Rare diseases in disabled children: an epidemiological survey.

AIM: To estimate the contribution of rare diseases (RD) to severe impairment in 7-year-old children. METHODS: Data from a morbidity register of childhood impairments in a single French region were used. Impairments were classified as a mental, sensorial, neuromuscular (skeletal or movement-related) impairment (MSN_I) according to the International Classification of Functioning. Details of children born from 1980 to 1994 and resident in the county under study when they were 7 years old were recorded. A rare disease was defined as a prevalence rate of <1 per 2000 general population. RESULTS: 26% of children with severe MSN_I had a rare disease; in 36% the MSN_I was of unknown origin. The proportion of impairments that were due to a rare disease varied according to the type of impairment: 3.3% for severe psychiatric disorders; 16.0% for intellectual impairment; 37.2% for hearing impairment; 41.2% for neuromuscular, skeletal and movement impairment; and 81.1% for visual impairment. The overall prevalence rate of rare diseases was 2.1 per 1000 (459/218 283), and it increased significantly over time (p = 0.003). The latter increase was not associated with a decrease in the proportion of impairments of unknown origin, indicating an improvement in the survival of the children with a rare disease. CONCLUSIONS: In this study, a rare disease was at the origin of 26% of cases of severe MSN_I. This proportion remained stable over time, whereas the prevalence rate, as well as the prevalence rate of MSN_I disability, increased over time.

Effects of residential distance to hospitals with neonatal surgery care on prenatal management and outcome of pregnancies with severe fetal malformations.

OBJECTIVES: To examine the effect of maternal origin and distance between maternal residence and the nearest maternity ward with a neonatal surgical center in the same hospital, on prenatal diagnosis, elective termination of pregnancy, delivery in an adequate place and neonatal mortality for pregnancies with severe malformations requiring neonatal surgery, and to examine the effect of the place of delivery on neonatal mortality. METHODS: This was a retrospective study, through the France Central-East malformation registry, of 706 fetuses with omphalocele (n = 123), gastroschisis (n = 99), diaphragmatic hernia (n = 222), or spina bifida (n = 262), but without chromosomal anomalies. Maternal origin was classified as Western European and non-Western European. Adequate place for delivery was defined as birth in a Level-III maternity ward with a neonatal surgical center in the same hospital. RESULTS: The prenatal diagnosis rate was 67.7% in 1990-1995 and 80.2% in 1996-2001 (odds ratio (OR), 2.07 (95% CI, 1.24-3.45)). On multivariate analysis, the rate was significantly lower for women living 11-50 km (adjusted OR, 0.49 (95% CI, 0.25-0.94)), or > 50 km (adjusted OR, 0.39 (0.20-0.74)) from the closest adequate place of delivery, compared with those living < 11 km from it, but there was no difference for maternal origin. Non-Western European women had fewer elective terminations of pregnancy (adjusted OR, 0.34 (95% CI, 0.14-0.81)) and fewer deliveries in an adequate place (adjusted OR, 0.40 (95% CI, 0.18-0.89)). Neonatal mortality was lower in the case of delivery in an adequate place (adjusted OR, 0.22 (95% CI, 0.07-0.72)) and was not associated with maternal origin and distance from nearest maternity ward with a neonatal surgical center. CONCLUSION: Rate of prenatal diagnosis decreases with increasing distance between parental residence and referral center. Non-Western European women are diagnosed prenatally as often as are Western Europeans, but terminate their pregnancy less often, perhaps for cultural reasons. Non-Western European women with malformed fetuses deliver in adequate centers less often, probably because of the way the perinatal care system is run.

Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study.

OBJECTIVES: To describe the true incidence, prenatal detection rate and fetal outcome of congenital diaphragmatic hernia (CDH) in a systematically registered population over an 18-year period and to determine any change in trends over time. METHODS: This was a retrospective study of all cases of CDH registered in the Central-Eastern France Birth Defects Registry from 1986 to 2003. All fetuses and infants up to 1 year of age diagnosed with CDH were registered, including miscarriages later than 22 weeks of gestation, stillbirths and terminations of pregnancy (TOP). Routine prenatal screening consisted of three ultrasound examinations and there was no upper limit of gestational age for TOP. RESULTS: Five hundred and one cases of CDH were identified from a total of 1 835 022 live births (2.7 cases per 10 000 live births). The overall prenatal detection rate was 54%. There was a significant increase over time in the detection rate mainly for associated CDH and left-sided CDH (P < 0.0001), and in the proportion of neonates delivered in tertiary centers (P < 0.0001). The overall survival rate at discharge was 47% and this increased significantly over time for isolated CDH (P = 0.04), whereas it was lower and remained stable for associated CDH (P = 0.64). The TOP rate for isolated CDH did not vary significantly in contrast to that for associated CDH cases in which the TOP rate increased over time, progressively replacing the neonatal death rate (P = 0.01). CONCLUSIONS: Over an 18-year period, this large population-based study demonstrated increasing prenatal detection rates for associated CDH and left-sided CDH and confirmed an increasing survival rate mainly for isolated CDH.

Occupational exposure to organic solvent mixtures during pregnancy and the risk of non-syndromic oral clefts.

OBJECTIVES: To examine the association between maternal occupational exposure to mixtures of organic solvents during pregnancy and the risk of non-syndromic oral clefts. METHODS: A case-control study (164 cleft lip with/without cleft palate (CL/P), 76 cleft palate (CP), 236 controls) was conducted in France to investigate the role of maternal occupational exposure to organic solvents at the beginning of pregnancy in the risk of non-syndromic oral clefts. An expert chemist, guided by a detailed description of the women's occupational tasks, assessed exposure for each. Analysis of the findings used logistic regression. RESULTS: In the control group, 39% of the women who reported working during pregnancy were exposed to at least one type of organic solvent. The risk of oral clefts was associated with oxygenated (for CL/P: OR = 1.8, 95% CI 1.1 to 2.9; and for CP, OR = 1.4, 95% CI 0.7 to 2.7), chlorinated (OR = 9.4, 95% CI 2.5 to 35.3; OR = 3.8, 95% CI 0.7 to 20.7), and petroleum (OR = 3.6, 95% CI 1.5 to 8.8; OR = 1.2, 95% CI 0.3 to 4.9) solvents. The risk of oral clefts increased linearly with level of exposure within the three subgroups of oxygenated solvents we considered (aliphatic alcohols, glycol ethers, and other oxygenated solvents, including esters, ketones, and aliphatic aldehydes). CONCLUSIONS: Results suggest that maternal occupational exposure to organic solvents during pregnancy may play a role in the aetiology of oral clefts. The limited number of subjects and the problem of multiple exposures require that these results be interpreted cautiously.

[Periconceptional folates and the prevention of orofacial clefts: role of dietary intakes in France]. / Folates en période péri-conceptionnelle et prévention du risque de fente orofaciale: rôle des apports alimentaires en France.

BACKGROUND: Orofacial clefts are among the most frequent congenital malformations at birth with a prevalence of 1 in 700 births in Europe. The implication of environmental factors in their etiology has been demonstrated. The role of folic acid, or folates, in the prevention of orofacial clefts is still debated although its efficacy has been demonstrated for the prevention of neural tube defects. METHODS: A case-control study was conducted in 7 hospitals in 4 centers in France. Cases (N=240) were children with non-syndromic orofacial cleft referred to one of the study hospitals for initial surgical repair in 1998 and 1999. Controls (N=236) matched for gender, geographic origin, and age were chosen in paediatric departments of the same hospitals. Usual dietary intake of folates was estimated using a food frequency questionnaire submitted to the mother at hospital. During the same interview, data on sociodemographic characteristics, medical and obstetrical history, tobacco and alcohol consumption, and vitamin supplements, were obtained. Odds ratios associated with quintiles of dietary intake of folates were estimated using logistic regression adjusting for known confounders. RESULTS: A significant dose-response relationship between the risk of orofacial clefts and a decrease in the intake of folates from diet was found, stronger for cleft palate without cleft lip. Only few women (<1%) declared having taken vitamin supplements containing folic acid when planning their pregnancy. CONCLUSION: Our study further suggests that folates are useful for the prevention of orofacial clefts during the periconceptual period. In our study, the estimated average daily intake of folates (270 microg/day) was below French national recommendations for the prevention of neural tube defects (400 microg/day). Since those insufficient folate intakes during the periconceptual period are not presently met by vitamin supplementation, the solution may come from the food fortification program proposed and implemented by the National Agency for Food Safety (AFSSA).

The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study.

BACKGROUND: Proton pump inhibitors are used to treat gastro-oesophageal reflux and peptic ulcers. Gastro-oesophageal reflux is a common condition in pregnancy. Human pregnancy experience with lansoprazole or pantoprazole is very limited. More data exist on the safety of omeprazole in pregnancy. AIM: To assess the safety of proton pump inhibitors in pregnancy. METHODS: The rate of major anomalies was compared between pregnant women exposed to omeprazole, lanzoprazole, or pantoprazole and a control group counselled for non-teratogens. The study design is a multicentre (n = 8), prospective, controlled study of the European Network of Teratology Information Services. RESULTS: We followed up 295 pregnancies exposed to omeprazole [233 in the first trimester (T1)], 62 to lansoprazole (55 in T1) and 53 to pantoprazole (47 in T1), and compared pregnancy outcome to that of 868 European Network of Teratology Information Services controls. The rate of major congenital anomalies did not differ between the exposed and control groups [omeprazole nine of 249 (3.6%), lansoprazole two of 51 (3.9%) and pantoprazole one of 48 (2.1%) vs. controls 30 of 792 = 3.8%]. No differences were found when exposure was limited to the first trimester after exclusion of genetic, cytogenetic or infectious anomalies. CONCLUSIONS: This study suggests that proton pump inhibitors do not represent a major teratogenic risk in humans.

Renal outcome of children exposed to cyclosporine in utero.

The number of pregnancies in immunosuppressed women has increased during the recent years and this has become a major part of the rehabilitation and quality of life of treated patients. Most of them are organ transplant recipients and large series from the literature have shown that children born to such women may present with intrauterine growth retardation, a condition which may be associated with significant reduction in nephron number and oligomeganephronia. On the other hand, experimental data in animals have demonstrated that in utero exposure to CsA may alter nephrogenesis and further alter renal function. Therefore offspring of organ transplant women treated with CsA exhibit a theoretical risk of renal impairment, due to both IUGR and fetal nephrotoxicity. However, despite the limited experience of long term studies in children, there is no evidence of any significant deleterious adverse effect of in utero exposure to CsA. However further studies based on large series are required in order to demonstrate that renal fetal effects have limited clinical consequences.

Risk of congenital anomalies in the vicinity of municipal solid waste incinerators.

BACKGROUND: Although municipal solid waste incineration (MSWI) has contributed to increase the overall environmental load of particulate matter containing dioxins and metals, evidence of health consequences to populations is sparse. AIMS: To assess at a regional level (in southeast France) the impact of these emissions on birth defect rates. METHODS: Communities with fewer than 50 000 inhabitants surrounding the 70 incinerators that operated at least one year from 1988 to 1997 were studied. Each exposed community (n = 194) was assigned an exposure index estimated from a Gaussian plume model. Poisson models and a reference population of the 2678 unexposed communities in the region were used to calculate relative risks for congenital malformations, adjusted for year of birth, maternal age, department of birth, population density, average family income, and when available, local road traffic. RESULTS: The rate of congenital anomalies was not significantly higher in exposed compared with unexposed communities. Some subgroups of major anomalies, specifically facial clefts and renal dysplasia, were more frequent in the exposed communities. Among exposed communities, a dose-response trend of risk with increasing exposure was observed for obstructive uropathies. Risks of cardiac anomalies, obstructive uropathies, and skin anomalies increased linearly with road traffic density. CONCLUSIONS: Although both incinerator emissions and road traffic may plausibly explain some of the excess risks observed, several alternative explanations, including exposure misclassification, ascertainment bias, and residual confounding cannot be excluded. Some of the effects observed, if real, might be attributable to old-technology MSWIs and the persistent pollution they have generated.

Trends in elective terminations of pregnancy between 1989 and 2000 in a French county (the Isère).

OBJECTIVES: This study was performed in order to provide a description of indications for induced elective terminations of pregnancy (ETOP), their characteristics (e.g. gestational age), and their evolution over time. DESIGN OF THE STUDY: This is an epidemiological study. The geographic area covered is the French county of 'Isère', which represents a mean of 14 000 births per year over the study period. MATERIALS AND METHODS: Data on ETOPs were collected actively from medical records by a register of childhood deficiencies and adverse perinatal events in this county. Between 1989 and 2000, 996 ETOPs were notified. RESULTS: Four main grounds for ETOPs were identified: (1) morphological anomalies with normal karyotype (39%), (2) chromosomal anomalies (35%), (3) other fetal grounds (16%), and (4) maternal indications (10%). Prevalence rates for the first two grounds increased significantly over the study period respectively from 2.0 to 2.9 and from 1.4 to 2.7 per 1000. Among the ETOPs carried out because of fetal indications, the percentage of late ETOPs (from 24 weeks of gestation) was 34.6%, and remained stable over the studied period. In some cases, a medical consensus was not reached with respect to indications for termination (sex chromosome anomalies, limb defects). We estimated the percentage of these cases as being 2.7% of the figure for fetal indications, without any variation in prevalence over the whole period (p = 0.59). The increasing number of ETOPs that occurred in the chromosomal aberrations group during the study period is thought to be due to an increase in diagnostic sensitivity. The increase that occurred in the morphological anomalies group is thought to be due both to an increase in sensitivity and to a widening of the field with respect to indications, some of which have an uncertain prognosis (e.g. agenesis of the corpus callosum). CONCLUSION: This study provides useful data for monitoring medical practice consistency within the field of prenatal diagnosis, and for the drive to keep medical practice within ethically acceptable limits.

The congenital anomalies registry in Belarus: a tool for assessing the public health impact of the Chernobyl accident.

A national population-based malformation registry (BNR) has been in operation since 1979 in Belarus, one of the countries most heavily exposed to the contamination from the Chernobyl accident of 26 April 1986. We describe its methodology and its compliance with established criteria, evaluate the completeness of its reporting, and analyze the data collected in four administrative regions with contrasting contamination levels from 1983 through 1999. Nine easily diagnosed malformations have been monitored since 1983. Reporting completeness exceeds 85% for all periods and all regions. In all periods, the prevalence at birth of these malformations was lower in the most contaminated regions and showed a similar positive time trend in areas of low and high contamination. We conclude that the BNR is a reliable tool for studying the possible effects on congenital malformations caused by the Chernobyl accident. Although the trend we observed may be explained by better ascertainment and prenatal diagnosis, a real increase cannot be ruled out.

[Methods of evaluation of risks tied to drug exposure during pregnancy. Advantages and limits of epidemiology, interpretation of results]. / Méthodes d'évaluation des risques liés aux prises médicamenteuses pendant la grossesse. Avantages et limites de l'épidémiologie, interprétation des résultats.

Various epidemiologic designs permit an evaluation of drug teratogenicity, but none is sufficient to establish the risk. Only concordance of results of several studies lead a substance to be considered teratogenic. The usual designs of analytical epidemiology can be used: prospective studies of total populations, case-control, cohort. Case series may be useful when no good epidemiologic study is available. Most of those published were collected by teratogen information services (TISs). These series of exposures are not representative samples of the general population, and when interpreting the pregnancy outcomes, it is difficult to define an unexposed group for comparison. In practice, if 50 pregnancies are reported with early exposure to a given drug and without unwanted effects, one can exclude a strong teratogenic effect, and reassure a woman inadvertently exposed. TISs have published several of such exposure series, and they are often used. On the contrary, if the question arises whether or not to prescribe a drug to a woman in early pregnancy, a much larger sample of pregnancy with known outcomes is needed to answer "yes": this is a situation of population risk assessment, because one would give the same answer to all similar questions, which may be many. Birth-defect monitoring systems are in a better position to do this and several examples can be given (valproate and spina bifida, corticosteroids and orofacial clefts).