IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families.

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.

Association of certain chronic maternal diseases with the risk of specific congenital heart defects: a population-based study.

OBJECTIVE: Previous epidemiological studies have evaluated cases with all congenital heart defects (CHDs), rather than analysing different types of CHD. The objective of this study was to evaluate the possible association of certain chronic maternal diseases with the risk of different types of CHD, because the role of possible environmental factors in the origin of CHDs is unclear in the vast majority of patients. STUDY DESIGN: Different types of CHD, diagnosed after lethal outcome (autopsy report) or after surgical intervention (catheter or correction), were evaluated in order to estimate the possible role of chronic maternal diseases in their origin. This analysis was based on the rates of medically recorded chronic maternal diseases in 3562 live-born cases with CHDs, 38,151 population controls without any birth defects, and 16,602 malformed controls with other isolated congenital abnormalities, using the data set of the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996). RESULTS: Maternal epilepsy treated with carbamazepine and migraine were found to be associated with higher risk of ventricular septal defect; panic disorders were associated with higher risk of hypoplastic left heart; type I diabetes mellitus was associated with higher risk of coarctation of the aorta; chronic hypertension was associated with higher risk of ventricular septal defect, common atrioventricular canal and common truncus; and paroxysmal supraventricular tachycardia was associated with higher risk of atrial septal defect secundum, common atrioventricular canal and ventricular septal defect. CONCLUSION: In conclusion, certain chronic maternal diseases were found to be associated with higher risk of specific CHDs. Appropriate treatment of these diseases may help to prevent these CHDs.

Association of AXIN2 with non-syndromic oral clefts in multiple populations.

We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts.

Experience of the Hungarian Preconception Service between 1984 and 2010.

The objective of this historical account is to summarize the concept, objectives, methods, results and general experience of the Hungarian Preconception Service, Budapest, based on 27 years (1984-2010) and 25,313 women and couples. The service includes counseling and care (examinations and medical interventions) based on three steps: (1) preconception screening for reproductive risk factors ("reproductive health check-up"), (2) a 3-month preparation for conception, because conception is when some major developmental events, such as the sex of the conceptus and the foundation of health and many diseases, are determined, and (3) achievement of optimal conception and better protection of the embryo in early pregnancy. With normal prenatal care, pregnant women visit clinics between the 7th and 12th gestational weeks, but the embryo has passed through his/her most vulnerable period before the 10th week, and thus prenatal care is too late to reduce the risk of congenital abnormalities. The new primary health care infrastructure for preconception care is performed by qualified and trained nurses and midwifes. Couples at risk are selected and are referred to specialists who can reject or confirm the supposed risks and treat the couples if necessary as part of their secondary health care. The most important results of the Hungarian preconception service were (i) a significant reduction in the rate of preterm births (5.0% vs. 9.2%) which has been linked mainly to preconception screening of sexually transmitted infections of female participants followed by appropriate treatment, (ii) a very significant reduction of congenital abnormalities (2.9% vs. 4.0%), particularly neural-tube defects and cardiovascular malformations, due to periconception multivitamin supplementation, (iii) reduction of smoking among female participants, (iv) involvement of male partners in the family planning health system, (v) much improved identification of couples at high risk and greater access to the secondary care of specialists. In conclusion, the Hungarian experience demonstrates the feasibility and usefulness of preconception care in the prevention of adverse birth outcomes including congenital abnormalities and preterm births.

Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study.

OBJECTIVE: Periconceptional folic acid or multivitamin supplementation is recommended for prospective pregnant women to prevent neural-tube defects. The question is whether it is worth continuing these supplementations after the first trimester of pregnancy or not. Thus the possible fetal growth promoting and/or preterm birth reducing effect of vitamin supplements in the second and mainly in the third trimester was studied. STUDY DESIGN: Comparison of birth outcomes of singletons born to primiparous pregnant women with prospectively and medically recorded vitamin supplement in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996 contained 6293, 169, and 311 primiparae with folic acid alone, multivitamins and folic acid+multivitamin supplementation, respectively, and their data were compared to the data of 7319 pregnant women without folic acid and folic acid-containing multivitamin supplementation as reference. RESULTS: Mean gestational age was 0.3 week longer and mean birth weight was by 37 g higher in the group of folic acid alone, than in the reference group (39.2 weeks; 3216 g). The rate of preterm births (7.6%) was significantly lower compared with the reference sample (11.8%), but the rate of low birth weight newborns did not show significant reduction. Folic acid alone in the third trimester associated with 0.6 week longer gestational age and a more significant reduction in the rate of preterm births (4.8%). CONCLUSIONS: Minor increase in mean birth weight after high dose of folic acid supplementation during pregnancy would not be expected to result in too large babies; however, the significant reduction in the rate of preterm births may have great public health benefit.

Introduction and history of the Hungarian project for monitoring suicide attempts in pregnant women.

The introduction describes the series of manuscripts resulting from the Hungarian Project for monitoring suicide attempts in pregnant women, as well as a history of the project, its various phases and participating individuals. This unique database contains information on all patients who attempted suicide by "self-poisoning" and were cared for at central toxicological inpatient clinic in Budapest, between 1960 and 1993. A total of 1044 patients were pregnant women, of which 19 died and 411 delivered live-born babies. Of these 411 live-born children, 367 exposed children were examined and/or evaluated. This is the first report of data on the human teratogenic potential of 93 medicinal products separately used for a suicide attempt during pregnancy. Each manuscript presents results for drugs used by at least 10 pregnant women for a suicide attempt, whereas the final paper summarizes the data of drugs used rarely for suicide attempt by pregnant women. Each patient consented to participate in the study. Critical information collected under medical supervision included examination of the patients upon admittance, stage of pregnancy at suicide attempt, blood levels of the drug(s) taken for the suicide attempt (at admittance), evaluation of the infant at birth for gestational age, weight and congenital abnormalities, and follow-up studies for 2 years after a child's birth. These studies provide insight into the potential effects of a high dose of a drug or drugs taken during pregnancy because it is well accepted that "pulse high doses" of a drug during the initial susceptible period of pregnancy are those most likely to result in congenital abnormality. Although it is obvious that these data are not sufficient to ensure safety, and that it is necessary to have a larger population of exposed children, to achieve better statistical power, as well as to include data on other populations, this collection of papers provides an important introduction of the so-called disaster epidemiological approach in human teratology. It shows the feasibility of such studies and suggests that an international surveillance system of self-poisoned pregnant women would be useful to better estimate risk and benefit of drug use during pregnancy. It is envisioned that the information provided will assist physicians and mothers in making better decisions regarding drug exposure during pregnancy.

No association found between use of very large doses of diazepam by 112 pregnant women for a suicide attempt and congenital abnormalities in their offspring.

The teratogenic potential of diazepam is debated. The objective of this study was to examine the effects of extremely high doses of diazepam used for attempted suicide during pregnancy on embryo-fetal development. Pregnant women were identified from the female patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who had been admitted as self-poisoned subjects from the three million people of Budapest and the surrounding region. This evaluation compares the incidences and types of congenital abnormalities observed in exposed children born to mothers who attempted suicide with diazepam alone or in combination with other drugs during pregnancy with their sib controls. The database consists of a total of 1044 women with self-poisoning during pregnancy between 1960 and 1993. Of these 1044 self-poisoned pregnant women, 229 (21.9%) used diazepam with or without other drugs for a suicide attempt; 112 of these women delivered live-born infants. Doses of diazepam taken ranged between 25 and 800 mg. Of 112 exposed children, 15 (13.4%) had congenital abnormalities, whereas of their 112 matched sibs, eight (7.1%) had congenital abnormalities (odds ratios with 95% confidence intervals: 2.0, 0.8-5.0). Of 37 pregnant women who attempted suicide between the 4th and 12th postconceptional weeks, five (13.5%) delivered live-born babies with a congenital abnormality (undescended testis in two exposed children; congenital dysplasia of the hip, talipes equinovarus deformation type, congenital inguinal hernia-each in one exposed child). The suicide attempts of the mothers of these children did not occur during the critical periods for induction of these defects, indicating that the observations were unrelated to diazepam. The very large doses of diazepam used for self-poisoning during pregnancy did not increase the rate of congenital abnormalities in the offspring.

An evaluation of data for 10 children born to mothers who attempted suicide by taking large doses of alprazolam during pregnancy.

FDA has identified alprazolam, a new type of benzodiazepine, as pregnancy category D. The objective of this study was to evaluate the effects on fetal development of very large doses of alprazolam that were used for suicide attempts during pregnancy. Pregnant women were identified among the patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who were admitted as self-poisoned subjects from a total population of the three million people of Budapest and its surrounding region. Rates of congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status were compared between children born to mothers who attempted suicide during pregnancy using alprazolam alone or in combination with other drugs and in their sib controls. Between 1984 and 1993, 559 pregnant women attempted suicide during pregnancy with drugs: 30 of these women self-poisoned with alprazolam, 10 delivered live-born infants who were examined. Doses of alprazolam used were between 7.5 and 100 mg, with a mean of 30 mg. Six of the 10 exposed children were born to mothers who attempted suicide between the 6th and 12th postconceptional weeks. Of the 10 exposed children, two had congenital abnormalities. One had a multiple congenital abnormality that included atypical gastroschisis and minor anomalies; an association of this defect and the 30 mg alprazolam used for self-poisoning in the 14th postconceptional week cannot be excluded. Another exposed child had mild pectus excavatum, but the times of the suicide attempt and the critical period for producing this defect did not overlap. Of 12 sibs, one had a multiple congenital abnormality. Thus, the rate of congenital abnormalities did not significantly differ between exposed children and their sibs. Mean birth weight was higher for babies born to mothers who attempted suicide by alprazolam during pregnancy than in their sib controls. Cognitive status and behavioral scale of the exposed children did not indicate fetotoxic effects, including neurotoxic effects, of large doses of alprazolam. The large doses of alprazolam used for self-poisoning during pregnancy did not result in a significantly higher rate of congenital abnormalities; however, there were only 10 self-poisoned pregnant women, and an association of one multiple congenital abnormality with a large dose of alprazolam cannot be excluded. The findings in this study did not identify fetotoxicity, including neurotoxicity, of very large doses of alprazolam. Our study shows that the self-poisoning model is feasible and provides beneficial information for use in estimating human teratogenic and fetotoxic risks of drugs.

A study of the potential teratogenic effect of large doses of promethazine used for a suicide attempt by 32 pregnant women.

In Hungary, promethazine, a phenothiazine antihistamine, is the second most frequently used drug during pregnancy. The purpose of this study was to examine the effects of very large doses of promethazine that were used for a suicide attempt during pregnancy on embryo-fetal development. Self-poisoned pregnant women were identified from patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who were admitted from the three million people of Budapest and surrounding region. The rate of congenital abnormalities, intrauterine development (based on pregnancy age at delivery and birth weight), and cognitive-behavioral status of exposed children born to mothers who attempted suicide with promethazine alone or in combination with other drugs during pregnancy was compared with their sib controls. In all, 89 of the 1044 women with self-poisoning during pregnancy between 1960 and 1993 used promethazine for a suicide attempt. Of these 89 women, 32 delivered newborn babies. The dose of promethazine taken by these women for self-poisoning ranged between 125 mg and 1750 mg (mean of 544 mg, i.e., 21.8 tablets). Of the 32 promethazine-exposed children, nine (28.1 %) were affected with congenital abnormalities. However, of 11 pregnant women who attempted suicide with promethazine between the 3rd and 12th postconceptional week, that is, the critical period for production of most major congenital abnormalities, only three were affected with defects, and the critical periods for producing these defects did not overlap with the time of the suicide attempt during pregnancy. Of 34 unexposed sibs, five (14.7%) had congenital abnormalities; the difference in the total rate of congenital abnormalities between the exposed children and their sib controls was not significant. There also was no difference in pregnancy age-specific birth weight between exposed children and their sibs. Mean intelligence quotient was not reduced, and the incidence of behavioral deviation was not increased in the exposed children. The findings of this study did not indicate teratogenic or fetotoxic (including neurotoxic) effects of large doses of promethazine in children born to mothers who self-poisoned during pregnancy, although the total rate of congenital abnormalities was very high. Our experience shows the feasibility and benefits of using the self-poisoning model in estimating human teratogenic/fetotoxic risks of exposure to drugs.

A study of the teratogenic and fetotoxic effects of large doses of chlordiazepoxide used for self-poisoning by 35 pregnant women.

The human teratogenic potential of chlordiazepoxide is debated. To study the effects on the fetal development of very large doses of chlordiazepoxide that were used for a suicide attempt during pregnancy, self-poisoned pregnant women were identified from patients in a toxicological inpatient clinic in Budapest, Hungary. Comparisons were made between congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status of the exposed children born to mothers who attempted suicide with chlordiazepoxide alone or in combination with other drugs during pregnancy and their sib controls. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 88 (8.4%) used chlordiazepoxide with or without other drugs for suicide attempt; 35 of these women delivered live-born infants. Doses of chlordiazepoxide taken ranged between 20 and 300 mg, with a mean of 117 +/- 86 mg. Of 35 exposed children, six (17.1 %) were affected with congenital abnormalities compared with three (13.6%) of their 22 sibs (OR with 95% CI: 1.3 (0.3-4.4). Of 18 pregnant women who attempted suicide between the 4th and 12th postconceptional week, the period most sensitive to congenital malformation, four delivered live-born children affected with a congenital abnormality (atrial septal defect type II, complex defect of respiratory system, mild pyelectasis because of the stenosis of ureteropelvic junction, congenital inguinal hernia). Two other children had fetal alcohol syndrome and unrecognized multiple congenital abnormality including talipes equinovarus, deformation type, and four minor anomalies. The pregnancy age-specific mean birth weight indicated intrauterine fetal growth retardation, which was confirmed by a dose-response relationship and by the higher rate of low birth-weight newborns. Cognitive status and behavioral scale of exposed children did not indicate neurotoxic effects. Very large doses of chlordiazepoxide used for suicide attempts during pregnancy did not induce a higher rate of congenital abnormalities but were associated with dose-dependent intrauterine growth retardation.

Self-poisoning during pregnancy as a model for teratogenic risk estimation of drugs.

The results of animal investigations cannot be directly extrapolated to pregnant women. Clinical and analytical epidemiological studies for human teratogenic risks have many inherent methodological problems and their predictions must be regarded with caution. Evaluation of the potential teratogenicity of extremely large doses of drugs in self-poisoned pregnant women who attempted suicide offers a unique model for finding associations between congenital abnormalities and different drugs. All self-poisoned patients were cared for at a toxicological inpatient clinic in Budapest, between 1960 and 1993. Out of 1044 pregnant women identified from three different periods of the project, 19 died. Women who survived were visited at home to reveal birth outcomes, and their children were evaluated medically to identify congenital abnormalities and to estimate cognitive-behavioral status. The previous or subsequent children of these pregnant women were used as controls. In general, self-poisoned pregnant women were young (peak age was 18 to 20 years) and primiparous; 55% were unmarried and of lower socioeconomic status. Suicide attempts with drugs were most frequent in the fourth postconceptional week and second pregnancy month. Of 1044 self-poisoned pregnant women, 411 delivered live-born babies, of which 367 children (89.3%) were evaluated. The self-poisoning model appears to have several benefits (e.g., dose-response estimation) in comparison with other methods. It is suggested that an international monitoring system of self-poisoned pregnant women should be established to provide a larger database.

A study of the effects of large doses of glutethimide that were used for self-poisoning during pregnancy on human fetuses.

Animal investigations showed some embryolethal and teratogenic effects of glutethimide, a piperidindion derivative non-barbital hypnotic drug. Thus, the objective of this study was to evaluate the effects of very large doses of glutethimide that were used for a suicide attempt during pregnancy on the embryo-fetal development of exposed children. Self-poisoned pregnant women were identified from the population of female patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest who had been admitted from the 3 million people of Budapest and its surrounding region. The rates of congenital abnormalities, intrauterine fetal development (based on birth weight and pregnancy age at delivery) and cognitive-behavioral status of exposed children born to mothers who attempted suicide with glutethimide alone or in combination with other drugs during pregnancy were compared with their sib controls. Of 1044 pregnant women with self-poisoning during pregnancy between 1960 and 1993, 33 used glutethimide for a suicide attempt sixteen of these women delivered live-born infants. The dose of glutethimide ranged between 1000 and 15,000 mg with a mean of 4234 mg. Of the 16 exposed children, five were male and 11 were female. Three exposed children were affected with congenital abnormalities (atrial septal defect type II, pectus carinatum, fetal alcohol syndrome). Of their 16 matched unexposed sib pairs, two had congenital abnormalities. The mean birth weight of the exposed children was somewhat larger due to somewhat longer pregnancy age at delivery. Cognitive status and behavioral scale of the exposed children did not indicate a fetotoxic (including neurotoxic) effect of large doses of glutethimide. Very large doses of glutethimide used for a suicide attempt by 16 pregnant women did not produce teratogenic or fetotoxic (including neurotoxic) effects in their children.

A study of the teratogenic and fetotoxic effects of large doses of amobarbital used for a suicide attempt by 14 pregnant women.

The teratogenic effect of barbitals is debated, and this study was performed to identify the effects of very large doses of amobarbital used for suicide attempts during pregnancy on embryo-fetal development. Self-poisoned pregnant women were identified from patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, Hungary, who were admitted from the 3 million people of Budapest and its surrounding region. A comparison was made between outcomes of pregnancies of women who attempted suicide with amobarbital alone or in combination with other drugs during pregnancy with sib controls. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 33 used amobarbital for a suicide attempt. Of these 33 women, 14 delivered live-born babies. The dose of amobarbital taken by these women ranged between 600 and 10,000 mg, with a mean of 3886 mg. Of the 14 amobarbital-exposed children, 9 had mothers who attempted suicide between the 3rd and 12th post-conceptional weeks. None of these children had a congenital abnormality, and there was no evidence of fetal growth retardation. The distribution of cognitive status and behavioral scale of the exposed children were comparable with those of their sibs although one exposed child had a very low (about 75) IQ, whereas another one was treated because of a very severe aggressive behavioral deviation. Exposure to very large doses of amobarbital that were used for self-poisoning during pregnancy did not produce teratogenic effects in this study.

A study of teratogenic and fetotoxic effects of large doses of meprobamate used for a suicide attempt by 42 pregnant women.

The human teratogenic effect of meprobamate is debated. Thus, the available data set regarding very large doses of meprobamate used for a suicide attempt during pregnancy was evaluated for effects on fetal development. Pregnant women were identified from self-poisoned subjects of a total population of approximately three million people (Budapest and surrounding region) who were admitted to the Department of Toxicology Internal Medicine, Koranyi Hospital, Budapest. Comparisons were made of congenital abnormalities, intrauterine fetal growth, and cognitive-behavioral status in exposed children born to mothers who attempted suicide with meprobamate alone or in combination with other drugs during pregnancy with their control sibs. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 107 (10.3%) used meprobamate, with or without other drugs for a suicide attempt; 42 of these 107 women delivered live-born infants. The dose of meprobamate used for the suicide attempt ranged between 1000 and 26,000 mg, with a mean of 3690 mg. Of 42 exposed children, seven (16.7%) were affected with congenital abnormalities, however, of their 27 sib controls, four had a CA (14.8%) (OR with 95% CI: 1.7, 0.5-4.9) of 14 had a congenital abnormality. Of 14 mothers who attempted suicide during the 4-12th postconceptional week, two delivered live-born babies affected with mild isolated congenital abnormality: undescended testis and congenital dysplasia of the hip. However, the critical period for production of these two defects did not overlap with the time of the mother's suicide attempt. Mean birth weight and pregnancy age, cognitive status, and behavioral scale of the exposed children did not indicate fetotoxic, including neurotoxic, effects of large doses of meprobamate. Very large doses of meprobamate that were used for self-poisoning during pregnancy did not result in teratogenic or fetotoxic, including neurotoxic, effects on fetal development.

A study of the effects of large doses of medazepam used for self-poisoning in 10 pregnant women on fetal development.

The purpose of this article is to report an evaluation of the teratogenic and fetotoxic potential of medezepam in humans based on pregnant women who used very large doses of medazepam for a suicide attempt. All self-poisoned patients were cared for at the Department of Toxicology Internal Medicine, Koranyi Hospital, a toxicological inpatients clinic in Budapest, Hungary, between 1960 and 1993. Pregnant women were identified from self-poisoned subjects admitted from a population base of three million people of Budapest and the surrounding region. The rates of congenital abnormalities (CAs), intrauterine fetal development, cognitive and behavioral status in children born to mothers who attempted suicide with medazepam alone or in combination with other drugs during pregnancy was compared in their sib controls. Between 1980 and 1993, 835 pregnant women in our study attempted suicide during pregnancy with drugs. Of these, 314 delivered live-born infants and 283 were examined and/or evaluated. Thirty-two (3.8%) of these 835 pregnant women used medazepam with or without other drugs for self-poisoning; 10 of these women delivered live-born babies. The dose of medazepam used for the suicide attempt ranged between 60 and 500 mg, with a mean of 276 mg. Eight of the 32 suicide attempts involving medazepam occurred between the 4th and 12th postconceptional weeks. Of the 10 live-born exposed children, one was affected with congenital inguinal hernia; one of the 13 sib controls had a lethal hydronephrosis. No adverse effects were observed on intrauterine growth, cognitive status, or behavioral deviations in the 10 children born to mothers who attempted suicide with medazepam during pregnancy. Very large doses of medazepam were used for self-poisoning during pregnancy. These doses did not increase the rate of CAs even though eight mothers attempted suicide during the most critical period for production of CAs. No fetotoxic, including neurotoxic, effects of exposure of live-born children to a very large dose of medazepam were observed. Our experiences show the feasibility and benefits of use of the self-poisoning model in estimating human teratogenic and fetotoxic risks of drugs.

A study of the teratogenic and fetotoxic effects of large doses of barbital, hexobarbital and butobarbital used for suicide attempts by pregnant women.

The teratogenic potential of barbiturates is debated. The objective of this study was to evaluate the effects of very large doses of different barbiturates, except phenobarbital and amobarbital, on fetal development in pregnant women who attempted suicide. These self-poisoned pregnant women were identified among the patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest. The prevalence at birth of congenital abnormalities and intrauterine fetal growth, based on pregnancy age at delivery and birth weight, as well as cognitive-behavioral status in exposed children born to mothers who attempted suicide with barbiturates alone or in combination with other drugs, during pregnancy, were compared with their sibs as controls. Of 1044 women with self-poisoning during pregnancy between 1960 and 1993, 411 delivered live-born babies; of these, 367 (89.3%) exposed children were evaluated. Of the 367 exposed children, 6, 5, 4 and 4 were born to mothers who attempted suicide with very large doses of Barbamid (butobarbital and aminophenazone), hexobarbital, butobarbital and Belloid (butobarbital, hyoscyamine and secalis cornuti alkaloida) tablets, respectively. Of 19 exposed children, two children with a congenital inguinal hernia were born to mothers who attempted suicide with 30 tablets of Belloid (900 mg butobarbital) in the 20th postconceptional week or with 20 tablets of Belloid in combination with chlordiazepoxide (100 mg) and nitrazepam (100 mg) in 12th postconceptional week. However, the critical period for production of congenital inguinal hernia is in the last months of pregnancy. None of the exposed children born to the other 12 pregnant women who attempted suicide with these barbiturates between the third and 12th postconceptional week, i.e., during the critical period for production of most major congenital abnormalities, had a congenital abnormality. Congenital abnormalities did not occur among 16 sib controls. Intrauterine fetal growth was similar between sibs and exposed children; cognitive status and behavioral scale also did not indicate any neurotoxic effects from large doses of these barbiturates. The very large doses of barbital, hexobarbital and/or butobarbital used for self-poisoning during pregnancy were not teratogenic to the children, although it must be recognized that the number of exposed children was limited.

A study of the potential teratogenic effects of large doses of drugs rarely used for a suicide attempt during pregnancy.

The available data set regarding pregnant women who attempted suicide during pregnancy was evaluated to estimate the teratogenic effect of very large doses of drugs based on the rate and distribution of congenital abnormalities of exposed children. These pregnant women were identified from patients of central toxicological inpatients clinic, Budapest, Hungary, 1960-1993. Of 1044 women with self-poisoning during pregnancy, 411 delivered live-born babies; 367 of these children were examined in this study. Data for 12 frequently used (10 or more times) drugs were published previously; this paper presents 77 medicines (58 drugs and 19 medicinal products including multiple components) that were rarely used for a suicide attempt by 197 pregnant women. Although 23 (11.7%) exposed children had congenital abnormalities (CAs), in general, a causal relationship of the CA and the drug taken by the pregnant woman cannot be assumed. This is because the suicide attempt often did not occur during a critical period for producing the CA. Of 67 pregnant women who attempted suicide between the 3rd and 12th postconceptional week, that is, the critical period of most major CAs, 7 (10.5%) children were affected with CAs. This high rate of CAs in exposed children can be explained by the intensive medical examinations, including diagnosis of mild CAs and minor anomalies, or the low socioeconomic status and hazardous lifestyle of mothers. None of the rarely used drugs was identified as a potential human teratogen. Experience of the authors shows the feasibility and benefits of using the self-poisoning model in estimating human teratogenic/fetotoxic risks of exposure to drugs.

Phenolphthalein treatment in pregnant women and congenital abnormalities in their offspring: A population-based case-control study.

Phenolphthalein is frequently used laxative drug since 1930s, but the possible teratogenic effect of phenolphthalein was not checked in casecontrol eptedmiological study. In addition US Food and Drug Administration (FDA) declared the mutagenic and carcinogenic effect of phenolphthalein in 1999, thus we decided to evaluate the birth outcomes particularly congenital abnormalities (CAs) of newborn infants born to women treated with phenolphthalein during pregnancy. Cases with CA and their matched controls without CA born to mothers with phenolphthalein use during pregnancy were compared in the population-based large data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities. Of 22,843 cases with CA, 191 (0.83%) while of 38,151 controls, 247 (0.64%) were born to mothers with phenolphthalein treatment (adjusted OR with 95% CI: 1.3, 1.0-1.5). The mean gestational week at delivery was somewhat longer in both the case (0.3 week) and control (0.2 week) groups while the mean birth weight was somewhat larger in cases (46 g) and controls (12 g) born to mothers with phenolphthalein treatment during the study pregnancy compared with mothers without phenolphthalein treatment. These differences were in agreement with the lower rate of preterm births and low birth weight in controls born to mothers with phenolphthalein treatment during pregnancy. The detailed analysis of different CA groups showed an association between maternal phenolphthalein treatment during pregnancy and a higher risk for Hirschsprung's disease (p = 0.01) based on 4 cases in the so-called other isolated CA-group. In conclusion phenolphthalein treatment in pregnant women associates with a higher risk for Hirschsprung's disease in their children, but this finding is only a signal which needs confirmation or rejection in other studies.

Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study.

OBJECTIVE: To investigate whether folic acid supplementation in early pregnancy modifies the association between the prevalence of congenital abnormalities in the offspring and maternal use of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and primidone (PRI). DESIGN: A population-based case-control study. SETTING: The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) (1980-1996) and its information on children from the Hungarian Congenital Abnormality Registry and the Hungarian National Birth Registry. POPULATION: Children with congenital abnormalities (cases; n= 20 792, of whom 148 had been exposed to antiepileptic drugs [AEDs]) and unaffected children (controls; n= 38 151, of whom 184 had been exposed to AEDs). METHODS: Information on drug exposure and background variables for the mothers were collected from antenatal logbooks, discharge summaries, and structured questionnaires completed by the mothers at the time of HCCSCA registration. MAIN OUTCOME MEASURES: Congenital abnormalities detected at termination of pregnancy, at birth or until 3 months of age according to CBZ, PB, PHT, or PRI exposure at 5-12 weeks from first day of the last menstrual period (LMP), stratified by folic acid supplementation. RESULTS: Compared with children unexposed to AEDs and folic acid, the odds ratio of congenital abnormalities was 1.47 (95% CI 1.13-1.90) in children exposed to AEDs without folic acid supplementation and 1.27 (95% CI 0.85-1.89) for children exposed to AEDs with folic acid supplementation. CONCLUSION: The results indicate that the risk of congenital abnormalities in children exposed in utero to CBZ, PB, PHT, and PRI is reduced but not eliminated by folic acid supplementation at 5-12 weeks from LMP. The statistical precision in our study is limited due to rarity of the exposures, and further studies are needed.