groups of malformed infants. The defects most specifically associated with SUA were bilateral renal agenesis and imperforate anus, followed by unilateral renal agenesis, and vertebral defects, the RF of which indicated that they were between 7.99 and 9.93 times more frequent among malformed infants with SUA than among malformed infants without SUA. However, these defects were not as frequent in the group of infants with SUA, as cardiovascular anomalies. Regarding the association of SUA in the groups of malformed infants, the most specific groups were body stalk defects and sirenomelia. Finally, we analyzed the association of the individual defects by different groups of malformed infants in order to identify if the individual defects are associated with SUA in any type of clinical presentation, and in relation to some groups of infants with genetic disorders. The results, together with the embryonic development of the umbilical cord, strongly suggest that not all cases of SUA have the same cause, and that all previously suggested mechanisms may be possible but with different frequencies.

Consumo de tabaco durante el embarazo en España: análisis por años, comunidades autónomas y características maternas

Fundamento y objetivo: Desde hace anos se ha venido informado sobre la conveniencia de que las mujeres embarazadas no fumen. Por ello, hemos estudiado si se ha producido alguna variacion en el habito de fumar durante el embarazo en Espana. Sujetos y metodo: Utilizamos datos de 31.056 madres de ninos sin defectos congenitos, procedentes de todas las autonomias, recogidos con la misma metodologia en todo el pais. Se analiza la evolucion del habito de fumar por anos, comunidades autonomas, caracteristicas y otros habitos maternos. Resultados: En los ultimos anos del estudio (1995-2002), el 30,31% de las madres fumo durante el embarazo, con variaciones entre diferentes grupos etnicos. Se observa un incremento secular de la prevalencia de madres fumadoras entre 1978 y 1991, estabilizandose posteriormente en el 27-28%. No se observa una disminucion secular en los analisis por edades maternas, cantidades y autonomias. Solo las madres de mayor nivel de escolaridad muestran un descenso del habito de fumar en 1993, estabilizandose en alrededor del 23%. Las madres con menos de 25 anos son las que mas fuman en todos los anos. Se ha confirmado la estrecha relacion entre el tabaco, el alcohol y otras drogas comentada por otros autores. Conclusiones: Nuestros datos indican que no ha disminuido la prevalencia de mujeres que fuman durante la gestacion ni por anos ni por comunidades, aunque el 19,19% dejo de hacerlo en los primeros meses de embarazo. Ademas, las madres mas fumadoras en todos los anos son las mas jovenes. Estos resultados muestran la necesidad de aumentar la informacion para que las mujeres dejen de fumar antes del embarazo

Lethal short rib-polydactyly syndromes: further evidence for their overlapping in a continuous spectrum.

We report two new unrelated infants with short rib-polydactyly syndrome (SRPS) whose clinical and radiological features overlap the four established forms of lethal SRPS, so that it is difficult to classify them into any one particular type. One of the babies had one of the most radiologically severe SRPS ever published. The patients presented here support the previously reported hypothesis that this group of disorders might be a continuous spectrum rather than separate entities.

Análisis de la situación en España sobre el consumo de ácido fólico/folinato cálcico para la prevención de defectos congénitos

Fundamento y objetivo Desde 1992, en los paises desarrollados se ha generalizado la recomendacion de tomar un aporte complementario de acido folico (AF) para prevenir defectos congenitos. En este trabajo analizamos como es la situacion en Espana en los ultimos anos. Pacientes y metodo Utilizamos la informacion sobre las madres de los ninos controles de la base de datos del Estudio Colaborativo Espanol de Malformaciones Congenitas (ECEMC), que constituye una muestra de las mujeres embarazadas de la poblacion general. Analizamos la evolucion temporal del consumo de AF/folinato calcico (FC) (tanto en productos multivitaminicos como en los que se encuentra solo), por las mujeres embarazadas en los ultimos 22 anos, considerando momento de la ingestion de esta vitamina y las dosis utilizadas. Resultados La proporcion de mujeres que ingiere AF/FC durante el primer trimestre del embarazo ha experimentado un importante incremento a lo largo de los ultimos 9 anos, llegando a cerca del 80% en 2002. Sin embargo, solo alrededor del 9% de las mujeres inicio ese aporte desde antes de estar embarazadas. Ademas, las dosis medias diarias utilizadas son muy superiores a las internacionalmente recomendadas para la poblacion general de mujeres que planean un embarazo. Conclusiones En Espana, el consumo de AF/FC para la prevencion de defectos congenitos solo se esta realizando de forma adecuada en una pequena fraccion de la poblacion. Sigue, pues, siendo necesario difundir sus pautas de utilizacion correctas.