Search

Holt Oramov sindrom (HOS, OMIM 142900) rijedak je autosomno dominantan poremećaj koji obilježavaju koštane abnormalnosti gornjih udova i srčane grješke/smetnje provođenja. HOS ima visoku penetrantnost i veliku varijabilnost izraženosti kliničke slike. U oko 75% slučajeva uzrokovan je mutacijama u genu TBX5.Cilj ovog istaživanja bio je utvrditi epidemiologijska i klinička obilježja HOS-a dijagnosticiranog prenatalno ili u prvim godinama života upotrebom baze podataka mreže registara prirođenih mana EUROCAT (European Surveillance of Congenital Anomalies). Metode: Analizirani su podatci o bolesnicima prikupljeni u razdoblju od 1990.-2011. god. u 34 EUROCAT registra iz 16 zemalja, koji prate oko 30% porođaja godišnje u Europi. Svi su registri populacijski, služe se s više izvora podataka i bilježe živorođene, mrtvorođenja ≥ 20 tj. gestacije, kao i medicinski indicirane prekide trudnoća, služeći se standardiziranom metodologijom. defi nicijom i načinom kodiranja. Rezultati: U promatranom razdoblju registrirana su 73 slučaja HOS-a. Prosječna prevalencija iznosila je 0, 7 na 100 000, a postoje značajne regionalne razlike (raspon 0, 2 - 2, 4). Bilo je 62-je (84, 9%) živorođenih, od kojih dvije (3, 2%) novorođenačke smrti te 11(15, 1%) prekida trudnoće uz medicinsku indikaciju. Prenatalno je otkriveno 30, 8%, pri porođaju 55, 4%, tijekom prvog tjedna života 10, 7%, a tijekom prve godine 3, 1% bolesnika. Stopa prenatalne detekcije nije se značajno mijenjala tijekom promatranog razdoblja. Ultrazvučne abnormalnosti prenatalno se u prosjeku otkrivaju sa 18, 6±4, 6 tjedana gestacije. Roditelji su se odlučili na prekid trudnoće u 55% slučajeva, a prekid je obavljen s 21, 1±1, 8 tjedana. Od koštanih abnormalnosti najčešće su bile anomalije palčeva, ageneza/hipoplazija radijusa bila je prisutna u 49, 2%, anomalije ulne u 24, 6%, a anomalije nadlaktice u 42, 6%. Srčane grješke imalo je 77% bolesnika, većinom izolirane defekte septuma (41%). Uočen je visok udio složenih srčanih grješaka (23, 4%) koje su dijagnosticirane samo u izoliranim slučajevima. U familjarnim slučajevima 90% je imalo srčane grješke, uvijek septalne defekte. Zaključak: HOS je rijedak sindrom koji pokazuje regionalnu varijaciju u prevalenciji. Često se ne otkriva prenatalno, usprkos prisutnosti većih malformacija. U slučajevima kad su anomalije otkrivene prenatalno, roditelji u oko polovice slučajeva odlučuju nastaviti trudnoću, usprkos prisutnosti težih anomalija udova i srca. Premda gotovo četvrtina bolesnika ima teške srčane grješke, ukupno preživljavanje nakon prvog tjedna je vrlo dobro, što je važan podatak za genetičko savjetovanje zahvaćenih obitelji.

Beckwith Wiedemannov sindrom - europska epidemiologijska studija.

Objective To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy.Design A review of all published cohort studies to identify key indications and a population based case-control study to test these indications.Setting Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005.Participants The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births.Main outcome measures Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes.Results The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect.Conclusion Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.

EUROCAT (European Surveillance of Congenital Anomalies) is the network of population-based registers of congenital anomaly in Europe, with a common protocol and data quality review, covering 1.5 million annual births in 22 countries. EUROCAT recorded a total prevalence of major congenital anomalies of 23.9 per 1,000 births for 2003-2007. 80% were livebirths. 2.5% of livebirths with congenital anomaly died in the first week of life. 2.0% were stillbirths or fetal deaths from 20 weeks gestation. 17.6% of all cases were terminations of pregnancy following prenatal diagnosis (TOPFA). Thus, congenital anomalies overwhelmingly concern children surviving the early neonatal period, who have important medical, social or educational needs. The prevalence of chromosomal anomalies was 3.6 per 1,000 births, contributing 28% of stillbirths/fetal deaths from 20 weeks gestation with congenital anomaly, and 48% of all TOPFA. Congenital heart defects (CHD) were the most common non-chromosomal subgroup, at 6.5 per 1,000 births, followed by limb defects (3.8 per 1,000), anomalies of urinary system (3.1 per 1,000) and nervous system defects (2.3 per 1,000). In 2004, perinatal mortality associated with congenital anomaly was 0.93 per 1,000 births, and TOPFA 4.4 per 1,000 births, with considerable country variation. Primary prevention of congenital anomalies in the population based on controlling environmental risk factors is a crucial policy priority, including preconceptional care and whole population approaches.

Fryns syndrome (OMIM 229850) is a rare autosomal recessive malformation syndrome. The main features include diaphragmatic hernia, characteristic dysmorphic features, and distal limb anomalies. Additional malformations of central nervous system, gastrointestinal and genitourinary system can be present as well. Because of the rarity and observed phenotypic variability there is a need for better delineation of epidemiological and clinical aspects of this condition. We present data on 22 cases of Fryns syndrome reported to a large European network of congenital malformation registries (EUROCAT) in the 1980-2002 period. Prenatal ultrasound examination detected abnormalities in 13/22 (59%) fetuses. Mean gestational age at discovery of an abnormality by prenatal ultrasound was 22± ; 3.9(18-33) gestational weeks. Congenital diaphragm362880 atic hernia (20/22 or 91%), limb defects (16/22 or 72.7%), genitourinary tract anomalies (16/22 or 72.7%) and cleft palate (10/22 or 45.5%) were the most frequently found malformations. There were 4/24 (18.2%) fetal deaths, 12/22 (54.54%) pregnancy terminations and only 6/22 (27.3%) live born. Male: female ratio was 2 (14/7). The mean gestational age at birth was 33 weeks. The mean live birth weight was 1591± ; 967g for males and 2075± ; 125g for females. Only one newborn survived the first week of life. Parental consanguinity was present in 11/22 (50%) instances. In 9/22 (41%) cases previous siblings with anomalies were noted, but in only one case Fryns syndrome was confirmed. Karyotyping was performed in 9 cases and no chromosomal abnormality was found. No evidence of specific teratogenic exposure was observed.

Cornelia de Lange syndrome (CdL) is a rare multiple congenital anomaly syndrome characterized by specific facial dysmorphic features, hypertrichosis, upper limb deficiency, intrauterine growth retardation, developmental delay and various associated anomalies. The aim of our study was to determine the spectrum and the proportion of congenital heart disease (CHD) in CdLS, their possible effects on prenatal detection, type of birth, time of diagnosis and survival. Methods: we analyzed 93 cases of CdL syndrome reported in 1980-2002 period to 33 European congenital malformation registries included in EUROCAT (European Surveillance of Congenital Anomalies) network. Results: CHD was found in 45% of patients with classical CdLS. The most common cardiac anomalies were ventricular septal defect (VSD) (13/93 or 31%), atrial septal defect (ASD) (10/93 or 23.8%) and pulmonary valve stenosis (PS) (9/93 or 21.4%). Comparing group of patients with CHD and without CHD, no significant differences were found regarding prenatal detection rate, gestational age at discovery, time of diagnosis, length of gestation, birth weight by sex, type of birth, or the first week survival. Conclusions: we have found a very high rate of CHD in classical CdLS, although the type/severity of CHD was such that it did not influence the outcome of pregnancy and survival. PS is found more often than expected from the distribution of CHD in general population. High rate of CHD in CdLS warrants a detailed cardiac examination in affected newborns.

Fryns syndrome (OMIM 229850) is a rare autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, dysmorphic features and distal limb hypoplasia. Additional anomalies of genitourinary, gastrointestinal and central nervous system are also often present. Because of the severity of the disorder most cases can be detected prenatally by routine ultrasound examination, particularly if they are associated with a major malformation. The aim of this study was to present data on prenatal diagnosis of this rare syndrome in the European region. We evaluated 22 cases of Fryns syndrome, registered and confirmed in Eurocat (European Surveillance of Congenital Anomalies) network of congenital malformation registries in 1980-2002 period. Ultrasound led to the prenatal detection of 13/22 (59%) cases. Mean gestational age at discovery was 22± 1.3 (range 12-33) weeks. In 7/13 (46.2%) karyotyping was done and gave normal results. Amniocentesis was performed in 4/13 (30.8 %) and chorionic willi sampling in 3/13 (23.1 %) cases. In all prenatal detected cases we found congenital diaphragmatic hernia with associated anomalies. Of 13 prenatally detected cases, two were live born, 1 was stillbirth at 38 weeks of gestation and 10 pregnancies were terminated. Mean gestational age at termination of pregnancy was 25± 1.4 (range 17- 34) weeks. In conclusion, our data show that prenatal ultrasound examination has an important impact on the birth prevalence of Fryns syndrome in Europe, because is resulted in its 45.5% reduction as a consequence of the pregnancy termination.

OBJECTIVES: To determine the excess risk of non- chromosomal congenital anomaly (NCA) among teenage mothers and older mothers. DESIGN AND SETTING: Population-based prevalence study using data from EUROCAT congenital anomaly registers in 23 regions of Europe in 15 countries, covering a total of 1.75 million births from 2000 to 2004. PARTICIPANTS: A total of 38, 958 cases of NCA that were live births, fetal deaths with gestational age > or = 20 weeks or terminations of pregnancy following prenatal diagnosis of a congenital anomaly. MAIN OUTCOME MEASURES: Prevalence of NCA according to maternal age, and relative risk (RR) of NCA and 84 standard NCA subgroups compared with mothers aged 25-29. RESULTS: The crude prevalence of all NCA was 26.5 per 1000 births in teenage mothers (

Fraser syndrome (FS) is rare autosomal recessive condition with classical features of cryptophtalmos, syndactyly, and genitourinary malformations.Abnormalities of the skull, ears, nose and larynx are also present as well.Due to the rarity of FS, population based epidemiological studies are lacking.We present the result of analysys of 24 cases identified among 10 318 446 pregnancies registered in the EUROCAT network of congenital malformation registries in 1980-2004 period. This corresponds to a prevalence of 0.23/100000 or 1 in 429.935 births. Prenatal ultrasound examination detected abnormalities in 13/24 (54, 2%)features. Mean gestational age at discovery of an abnormality by prenatal ultrasound was 22.3+-3.2 (18-27)gestational weeks.There were 2/24 (8, 3%)fetal deaths, 9/24 (37, 5%) pregnancy termination and 13/24 (54, 2%) were live born.One third of live births did not survive the first week of life. Male:female ratio was 3.4 (17/5).The mean birth weight in live births was 2363+- 622 g for males and 2133 +- 413 g for females.The mean gestational age at birth was 37 weeks for both sexes.The most frequent associated congenital malformations were urogenital (81, 8% ; 18/22), eye (72.7% ; 16/22), and limb 59, 1% ; 13/22)anomalies. The mean maternal ageat birth was 28+- 5 years and the mean paternal age 31+-4 years. Parental consanguinity was present in 7/14 cases and four families had aldready one affected child 4/13.All cases were registered in the Western part of Europe, 12/24 (50%) cases being from Great Britain and Portugal, (prevalence 0, 49/ 100000 or 1 in 202859 births)

Objective To ‘map’ the current (2004) state of prenatal screening in Europe. Design (i) Survey of country policies and (ii) analysis of data from EUROCAT (European Surveillance of Congenital Anomalies) population-based congenital anomaly registers. Setting Europe. Population Survey of prenatal screening policies in 18 countries and 1.13 million births in 12 countries in 2002–04. Methods (i) Questionnaire on national screening policies and termination of pregnancy for fetal anomaly (TOPFA) laws in 2004. (ii) Analysis of data on prenatal detection and termination for Down's syndrome and neural tube defects (NTDs) using the EUROCAT database. Main outcome measures Existence of national prenatal screening policies, legal gestation limit for TOPFA, prenatal detection and termination rates for Down's syndrome and NTD. Results Ten of the 18 countries had a national country-wide policy for Down's syndrome screening and 14/18 for structural anomaly scanning. Sixty-eight percent of Down's syndrome cases (range 0–95%) were detected prenatally, of which 88% resulted in termination of pregnancy. Eighty-eight percent (range 25–94%) of cases of NTD were prenatally detected, of which 88% resulted in termination. Countries with a first-trimester screening policy had the highest proportion of prenatally diagnosed Down's syndrome cases. Countries with no official national Down's syndrome screening or structural anomaly scan policy had the lowest proportion of prenatally diagnosed Down's syndrome and NTD cases. Six of the 18 countries had a legal gestational age limit for TOPFA, and in two countries, termination of pregnancy was illegal at any gestation. Conclusions There are large differences in screening policies between countries in Europe. These, as well as organisational and cultural factors, are associated with wide country variation in prenatal detection rates for Down's syndrome and NTD. Please cite this paper as: Boyd P, DeVigan C, Khoshnood B, Loane M, Garne E, Dolk H, and the EUROCAT working group. Survey of prenatal screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down's syndrome. BJOG 2008;115:689–696.

To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk. Population-based case- control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995-2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5, 511 nonsyndromic OC registrations, of whom 4, 571 were isolated, 1, 969 were cleft palate (CP), and 1, 532 were isolated CP. Controls were 80, 052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use. There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10-2.34) for OC relative to other malformations, 0.80 (95% CI 0.11-2.85) for isolated OC, 0.79 (95% CI 0.03- 4.35) for CP, and 1.01 (95% CI 0.03-5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03-1.93) for OC, 1.21 (95% CI 0.82-1.72) for isolated OC, 2.37 (95% CI 1.54- 3.43) for CP, and 1.86 (95% CI 1.07-2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed. We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.

Fraserov sindrom izuzetno je rijedak poremećaj obilježen kriptoftalmosom, sindaktilijom, dismorfičnim crtama i urogenitalnim anomalijama. Uz to se često nalaze pridružene malformacije uške, nosa i larinksa. Prikazujemo rezultate analize 17 slučajeva Fraserovog sindroma otkrivenih među 10 318 446 trudnoća praćenih u mreži europskih registara prirođenih mana u razdobju od 1980.-2004. godine. Prevalencija Fraserovog sindroma bila je 0, 16/100 000 ili 1/625 000. Od ukupno 17 slučajeva dva su bila mrtvorođena, a osam je trudnoća prekinuto uz medicinsku indikaciju. Prenatalno je ultrazvučnim pregledom postavljena sumnja na malformacijski sindrom u deset plodova. Prosječna gestacijska dob kod postavljanja sumnje na oštećenje ploda bila je 21, 5&plusmn ; 3 (18-27) gestacijskih tjedana. Sedmero djece je bilo živorođeno. Odnos muške i ženske djece bio je 3 (12/4). Prosječna tjelesna masa novorođene muške djece je bila 2648 &plusmn ; 794 g, ženske djece 2125&plusmn ; 505 g, a prosječna gestacijska dob pri porođaju za oba spola 37 tjedana. Trećina novorođenčadi je umrla tijekom prvog tjedna života. Najčešće malformacije bile su anomalije urogenitalnog sustava 80% ; 12/15), oka (66, 7% ; 10/15) i udova (53, 3% ; 8/15). Prosječna dob majki bila je 27, 6 &plusmn ; 5, 5 godina, a prosječna dob očeva 30&plusmn ; 5 godina. Srodstvo među roditeljima registrirano je u 6 slučajeva (6/13), a u četiri obitelji već je bilo rođeno dijete s Fraserovim sindromom (4/13). Svi slučajevi su dijagnosticirani u zapadnom dijelu Europe, a 59% (10/17) ih je iz Velike Britanije i Portugala.

Oculoariculovertebral spectrum (OAVS) is a phenotypically and genetically heterogenous disorder grouping together different conditions thought to be caused by impaired development of the first and second branchial arches including Goldenhar syndrome, facioauriculovertebral syndrome, hemifacial microsomia, and otomandibular dysostosis. We present the results of the population-based epidemiological study on the severe end of OAV spectrum. The data were extracted from the database of EUROCAT (European Surveillance of Congenital Anomalies), a large European network of birth defect registries that use the same epidemiological methodologies. Based on data collected during the 1980-2004 period, we found the prevalence of the severe OAVS cases to be 2.63/100 000 births or 1/38022. The most frequently associated congenital malformations were major ear malformations that accounted for 30% of cases (68/224). Vertebral anomalies were reported in 30% of cases (67/224), and cardiac defects were present in 25% of cases (57/224). Severe central nervous system involvement was rare (17/224 – 8%). Prenatal ultrasound examination in the period 2000-2004 detected abnormalities in 15% (16/111) of cases. Live born infants with OAVS have a high first week survival (98.5%). Maternal and paternal ages do not seem to be risk factors for OAVS. Almost 35% of patients, born after the 37th week of gestation, weighed less than 2500 g. Among 272 patients, consanguinity of parents was registered in 5 cases. OAVS among sibs was found in 4 cases, while family history for OAVS was positive in additional 10 cases. No evidence of exposure to consistent teratogenic agents including maternal diabetes was noted.

Okuloaurikulovertebralni spektar (OAVS) (MIM 164210) obuhvaća više kliničkih entiteta uključujući Goldenharov sindrom, facioaurikulovertebralni sindrom, hemifacijalnu mikrosomiju i otomandibularnu dizostozu. Ima varijabilnu kliničku ekspresiju koja se očituje prvenstveno u poremećaju razvoja kraniofacijalnih struktura i kralježnice. Karakteristične promjene na licu obuhvaćaju različit stupanj anomalija uha i oka te unilateralnu hipoplaziju lica. Uz anomalije kralježnice, nerijetko su prisutne i malformacije drugih organa i sustava. Prikazujemo rezultate ispitivanja epidemiologijskih obilježja spektra OAVS u europskoj populaciji. Služili smo se podatcima mreže 33 europska populacijska registra prirođenih mana koji se služe istom metodologijom, što omogućava zajedničku analizu podataka. U promatranom razdoblju od 1980.-2004. godine prevalencija OAVS-a bila je 2, 63/100000 (272/10318446) ili 1/38022. Prevalencija je bila stalna tijekom cijelog promatranog razdoblja. Živorođeno je bilo 94, 5% (257/272) djece, 0, 7% (2/272) je bilo mrtvorođeno, dok je 4, 8% (13/272) pobačeno uz medicinsku indikaciju. Prvi tjedan života preživjelo je visok 98, 5% živorođenih. U razdoblju od posljednjih pet godina prenatalno je otkriveno 19, 8% slučajeva u dobi od 22, 7&plusmn ; 5 tjedana gestacije. Omjer muške i ženske djece bio je 1, 24 (150/121). Najčešće pridružene anomalije uz one definicijom uključene u OAVS bile su srčane mane 25, 4% (57/224) i urogenitalne anomalije (14, 3% ; 32/224). Roditelji 5-ero djece su u srodstvu, dok je obiteljska anamneza bila pozitivna u 14 slučajeva. Šećerna bolest majki bila je prisutna u 3.1% trudnoća.

Objectives: to determine the presence of congenital heart defects (CHD) in the three selected rare dysmorphic syndromes (Cornelia de Lange syndrome (CdLS), oculo-auriculo-vertebral spectrum (OAVS) including Goldenhar syndrome, and Fraser syndrome (FS)). Design and Participants: the data were extracted from the database of EUROCAT (European Surveillance of Congenital Anomalies), a large European network of population-based congenital anomaly registries that use the same epidemiological methodologies. Main Outcome Measures: establishing the frequency and distribution of specific types of CHD on the large population-based sample of patients affected with these rare syndromes and determining the impact of the presence of CHD on the time of the diagnosis and survival. Results: cardiac anomalies were the most common in CdLS, being present in 46% (42/93) of patients. Congenital heart defects were found in 25% (57/224) of OAVS cases and in 20% (3/15) of Fraser patients. Ventricular septal defect was the most frequent anomaly in all analysed syndromes and was recorded in 14% (13/93) of CdLS, 12% (27/224) of OAVS patients and in 7% (1/15) of FS patients. Atrial septal defect followed, with 11% (10/93), 8% (17/224) and 7% (1/15) of cases, respectively. Pulmonary valve stenosis was also frequent in CdLS (10% - 9/93). Dextrocardia was noted in 4 patients with OAVS (2%). CHD in CdLS, OAVS or FS had no significant impact on the time of the diagnosis (p=0.983, p=0.078, p= 0.164, respectively) or survival (p=0.750, p= 0.124, p= 0.261, respectively) of the cases. Conclusion: the CHD proportion in CdLS, OAVS and FS in EUROCAT population is comparable with the data from literature. Survival and time of diagnosis have not significantly affected the time of diagnosis or survival of cases.

Background European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than I million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance.Methods The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members.Results Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries.Conclusions Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry. Copyright (c) 2006 John Wiley & Sons, Ltd.

CdLS is a multiple congenital anomaly/metal retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay and a variety of associated major malformations. We present results of the population-based epidemiological study of the classical form of Cornelia de Lange Syndrome (CdLS). The data were provided by 33 registries from 16 European countries. Registries participate in the large European network of birth defect registries – EUROCAT, using the same epidemiological methodologies. 106 cases of CdLS have been identified in the total of 8 604 049 births, which corresponds to a prevalence of 1.23/100000 births. There were 96 live births, 3 still births, and 6 terminations of pregnancy. Prenatal diagnosis by ultrasound examination accounts for 23.5 % of all diagnosed cases. Live born infants with CdLS have a high first week survival rate (81%). The most frequent major congenital malformations associated with CdLS are limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (49.2%) and cleft palate (21.7%). In the majority of cases the karyotype is normal. Identified abnormal karyotypes (46, XYdel83)(q12q21), inv(5)(p13q13) and 46, XX t(X ; 22)(p11 ; qter)) presumably disrupt genes identified to be responsible for CdLS. Maternal age and paternal age do not seem to be the risk factors for CdLS. Almost 80% of the cases born after the 37th week of gestation weight less than 2500 g ; low birth weight correlates with a more severe phenotype, including severe limb anomalies. We found no evidence of exposure to consistent teratogenes.

NEPHIRD is a network of Public Health Institutions working on rare diseases (RD) in Europe funded by European Commission and involving 18 countries. Seven RD including Prader Willi syndrome, neurofibromatosis type 1, Rett syndrome, myastenia gravis, propionic acidemia, Cornelia de Lange and limb defects, have been identified as a working list of NEPHIRD activities. The objectives of NEPHIRD are 1) collection and evaluation of epidemiological data (i.e. incidence, prevalence) of selected RD ; 2) assessment of quality and accessibility of health and social care services ; 3) assessment of quality of life of people affected by RD. 1. A review of available epidemiological studies was performed on myastenia gravis as a model. Thirteen population-based studies performed during the last twenty years were examined. Heterogeneity in the annual occurrence was observed ; this may be partly due to differences in the study designs. 2. A pilot survey involving patients' associations was carried out in several EU countries to assess accessibility and quality of health care and social services in patients with myastenia gravis, neurofibromatosis type 1, Prader Willi syndrome and Rett syndrome. Negative issues were identified in particular for MG, concerning availability of information, support by social services and vocational training. For all diseases, readiness to help by health operators was the most positive point. 3. To assess the health-related quality of life (HRQoL) we selected NF1 and Prader Willi syndrome as case-study. All patients affected by NF1 and PW underwent a) clinical examination and b) patients oriented evaluation. a) With regards to clinical examination, we performed extensive and standardized clinical examination, specific for each disease. b) Patient-oriented evaluation was assessed by Health Related Quality of Life Questionnaire, such as SF-36 and CHQ. Patients with NF1 and PW had lower scores than the healthy general population, for all domains of SF-36 profile and CHQ. In conclusion, data produced in the frame of NEPHIRD projects highlights the following key issues:  A systematic review of met analysis will be necessary to produce epidemiological indices for diseases without epidemiological data collection.  The need to carry out surveys on the opinion and degree of empowerment of health and social services users  The importance of HRQoL survey to evaluate the impact of diseases on QoL

Congenital anomalies, including chromosomal abnormalities, single gene disorders, and isolated/multiple anomalies due to teratogenic exposure or of unknown origin are an important medical and public health problem. They are the leading cause of stillbirth and infant mortality and an important contributor to childhood morbidity in developed countries. Although as a group they represent a signifidcant health care problem, birth defects are an assembly of numerous individually rare diseases. The available knowledge on their aetiology, epidemiology, prevention, diagnosis and treatment is inadequate. To bring together data on the individuals affected by genetic disorders and to promote the research on the causes and prevention of congenital anomalies, population - based networks of registries for the surveillance of birth defects have been set in different parts of the world. In 1979 started the EUROCAT, European network of registries covering today 1.5 million births per year, or a quarter of births in Europe. It is designed to provide epidemiological data and to identify genetic and environmental factors immportant in the aetiology of birth defects. Epidemiological data on congenital anomalies reported among live births, stillbirths, and termitantions of pregnancy after prenatal diagnosis are recorded. This makes possible the identification of teratogenic exposures and the assessment of the impact of primary prevention and prenatal screening policies and prectice at a population level. Recent studies performed by the EUROCAT will be presented, pointing out to the importance of the joint approach to European public health questions concerning surveillance of birth defects.

Prevalence of syndromes

Genetic syndromes mostly occur sporadically in couples with no prior risk. Ultrasound (US) screening provides a potential tool to detect them successfully. Due to the fact that many of these syndromes are quite rare, the clinical use of routine prenatal ultrasound in their detection has not been fully investigated. We present data on the prenatal diagnosis of nine non-chromosomal genetic syndromes provided by 25 congenital malformation registries across Europe. US led to the prenatal detection of 32% of 536 cases of analysed genetic syndromes, thereby resulting in a 24% reduction in their prevalence at birth, due to termination of pregnancy. The detection rate varies with the different countries’ policies of prenatal screening, the operator's skill, equipment used, the time of the screening and the type and severity of the syndrome presentation.

Epidemiology of rare syndromes in Europe

Background: Neural Tube Defects (NTDs) are among the most commonly occurring fetal abnormalities and although it has been established for a decade that periconceptional folic acid supplementation reduces the risk of both recurrence and of first occurrence, implementation has proved to be and enormous public health challenge. This has been met in a variety of ways in different parts of the world with varying degrees of success. The aim of this study was to establish what action was being taken across Europe in relation to periconceptional folic acid supplementation and what effect this was having on the prevalence of NTDs in Europe. Methods: EUROCAT is a network of 36 congenital anomaly registries in Europe collaborating in the epidemiological surveillance of congenital anomalies. Representatives from 17 countries participating in EUROCAT agreed to provide information about the folic acid situation in their country, and NTD rates were extracted form Central Registry database for 1980-1999. Findings presented here are preliminary. Results: At the beginning of 2001, official governmental recommendation that women planning a pregnancy should take 0.4 mg of folic acid supplementation daily was in operation in ten of the 17 countries. The earliest of those countries to introduce an official supplementation policy was the UK in 1992 and the latest was Spain in 2001. In the remaining seven participating countries, no official government recommendation about supplementation was in place, however, professional bodies within a subset had in fact recommended supplementation. While foods fortified with folic acid are available in many of the countries surveyed, only Germany has legislation covering fortification (100 g of grain must be fortified with not less than 30 μ g of folic acid). Mandatory fortification is currently under consideration in Denmark, Switzerland and the United Kingdom. Only six countries had official health education initiatives: UK, Ireland, France, Netherlands, Norway and Denmark. Studies in most countries suggest that the majority of women remained unaware of the protective effect of folic acid and only a tiny minority took it at the appropriate time. Women in Ireland, the UK and Norway were found to be more likely to know about and take supplementation. Commencement of folic acid supplementation may be affected by the mother's approach to "planning" pregnancy. In most countries, it is not known what percentage of pregnancies are "planned". In Germany, a number of studies found that between 66-72% of pregnancies were "planned", estimates were found to be lower elsewhere. The prevalence of NTDs (including terminations) has not shown any steady decline in the 1990s across Europe. Conclusions: The potential for preventing neural tube defects by periconceptional folic acid supplementation is still far from being fulfilled in Europe.

Valproic acid has a long history of use for the treatment of seizures but is a recognized teratogen. During the first trimester of pregnancy, maternal exposure to valproic acid monotherapy is associated with increased risk of spina bifida, and several studies have suggested an increased risk of other major congenital malformations. However, individual studies generally have limited power to detect an excess risk of specific major malformations. These authors first conducted a case-control study using combined data from 8 individual cohort studies in the medical literature, including a total of 1565 pregnancy outcomes in which the fetus was exposed to valproic acid; this large study sample had increased power to identify other major malformations associated with valproic acid monotherapy during the first trimester. A total of 118 (7.5%) major congenital malformations were observed; of these, 14 appeared to be significantly increased in association with first trimester exposure to valproic acid monotherapy. The investigators then performed a population-based, case-control study using the EUROCAT (European Surveillance of Congenital Anomalies) antiepileptic study database, which included 98,075 births, stillbirths, and terminations with major congenital malformations among 3.8 million births in 14 European countries from 1995 to 2005, to evaluate the incidence of these 14 malformations in exposed and unexposed fetuses. The association between valproic acid exposure and congenital malformations was evaluated in cases which had the 14 congenital anomalies shown to be associated with valproic acid (n = 37,154) and in 2 control groups. Control group 1 (n = 39,472) was comprised of infants with anomalies that have not been linked to valproic acid exposure and control group 2 (n = 11,763) was comprised of infants with chromosome abnormalities. The frequency of exposure to valproic acid was 3 times higher among cases (3.3 per 1000) than among control groups 1 and 2 (1.1 per 1000 for each). Multiple logistic regression analysis showed that, compared with no exposure to any antiepileptic drug, exposure to valproic acid monotherapy during the first trimester was associated with a significantly increased risk of 6 of the 14 malformations; the adjusted odds ratios were increased for spina bifida (adjusted odds ratios, 12.7; 95% confidence interval [CI], 7.7-20.7); atrial septal defect (2.5; 95% CI, 1.4-4.4); cleft palate (5.2; 95% CI, 2.8-9.9); hypospadias (4.8; 95% CI, 2.9-8.1); polydactyly (2.2; 95% CI, 1.0-4.5); and craniosynostosis (6.8; 95% CI, 1.8-18.8). The odds ratios were similar when valproic acid exposure was compared to exposure to other antiepileptic drugs. These findings show that exposure of the fetus to valproic acid during the first trimester is associated with an increased risk of 6 specific malformations, as compared with no exposure to antiepileptic drugs or exposure to other antiepileptic drugs.