Publications by authors named "Hanitra Randrianaivo"

39 Publications

Epidemiology of Pierre-Robin sequence in Europe: A population-based EUROCAT study.

Paediatr Perinat Epidemiol 2021 Sep 16;35(5):530-539. Epub 2021 Jun 16.

French West Indies Registry, Registre des Malformations des Antilles (REMALAN), Maison de la Femme de la Mère et de l'Enfant, University Hospital of Martinique, Fort-de-France, France.

Background: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden.

Objective: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies.

Methods: We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model.

Results: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%).

Conclusions: This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS.
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http://dx.doi.org/10.1111/ppe.12776DOI Listing
September 2021

Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders.

Genome Med 2021 May 21;13(1):90. Epub 2021 May 21.

Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.

Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.

Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.

Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.
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http://dx.doi.org/10.1186/s13073-021-00900-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140440PMC
May 2021

Signal Detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference.

Drug Saf 2021 Jul 9;44(7):765-785. Epub 2021 May 9.

Population Health Research Institute, St George's, University of London, London, UK.

Introduction: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications.

Aims: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals.

Methods: Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation.

Results: EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly.

Conclusion: EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.
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http://dx.doi.org/10.1007/s40264-021-01073-zDOI Listing
July 2021

Cost and outcomes of the ultrasound screening program for birth defects over time: a population-based study in France.

BMJ Open 2020 07 20;10(7):e036566. Epub 2020 Jul 20.

AP-HP Health economics research unit & Department of Public Health, Henri Mondor Hospital,CRESS-UMR1153 - INSERM & UPEC, Paris, France

Objective: To assess trends in the average costs and effectiveness of the French ultrasound screening programme for birth defects.

Design: A population-based study.

Setting: National Public Health Insurance claim database.

Participants: All pregnant women in the 'Echantillon Généraliste des Bénéficiaires', a permanent representative sample of 1/97 of the individuals covered by the French Health Insurance System.

Main Outcomes Measures: Trends in the costs and in the average cost-effectiveness ratio (ACER) of the screening programme (in € per case detected antenatally), per year, between 2006 and 2014. incremental cost-effectiveness ratio (ICER) from 1 year to another were also estimated. We assessed costs related to the ultrasound screening programme of birth defects excluding the specific screening of Down's syndrome. The outcome for effectiveness was the prenatal detection rate of birth defects, assessed in a previous study. Linear and logistic regressions were used to analyse time trends.

Results: During the study period, there was a slight decrease in prenatal detection rates (from 58.2% in 2006 to 55.2% in 2014; p=0.015). The cost of ultrasound screening increased from €168 in 2006 to €258 per pregnancy in 2014 (p=0.001). We found a 61% increase in the ACER for ultrasound screening during the study period. ACERs increased from €9050 per case detected in 2006 to €14 580 per case detected in 2014 (p=0.001). ICERs had an erratic pattern, with a strong tendency to show that any increment in the cost of screening was highly cost ineffective.

Conclusion: Even if the increase in costs may be partly justified, we observed a diminishing returns for costs associated with the prenatal ultrasound screening of birth defects, in France, between 2006 and 2014.
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http://dx.doi.org/10.1136/bmjopen-2019-036566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375504PMC
July 2020

High prevalence of Bardet-Biedl syndrome in La Réunion Island is due to a founder variant in ARL6/BBS3.

Clin Genet 2020 08 22;98(2):166-171. Epub 2020 Jun 22.

Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, renal abnormalities, obesity, cognitive impairment, and hypogonadism. Biallelic pathogenic variants have been identified in 24 genes, leading to BBS in an autosomal recessive inheritance pattern. In this study, we investigated a cohort of 16 families (20 individuals) presenting with typical BBS originating from La Réunion Island using sequencing (Sanger and high-throughput methods) and SNP array. In eight families (12 individuals) we identified the same ARL6/BBS3 variation [c.535G > A, p.(Asp179Asn)]. Bioinformatics and functional analyses revealed an effect of this variant on the splicing of ARL6/BBS3. Owing to the relatively high frequency of this variant, a possible founder effect was suspected. Genotyping of six individuals revealed a common 3.8-Mb haplotype and estimated the most recent common ancestor to about eight generations confirmed by the known genealogy. Knowledge of this founder effect modifies our diagnostic strategy and enables a personalized genetic counseling for patients from La Réunion Island. Being the first description of BBS patients from La Réunion Island, we could estimate its prevalence between ~1/45000 and ~ 1/66000 individuals.
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http://dx.doi.org/10.1111/cge.13768DOI Listing
August 2020

Maternal risk factors for the VACTERL association: A EUROCAT case-control study.

Birth Defects Res 2020 05 22;112(9):688-698. Epub 2020 Apr 22.

CARIS, Public Health Wales, Singleton Hospital, Swansea, UK.

Background: The VACTERL association (VACTERL) is the nonrandom occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. Despite suggestions for involvement of several genes and nongenetic risk factors from small studies, the etiology of VACTERL remains largely unknown.

Objective: To identify maternal risk factors for VACTERL in offspring in a large European study.

Methods: A case-control study was performed using data from 28 EUROCAT registries over the period 1997-2015 with case and control ascertainment through hospital records, birth and death certificates, questionnaires, and/or postmortem examinations. Cases were diagnosed with VACTERL, while controls had a genetic syndrome and/or chromosomal abnormality. Data collected included type of birth defect and maternal characteristics, such as age, use of assisted reproductive techniques (ART), and chronic illnesses. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) with 95% confidence intervals (95% CI).

Results: The study population consisted of 329 VACTERL cases and 49,724 controls with recognized syndromes or chromosomal abnormality. For couples who conceived through ART, we found an increased risk of VACTERL (aOR 2.3 [95% CI 1.3, 3.9]) in offspring. Pregestational diabetes (aOR 3.1 [95% CI 1.1, 8.6]) and chronic lower obstructive pulmonary diseases (aOR 3.9 [95% CI 2.2, 6.7]) also increased the risk of having a child with VACTERL. Twin pregnancies were not associated with VACTERL (aOR 0.6 [95% CI 0.3, 1.4]).

Conclusion: We identified several maternal risk factors for VACTERL in offspring befitting a multifactorial etiology.
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http://dx.doi.org/10.1002/bdr2.1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319423PMC
May 2020

Pregnancy outcomes of Q fever: prospective follow-up study on Reunion island.

BMC Infect Dis 2019 Nov 27;19(1):1001. Epub 2019 Nov 27.

INSERM CIC 1410 Epidémiologie Clinique, CHU Réunion, Centre Hospitalier Universitaire, Groupe Hospitalier Sud Réunion, BP 350, 97448, Saint Pierre, Cedex - Reunion, France.

Background: Q fever has been associated with perinatal complications. We conducted a prospective follow-up study to assess both the incidence of adverse pregnancy outcomes (APOs) associated with Coxiella burnetii infection and the contribution of Q fever to APOs.

Methods: Between May 1 and October 31, 2013, within the regional perinatal health care centre of Saint Pierre, Reunion island, we investigated unexplained miscarriages, stillbirths, preterm births or small-for-gestational age children. Seropositivity for C. burnetii antibodies was defined using indirect immunofluorescence for a phase 2 IgG titre ≥1:64. Acute Q fever was defined for a high phase 2 IgG titre ≥1:256 (compatible with recent or active infection) or the detection of C. burnetii genome in miscarriage products and placentas. Incidence rate ratios (IRR) for Q fever related APOs (taken as a composite outcome or individually) were assessed using Poisson regression models for dichotomous outcomes controlling major confounders.

Results: Over a 6-month period, 179 pregnant women suspected or diagnosed with an APO were investigated for Q fever, of whom 118 met the definition for an APO. Of these, 19 were seropositive and 10 presented a profile indicative of an acute infection. For three women with an acute Q fever, the chronology between the onset of infection, the APO (2 miscarriages, 1 preterm birth) and the seroconversion suggested causality in the pathogenesis. The cumulative incidence of Q fever related APOs was estimated between 2.2‰ and 5.2‰, whether causality was required or not. Both C. burnetii exposure and acute Q fever were independently associated with APOs (IRR 1.55, 95% CI 1.31-1.84; IRR 1.47, 95% CI 1.15-1.89, respectively).

Conclusions: In the endemic context of Reunion island, acute Q fever may lead to APOs. To limit the burden of Q fever on reproduction, pregnant women should be kept away from farms and avoid direct contact with ruminants.
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http://dx.doi.org/10.1186/s12879-019-4619-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880502PMC
November 2019

Spectrum of congenital anomalies among VACTERL cases: a EUROCAT population-based study.

Pediatr Res 2020 02 9;87(3):541-549. Epub 2019 Sep 9.

French West Indies Registry, Registre des Malformations des Antilles (REMALAN), Maison de la Femme de la Mère et de l'Enfant, University Hospital of Martinique, Fort-de-France, France.

Background: The VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association is the non-random occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. Diagnosing VACTERL patients is difficult, as many disorders have multiple features in common with VACTERL. The aims of this study were to clearly outline component features, describe the phenotypic spectrum among the largest group of VACTERL patients thus far reported, and to identify phenotypically similar subtypes.

Methods: A case-only study was performed assessing data on 501 cases recorded with VACTERL in the JRC-EUROCAT (Joint Research Centre-European Surveillance of Congenital Anomalies) central database (birth years: 1980-2015). We differentiated between major and minor VACTERL features and anomalies outside the VACTERL spectrum to create a clear definition of VACTERL.

Results: In total, 397 cases (79%) fulfilled our VACTERL diagnostic criteria. The most commonly observed major VACTERL features were anorectal malformations and esophageal atresia/tracheo-esophageal fistula (both occurring in 62% of VACTERL cases), followed by cardiac (57%), renal (51%), vertebral (33%), and limb anomalies (25%), in every possible combination. Three VACTERL subtypes were defined: STRICT-VACTERL, VACTERL-LIKE, and VACTERL-PLUS, based on severity and presence of additional congenital anomalies.

Conclusion: The clearly defined VACTERL component features and the VACTERL subtypes introduced will improve both clinical practice and etiologic research.
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http://dx.doi.org/10.1038/s41390-019-0561-yDOI Listing
February 2020

Epidemiology of Dandy-Walker Malformation in Europe: A EUROCAT Population-Based Registry Study.

Neuroepidemiology 2019 12;53(3-4):169-179. Epub 2019 Jul 12.

Congenital Anomaly Register and Information Service for Wales (CARIS), Public Health Wales, Swansea, United Kingdom.

Background: Dandy-Walker (DW) malformation is a rare and severe congenital anomaly of the posterior fossa affecting the development of the cerebellum and the fourth ventricle.

Objective: The aim of this study was to investigate the epidemiology of DW malformation, using data from the European population-based registries of congenital anomalies in the European Surveillance of Congenital Anomalies network.

Methods: Anonymous individual data on cases of DW malformation diagnosed in 2002-2015 from 28 registries in 17 countries were included. Prevalence, prenatal detection rate, proportions and types of associated anomalies were estimated. Cases of DW variant were considered and analysed separately.

Results: Out of 8,028,454 surveyed births we identified a total of 734 cases, including 562 DW malformation cases and 172 DW variant cases. The overall prevalence of DW malformation was 6.79 per 100,000 births (95% CI 5.79-7.96) with 39.2% livebirths, 4.3% foetal deaths from 20 weeks gestational age, and 56.5% terminations of pregnancy after prenatal diagnosis of foetal anomaly at any gestation (TOPFA). The livebirth prevalence was 2.74 per 100,000 births (95% CI 2.08-3.61). The prenatal detection rate was 87.6%. Two-hundred and seventy-three cases (48.6%) had an isolated cerebral anomaly and 24.2, 19.2 and 5.5% cases were associated with other structural non-cerebral anomalies, chromosomal anomalies and genetic syndromes respectively. The prevalence of DW variant was 2.08 per 100,000 (95% CI 1.39-3.13).

Conclusions: This European population-based study provides the epidemiological profile of DW malformation. All birth outcomes were analysed and TOPFA represented more than half of the cases. About 50% of the cases of DW malformation were associated with other non-cerebral anomalies. Large populations and all birth outcomes are essential in epidemiological studies of rare and severe congenital anomalies.
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http://dx.doi.org/10.1159/000501238DOI Listing
June 2020

Epidemiology of congenital cerebral anomalies in Europe: a multicentre, population-based EUROCAT study.

Arch Dis Child 2019 12 26;104(12):1181-1187. Epub 2019 Jun 26.

European Commission, Joint Research Centre (JRC), Ispra, Italy.

Objectives: To describe the epidemiology and geographical differences in prevalence of congenital cerebral anomalies in Europe.

Design And Setting: Congenital cerebral anomalies (International Classification of Diseases, 10th Revision code Q04) recorded in 29 population-based EUROCAT registries conducting surveillance of 1.7 million births per annum (29% of all European births).

Participants: All birth outcomes (live births, fetal deaths from 20 weeks gestation and terminations of pregnancy after prenatal diagnosis of a fetal anomaly (TOPFA)) from 2005 to 2014.

Main Outcome Measures: Prevalence, proportion of associated non-cerebral anomalies, prenatal detection rate.

Results: 4927 cases with congenital cerebral anomalies were identified; a prevalence (adjusted for under-reporting) of 9.8 (95% CI: 8.5 to 11.2) per 10 000 births. There was a sixfold difference in prevalence across the registries. Registries with higher proportions of prenatal diagnoses had higher prevalence. Overall, 55% of all cases were liveborn, 3% were fetal deaths and 41% resulted in TOPFA. Forty-eight per cent of all cases were an isolated cerebral anomaly, 25% had associated non-cerebral anomalies and 27% were chromosomal or part of a syndrome (genetic or teratogenic). The prevalence excluding genetic or chromosomal conditions increased by 2.4% per annum (95% CI: 1.3% to 3.5%), with the increases occurring only for congenital malformations of the corpus callosum (3.0% per annum) and 'other reduction deformities of the brain' (2.8% per annum).

Conclusions: Only half of the cases were isolated cerebral anomalies. Improved prenatal and postnatal diagnosis may account for the increase in prevalence of congenital cerebral anomalies from 2005 to 2014. However, major differences in prevalence remain between regions.
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http://dx.doi.org/10.1136/archdischild-2018-316733DOI Listing
December 2019

Discordant malformations in monochorionic twins: a retrospective cohort study in La Reunion Island.

J Matern Fetal Neonatal Med 2020 Dec 25;33(24):4069-4075. Epub 2019 Mar 25.

Service de Gynécologie - Obstétrique, Centre Hospitalier Universitaire Sud-Réunion, Saint-Pierre, France.

Discordant malformation between monochorionic twins is a rare and unknown phenomenon. To estimate the incidence of discordant monochorionic twins and to describe their characteristics. A retrospective multicenter cohort of pregnancies between 2002 and 2015 in La Reunion Island was analyzed, thanks to a population-based register. Only monochorionic pregnancies were included in order to analyze specifically monozygotic twins. We defined as discordant twin pairs those in which different malformations were identified for each twin and those with only one fetus showing a malformation. During the study period, 203,807 births occurred, including 410 monochorionic twin pairs. Congenital anomalies rate for monochorionic twin pairs was 10.7%. We included 38 monochorionic twin pairs with discordant phenotypes, which represent 9.3% of monochorionic twin pairs and 86.4% of monochorionic twin pairs affected by congenital anomalies. Among them, both twins were affected by different congenital anomalies in 7 pairs (18.4%), and only one twin was affected in 31 pairs (81.6%). We identified 20 congenital heart anomalies (44.4%), 5 brain anomalies (11.1%), 5 genital anomalies (11.1%), 4 axial bones and skull anomalies (8.9%), 4 limb anomalies (8.9%), 4 facial anomalies (8.9%), 3 urological anomalies (6.6%), 2 thoracic anomalies (4.4%), 1 bile duct anomaly (2,2%), 1 abdominal parietal defect (2.2%), and 1 aneuploidy (2.2%). Among them, 3 (6.6%) fetuses had an association of malformations. Among the 45 fetuses with malformations, 37 fetuses (82.2%) were born alive and 21 (46.6%) had postnatal surgery. Despite a supposed identical genome, discordant congenital anomalies in monochorionic twin pregnancies are not exceptional and related to genetic and epigenetic mechanisms. Sonographers and pediatricians should know that in monochorionic twin a pair, the occurrence of discordant phenotypes is high (9.3%).
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http://dx.doi.org/10.1080/14767058.2019.1594767DOI Listing
December 2020

Trends in resource use and effectiveness of ultrasound detection of fetal structural anomalies in France: a multiple registry-based study.

BMJ Open 2019 02 15;9(2):e025482. Epub 2019 Feb 15.

Fetal Medicine Department, Sorbonne University, AP-HP, Armand Trousseau Hospital, Paris, France.

Objective: To analyse trends in the number of ultrasound examinations in relation to the effectiveness of prenatal detection of birth defects using population-based data in France.

Design: A multiple registry-based study of time trends in resource use (number of ultrasounds) and effectiveness (proportion of cases prenatally diagnosed).

Setting: Three registries of congenital anomalies and claims data on ultrasounds for all pregnant women in France.

Participants: There were two samples of pregnant women. Effectiveness was assessed using data from three French birth defect registries. Resource use for ultrasound screening was based on the French national healthcare database.

Main Outcome Measures: The main outcome measures were prenatal diagnosis (effectiveness) and the average number of ultrasounds (resource use). Statistical analyses included linear and logistic regression models to assess trends in resource use and effectiveness of prenatal testing, respectively.

Results: The average number of ultrasound examinations per pregnancy significantly increased over the study period, from 2.47 in 2006 to 2.98 in 2014 (p=0.005). However, there was no significant increase in the odds of prenatal diagnosis. The probability of prenatal diagnosis was substantially higher for cases associated with a chromosomal anomaly (91.2%) than those without (51.8%). However, there was no evidence of an increase in prenatal detection of either over time.

Conclusions: The average number of ultrasound examinations per pregnancy increased over time, whereas the probability of prenatal diagnosis of congenital anomalies did not. Hence, there is a need to implement policies such as high-quality training programmes which can improve the efficiency of ultrasound examinations for prenatal detection of congenital anomalies.
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http://dx.doi.org/10.1136/bmjopen-2018-025482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398629PMC
February 2019

Beckwith Wiedemann syndrome: A population-based study on prevalence, prenatal diagnosis, associated anomalies and survival in Europe.

Eur J Med Genet 2018 Sep 31;61(9):499-507. Epub 2018 May 31.

Queen Mary University of London, UK.

Beckwith Wiedemann syndrome is a complex developmental disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. We present epidemiological and clinical aspects of patients with Beckwith Wiedemann syndrome diagnosed prenatally or in the early years of life, using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. The study population consisted of 371 cases identified between January 1990 and December 2015 in 34 registries from 16 European countries. There were 15 (4.0%) terminations of pregnancy after prenatal detection of severe anomaly/anomalies, 10 fetal deaths (2.7%), and 346 (93.3%) live-births. Twelve (3.6%) of the 330 live-births with available information on survival died in the first week of life, of those eleven (91.6%) were preterm. First-year survival rate was 90.9%. Prematurity was present in 40.6% of males and 33.9% of females. Macrosomia was found in 49.2% and 43.3% of preterm males and females, respectively. Of term newborns, 41.1% of males and 24% of females were macrosomic. Out of 353 cases with known time of diagnosis, 39.9% were suspected prenatally, 36.3% at birth, 7.6% were diagnosed in the first week of life, and 16.2% in the first year of life. The mean gestational age at prenatal diagnosis by obstetric ultrasound was 19.8 ± 6.2 (11-39) gestational weeks. The mean prenatal diagnosis of cases where parents opted for termination of pregnancy was 15.3 ± 2.4 (11-22) gestational weeks, and the mean gestational age at termination was 19.3 ± 4.1 (13-26) gestational weeks. The prenatal detection rate was 64.1% (141/220) with no significant change over time. There were 12.7% of familial cases. The study confirmed the association of assisted reproductive technologies with Beckwith Wiedemann syndrome, as 7.2% (13/181) of patients were conceived by one of the methods of assisted reproductive technologies, which was three times higher compared to the general population of the countries included in the study. Twin pregnancies of undetermined zygosity were recorded in 5.7% (21/365) cases, and were on average three to four times more common than in European countries that participated in the study. The estimated mean prevalence of classical Beckwith Wiedemann syndrome in Europe was 3.8 per 100,000 births or 1:26,000 births.
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http://dx.doi.org/10.1016/j.ejmg.2018.05.014DOI Listing
September 2018

Epidemiology of septo-optic dysplasia with focus on prevalence and maternal age - A EUROCAT study.

Eur J Med Genet 2018 Sep 10;61(9):483-488. Epub 2018 May 10.

European Commission, DG Joint Research Centre, Ispra, Italy.

Septo-optic nerve dysplasia is a rare congenital anomaly with optic nerve hypoplasia, pituitary hormone deficiencies and midline developmental defects of the brain. The clinical findings are visual impairment, hypopituitarism and developmental delays. The aim of this study was to report prevalence, associated anomalies, maternal age and other epidemiological factors from a large European population based network of congenital anomaly registries (EUROCAT). Data from 29 full member registries for the years 2005-2014 were included, covering 6.4 million births. There were 99 cases with a diagnosis of septo-optic dysplasia. The prevalence of septo-optic dysplasia in Europe was calculated to lie between 1.9 and 2.5 per 100,000 births after adjusting for potential under-reporting in some registries. The prevalence was highest in babies of mothers aged 20-24 years of age and was significantly higher in UK registries compared with other EUROCAT registries (P = 0.021 in the multilevel model) and the additional risk for younger mothers was significantly greater in the UK compared to the rest of Europe (P = 0.027). The majority of septo-optic dysplasia cases were classified as an isolated cerebral anomaly (N = 76, 77%). Forty percent of diagnoses occurred in fetuses with a prenatal diagnosis. The anomaly may not be visible at birth, which is reflected in that 57% of the postnatal diagnoses occurred over 1 month after birth. This is the first population based study to describe the prevalence of septo-optic dysplasia in Europe. Septo-optic dysplasia shares epidemiological patterns with gastroschisis and this strengthens the hypothesis of vascular disruption being an aetiological factor for septo-optic dysplasia.
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http://dx.doi.org/10.1016/j.ejmg.2018.05.010DOI Listing
September 2018

Trends in congenital anomalies in Europe from 1980 to 2012.

PLoS One 2018 5;13(4):e0194986. Epub 2018 Apr 5.

Faculty Life & Health Sciences, University of Ulster, Newtownabbey, United Kingdom.

Background: Surveillance of congenital anomalies is important to identify potential teratogens.

Methods: This study analysed the prevalence of 61 congenital anomaly subgroups (excluding chromosomal) in 25 population-based EUROCAT registries (1980-2012). Live births, fetal deaths and terminations of pregnancy for fetal anomaly were analysed with multilevel random-effects Poisson regression models.

Results: Seventeen anomaly subgroups had statistically significant trends from 2003-2012; 12 increasing and 5 decreasing.

Conclusions: The annual increasing prevalence of severe congenital heart defects, single ventricle, atrioventricular septal defects and tetralogy of Fallot of 1.4% (95% CI: 0.7% to 2.0%), 4.6% (1.0% to 8.2%), 3.4% (1.3% to 5.5%) and 4.1% (2.4% to 5.7%) respectively may reflect increases in maternal obesity and diabetes (known risk factors). The increased prevalence of cystic adenomatous malformation of the lung [6.5% (3.5% to 9.4%)] and decreased prevalence of limb reduction defects [-2.8% (-4.2% to -1.5%)] are unexplained. For renal dysplasia and maternal infections, increasing trends may be explained by increased screening, and deceases in patent ductus arteriosus at term and increases in craniosynostosis, by improved follow up period after birth and improved diagnosis. For oesophageal atresia, duodenal atresia/stenosis and ano-rectal atresia/stenosis recent changes in prevalence appeared incidental when compared with larger long term fluctuations. For microcephaly and congenital hydronephrosis trends could not be interpreted due to discrepancies in diagnostic criteria. The trends for club foot and syndactyly disappeared once registries with disparate results were excluded. No decrease in neural tube defects was detected, despite efforts at prevention through folic acid supplementation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194986PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886482PMC
July 2018

Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome.

Eur J Hum Genet 2018 03 12;26(3):340-349. Epub 2018 Jan 12.

INSERM UMR 1231 GAD team, Genetics of Developmental Anomalies, Université de Bourgogne-Franche Comté, Dijon, France.

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.
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http://dx.doi.org/10.1038/s41431-017-0087-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839001PMC
March 2018

Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies: A European Case-Malformed Control Study.

Drug Saf 2018 04;41(4):415-427

Department of Genetics, EUROCAT Northern Netherlands, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Introduction: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy.

Objective: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring.

Methods: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies.

Results: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0).

Conclusion: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings.
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http://dx.doi.org/10.1007/s40264-017-0627-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878198PMC
April 2018

Gastroschisis in Europe - A Case-malformed-Control Study of Medication and Maternal Illness during Pregnancy as Risk Factors.

Paediatr Perinat Epidemiol 2017 11 25;31(6):549-559. Epub 2017 Aug 25.

Institute of Nursing and Health Research, Ulster University, Newtownabbey, UK.

Background: Gastroschisis, a congenital anomaly of the abdomen, is associated with young maternal age and has increased in prevalence in many countries. Maternal illness and medication exposure are among environmental risk factors implicated in its aetiology.

Methods: A population-based case-malformed control study was conducted using data from 18 European congenital anomaly registries, with information on first trimester medication use, covering 8 million births 1995-2012. 1577 gastroschisis cases (of which 4% stillbirths, 11% terminations of pregnancy) were compared to 153 357 non-chromosomal/monogenic controls. Literature review identified previous associations concerning maternal illness and medication exposure to be tested as signals. Logistic regression adjusted for maternal age group, registry, and time period was used to evaluate associations.

Results: Comparing gastroschisis to other congenital anomalies, the data supported signals concerning maternal depression (aOR 2.52, 95% CI 1.45, 4.39), antidepressant use (aOR 2.03, 95% CI 1.22, 3.38), postnatal depression/psychosis following a previous pregnancy (aOR 8.32, 95% CI 2.56, 27.01), sexually transmitted infections (aOR 2.85, 95% CI 1.13, 7.24), topical antivirals (aOR 5.31, 95% CI 1.63, 17.33), and continuation of oral contraceptives in early pregnancy (aOR 2.17, 95% CI 1.13, 4.18). Exploratory analyses suggested associations with a wider range of maternal infections and medications, including tonsillitis and the expectorant bromhexine.

Conclusions: While it is difficult to disentangle the effects of the medication and underlying indication, our results add to the evidence base on preventable risk factors for gastroschisis. These risk factors may contribute to the higher risk among young mothers, and geographical and temporal variation in prevalence.
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http://dx.doi.org/10.1111/ppe.12401DOI Listing
November 2017

Estimating Global Burden of Disease due to congenital anomaly: an analysis of European data.

Arch Dis Child Fetal Neonatal Ed 2018 Jan 30;103(1):F22-F28. Epub 2017 Jun 30.

Khmelnytsky Perinatal Center, OMNI-Net Ukraine Birth Defects Program, Khmelnytsky, Ukraine.

Objective: To validate the estimates of Global Burden of Disease (GBD) due to congenital anomaly for Europe by comparing infant mortality data collected by EUROCAT registries with the WHO Mortality Database, and by assessing the significance of stillbirths and terminations of pregnancy for fetal anomaly (TOPFA) in the interpretation of infant mortality statistics.

Design, Setting And Outcome Measures: EUROCAT is a network of congenital anomaly registries collecting data on live births, fetal deaths from 20 weeks' gestation and TOPFA. Data from 29 registries in 19 countries were analysed for 2005-2009, and infant mortality (deaths of live births at age <1 year) compared with the WHO Mortality Database. Eight EUROCAT countries were excluded from further analysis on the basis that this comparison showed poor ascertainment of survival status.

Results: According to WHO, 17%-42% of infant mortality was attributed to congenital anomaly. In 11 EUROCAT countries, average infant mortality with congenital anomaly was 1.1 per 1000 births, with higher rates where TOPFA is illegal (Malta 3.0, Ireland 2.1). The rate of stillbirths with congenital anomaly was 0.6 per 1000. The average TOPFA prevalence was 4.6 per 1000, nearly three times more prevalent than stillbirths and infant deaths combined. TOPFA also impacted on the prevalence of postneonatal survivors with non-lethal congenital anomaly.

Conclusions: By excluding TOPFA and stillbirths from GBD years of life lost (YLL) estimates, GBD underestimates the burden of disease due to congenital anomaly, and thus declining YLL over time may obscure lack of progress in primary, secondary and tertiary prevention.
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http://dx.doi.org/10.1136/archdischild-2016-311845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750368PMC
January 2018

Congenital Zika syndrome: time to move from case series to case-control studies and data sharing.

BMJ 2016 Sep 14;354:i4850. Epub 2016 Sep 14.

Department of Pediatrics, Stanford School of Medicine, Palo Alto, CA, USA.

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http://dx.doi.org/10.1136/bmj.i4850DOI Listing
September 2016

Prevalence of microcephaly in Europe: population based study.

BMJ 2016 Sep 13;354:i4721. Epub 2016 Sep 13.

University of Ulster, Newtownabbey, Co Antrim, Northern Ireland, UK.

Objectives:  To provide contemporary estimates of the prevalence of microcephaly in Europe, determine if the diagnosis of microcephaly is consistent across Europe, and evaluate whether changes in prevalence would be detected using the current European surveillance performed by EUROCAT (the European Surveillance of Congenital Anomalies).

Design:  Questionnaire and population based observational study.

Setting:  24 EUROCAT registries covering 570 000 births annually in 15 countries.

Participants:  Cases of microcephaly not associated with a genetic condition among live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly at any gestation.

Main Outcome Measures:  Prevalence of microcephaly (1 Jan 2003-31 Dec 2012) analysed with random effects Poisson regression models to account for heterogeneity across registries.

Results:  16 registries responded to the questionnaire, of which 44% (7/16) used the EUROCAT definition of microcephaly (a reduction in the size of the brain with a skull circumference more than 3 SD below the mean for sex, age, and ethnic origin), 19% (3/16) used a 2 SD cut off, 31% (5/16) were reliant on the criteria used by individual clinicians, and one changed criteria between 2003 and 2012. Prevalence of microcephaly in Europe was 1.53 (95% confidence interval 1.16 to 1.96) per 10 000 births, with registries varying from 0.4 (0.2 to 0.7) to 4.3 (3.6 to 5.0) per 10 000 (χ(2)=338, df=23, I(2)=93%). Registries with a 3 SD cut off reported a prevalence of 1.74 per 10 000 (0.86 to 2.93) compared with those with the less stringent 2 SD cut off of 1.21 per 10 000 (0.21 to 2.93). The prevalence of microcephaly would need to increase in one year by over 35% in Europe or by over 300% in a single registry to reach statistical significance (P<0.01).

Conclusions:  EUROCAT could detect increases in the prevalence of microcephaly from the Zika virus of a similar magnitude to those observed in Brazil. Because of the rarity of microcephaly and discrepant diagnostic criteria, however, the smaller increases expected in Europe would probably not be detected. Clear diagnostic criteria for microcephaly must be adopted across Europe.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021822PMC
http://dx.doi.org/10.1136/bmj.i4721DOI Listing
September 2016

Use of hierarchical models to analyze European trends in congenital anomaly prevalence.

Birth Defects Res A Clin Mol Teratol 2016 Jun;106(6):480-8

Wolfson Institute of Preventive Medicine, Queen Mary University of London, United Kingdom.

Background: Surveillance of congenital anomalies is important to identify potential teratogens. Despite known associations between different anomalies, current surveillance methods examine trends within each subgroup separately. We aimed to evaluate whether hierarchical statistical methods that combine information from several subgroups simultaneously would enhance current surveillance methods using data collected by EUROCAT, a European network of population-based congenital anomaly registries.

Methods: Ten-year trends (2003 to 2012) in 18 EUROCAT registries over 11 countries were analyzed for the following groups of anomalies: neural tube defects, congenital heart defects, digestive system, and chromosomal anomalies. Hierarchical Poisson regression models that combined related subgroups together according to EUROCAT's hierarchy of subgroup coding were applied. Results from hierarchical models were compared with those from Poisson models that consider each congenital anomaly separately.

Results: Hierarchical models gave similar results as those obtained when considering each anomaly subgroup in a separate analysis. Hierarchical models that included only around three subgroups showed poor convergence and were generally found to be over-parameterized. Larger sets of anomaly subgroups were found to be too heterogeneous to group together in this way.

Conclusion: There were no substantial differences between independent analyses of each subgroup and hierarchical models when using the EUROCAT anomaly subgroups. Considering each anomaly separately, therefore, remains an appropriate method for the detection of potential changes in prevalence by surveillance systems. Hierarchical models do, however, remain an interesting alternative method of analysis when considering the risks of specific exposures in relation to the prevalence of congenital anomalies, which could be investigated in other studies. Birth Defects Research (Part A) 106:480-10, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdra.23515DOI Listing
June 2016

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease.

J Am Soc Nephrol 2016 Mar 2;27(3):722-9. Epub 2015 Jul 2.

Assistance Publique des Hôpitaux de Paris, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Department of Pediatric Nephrology, University Hospital Necker-Enfants Malades Paris, France;

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.
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http://dx.doi.org/10.1681/ASN.2014101051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769188PMC
March 2016

Treacher Collins syndrome: a clinical and molecular study based on a large series of patients.

Genet Med 2016 Jan 19;18(1):49-56. Epub 2015 Mar 19.

Service de Génétique Médicale, CHU Strasbourg, Strasbourg, France.

Purpose: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C.

Methods: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene.

Results: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature.

Conclusion: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.
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http://dx.doi.org/10.1038/gim.2015.29DOI Listing
January 2016

Epidemiology of hypospadias in Europe: a registry-based study.

World J Urol 2015 Dec 25;33(12):2159-67. Epub 2015 Feb 25.

Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Background: Hypospadias is a common congenital malformation. The prevalence of hypospadias has a large geographical variation, and recent studies have reported both increasing and decreasing temporal trends. It is unclear whether hypospadias prevalence is associated with maternal age.

Aim: To analyze the prevalence and trends of total hypospadias, isolated hypospadias, hypospadias with multiple congenital anomalies, hypospadias with a known cause, and hypospadias severity subtypes in Europe over a 10-year period and to investigate whether maternal age is associated with hypospadias.

Methods: We included all children with hypospadias born from 2001 to 2010 who were registered in 23 EUROCAT registries. Information on the total number of births and maternal age distribution for the registry population was also provided. We analyzed the total prevalence of hypospadias and relative risks by maternal age.

Results: From 2001 to 2010, 10,929 hypospadias cases were registered in 5,871,855 births, yielding a total prevalence of 18.61 per 10,000 births. Prevalence varied considerably between different registries, probably due to differences in ascertainment of hypospadias cases. No significant temporal trends were observed with the exceptions of an increasing trend for anterior and posterior hypospadias and a decreasing trend for unspecified hypospadias. After adjusting for registry effects, maternal age was not significantly associated with hypospadias.

Conclusions: Total hypospadias prevalence was stable in 23 EUROCAT registries from 2001 to 2010 and was not significantly influenced by maternal age.
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http://dx.doi.org/10.1007/s00345-015-1507-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655014PMC
December 2015

Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study.

Arch Dis Child Fetal Neonatal Ed 2015 Mar 19;100(2):F137-44. Epub 2014 Nov 19.

National Registry of Congenital Anomalies, Department of Medical Genetics, Thomayer Hospital, Prague, Czech Republic.

Introduction: Published prevalence rates of congenital diaphragmatic hernia (CDH) vary. This study aims to describe the epidemiology of CDH using data from high-quality, population-based registers belonging to the European Surveillance of Congenital Anomalies (EUROCAT).

Methods: Cases of CDH delivered between 1980 and 2009 notified to 31 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept.

Results: There were 3373 CDH cases reported among 12 155 491 registered births. Of 3131 singleton cases, 353 (10.4%) were associated with a chromosomal anomaly, genetic syndrome or microdeletion, 784 (28.2%) were associated with other major structural anomalies. The male to female ratio of CDH cases overall was 1:0.69. Total prevalence was 2.3 (95% CI 2.2 to 2.4) per 10 000 births and 1.6 (95% CI 1.6 to 1.7) for isolated CDH cases. There was a small but significant increase (relative risk (per year)=1.01, 95% credible interval 1.00-1.01; p=0.030) in the prevalence of total CDH over time but there was no significant increase for isolated cases (ie, CDH cases that did not occur with any other congenital anomaly). There was significant variation in total and isolated CDH prevalence between registers. The proportion of cases that survived to 1 week was 69.3% (1392 cases) for total CDH cases and 72.7% (1107) for isolated cases.

Conclusions: This large population-based study found an increase in total CDH prevalence over time. CDH prevalence also varied significantly according to geographical location. No significant association was found with maternal age.
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http://dx.doi.org/10.1136/archdischild-2014-306174DOI Listing
March 2015

Major congenital anomalies in babies born with Down syndrome: a EUROCAT population-based registry study.

Am J Med Genet A 2014 Dec 24;164A(12):2979-86. Epub 2014 Sep 24.

Queen Mary University of London, London, United Kingdom.

Previous studies have shown that over 40% of babies with Down syndrome have a major cardiac anomaly and are more likely to have other major congenital anomalies. Since 2000, many countries in Europe have introduced national antenatal screening programs for Down syndrome. This study aimed to determine if the introduction of these screening programs and the subsequent termination of prenatally detected pregnancies were associated with any decline in the prevalence of additional anomalies in babies born with Down syndrome. The study sample consisted of 7,044 live births and fetal deaths with Down syndrome registered in 28 European population-based congenital anomaly registries covering seven million births during 2000-2010. Overall, 43.6% (95% CI: 42.4-44.7%) of births with Down syndrome had a cardiac anomaly and 15.0% (14.2-15.8%) had a non-cardiac anomaly. Female babies with Down syndrome were significantly more likely to have a cardiac anomaly compared to male babies (47.6% compared with 40.4%, P < 0.001) and significantly less likely to have a non-cardiac anomaly (12.9% compared with 16.7%, P < 0.001). The prevalence of cardiac and non-cardiac congenital anomalies in babies with Down syndrome has remained constant, suggesting that population screening for Down syndrome and subsequent terminations has not influenced the prevalence of specific congenital anomalies in these babies.
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http://dx.doi.org/10.1002/ajmg.a.36780DOI Listing
December 2014

Hirschsprung's disease prevalence in Europe: a register based study.

Birth Defects Res A Clin Mol Teratol 2014 Sep 26;100(9):695-702. Epub 2014 Jul 26.

Institute of Health & Society, Newcastle University, Newcastle upon Tyne, England, United Kingdom.

Background: Hirschsprung's disease is a congenital gut motility disorder, characterised by the absence of the enteric ganglion cells along the distal gut. The aim of this study was to describe the epidemiology of Hirschsprung's disease, including additional congenital anomalies, total prevalence, trends, and association with maternal age.

Methods: Cases of Hirschsprung's disease delivered during 1980 to 2009 notified to 31 European Surveillance of Congenital Anomaly registers formed the population-based case-series. Prevalence rates and 95% confidence intervals were calculated as the number of cases per 10,000 births. Multilevel Poisson regression was performed to investigate trends in prevalence, geographical variation and the association with maternal age.

Results: There were 1,322 cases of Hirschsprung's disease among 12,146,210 births. The total prevalence was 1.09 (95% confidence interval, 1.03-1.15) per 10,000 births and there was a small but significant increase in prevalence over time (relative risk = 1.01; 95% credible interval, 1.00-1.02; p = 0.004). There was evidence of geographical heterogeneity in prevalence (p < 0.001). Excluding 146 (11.0%) cases with chromosomal anomalies or genetic syndromes, there were 1,176 cases (prevalence = 0.97; 95% confidence interval, 0.91-1.03 per 10,000 births), of which 137 (11.6%) had major structural anomalies. There was no evidence of a significant increased risk of Hirschsprung's disease in cases born to women aged ≥35 years compared with those aged 25 to 29 (relative risk = 1.09; 95% credible interval, 0.91-1.31; p = 0.355).

Conclusion: This large population-based study found evidence of a small increasing trend in Hirschsprung's disease and differences in prevalence by geographic location. There was also no evidence of an association with maternal age.
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http://dx.doi.org/10.1002/bdra.23269DOI Listing
September 2014

Spectrum of the mutations in Bernard-Soulier syndrome.

Hum Mutat 2014 Sep 15;35(9):1033-45. Epub 2014 Jul 15.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy; Department of Medical Sciences, University of Trieste, Trieste, Italy.

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.
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http://dx.doi.org/10.1002/humu.22607DOI Listing
September 2014
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