The delicate anatomical structures involved in infant cry production require intricate neurophysiological control especially in premature infants or those with a reduced respiratory or laryngeal function. Certain features like phonatory noise or subharmonics can be observed in infant cries using spectrograms. These features have a certain indicative valence for characterising the maturation stage of vocal control or its performance. One possible cause of deviation in neurophysiological coordination during voice production is disturbed CNS mechanisms, finally the consequences of orofacial clefts. Another is the influence of a familiar disposition for speech development disorders. The present paper studied the latter two relationships. For the evaluation and interpretation of a noise index (= average value of the noise portion within a cry) in infant’s pre-speech utterances, we analysed 1423 voice-signals emitted during the first 15 weeks of life by 10 orofacial cleft infants (5 females and 5 males), comparing these with a control group. The control group B of healthy infants was subdivided into B1 (FH- infants with a negative family history of speech developmental disorders) and B2 (FH+ infants with a positive family history of speech developmental disorders). Infants born with orofacial clefts are substantially exposed to severe difficulties for speech and language acquisition. Coupled with a premature muscle network, cleft infants are deprived in various ways (vocal nasality, limited consonant repertetoire, backward articulation etc) and their coordination of respiration, phonation and articulation is limited from a very early age. From birth until about 2 months of age, an infant's cry is characterised by a tuning phase between respiration and phonation. After training the production of more complex cry melodies with different rhythms, infants begin at 3 - 4 months of age (Wermke et al., 2005) to tune their phonation and articulation. Successfully absolving these stages of development is presumably a prerequisite for later acquisition of inconspicuous speech and language competence. The development of articulation is based on the tuning of melodies produced in the larynx and resonant frequencies from the vocal tract (Kempf, 2008). For an objective evaluation of pre-speech development in healthy and sick infants, this study produced comparable data on the appearance of selected parameters in age-appropriate control groups. In order to examine the connection between these selected cry properties and the physiological condition in infants, we made comparisons to 2623 voice-signals from 10 FH+ infants and 3002 voice-signals from 10 FH- infants (all without orofacial clefts and age-appropriates). For interpretations of future results, we also analysed 2684 voice-signals from 4 infants in the control group B1 (FH-) taken at closer time intervals until the 20th week of life. This study showed that the appearance of noise-like elements (NI) in the vocalizations of orofacial cleft infants and FH+ infants were identical during the first 15 weeks of life. Also, we could show that in both these groups (A and B2) there was a delayed development in the average signal length (phonation time). Although cleft infants and FH+ infants differ from each other physiologically, our results may propose a common neurophysiological retardation. Comparing prosodic elements in cries from FH+ and FH- infants showed differences (Blohm, 2007; Denner, 2007). Therefore, future research could apply this knowledge to a larger sample of infants in order to establish a better therapy concept, thus preventing late interventions. Infants from our control group B1 (FH-) met our expectations because when they got older, a development in their pre-speech capability was noticed. Our results support the hypothesis that in cry research, physiological differences (orofacial clefts or a family history for speech development disorders) in infants may encourage the appearance of noise-like elements in their vocalisations. However we believe that a period of training enables the infants to reduce their mean NI. The production of more complex melodies with age was better managed by the FH- infants and they also produced longer cries. To avoid a developmental retardation in speech and learning capabilities, it may be necessary in future to make more compact studies considering many other parameters and making comparisons with age-appropriates. Further studies also have to correlate these findings while investigating the consequences of these maturation processes on sound production. Despite physiological differences in the three groups of infants, the noise index (NI) as applied in this study can be used as an objective parameter for daily clinical diagnosis during the first four months of life. / Säuglinge mit einer orofazialen Spaltbildung sind bezüglich vieler Aspekte in ihrer sprachlichen Entwicklung benachteiligt (hypernasale Resonanz, eingeschränktes Konsonantenrepertoire, Rückverlagerung der Artikulation usw.) sowie bei der Koordination von Respiration, Phonation und Artikulation vor der chirurgische Behandlung. Ab Geburt bis zum Alter von 2 Monaten sind Säuglingslaute durch ausgeprägte Frequenzmodulationen charakterisiert, die auf einer Abstimmung von Respiration und Phonation beruhen. Nachdem Säuglinge in den ersten Wochen die Produktion komplexer Schrei-Melodien mit unterschiedlichen Rhythmen geübt haben, beginnen sie im Alter zwischen 3 - 4 Monaten die Phonation und die Artikulation fein abzustimmen (Wermke et al., 2005). Das erfolgreiche Absolvieren dieser Entwicklungsstadien ist möglicherweise eine Voraussetzung für einen späteren unauffälligen Sprech- und Spracherwerb. Die Artikulation beginnt sowohl mit einen intentionalen Tuning der Melodien, die laryngeal erzeugt werden, als auch mit der Bildung von Resonanzfrequenzen des Vokaltraktes (Kempf, 2008). Diese Entwicklungsprozesse sind bei Säuglingen mit orofazialen Spaltbildungen gestört. Die erhöhte nasale Impedanz führt durch einen rückgekoppelten Regelkreis zu einem Anstieg des subglottischen Druckes (Hauschildt, 2006). Die winzigen Stimmlippen der jungen Säuglinge sind diesem Druck nicht ausreichend gewachsen, so dass es regelmäßig zu phonatorischen Rauschphänomenen in deren erzeugten Lauten kommt. Dies verhindert das "Trainieren" melodisch-rhythmischer Elemente als Vorstufe für die spätere muttersprachliche Prosodie. Für eine objektive Auswertung solcher Phänomene in den vorsprachigen Entwicklungen wurden in dieser Studie das Auftreten und der Grad ihrer Ausprägung anhand ausgesuchter Parameter bei Säuglingen mit orofazialen Spalten (Gruppe A)) und bei solchen in einer altersähnlichen Kontrollgruppe (B) untersucht. Die Kontrollgruppe B bestand aus gesunden Säuglingen ohne (FH- oder B1) bzw. mit (FH+ oder B2) einem familiären Risiko für eine spezifische Spracherwerbsstörung. Letztere wurden einbezogen, da Säuglinge mit orofazialen Spalten (A) und Säuglinge mit einer familiären Disposition für Spracherwerbsstörungen (FH+) ähnlichen Abweichungen in der neurophysiologische Koordination der Lautproduktion aufweisen (Denner, 2007). In der Kontrollgruppe wurden 2623 einzelne Laute von 10 FH+ Kindern und 3002 Laute von 10 FH- Kindern miteinander verglichen. Um Entwicklungstrends besser beurteilen zu können, wurden in dichteren Intervallen (wöchentlich statt monatlich) 2686 Laute aus der Gruppe B1 (FH-) bis zur 20 Lebenswoche analysiert. Diese Studie konnte zeigen, dass während der ersten 15 Lebenswochen sehr identische, geräuschähnliche Phänomene (RI) in der Vokalisation von Spaltkindern und FH+ Kindern auftreten. Außerdem konnte gezeigt werden, dass in diesen beiden Gruppen eine verzögerte Entwicklung der durchschnittlichen Signallänge (Phonationszeit) einzelner Laute auftrat. Trotz allen physiologischen Unterschieden zwischen den Spaltkindern und den FH+ Kindern deuten unsere Ergebnisse auf eine gemeinsame neurophysiologische Entwicklungsverzögerung hin. Ein Vergleich prosodischer Elemente in der Vokalisationen von älteren FH+ und FH- Kindern ergab auch Unterschiede (Blohm, 2007; Denner, 2007). Die vorliegende Studie bestätigt dies und die Erkenntnisse könnten zukünftig verwendet werden um geeignete Therapieverfahren zu entwickeln. Säuglinge aus der Kontrollegruppe B1 (FH-) bestätigen die gestellten Hypothesen, da mit zunehmendem Alter eine signifikante Reduktion von Rauschphänomenen beobachtet wurde. Keine andere Studie hat bis heute eine vergleichbare objektive und detaillierte Analyse der Rauschelemente in Säuglingslauten durchgeführt. Die Ergebnisse bestätigen die Hypothese, dass neurophysiologische Besonderheiten, die auf eine orofaziale Spalte oder eine familiäre Disposition für eine Spracherwerbsstörung zurückzufuhren sind, das Auftreten von rauschähnlichen Elementen in der Vokalisation von Säuglingen beeinflussen könnten. Ganz offenbar gehört eine 'Trainingphase' dazu, um den mittlere RI zu reduzieren. Komplexere Melodien konnten mit zunehmendem Alter von den FH- Kindern besser beherrscht werden, da sie wohl auch längere Schreie koordinierter erzeugten. Die Arbeit bestätigt auch, dass der Rauschindex (RI), wie er in dieser Studie angewandt wurde, geeignet ist, um bei der klinischen Betreuung von orofazialen Spaltkindern, insbesondere während der ersten vier Lebensmonate, als Entwicklungsstandindikator dienen kann. Um einem Entwicklungsrückstand in der Spracherwerbsfähigkeit gefährdeter Säuglinge zu belegen, wird es in Zukunft nötig sein, umfassendere Studien durchzuführen, wobei weitere akustische Parameter berücksichtigt werden sollten.

Orofacial clefts (OFCs) are among the most common congenital birth defects and are characterized by incomplete development of the lip or the palate or both. The lip and palate develop separately at different times during the first trimester of pregnancy. The etiology of OFCs is multifactorial and includes a combination of genetic and environmental factors. This project aims to examine role of maternal diabetes mellitus in orofacial clefts through studies of medical histories, biomarkers, and genes. In a study of Utah birth certificates, mothers with pre-existing diabetes and gestational diabetes mellitus (GDM) had an increased risk of OFCs, and obese mothers also had an increased risk. Mothers of children with OFCs were more likely than mothers of unaffected children to develop obesity, metabolic syndrome and gestational diabetes mellitus later in life. These result were more strongly related to cleft palate than cleft lip. Many genes related to GDM were associated with OFCs through genetic effects alone and gene-environment interaction effects with periconceptional maternal multivitamin use, maternal smoking, and environmental tobacco smoke. These results support the hypothesis that GDM may be causally related to OFCs via multiple GDM susceptibility genes and interactions with environmental factors. Individuals with OFCs face both physical and mental health problem, which require multi-specialty team care. OFC prevention and prediction are important to public health. This dissertation reported that maternal diabetes mellitus, maternal pre-pregnancy weight and genes related to GDM had an association with the risk of OFCs. Mothers having an OFC child had an increased risk of developing metabolic abnormalities later in life. Potential risk factors were reported in this dissertation that may be useful for OFC prevention. This dissertation also reported potential biomarkers for predicting OFCs. Moreover, mothers having an OFC child may require regular monitoring of metabolic abnormalities later in life.

As fissuras orofaciais não-sindrômicas (FO-NS) correspondem a 70% de todos os casos de FO, possuem etiologia complexa e pouco compreendida, sendo consideradas de herança multifatorial com forte influência de fatores genéticos e ambientais. Apesar de estudos de análise de ligação e associação apontarem vários loci de susceptibilidade às FO-NS, o componente genético ainda não está totalmente explicado. Fatores ambientais também possuem um importante papel na etiologia das FO, e alguns já foram replicados em várias populações. Fatores como exposição materna ao álcool, drogas, tabaco, medicamentos, desnutrição e baixo nível socioeconômico são alguns dos fatores já associados a esta condição. As infecções periodontais são comuns em mulheres grávidas e estão associadas a parto prematuro, baixo peso fetal e, mais recentemente, foram reportadas como fator de risco aumentado para FO-NS nos fetos. Adicionalmente, o avanço das tecnologias de sequenciamento do DNA melhorou exponencialmente a compreensão do microbioma humano e sua influência no estado de saúde e doença, e, mais especificamente, o conhecimento sobre o impacto do microbioma na gravidez. O objetivo deste projeto foi identificar novos fatores etiológicos genéticos e ambientais das FO-NS. Para isso, primeiramente, sequenciamos 68 genes candidatos a FO por sequenciamento de nova geração em 193 indivíduos com FO-NS familial. Nós encontramos enriquecimento significativo de variantes raras e patogênicas de perda de função nos indivíduos com FO-NS e observamos que essas variantes estão em genes intolerantes a esse tipo de mutação. Também reportamos novas variantes raras do tipo perda de função no gene ARHGAP29 e sua importância na susceptibilidade as FO-NS familiais. Além disso, sugerimos o uso de um ponto de corte baseado no escore pLI do banco de dados ExAC como parâmetro para priorizar variantes em estudos de FO-NS familiares, assumindo modelo de herança mono ou oligogênico. Adicionalmente, estudamos o microbioma oral de mães de crianças com FO-NS e mães de crianças sem malformações, utilizando o sequenciamento da subunidade 16S do rRNA das bactérias com o objetivo de verificar diferenças consistentes na composição do microbioma oral de mães de crianças com FO-NS, levando em consideração a presença ou não de doenças infecciosas periodontais maternas. A casuística foi composta de 6 mães de recém-nascidos de até 1 mês que apresentaram FO-NS ao nascimento e mães de crianças sem qualquer malformação congênita. As análises de alfa e beta diversidades não demonstraram diferença significativa na composição do microbioma oral de mães de crianças com FO-NS e mães de crianças controle, contudo observamos que o grupo com infecções periodontais possui a diversidade taxonômica mais abundante do que o grupo hígido. Em resumo, nesse estudo piloto não foi possível identificar alterações no microbioma oral como um fator etiológico das FO-NS. Novas análises em uma casuística maior são necessárias para a confirmação desse achado / The non-syndromic orofacial clefts (nsOFC) correspond to 70% of all OFC cases, have complex etiology and are poorly understood, being considered multifactorial inheritance with a strong influence of genetic and environmental factors. Although linkage and association analysis studies point to several nsOFC susceptibility loci, the genetic component is not yet fully explained. Environmental factors also play an important role in OFC etiology, and some have been replicated in several populations. Factors such as maternal exposure to alcohol, drugs, tobacco, drugs, malnutrition and low socioeconomic status are some of the factors already associated with this condition. Periodontal infections are common in pregnant women and are associated with preterm birth, low birth weight and, more recently, have been reported as an increased risk factor for nsOFC in fetuses. Additionally, the advancement of DNA sequencing technologies has exponentially improved the understanding of the human microbiome and its influence on health and disease status, and, more specifically, knowledge about the impact of the microbiome on pregnancy. The objective of this project was to identify new genetic and environmental etiological factors of nsOFC. For this, we first sequenced 68 candidate genes by next generation sequencing in 193 individuals with familial nsOFC. We found significant enrichment of rare and pathogenic loss of function variants in individuals with nsOFC and we observed that these variants were in genes intolerant to this type of mutation. We also reported new rare loss-of-function variants in the ARHGAP29 gene and its importance in the liability of familial nsOFC. In addition, we suggested the use of a cutoff point based on the ExAC database pLI score as a parameter to prioritize variants in familial nsOFC studies, assuming a mono or oligogenic inheritance model. In addition, we studied the oral microbiome of 6 mothers of newborns up to 1-month-old with nsOFC and 6 mothers of newborns without congenital malformations using the 16S rRNA sequencing in order to verify consistent differences in the composition of the oral microbiome of mothers of children with nsOFC, taking into account the presence or absence of maternal periodontal infectious diseases. The analysis of alpha and beta diversities did not show a significant difference in the composition of the oral microbiome of mothers of nsOFC children and mothers of control children, however, we observed that the group with periodontal infectious diseases has more abundant taxonomic diversity than the healthy group. In summary, in this pilot study, it was not possible to identify alterations in the oral microbiome as an etiological factor of FO-NS. New analyzes in a larger cohort are necessary to confirm this finding

OBJECTIVE: The goal of this study was to gather information from mothers’ of children born with orofacial clefts (OFC) in order to more accurately describe their early feeding experiences, from the time of diagnosis through the first six months of life. METHODS: We surveyed mother’s whose babies with OFC were treated at Seattle Children’s Hospital (SCH) Craniofacial Clinic and were born on or after 1/1/2013 through 12/31/2016. Survey questions were geared toward understanding overall difficulty with feeding, access to supplies for feeding, and methods and duration of any breast milk feeding. RESULTS: Eighty-two percent of mothers wanted to exclusively breastfeed for the first 16 weeks prior to the OFC diagnosis, of which 79% attempted breastfeeding and 74% attempted any breast milk feeding. Donor milk was used in 18% of mothers and 41% supplemented with formula in the delivery hospital. The majority of women were knowledgeable about facts of breastfeeding and 41% reported they received information from a lactation specialist in their delivery hospital. The level of stress reported by mothers stayed relatively the same over first 4 weeks of life and dropped by 16 weeks. The majority of women who used a breast pump pumped for 0 to 20 minutes in first week and then 0 to 30 minutes between weeks 4 to 16. Thirty percent of mothers reported receiving information specifically from a craniofacial nurse and craniofacial pediatrician before delivery and 36% reported receiving information from a craniofacial nurse and craniofacial pediatrician after their birth hospital stay. CONCLUSION: Initial study results of feeding practices, knowledge of breast milk feeding, and feeding experiences of mothers with babies born with OFCs show that most mother’s intended to exclusively breastfeed prior to their birth and that the majority of women were reasonably informed about the benefits of breastfeeding. We also found that after the delivery of their child with an OFC more mothers reported having difficulty with feeding and wanted to provide breast milk longer than they were able to do so. Once the data collection is complete the survey data will be stratified for prenatal versus postnatal diagnosis and also when a breast pump was obtained. This information and additional data will be collected from a second phase of the study, which is a medical chart abstraction to look at the child’s demographics and growth chart data for the first six months of life.

Objective: To investigate the association of previously reported single nucleotide polymorphisms (SNPs) in relation to orofacial clefts and assess their interaction with environmental factors. Methods: Genome-wide SNP genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate SNPs were selected from a previous genome-wide association study (Shi et al., 2012) along with surrounding SNPS for a total of 2142 genotyped and imputed SNPs. A total of 411 case-parent triads and 25 case-parent dyads were analyzed using log-linear models to test for maternal and parent-of-origin effects along with their interaction with maternal smoking and maternal folic acid consumption. Results: A significant association (q = 0.025) was detected for a region in the ATXN3 gene. This significance refers to the interaction between maternal periconceptional smoking and maternal genetic effects. Nominally significant associations in genes relating to the brain were also detected. Conclusion: SNPs in the ATXN3 region warrant further investigation.

Orofacial clefts (OFCs) are among the most common structural birth defects and a public health problem. Several studies suggest that maternal obesity pre-existing diabetes mellitus (DM), and the underlying metabolic abnormalities, may be involved in the pathogenesis of cleft lip (CL) and cleft palate (CP) birth defects. Although hypertension and gestational diabetes mellitus (GDM) have been associated in a few studies with congenital birth defects, studies examining the risk associated with OFCs are limited. The overall objective of this dissertation was to examine the association between maternal obesity, DM, GDM, and hypertension and the risk of OFCs in case-control studies. Analyses of data from an international consortium revealed that maternal obesity (pre-pregnancy BMI >30), compared to normal weight (18.525), was associated with an increased risk of cleft palate with or without cleft lip (CP/L) (adjusted odds ratio (aOR) =1.13 [95% confidence intervals (CI) 1.01-1.25]). We also found a marginal association between maternal underweight and CP/L (1.0 [reference]; aOR=1.14 [0.97-1.34]. CL only was not associated with maternal bodyweight. Interestingly, among college-graduates, there was no increased risk of CP, but mothers with less than a completed college education had an increased risk of CP for underweight and obesity. Investigation of the Utah OFC data provided evidence that maternal GDM is significantly associated with isolated (aOR=2.63 [1.30-5.34]) and non-isolated clefts (aOR=2.66 [1.02-6.97]). Maternal hypertension is significantly associated with non-isolated clefts (aOR=6.56 [2.18-19.77]). We found a further elevated risk of OFCs among GDM mothers and those with hypertension who were also obese. The analyses of data from an international consortium revealed significant associations between maternal diabetes and the risk of OFCs. The estimated relative risk of DM for isolated OFCs was 1.33 [1.14-1.54] and was slightly higher for multiple OFCs (aOR=1.86 [1.44-2.40]). Diabetic mothers with abnormal body-mass-index had an increased risk for having inborn with OFCs. Throughout the dissertation, we demonstrated the extent in which maternal obesity, pre-existing DM, GDM, and maternal hypertension may increase the risk of OFC birth defects. The results highlight the need for pre-conceptional program planning for the prevention of OFCs with screening for abnormal glucose tolerance and hypertension.

Association of type and severity of nonsyndromic OROFACIAL CLEFTS with combined genotypes of RFC1 80 GA, MTHFR 677 CT, IRF6 rs642961 and rs2235371 gene polymorphisms in an Indian population Abstract By Chantal Hakim University of the Pacific. Arthur Dugoni School of Dentistry 2020 Introduction. Genetic etiology of nonsyndromic orofacial clefts comprises many genes acting together. However, little is known about their interactions. The purpose of our study was to analyze associations of phenotypic subtypes of nonsyndromic orofacial clefts with combinations of four genotypes involving candidate gene polymorphisms. Materials and Methods. We analyzed a large dataset of cases and controls collected in one location (Karaikal in India) and genotyped for four gene polymorphisms: RFC1 G80A, MTHFR C677T, IRF6 GA rs642961 and IRF6 CT rs2235371 (IRB approval Nr. 17-118 for existing data). The samples were tested for Hardy-Weinberg genetic equilibrium. Combinations of genotypes in cleft subsamples were compared with controls using Odds Ratio and Confidence Interval (95% significance level) calculations. Results. The Hardy-Weinberg equilibrium test showed that all samples were in genetic equilibrium. Some combinations of RFC1 G80A, MTHFR C677T, IRF6 GA rs642961 and IRF6 CT rs2235371 yielded increased or decreased Odds Ratio (OR>1 or OR<1).This means that subtypes of orofacial clefts were differentially determined by genotype combinations of four gene polymorphisms. Conclusions. Our results suggest that combinations of gene polymorphisms may modulate genetic risk in subtypes of nonsyndromic orofacial clefts. Such studies seem to be important for development of a general procedure and how a prevention plan for a specific location needs to be prepared, which data needs to be collected and which analyses need to be performed.

Hintergrund: Zahlreiche Studien beschreiben weltweit eine Zunahme angeborener Fehlbildungen. Diese sind in Deutschland die häufigste Todesursache im frühen Kindesalter. Die hier vorliegende Studie untersuchte lokale und nationale Trends der Prävalenz von Gastroschisis, Omphalozele, Spina bifida und orofazialen Spaltbildungen von 2000 bis 2010. Methoden: Die Prävalenz der 4 Fehlbildungen wurde im Zeitraum Januar 2000–Dezember 2010 mithilfe von 4 Datenquellen aus Leipzig, Sachsen, Sachsen-Anhalt und Deutschland untersucht. Ergebnisse: Die Prävalenz der Fehlbildungen betrug im Untersuchungszeitraum in Deutschland bzw. in Sachsen 1,97/2,12 (Gastroschisis), 1,63/1,48 (Omphalozele), 5,80/8,11 (orofaziale Spaltbildungen) und 2,92/2,50 (Spina bifida) je 10 000 Lebendgeborene. In Sachsen zeigte sich ein Trendanstieg, dessen Effektstärken jedoch sehr gering sind (OR/Jahr zwischen 1,01–1,09). Auch in Deutschland insgesamt wurde eine signifikante Zunahme der Fehlbildungen beobachtet (OR/Jahr zwischen 1,01–1,04), ausgenommen davon war die Lebendgeborenenprävalenz der Spina bifida, die abzunehmen schien (OR/Jahr 0,986 (0,97–1,0), p-korrigiert = 0,04). Schlussfolgerung: Ob ein tatsächlicher Anstieg der Prävalenzen besteht oder lediglich Artefakte einen Anstieg vortäuschen, ist unklar. Änderungen in der Erfassungs- und Verschlüsselungspraxis, Fehlcodierungen, Doppel- und/oder lückenhafte Erfassung der Fehlbildungen könnten die Daten verfälschen. Da nur in Sachsen-Anhalt und Rheinland-Pfalz das Auftreten von Fehlbildungen prospektiv erfasst wird, könnten im Übrigen auch nur in diesen Bundesländern zeitnah Veränderungen der Fehlbildungsprävalenz erkannt werden. Angesichts der anscheinenden oder scheinbaren Zunahme von Fehlbildungen und der offensichtlich fehlerhaften Datenlage ist ein berücksichbundesweites oder sind weitere regionale Register für eine bessere und zeitnahe Erkennung und Erfassung von Fehlbildungen in Deutschland notwendig.

Hintergrund: Zahlreiche Studien beschreiben weltweit eine Zunahme angeborener Fehlbildungen. Diese sind in Deutschland die häufigste Todesursache im frühen Kindesalter. Die hier vorliegende Studie untersuchte lokale und nationale Trends der Prävalenz von Gastroschisis, Omphalozele, Spina bifida und orofazialen Spaltbildungen von 2000 bis 2010. Methoden: Die Prävalenz der 4 Fehlbildungen wurde im Zeitraum Januar 2000–Dezember 2010 mithilfe von 4 Datenquellen aus Leipzig, Sachsen, Sachsen-Anhalt und Deutschland untersucht. Ergebnisse: Die Prävalenz der Fehlbildungen betrug im Untersuchungszeitraum in Deutschland bzw. in Sachsen 1,97/2,12 (Gastroschisis), 1,63/1,48 (Omphalozele), 5,80/8,11 (orofaziale Spaltbildungen) und 2,92/2,50 (Spina bifida) je 10 000 Lebendgeborene. In Sachsen zeigte sich ein Trendanstieg, dessen Effektstärken jedoch sehr gering sind (OR/Jahr zwischen 1,01–1,09). Auch in Deutschland insgesamt wurde eine signifikante Zunahme der Fehlbildungen beobachtet (OR/Jahr zwischen 1,01–1,04), ausgenommen davon war die Lebendgeborenenprävalenz der Spina bifida, die abzunehmen schien (OR/Jahr 0,986 (0,97–1,0), p-korrigiert = 0,04). Schlussfolgerung: Ob ein tatsächlicher Anstieg der Prävalenzen besteht oder lediglich Artefakte einen Anstieg vortäuschen, ist unklar. Änderungen in der Erfassungs- und Verschlüsselungspraxis, Fehlcodierungen, Doppel- und/oder lückenhafte Erfassung der Fehlbildungen könnten die Daten verfälschen. Da nur in Sachsen-Anhalt und Rheinland-Pfalz das Auftreten von Fehlbildungen prospektiv erfasst wird, könnten im Übrigen auch nur in diesen Bundesländern zeitnah Veränderungen der Fehlbildungsprävalenz erkannt werden. Angesichts der anscheinenden oder scheinbaren Zunahme von Fehlbildungen und der offensichtlich fehlerhaften Datenlage ist ein berücksichbundesweites oder sind weitere regionale Register für eine bessere und zeitnahe Erkennung und Erfassung von Fehlbildungen in Deutschland notwendig.:Inhaltsverzeichnis Bibliografische Beschreibung 4 I. Abkürzungsverzeichnis 6 1. Einleitung 7 1.1 Hintergrund 7 1.2 Gastroschisis 8 1.3 Omphalozele 12 1.4 Orofaziale Spaltbildungen 15 1.5 Spina bifida 19 1.6 Fragestellung der Studie 22 2. Publikation 25 3. Zusammenfassung der Arbeit 33 4. Literaturverzeichnis 40 II. Erklärung über die Eigenständigkeit der Arbeit 49 III. Lebenslauf 50 IV. Danksagung 52