[Trends in antenatal diagnosis, pregnancy termination and perinatal mortality in infants with congenital heart disease: evaluation in the general population of Paris 1983-2000]. / Evolution du diagnostic prénatal, des interruptions de grossesse et de la mortalité périnatale des enfants avec cardiopathie congénitale: évaluation en population générale à Paris entre 1983 et 2000.

OBJECTIVE: To examine population-based overall and malformation-specific trends in the prenatal diagnosis, pregnancy termination, and perinatal mortality for congenital heart disease (CHD) during a period of rapid progress in prenatal diagnosis and medical management of CHD and to explore the impact of prenatal diagnosis on early neonatal mortality for specific (isolated) cardiac malformations. METHODS: A total of 1982 cases of CHD, which were not associated with a known chromosomal anomaly, were obtained from the Paris Registry of Congenital Malformations. Main outcome measures were trends in the proportions diagnosed and terminated prior to birth, stillbirth and early (<1 day, one-week) neonatal mortality for (1) all cases; (2) all cases excluding isolated ventricular septal defects; and (3) malformation-specific trends for transposition of great arteries, hypoplastic left heart syndrome, coarctation of aorta, and tetralogy of Fallot. Analyses included cusum and binomial regression models for analysis of the trends during 1983-2000. RESULTS: Prenatal diagnosis rates for CHD increased from 23.0% (95%CI: 19.0-27.4) in 1983-1988 to 47.3% (95%CI: 43.8-50.8) in 1995-2000. Termination rates increased between 1983 and 1989 (9.9%; 95%CI: 7.2-13.2) and 1989 and 1994 (14.7%; 95%CI: 12.3-17.4) but seemed to remain stable thereafter. Other than for hypoplastic left heart syndrome, pregnancy termination was exceptional for the other 3 specific malformations examined. Early neonatal mortality decreased to less than a third in the period 1995-2000 as compared with 1983-1989 (risk ratio, first week mortality: 0.31; 95%CI: 0.18-0.53). First week mortality was significantly lower for cases of transposition of great arteries diagnosed before birth (risk difference: 15.4%; 95% CI: 4.0-26.7). CONCLUSION: Progress in clinical management, together with policies for increased access to prenatal diagnosis, has resulted in both a substantial increase in the prenatal diagnosis and considerable reductions in early neonatal mortality of CHD in the Parisian population.

[Prevalence and prenatal diagnosis of congenital malformations in the Parisian population: twenty years of surveillance by the Paris Registry of congenital malformations]. / Prévalence et diagnostic prénatal des malformations en population parisienne. Vingt ans de surveillance par le Registre des malformations congénitales de Paris.

OBJECTIVES: To assess overall and malformation-specific trends in the prevalence, prenatal diagnosis and pregnancy termination of congenital malformations in the Parisian population. METHODS: We used data from the Paris Registry of Congenital Malformations, which includes all births and pregnancy terminations with structural birth defects or chromosomal anomalies. Data on total and live birth prevalence were available for the period 1981-2000 and for prenatal diagnosis and pregnancy terminations for 1983-2000. Twenty malformations were selected for malformation-specific analyses due to their higher frequency and consistent definitions in different classification systems. RESULTS: For the period 1981-2000, the overall total prevalence of malformations was 3.2%. Prenatal diagnosis rates consistently increased from 16.2% (95% CI, 13.8-18.6) of cases with malformation in 1983 to 69.1% (95% CI, 66.7-71.5) in 2000. Pregnancy terminations increased from 8.8% (95% CI, 7.0-10.8) of cases with malformation in 1983 to 30.1% (95% CI, 27.7-32.6) in 2000. CONCLUSION: Registries of congenital malformations provide population-based data on the prevalence of malformations and their associations with other anomalies. Registry-based data can also be used to evaluate the impact of prenatal testing policies for congenital malformations.

Prenatal diagnosis in France.

Prenatal diagnosis (PND) is very developed in France, especially in the area of ultrasound (US) screening. The activity is regulated by law, and laboratories have to be authorized to perform any type of prenatal biological test if the purpose is to diagnose fetal defects. There are 70 cytogenetics laboratories and 50 biochemistry laboratories performing serum marker screening, about half of them being private. PND of chromosomal anomalies is offered to women over 37 years of age, to women who already had a child with a chromosomal anomaly, in case of abnormal US findings, if one of the parents has a balanced chromosomal anomaly and if the risk of chromosomal anomaly is higher than 1:250 according to the serum markers. Half of the trisomy 21 cases are now detected prenatally and pregnancies terminated. Fetal cell sampling is performed by amniocentesis in 70% of cases, by chorionic villus sampling in 7% of cases and by fetal blood sampling in 23% of cases. There are no professional guidelines and no quality assessment networks for any of the techniques in use. PND is regulated by two major laws: the Law on Abortion (1975) and the Law on Bioethics (1994).

Congenital malformations in twins: an international study.

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

Limb defects associated with major congenital anomalies: clinical and epidemiological study from the International Clearinghouse for Birth Defects Monitoring Systems.

Although limb defects associated with other congenital anomalies are rarely studied, they may provide insights into limb development that may be useful for etiologic studies and public health monitoring. We pooled data from 11 birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring Systems. We identified 666 infants, born from 1983 through 1993, who had a non-syndromal limb defect plus at least one other major malformation (rate 12.9/100,000 population). We used observed/expected ratios and log-linear models to detect association patterns. We found that specific limb defects occurred with relatively distinct sets of malformations. Preaxial limb defects occurred more frequently with microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeleton defects; postaxial defects with hypospadias; transverse defects with craniofacial defects, micrognathia, ring constrictions, and muscular defects; intercalary defects with omphalocele; split hand/foot with encephalocele; and amelia with anorectal atresia, omphalocele, severe genitalia defects, unilateral kidney dysgenesis, gastroschisis, and ring constriction. Log-linear modeling identified higher order associations among some of these same malformations.

The spectrum of congenital anomalies of the VATER association: an international study.

The spectrum of the VATER association has been debated ever since its description more than two decades ago. To assess the spectrum of congenital anomalies associated with VATER while minimizing the distortions due to small samples and referral patterns typical of clinical series, we studied infants with VATER association reported to the combined registry of infants with multiple congenital anomalies from 17 birth defects registries worldwide that are part of the International Clearinghouse for Birth Defects Monitoring Systems (ICB-DMS). Among approximately 10 million infants born from 1983 through 1991, the ICB-DMS registered 2,295 infants with 3 or more of 25 unrelated major congenital anomalies of unknown cause. Of these infants, 286 had the VATER association, defined as at least three of the five VATER anomalies (vertebral defects, anal atresia, esophageal atresia, renal defects, and radial-ray limb deficiency), when we expected 219 (P<0.001). Of these 286 infants, 51 had at least four VATER anomalies, and 8 had all five anomalies. We found that preaxial but not other limb anomalies were significantly associated with any combination of the four nonlimb VATER anomalies (P<0.001). Of the 286 infants with VATER association, 214 (74.8%) had additional defects. Genital defects, cardiovascular anomalies, and small intestinal atresias were positively associated with VATER association (P<0.001). Infants with VATER association that included both renal anomalies and anorectal atresia were significantly more likely to have genital defects. Finally, a subset of infants with VATER association also had defects described in other associations, including diaphragmatic defects, oral clefts, bladder exstrophy, omphalocele, and neural tube defects. These results offer evidence for the specificity of the VATER association, suggest the existence of distinct subsets within the association, and raise the question of a common pathway for patterns of VATER and other types of defects in at least a subset of infants with multiple congenital anomalies.

Therapeutic drug use during pregnancy: a comparison in four European countries. OECM Working Group. Occupational Exposures and Congenital Anomalies.

A drug utilization study was performed using data of the OECM study on Occupational Exposures and Congenital Malformations, which was conducted in six European Registries of Congenital Anomalies (two in France, two in Italy, one in Great Britain, and one in The Netherlands): the mothers were interviewed after delivery for exposures during pregnancy, including use of therapeutic drugs. The analysis of drug use considered only the 1134 control mothers of healthy newborns, and focused on the first trimester of pregnancy: 36.2% of the interviewed mothers used at least one drug (excluding vitamins and minerals) during the first trimester. This rate varied from 22.5% in Glasgow to 50.3% and 44.2% in the French centers. Anti-infectives were the most frequent drugs (12.3% of mothers), then antinauseants (10.6%), and treatments for threatened abortion (5.5%). Important variations between countries were observed, reflecting different medical attitudes towards drug use during pregnancy.

Human pituitary growth hormone (hGH) and Creutzfeldt-Jakob disease: results of an epidemiological survey in France, 1986.

An epidemiological inquiry has been done in France after the notification in the USA and England of four cases of Creutzfeldt-Jakob disease in patients previously treated with hGH. Between 1959, when hGH treatment in France was started, and August 1985, the date the survey began, 1698 patients were registered for treatment. Current information (less than three months old) was obtained for 1620 patients (95.4%). Death was reported in 31 patients, but none could be related to Creutzfeldt-Jakob or similar disease. Pathological events were observed in 213 living patients (13.1%). Among them, four were diseases classified as possibly related to a viral infection. The first case had acute lymphoid leukaemia; the second case had polyradiculoneuritis associated with hepatitis. In both cases the disease resolved completely. Two other patients had acute encephalitis which started less than two years after the onset of treatment and which resolved spontaneously. Even though the acute evolution and the spontaneous clinical recovery are not consistent with Creutzfeldt-Jakob disease, a relationship with hGH therapy could not be completely excluded. Finally, five treated children had later malignancies which raises the question of the long-term secondary effects of hGH upon cellular proliferation.

A comparison of two policies of ante-natal supervision for the prevention of prematurity.

The performance of 2 maternity units is compared. In comparable groups of average risk the prematurity rate was significantly lower in the unit practising intensive supervision during pregnancy.

Time trends in neural tube defects prevalence in relation to preventive strategies: an international study.

OBJECTIVE: To examine time trends in neural tube defects (NTD) prevalence from 1987 to 1996 in relation to the primary prevention policies for folic acid supplementation strategies in different countries. DESIGN: Retrospective time trends analysis of NTD prevalence. SETTING: 11 birth defect registries of congenital malformations participating in the International Clearinghouse for Birth Defects Monitoring System, in the period from 1 July 1987 to 30 June 1996. SUBJECTS: 8207 live births, stillbirths and terminated pregnancies affected by anencephaly or spina bifida registered by the 11 participating centres 1987-1996. OUTCOME MEASURES: Prevalence rate ratios based on the annual rates, using the Poisson regression model. RESULTS: During the study period a significant fall in prevalence rates for all NTD is present in Atlanta (USA), England and Wales, Hungary and Japan, and a significant rise in Norway and South America. After adjusting for the secular trends observed in the earlier years of the study, no significant trend can be attributed to preventive strategies. Data on NTD prevalence are supplemented with information on folate awareness among some of the populations studied. CONCLUSION: There is no evidence that, up to the middle of 1996, any change in time trend was attributable to the introduction of national folate supplementation policies. The possible effectiveness of folate supplementation policies for the reduction of NTD clearly needs to be tried and studied for several more years. Considering that in the Western world about 50% of pregnancies are unplanned, a policy that rests on action taken before conception can only have limited success. Strategies based on food enrichment, such as was introduced in the USA from the beginning of 1998, may prove to be more successful.

Epidemiologic survey of juvenile chronic arthritis in France. Comparison of data obtained from two different regions.

An epidemiologic survey of JCA was carried out in two regions of France, the western part of Paris and Brittany, differing in terms of geological background and demography. The prevalence was 0.77 and 0.100% and the incidence 0.019 and 0.013%, respectively. The type of onset, the course of the disease, the immunological data and the degree of final disability were similar in both regions. These data were compared to other studies and the factors of possible discrepancy analysed.

Maternal occupational exposure and congenital malformations.

A case-referent study was conducted to assess the risk of congenital malformations in relation to maternal occupational exposure before and during pregnancy. Three hundred and twenty-five cases of major malformations and 325 normal (at birth) referents identified in 15 maternity hospitals were included in the study. The occupational history obtained from an interview of the mother was blindly reviewed by an industrial hygienist who assessed the presence of chemical exposure and the probability of exposure. The results suggested that mothers of the case children with oral clefts were more often exposed to solvents during pregnancy [odds ratio (OR) 7.9, 90% confidence interval (90% CI) 1.8-44.9] and worked more often as cleaners (four cases, no referents). Digestive anomalies (OR 11.9, 90% CI 2.0-149) and multiple anomalies (OR 4.5, 90% CI 1.4-16.9) were also associated with occupational exposure to solvents at work. These results were not modified when differences in maternal age, area of residence, and socioeconomic status were taken into account.

Maternal occupational risk factors for oral clefts. Occupational Exposure and Congenital Malformation Working Group.

OBJECTIVES: This study investigated the role of maternal exposures at work during pregnancy in the occurrence of oral clefts. METHODS: The occupational exposures of 851 women (100 mothers of babies with oral clefts and 751 mothers of healthy referents) who worked during the first trimester of pregnancy were studied. All the women were part of a multicenter European case-referent study conducted using 6 congenital malformation registers between 1989 and 1992. In each center, the mother's occupational history, obtained from an interview, was reviewed by industrial hygienists who were blinded to the subject's status and who assessed the presence of chemicals and the probability of exposure. Odds ratios (OR) were estimated by a multivariate analysis including maternal occupation or occupational exposures during the first trimester of pregnancy and possible confounding factors such as center of recruitment, maternal age, urbanization, socioeconomic status, and country of origin. RESULTS: After adjustment for confounding factors, cleft palate only was significantly associated with maternal occupation in services such as hairdressing [OR 5.1, 95% confidence interval (95% CI) 1.0-26.0] and housekeeping (OR 2.8, 95% CI 1.1-7.2). The analysis suggests that the following occupational exposures are associated with orofacial clefts: aliphatic aldehydes (OR 2.1, 95% CI 0.8-5.9) and glycol ethers (OR 1.7, 95% CI 0.9-3.3) for cleft lip with or without cleft palate and lead compounds (OR 4.0, 95% CI 1.3-12.2), biocides (OR 2.5, 95% CI 1.0-6.0), antineoplastic drugs (OR 5.0, 95% CI 0.8-34.0), trichloroethylene (OR 6.7, 95% CI 0.9-49.7), and aliphatic acids (OR 6.0, 95% CI 1.5-22.8) for cleft palate only. CONCLUSIONS: Due to the limited number of subjects, these results must be interpreted with caution. However, they point out some chemicals already known or suspected as reproductive toxins.

Outborn status with a medical neonatal transport service and survival without disability at two years. A population-based cohort survey of newborns of less than 33 weeks of gestation.

OBJECTIVE: Prenatal events are thought to play an important role in long-term handicap, but the specific role of perinatal factors remains controversial. Our study, conducted in the context of this debate, aimed to break down the various components of perinatal management and to assess the relationship between these components and survival without disability at the age of two years. STUDY DESIGN: A prospective geographically-defined study was conducted in 1985 in the Paris metropolitan area. It covered 53430 births (stillbirths and live births), including 539 that occurred between 25 and 32 weeks gestation. The relationship between perinatal management and survival without disability was studied by a multivariate analysis (logistic regression). The analysis was restricted to a group of 202 infants born at 31 or 32 week's gestation, to avoid indication bias. RESULTS: An inborn status (delivery in a tertiary care facility) exerted a protective effect on survival without disability at the age of two years (Adjusted Odds Ratio (OR)=7.51 [1.51; 37.4]), even though the area we studied possessed an excellent Medical Neonatal Transport Service. Multiple pregnancies also seemed to have a protective effect (Adjusted OR=2.45 [0.96; 6.27]). No statistically significant association was seen between survival without disability at two years and the presence of a hospital staff paediatrician in the delivery room. CONCLUSION: These results lead us to consider what the concept of inborn/outborn represents in the perinatal management of infants at high risk.

Mothers' knowledge of screening for trisomy 21 in 1999: a survey in Paris maternity units.

OBJECTIVE: To assess mothers' knowledge of screening tests for trisomy 21. STUDY DESIGN: Interview of all women who had recently delivered a healthy child and were present in 15 Paris maternity units during one of the two non-consecutive days in June 1999 (N = 734). RESULTS: Two-third said that they had access to a nuchal translucency measurement (NTM) and to maternal serum screening (MSS), and 16% to amniocentesis. Thirty-eight percent of the women who had NTMs and 69% of those who had serum screening said that they had been informed of the need for amniocentesis if the results were abnormal. Among the women who had amniocentesis, 20% did not know the risk of miscarriage and 41% had not been informed about the possibility of terminating the pregnancy if trisomy 21 was diagnosed. CONCLUSIONS: Mothers' knowledge about the screening tests for trisomy 21 remains fragmentary. Providing comprehensive information about all these tests should be considered in early pregnancy so that women can make informed choices.

[Research on teratogenic risks using a register of congenital malformations]. / la recherche de risques tératogènes à partir de registres de malformations congénitales.

Etiologic research in the field of congenital malformations, besides specific difficulties, meets the usual methodologic problems in the study of uncommon phenomena. In this situation, registries may be valuable tools due to their specific way of functioning. They appear optimal for an urgent evaluation of an environmental risk. Due to the material available, they are also efficient for analytic research, especially in the frame of international collaboration. This etiological approach, which is not the primary aim of registries of congenital malformations, seems indeed a supplementary contribution to take into account in a cost/benefit evaluation of the epidemiological instrument.

[Risk related to methodologically disputable studies: the example of vitamin therapy for the prevention of neural tube defects]. / Le risque lié aux enquêtes méthodologiquement discutables: l'exemple de la vitaminothérapie pour la prévention des anomalies de fermeture du tube neural.

Due to the non acceptance by ethics committees of its double blind controlled study for prevention of neural-tube defects recurrence by vitamin supplementation versus mineral components, a British group underwent methodologically debatable epidemiological study which has become quite controversial. This survey concluded that vitaminotherapy is effective. The aim of this article was to analyze the consequences induced by such a procedure which probably resulted in delaying the onset of the Medical Research Council controlled trial, performed with the necessary rigorous methodology, and which gave the final answer only 11 years later, a time during which concerned women could not take advantage of a valuable preventive treatment.

[Occupational exposure to chemical substances and congenital anomalies: state of the art]. / Expositions professionnelles à des substances chimiques et anomalies congénitales: état des connaissances.

Several thousands of compounds with a potential reproductive toxicity have been identified in animals, some of them are teratogens. In humans, only a small number of chemicals, administered as drugs, present in the diet, or in the occupational environment are recognized human teratogens. In parallel, about 60% of congenital anomalies have no identified cause and most probably some compounds present in the environment may contribute to certain anomalies. This paper presents a review of published epidemiological studies on the association between occupational exposures and congenital anomalies, focusing more particularly on some groups of compounds or some occupations such as: anaesthetic gases, laboratory work, solvents, pesticides and lead.

[Economic analysis of the dissemination of a medical innovation: prenatal diagnosis by early amniocentesis as an example. Part 1. Epidemiologic, medical and socioeconomic bases. The dissemination of a diagnostic innovation]. / Analyse économique de la diffusion d'une innovation médicale: l'exemple du diagnostic prénatal par amniocentèse précoce. 1re partie: les fondements épidémiologiques, médicaux et socio-économiques. La diffusion d'une innovation diagnostique.

The article offers a detailed analysis of the characteristics of the supply and demand of prenatal diagnosis by amniocentesis in order to identify the major problems that must be faced in formulating a policy designed to diffuse the use of this technique. The data collected for the whole of France made it possible to evaluate exhaustively the increase in the number of prenatal diagnoses during the years 1972-1981; to determine the number and geographic distribution of the diagnostic centers; to identify the medical criteria justifying the examinations. A comprehensive survey covering all examinations performed in the Ile de France (Paris region) in 1979--which constituted 46.5% of all the prenatal diagnoses performed in France that year--made it possible to determine the predominant socioeconomic characteristics of the women who took this examination, revealing, particularly, the significant inequalities of access, with an underrepresentation of the least privileged socioprofessional categories. The confirmation of the influence of socioeconomic status on access to this medical innovation is further reinforced by the fact that usage rates vary widely according to place of residence; furthermore, it adds to the financial barriers implicit in any policy of having reimbursement of the examinations dependent upon Social Security conventions. A public health policy regulating the diffusion of this innovation must take into account the discriminatory aspects of the first phase of diffusion, as analyzed here.

[Administration of diethylstilbestrol during pregnancy, a public health problem]. / L'administration de diéthylstilboestrol (DES) pendant la grossesse, un problème de santé publique.

The analysis of the health risks associated with the administration of diethylstilbestrol (DES) during pregnancy (for the prevention or treatment of threatened abortions) has been largely published. Concerning mothers, a relationship between DES exposure during pregnancy and risk of cancer is unproved. However, existing studies are sufficient cause for serious concern over drug's carcinogenic potential, and further follow-up studies are required. Concerning daughters, a clear association between in utero exposure to DES and clear cell adenocarcinoma of the vagina or cervix is established (incidence between 0.14 and 1.4 per 1000 through age 24). The risk for squamous cell cancer of the vagina and cervix does not seem to be increased. Cervico-vaginal adenosis is frequent (20% to 60% of exposed subjects). This is not a pre-cancerous lesion, its spontaneous evolution is towards regression. No treatment is prescribed. Morphological changes of the genital tract have been described, their consequences on fertility and pregnancy are not clear. Concerning sons, an excess of genital abnormalities (especially of the epididymis and undescended testis) has been reported, but information on the fertility implications of these findings is not available. There is no evidence of an increased risk of testicular cancer. The analysis of all these informations should allow to bring up a policy to take into account these risks in the population.