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1.  Interpretation of Controversial Teratogenic Findings of Drugs Such As Phenobarbital 
ISRN Obstetrics and Gynecology  2011;2011:719675.
Objective. To check the debated association between phenobarbital treatment during pregnancy and risk for congenital abnormalities (CAs) in their children. Study Design. It is a comparison of phenobarbital treatment in the mothers of cases with CA and matched controls without CAs in the Hungarian Case-Control Surveillance System of Congenital Abnormalities. Results. Of 22,843 cases with CA, 149 (0.65%) had mothers with phenobarbital treatment, while of 38,151 control newborn infants without CA, 209 (0.55%) were born to mothers with phenobarbital treatment (100–400 mg daily) (OR with 95% CI : 1.3, 1.1–1.7). Of 16 CA groups, only hypospadias had a higher risk after phenobarbital treatment in the critical period of this CA (OR with 95% CI : 2.4, 1.1–5.4). However, if only medically recorded phenobarbital treatments were evaluated and multiple testing bias was considered, this association would disappear. Conclusions. This study stresses the importance of the exclusion of recall bias and multiple testing bias.
PMCID: PMC3166760  PMID: 21904684
2.  A study of the risk of mental retardation among children of pregnant women who have attempted suicide by means of a drug overdose 
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.
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.
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.
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.
PMCID: PMC3291287  PMID: 21502792
3.  Attempted suicide and pregnancy 
The aim of the Budapest Monitoring System of Self-Poisoning Pregnant Women was to evaluate the potential congenital abnormality inducing effect of extremely large doses of drugs among pregnant women who attempted suicide. This system was appropriate to describe the characteristics of these pregnant women as a secondary finding from this model.
All self-poisoned patients were cared for at a toxicological inpatient clinic in Budapest, between 1960 and 1993. Of a total of 1,044 pregnant women identified from the three different periods of the project, only 19 (1.8%) died. Women who survived were visited at home to reveal birth outcomes, and their exposed children were examined medically to identify congenital abnormalities and tested to estimate their cognitive-behavioral status. The previous or subsequent children of these pregnant women were used as controls with a similar examination protocol.
In general, self-poisoned pregnant women were young (peak age was between 18 and 20 years), 62% had their first pregnancy, 55% were unmarried, they had lower socioeconomic status, 46% were smokers and 22.5% drinkers, but depression/panic disorder occurred only among 17 pregnant women. Suicide attempts with drugs were most frequent in the fourth post-conceptional week and second month of pregnancy. In general they used smaller doses of drugs for suicide than non-pregnant age-matched women. Of 1,044 self-poisoned pregnant women, 926 had known pregnancy outcomes and 411 (44.4%) delivered live-born babies.
The self-poisoning model appears to have several benefits (e.g., dose-response estimation of drugs) in comparison with other methods when evaluating teratogenic/fetotoxic effect of drugs. It is suggested that an international monitoring system of self-poisoned pregnant women should be established to provide a larger data base.
PMCID: PMC3134915  PMID: 21483214
4.  Birth Outcomes of Newborns after Folic Acid Supplementation in Pregnant Women with Early and Late Pre-Eclampsia: A Population-Based Study 
Objective. To evaluate the rate of preterm birth and low birth weight in the newborns of pregnant women with early and late onset pre-eclampsia according to folic acid supplementation. Study design. Birth outcomes of newborns were evaluated in 1,017 (2.7%) pregnant women with medically recorded pre-eclampsia and 37,134 pregnant women without pre-eclampsia as reference in the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980–1996, in addition these study groups were differentiated according to the supplementation of high dose of folic acid alone from early pregnancy. Results. Pregnant women with pre-eclampsia associated with a higher rate of preterm birth (10.2% versus 9.1%) and low birthweight (7.9% versus 5.6%). There was a lower risk of preterm birth (6.8%) of newborn infants born to pregnant women with early onset pre-eclampsia after folic acid supplementation from early pregnancy though the rate of low birthweight was not reduced significantly. There was no significant reduction in the rate of preterm birth and low birthweight in pregnant women with late onset pre-eclampsia after folic acid supplementation. Conclusion. The rate of preterm birth in pregnant women with early onset pre-eclampsia was reduced moderately by high doses of folic acid supplementation from early pregnancy.
PMCID: PMC3168906  PMID: 21991429
5.  Sex ratio of newborn infants born to pregnant women with severe chronic constipation 
Clinical Epidemiology  2010;2:217-219.
There was a significant male excess in the newborns of pregnant women with severe chronic constipation during pregnancy compared to pregnant women without constipation and pregnant women with new onset severe constipation, during pregnancy.
PMCID: PMC2964076  PMID: 21042554
constipation; pregnancy; birth outcomes; sex ratio; male excess
6.  Folate Deficiency and Folic Acid Supplementation: The Prevention of Neural-Tube Defects and Congenital Heart Defects 
Nutrients  2013;5(11):4760-4775.
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”.
PMCID: PMC3847759  PMID: 24284617
neural-tube defects; congenital heart defects; folic acid; multivitamins; primary prevention
7.  Evaluation of maternal infusion therapy during pregnancy for fetal development 
The aim of this project was to study the possible association between maternal infusion treatments during pregnancy and variables of fetal development as well as the occurrence of congenital abnormalities (CA) in a case-control design. The large population-based data set of the Hungarian Case‑Control Surveillance of Congenital Abnormalities (HCCSCA) was evaluated based on the medically recorded infusion treatment during pregnancy. Of 22,843 case pregnant women who had newborns or fetuses with congenital abnormalities, 112 (0.5%), while of 38,151 control pregnant women who had newborn infants without any defects, 262 (0.7%), had infusion treatment during pregnancy. Infusion treatment was more frequent in the control group than in the case group with congenital abnormalities (adjusted POR with 945 95% CI: 0.7, 0.6-0.9) and there was no higher rate of maternal infusion treatments in any congenital abnormality group. Mean gestational age was shorter and mean birth weight was smaller in control newborn infants without CA born to mothers with infusion treatment during pregnancy than in the babies of mothers without infusion treatment. The prevalence of mild intrauterine growth retardation was more frequent in the fetuses of pregnant women with hyperemesis gravidarum treated with infusion. The results of the study suggest that infusion treatment of pregnant women did not associate with a higher risk of congenital abnormalities. In addition, the intravenous infusion of drugs has some, but limited efficacy to prevent the adverse effects of hyperemesis gravidarum and threatened preterm delivery.
PMCID: PMC1252725  PMID: 16239951
Infusion treatment; underlying pregnancy complications; congenital abnormalities; preterm birth; intrauterine growth retardation.
8.  Risk and Benefit of Drug Use During Pregnancy 
Environmental teratogenic factors (e.g. alcohol) are preventable. We focus our analysis on human teratogenic drugs which are not used frequently during pregnancy. The previous human teratogenic studies had serious methodological problems, e.g. the first trimester concept is outdated because environmental teratogens cannot induce congenital abnormalities in the first month of gestation. In addition, teratogens usually cause specific congenital abnormalities or syndromes. Finally, the importance of chemical structures, administrative routes and reasons for treatment at the evaluation of medicinal products was not considered. On the other hand, in the so-called case-control epidemiological studies in general recall bias was not limited. These biases explain that the teratogenic risk of drugs is exaggerated, while the benefit of medicine use during pregnancy is underestimated. Thus, a better balance is needed between the risk and benefit of drug treatments during pregnancy. Of course, we have to do our best to reduce the risk of teratogenic drugs as much as possible, however, it is worth stressing the preventive effect of drugs for maternal diseases (e.g. diabetes mellitus and hyperthermia) related congenital abnormalities.
PMCID: PMC1168874  PMID: 16007261
human teratogenic drugs; congenital abnormalities; critical period; recall bias; congenital abnormality; preventive effect of drugs.
10.  The primary prevention of birth defects: Multivitamins or folic acid? 
Periconceptional use of folic acid alone or in multivitamin supplements is effective for the primary prevention of neural-tube defects. The Hungarian randomized and two-cohort controlled trials showed that periconceptional multivitamin supplementation can reduce the occurrence of some other structural birth defects, i.e. congenital abnormalities. These findings were supported by many, but not all observational studies. Recently there have been two main debated questions. The first one is whether the use of folic acid alone or folic acid-containing multivitamins is better. The second one is connected with the dilemma of whether high dose of folic acid (e.g. 5 mg) might be better than a daily multivitamin with 0.4 – 0.8 mg of folic acid. Comparison of the pooled data of two Hungarian trials using a multivitamin containing 0.8 mg folic acid and the data of the Hungarian Case-Control Surveillance of Congenital Abnormalities using high dose of folic acid seemed to be appropriate to answer these questions. Multivitamins containing 0.4 – 0.8 mg of folic acid were more effective for the reduction of neural-tube defects than high dose of folic acid. Both multivitamins and folic acid can prevent some part of congenital cardiovascular malformations. Only multivitamins were able to reduce the prevalence at birth of obstructive defects of urinary tract, limb deficiencies and congenital pyloric stenosis. However, folic acid was effective in preventing some part of rectal/anal stenosis/atresia, and high dose of folic acid had effect in preventing some orofacial clefts. The findings are consistent that periconceptional multivitamin and folic acid supplementation reduce the overall occurrence of congenital abnormalities in addition to the demonstrated effect on neural-tube defects.
PMCID: PMC1074510  PMID: 15912190
Folic acid; multivitamins; prevention; neural-tube defects; other congenital abnormalities
11.  The Participation of Prospective Fathers in Preconception Care 
We present the data of male participants in the Coordinating Center of the Hungarian Preconception Service (HPS), Budapest, 1984–2010. One of main objectives of the HPS was the incorporation of male partners of female participants into the preparation of childbirth. The HPS is based on three steps: (I) Reproductive health check-up. (II) A 3-month preparation for conception with the major determinants of the development of new life such as sex, health and/or some diseases. Smoking and illicit drug use cessation and limitation of alcohol intake was suggested in the male participants (III) to achieve optimal conception and better protection of early pregnancy. Pregnant women usually visit prenatal care clinics between the 7th and 12th gestational week when it is too late to reduce the risk of congenital abnormalities. Male participation in HPS will help to enhance use of appropriate preconception methods at the appropriate time.
PMCID: PMC3888083  PMID: 24453513
preconception care; male participation; reproductive risk; genetic diseases of prospective fathers; paternal age; sperm examination
13.  Primary prevention of neural-tube defects and some other congenital abnormalities by folic acid and multivitamins: history, missed opportunity and tasks 
The history of intervention trials of periconception folic acid with multivitamin and folic acid supplementation in women has shown a recent breakthrough in the primary prevention of structural birth defects, namely neural-tube defects and some other congenital abnormalities. Recently, some studies have demonstrated the efficacy of this new method in reducing congenital abnormalities with specific origin; for example, in the offspring of diabetic and epileptic mothers, and in pregnancy with high fever. The benefits and drawbacks of four possible uses of periconception folate/folic acid and multivitamin supplementation are discussed: we believe there has been a missed opportunity to implement this preventive approach in medical practice. The four methods are as follows: (i) dietary intake of folate and other vitamins, (ii) periconception folic acid/multivitamin supplementation, (iii) food fortification with folic acid, and (iv) the combination of oral contraceptives with 6S-5-methytetrahydrofolate (‘folate’).
PMCID: PMC4110861  PMID: 25083211
cardiovascular malformations; contraception; folic acid; multivitamins; neural-tube defects; prevention
To assess association between nonsyndromic (NS) cleft lip with or without cleft palate (CL(P)) and SNPs within the CRISPLD2 gene (cysteine-rich secretory protein LCCL domain containing 2).
Four SNPs within the CRISPLD2 gene domain (rs1546124, rs8061351, rs2326398, rs4783099) were genotyped to test for association via family-based association methods.
5,826 individuals from 1,331 families in which one or more family member is affected with CL(P).
Evidence of association was seen for SNP rs1546124 in USA (p=0.02) and Brazilian (p=0.04) Caucasian cohorts. We also found association of SNP rs1546124 with cleft palate alone (CP) in South Americans (Guatemala and ECLAMC) and combined Hispanics (Guatemala, ECLAMC and Texas Hispanics) (p=0.03 for both comparisons), and with both cleft lip with cleft palate (CLP; p=0.04) and CL(P) (p=0.02) in North Americans. Strong evidence of association was found for SNP rs2326398 with CP in Asian populations (p=0.003) and with CL(P) in Hispanics (p=0.03), and also with bilateral CL(P) in the Brazilians (p=0.004). In the Brazilians, SNP rs8061351 showed association with cleft subgroups incomplete CL(P) (p=0.004), and unilateral incomplete CL(P) (p=0.003). Prediction of SNP functionality revealed that the C allele in the C471T silent mutation (overrepresented in cases with CL(P) presents two putative exonic splicing enhancer motifs and creates a binding site AP-2 alpha, a transcription factor involved in craniofacial development.
Our results support the hypothesis that variants in the CRISPLD2 gene may be involved in the etiology of NS CL(P).
PMCID: PMC3000893  PMID: 20815724
CRISPLD2 gene; cleft lip; cleft palate; subphenotypes
15.  No association of maternal vitamin E intake with higher risk of cardiovascular malformations in children: a population-based case–control study 
In Hungary, vitamin E is frequently used to prevent repeated or threatened abortion. A previous study showed a higher risk of cardiovascular malformations in the children of pregnant women who had a high vitamin E intake either in their diet or by taking supplements. The objective was to examine this association.
The Hungarian Case–Control Surveillance System of Congenital Abnormalities, 1980–1996, is a large, population-based dataset including 22,843 cases with congenital abnormalities, 38,151 healthy controls matched to the cases, and 834 patient controls with Down syndrome. Vitamin E treatment was compared in the mothers of these children.
The mothers of 1418 cases with congenital abnormalities (6.2%), 2267 controls (6.0%) and 43 patient controls (5.2%) had vitamin E treatment during pregnancy. A preliminary comparison of cases and controls showed a higher risk for four congenital abnormality groups, including cardiovascular malformations. However, if only prospectively and medically recorded vitamin E treatments in the prenatal maternity logbook were evaluated during the critical period of different congenital abnormalities, the higher risk for these congenital abnormalities was not found.
The results of this study were based on relatively high-dose vitamin E intake in pregnant women and were not able to confirm the previously reported teratogenic effect of vitamin E.
PMCID: PMC4110813  PMID: 25083203
cardiovascular malformations; congenital abnormalities; population-based case–control study; pregnancy; vitamin E
16.  Whorl Patterns on the Lower Lip are Associated with Nonsyndromic Cleft Lip with or without Cleft Palate 
Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect due to both genetic and environmental factors. Whorl lip print patterns are circular grooves on the central upper lip and/or the left and right lower lip. To determine if whorls are more common in families with CL/P than in controls, the Pittsburgh Orofacial Cleft Study collected lip prints from over 450 subjects, i.e., individuals with CL/P, their relatives, and unrelated controls—from the U.S., Argentina, and Hungary. Using a narrow definition of lower-lip whorl, the frequency of whorls in the U.S sample was significantly elevated in cleft individuals and their family members, compared to unrelated controls (14.8% and 13.2% versus 2.3%; P = 0.003 and 0.001, respectively). Whorls were more frequent in CL/P families from Argentina than in CL/P families from the U.S. or Hungary. If these results are confirmed, whorl lip print patterns could be part of an expanded phenotypic spectrum of nonsyndromic CL/P. As such, they may eventually be useful in a clinical setting, allowing recurrence risk calculations to incorporate individual phenotypic information in addition to family history data.
PMCID: PMC2787912  PMID: 19921634
lip prints; lip whorls; cheiloscopy; cleft lip; cleft palate
17.  A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4 
Nature genetics  2010;42(6):525-529.
Case-parent trios were used in a genome wide association study of cleft lip with/without cleft palate (CL/P). SNPs near two genes not previously associated with CL/P [MAFB: most significant SNP rs13041247, with odds ratio per minor allele OR=0.704; 95%CI=0.635,0.778; p=2.05*10−11; and ABCA4: most significant SNP rs560426, with OR=1.432; 95%CI=1.292,1.587; p=5.70*10−12] and two previously identified regions (chr. 8q24 and IRF6) attained genome wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes were similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24 while Asian families showed stronger evidence for MAFB and ABCA4. Expression studies support a role for MAFB in palate development.
PMCID: PMC2941216  PMID: 20436469
18.  Ergotamine treatment during pregnancy and a higher rate of low birthweight and preterm birth 
What is already known about this subjectPreviously the association between oral ergotamine treatment during pregnancy and gestational age, birthweight, the frequency of preterm birth and low birthweight has not been studied.Ergotamine is a drug that is not used frequently nowadays.What this study addsThe association between low birthweight and/or preterm birth and ergotamine treatment may be connected with ergotamine-induced vasoconstriction in the placenta of pregnant women.The pharmacological model used in this study could be used to evaluate the placental effects of other drugs.
Previously the association between oral ergotamine treatment during pregnancy and gestational age at delivery, birthweight, the rate of preterm birth and low birthweight has not been studied.
Newborn infants without congenital abnormalities born to mothers with or without ergotamine treatment during pregnancy were evaluated in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996.
Of 38 151 newborn infants with medically recorded gestational age and birth weight, 77 were born to mothers who had received ergotamine treatment during pregnancy. A statistically significant decrease was found in the mean gestational age (0.7 weeks) and birth weight (196 g) among exposed relative to unexposed infants, though these differences were not obstetrically significant. However, there was a significant increase in the proportion of low birthweight newborns (16.4% vs. 5.7%) and preterm births (16.4% vs. 9.2%) after the use of ergotamine during pregnancy. The effect of ergotamine was more obvious in male newborn infants, particularly after treatment in the third trimester.
The association between low birthweight and/or preterm birth and ergotamine treatment may be connected with the effect of ergotamine on the placenta of pregnant women.
PMCID: PMC2048564  PMID: 17506783
ergotamine; intrauterine growth retardation; low birth weight; pregnancy; preterm birth
19.  Oral clefts with associated anomalies: findings in the Hungarian Congenital Abnormality Registry 
BMC Oral Health  2005;5:4.
Over the years, great efforts have been made to record the frequency of orofacial clefts in different populations. However, very few studies were able to account for the etiological and phenotypic heterogeneity of these conditions. Thus, data of cases with syndromic orofacial clefts from large population-based studies are infrequent.
Clinically recognized and notified syndromes and associations including cleft lip with or without cleft palate and other congenital anomalies were selected from the Hungarian Congenital Abnormality Registry (HCAR) between 1973 and 1982 and prevalence rates were calculated.
Of 3,110 cases reported as having orofacial clefts, 653 had multiple congenital abnormalities. Of these, 60 (9.2%) had a known etiology (monogenic: 25 or 3.8%, chromosomal: 31 or 4.7%, teratogenic: 4 or 0.6%). Seventy-three subjects (11.2%) had schisis in addition to the oral cleft. Skeletal anomalies were the most common malformations among cases with cleft lip with/without cleft palate (CL/P) and cleft palate (CP). Disorders of the central nervous system and cardiovascular malformations were also frequently associated.
Surveillance systems, such as the HCAR, provide useful information about prevalence rates of congenital anomalies in a population. However, in a field where new syndromes are being discovered and classifications regularly updated, these rates should only be accepted as provisional.
PMCID: PMC1182377  PMID: 15985166
21.  Risk of malformations and other outcomes in children exposed to fluconazole in utero 
Fluconazole is an active drug systematically used in the oral treatment of vaginal candidiasis and other fungal diseases. We examined the risk of malformations and other birth outcomes following pregnancy related exposures.
From 1 January 1991 to 31 December 1996 we identified 165 women who had taken fluconazole just before or during pregnancy in the Pregnancy Outcome Section of the North Jutland Pharmacoepidemiological Prescription Database, Denmark, which is linked to the Danish Medical Birth Registry. We compared their birth outcomes (malformation, low birth weight and preterm delivery) with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies.
The prevalence of malformation was 3.3% (four cases) among the 121 women, who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (odds ratio: 0.65, 95% confidence limits: 0.24–1.77). Furthermore, we did not find any significantly elevated risk of preterm delivery (odds ratio: 1.17, 95% confidence limits: 0.63–2.17) and low birth weight (odds ratio: 1.19, 95% confidence limits: 0.37–3.79).
The study showed no increased risk of congenital malformations, low birth weight or preterm birth in offspring to women who had used single dose fluconazole before conception or during pregnancy.
PMCID: PMC2014300  PMID: 10417502
fluconazole; malformations; pregnancy; safety

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