Perinatal and perioperative factors associated with mortality and an increased need for hospital care in infants with transposition of the great arteries: A nationwide 11-year population-based cohort.

INTRODUCTION: Newborn infants with transposition of the great arteries (d-TGA) need immediate care for an optimal outcome. This study comprised a nationwide 11-year population-based cohort of d-TGA infants, and assessed whether the implementation of a nationwide systematic fetal screening program, or other perinatal, or perioperative factors, are associated with mortality or an increased need for hospital care. MATERIAL AND METHODS: The national cohort consisted of all live-born infants with simple d-TGA (TGA ± small ventricular septal defect, n = 127) born in Finland during 2004-2014. Data were collected from six national registries. Prenatal diagnosis and perinatal and perioperative factors associated with mortality and length of hospitalization were evaluated. RESULTS: Preoperative mortality was 7.9%, and the total mortality was 8.7%. The prenatal detection rate increased after introducing systematic fetal anomaly screening from 5.0% to 37.7% during the study period (P < .0001), but the total mortality rate remained unchanged. All prenatally diagnosed infants (n = 27) survived. Lower gestational age (odds ratio 0.68, P = .012) and higher maternal age at birth (odds ratio 1.16, P = .036) were associated with increased mortality in multivariable analysis. Older infant age at time of operation (P = .002), longer aortic clamp time (P < .001), and higher maternal body mass index (P = .027) were associated with longer initial hospital stay. An extended need for hospital care during the first year of life was multi-factorial. CONCLUSIONS: In our cohort, none of the prenatally diagnosed d-TGA infants died. As a result of the limited prenatal detection rates, however, the sample size was insufficient to reach statistical significance. The d-TGA infants born with lower gestational age and to older mothers had increased mortality.

Congenital diaphragmatic hernia with heart defect has a high risk for hypoplastic left heart syndrome and major extra-cardiac malformations: 10-year national cohort from Finland.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) has a well-known risk of congenital heart defects with poor prognosis. This study was conducted to determine the national total prevalence and prenatal detection rates of CDH with heart defects and its association with major extra-cardiac malformations and to further evaluate the impact of the heart defect severity on survival. MATERIAL AND METHODS: A 10-year national cohort was derived from four national registries, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. The study cohort was sorted according to cardiac defect severity. RESULTS: The total prevalence of CDH with heart defects was 0.6/10 000 births and live birth prevalence 0.3/10 000 live births. Of 145 cases with CDH, 37 (26%) had a concurrent heart defect. The overall prenatal detection rate of heart defects was 41%. The total prevalence (483/10 000) and live birth prevalence (500/10 000) of hypoplastic left heart syndrome were 124 and 250 times higher than in the general population in Finland, respectively. Additional major extra-cardiac malformations were found in 68% of cases. The survival rate for CDH with major heart defects was 11 and 38% with minor heart defects. CONCLUSIONS: The total prevalence of hypoplastic left heart syndrome was significantly higher in CDH patients than in the general population in Finland. Prenatal detection rate for heart defects in CDH patients was 41%. Major extra-cardiac malformations were more common than previously reported. The prognosis of CDH with major heart defects remained poor.

Pediatric ocular disorders and visual handicap in Finland - what do the registers tell?

INTRODUCTION: There is no published data from the last few years on the frequency of pediatric ocular disorders and visual handicap in Finland. METHODS: We surveyed the registers of THL (National Institute for Health and Welfare) and statistics of Kela (The Social Insurance Institution of Finland). RESULTS: The majority of visual defects are neurologic or congenital. Retinopathic lesions were reported in 11% of small premature infants. In the years from 1993 to 2011, significant abnormalities of the eye or its accessory organs were on the average registered annually in 94 liveborn infants, and the number of corresponding cancers was less than five. CONCLUSIONS: Ocular disorders in children are rare. They are significant because of the special attention required in everyday life.

Risk for congenital anomalies in offspring of childhood, adolescent and young adult cancer survivors.

Offspring of cancer survivors (CS) may be at risk for congenital anomalies due to the mutagenic therapies received by their parents. Our population-based cohort study aimed to investigate the risk for congenital anomalies in offspring of CS compared to offspring of their siblings. Using the Finnish Cancer Registry, Central Population Register, and Hospital Discharge Register, we identified hospital contacts due to congenital anomalies in 6,862 offspring of CS (early-onset cancer between 1953 and 2004) and 35,690 offspring of siblings. Associations between congenital anomalies and cancer were evaluated using generalized linear regression modelling. The ratio of congenital anomalies in offspring of CS (3.2%) was slightly, but non-significantly, elevated compared to that in offspring of siblings (2.7%) [prevalence ratio (PR) 1.07, 95% confidence interval (CI) 0.91-1.25]. When offspring of childhood and adolescent survivors (0-19 years at cancer diagnosis) were compared to siblings' offspring, the risk for congenital anomalies was non-significantly increased (PR 1.17, 95% CI 0.92-1.49). No such increase existed for offspring of young adult survivors (20-34 years at cancer diagnosis) (PR 1.01, 95% CI 0.83-1.23). The risks for congenital anomalies were elevated among offspring of CS diagnosed with cancer in the earlier decades (1955-1964: PR 2.77, 95% C I 1.26-6.11; and 1965-1974: PR 1.55, 95% C I 0.94-2.56). In our study, we did not detect an overall elevated risk for congenital anomalies in offspring of survivors diagnosed in young adulthood. An association between cancer exposure of the parent and congenital anomalies in the offspring appeared only for those CS who were diagnosed in the earlier decades.

Maternal Antibodies to Herpes Virus Antigens and Risk of Gastroschisis in Offspring.

Gastroschisis risk is highest in offspring of young women and is increasing in prevalence, suggesting that exposures that are increasingly common among younger females may be causal. Some infections by viruses in the herpes family are more common in the earlier childbearing years and have been increasing in prevalence over time. Data from the Finnish Maternity Cohort were linked to Finnish malformation and birth registers (1987-2012) for this study, a nested case-control study of mothers of offspring with gastroschisis and age-matched controls. Maternal antibody responses in early pregnancy (mean gestational age = 11.1 weeks) to Epstein Barr virus (EBV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), and cytomegalovirus were measured. Conditional logistic regression models were used to estimate odds ratios (and 95% confidence intervals) for high immunoglobulin reactivity. Odds ratios for high immunoglobulin M (IgM) reactivity to EBV-viral capsid antigen and HSV-1 or HSV-2 (as indicators of recent infection) were 2.16 (95% confidence interval (CI): 0.97, 4.79) and 1.94 (95% CI: 0.74, 5.12), respectively. For higher immunoglobulin G (IgG) reactivity to EBV-viral capsid antigen and HSV-2 IgG, odds ratios were 2.16 (95% CI: 0.82, 5.70) and 2.48 (95% CI: 1.50, 4.10), respectively. Reactivities to HSV-1 IgG, cytomegalovirus IgM, or cytomegalovirus IgG did not appear to increase gastroschisis risk. Primary EBV infection was not associated with gastroschisis, but observed associations with both IgM and IgG reactivities to EBV and HSV suggest that reactivations may be risk factors for it.

Fetal Alcohol Syndrome and Maternal Alcohol Biomarkers in Sera: A Register-Based Case-Control Study.

BACKGROUND: Fetal alcohol syndrome (FAS) is a well-known consequence of prenatal alcohol exposure. However, women tend to deny or underreport their alcohol use during pregnancy. The aim of this study was to explore the usability of various alcohol biomarkers for FAS screening in a data set without information on self-reported alcohol use. METHODS: A nationwide register study with a case-control design was conducted. The target population consisted of all live births in Finland from 1987 to 2005. FAS cases (n = 565) were identified from the Finnish Register of Congenital Malformations. Mothers of FAS cases and their controls were selected in a ratio of 1 to 2 from the Finnish Maternity Cohort (FMC). Background information was obtained from the Finnish Medical Birth Register. Serum samples, collected at the mother's first visit to the maternity care, were obtained from the national FMC biobank. Biomarkers of alcohol consumption, gamma-glutamyltransferase (GGT), carbohydrate-deficient transferrin (%CDT), combination of GGT and CDT (GGT-CDT), and ethylglucuronide (EtG) were analyzed from mothers of FAS cases (n = 385) and their controls (n = 745). RESULTS: Median levels of all biomarkers were significantly higher among the mothers of FAS children than in control mothers. Using previously validated cutoffs for EtG, GGT, %CDT, and GGT-CDT, nearly half (46%) of the mothers with affected offspring could be identified. The predictive association was highest for GGT-CDT combination and significant also for all the other biomarkers. CONCLUSIONS: In this explorative case-control study, we demonstrate that the FMC biobank can be used to screen alcohol biomarkers for epidemiological research purposes. According to our results, the use of alcohol biomarkers during the first trimester may help to identify the high-risk pregnancies for FAS. A more systematic use of alcohol biomarkers at maternity care may open new possibilities for screening and intervention of alcohol use among pregnant mothers.

Assays of Gamma-Glutamyl Transferase and Carbohydrate-Deficient Transferrin Combination from Maternal Serum Improve the Detection of Prenatal Alcohol Exposure.

BACKGROUND: Alcohol use during pregnancy leads to detrimental effects on fetal development. As self-reports by mothers are known to be unreliable for assessing prenatal alcohol exposure, there is a need for sensitive and specific biomarkers for identifying those at risk for alcohol-affected offspring. METHODS: We measured serum gamma-glutamyl transferase (GGT), carbohydrate-deficient transferrin (CDT), a mathematically formulated combination of GGT and CDT (GGT-CDT), and ethylglucuronide (EtG) concentrations from 1,936 mothers with a positive (n = 480) or negative (n = 1,456) history of alcohol use at the time of pregnancy. The material included 385 alcohol-abusing mothers who subsequently gave birth to children with fetal alcohol syndrome (FAS) and 1,551 mothers without FAS children including 95 women who reported a median of 1.0 standard drinks of alcohol per day during pregnancy and 1,456 nondrinking controls. Among those without FAS outcome, there were 405 mothers with gestational diabetes mellitus (GDM) and 745 mothers representing lifelong abstainers. RESULTS: Mothers of FAS children had higher mean GGT, CDT, GGT-CDT, and EtG levels than abstainers (p < 0.001 for all comparisons) or mothers reporting some alcohol consumption but whose children were not diagnosed with FAS (p < 0.001 for all comparisons). In receiver operating characteristic analyses using cutoffs based on abstainers, the area under the curves (AUCs) for GGT-CDT (0.873) were higher than those of GGT (0.824), CDT (0.776), or EtG (0.584) for differentiating the mothers of FAS children and abstainers. Unlike CDT, this combination marker also differed significantly between drinking mothers without FAS outcome and abstainers (AUC = 0.730, p < 0.001). In comparisons adjusted for GDM and body mass index, the group of mothers who had reported a median of 1.0 standard drinks of alcohol per day during pregnancy also differed from the group reporting no current alcohol intake in GGT (p < 0.02) and GGT-CDT (p < 0.01) levels. CONCLUSIONS: Combination of GGT and CDT improves the identification of prenatal alcohol exposure and associated high-risk pregnancies. A more systematic use of biomarkers may help intervention efforts to prevent alcohol-induced adverse effects on fetal development.

Prevalence of craniosynostosis in Finland, 1987-2010: A population-based study.

BACKGROUND: Craniosynostosis is a prevalent craniofacial malformation in Finland; however, comprehensive population-based epidemiological data are limited. This study aimed to estimate the total and birth prevalence of craniosynostosis in Finland from 1987 to 2010 and examine temporal trends. METHODS: We collected the data from nationwide registers maintained by the Finnish Institute for Health and Welfare and Statistics Finland, as well as treating hospitals, encompassing live births, stillbirths, terminations for fetal anomalies, and infant deaths with suspected or diagnosed craniosynostosis or skull deformation. A craniofacial surgeon and a clinical geneticist reviewed 1878 medical records for diagnostic confirmation. RESULTS: Out of 877 craniosynostosis cases, 83% were single-suture synostoses (all live births), 10% craniosynostosis syndromes, and 7% multisutural non-syndromic synostoses. Live birth prevalence from 1987 to 2010 was 6.0/10,000 live births, ranging from 5.0/10,000 in 1987 to 7.5/10,000 in 2010. Total prevalence, including live births, stillbirths, and terminations, varied from 5.0/10,000 in 1987 to 8.0/10,000 in 2010. Sagittal synostosis was the most common synostosis, with a prevalence of 3.9/10,000 live births, followed by metopic (0.6/10,000), unicoronal (0.4/10,000), and unilambdoid (0.1/10,000) synostoses. CONCLUSIONS: The total combined prevalence of all craniosynostosis types significantly increased driven by a nonsignificant rise across all subgroups and a significant increase in the syndrome group. In live births increase was significant only within the syndrome subgroup, primarily due to an increase in Muenke syndrome patients. The rising prevalence of syndromes necessitates further investigation. Contrasting with trends in Europe, Australia, and the USA, Finland showed no significant increase in metopic craniosynostosis.

Epidemiology of neural tube defects in Finland: a nationwide register study 1987-2018.

BACKGROUND: Our aim was to evaluate the prevalence, mortality, regional and sex distribution of neural tube defects (NTDs) in Finland. METHODS: Data for this population-based study were collected from 1987 to 2018 from the national health and social welfare registers. RESULTS: There were in total 1634 cases of NTDs, of which 511 were live births, 72 pregnancies ended in stillbirth and 1051 were terminations of pregnancy due to fetal anomaly (TOPFA). The total prevalence of NTDs was 8.6 per 10 000 births and it increased slightly annually (OR 1.008; 95% CI: 1.002, 1.013) during the 32-year study period. The birth prevalence of NTDs decreased (OR 0.979; 95% CI: 0.970, 0.987), but the prevalence of TOPFA increased annually (OR 1.024; 95% CI 1.017, 1.031). The perinatal mortality of NTD children was 260.7 per 1000 births and the infant mortality was 184.0 per 1000 live births, whereas these measures in the general population were 4.6 per 1000 births and 3.3 per 1000 live births, respectively. There was no difference in the NTD prevalence between males and females (P-value 0.77). The total prevalence of NTDs varied from 7.1 to 9.4 per 10 000 births in Finland by region. CONCLUSIONS: Although the majority of NTDs are preventable with an adequate folic acid supplementation, the total prevalence increased in Finland during the study period when folic acid supplementation was mainly recommended to high-risk families and to women with folic acid deficiency. NTDs remain an important cause of infant morbidity and mortality in Finland.

Characteristics and associated anomalies in radial ray deficiencies in Finland--a population-based study.

Upper-limb defects with deficiencies of the radial ray have varying etiologies, with a low proportion of true Mendelian disorders. We carried out a population-based study to elucidate the birth prevalence and clinical spectrum of radial ray deficiencies in Finland. We identified all births with radial ray deficiency reported to the Finnish Register of Congenital Malformations in 1993-2005. Altogether 138 cases were identified (123 live births), with a birth prevalence of 1.83 per 10,000 births and a live birth prevalence of 1.64 per 10,000 live births. The proportion of infant deaths was as high as 35%. The majority of the cases were associated with known syndromes or multiple anomalies; only 13% were true isolated radial ray deficiencies. The most common syndrome was trisomy 18, and the most common in multiple anomalies was VACTERL association. In 8.7% of cases an association between radial ray deficiency and heart anomaly was observed. The high proportion of cases with associated major anomalies indicates that radial ray deficiency can be regarded isolated only after thorough assessment of the various organ systems in an affected infant.

Decreasing perinatal mortality in placental abruption.

OBJECTIVE: To study perinatal mortality associated with placental abruption. DESIGN: Retrospective population study using the Finnish Hospital Discharge Register and Medical Birth Register data. SETTING: Finland, 1987-2005. POPULATION: Pregnancies with placental abruption and all other births without placental abruption. METHODS: The national Hospital Discharge Register and Medical Birth Register were used to identify all pregnancies with placental abruption. Demographic data and delivery outcomes were collected retrospectively. Perinatal mortality associated with placental abruption was compared with that in other births. Potential risk factors were analysed. MAIN OUTCOME MEASURES: Perinatal mortality in placental abruption. RESULTS: The study consisted of 618 735 women with 1.14 million pregnancies, 4336 of whom had placental abruption. Overall perinatal mortality with abruption was 119 per 1000 births. Placental abruption explained 7% of all perinatal deaths. The mortality among singleton births (125 per 1000) was higher than among multiple births (40 per 1000). The majority of deaths (77%) occurred in utero. Singleton perinatal mortality with abruption decreased from 173 per 1000 in 1987-1990 to 98 per 1000 in 2000-2005 (p < 0.001). In singleton births at <32 gestational weeks, overall perinatal mortality was high (345 per 1000) and was not increased by placental abruption. Prematurity, low birthweight, male fetal sex and maternal smoking were independent risk factors for placental abruption-related perinatal mortality. CONCLUSIONS: Although mortality associated with placental abruption decreased during the study period, placental abruption still remains an important cause of perinatal mortality.

High prevalence of sacrococcygeal teratoma in Finland - a nationwide population-based study.

AIM: The birth prevalence of sacrococcygeal teratoma (SCT) has been reported to range from 1:27 000 to 1:40 000. We assessed the population-based prevalence and clinical presentation of SCT over 22 years. METHODS: We identified all cases of SCT, including live births, stillbirths and terminations of pregnancy (TOPs), in the Finnish Register of Congenital Malformations, covering 1987-2008. Data on prenatal diagnoses, pregnancy outcomes, infant deaths and associated anomalies were collected. RESULTS: One hundred and twenty four SCT cases were identified among 1 331 699 pregnancies. There were 89 (72%) live births, 13 (10%) stillbirths and 22 (18%) TOPs. The total prevalence of SCT was 1:10 700. Tumours were detected in utero in 55% of the pregnancies with SCT. The proportion of perinatal deaths among all SCT births was 28%. Thirty percentage of the cases had associated abnormalities (mainly of the urinary tract and various syndromes). CONCLUSION: This nationwide, population-based study on SCT shows that the total and birth prevalence of SCT in Finland is markedly higher than previously reported. This may reflect true differences between populations, but may also be explained by accurate nationwide registration of SCTs. The high perinatal mortality rate has an impact on counselling of families and planning of deliveries.

[Prenatal screening and diagnosis of severe congenital heart defects in Finland]. / Synnynnäisten sydänvikojen raskaudenaikainen seulonta ja diagnostiikka.

INTRODUCTION: Careful investigation of the heart for finding structural heart defects is an essential part of nationwide fetal anomaly screening at 20th weeks of gestation which took effect in 2010. PATIENTS AND METHODS: We studied the results of fetal cardiac screening in infants having a major congenital cardiac defect in 2005-2011. RESULTS: 28% of severe cardiac defects were detected prenatally. Univentricular heart defects were prenatally found in 87% of all cases. Screening for transposition of great arteries and conotruncal defects remains challenging. CONCLUSIONS: More active approach with a rapid referral is recommended for abnormal cardiac findings in fetal structural screening.

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

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.

Decreasing incidence of placental abruption in Finland during 1980-2005.

OBJECTIVE: To study the incidence trends of placental abruption. DESIGN: Register-based retrospective study. SETTING: The Finnish Medical Birth Register and Hospital Discharge Register. POPULATION: A total of 6231 placental abruption cases among 1 576 051 deliveries. METHODS: Data on demographic and pregnancy and delivery associated outcomes were collected. Data on overall incidence and maternal age were available 1980-2005. Data on other variables were available 1987-2005. MAIN OUTCOME MEASURE: Placental abruption RESULTS: The overall incidence of placental abruption was 395/100 000 (0.4%). The incidence decreased 31%, from 487/100 000 in 1980 to 337/100 000 in 2005 (p < 0.001). The incidence was lowest among women aged 20-24 years (305/100 000) and highest among women aged ≥45 years (1309/100 000). During 1987-2005 the incidence was lowest among women with one or two deliveries (353/100 000) and highest in nulliparous women (382/100 000) and in women with three or more deliveries (595/100 000). The incidence was nearly double (577/100 000) among smoking compared with non-smoking women (341/100 000). The incidence was highest between gestational weeks 26 and 29. Among newborns weighing <1500 g the incidence was higher (5734/100 000) than among those weighing ≥2500 g (251/100 000). The incidence was higher in multiple (903/100 000) than in singleton pregnancies (374/100 000). CONCLUSION: The incidence of placental abruption decreased during 1980-2005. The incidence was highest among women aged 45 years or more, multiparous and smoking women, in multiple pregnancies and in women with low birthweight newborns.

Cyclopia: an epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research.

Cyclopia is characterized by the presence of a single eye, with varying degrees of doubling of the intrinsic ocular structures, located in the middle of the face. It is the severest facial expression of the holoprosencephaly (HPE) spectrum. This study describes the prevalence, associated malformations, and maternal characteristics among cases with cyclopia. Data originated in 20 Clearinghouse (ICBDSR) affiliated birth defect surveillance systems, reported according to a single pre-established protocol. A total of 257 infants with cyclopia were identified. Overall prevalence was 1 in 100,000 births (95%CI: 0.89-1.14), with only one program being out of range. Across sites, there was no correlation between cyclopia prevalence and number of births (r = 0.08; P = 0.75) or proportion of elective termination of pregnancy (r = -0.01; P = 0.97). The higher prevalence of cyclopia among older mothers (older than 34) was not statistically significant. The majority of cases were liveborn (122/200; 61%) and females predominated (male/total: 42%). A substantial proportion of cyclopias (31%) were caused by chromosomal anomalies, mainly trisomy 13. Another 31% of the cases of cyclopias were associated with defects not typically related to HPE, with more hydrocephalus, heterotaxia defects, neural tube defects, and preaxial reduction defects than the chromosomal group, suggesting the presence of ciliopathies or other unrecognized syndromes. Cyclopia is a very rare defect without much variability in prevalence by geographic location. The heterogeneous etiology with a high prevalence of chromosomal abnormalities, and female predominance in HPE, were confirmed, but no effect of increased maternal age or association with twinning was observed.

Phocomelia: a worldwide descriptive epidemiologic study in a large series of cases from the International Clearinghouse for Birth Defects Surveillance and Research, and overview of the literature.

Epidemiologic data on phocomelia are scarce. This study presents an epidemiologic analysis of the largest series of phocomelia cases known to date. Data were provided by 19 birth defect surveillance programs, all members of the International Clearinghouse for Birth Defects Surveillance and Research. Depending on the program, data corresponded to a period from 1968 through 2006. A total of 22,740,933 live births, stillbirths and, for some programs, elective terminations of pregnancy for fetal anomaly (ETOPFA) were monitored. After a detailed review of clinical data, only true phocomelia cases were included. Descriptive data are presented and additional analyses compared isolated cases with those with multiple congenital anomalies (MCA), excluding syndromes. We also briefly compared congenital anomalies associated with nonsyndromic phocomelia with those presented with amelia, another rare severe congenital limb defect. A total of 141 phocomelia cases registered gave an overall total prevalence of 0.62 per 100,000 births (95% confidence interval: 0.52-0.73). Three programs (Australia Victoria, South America ECLAMC, Italy North East) had significantly different prevalence estimates. Most cases (53.2%) had isolated phocomelia, while 9.9% had syndromes. Most nonsyndromic cases were monomelic (55.9%), with an excess of left (64.9%) and upper limb (64.9%) involvement. Most nonsyndromic cases (66.9%) were live births; most isolated cases (57.9%) weighed more than 2,499 g; most MCA (60.7%) weighed less than 2,500 g, and were more likely stillbirths (30.8%) or ETOPFA (15.4%) than isolated cases. The most common associated defects were musculoskeletal, cardiac, and intestinal. Epidemiological differences between phocomelia and amelia highlighted possible differences in their causes.

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.

Sirenomelia: an epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and literature review.

Sirenomelia is a very rare limb anomaly in which the normally paired lower limbs are replaced by a single midline limb. This study describes the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance and Research, and were reported according to a single pre-established protocol. Cases were clinically evaluated locally and reviewed centrally. A total of 249 cases with sirenomelia were identified among 25,290,172 births, for a prevalence of 0.98 per 100,000, with higher prevalence in the Mexican registry. An increase of sirenomelia prevalence with maternal age less than 20 years was statistically significant. The proportion of twinning was 9%, higher than the 1% expected. Sex was ambiguous in 47% of cases, and no different from expectation in the rest. The proportion of cases born alive, premature, and weighting less than 2,500 g were 47%, 71.2%, and 88.2%, respectively. Half of the cases with sirenomelia also presented with genital, large bowel, and urinary defects. About 10-15% of the cases had lower spinal column defects, single or anomalous umbilical artery, upper limb, cardiac, and central nervous system defects. There was a greater than expected association of sirenomelia with other very rare defects such as bladder exstrophy, cyclopia/holoprosencephaly, and acardia-acephalus. The application of the new biological network analysis approach, including molecular results, to these associated very rare diseases is suggested for future studies.

Bladder exstrophy: an epidemiologic study from the International Clearinghouse for Birth Defects Surveillance and Research, and an overview of the literature.

Bladder exstrophy (BE) is a complex congenital anomaly characterized by a defect in the closure of the lower abdominal wall and bladder. We aimed to provide an overview of the literature and conduct an epidemiologic study to describe the prevalence, and maternal and case characteristics of BE. We used data from 22 participating member programs of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). All cases were reviewed and classified as isolated, syndrome, and multiple congenital anomalies. We estimated the total prevalence of BE and calculated the frequency and odds ratios for various maternal and case characteristics. A total of 546 cases with BE were identified among 26,355,094 births. The total prevalence of BE was 2.07 per 100,000 births (95% CI: 1.90-2.25) and varied between 0.52 and 4.63 among surveillance programs participating in the study. BE was nearly twice as common among male as among female cases. The proportion of isolated cases was 71%. Prevalence appeared to increase with increasing categories of maternal age, particularly among isolated cases. The total prevalence of BE showed some variations by geographical region, which is most likely attributable to differences in registration of cases. The higher total prevalence among male cases and older mothers, especially among isolated cases, warrants further attention.