Other aspects of the epidemiological surveillance performed by ECEMC: Time distribution and distribution by Autonomous Regions of births from the immigrant population in Spain

Aspectos EpidemiológicosIt is well known that immigration has increased along the time in Spain, especially in the most recent years. We have analyzed data from ECEMC in order to quantify this phenomenon in the sample of 35,441 controls (newborn infants without congenital defects) registered by ECEMC in the period 1980-2009, since the group of immigrants usually has a set of characteristics which increase their offspring’s risk for being born with congenital anomalies. ECEMC gathers information on the birth place and ethnic group of parents and grandparents of both controls and cases registered with congenital anomalies. Most of immigrant parents (62.82%) come from non-european countries. Globally, the Autonomous Regions with the higher percentages of immigrant parents were the Balearic Islands (18%), Community of Madrid (15.84%), Comunidad Valenciana (15.16%) and Catalonia (13.08%). In the year 2009, however, the higher percentages were registered in Catalonia, followed by Community of Madrid, Balearic Islands and Comunidad Valenciana. There has been a statistically significant increase of births from immigrants along the time, from 1.89% of total control births in 1980-1985, up to 23.92% in the year 2009. This increase has been more pronounced for the group of immigrants from non-european countries. Since 1996, the proportion of births from non-European countries is higher than the counterpart of infants being born to European immigrants in Spain. Data from the different Autonomous regions mostly reflect this general tendency. In the groups of immigrants, the most frequent ethnic group was that of whites (96.84% among immigrants coming from European countries, and 41.73% among those coming from non-european countries). There is almost total concordance of data from ECEMC with the official data registered by INE (Spanish National Institute for Statististics). Knowing the magnitude of the different groups of immigrants in Spain is very important in order to properly design the different plans for prevention of congenital anomalies, according to the special risks of each population groupN

Clinical aspects and etiologic distribution of the newborn infants with congenital defects registered in the ECEMC

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCAn epidemiological analysis of the main clinical aspects of the infants with congenital defects registered by the ECEMC (Spanish Collaborative Study of Congenital Malformations) between 1980 and 2006, has been performed. Among a total of 2,254,439 newborn surveyed, 35,246 (1.56%), had congenital defects detected during the first 3 days of life. This group of malformed infants was distributed according to their clinical presentation as isolated (74.01%), multiply malformed (13.43%), and syndromes (12.56%). The etiologic distribution of infants with congenital anomalies in the ECEMC showed a 20.42% of genetic cause, 21.03% multifactorial, 1.22% produced by environmental cause, and in the remaining 57.33% the etiology of the defects was unknown. The secular distribution of the 3 main groups of clinical presentation (isolated, multiply malformed and syndromes) was studied and all of them showed a decreasing trend along the years, probably as a consequence of the impact of the interruption of pregnancy of some affected fetuses. The different types of syndromes and their minimal frequency values were also presented separated by type of cause.N

Integration of the clinical aspects into the epidemiological analysis of the newborn infants with congenital defects registered through the ECEMC: 30 years getting ready for the future

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCAn epidemiological analysis of the main clinical aspects of the infants with congenital defects registered by the ECEMC (Spanish Collaborative Study of Congenital Malformations) between 1980 and 2005, has been performed. It is remarkable that the ECEMC programme is defined, as stated in its Operating Manual, as a clinical and epidemiological research program on congenital defects, based on an ongoing case-control, hospital-based registry of newborn infants in Spain. The analyzed material corresponds to 2,152,479 total newborns surveyed, of which 34,066 (1.58%) had congenital defects detected during the first 3 days of life. All these infants with congenital anomalies were analyzed by applying the classification system developed in the ECEMC [Martínez-Frías et al., 1991: Am J Med Genet 41:192-195; Martínez-Frías and Urioste, 1994: Am J Med Genet 49:36-44; Martínez-Frías et al., 2000: Am J Med Genet 90:246-249], based on the most modern concepts in Dysmorphology [Martínez-Frías et al., 1998: Am J Med Genet 76:291-296]. Infants registered were distributed according to their clinical presentation as isolated, multiply malformed, and syndromes, and other subgroups into these 3 groups. The time distribution of the 3 main groups of clinical presentation was studied and all of them have decreased along the years, probably as a consequence of the impact of interruption of pregnancy of some affected fetuses. Apart from the study for all infants with congenital defects, the clinical presentation of a group of 17 defects (selected according to: their relatively high frequency at birth, or the high morbidity/mortality that they bear, and their monitoring in other countries) was also analysed. There was a considerable clinical heterogeneity in most of them, although some (gastroschisis, hypospadias, or anencephaly) tend to present as isolated anomalies, and other (anophthalmia/microphthalmia, abdominal wall defects and bilateral renal agenesis) appear more frequently associated to other defects. The etiologic distribution of infants with congenital anomalies in the ECEMC resulted similar to that shown by other authors, and the lists of syndromes, classified by their etiology, is also provided, detailing their gene map locations if known (OMIM database accessed in June 2006), and their minimum birth prevalence in Spain (according the ECEMC database). To conclude, a commentary is made on the possibility of including not only clinical and genetic information, but also molecular data in the registries coding systems, in order to integrate all the available biological knowledge in the epidemiological approach to identify the causes of congenital defects, to be prevented.N

Clinical and genetic aspects of the hamartoneoplastic syndromes that can be diagnosed during the three first days of life.

Dismorfología, Citogenética y Clínica: Resultados de estudios sobre los datos del ECEMCThe hamartoneoplastic syndromes are an heterogeneous group of diseases characterized by their risk to develop malignant tumors among other clinical features that vary from one syndrome to another. Most of these pathologies also share endocrinological abnormalities and sometimes, genetic characteristics, including the autosomal dominant mode of inheritance. Therefore, pediatricians must be aware of their main characteristics in order to prevent as soon as possible further complications and to provide the appropiate genetic counseling to the affected patients and their families. In this chapter, we have classified these pathologies in seven different groups according to the more frequently affected tissue by the development of hamartomas. For each of these groups we reviewed the hamartoneoplastic syndromes that have some manifestations at birth. Finally, some practical guidelines are provided for their clinical, genetic diagnosis, and management.N

Annual Report of epidemiological surveillance of congenital anomalies in Spain: Data of the period 1980-2010

Aspectos EpidemiológicosThe Spanish Collaborative Study of Congenital Malformations (ECEMC) annually undertakes the preparation and updating of the report of epidemiological surveillance of congenital anomalies in Spain. ECEMC is a research programme for congenital anomalies, based on an ongoing registry of births in Spain, which is hospital-based and has a case-control design. It has surveyed about 2.8 million births (Table 1), and gathered data on 41,800 consecutive infants with congenital anomalies and a similar number of healthy controls. Present coverage of the registry is 19.8% of total births in Spain (Table 2). The basal frequency of infants with congenital defects in our country is 2.22% (registered in 1980-1985), and it fell up to 1.07% in 2010, mainly as a result of the impact of elective termination of pregnancy after the detection of foetal anomalies (ETOPFA). ETOPFA has been legal in Spain since the end of the year 1985. Such a statistically significant decrease of the global frequency can be observed (Table 3) in many of the participating hospitals and most Spanish Autonomic Regions (see Fig. 1). Some increases in six hospitals were studied in detail. The only Autonomic Region in which an increase was detected is Extremadura, but this finding is probably due to methodological reasons in the first years, and referrals of high-risk pregnancies to other regions in those years, with considerable further changes that allow a better detection and reporting of cases in this region. The corrected global frequency by hospital and Autonomic Region, taking ETOPFA into account, was also analysed. The evolution of the frequency of a selected group of 33 defects with a relatively high base frequency and/or bearing a high morbidity/mortality was studied (Table 4). Most of them diminished along the time, the only increases being observed for heart/great vessels defects and unilateral renal agenesis, possibly as a result of better diagnostic procedures. Down syndrome is the defect for which a more marked decrease was measured (Graphs-1)A group of 18 defects were selected for the temporal-spatial analyses of the frequency, and also many statistically significant decreases were observed in most Spanish Autonomic Regions (Tables 5-10). The only increase was detected for anencephaly in the Balearic Islands, based on two births, and no clue on a local cause was obtained. Geographical heterogeneity could be detected in 2010 for anencephaly, spina bifida, anal/rectal atresia/stenosis, and hypospadias. For anencephaly, heterogeneity was attributable to the previously mentioned relatively high frequency registered in the Balearic Islands. For spina bifida, it was due to a high frequency observed in La Rioja, but based on the birth of just one case. For anal/rectal atresia/stenosis it was due to the high frequency registered in the quite distant regions of the Balearic Islands and La Rioja, and no common factor was identified as a possible cause. In all these cases it is noticeable that in regions where a small number of births is surveyed, the birth of just one case can bring the frequency to unusually high levels, and this can generate some geographical heterogeneity. For hypospadias, it was due to the low frequency observed in 2010 in the Comunidad Valenciana, and the relatively high frequency registered in Andalucia; all cases were balanic and isolated, and the higher frequency was observed in three hospitals in the provinces of Córdoba, Jaén and Malaga. All these findings will be subject to close scrutiny until the next surveillance report. Due to the importance of immigration in Spain in the last years, the ethnic origin of cases and foreign extraction of their parents were also analysed. The percentage of foreign parents has significantly increased with time, and was higher among the cases than among the controls (Graph 4). All ethnic groups had a higher risk for congenital anomalies than the native white group (Graph 6) and, except the oriental group, have increased with time (Graph 5). A reflection is included as a final comment, regarding the need of research on causes of birth defects, as expressed by Olshan et al. [Am J Med Genet A. 2011;155:1794–1797]: ‘For future generations, it is essential that we identify causes so that effective public health and clinical prevention programs can be established’. ECEMC, and other programmes worldwide, collaborate with that aim. For that purpose, ECEMC has a considerable background and experience of more than 35 years, as well as enough flexibility to adapt itself to new challenges, working for the prevention of birth defects.N

Surveillance of congenital anomalies in Spain: Analysis of the ECEMC's data during the period 1980-2006

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMCThis chapter summarizes the main results of the current epidemiological surveillance of congenital anomalies performed in the Spanish Collaborative Study of Congenital Malformations (ECEMC). This is a research programme developed as a hospital-based case-control study and surveillance system, aimed at investigating the characteristics and causes of congenital defects. It started in 1976, with a common methodology for all the participants in the programme. According to the most recent data, it covers 22.96% of births in Spain. It has been found that the general tendency of the neonatal frequency of congenital defects in Spain is decreasing since the passing, in 1985, of the law allowing voluntary termination of pregnancy (TOP) after the detection of fetal anomalies. The frequency has fallen from the base frequency registered in 1980-1985 (2.22%) up to 1.16% in the year 2006. This general tendency has also been proven for most of the defects under systematic surveillance in the ECEMC. The most noticeable decrease has been observed for the global frequency of Down syndrome, and this decrease is even more pronounced for the oldest maternal ages, as a result of the impact of TOPs. In the analyses by Autonomous Regions (look at the map in Figure 1 to see their location), there was only a statistically significant increase of the global frequency, in Extremadura, that can be attributable to the improvements in the neonatal and obstetrical care in this region, not being necessary to move deliveries at risk to other Autonomous Regions. Regarding the frequency of specific defects, there have been increases in the frequency of esophageal atresia/stenosis in Castilla-La Mancha, anal-rectal atresia/stenosis in Tenerife (Islas Canarias), gastroschisis also in Tenerife, and hypospadias in Castilla y León. For the first two defects, after excluding cases with syndromes with multiple congenital anomalies, they lost statistical significance. For gastroschisis in Tenerife, there were some risk factors among the cases (young maternal age, change in paternity of the different infants of the mother) that could account for the cluster, although it will be closely followed up. For hypospadias, there has not been found any common denominator in the cases that could be considered as the cause of the cluster in Castilla y León, that will also be closely monitored. In conclusion, the ECEMC system of epidemiological surveillance has demonstrated being effective in determining the birth frequency of congenital defects in Spain, its secular trend and geographical distribution, as well as for detecting several increases in the frequency of some congenital defects, leading to a close monitoring of the clusters, which is important for determining their causes and for the prevention of congenital defects, apart from their usefulness in the planning of health and social resources.N

Clinical-epidemiological aspects of newborn infants with congenital anomalies

Dismorfología, Citogenética y Clínica: Resultados sobre los datos del ECEMCWe have used the data gathered by the Spanish Collaborative Study of Congenital Malformations (ECEMC) during the period 1980-2002, in order to epidemiologically analyze some clinical aspects of a consecutive series of malformed newborn infants. Among a total of 1,838,654 newborns surveyed, 30,531 (1.66%) presented with congenital anomalies detected at birth. Data were analysed before and after the pass of the law permitting voluntary interruption of gestation (VIG) following the detection of anomalies in the fetus. Malformed infants were distributed by clinical presentation as isolated, multiply malformed or syndromes, according to our own classification system [Martínez-Frías et al, 2002: Rev Dismor Epidemiol V(1):2-8]. The 3 forms of clinical presentation are decreasing along the time, as a result of the impact of prenatal detection of anomalies and further VIG in some cases. We also analyzed 17 defects that were selected because of their relatively high frequency at birth, or due to the high morbidity/mortality that they bear, and because their frequency at birth is also monitored in other countries. Most of them show a high clinical heterogeneity, although some (such as gastroschisis, hypospadias, spina bifida, cleft lip, or diaphragmatic hernia) tend to present in their isolated form, while other (such as anophthalmia/microphthalmia) tend to associate to other anomalies. We also performed the etiologic distribution of infants with congenital anomalies in 3 study periods, and showed the number of cases in which the different types of syndromes were identified, as well as the minimal estimate of their frequency at birth and their gene map location, based on the OMIM database. We emphasize the importance of applying all known primary prevention measures, even more during blastogenesis, at the very early stages of pregnancy. On the other hand, we also underline the relevance of clinical analysis of malformed infants in order to organize homogeneous groups to which the epidemiological techniques can be applied. In this way, the statistical findings also will be clinically relevant. This is also important for the molecular studies that may give clues on the causes of congenital defects, as epidemiology of Human Genome can contribute to this kind of research, opening big opportunities in this field.N

Consumption of H1 antihistamines during the first trimester of pregnancy in Spain, and estimation of the overall risk for congenital defects in the newborn

Teratología ClínicaH1 antihistamines (H1A) are drugs that have been used for many years for treatment of allergic diseases, as for the control of nausea and morning sickness in pregnant women. Here it is analyzed the evolution of their global use during gestation and by the different groups of H1A, along the last 31 years in the ECEMC data. In addition, their potential risk on the embryo development regarding congenital defects is analysed. The data belongs to the Spanish Collaborative Study of Congenital Malformations (ECEMC), for the period 1977-2008. The ECEMC is a hospital-based, case-control study and surveillance system, aimed at performing clinical and epidemiological studies on congenital defects, the methodology of which includes the collection of about 310 items on each newborn infant registered, whether case or control, on their pregnancy and family history, and many types of prenatal exposures. During the study period the ECEMC surveyed and examined a total of 2,607,822 consecutive newborns, and a total of 39,561 out of them had congenital defects identifiable during the first three days of life. After having excluded those cases diagnosed centrally at ECEMC as presenting with syndromes, the studied samples were 33,056 cases and 32,258 controls. The total data of the different tables may not be the same because they include only the cases and controls with each data specified. The analysis of the evolution of H1A consumption by pregnant women in Spain along the years showed a statistically significant increasing trend, from 12.66% and 11.51% for cases and controls, respectively, in 1977 to 13.90% and 15.86%, respectively, in 2008. This increase has occurred at the expense of doxilamine (combined with vitamin B6) used as an antiemetic, and of three subgroups of H1A used in the control of allergic processes (Alquilamines, Piperazines, and Piperidines). None of the subgroups of H1A has shown an increased risk for birth defects (after its use during the first trimester of pregnancy), except the group of Piperidines (OR=6.83; p=0.003). However, due to the small samples of exposed infants, it is not possible to perform any type of multivariate analysis to control for possible confounders. Hence, we cannot rule out that the observed risk could be due to uncontrolled factors. If a pregnant woman had allergic problems and needs to be treated, she has to be treated because the risks for her and for the embryo overwhelm the ones derived from the treatment if any. For such treatment, if the allergic process only can be controlled with a piperidine, this product could be used, although not as the first option. On the other hand, the combination of doxilamine and pyridoxine (vitamin B 6) is a safe option for the control of nausea and vomiting during pregnancy.N

The activity of the Spanish Teratology Information Services (SITTE and SITE) during the year 2010

Otros Resultados: Actividad TraslacionalWe present a summary of the activity of the two Teratology Information Services: SITTE (for health professionals) and SITE (for the general population) during the year 2010. The total number of calls received in both services was 5,087 (814 received by SITTE and 4,273 by SITE). We present the distribution of calls along the years, as well as by the types of health professionals who performed the calls and the types of questions. Also, we show the distribution by different groups of exposures, including maternal diseases and their treatments, professional exposures, life styles, and others. Quantitatively, drug use has been the main reason for these queries. In addition, we have analyzed for the first time, the question regarding paternal diseases, treatments and professional exposures.N

Analysis of the structural chromosomal anomalies and distribution by chromosomes in the ECEMC’s series of newborn infants with congenital defects

Citogenética y Genética MolecularThis study was aimed at estimating the frequency of unbalanced structural chromosomal anomalies identified in the consecutive series of newborn infants with congenital defects, registered in the Spanish Collaborative Study of Congenital Malformations (ECEMC). These cases were cytogenetically studied at its laboratory since 1981 up to December 2009. A total of 4,681 cases were studied following a protocol established by ECEMC program, which starts by performing a high resolution karyotype (550-850 bands), and if the results are normal, it is followed by the analysis of subtelomeric regions and depending on the clinical manifestations, some FISH and MLPA analyses were applied in order to also rule out microdeletion syndromes. The parents and other relatives were also studied when necessary, according to ECEMC’s protocol. A total of 136 cases had unbalanced chromosomal structural anomalies. Data were analyzed either globally or in two periods including the years 1981-1994, and 1995-2009 which are before and after starting the use of FISH techniques in the ECEMC`s laboratory. Among the 136 total cases having unbalanced structural anomalies, 71.32% were cytogenetically detected, and the remaining 28.68% by FISH. Each type of anomaly was distributed by involved chromosome separating those affecting p and q arms. In the group of cytogenetically detected anomalies, deletions (42.55% of cases) were 2.1 times more frequent than duplications (20.22%). Deletions affecting short arms were 3 times more frequent than duplications. Among cases detected by FISH techniques, deletions were 15.49 times more frequent than duplications, the 22q11.2 microdeletion being the most common (38.46% of the cases), followed by the deletions in chromosomes 15 (15.38%) and 4 (10.26%). Some of these alterations were identified by the clinical suspicion of their specific syndromes (Wolf-Hirschhorn, Prader-Willi, Williams-Beuren, Miller-Dieker, etc), and this could somehow bias their frequencies (see Table 3). In addition, some other unexpected microdeletion syndromes were detected such as two cases with microdeletion 1p36, one case with each of the following microdeletions: 2q23.1, 5q31, and a deletion 12q13.3-q21.2, including the region of the known microdeletion syndrome 12q14, but it is possible that may be other not hitherto identified. To our knowledge, this study represents the first one analyzing the frequency of chromosomal alterations globally and by each one of the 23 chromosomes on a consecutive series of newborn infants with congenital defects which are detectable during the first three days of life. It is also remarkable that all the cases were studied with the same protocol and the same team of specialists.N