Maternal residence near municipal waste incinerators and the risk of urinary tract birth defects.

OBJECTIVES: Waste incineration releases a mixture of chemicals with high embryotoxic potential, including heavy metals and dioxins/furans, into the atmosphere. In a previous ecological study we found an association between the risk of urinary tract birth defects and residence in the vicinity of municipal solid waste incinerators (MSWIs). The objective of the present study was to specifically test this association. METHODS: A population-based case-control study compared 304 infants with urinary tract birth defects diagnosed in the Rhône-Alpes region (2001-2003) with a random sample of 226 population controls frequency-matched for infant sex and year and district of birth. Exposure to dioxins in early pregnancy at the place of residence, used as a tracer of the mixture released by 21 active waste incinerators, was predicted with second-generation Gaussian modelling (ADMS3 software). Other industrial emissions of dioxins, population density and neighbourhood deprivation were also assessed. Individual risk factors including consumption of local food were obtained by interviews with 62% of the case and all control families. RESULTS: Risk was increased for mothers exposed to dioxins above the median at the beginning of pregnancy (OR 2.95, 95% CI 1.47 to 5.92 for dioxin deposits). When only interviewed cases were considered, risk estimates decreased mainly because the non-interviewed cases were more likely to live in exposed residential environments (OR 2.05, 95% CI 0.92 to 4.57). The results suggest that consumption of local food modifies this risk. CONCLUSIONS: This study confirms our previous observation of a link between the risk of urinary tract birth defects and exposure to MSWI emissions in early pregnancy and illustrates the effect of participation bias on risk estimates of environmental health impacts.

Surveillance of adverse fetal effects of medications (SAFE-Med): findings from the international Clearinghouse of birth defects surveillance and research.

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.

Preferential associations between oral clefts and other major congenital anomalies.

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

Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft.

Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A1*2C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A1*2C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators.

The safety of calcium channel blockers during pregnancy: a prospective, multicenter, observational study.

OBJECTIVE: To assess the safety of calcium channel blockers during the first trimester of pregnancy. STUDY DESIGN: A multicenter (n=11), prospective observational study of the European Network of Teratology Information Services (ENTIS). The rate of major birth defects was compared between a cohort of pregnant women exposed to calcium channel blockers during the first trimester (n=299) and a control group not exposed to potential teratogens (n=806). RESULTS: Major birth defects were not more common in the study group than in the control group. Birth weight was significantly lower in exposed term newborns. There were more preterm infants in the study group than in the control group (23.8% vs. 6.5%). These adverse effects are more likely due to the underlying disease than to the medication. CONCLUSION: This study suggests that calcium channel blockers during the first trimester of pregnancy do not represent a major teratogenic risk.

Antiepileptic drug exposure and major congenital malformations: the role of pregnancy registries.

The use of antiepileptic drugs (AEDs) in pregnancy is associated with an increased risk of fetal malformations. Although it is known that AEDs may differ with respect to the type of malformations they can induce, earlier studies have generally lacked the power to demonstrate differences between AEDs in their overall teratogenic potential. Furthermore, there is an urgent need to assess the clinical teratogenic potential of the newer-generation AEDs. Epilepsy and pregnancy registries have been established to provide such information, which is essential for the rational management of women with epilepsy with childbearing potential. The registries also provide opportunities for additional studies of seizures observed during pregnancy and labor and, with the enrolled woman's consent, for separate studies on cognitive outcomes and pharmacogenetics. Although most are prospective, the existing registries vary somewhat in design, which needs to be considered when their results are compared. Some registries are driven by pharmaceutical companies (often compelled by national or international drug licensing agencies) and provide data on pregnancy outcome related to the sponsor's own product. Others are organized by independent research groups and are potentially more useful in that they publish comparative data. This review provides a critical discussion and comparison of important methodological aspects of AED and pregnancy registries along with a summary of results published so far.

Down syndrome time-clustering in January 1987 in Belarus: link with the Chernobyl accident?

The Chernobyl accident (April 26, 1986) exposed a large part of the Belarus population to ionizing radiation. We analyzed the time trends of Down syndrome (DS) in Belarus to evaluate whether either brief exposure at high dose rates during the plume passage or continuous exposure at low doses and dose rates of the residents of contaminated areas had any detectable impact on DS prevalence at birth. DS data came from the Belarus National Registry of Congenital Malformations (1981-2001). We observed a significant peak of DS in January 1987 (26 cases observed and 9.84 expected; observed/expected ratio=2.64; 95% CI=1.72-3.76), but found no positive long-term time trends in contaminated or control areas. The time occurrence of the January peak, high dose rates during the plume passage and experimental data showing a radiosensitive phase of oogenesis around conception time in mammals suggest that the January peak may be linked to the Chernobyl plume.

Gastroschisis and associated defects: an international study.

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.

Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts.

The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.

Trends of selected malformations in relation to folic acid recommendations and fortification: an international assessment.

BACKGROUND: Two crucial issues relative to the benefits and impact of folic acid in the prevention of birth defects are whether supplementation recommendations alone, without fortification, are effective in reducing the population-wide rates of neural tube defects (NTDs), and whether such policies can reduce the occurrence of other birth defects. Using data from 15 registries, we assessed rates and trends of 14 major defects, including NTDs, in areas with official recommendations or fortification to assess the effectiveness of recommendations and fortification on a wide range of major birth defects. METHODS: We evaluated surveillance data through 2003 on major birth defects from population-based registries from Europe, North America, and Australia. All included ascertainment of pregnancy terminations (where legal). Trends before and after policies or fortification were assessed via Poisson regression and were compared via rate ratios. RESULTS: Significant changes in trends were seen for NTDs in areas with fortification but not in areas with supplementation recommendations alone. For other major birth defects, there was an overall lack of major trend changes after recommendations or fortification. However, some significant declines were observed for select birth defects in individual areas. CONCLUSIONS: Recommendations alone remain an ineffective approach in translating the known protective effect of folic acid in population-wide decline in NTD rates. Fortification appears to be effective in reducing NTDs. The effect on other birth defects remains unclear.

Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study.

Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.

Fostering international collaboration in birth defects research and prevention: a perspective from the International Clearinghouse for Birth Defects Surveillance and Research.

The International Clearing-house for Birth Defects Surveillance and Research, formerly known as International Clearinghouse of Birth Defects Monitoring Systems, consists of 40 registries worldwide that collaborate in monitoring 40 types of birth defects. Clearinghouse activities include the sharing and joint monitoring of birth defect data, epidemiologic and public health research, and capacity building, with the goal of reducing disease and promoting healthy birth outcomes through primary prevention.We discuss 3 of these activities: the collaborative assessment of the potential teratogenicity of first-trimester use of medications (the MADRE project), an example of the intersection of surveillance and research; the international databases of people with orofacial clefts, an example of the evolution from surveillance to outcome research; and the study of genetic polymorphisms, an example of collaboration in public health genetics.

Analysis of reproductive toxicity and classification of glufosinate-ammonium.

CONCLUSION REGARDING CLASSIFICATION OF GLUFOSINATE-AMMONIUM: Science Partners' Evaluation Group (Evaluation Group) has conducted an independent analysis of the herbicide glufosinate-ammonium (GA) relative to its potential to cause reproductive toxicity in humans. Further, the Evaluation Group has evaluated the implementation of Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC) and Council Directive 91/414/EEC, with respect to classification of chemicals posing potential reproductive hazards. After consideration of all information available to us relevant to the potential of glufosinate-ammonium (GA) to cause reproductive toxicity, the Science Partners Evaluation Group concludes that no classification of GA is justified. The following form the basis of this conclusion. There are no human data to suggest that GA causes reproductive toxicity in women or in their conceptus. The issue concerning possible reproductive hazard to humans is raised solely on the basis of positive animal test results that show GA to cause preimplantation or implantation losses in rats. SPECIFICALLY: a. Daily treatment with GA had no detectable effect on the earliest stages of the reproductive sequence including gametogenesis, ovulation, mating and conception; b. Treatment with GA interfered with rat gestation before and at the stage when the conceptus implants into the uterus. This effect occurred at doses of 360 ppm in the feed (corresponding to daily doses of 27.8 mg/kg bw) and above; and c. After implantation, no further effect of GA on prenatal and post-natal development was recognized. Previous concerns that GA might be toxic to embryonic stages after implantation were not supported by the data. Abortions and stillbirth seen were associated with, and regarded as secondary to, maternal toxicity. There was no evidence suggesting the induction of malformations in the offspring. The mechanism underlying this adverse effect in experimental laboratory animals is identified-inhibition of glutamine synthetase. Glutamine is essential to the viability of the embryo. The embryo is dependent on a maternal source of the amino acid. For embryo lethality to occur, a significant reduction of maternal glutamine is required. Such reduction in maternal glutamine depends on a significant inhibition of glutamine synthetase by GA. This can only occur when the mother is exposed to very high levels of GA. SPECIFICALLY: a. The reproductive toxicity of GA is confined to very short, early stages of reproduction, during which the conceptus is dependent on maternal glutamine; and b. In order for the effect to occur, significant reduction in maternal blood glutamine level is required, which in turn depends on a significant inhibition of glutamine synthetase, induced by high levels of GA in the maternal system. There is no evidence for accumulation of GA in the mammalian organism beyond a factor of two and no evidence for its metabolic toxification. To raise a concern in humans, women would have to be exposed to GA during the very limited time frame of preimplantation or implantation and the exposure would have to be to the exceedingly high levels necessary to alter the maternal metabolism and, correspondingly, result in glutamine levels in maternal tissue and blood plasma being drastically reduced. There is no basis to suggest that such exposures would occur under conditions of normal handling and use. SPECIFICALLY: a. Under conditions of normal handling and use, operators would never be exposed to GA levels that could potentially inhibit glutamine synthetase to the extent that this inhibition could impair preimplantation or implantation. b. All acceptable exposure measurements and predictive calculations confirm this conclusion, and in fact demonstrate that reasonably foreseeable exposure of workers would be to levels significantly below the AOEL. c. The evidence is also clear that there is no reproductive toxicity hazard to workers upon reentry tosprayed fields, bystanders, consumers or toddlers. The safety margin compared to the NOAEL in animal studies is sufficiently large to assure protection of the health of workers using GA as well as bystanders, consumers, and toddlers. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 2 there must be sufficient evidence to produce a strong presumption that human exposure to the substance may result in impaired fertility in humans. It is the conclusion of the Science Partners Evaluation Group that there is no reasonable evidence to suggest a strong presumption of impairment. To the contrary, there is clear evidence demonstrating a strong presumption that exposure to GA would not cause the adverse effect demonstrated in rats. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 3, there must be sufficient evidence to provide a strong suspicion of impaired fertility in humans. There is no basis to conclude that the animal data demonstrating impaired preimplantation or implantation has any relevance to humans in that the effect found in rats only occurs at levels which would never be experienced by workers under conditions of normal handling and use or by bystanders, consumers, or toddlers.

Maternal drug use, fertility problems, and infant craniostenosis.

OBJECTIVE: To test the hypothesis that maternal drug use or treatment for infertility is related to the occurrence of infant craniostenosis. DESIGN AND MATERIAL: Maternal drug use and infertility treatment were studied in 398 cases of craniostenosis, identified from various Swedish health registers. Exposure information was ascertained in early pregnancy, and comparisons after adjustment for some confounders were made with all infants born. In order to validate some findings, data from the Central-East France Registry were studied for first trimester drug exposure in 235 infants, and use of ovarian stimulation in 315 infants with craniostenosis. RESULTS: A statistically significant association between maternal use of anticonvulsants and infant craniostenosis was found (risk ratio [Swedish data], 6.9; 95% confidence interval, 1.10 to 7.94). With the Swedish data, an association was found with three nitrosatable drugs (risk ratio, 3.4; 95% confidence interval, 1.10 to 7.94), previously associated with the occurrence of craniostenosis, but this was based on only five exposures, and no such exposure occurred in the French data set. No association with subfertility (odds ratio, 0.72; 95% confidence interval, 0.60 to 1.86) or infertility treatment (odds ratio, 1.06; 95% confidence interval, 0.60 to 1.87) was found in the Swedish data and no statistically significant increase in the use of ovulation stimulation in the French data. CONCLUSIONS: A strong association was found between the maternal use of anticonvulsants and infant craniostenosis, and a tentative association was found with the use of nitrofurantoin and two other nitrosatable drugs. There was no association with maternal subfertility or infertility treatment.

Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development?

Congenital diaphragmatic hernia (CDH) usually occurs sporadically. The prognosis remains poor, with a 50% perinatal mortality rate. Most deaths result from hypoxemia due to lung hypoplasia and abnormal development of pulmonary vasculature that results in persistent pulmonary hypertension. Our current understanding of the pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. Pulmonary hypoplasia, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Moreover, a nitrofen-induced CDH model shows that lung hypoplasia precedes the diaphragmatic defect, leading to a "dual-hit hypothesis." Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the clinical and epidemiological aspects of human CDH, the metabolic and molecular aspects of the retinoid-signaling pathway, and the implications of retinoids in the development of the diaphragm and the lung. Finally, we highlight the existing links between CDH and disruption of the retinoid-signaling pathway, which may suggest an eventual use of retinoids in the treatment of CDH.

Biliary lithiasis in early pregnancy and abnormal development of facial and distal limb bones (Binder syndrome): a possible role for vitamin K deficiency.

BACKGROUND: Binder syndrome is a maxillonasal dysostosis characterized by midface and nasal hypoplasia, sometimes associated with short terminal phalanges of fingers and toes and transient radiological features of chondrodysplasia punctata. Warfarin- or phenytoin-induced vitamin K deficiency during early pregnancy is a well-established etiology for this syndrome, which occurs nevertheless sporadically in most cases. CASE(S): We describe here the first case, to our knowledge, of Binder syndrome in a child whose mother presented with biliary lithiasis in early pregnancy. The mother proved to have a decrease in clotting factors II, VII, and X, and in prothrombin time, at 11 weeks of gestation, which was highly suggestive of vitamin K deficiency. CONCLUSIONS: The biliary lithiasis-induced vitamin K deficiency in early pregnancy is likely to have resulted in Binder syndrome. This observation should prompt physicians to carefully check for vitamin K deficiency in pregnant women presenting with biliary lithiasis, in order to prevent Binder syndrome in the fetus by providing intravenous vitamin K supplementation as soon as possible. Finally, reassuring genetic counseling regarding the genetic risk for future pregnancies is to be provided to the parents.

Pregnancy outcome after exposure to ranitidine and other H2-blockers. A collaborative study of the European Network of Teratology Information Services.

BACKGROUND: Published data on pregnancy outcome after exposure to H2-blockers is scarce. The aim of the present study was to evaluate the data collected by the memberships of the European Network of Teratology Information Services (ENTIS). METHODS: The patients were pregnant women who or whose doctor or midwife did contact a Teratology Information Service for risk assessment after the use of a H2-blocker in pregnancy. The data were prospectively collected, i.e. before the outcome of pregnancy was known. Standardized procedures for data collection were used by each centre. The data of the exposed women were compared to those of a control group exposed to non-teratogenic substances. RESULTS: Data on the outcome of 553 pregnancies with exposure to an H2-blocker were evaluated (ranitidine n=335; cimetidine n=113, famotidine n=75; nizatidine n=15, roxatidine n=15). Most of them had been exposed at least in the first trimester. The incidence of premature deliveries was higher in the exposed group compared to the control group. There was no increase in the incidence of major malformations. Two pregnancies with maternal use of famotidine in early pregnancy were terminated after the prenatal diagnosis of a neural tube defect. CONCLUSION: There is no indication for an increased risk of major malformations after the use of H2-blockers during pregnancy.

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

OBJECTIVES: To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects. DESIGN: Retrospective cohort study of births monitored by birth defect registries. SETTING: 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review. MAIN OUTCOME MEASURES: Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable). RESULTS: The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects. CONCLUSIONS: Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

Interaction between the ADH1C polymorphism and maternal alcohol intake in the risk of nonsyndromic oral clefts: an evaluation of the contribution of child and maternal genotypes.

BACKGROUND: Maternal alcohol consumption has been associated with an increased risk of nonsyndromic oral clefts in some studies. Study of gene-environment interaction may provide insight into the reasons for their discrepancies observed. We focused on a polymorphism of the ADH1C gene (third gene of the class I alcohol dehydrogenase family), involved in the metabolism of ethanol and other alcohols. METHODS: Data come from a French case-control study (1998-2001), which tested the association between maternal alcohol consumption during the first trimester of pregnancy and the risk of nonsyndromic oral clefts (240 cases, 236 controls). A case-parent study design looked at the association with an ADH1C polymorphism (Ile349Val site) and potential gene-environment interaction effects. A log-linear model was used to distinguish the direct effect of the child's genotype from the maternally mediated effects. RESULTS: An increased risk of nonsyndromic oral clefts was observed for women who reported drinking alcohol during the first trimester, compared with women who did not. The mutated ADH1C allele carried by the child seemed to have a protective effect against the risk of oral clefts (RRone copy, 0.71; 95% confidence interval [CI], 0.50-1.02; RRtwo copies, 0.63; 95% CI, 0.3-1.3). The maternal genotype played a less important role than the child's, and its action remains unclear. No significant evidence of interaction effects between the ADH1C genotype and maternal alcohol consumption was observed. CONCLUSIONS: Because the ADH1C gene is involved in the metabolic pathways of many alcohols, we propose several hypotheses about the causal pathway, including ethanol oxidation activity and, more probably, retinol oxidation.