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We compared Brazilian oral cleft (OC) frequencies between the population-based Brazilian System of Live Birth (SINASC) and the hospital-based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD-10) for congenital defects coding, ECLAMC uses ICD-8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1.7-1.8), cleft lip (CL) 1.6 (1.5-1.7), and cleft palate (CP) 2.0 (1.9-2.1). In ECLAMC, the CLP frequency was 10.4 per 10,000 (9.0-12.1), CL 5.5 (4.5-6.7), and CP 4.4. (4.5-6.7). In SINASC, only 33% of the oral clefts were CLP, versus 51% in ECLAMC. Part of this discrepancy may have been due to the relative excess of CP and CL cases. Although congenital defect frequencies are usually lower in population than in hospital-based registries, differences in the proportion of the main OC categories are not expected and are probably due to ICD-10 coding issues, such as lumping of unilateral CL and CL without other specifications. ICD-10 codes, whose deficiency for oral clefts is fully explained in the literature, lack modifiers for severity, or clinical subtypes. This paper shows the practical aspect of the ICD-10 system deficiency in capturing cleft lip and palate (CLP) subtypes, as demonstrated in SINASC covering three million births per year. Such errors are expected to occur in any registry that uses the ICD-10 coding system, and must be adjusted, given its relevance worldwide.

BACKGROUND—The etiopathogenesis of microtia is still unknown in the majority of the cases, particularly for individuals presenting with isolated microtia. Our aim was to evaluate potential risk factors for this condition using a case-control approach. METHODS—We analyzed data from 1,194 livebirths with isolated microtia enrolled in the ECLAMC study (Estudio Colaborativo Latino Americano de Malformaciones Congenitas) from 1982 to 2011 and their respective controls. Odds ratios were estimated with conditional logistic regression models along with 95% confidence intervals for the resulting odds ratio estimates controlling for the effects of potential confounders (sex, maternal age, hospital and year of birth) for an adjusted OR (aOR). RESULTS—Multiparity was associated with a higher risk of microtia compared to primiparity (aOR 1.5, 95%CI 1.2–1.8), with women who had eight or more prior pregnancies having the highest risk (aOR 2.8, 95%CI 1.6–5.2). Women who presented with cold-like symptoms were at higher risk for microtia (aOR 2.2, 95%CI 1.2–3.9) as well as those that used tobacco or alcohol during pregnancy (aOR 1.7, 95%CI 1.1–2.5 and aOR 1.4, 95%CI 0.9–2.1, respectively). The association with alcohol use appeared to be limited to those women who reported binge drinking during pregnancy (aOR 1.4, 95% 0.7–2.9). Cases from hospitals at low altitude (< 2,500 m) tended to have more severe types of microtia than those from hospitals at high altitude. CONCLUSIONS—These results support the hypothesis that in addition to teratogens other nongenetic risk factors contribute to the occurrence of isolated microtia.

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. (C) 2011 Wiley Periodicals, Inc.

To evaluate whether the routinely collected data in birth defect registries could be used to assess association between medications and risk for congenital anomalies an "exposed case-only" design was performed.Twelve registries provided 18,131 cases exposed to a medication during the first trimester of pregnancy and with at least one major malformation. Odds ratios for malformations associated with maternal use of selected medications were computed.Among seven most commonly used medications very few significant associations with malformations were identified. Among fourteen potentially teratogenic medications several strong associations were found, including valproic acid with spina bifida, and insulin (as proxy for diabetes) with several types of cardiac defects.Finding known associations provides assurance on the validity of this approach, whereas identifying new associations provides a signal to be followed by confirmatory studies. Through this activity, international networks of birth defect registries can contribute with limited resources to post-marketing surveillance of the teratogenicity of medications. (C) 2010 Elsevier Inc. All rights reserved.

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 Congenitas (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.

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 mother's 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 multi-para 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.

Awareness of the benefit of periconceptional supplementation with folic acid was surveyed in 2,810 postpartum women by the Latin American Collaborative Study of Congenital Malformations (ECLAMC) during 1996. While 48.8% of the women claimed to know that some vitamins were good for the baby in gestation, only 0.5% mentioned folic acid. Although 13.9% of the women declared to know about the beneficial role of folic acid, only 2.2% were able to mention a correct list of foods rich in folic acid. Women delivering in private (n = 1,065) hospitals had taken vitamins, including folic acid, and had heard about its beneficial role more frequently than those within the public system (n = 1,745). Nevertheless, the public series had a larger proportion of vitamin users who started taking vitamins during the first month of gestation. Women aged 20–34 years rated better than both age extremes in stating they had taken vitamins, in actually having taken vitamins, and in having taken vitamins including folic acid. There was no significant difference between age groups, as to the time of pregnancy when vitamins were started, nor to the women`s knowledge about beneficial vitamins. Adolescent women had the lowest awareness rate concerning folic acid (11%), when compared with the two older groups (15%). Based on these results, staple food fortification seems to be the recommended strategy for the prevention of birth defects in South America.

Data on polydactyly were obtained from two large samples: the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and from a migrant Northeastern Brazilian population of rural origin (Hospedaria). ECLAMC is a case-control clinical epidemiological program comprising 10,035 individuals distributed among 2,030 segregating nuclear families. Hospedaria data consisted of 6,586 examined individuals belonging to 1,040 nuclear families. Using complex segregation analysis methodology we found no evidence of two loci (a major gene and a modifier locus) acting on postaxial polydactyly in the present study. Very high heritability values (in a classical multifactorial model) of postaxial polydactyly were detected, for several sets of analyses in ECLAMC and in Hospedaria. For the whole ECLAMC sample there is a peculiar suggestion of a major recessive gene effect responsible for the trait; however, no comparison with a model involving transmission probabilities (tau) was possible in this highly heterogeneous sample. If the whole ECLAMC sample is divided in subsamples, according to Black admixture proportions, the same multifactorial picture emerges. Two different inheritance patterns were verified for hand (HP) and foot (FP) postaxial polydactyly: For HP there is evidence of a non-Mendelian transmission mechanism, while for FP the parental/sib transmission appears to be due only to multifactorial causes.

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.

The first step of all healthcare actions aimed at promoting an appropriate quality of life for infants affected by Down syndrome (DS) is to ensure their survival. This investigation was aimed at estimating the infant mortality rate of infants affected with DS in urban populations of South America. Thirty-three hospitals included in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) distributed in 23 cities of 5 South American countries followed 360 liveborn DS cases born during the 1988-1992 period. Families were recontacted after the infant should have reached the age of one year. The collected data included information about health status; i.e., frequency and dates of diagnosed illnesses and hospital admissions, and, in case of death, information on date, place and cause of death, and illness immediately before death. Information about the interviews included place, date, and name of the interviewer. A closed questionnaire was employed by the interviewers, mostly physicians, nurses, and social workers. Life table analysis up to the age of one year was performed by the actuarial survival method. The overall mean survival at age one year was 0.736 (SE=0.023). Thirty-three (9.2%) of the 360 cases died neonatally, and 62 (17.2%) within the remaining 2-to-12-month interval. The probability of survival at one year of age did not differ between public (209 cases; mean 0.718; SE=0.031) and private (151 cases; mean: 0.762; SE=0.035) (chi2:0.87; df:1; P >0.05) health systems. The 150 DS cases with a congenital heart defect (CHD) had a significantly lower P robability of survival at the age of one year (mean: 0.660; SE: 0.039) than did the 210 cases without CHD (mean: 0.790; SE: 0.028) (chi2:6.67; df:1; P

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.

The etiology of microtia remains unknown in most cases. The identification of patterns of associated anomalies (i.e., other anomalies that occur with a given congenital anomaly in a higher than expected frequency), is a methodology that has been used for research into the etiology of birth defects. We conducted a study based on cases of microtia that were diagnosed from more than 5 million live (LB)- and stillbirths (SB) examined in hospitals participating in ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 1967 and 2009. We identified 818 LB and SB with microtia and at least one additional non-related major congenital anomaly (cases) and 15,969 LB and SB with two or more unrelated major congenital anomalies except microtia (controls). A logistic regression analysis was performed to identify the congenital anomalies preferentially associated with microtia. Preferential associations were observed for 10 congenital anomalies, most of them in the craniofacial region, including facial asymmetry, choanal atresia, and eyelid colobomata. The analysis by type of microtia showed that for anomalies such as cleft lip and palate, macrostomia, and limb reduction defects, the frequency increased with the severity of the microtia. In contrast, for other anomalies the frequency tended to be the same across all types of microtia. Based on these results we will integrate data on the developmental pathways related to preferentially associated congenital anomalies for future studies investigating the etiology of microtia., Instituto Multidisciplinario de Biología Celular

The etiopathogenesis of microtia is still unknown in the majority of the cases, particularly for individuals presenting with isolated microtia. Our aim was to evaluate potential risk factors for this condition using a case-control approach.We analyzed data from 1,194 live births with isolated microtia enrolled in the ECLAMC study (Estudio Colaborativo Latino Americano de Malformaciones Congénitas) from 1982 to 2011 and their respective controls. Odds ratios (ORs) were estimated with logistic regression models along with 95% confidence intervals for the resulting OR estimates controlling for the effects of potential confounders (sex, maternal age, hospital, and year of birth) for an adjusted OR (aOR).Multiparity was associated with a higher risk of microtia compared with primiparity (aOR, 1.5; 95% confidence interval [CI], 1.2-1.8), with women who had eight or more prior pregnancies having the highest risk (aOR, 2.8; 95% CI, 1.6-5.2). Women who presented with cold-like symptoms were at higher risk for microtia (aOR, 2.2; 95% CI, 1.2-3.9) as well as those that used tobacco or alcohol during pregnancy (aOR, 1.7; 95% CI, 1.1-2.6 and aOR, 1.4; 95% CI, 0.9-2.1, respectively). The association with alcohol use appeared to be limited to those women who reported binge drinking during pregnancy (aOR, 1.4; 95% CI, 0.7-3.1). Cases from hospitals at low altitude (2500 m) tended to have more severe types of microtia than those from hospitals at high altitude.These results support the hypothesis that, in addition to teratogens, other nongenetic risk factors contribute to the occurrence of isolated microtia.

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.

A simple model is proposed, using the method of maximum likelihood to estimate malformation frequencies in racial groups based on data obtained from hospital services. This model uses the proportions of racial admixture, and the observed malformation frequency. It was applied to two defects: postaxial polydactyly and cleft lip, the frequencies of which are recognizedly heterogeneous among racial groups. The frequencies estimated in each racial group were those expected for these malformations, which proves the applicability of the method.

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. Design Using data collected in the period 1967 to 1992 within the frame of the Latin American Collaborative Study of Congenital Malformations which clinically examined 2,917,074 newborn infants, a total of 1715 with limb reduction defects were found. All cases were classified and analysed in 25 categories. Geographic differences in recorded rates were tested by χ2 for homogeneity. Secular trends were analysed using χ2 test for linear trends. Results The overall birth prevalence rate of limb reduction defects among liveborn infants was 4.91 (per 10,000 births) (3.05 for isolated and 1.85 for associated cases). For stillbirths, the total prevalence was 2673/10,000 (553 for isolated and 21.20 for associated cases). The inclusion of the brachydactylies increased those figures to 5.55110,000 (3.39 for isolated and 2.16 for associated cases), and 27.42, respectively, (5.53 for isolated and 21.89 for associated cases). When isolated and associated cases were considered together, a geographic heterogeneity was found in pre-axial limb reduction defects; there was also some heterogeneity for amputations. A maternal age effect was found for the isolated hypoplasias. Standardising by maternal age, the overall prevalence of limb reduction in liveborn infants was 5.66 per 10,000 (95% CI = 5.38–5.93). An increasing trend was suggested by the isolated form of distal amputations which involved hands, feet, or digits. Conclusions Our data suggest that clustering limb reduction defects in wide groups as transverse and longitudinal may lead to heterogeneous entities. When a possible association is suspected, it would be preferable to present and analyse data in the most discriminant form available. Due to the maternal age effect, it would be advisable to standardise the rates of transversal limb reduction defects by this variable.

Esta dissertação tem como objetivo investigar os zoneamentos do uso do solo propostos pelos planos diretores municipais a partir da Lei Federal 10.257/01 conhecida como o Estatuto da Cidade e os seus reflexos no espaço territorial regional. A expansão urbana e os possíveis comprometimentos no espaço regional podem gerar impactos urbanos e ambientais negativos na ausência de um planejamento integrado previsto nos planos diretores municipais. Soma-se a isso a pré-existência consolidada onde os zoneamentos mapeados não consideram as probabilidades de reversão e controle de cenários atuais bem como a dificuldade em prospectar cenários futuros melhores para determinada região, no caso o Litoral Norte do Rio Grande do Sul. Não tendo encontrado metodologia correlata a ser aplicada na pesquisa, o estudo baseou-se na análise comparativa entre os zoneamentos de uso do solo aplicados aos limites físico-territoriais entre três municípios da região do litoral: Osório, Tramandaí e Imbé.. A pesquisa revelou que o planejamento regional integrado de planos, programas e ações dos planos diretores possui baixa aplicabilidade, sendo praticamente inexistente nos textos analisados. Os zoneamentos de uso do solo entre as fronteiras municipais, secas ou molhadas, desconsideraram compatibilizações mínimas entre seus territórios. Complementarmente, a pesquisa indicou a ausência de instrumentos efetivos para a gestão urbana e regional, bem como a vulnerabilidade territorial da região relacionada à aplicabilidade da legislação municipal vigente. This thesis objective is to zone the use of the land proposed by the civic directors plans from the Federal Law 10.257/01 known as the Estatuto da Cidade and its reflexes at the regional territory space. The urban expansion and the possible commitments at the regional spaces can cause urban and environmental negative impacts in the absence of a good integrated planning foreseen in the civic directors plans. Add to it, the consolideted pre existence where the mapped zoning doesn’t consider the reverse probabilities and current scenario control reversion, as the difficulties in prospect better future scenarios to certain region, in this case the Rio Grande do Sul coast. Having not found the related the methodology to be applied in the research, the thesis is based in the comparative analysis among the soil use of the zoning, applied to the physic territorial limits among the municipalities: Osório, Tramandaí e Imbé. It has been revealed, in the research, that the integrated regional planning, programs and directors action plans have low applicability, being almost inexistent in the analyzed texts. The land use zoning among the civic boarders, wet or dry, have disregarded minimum reconciliations among its territories. Still, the research indicated the absence of effective instruments to the urban and regional management, like the territorial vulnerability related to the applicability of the present current municipal law.

The thalidomide tragedy of the 1960s resulted in thousands of children being born with severe limb reduction defects (LRD), among other malformations. In Brazil, there are still babies born with thalidomide embryopathy (TE) because of leprosy prevalence, availability of thalidomide, and deficiencies in the control of drug dispensation. Our objective was to implement a system of proactive surveillance to identify birth defects compatible with TE. Along one year, newborns with LRD were assessed in the Brazilian hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). A phenotype of LRD called thalidomide embryopathy phenotype (TEP) was established for surveillance. Children with TEP born between the years 2000-2008 were monitored, and during the 2007-2008 period we clinically investigated in greater detail all cases with TEP (proactive period). The period from 1982 to 1999 was defined as the baseline period for the cumulative sum statistics. The frequency of TEP during the surveillance period, at 3.10/10,000 births (CI 95%: 2.50-3.70), was significantly higher than that observed in the baseline period (1.92/10,000 births; CI 95%: 1.60-2.20), and not uniformly distributed across different Brazilian regions. During the proactive surveillance (2007-2008), two cases of suspected TE were identified, although the two mothers had denied the use of the drug during pregnancy. Our results suggest that TEP has probably increased in recent years, which coincides with the period of greater thalidomide availability. Our proactive surveillance identified two newborns with suspected TE, proving to be a sensitive tool to detect TE. The high frequency of leprosy and the large use of thalidomide reinforce the need for a continuous monitoring of TEP across Brazil., Instituto Multidisciplinario de Biología Celular

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.

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 microg 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.

Unintended pregnancies are accepted as associated with social, maternal and perinatal risks, but few data exist in South America. In a selected network of hospitals participating in the ECLAMC (Spanish acronym for Latin American Collaborative Study of Congenital Malformations), the frequency of unintended pregnancies was 49.8% in 5155 mothers of normal liveborns, as interviewed in the post-partum period (1992-1994). Compared with the intended pregnancy group, these mothers were more frequently multiparous, conceived easily, had a surprisingly higher mean maternal age, lower educational level, and Black ancestors. The frequency of mistimed pregnancies was the highest among primiparae. No adverse perinatal outcome could be found with regard to low birthweight (< 2500 g), prematurity (< 37 weeks), and early neonatal death. The rates of Caesarean delivery, twinning and sex ratio were similar in intended and unintended groups. Logistic regression analysis showed that maternal education could be a confounding factor associated with other maternal variables. The rate of unintended pregnancies in the present study is significantly higher than that described for other regions. Knowledge of the characteristics of women experiencing unintended pregnancies would allow proper public health strategies.

Genetic and environmental risks factors were investigated in a sample of 989 non-malformed newborn infants with skin pigmented naevi (PN), and in 989 non-malformed non-PN, control babies. The samples were obtained from a population of 531,831 livebirths, from fifty-nine South-American maternity hospitals. No significant differences were observed between the PN and control groups for the following risk factors: sex, twinning, parental consanguinity, socioeconomic level, parental ages, birth order, fetal presentation, type of delivery, postnatal mortality, and first trimester of pregnancy histories for maternal chronic illnesses or immunizations, radiation exposure, drug intake, and vaginal bleeding. PN infants were associated with high frequencies of Black racial ancestry, positive prenatal history for maternal acute illnesses, and high mean values for length of gestation and birth weight. The observed association of PN with maternal acute illnesses could be a spurious one, due to partial dependence upon Black racial ancestry, and to maternal memory bias. The analysis of the intrauterine growth curves showed that PN infants have a low prematurity rate, and a high mean by the control newborn group. This observation suggest that congenital PN appear in the latest stages of intrauterine development. No evidence was obtained to allow us to consider congenital PN as true developmental anomalies.

The presence of Native Americans, Europeans, and Africans has led to the development of a multi-ethnic, admixed population in Chile. This study aimed to contribute to the characterization of the uniparental genetic structure of three Chilean regions. Newborns from seven hospitals in Independencia, Providencia, Santiago, Curicó, Cauquenes, Valdívia, and Puerto Montt communes, belonging to the Chilean regions of Santiago, Maule, and Los Lagos, were studied. The presence of Native American mitochondrial DNA (mtDNA) haplogroups and two markers present in the non-recombinant region of the Y chromosome, DYS199 and DYS287, indicative of Native American and African ancestry, respectively, was determined. A high Native American matrilineal contribution and a low Native American and African patrilineal contributions were found in all three studied regions. As previously found in Chilean admixed populations, the Native American matrilineal contribution was lower in Santiago than in the other studied regions. However, there was an unexpectedly higher contribution of Native American ancestry in one of the studied communes in Santiago, probably due to the high rate of immigration from other regions of the country. The population genetic sub-structure we detected in Santiago using few uniparental markers requires further confirmation, owing to possible stratification for autosomal and X-chromosome markers.