Évaluer l'aptitude à réaliser le diagnostic prénatal de la hernie diaphragmatique congénitale (HDC) et son retentissement sur le devenir fœtal et néonatal. Étude rétrospective de l'ensemble des cas de HDC recensés par le registre centre-est des malformations (Institut Européen des Génomutations) de janvier 1986 à décembre 2003. Ce registre comprend tous les cas de HDC que le diagnostic soit porté en anténatal, en post-natal ou à l'occasion d'un examen nécropsique. Nous avons évalué les taux de détection prénatale et leur évolution ainsi que le devenir des enfants atteints (interruption médicale de grossesse IMG, mort in utero MFIU, mort néonatale, survie). 501 cas sont recensés dont 232 diagnostiqués en anténatal (46,3 %) à un âge moyen de 25,05,8 SA. Dans 315 cas (62,9 %), la HDC est isolée (groupe 1) et le diagnostic prénatal est porté 145 fois (46,1 %) à un âge gestationnel moyen de 25,55,4 SA. Dans 148 cas (29,5 %), la HDC est associée à d'autres anomalies avec un caryotype normal (groupe 2). Le diagnostic prénatal d'au moins un signe d'appel est alors porté dans 100 cas (67,6 %) et le diagnostic formel de l'atteinte diaphragmatique dans 69 cas (46,6 %). Dans 38 cas (7,6 %), la HDC est associée à une anomalie caryotypique et, éventuellement, à d'autres anomalies (groupe 3). Le diagnostic prénatal d'au moins un signe d'appel est alors porté dans 27 cas (71,1 %) et le diagnostic formel de l'atteinte diaphragmatique dans 18 cas (47,4 %). Alors que le taux de dépistage de la HCD reste constant quel que soit le groupe (environ 46 % ; p = 0,99), le taux de détection des fœtus « à risque » (au moins un signe d'appel repéré) est significativement différent (p < 0,0001). Notre capacité de dépistage est significativement différente selon le caractère droit (33,3 %), gauche (58,9 %) ou bilatéral (85,7 %) de la HCD (p = 0,0003). Elle s'est améliorée de manière significative au cours de la période d'étude : moins de 40 % pour les années 1986-1992, de 40 à 60 % pour les années 1993-1999, toujours plus de 60 % depuis l'année 2000 (p < 0,0001 ; extrêmes de 9,5 % en 1987 à 76,9 % en 2000). La survie au-delà de la période néonatale est de 65,5 % lorsqu'aucun signe d'appel n'a été détecté en anténatal (34,5 % de MFIU ou décès néonatal, 0 % IMG). Cette survie est réduite à 31,3 % (p < 0,0001) lorsqu'au moins un signe d'appel a été détecté (35,3 % IMG, 33,5 % de MFIU ou décès néonatal). Dans le groupe 1, la survie passe de 74,0 % à 51,0 % si le diagnostic prénatal est établi (p < 0,0001). Le taux de détection prénatale de la HDC est en amélioration. Les anomalies associées favorisent le repérage des fœtus à risque mais n'augmentent pas le taux de détection de la HDC. Les cas repérés en anténatal constituent un groupe de pronostic plus sévère par la fréquence des malformations associées et du taux de survie plus faible malgré des conditions d'accueil obstétrico-pédiatrique optimales.

The study evaluated the sex distribution of major isolated malformations and common trisomies among a large and geographically varied sample. Eighteen registries from 24 countries contributed cases, which were centrally reviewed and classified in three clinical types as isolated, associated, or syndromic. We selected cases of 26 major defects (n = 108,534); trisomy 21, 18, and 13 (n = 30,114); other syndromes (n = 2,898); and multiple congenital anomalies (n = 24,197), for a total of 165,743 cases. We observed a significant deviation of sex distribution (compared to a sex ratio of 1.06 or male proportion of 51.4%) for 24 of the 29 groups (a male excess in 16, a female excess in 8), and in 8 of such groups these estimates varied significantly across registries. A male excess was noted for two left obstructive cardiac defects (hypoplastic left heart and coarctation of the aorta) and a female excess for all the main types of neural tube defects. A male excess was seen for omphalocele but not gastroschisis. For neural tube defects the female excess tended to be stronger in areas with historically high prevalence for these defects. For 15 of the 26 birth defects the sex distribution differed among isolated, associated, and syndromic cases. Some of these epidemiologic commonalities are consistent with known or putative developmental processes. Further, the geographic variation for some defects may reflect local prevalence rates and risk factors. Finally, the findings underscore the need for clinical classification (e.g., into isolated, multiple, syndromes) in studies of birth defects. Published 2005 Wiley-Liss, Inc.

To examine the effect of maternal origin and distance between parental residence to the nearest maternity ward with neonatal surgical centre in the same hospital, on the prenatal diagnosis, elective termination of pregnancy, delivery in adequate place and neonatal mortality for pregnancies with severe malformations requiring neonatal surgery, and to investigate the impact of place of delivery on neonatal mortality. Through the France Central-East Malformation Registry, 706 fetuses with omphalocele (n=123), gastroschisis (n=99), diaphragmatic hernia (n=222), or spina bifida (n=262), excluding chromosomal anomalies, were included in the study. Maternal origin was classified as European or non-European. Adequate place for delivery was defined as birth in a level-3 maternity ward with a neonatal surgical centre. Data were analyzed by univariate and multivariable logistic regression analysis. The prenatal diagnosis rate was 67.7% in 1990-1995, 80.2% in 1996-2001 (OR 2.07, 95%CI 1.24-3.45). With multivariate analysis, the rate was significantly lower for women living 11-50 km (adjOR 0.49, 95%IC:0.25-0.94) or >50 km (adjOR 0.39, 95%IC 0.20-0.74) to the closest adequate site of delivery, but no differences was observed for maternal origin. Non-European women had fewer elective terminations of pregnancy (adjOR 0.34 95%IC:0.14-0.81) and fewer deliveries in adequate sites [adjOR 0.40 (0.18-0.89)]. Neonatal mortality was lower in case of delivery in an adequate site (adjOR 0.31 95%IC:0.13-0.7) and was not associated with maternal origin and distance. The rate of prenatal diagnosis decreases with increasing distance between parental residence and reference centre. Non-European women have prenatal diagnosis as often as European, but terminate their pregnancy less often, perhaps for cultural reasons. Non-European women with malformed babies deliver less often in adequate centres, probably because of difficulties in the perinatal care system. Minority ethnic groups should be studied to understand and improve pregnancy outcomes.

Drugs of the Benzodiazepine family are among the most frequently prescribed in France. Since anxiety disorders, for which these substances are mostly indicated, affect 10% of pregnant women, it is very likely that such a treatment could expose many foetuses to BZD during the first three Months of pregnancy. We know that the teratologic effect is not necessarily based on dose rate, but that it is associated with fetal drug exposure during the first 12 weeks of gestation, when organ formation occurs. Most epidemiologists concur that the baseline incidence of congenital damage is 2-2,5% in Europe. The results from a large number of stu-dies on associations between the use of BZDs in pregnancy and congenital malformations are conflicting. An in-depth analysis of existing literature shows results that are hardly comparable, if not contradictory, due to extreme differences in methodological approaches. In a recent meta-analysis case-control studies and cohort studies were analyzed separately. Among the case-control studies significant associations were found between BZD exposure and both, major malformations and oral clefts, whereas the cohort studies showed no association between BZD and any kind of malformation. The purpose of our study is to search for a specific teratogenic effect of this class of drugs, using data collected (1976-1997) by the French Central-East (FCE) registry of congenital malformations, member of the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) located in Lyon, France. This registry monitor malformations among 100,000 births per Year. We analyzed 13,703 cases where information is available on whether or not the mother took a drug during her first trimester of pregnancy. Among them, 3,603 (28%) actually took a drug, and 262 (6.8%) took some sort of benzodiazepine (BDZ). BZD were divided into 9 categories, 8 being the most frequently present, plus one broad category of "others". Malformations were divided into ten categories: congenital anomalies of heart, cleft lip and/or cleft palate, neural tube defects, other anomalies of central nervous system, hypospadias, urinary malformations, anal atresia, other digestive anomalies, limb reduction defects, and genetic anomalies, including chromosome aberrations and monogenic conditions. Other malformations were grouped in an eleventh category. The interesting aspect of this study is that it takes into account the BZD metabolism. It is worth noting that the hepatic catabolism of benzodiazepine is a very complex one, because it leads to derived molecules which are sometimes active and/or present in the common metabolic route of major commercial drugs. Our hypothesis is that if one BZD is associated specifically to a certain type of congenital defect, we may find this BZD to be overrepresented, as compared with other BZDs, in newborns exhibiting some type of congenital defect. The analysis was run according to a case-control approach. Odd ratios (OR) and their 95% confidence intervals were calculated by logistic regression with adjustment for maternal age and parity. When one category of defects was considered, infants having the corresponding malformation were considered as cases, while infants with other malformations were considered as controls. In a similar way infants having being exposed to a given drug were considered as exposed, while infants exposed to any other drug were considered as unexposed. The analysis then was run in 4 steps. Step 1: full sample. With 13,703 cases. We observed no increased risk for any specific malformation type associated with use of BZD. Step 2: further defining drug exposure as a specific BZD, and all others unexposed, a significant association was seen between lorazepam and anal atresia. OR=6.2 (95% CI2.4-15.7, p=0.01). Step 3: this finding was upheld and no other emerged when exposure was defined as the drug or any of its active metabolites. This step was performed because hepatic catabolism of BDZs leads to derived molecules that are sometimes active and/or present in the common metabolic route of major marketed BZDs. Step 4: similarly, the lorazepam/anal atresia finding was upheld when the analysis was restricted to the 262 malformed infants exposed to BZDs in utero. Six cases of anal atresia were found among all newborns exposed to BZD in utero, and five of them were exposed to lorazepam, representing a hypothesis to be tested in further. We are not aware of other reports of this association, and it should be regarded as preliminary until confirmed in other data sets.

Using a statistical methodology, we aimed to identify a group of probable cases of oculo‐auriculo‐vertebral (OAV) dysplasia and to investigate possible relationships between different patterns of congenital malformations. Among 5,260 infants with multiple malformations collected from 4 large registers of congenital malformations, we identified 312 probable OAV cases. With the same technique, we have earlier defined epidemiological delineations of three other well‐known non‐random associations of congenital malformations (CHARGE, VATER, and OEIS). We found convincing relationships between OAV and VATER or CHARGE but none between OAV and OEIS or between the three malformation complexes CHARGE, VATER, and OEIS. An association between two conditions indicates similarities in pathogenesis or in etiology. We suggest that the connection between OAV and CHARGE could be related to a common pathogenetic mechanism: disturbed neural crest development. © 2003 Wiley‐Liss, Inc.

There were three objectives of this study: to investigate possible specificity in the association between specific cardiac defects and chromosomal anomalies; to evaluate ways of categorizing cardiac defects into larger groups with epidemiological similarities that could indicate similarities in etiology or pathogenesis; and to analyze the relationship between specific cardiac defects and diabetes. We pooled data on infants (aged I year or younger) with congenital cardiovascular defects from three large birth defect registries in California, Sweden, and France. The registries in Sweden and France obtained data through reporting from various sources; in California, medical records were reviewed. For severe congenital heart defects, the percentage of infants with identified chromosomal anomalies varied between 0.9% for d-TGV to 68.4% for ECD. In general, specific cardiac conditions have different risk factors. For example, conotruncal defects have been traditionally grouped, but the data presented in this paper indicates more differences for risk factors for the components of conotruncal defects: tetralogy of Fallot, d-TGV, common truncus, and DORV. In general, we suggest the strategy of "splitting" rather than "Jumping" when searching for specific genetic factors and/or teratogens. Adequate analysis thus requires large registries or collaboration among registries. The findings did not support constellations between mothers' diabetes and specific defects.

Previous findings of the EUROHAZCON study showed a 33% increase in risk of non-chromosomal anomalies near hazardous waste landfill sites. Here, we studied 245 cases of chromosomal anomalies and 2412 controls who lived near 23 such sites in Europe. After adjustment for confounding by maternal age and socioeconomic status, we noted a higher risk of chromosomal anomalies in people who lived close to sites (0-3 km) than in those who lived further away (3-7 km; odds ratio 1.41, 95% CI 1.00-1.99). Our results suggest an increase in risk of chromosomal anomalies similar to that found for non-chromosomal anomalies.

Bonnot, Olivier MD; Vollset, Stein Emil PhD; Godet, Pierre François MD; D’Amato, Thierry MD, PhD; Robert, Elisabeth MD, PhD Author Information

BACKGROUNDA specific phenotype of methimazole (MMI) induced malformations has recently been postulated. MMI embryopathy is characterized by minor dysmorphic features, choanal atresia and/or esophageal atresia, growth retardation, and developmental delay.METHODSWe prospectively studied the outcome of pregnancy in 241 women counseled by 10 Teratology Information Services (TIS) of the European Network of Teratology Information Services (ENTIS) because of MMI exposure, and compared them with those of 1,089 pregnant women referred to TIS because of exposure to nonteratogenic drugs (control group). Information was obtained by mail or telephone interview.RESULTSThere was no increase in the general rate of major anomalies or of spontaneous or induced abortions in the MMI-exposed group in comparison with the control group. Two newborns were affected with one of the major malformations that are part of the postulated embryopathy.CONCLUSIONSThe results of this study indicate that choanal as well as esophageal atresia may have a higher incidence than expected in fetuses exposed to MMI between 3 and 7 gestational weeks. Until further data are available, thyrotoxicosis should be treated with propylthiouracil, as it is apparently safer for use during the fertile period.

This study was undertaken to find a strict, unbiased epidemiological delineation of the VATER non-random association of congenital malformations and, based on registry information, to identify a group of probable VATER association infants suitable for etiological analyses. Information on 5,260 infants with multiple malformations was collected from four large registers of congenital malformations. Data were analyzed using a statistical method in which various putative confounders were controlled for. Our results indicate the existence of a distinct group of malformations corresponding to the VATER association: esophageal atresia, anal atresia, upper preaxial limb reduction defects, and costo-vertebral malformations. A subdivision into an upper and a lower group of VATER association was indicated, with heart malformations associated with the upper group and kidney malformations associated with the lower group. Restricting the inclusion criteria for VATER association to the above mentioned core malformations, few infants seem to belong to the VATER association, thus limiting the possibilities of carrying out etiological analyses. A relatively large number of infants may belong to a family of related conditions among which VATER association is a subgroup. In the search for risk factors, a strict definition of the VATER association is needed in order to not dilute the study material with irrelevant cases. The present study provides such strict inclusion criteria.

Infants with kidney agenesis or dysgenesis, infants with cystic kidneys, and infants with horseshoe kidneys were studied, based on data from three large and population-based congenital malformation registers: a total of 2666 infants among 5.83 million births. There is a strong variability between programs of the rates of registered unilateral kidney malformations and these are strongly over-represented in dead infants or infants with other malformations. There is a male excess but this varies in strength between different types of kidney malformations and between bilateral and unilateral forms. An increased twinning rate was found. The different types of kidney malformation differed with respect to kind of associated non-urological malformations in multimalformed infants. We conclude that for monitoring purposes one should restrict analysis to bilateral forms but that unilateral forms can be of interest in epidemiological analyses.

Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations.Methods: Information on all malformed infants (1990-1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries.Results: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs, Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid.Conclusions: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports.

By using the Swedish Medical Birth Registry and official data on drinking water chlorination, three cohorts were identified and compared: women who lived in areas where drinking water was disinfected with chlorine dioxide, women who lived in areas that used sodium hypochlorite disinfection, and women who lived in areas where there was no chlorination of the drinking water. There was a statistically significant increase in short gestational duration and low birth weight and especially in short body length and very small head circumference in areas using sodium hypochlorite, but no significant effects on these variables were found in areas using chlorine dioxide. No effects on congenital malformations, childhood cancer, infant mortality, low Apgar score, neonatal jaundice, or neonatal hypothyroidism were associated with either of the two drinking water chlorination methods. Because the exposure information in this study was based on the chlorination method and not the amount of byproducts in the water, the general lack of significant effects could be due to a low concentration of such byproducts.

TeratologyVolume 62, Issue 1 p. 8-9 Letters to the Editor Response to “case-control study using only malformed infants who were prenatally exposed to drugs. What do the results mean?” by Prieto L and Martínez-Frías ML Bengt Källén, Corresponding Author Bengt Källén Tornblad InstituteUniversity of LundLund, SwedenTornblad Institute, Biskopsgatan 7, S-223 62 Lund, SwedenSearch for more papers by this authorElisabeth Robert, Elisabeth Robert Institut Européen des Génomutations, Création de GROUPAMA, Lyon, FranceSearch for more papers by this author Bengt Källén, Corresponding Author Bengt Källén Tornblad InstituteUniversity of LundLund, SwedenTornblad Institute, Biskopsgatan 7, S-223 62 Lund, SwedenSearch for more papers by this authorElisabeth Robert, Elisabeth Robert Institut Européen des Génomutations, Création de GROUPAMA, Lyon, FranceSearch for more papers by this author First published: 15 June 2000 https://doi.org/10.1002/1096-9926(200007)62:1<8::AID-TERA4>3.0.CO;2-GCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume62, Issue1July 2000Pages 8-9 RelatedInformation

BACKGROUND:Infants with multiple malformations are important in birth defect epidemiology and malformation monitoring because human teratogens have often caused complex malformations. Various methods for the analysis of multimalformed infants have been tried.METHOD:By using data from four large registries of congenital malformations, 5256 infants were identified with two or more among 73 selected malformations. Pairwise associations between malformations were detected by multiple logistic regression analyses, and putative confounders (programme, maternal age, autopsy, etc.) were controlled for. For each significant pairwise association, further analyses were performed in order to find associations with a possible third malformation.RESULTS:The importance of controlling for several confounders was demonstrated. Several well-known associations were found, which supports the technique used. The interpretation of three-way associations was discussed. Results from the present study were compared with those obtained using some other methods.CONCLUSIONS:Different confounders can cause biased associations. The method presented in the paper takes this into consideration and is therefore more likely than previously used techniques to give unbiased information on the clustering of different malformations among multimalformed infants.