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In most patients affected by isolated infantile hypertrophic pyloric stenosis (IHPS) the etiology is largely unknown. Thus, the aim of this study was to estimate possible maternal risk factors in the origin of IHPS. The study samples included 241 cases with IHPS, 357 matched controls and 38,151 population controls without any defect in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Exposures that had been medically recorded in prenatal maternity logbooks during the critical period of IHPS were evaluated separately. The findings of this case-control study suggested that--beyond the well-known robust male excess (85.5%)--maternal hyperthyroidism (OR with 95% CI: 4.17, 1.53-11.38) and oral nalidixic acid treatment (OR with 95% CI: 6.53, 3.03-14.06) associated with a higher risk for IHPS in their children. In conclusion, our findings suggest that cases with IHPS had mothers with a higher proportion of hyperthyroidism and nalidixic acid treatment during pregnancy.

In most patients affected by isolated anorectal malformation (IARM) the etiology is largely unknown. Thus, the aim of our project was to analyze possible risk factors for IARM. In the first step, birth outcomes of cases with IARM were analyzed on the basis of maternal socio-demographic variables, and these data are presented in this paper. Gestational age at delivery, birthweight, preterm birth, low birthweight and small for gestational age of cases with IARM were evaluated in the function of maternal age, birth/pregnancy order, marital and employment status of mothers in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. The study samples included 231 live-born cases with IARM, 361 matched and 38 151 population controls without any defect. IARMs are more frequent in males, twins and newborn infants with low birthweight and small-for-gestational-age, the latter being the consequence of intrauterine growth restriction. In addition, mothers of cases were younger but with higher birth order, and had lower socio-economic status. These maternal variables are characteristic for the gypsy population in Hungary. The higher proportion of gypsy women among the mothers of cases with IARM was confirmed during the home visits of the study. Male sex and intrauterine growth restriction of cases, in addition to low socioeconomic status and gypsy origin of mothers may have a role in the risk of IARMs.

Objective: In most patients affected by isolated anorectal malformation (IARM), the etiology is unknown. Thus, the aim of this study was to analyze the possible role of maternal risk factors in the origin of IARM.Methods: The study samples included 231 cases with IARM, 361 matched and 38 151 population controls without any defect in the population-based large dataset of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996. Cases with IARM were evaluated in the function of maternal diseases and related drug use.Results: The findings of this case–control study suggested that cases with IARM have an obvious male excess. The mothers of cases with IARM had a lower incidence of severe nausea and vomiting in pregnancy and a higher incidence of acute infectious diseases in the urinary tract.Conclusions: Lack of nausea and vomiting in pregnancy and the higher incidence of urinary tract infections may have a role in the development of IARM.

The aim of the study was to estimate the possible association of pregnant women with paroxysmal supraventricular tachycardia (PSVT) with the possible risk for adverse birth outcomes, particularly different congenital abnormalities (CAs) in their children. Prospectively and medically recorded PSVT was evaluated in 103 pregnant women who later had offspring with CA (case group) and 149 pregnant women who later delivered newborn infants without CA (control group) and matched to cases in the population-based data set of the Hungarian Case–Control Surveillance System of Congenital Abnormalities, 1980–1996. Of 252 pregnant women with PSVT, 115 (45.6%) had the onset of this condition before the study pregnancy, that is, their PSVT was a chronic condition, while the rest (N = 137) of PSVT was considered as new onset in the study pregnancy. The comparison of occurrence of PSVT in pregnant women who had offspring with different CA groups and in control mothers showed a higher risk for cardiovascular CAs (adjusted OR with 95% CI: 2.1, 1.1–3.8) explained mainly by secundum atrial septal defect. This association was confirmed in pregnant women with PSVT in the second and/or third gestational month, that is, critical period of cardiovascular CAs. In conclusion PSVT in pregnant women associates with a higher risk of secundum atrial septal defect in their children. © 2015 Wiley Periodicals, Inc.

Previously an unexpected association of maternal angina pectoris (MAP) during pregnancy with a higher risk of orofacial clefts in their children was found. There were three objectives of this study: (i) to evaluate the validity of MAP-diagnoses in the previous study and the recent history of mothers with MAP in a follow-up study; (ii) to estimate the prevalence of other congenital abnormalities in the offspring of mothers with MAP; and (iii) to analyze the possible effect of confounders for the risk of orofacial clefts. The large dataset of population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980–1996 was evaluated including 22 843 cases with congenital abnormalities and 38 151 controls without any defect. Twenty-two cases (0.10%) and 12 controls (0.03%) were born to mothers with medically recorded MAP (odds ratio [OR] with 95% confidence interval [CI]: 3.7, 1.8–7.3). Of 22 cases, six had isolated cleft lip ± palate (OR with 95% CI: 13.3, 4.9–35.9) and two were affected with isolated cleft palate (OR with 95% CI: 10.5, 2.3–47.6). The diagnosis of MAP was confirmed in seven women visited at home in 2009–2010, two had recent myocardial infarction and five were smokers. There was no higher risk for other congenital abnormalities. In conclusion the higher risk of orofacial clefts was confirmed in the children of mothers with MAP and smoking may trigger the genetic predisposition of both MAP and orofacial clefts. However, the number of cases was limited and therefore further studies are needed to confirm or reject this theoretically and practically important observation.

Background: The aim of the study was to estimate the effect on the fetal development of high doses of prescription drugs taken as a suicide attempt during pregnancy. Methods: Pregnant women were identified among self-poisoned females in the toxicological inpatient clinic in Budapest between 1960 and 1993. Congenital abnormalities, intrauterine development based on birth weight and post-conceptional age, mental retardation, cognitive-behavioral status were compared in exposed children born to mothers who had attempted suicide by means of a drug overdose during pregnancy with their siblings, born either before or after the affected pregnancy, as sib controls. Results: Of a total of 1 044 pregnant women, 74 used the combination of amobarbital, glutethimide and promethazine (Tardyl®, one of the most popular drugs for treatment of insomnia in Hungary) for suicide attempt. Of these 74 women, 27 delivered live-born babies. The mean dose of Tardyl® used for suicide attempts was 24 times the usually prescribed clinical dose. The rate of congenital abnormalities and intrauterine retardation was not higher in exposed children than in their sib controls. However, of the 27 exposed children, eight (29.6%) were mentally retarded (Χ\documentclass[12pt]{minimal} \usepackage{wasysym} \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs} \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} { linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n} \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $$ {\mathrm{_{{1}}^{{2}}}} $$ \end{document} )=79.7, p= Sig) while mental retardation did not occur among 46 sib controls. These exposed children were born to mothers who attempted suicide with Tardyl® between the 14th and 20th post-conceptional weeks. The components of Tardyl® used separately for a suicide attempt during pregnancy were not associated with a higher risk of mental retardation. Therefore the high doses of Tardyl® associated with the high risk for mental retardation may be due to the interaction of its three drug components. Conclusions: The findings of the study showed that the high doses of a drug containing three components may be associated with a significantly increased risk for mental retardation without any structural defects, whereas each of these three component drugs taken alone was not associated with this adverse effect.

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.

Hypospadias is a common structural birth defect (congenital abnormality) of the male genital organ. The objective of this study was to test the hypothesis regarding the possible preventive effect of folic acid for isolated hypospadias (IH). Folic acid use was compared in 3,038 cases with IH and 24,814 male controls without any defects in the national population-based Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996. In Hungary only one kind of folic acid tablet, containing 3 mg/tablet was available during the study period. Hungarian obstetricians recommended daily use of 1–3 tablets, that is, 3–9 mg of folic acid during pregnancy; the estimated daily dose was 5.7 or 5.6 mg in the mothers of cases with IH and controls, respectively. Of 3,038 mothers of cases 1,474 (48.5%) were supplemented with high doses of folic acid during pregnancy and 13,509/24,814 mothers of controls (54.9%) as reference were supplemented at this level as well (OR 95% CI: 0.79, 0.73–0.85). If only medically recorded folic acid use in the critical period of IH was evaluated, the preventive effect was more apparent (OR 95% CI: 0.36, 0.32–0.41). The intake of folic acid among mothers of infants with severe IH was lower than among mothers of infants with mild IH, suggesting a dose–response relationship. In conclusion, this study suggests that high doses of folic acid are associated with a reduced risk of IH. However, this analysis was based on observational data; therefore, confirmation in a well-controlled study is needed. © 2014 Wiley Periodicals, Inc.

Objective. To evaluate the effect of hydroxyethylrutoside (HER) for fetal development because this flavonoid derivate drug is frequently used in pregnant women for the treatment of vascular diseases. Method. Comparative analysis of exposure (HER treatment) during pregnancy in the newborn infants without any defects born to mothers with or without HER treatment in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. Main outcomes measures were gestational age at delivery, birth weight, pre- and post-term birth, low and large birth weight. Results: Of 38,151 newborn infants, 1,143 (3.0%) were born to mothers with oral HER treatment. The mean birth weight of newborn infants born to mothers with HER was 115 grams larger and is associated with a lower rate of low birth weight and a higher rate of large birth weight. Conclusions. Oral HER treatment during pregnancy associates with a fetal growth promotion effect.

The objective of the study was to evaluate the possible association of maternal factors with the risk of isolated true undescended testis (ITUT) diagnosed at the third postnatal month because our knowledge is limited regarding the origin of ITUT. Acute and chronic diseases with related drug treatments were compared in the mothers of 2052 cases with ITUT, 24 814 male controls without any defects and 12 082 malformed male controls with other isolated defects in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980–1996. Prospective medically recorded endometriosis before conception of the study pregnancy in the mothers of 39 cases was associated with a higher risk of ITUT in their sons (odds ratio (OR) with 95% confidence interval [CI]: 2.42, 1.71–3.42). Dihydrogesterone treatment in the first trimester of pregnancy also showed association with the higher risk of ITUT but based on only five pregnant women. In conclusion, endometriosis before pregnancy may have a role in the origin of ITUT.

The evaluation of pregnancy complications of mothers who delivered boys with isolated hypospadias (IHS) to estimate their roles in the higher rate of low birthweight and preterm birth in cases with IHS.The incidence of prospectively and medically recorded pregnancy complications in the prenatal maternity logbook was compared in the mothers of 3038 cases with IHS and their 4981 matched controls, in addition, 24 814 population male controls without any defects in the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996.The well-known higher rate of preterm birth and mainly of low birthweight was confirmed in cases with IHS. The incidence of preeclampsia/eclampsia (OR with 95% CI: 1.92, 1.62-2.27) and gestational diabetes (1.94, 1.34-2.81) was higher, while severe nausea and vomiting in pregnancy (0.77, 0.66-0.88) showed a lower incidence in the mothers of cases.The higher rate of preeclampsia/eclampsia may have a role in the intrauterine growth restriction of fetuses affected with IHS while the lower rate of nausea and vomiting in pregnancy may associate with the higher risk of preterm birth.

The aim of this study was to evaluate the birth outcomes of cases with four types of conotruncal defects (CTDs), i.e. common truncus, transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle.Birth outcomes of 597 live-born cases with CTD and 38,151 population controls without any defects were compared in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities completed by socio-demographic variables of their mothers.There was a male excess in cases with CTD (56.8%) with the same mean gestational age (39.4 versus 39.4 weeks) and preterm birth rate (8.2 versus 9.2%), but their mean birth weight was smaller (3077 versus 3276 g) with a high rate of low birthweight (14.6 versus 5.7%) compared to the birth outcomes of population controls. These data indicate intrauterine growth restriction of fetuses affected with transposition of great arteries, tetralogy of Fallot and double-outlet right ventricle particularly in females, while there were a shorter mean gestational age and smaller mean birth weigh in cases with common truncus.In general CTD, except common truncus, had no effect for gestational age but associated with a high risk for intrauterine fetal growth restriction particularly in female cases.

The aim of this study was to assess the risk factors in the origin of lethal or surgically corrected isolated atrial septal defect secundum. The population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (conducted between 1980 and 1996) comprised 472 atrial septal defect secundum cases, 678 matched controls and 38,151 available controls without any defects; in addition, 21,022 malformed controls with other isolated defects. Medically recorded chronic disorders in the prenatal maternity logbook were evaluated, while acute maternal diseases, drug treatments and pregnancy supplements were analyzed on the basis of both prospective medically recorded data and retrospective maternal information. Acute pelvic inflammatory disease, paroxysmal supraventricular tachycardia and phenolphthalein treatment due to severe constipation of mothers were shown to contribute to the development of atrial septal defect secundum of their children. High doses of folic acid in early pregnancy had positively influenced a minor part of isolated atrial septal defect secundum in foetuses. In conclusion, the obvious genetic predisposition for atrial septal defect secundum is connected with maternal paroxysmal supraventricular tachycardia and triggered by acute pelvic inflammatory diseases and phenolphthalein treatment, while the manifestation of atrial septal defect secundum can be reduced by high doses of folic acid supplementation in early pregnancy.

Hydroxyethylrutoside (HER), a flavonoid derivate drug, used frequently in pregnant women for the treatment of vascular diseases. The aim of this case-control study was to evaluate the teratogenic potential of oral HER treatment in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities.Comparative analysis of exposure (HER treatment) during pregnancy in the mothers of cases with congenital abnormalities and matched control newborns without any defect in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities.Of the 22,843 cases with congenital abnormalities, 567 (2.5%) had mothers with HER treatment while of 38,151 matched controls, 1143 (3.0%) were born to mothers with HER treatment (OR with 95% CI: 0.8, 0.7-0.9). However, an association of HER treatment during the second and/or third month of pregnancy was found with the higher risk of unilateral ocular coloboma (OR with 95% CI: 5.4, 2.2-12.9) and a new congenital abnormality syndrome including anotia/microtia, poly/syndactyly and caudal (genital and anal) defects (OR with 95% CI: 3.0, 1.3-27.4).Oral HER treatment during early pregnancy associates with a higher risk for ocular coloboma and for a newly delineated congenital abnormality syndrome.

Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin’s statement: “An ounce of prevention is better than a pound of care”.

The aim of our project was to study possible etiological factors in the origin of congenital heart defects (CHDs) because in the majority of patients the underlying causes are unclear. Cases with different CHD entities as homogeneously as possible were planned for evaluation in the population-based large data set of the Hungarian Case Control Surveillance of Congenital Abnormalities. Dead or surgically corrected 302 live-born cases with different types of left-ventricular outflow tract obstructive defects (LVOT, i.e., valvular aortic stenosis 76, hypoplastic left heart syndrome 76, coarctation of the aorta 113, and other congenital anomalies of aorta 32) were compared with 469 matched controls, 38,151 controls without any defects, and 20,750 malformed controls with other isolated defects. Medically recorded pregnancy complications and chronic diseases were evaluated based on prenatal maternity logbooks, whereas acute diseases, drug treatments, and folic acid/multivitamin supplementation were analyzed both on the basis of retrospective maternal information and medical records. The results of the study showed the role of maternal diabetes in the origin of LVOT in general, while panic disorder was associated with a higher risk of hypoplastic left heart syndrome and ampicillin treatment with a higher risk of coarctation of the aorta (COA). High doses of folic acid had a protective effect regarding the manifestation of LVOT, particularly COA. In conclusion, only a minor portion of causes was shown in our study; thus, further studies are needed to understand better the underlying causal factors in the origin of LVOT.