Clinical analysis of newborn infants with congenital defects registered in ECEMC: Distribution by etiology and ethnic groups

Dismorfología y Genética ClínicaIn this chapter, the information gathered by ECEMC between January 1980 and December 2008 has been analysed. It corresponds to 2,463,134 consecutive newborn infants surveyed, among which 37,545 (1.52%) presented congenital defects detected during the first 3 days of life. When these were distributed by clinical presentation, all the groups showed a statistically significant diminishing trend since the base period, mainly attributable to the impact of termination of pregnancy after the diagnosis of foetal alterations. The distribution by clinical presentation was specifically analysed for 17 congenital defects which are usually monitored, this information being useful in the field of prenatal diagnosis. Blastogenic defects showed a statistically significant decrease in the study period, except in the last 6 years, which could be due to the influence of the immigrant population. All the infants registered were distributed by the causes of the defects, and those with syndromes were also distributed by etiology and frequency in the ECEMC data. Moreover, all infants with congenital defects were distributed by the organic system or area affected, and presented in 3 periods of time. Given the increase in the immigrant population in our country, the distribution of all infants with congenital defects by ethnic group is shown, with whites being distinguished as native or foreigner. This distribution by ethnic group is important for designing specific campaigns for prevention, education and information, according to their real needs. When analysing some selected defects in those groups, with respect to the group of native whites, a lower percentage of cases with neural tube defects was found among blacks; a higher percentage of cases with cardiovascular defects was registered among blacks, gipsies and arabs; a lower percentage of cases with hypospadias was observed among blacks and indoamericans, and a higher percentage of cases with postaxial polydactyly was found among blacks. This data provides useful information for identifying defects for which the gene frequencies of the native population could be modified by immigration, as well as to define specific needs of the different ethnic groups in Spain.N

Present situation in Spain regarding the etiologic diagnosis in foetuses from termination of pregnancy (ToP) due to congenital defects. Guidelines for a minimum protocol

Dismorfología y Genética ClínicaSince the passing of the Spanish law permitting termination of pregnancy (ToP) after the detection of foetal anomalies, in July 1985, the ECEMC has undertaken the commitment to register the maximum information regarding the cases of ToP due to congenital anomalies. This interest is not only prompted by the need of a proper surveillance of these pathologies, what is important for public health purposes, but also for getting an etiologic diagnosis for each case; although this is only possible by retrieving minimum clinical and non-clinical information, depending on each case. This is important, because not achieving an etiologic diagnosis implies not being able to provide the family with information regarding recurrence risk, the risk for possible carriers among their healthy children, and for future pregnancies, planning prenatal diagnosis, and pre-implantation diagnosis or assisted reproduction for certain pathologies. At present, in Spain, there is no official protocol for the study of foetuses from ToP with congenital anomalies, what precludes from getting prevention in all their different levels, starting by the possibility of having a correct diagnosis. To cover that need, and based on the experience of the ECEMC, we highlight a small protocol with the minimal data to be collected to increase the possibilities to reach to a proper diagnosis, and, therefore, provide the parents with complete information. From the point of view of the health practice, this is the correct way, not only for getting the diagnosis, but because this is the only way to also help to diminish the awful situation of couples undergoing ToP due to foetal malformations.N

Johnson-McMillin syndrome (JMS): description of the first patient in Spain.

Dismorfología y Genética ClínicaThe JMS (OMIM: 147770) is a rare autosomal dominant neuroectodermal disorder characterized by alopecia, ear malformations, conductive hearing loss, anosmia/hyposmia, and hypogonadotropic hypogonadism. Morover, some additional features have been described so far (congenital heart defect, cleft palate, mild facial asymmetry, tendency to caries, and mental retardation). Herein we report on a patient with this condition who exhibits many of the features previously described, including alopecia, malformed auricles, conductive hearing loss, facial asymmetry, and developmental delay. Interestingly, she also has features that have not been reported yet, such as preauricular pits and tags, broad depressions at the external lateral areas close to the eyes, and an abnormal left lower eyelid. This phenotype supports the involvement of the ectoderm and neuroectoderm of the first two branchial arches in the embryologic basis of this condition. Indeed, alopecia, dental anomalies, defects of the choanae, part of the palatal valves, hypothalamic axis and hypogonadotropic hypogonadism, of epidermic origin, are derived from the ectoderm. Other defects as craniofacial alterations, including inner ear, preauricular tags, ear pits, and even microtia, and facial palsy, are derived from the neural crest, as also are the cardiac malformations. As far as we have known, the patient described here, represents the first case published from SpainN

Characteristics of mothers following assisted reproductive technologies

Aspectos EpidemiológicosBackground: Assisted reproductive technologies (ART), such as in vitro fertilization, intracytoplasmic sperm injection (ICSI), assisted fecundation, and all the fertility treatments and procedures, have been successfully used to overcome infertility. Indeed, it has been estimated that between 1 and 4% of births in developed countries are conceived trough ART. But at the same time, rising concerns exist on their potential adverse effects on the embryo and fetal development. However, in spite of the huge amount of studies that have been published, big gaps in this knowledge still exist. To assess this association through epidemiological studies, it is necessary to recognize which maternal characteristics, among others, could confound the results. However, some of the maternal characteristics may be related with cultural and social aspects, as well as with other local influences. Therefore, it is advisable to identify those characteristics in the different populations. Objective and methods: Here we present the results of the analysis of several maternal characteristics on data from the cases and controls ´ mothers of the ECEMC database. The analysis included 20,233 mothers of consecutive live born infants with congenital defects, and 19,411 mothers of control infants. The studied characteristics were: maternal age ( 19, 20-30, 31-35, 36), level of education (primary, secondary, and university studies), body mass index (BMI) in three strata (30), maternal chronic diseases, maternal diabetes mellitus, hypertension, gestational diabetes, infectious diseases during pregnancy, tobacco and alcohol consumption while pregnant, multiple births, and caesarean section. Due to the number of analyses performed, the statistical significance was established in p<0.01. Results: We have observed that women undergoing ART are older, with higher educational levels, suffer more chronic diseases, higher frequency of gestational diabetes, and more infectious diseases than mothers with natural conceptions. Most of these results are observed either in cases´ mothers or controls´ mothers, but did no differ when we analyzed cases versus controls´ mothers, all of them using ART for conception. On the other hand, mothers following ART, are less smokers, do not have more frequency of both diabetes mellitus and hypertension. Regarding the BMI, the only statistically significant result is an increased frequency of women having a BMI of <25 among those following ART. Conclusions: Many of the studied characteristics can be confounder factors for epidemiological analyses to identify potential risks of ART to produce birth defects. In addition, although most of the results are similar to those observed in other studies, particularly in Sweden, some of the observed differences may be due to variations in social and educational aspects. Therefore, it is advisable to identify which maternal characteristics can be confounder factors in each population.N

Surveillance of congenital anomalies in Spain in the last 23 years (period 1980-2002)

Resultados de Vigilancia Epidemiológica de los defectos congénitos sobre los datos del ECEMCWe have analysed data from the ECEMC database, gathered in the period 1980-2002, during which a total of 1,838,654 newborn infants were surveyed. The ECEMC programme covered 25.6% of total births occurred in Spain in 2001. We have calculated the global frequency of infants with congenital anomalies in different periods of time (before or after the passing of the law permitting voluntary interruption of gestation -VIG- following prenatal detection of anomalies). This allows to figure out the baseline frequency of congenital anomalies (corresponding to the period 1980-1985), and to assess the impact of VIG on the birth prevalence by comparing the baseline frequency of congenital anomalies with the frequency registered after 1985. The global frequency is decreasing over the years, and in 11 out of 17 Spanish Autonomic Regions we have also observed significant decreases of the frequency along the time. All those decreases are attributable to VIG. We have also studied the time distribution of the frequency of some selected anomalies, as well as their geographical distribution, and both are highly influenced by VIG. Nevertheless, the information on VIG is rather scarce. We consider that if it is not registered on a routine basis, it will be impossible to perform analytic studies on the causes of birth defects and to evaluate any preventive measure. Another question that will have to be approached in years to come is the distribution of birth defects depending on the country the parents come from, as immigration from other countries is increasing in Spain. Finally, we consider that even though the birth prevalence of these pathologies is decreasing as a consequence of the prenatal diagnosis and the possibility of voluntarily interrupting the gestation, it is necessary to search for primary prevention measures in order to get infants being born healthy.N

Epidemiological surveillance of congenital anomalies in Spain: Analysis of the data from the ECEMC’s Registry in the period 1980-2008

Aspectos EpidemiológicosThe Spanish Collaborative Study of Congenital Malformations (ECEMC) is a programme for research on congenital anomalies. It was created in 1976 by Prof. Martínez-Frías, as a hospital-based, case-control registry of newborn infants in Spain. Since its foundation, it has surveyed a total population of more than 2.6 million births, and studied more than 39,900 consecutive infants with congenital anomalies. According to the most recent data, the coverage of the registry reaches 21.55% of total births in Spain. The global frequency of infants with congenital defects has significantly decreased along the time, from 2.22% in the base period (1980-1985), to 1.03% in 2008. This significant decrease is mainly attributable to the impact of prenatal diagnosis and further interruption of some affected pregnancies, which is legal in Spain since 1985. Such a decrease has been observed in most of the Spanish Autonomic Regions (see Fig. 1) and participating hospitals, being statistically significant in many of them. The only Autonomic Region in which an increase was detected is Extremadura, where the base frequency was quite low due to a small coverage of births, in a period during which the most complicated pregnancies, and infants with serious birth defects, had to be referred to other regions (a situation that has changed since the basal period). From the periodic analysis of the frequency of a group of 33 defects selected due to their relatively high base frequency or morbidity/ mortality that they bear, only the heart/great vessels defects, and unilateral renal agenesis, have increased along the time, possibly as a result of increasing facilities for their diagnosis. The temporal-spatial analyses mostly detected decreases in the frequency of many of the defects studied in several Spanish Autonomic Regions. However, there were also some increases. Specifically, in the frequency of anophthalmia/microphthalmia in the Región de Murcia, cleft palate in Aragón, oesophageal atresia/stenosis in Galicia, and anal-rectal atresia/stenosis in Canarias. Regarding anophthalmia/ microphthalmia in the Región de Murcia, after excluding one case with a chromosomal abnormality and another one with familial Waardenburg syndrome, the increase lost its statistical significance, and apparently there was not any common denominator among the other cases registered, apart from the area of birth. With respect to the increase of oesophageal atresia/stenosis in Galicia, this was due to the birth of 4 cases in 2008, without any known common characteristic from which a causal relationship could be inferred. This defect will be subject to a special surveillance during the next months. Concerning the increase of cleft palate in Aragón, there was not any sign of a common cause restricted to this geographical area either. The last increase was based on the birth of 3 clinically different cases with anal atresia in Canarias, and no causal agent could be specifically linked to this area. From this report, it is clear the crucial role of the ECEMC system in the epidemiological surveillance of congenital anomalies in Spain, given its long experience since 1976, its huge database, the network of hospitals established, and the close and dynamic collaboration between its participants. This has enabled not only to calculate the birth frequency of congenital defects in Spain on a consecutive series on non-selected newborn infants, in a live and active system, but also to study their evolution along the time, and their geographical distribution, as well as their clinical diagnosis.N

Clinical-epidemiological analysis of the newborn infants with congenital defects registered by ECEMC: Distribution by etiology and ethnic groups.

Dismorfología y Genética ClínicaIt is presented here the analysis of the main clinical aspects of the infants with congenital defects registered by ECEMC (Spanish Collaborative Study of Congenital Malformations) between 1980 and 2010. Among a total of 2,648,286 newborns surveyed, 39,434 (1.49%) had congenital defects detected during the first 3 days of life. This group of infants with congenital anomalies was distributed according to the clinical presentation of their defects as isolated (73.94%), multiply malformed (13.53%), and syndromes (12.53%). The etiologic distribution of infants with congenital anomalies in the ECEMC showed a 20.47% of genetic cause, 20.28% multifactorial, 1.35% produced by environmental causes, and the etiology of the defects was unknown in the remaining 57.90%. 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 foetuses. The different types of syndromes identified and their minimal frequency values are also presented, separated by type of cause (Tables 4-10). Finally, the proportion of cases with birth defects by ethnic groups, first including (Graph 8) and then excluding (Graph 9) two groups of whites, the autochthones and the immigrant whites group. Due to the small samples in most non-white groups, the differences are not statistically significant, except for a significant higher frequency among Gypsies than in the white groups (both native and foreigner), the black group, and the one of Other (including mix groups).N

Report of congenital anomalies surveillance in Spain, on the data registered by ECEMC during the period 1980-2011

Aspectos EpidemiológicosCongenital anomalies are a leading cause of perinatal mortality (according to EUROCAT’s data, it reaches a prevalence of 9.4 per 10,000 births). Moreover, the most recent Global Burden of Disease Project estimated that congenital anomalies in 2010 accounted for 732,000 Disability Adjusted Life Years Lost (DALYs) in Western Europe, 274,000 in Central Europe and 898,000 in Eastern Europe. Thus, like other Rare Diseases, congenital anomalies are individually rare but collectively a significant public health issue. This report performed by ECEMC (the Spanish Collaborative Study of Congenital Malformations) is the annual update of the congenital anomalies surveillance report, after having analysed data gathered by this research programme between 1980 and 2011, although ECEMC was created in 1976. It is hospital-based and has a case-control design. The report is based on data from 2,735,086 births surveyed, among which a total of 40,329 presented with congenital anomalies detected during the first 3 days of life. Present coverage of the program is 17.95% of total births in Spain. The time distribution, geographical distribution and spacialtemporal distribution of the frequency of congenital anomalies in Spain were studied. The global frequency of infants with congenital defects has significantly decreased along the time, from the basal frequency registered in 1980-1985 (2.22%) to 1.03% in 2011 (Tables 1 and 3), mainly as a consequence of the impact of terminations of pregnancy after the detection of foetal anomalies (ETOPFA), which has been legal in Spain since the end of 1985. This tendency has also been statistically significant in 14 out of 17 Autonomous Regions and in many participating hospitals (Table 3). Only in Extremadura (see Fig. 1) a significant increase was detected, although the frequency registered in 2011 was not significantly different from ECEMC’s global frequency in the same year. After applying the protocol specifically designed at ECEMC for the study of clusters of birth defects, it was concluded that this increase was probably due to both methodological issues during the first years (with some under-registration of birth defects) and the high quality scrutiny and reporting of newborn infants with congenital anomalies, especially in the province of Cáceres). After correcting the frequency in the different hospitals and Autonomic regions by including ETOPFA cases and referrals to tertiary care hospitals, little changes were observed, mainly due to the difficulties to report ETOPFA cases. The time distribution of the frequency of 33 selected birth defects (Table 4) revealed a statistically significant decrease for most of them, although significant increases were also detected for heart/great vessels defects and unilateral renal agenesis, that were interpreted as a result of the availability of better diagnostic procedures. Also, for the annual distribution of 16 selected birth defects (Graphs-1), significant decreases were observed for all global frequencies except for anotia/microtia and gastroschisis. Regarding the temporal-spatial analyses of the frequency of 18 selected defects (Tables 5-10), the global decreases were also evident in many Autonomous Regions. Only an increase was detected for anencephaly in Aragón, where no clue on a local cause for the increase was observed, and where only one case was registered in 2011. Geographical heterogeneity could be detected in 2011 for several defects and was attributable to the birth of a higher than expected number of cases of anencephaly in Aragón, of cleft lip in Galicia, oesophageal atresia/stenosis in the Canary Islands, and hypospadias in Cantabria. All these clusters were analysed and again no local cause was identified and it was concluded that possibly they are stochastic events, although they will be maintained under close scrutiny until the next surveillance report. Since immigration in Spain has been very remarkable in the last years, the ethnic origin of cases and foreign extraction of their parents were analysed. A statistically significant increase along the time in the percentage of foreign parents was detected (Graph 4), and this was more marked among cases than among controls. Also an increase in all ethnic groups except the oriental one was observed (Graph 5). A higher risk for congenital anomalies was observed for all the groups except the Indian group, with respect to the native white group (Graph 6). Some final comments are included regarding the importance of congenital anomalies registries as infrastructure for the research on their causes and prevention, as well as on the exceptional characteristics of ECEMC’s registry and network (including its international activities for birth defects surveillance), and the need for more campaigns for their primary prevention and more research on their causes. In this sense, a reference is made on Kirby and Browne’s 26 consideration of birth defects surveillance as “an essential public health function for primary prevention and health promotion”.N

Clinical-epidemiological analysis of the newborn infants with congenital defects registered by ECEMC: Distribution by etiology and ethnic groups

Dismorfología y Genética ClínicaThis chapter is aimed at epidemiologically analyze the main clinical aspects of the infants with congenital defects registered by ECEMC (Spanish Collaborative Study of Congenital Malformations) during the period 1980-2011. A total of 2,735,086 newborns were surveyed, and 1.47% of them (40,329) had congenital defects detected during the first 3 days of life. This global frequency has significantly diminished along the time, mainly as a consequence of terminations of pregnancy (ToP) after the detection of fetal anomalies. This decrease is very marked for blastogenetic defects. The distribution of cases by clinical presentation of their defects revealed that 73.91% had isolated defects, 13.58% were multiply malformed, and 12.51% had different syndromes. The decreasing trend along the time affects all forms of clinical presentation. The etiologic distribution of infants with congenital defects is also presented: 20.46% had a genetic cause, 1.37% was due to environmental causes, 20.19% were multifactorial, and 57.98% were of unknown cause. The different syndromes identified are listed in Tables 5-11, separated by type of cause, and the minimal estimate of their frequency is also included. A special attention was paid to the distribution of the different types of syndromes (regarding their etiology), by ethnic groups in Spain.N

Description of a new case of Bohring-Opitz (or Oberklaid-Danks) syndrome

Dismorfología y Genética ClínicaIn 1999, Bohring et al. reported a new syndrome clinically distinguishable from cases with C syndrome or Opitz trigonocephaly. All the patients showed failure to thrive, microcephaly with metopic suture ridging, nevus flammeus over the forehead, thick hair and forehead hirsutism, shallow orbits with prominent eyes, depressed nasal root, anomalous ears, retrognathia, cleft lip and palate, flexion deformities of the upper limbs with radial head dislocation and ulnar deviation of fingers. Patients have severe developmental delay, sucking and swallowing difficulties starting in the prenatal period, as suggested by the usual polyhydramnios. The brain anomalies include hydrocephaly/large ventricles, agenesis/hypoplasia of corpus callosum, Dandy- Walker malformation, myelin abnormalities, and cortical atrophy. Occasional symptoms are a small or closed fontanel at birth, inguinal hernias and cryptorchidism in males, and intestinal malrotation. Most patients die early in childhood because of bradycardia and apnea. Although there is an overlap between C-like syndrome and C syndrome, different manifestations in these patients suggest a different entity. This new syndrome has been called (apart from C-like syndrome) Bohring-Optiz or Oberklaid-Danks syndrome. Recently, it has been associated in some patients to heterozygous de novo nonsense mutations in ASXL1 gene, which is required for maintenance of both activation and silencing of Hox genes, suggesting that the syndrome is genetically heterogeneous. Here we describe the first case of this syndrome identified in the Spanish Collaborative Study of Congenital Malformations (ECEMC) Registry, and possibly in Spain. Therefore, its minimal frequency has been estimated in 1:2,648,286 newborn infants.N