Maria da Graça Dutra

Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile

To verify whether the decreasing neural tube defects birth prevalence rates in Chile are due to folic acid fortification or to pre‐existing decreasing trends, we performed a population survey using a network of Estudio Colaborativo Latino Americano de Malformaciones Congénitas (ECLAMC, Latin American Collaborative Study of Congenital Malformations) maternity hospitals in Chile, between the years 1982 and 2002. Within each maternity hospital, birth prevalence rates of spina bifida and anencephaly were calculated from two pre‐fortification periods (1982–1989 and 1990–2000), and from one fortified period (2001–2002). There was no historical trend for spina bifida birth prevalence rates before folic acid fortification, and there was a 51% (minimum 27%, maximum 66%) decrease in the birth prevalence rates of this anomaly in the fortified period. The relative risks of spina bifida were homogeneous among hospitals in the two period comparisons. There was no historical trend for the birth prevalence of anencephaly comparing the two pre‐fortified periods, but the relative risks were heterogeneous among hospitals in this comparison. There was a 42% (minimum 10%, maximum 63%) decrease in the birth prevalence rate of anencephaly in the fortified period as compared with the immediately pre‐fortified period, with homogeneous relative risks among hospitals. Within the methodological constraints of this study we conclude that the birth prevalence rates for both spina bifida and anencephaly decreased as a result of folic acid fortification, without interference of decreasing secular trends.

Preliminary Data on Changes in Neural Tube Defect Prevalence Rates After Folic Acid Fortification in South America

Several South American countries are fortifying wheat flour with folic acid. However, only Chile started in 2000 to add 2.2 mg/kg, providing 360 μg daily per capita, an acceptable dosage for preventing the occurrence of some neural tube defect (NTD) cases. ECLAMC (Spanish acronym for the Latin American Collaborative Study of Congenital Malformations) routinely monitoring birth defects in South America since 1976, surveyed the impact of this fortification. Data from 361,374 births occurred in 43 South American hospitals, distributed in five different countries, active throughout the 1999–2001 triennium, were selected from the ECLAMC network. Birth prevalence rates for three different congenital anomalies with similar expected prevalence rates, were surveyed by the Cumulative Sum Method (CUSUM) method. They were NTD, oral clefts (OC), and Down syndrome (DS). Expected values were derived from observations made in 1999, and CUSUM was applied to the consecutive series of 24 months covering years 2000 and 2001. Only one of three congenital anomaly types, NTDs, in only one of five sampled out countries, Chile, showed a significant decrease, of 31%, during the 2000–2001 biennium, corresponding to the birth of the periconceptionally fortified infants. The level of significance (P < 0.001) was reached in the 20th month after fortification started, corresponding to August 2001. This is the first observation of a significant decrease in the occurrence of NTD after folic acid food fortification in a population little influenced by confounders common in the developed world as pre‐existing secular decreasing trends, and partially unregistered induced abortions.

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.

Associated anomalies in individuals with polydactyly

An epidemiological analysis of the association of polydactyly with other congenital anomalies was performed in 5,927 consecutively born polydactyly cases. They were grouped into three categories: duplicated fifth digit, duplicated first digit, and rare polydactylies; also into isolated or associated groups, if other birth defects were or were not observed in the same infant. Associated cases were further subdivided into: combined, if the other defect was a limb defect; syndromic, if a non-limb defect constituted a recognized causal or pathogenetic entity; and MCA, if a non-limb defect did not constitute a recognized entity. In 14.6% of the 5,927 polydactyly cases studied, polydactyly was not the only congenital anomaly. This associated proportion was minimal for postaxial (11.8%), intermediate for preaxial-I (20.0%), and maximal for rare polydactyly (54.9%). Duplication of the fifth toe plus syndactyly of fourth and fifth toes, as well as other syndactylies adjacent to the duplicated digit is the most frequent type. Syndactyly of fourth and fifth toes was also combined with a duplicated fifth finger, suggesting the existence of an arrested or amputated in utero sixth toe. Polydactylies are rarely associated with other congenital anomalies except in recognizable syndromes. When syndromes are excluded, most of the significant positive associations disappear. Trisomy 13, Meckel, and Down syndrome explained 255 of the 338 syndromic polydactyly cases. Down syndrome is strongly associated with first-digit duplication, and negatively associated with postaxial polydactyly. The latter could not be explained by maternal age differences among Black and non-Black case sub-sets.

Epidemiological analysis of rare polydactylies

This work includes all cases with extra digits (polydactyly) registered from a birth sample of over four million births aggregated from two comparable birth series: the Latin-American Collaborative Study of Congenital Malformations: ECLAMC (3,128,957 live and still births from the 1967 to 1993 period), and the Spanish Collaborative Study of Congenital Malformations: ECEMC (1,093,865 livebirths from April 1976 to September 1993, and 7,271 stillbirths from January 1980 to September 1993). All but 2 of 6,912 registered polydactyly cases fit well into one of the following 11 preestablished polydactyly types (observed number of cases in parentheses): Postaxial hexadactyly (5,345), Preaxial-I hexadactyly (1,018), Seven or more digits (57), synpolydactyly (15), crossed polydactyly (45), 1st digit triphalangism (33), 2nd digit duplication (39), 3rd digit duplication (18), 4th digit duplication (22), Haas polysyndactyly (3), and high degree of duplication (4). The birth prevalence rates observed in both series were similar except for postaxial polydactyly, which was more frequent in the ECLAMC (150.2/100,000) than in the ECEMC (67.4/100,000), as expected due to the higher African Black ethnic extraction of the South-American than of the Spanish populations. This similar frequency for the rare polydactylies (5.4 per 100,000 in South America and 5.7 in Spain), and for each one of the 9 categories, suggests that the values reported here are valid for most populations. The rare polydactylies are frequently syndromal: one third of them (77/236) were found in association with other congenital anomalies, 11.0% (26/236) in MCA cases and 21.6% (51/236) in recognized syndromes.

Preferential associations between oral clefts and other major congenital anomalies

Objectives: To identify preferential associations between oral clefts (CL  =  cleft lip only, CLP  =  cleft lip with cleft palate, CP  =  cleft palate) and nonoral cleft anomalies, to interpret them on clinical grounds, and, based on the patterns of associated defects, to establish whether CL and CLP are different conditions. Design And Settings: Included were 1416 cleft cases (CL  =  131, CLP  =  565, CP  =  720), among 8304 live- and stillborn infants with multiple congenital anomalies, from 6,559,028 births reported to the International Clearinghouse for Birth Defects Surveillance and Research by 15 registries between 1994 and 2004. Rates of associated anomalies were established, and multinomial logistic regressions applied to identify significant associations. Results: Positive associations with clefts were observed for only a few defects, among which anencephaly, encephaloceles, club feet, and ear anomalies were the most outstanding. Anomalies negatively associated with clefts included congenital heart defects, VATER complex (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia), and spina bifida. Conclusion: The strong association between all types of clefts and anencephaly seems to be attributable to cases with disruptions; the association between CP and club feet seems to be attributable to conditions with fetal akinesia. Some negative associations may depend on methodologic factors, while others, such as clefts with VATER components or clefts with spina bifida, may depend on biological factors. The different patterns of defects associated with CL and CLP, indicating different underlying mechanisms, suggest that CL and CLP reflect more than just variable degrees of severity, and that distinct pathways might be involved.

Limb reduction defects in South America

Objective Limb reduction defects were considered as possible indicators of environmental teratogenesis; it was suggested that also invasive prenatal procedures could increase the risk for limb reduction defects. The purpose of this work is to give a baseline frequency for limb reduction defects, using data from a population not exposed to prenatal diagnosis procedures.

Hand and foot postaxial polydactyly: Two different traits

The aim of this work was to test whether postaxial hexadactyly had different clinical and epidemiological characteristics depending on hand or foot involvement. In the period 1967-1993, the Latin-American Collaborative Study of Congenital Malformations (ECLAMC) enrolled 1,582,289 births, and 2,271 cases with isolated (nonsyndromal) postaxial polydactyly (5th-digit hexadactyly). The prevalence was 14.3/10,000 births. Postaxial polydactyly (PP) of the hand (HPP) was the most frequent type (N:1,733; 76.3%; prevalence: 11.0/10,000), followed by foot PP (FPP=N:351; 15.5%; prevalence: 2.2), and hand and foot PP (BPP=N:187; 8.2%; prevalence: 1.2). Unlike HPP (55.0% bilateral; 77.2% left), FPP was less frequently bilateral (19.4%), with lower preference for the left side (55.5%). As expected, HPP was associated with African Black ethnicity, male sex, twinning, low maternal education, parental consanguinity, and there was frequent recurrence in 1st-degree relatives. Conversely, FPP was associated with Amerindian racial background, parental subfertility, and bleeding in the 1st trimester of pregnancy. BPP displayed the highest frequency of associated congenital defects (23.4%, vs HPP:6.6%, FPP: 15.4%). In its isolated form, BPP resembled HPP more than FPP with respect to left preference (90.9%), familial recurrence (11.0% of 1st degree relatives), and low maternal education. Although male sex preference and high frequency of twinning was observed in the 3 PP subtypes, statistical significance was present only in HPP. None of the 3 PP subtypes showed abnormal values for perinatal mortality, birth weight, length of gestation, parental ages, or parity. A logistic regression analysis showed Black race only to be associated with HPP, parental subfertility with FPP, parental consanguinity with BPP, and non-Black race with both FPP and BPP. The data presented here are the first indication that HPP and FPP are 2 different entities, with a larger genetic component in HPP than in FPP.

Search for ethnic, geographic, and other factors in the epidemiology of Down syndrome in South America: Analysis of data from the ECLAMC project, 1967–1997

We have analyzed data on 3,157 cases of Down syndrome (DS) from nine South American countries in consecutive series of hospital live births over a 30-year period, with particular emphasis on possible ethnic or geographic variations in maternal age-adjusted incidence. The data constitute the largest series of DS cases assembled to date from an area lacking advanced health care systems. Absolute incidence rates were estimated from total hospital live births; relative rates were estimated from matched case-control data using conditional logistic regression. Maternal age-adjusted rates were closely similar to those reported elsewhere, and showed little or no dependency on other factors investigated, including paternal age, birth order, ancestral origin, country of birth, maternal educational level, maternal ABO and Rhesus blood groups, interval to and outcome of mothers previous pregnancy, and parental consanguinity. The absence of an effect of high birth order was particularly notable because of the relatively large number of grand multipara resulting from high fertility in this population. The study adds to a body of evidence suggesting that maternal age-adjusted DS rates vary little across human populations, and are therefore unlikely to be greatly influenced by genetic or environmental factors that differ between them. An unusual finding was of a markedly lower sex ratio (98 males per 100 females) than has been reported in other DS samples.

Clinical epidemiology of skeletal dysplasias in South America

Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre‐established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9–3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL‐1) and according to international classification, 33% of cases fit into the G‐25 (osteogenesis imperfecta), 29% in Group‐1 (FGFR3), and 8% in Group‐18 (Bent bones). The prevalence of the main OCD types were: OI—0.74 (0.61–0.89); thanatophoric dysplasia—0.47 (0.36–0.59); and achondroplasia—0.44 (0.33–0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls (P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate.