The demise of preimplantation genetic testing for aneuploidy (PGT-A) in Hungary and its effect on patient care.

Preimplantation genetic testing for aneuploidy (PGT-A) is a suitable technique to identify euploid embryos, which have the highest potential to implant, thus increase the chance of a healthy live birth. The main indications of PGT-A are advanced maternal age, repeated implantation failure, repeated miscarriages and severe male infertility. Several studies have already proven that testing embryos for genetic abnormalities in the above cases results in higher implantation rate and reduced number of pregnancy loss. In spite of these - due to a legislative change in Hungary in 2015 - PGT-A was reclassified as an experimental procedure and its use became banned throughout the country. For this reason, after 4 years of successful practice, Hungarian patients were not able to participate in IVF procedure combined with PGT-A anymore. In this retrospective analysis, efficacy of PGT-A-based embryo selection was evaluated and was compared to the conventional morphology-based selection (MBS) in patients with advanced maternal age, between 2013 and 2017 at our private fertility clinic. PGT-A was performed with array comparative genomic hybridization. We found that implantation rate was significantly higher (43.62% vs. 27.88%; p = 0.0208) and miscarriage rate was significantly lower (17.07% vs. 37.93%; p = 0.0492) in the PGT-A group compared to the MBS group from 2013 to 2015. These outcomes were achieved with a significantly lower number of transferred embryos in the PGT-A group (1.25 vs. 1.58; p = 0.0003). In 2016-2017, the number of transferred embryos were significantly reduced in the MBS group as well (1.14 vs. 1.58; p < 0.0001). However, outcomes of the IVF treatments did not change significantly compared to the previous two years (2013-2015). Our results imply that PGT-A-based embryo selection is more efficient than morphology-based selection in patients with advanced maternal age. Therefore, prohibition of the use of PGT-A had significant consequences on the efficiency and safety of IVF treatment in the country.

[Unaffected child born following preimplantation genetic diagnosis with karyomapping]. / Egészséges gyermek születése karyomapping eljárással történo preimplantációs genetikai diagnózist követoen.

Preimplantation genetic diagnosis for single gene defects is a well established method in assisted reproductive technologies. Karyomapping is a genome wide parental haplotyping using a high density single nucleotide polymorphism array that allows the diagnosis of any single gene defects. A couple with an affected child with primary congenital glaucoma attended at our clinic. Six oocyte-cumulus-complex was retrieved and all three mature oocytes were inseminated. One zygote showed the signs of normal fertilization and was cultured for five days. Trophectoderm biopsy and karyomapping analysis were carried out. Result showed a heterozygous carrier for primary congenital glaucoma. Embryo was thawed and transferred and a healthy girl was delivered at term. Here we report the first live birth following in vitro fertilization combined with preimplantation genetic diagnosis using karyomapping in Hungary. Karyomapping is able to accurately detect single gene disorders from a limited amount of samples without a significant preclinical workup. Orv. Hetil., 2016, 157(51), 2048-2050.

Folic acid in pregnant women associated with reduced prevalence of severe congenital heart defects in their children: a national population-based case-control study.

OBJECTIVE: Previous Hungarian intervention trials have shown an association between periconceptional folic-acid-containing multivitamin supplementation and significantly reduced risk of congenital heart defects (CHDs). These findings were confirmed in observational multivitamin studies in the USA, and studies in the Netherlands and China regarding folic acid. The objective of this observational population-based study was to estimate the possible preventive effect of folic acid supplementation for different CHDs during their critical period of development. STUDY DESIGN: Evaluation of medically recorded use of folic acid (calculated daily average 5.6mg) during the critical period of development of eight types of CHD (verified through autopsy reports or after catheter examination and/or surgical correction) in the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996, containing 22,843 cases with congenital abnormalities and 38,151 population controls without any CHDs, including 5395 matched controls of 3567 live-born cases with various CHDs. A conditional logistic regression model was used to estimate the relative risk/protection [odds ratio (OR) with 95% confidence intervals (CI)] of folic acid in the mothers of cases with various types of CHD and their matched controls. RESULTS: There was a significant decrease in the prevalence of cases with ventricular septal defect (OR 0.57, 95% CI 0.45-0.73), tetralogy of Fallot (OR 0.53, 95% CI 0.17-0.94), d-transposition of great arteries (OR 0.47, 95% CI 0.26-0.86) and atrial septal defect secundum (OR 0.63, 95% CI 0.40-0.98) in infants born to mothers who had taken high doses of folic acid during the critical period of CHD development. CONCLUSIONS: The risk of development of certain types of CHD was significantly reduced in pregnant women who were supplemented with folic acid. Thus, CHDs should be included as a secondary assessment in neural-tube-defect preventive programs.

Higher risk of orofacial clefts in children born to mothers with angina pectoris: a population-based case-control study.

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.

Birth outcomes of cases with conotruncal defects of heart - a population-based case-control study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Risk and protective factors in the origin of atrial septal defect secundum--national population-based case-control study.

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.

Risk factors in the origin of congenital left-ventricular outflow-tract obstruction defects of the heart: a population-based case-control study.

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.

Maternal hypertension with nifedipine treatment associated with a higher risk for right-sided obstructive defects of the heart: a population-based case-control study.

OBJECTIVE: To establish possible aetiological factors contributing to congenital heart defects (CHD) overall and separately for different types of CHD, as causes are unknown for the vast majority of patients. DESIGN: To estimate a possible association with maternal diseases and related drug treatments as exposures in the mothers of cases with right-sided obstructive defects of the heart (RSODH). SETTING: A large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities data set. PATIENTS: Newborn infants with four types of RSODH based on autopsy or surgical records. INTERVENTIONS: Comparison of 200 live-born cases with RSODH including 72 (36.0%) with pulmonary valve stenosis, 13 (6.5%) with tricuspid atresia/stenosis, 7 (3.5%) with Ebstein's anomaly and 108 (54.0%) with pulmonary atresia, with 304 matched controls and 38 151 population controls without any defects. MAIN OUTCOME MEASURES: Risk of any RSODH and risk of each type of RSODH. RESULTS: High blood pressure, particularly chronic hypertension with nifedipine treatment, was associated with a risk for RSODH (OR 7.03, 95% CI 3.13 to 13.84). High doses of folic acid reduced the birth prevalence of pulmonary atresia (OR 0.29, 95% CI 0.16 to 0.53). CONCLUSIONS: The multifactorial threshold model provides the best explanation for the origins of RSODH. Genetic predisposition may be triggered by maternal hypertension with nifedipine treatment, while the risk for pulmonary atresia is reduced by high doses of folic acid in early pregnancy.

Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects.

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".

Risk and protective factors in the origin of conotruncal defects of heart--a population-based case-control study.

Congenital heart defect (CHD) cases have been evaluated together as a group in some previous epidemiological studies. However, different CHD entities have different etiologies, and the underlying causes are unclear in the vast majority of patients. Thus the aim of this study was to analyze the possible association of different maternal diseases with the risk of four types of conotruncal defects (CTD), that is, truncus arteriosus, d-transposition of the great arteries, tetralogy of Fallot, and double-outlet right ventricle based on autopsy or surgical report diagnosis. Acute and chronic diseases with related drug treatments and peri-conceptual folic acid or multivitamin supplementations were compared in mothers of 598 CTD cases, of 902 matched controls, and 38,151 population controls without any defects, and with 20,896 malformed controls with other isolated non-cardiac defects in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities. Mothers who had medically recorded influenza and the common cold with secondary complications in the prenatal maternity logbook during the second and/or third gestational months were associated with a higher risk of CTD (OR with 95% CI: 2.22, 1.19-3.88). The common denominator of these maternal diseases may be high fever, which could be prevented by antifever therapies. On the other hand, high doses of medically recorded folic acid in early pregnancy were able to reduce the birth prevalence of CTD (OR with 95% CI: 0.54, 0.39-0.73), and this reduction was significant in transposition of the great arteries (0.46, 0.29-0.71) as well. In conclusion, high fever related maternal diseases may have a role in the origin of CTD, while high doses of folic acid in early pregnancy were able to reduce of CTD, particularly transposition of great vessels.

Isolated atrioventricular canal defects: birth outcomes and risk factors: a population-based Hungarian case-control study, 1980-1996.

BACKGROUND: The role of possible environmental factors in the origin of congenital heart defects is unclear in the vast majority of patients. The objective of this study was to describe the birth outcomes and risk factors in isolated atrioventricular canal defect (AVCD) cases. METHODS: Medically recorded birth outcomes, maternal age, parity, acute and chronic maternal diseases with related drug treatments and folic acid/multivitamin supplementation were evaluated in isolated AVCD cases. The diagnosis of AVCD was based on the autopsy report or surgical description in the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, between 1980 and 1996. RESULTS: The birth outcomes and exposures of 77 isolated AVCD cases were compared with 38,151 controls without defect. Mean gestational age at delivery (38.6 week) and birth weight (2992 g), rate of preterm birth (20.8%) and low birthweight (23.4%) of cases with a female excess (59.7%) differed significantly from the controls. Mothers of cases had higher parity, higher prevalence of conduction disorders/cardiac dysrhythmias and chronic hypertension. The high doses of folic acid in early pregnancy associated with a reduced rate of AVCD. CONCLUSIONS: Conduction disorders/cardiac dysrhythmias and chronic hypertension of mothers may have a role in the origin of AVCD, while high doses of folic acid in early pregnancy may reduce the risk of the development of AVCD. Birth Defects Research (Part A) 97:217-224, 2013. © 2013 Wiley Periodicals, Inc.

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.

Vitamin D and pre-eclampsia: original data, systematic review and meta-analysis.

BACKGROUND/AIMS: Vitamin D may protect from pre-eclampsia through influences on immune modulation and vascular function. To evaluate the role of vitamin D in the development of pre-eclampsia, we conducted a systematic review and meta-analysis including novel data from 2 large-scale epidemiological studies. METHODS: PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for prospective observational studies of association between vitamin D supplementation or status (measured by maternal 25-hydroxyvitamin D, 25(OH)D) with a subsequent risk of pre-eclampsia, or randomised controlled trials using vitamin D supplementation to prevent pre-eclampsia. The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) and the Avon Longitudinal Study of Parents and Children (ALSPAC) were included in meta-analyses with published studies. RESULTS: Mothers receiving vitamin D supplementation earlier in pregnancy had lower odds of pre-eclampsia [pooled odds ratios (OR) 0.81 and 95% confidence interval (CI) 0.75-0.87, p = 2.4 × 10(-8), 2 studies] in the meta-analysis of published studies with HCCSCA. The meta-analysis of published studies with ALSPAC suggested an association between higher serum 25(OH)D levels and a reduced risk of pre-eclampsia (pooled OR 0.52 and 95% CI 0.30-0.89, p = 0.02, 6 studies). Randomised trials of supplementation were suggestive of protective association (pooled OR 0.66 and 95% CI 0.52-0.83, p = 0.001, 4 studies). CONCLUSIONS: This study suggests that low maternal serum 25(OH)D concentrations increase pre-eclampsia risk and that vitamin D supplementation lowers this risk. The quality of evidence is insufficient to determine a causal association, which highlights the need for adequately powered clinical trials.

Birth outcomes of cases with isolated atrial septal defect type II--a population-based case-control study.

OBJECTIVES: In general, epidemiological studies have evaluated cases with congenital cardiovascular abnormalities together. The aim of this study is to describe the birth outcomes of cases with isolated/single atrial septal defect type II (ASD-II, i.e. only a fossa ovalis defect) after surgical correction or lethal outcome in the light of maternal sociodemographic data. DESIGN: Comparison of birth outcomes and maternal characteristics of cases with ASD-II and controls without defect. SETTING: The population-based Hungarian Case-Control Surveillance of Congenital Abnormalities. POPULATION: Hungarian newborn infants with or without ASD-II. METHODS: Medically recorded birth outcomes, maternal age and birth order were evaluated. Marital and employment status was based on maternal information. The lifestyle factors were analyzed in a subsample of mothers visited at home based on a personal interview with mothers and their close relatives, and the family consensus was accepted. MAIN OUTCOME MEASURES: Mean gestational age at delivery and birthweight, rate of preterm birth and low birthweight, maternal age, birth order, marital and employment status. RESULTS: The evaluation of 471 cases with ASD-II and 38,151 controls without any defects showed a female excess in cases with ASD-II, having shorter gestational age and lower mean birthweight, and thus a higher rate of preterm births and low birthweight. CONCLUSIONS: Intrauterine growth restriction and shorter gestational age were found in cases with ASD-II, particularly in female children. These factors may have a general developmental process in which there was not closure of the foramen ovale, thus echocardiographic screening of these babies might be of value.

Association of maternal diseases during pregnancy with the risk of single ventricular septal defects in the offspring--a population-based case-control study.

OBJECTIVE: In general, the analytical epidemiological studies evaluated cases with congenital heart defects (CHDs) together. However, different CHD entities have different etiology, and in the vast majority of patients the underlying causes are unclear. Thus the objective of the study was to evaluate the possible etiological factors in the origin of single ventricular septal defect (VSD) after surgical intervention or lethal outcome, i.e. as homogeneous as possible. METHOD: In the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities acute and chronic maternal diseases with related drug treatments and pregnancy supplements in early pregnancy were evaluated in the mothers of 1661 cases with isolated/single VSD and their 2534 matched and 38,151 all controls without defect, and 19,833 malformed controls with other isolated non-cardiac defect. RESULTS: There was a higher risk of VSD in the children of mothers with high fever related influenza during the critical period of VSD and this risk was limited by antifever therapy. In addition paroxysmal supraventricular tachycardia and epilepsy treated with anticonvulsant drugs associated with higher risk of VSD. Finally, the high doses of folic acid alone in early pregnancy. CONCLUSIONS: High-fever-related maternal diseases may have a role in the origin of VSD which is preventable with antifever drug therapy, and the high doses of folic acid in early pregnancy reduced the risk of VSD.

Birth outcomes of cases with left-sided obstructive defects of the heart in the function of maternal socio-demographic factors: a population-based case-control study.

OBJECTIVE: To evaluate the birth outcomes and maternal variables of cases with different types of left-sided obstructive defects (LSOD) of the heart. METHODS: Live-born infants were selected from the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, and 302 cases with LSOD, 469 matched controls and 38,151 all controls without any defect, and 20,750 malformed controls with other isolated defects were compared. The diagnosis of LSOD was based on autopsy report or the documents of surgical intervention. RESULTS: Four types of LSOD were differentiated: 56 cases with valvular aortic stenosis (VAS), 76 cases with hypoplastic left heart syndrome (HLHS), 113 cases with coarctation of the aorta (COA) and 57 cases with other congenital abnormalities of aorta (OCA). Cases with LSOD had male excess (64.6%) with a higher rate of preterm birth (14.2 vs. 6.6%) and low birthweight (15.6 vs. 4.3%) compared to matched controls. The high rate of preterm birth was particularly characteristic for HLHS (17.1%) while intrauterine fetal growth restriction was found in cases OCA (22.8%) and COA (13.3%). The mothers of cases with LSOD had higher birth order and lower socio-economic status than controls without any defect. CONCLUSIONS: The general pattern of birth outcomes and maternal variables were similar in the types of LSOD cases, but the higher rate of preterm birth and low birthweight indicated some association with their adverse fetal development.