Annukka Ritvanen

Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase ( MTHFR ): findings from over 7000 newborns from 16 areas world wide

Since its biochemical characterisation in 19911 and its genetic identification in 1995,2 677C>T allele (T allele) of the 5,10 methylenetetrahydrofolate reductase ( MTHFR ) gene has been a focus of increasing interest from researchers world wide. The expanding spectrum of common conditions linked with the 677C>T allele now includes certain adverse birth outcomes (including birth defects), pregnancy complications, cancers, adult cardiovascular diseases, and psychiatric disorders.3–8 Although several of these associations remain unconfirmed or controversial,4 their scope is such that it becomes of interest to explore the geographical and ethnic distribution of the allele and associated genotypes.9 Accurate information on such distribution can contribute to studies of gene-disease associations (by providing reference population data) and population genetics (by highlighting geographical and ethnic variations suggestive of evolutionary pressures),10 as well as help to evaluate health impact (by allowing estimates of population attributable fraction). Current population data, however, show gaps and even for some ethnic groups or large geographical areas (for example, China) few data are available.3 Our aim was to supplement the available data by collecting a large and diverse sample of newborns from different geographical areas and ethnic groups, and to examine international variations in the distribution of the 677C>T allele. We present findings relating to more than 7000 newborns from 16 areas around the world. The study was conducted under the auspices of the International Clearinghouse for Birth Defect Monitoring Systems (ICBDMS) and was coordinated through its head office, the International Center on Birth Defects (ICBD). ### Sample selection Participating programmes, in consultation with the coordinating group, identified a population sampling approach that would be simple yet minimise sampling bias with respect to the MTHFR genotype. We made an explicit attempt to sample systematically the newborn population. Details of each programme’s approach are listed below, and further …

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

Abstract Objectives To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects. Design Retrospective cohort study of births monitored by birth defect registries. Setting 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review. Main outcome measures Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable). Results The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects. Conclusions Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

Selective Serotonin Reuptake Inhibitors and Risk for Major Congenital Anomalies

OBJECTIVE: To estimate the risk of major congenital anomalies after exposure to selective serotonin reuptake inhibitors during pregnancy. METHODS: A retrospective cohort study based on national population-based registers (years 1996–2006) of births, congenital anomalies, and terminations of pregnancy because of severe fetal anomalies (maintained by National Institute for Health and Welfare, source offspring population n=635,583) and drug reimbursements (Social Insurance Institution) linked by a personal identification number. Offspring exposed to selective serotonin reuptake inhibitors during the first trimester (n=6,976) were compared with unexposed referent offspring. RESULTS: Overall major congenital anomalies were not more common in selective serotonin reuptake inhibitor-exposed offspring compared with unexposed referent offspring (adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.96–1.22). Fluoxetine was associated with an increased risk of isolated ventricular septal defects (adjusted OR 2.03, 95% CI 1.28–3.21) and paroxetine was associated with an increased risk of right ventricular outflow tract defects (adjusted OR 4.68, 95% CI 1.48–14.74). Citalopram use was associated with neural tube defects (adjusted OR 2.46, 95% CI 1.20–5.07). Fetal alcohol spectrum disorders were 10-times more common in the selective serotonin reuptake inhibitor-exposed offspring than in unexposed referent offspring. CONCLUSION: Fluoxetine use is associated with an increased risk of isolated ventricular septal defects and paroxetine is associated with right ventricular outflow tract defects. The absolute risk for these specific cardiac anomalies is small but should guide clinicians not to consider fluoxetine or paroxetine the first option when prescribing selective serotonin reuptake inhibitors to women planning pregnancy. Special attention should be given to alcohol use in pregnant women using selective serotonin reuptake inhibitors. LEVEL OF EVIDENCE: II

Congenital malformations in twins: An international study

Data provided by nine registries based in European and Latin America countries were analyzed to assess whether there is an excess of malformations in twins compared to singletons. Specific congenital malformations were coded according to the ninth revision of the International Classification of Diseases (ICD). Malformation rates and rate ratios (RR) for twins compared to singletons were calculated for each registry, and the homogeneity of the RRs was tested using the test of Breslow and Day. If departure from homogeneity in the different registries was not significant, registry-adjusted RRs with 95% confidence intervals were calculated. Overall, among 260,865 twins, 5,572 malformations were reported. A total of 101 different types of malformations or groups of defects was identified, and a homogeneous estimate of the RRs among registries was found for 91.1% of the malformations. Thirty-nine of the 92 malformations with homogeneous estimates of RRs were more common in twins than in singletons. For the remaining nine malformations, heterogeneous estimates of RRs were obtained. This study confirms the majority of already known associations and further identifies previously unreported malformations associated with twins. In conclusion, there is an excess of malformations in twins compared with singletons, and all anatomical sites are involved. The number of specific malformations associated with twins is higher than that previously reported in smaller studies.

Paper 6: EUROCAT member registries: organization and activities

BACKGROUND EUROCAT is a network of population-based congenital anomaly registries providing standardized epidemiologic information on congenital anomalies in Europe. There are three types of EUROCAT membership: full, associate, or affiliate. Full member registries send individual records of all congenital anomalies covered by their region. Associate members transmit aggregate case counts for each EUROCAT anomaly subgroup by year and by type of birth. This article describes the organization and activities of each of the current 29 full member and 6 associate member registries of EUROCAT. METHODS Each registry description provides information on the history and funding of the registry, population coverage including any changes in coverage over time, sources for ascertaining cases of congenital anomalies, and upper age limit for registering cases of congenital anomalies. It also details the legal requirements relating to termination of pregnancy for fetal anomalies, the definition of stillbirths and fetal deaths, and the prenatal screening policy within the registry. Information on availability of exposure information and denominators is provided. The registry description describes how each registry conforms to the laws and guidelines regarding ethics, consent, and confidentiality issues within their own jurisdiction. Finally, information on electronic and web-based data capture, recent registry activities, and publications relating to congenital anomalies, along with the contact details of the registry leader, are provided. CONCLUSIONS The registry description gives a detailed account of the organizational and operational aspects of each registry and is an invaluable resource that aids interpretation and evaluation of registry prevalence data.

Long term trends in prevalence of neural tube defects in Europe : population based study

Study question What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? Methods This was a population based, observational study using data on 11 353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. Summary answer and limitations Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10 000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. What this study adds In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. Funding, competing interests, data sharing The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.

Epidemiology of cleft palate in Europe: implications for genetic research.

Objective To describe the epidemiology of cleft palate (CP) in Europe. Design and Setting A descriptive epidemiological study on 3852 cases of CP, identified (1980 through 1996) from more than 6 million births from the EUROCAT network of 30 registers in 16 European countries. Results Significant differences in prevalence in Europe between registries and within countries were observed. A total of 2112 (54.8%) CP cases occurred as isolated, 694 (18.0%) were associated with other defects such as multiple congenital anomalies, and 1046 (27.2%) were in recognized conditions. The study confirmed the tendency toward female prevalence (sex ratio [SR] = 0.83), particularly among isolated cases (SR = 0.78) even if SR inversion is reported in some registries. A specific association with neural tube defects (NTDs) in some registers is reported. Conclusion The differences identified in Europe (prevalence, sex, associated anomalies) can be only partially explained by methodological reasons because a common methodology was shared among all registries for case ascertainment and collection, and CP is an easy detectable condition with few induced abortions. The complex model of inheritance and the frequently conflicting results in different populations on the role of genes that constitute risk factors suggest the presence of real biological differences. The association of CP/NTD in an area with a high prevalence of NTDs can identify a group of conditions that can be considered etiologically homogeneous. The epidemiological evaluation can guide genetic research to specify the role of etiological factors in each different population

Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations

BACKGROUND Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. METHODS We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. RESULTS A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. CONCLUSIONS The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses.

Conjoined twins: A worldwide collaborative epidemiological study of the International Clearinghouse for Birth Defects Surveillance and Research†‡

Conjoined twins (CT) are a very rare developmental accident of uncertain etiology. Prevalence has been previously estimated to be 1 in 50,000 to 1 in 100,000 births. The process by which monozygotic twins do not fully separate but form CT is not well understood. The purpose of the present study was to analyze diverse epidemiological aspects of CT, including the different variables listed in the Introduction Section of this issue of the Journal. The study was made possible using the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) structure. This multicenter worldwide research includes the largest sample of CT ever studied. A total of 383 carefully reviewed sets of CT obtained from 26,138,837 births reported by 21 Clearinghouse Surveillance Programs (SP) were included in the analysis. Total prevalence was 1.47 per 100,000 births (95% CI: 1.32–1.62). Salient findings including an evident variation in prevalence among SPs: a marked variation in the type of pregnancy outcome, a similarity in the proportion of CT types among programs: a significant female predominance in CT: particularly of the thoracopagus type and a significant male predominance in parapagus and parasitic types: significant differences in prevalence by ethnicity and an apparent increasing prevalence trend in South American countries. No genetic, environmental or demographic significant associated factors were identified. Further work in epidemiology and molecular research is necessary to understand the etiology and pathogenesis involved in the development of this fascinating phenomenon of nature.

National centralization of biliary atresia care to an assigned multidisciplinary team provides high-quality outcomes

Abstract Background and aims. Effects of caseload and organization of care on outcomes of biliary atresia (BA) remain unclear. We compared outcomes before and after national centralization of BA treatment in Finland with a population of 5.4 million people and 60,000 live births/year. Methods. All children born in Finland from 1987 to 2010 with BA were included. Complete patient identification was ascertained from the national Register of Congenital Malformations. Hospital records were reviewed for confirmation of the diagnosis, treatment, and follow-up data. Clearance of jaundice (serum bilirubin ≤20 μmol/l) and survival modalities were compared before and after centralization from five centers to Helsinki. Results. The incidence of BA was 1 in 20,100 live births. A total of 72 BA patients of whom 64 had undergone surgery for BA were identified. After centralization, the median caseload per center increased from 0 (range, 0–3) to 4 (2–5) patients/year (p < 0.001), clearance of jaundice rate increased from 27% to 75% (p = 0.001), 2-year jaundice-free native liver survival from 25% to 75% (p = 0.002), transplant-free survival from 27% to 75% (p = 0.005), and overall survival from 64% to 92% (p = 0.082). Baseline patient characteristics including type of BA and age at portoenterostomy remained unaltered. In a logistic regression analysis including treatment era, operating center, BA splenic malformation syndrome, and age at portoenterostomy as variables, only treatment in Helsinki after centralization predicted clearance of jaundice (odds ratio 4.2; 95% confidence interval 1.05–16.5; p = 0.043). Conclusions. In small countries, BA treatment should be centralized to appointed multidisciplinary teams allowing high quality results with a median of four cases/year.