Distribution of maternal age and birth order groups in cases with unclassified multiple congenital abnormalities according to the number of component abnormalities: a national population-based case-control study.

BACKGROUND: Multiple congenital abnormalities are caused by chromosomal aberrations, mutant major genes and teratogens. A minor proportion of these patients are identified as syndromes but the major part belonging to the group of unclassified multiple CAs (UMCAs). The main objective of this study was to evaluate the maternal age and birth order in pregnant women who had offspring affected with UMCA. The strong association between numerical chromosomal aberrations, e.g., Down syndrome and advanced maternal age is well-known and tested here. METHODS: The Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980 to 1996, yielded a large population-based national data set with 22,843 malformed newborns or fetuses ("informative cases") included 1349 UMCA cases with their 2407 matched controls. Case-control comparison of maternal age and birth order was made for cases with UMCA, stratified by component numbers and their controls. In addition, 834 cases with Down syndrome were compared to 1432 matched controls. RESULTS: The well-known advanced maternal age with the higher risk for Down syndrome was confirmed. The findings of the study suggest that the young age of mothers associates with the higher risk of UMCA, in addition birth order 4 or more associates with the higher risk for UMCA with 2 and 3 component CAs. CONCLUSION: This study was the first to analyze the possible maternal and birth order effect for cases with UMCA, and the young age and higher birth order associated with a higher risk for UMCA.

Assessment of the potential impacts of the Chernobyl nuclear disaster on maternal and fetal health in Hungary.

Objective: Radiation exposure is known to be mutagenic and teratogenic. The aim of this study was to analyze the effects of the increased ionizing radiation emitted by the Chernobyl nuclear disaster on maternal and fetal outcomes in Hungary.Methods: A retrospective analysis of abortion, stillbirth, and congenital anomaly data for pregnancies in Hungary between 1 January 1981 and 31 December 1991 was conducted.Results: Trend analysis revealed increasing trends in spontaneous and voluntary abortion rates in Hungary during the study time period, while late pregnancy losses showed a decreasing trend. Overall, there were generally decreasing incidence rates for birth defects throughout the 1980s. Increased voluntary abortions over the study period might reflect, at least in part, maternal anxiety in the post-Chernobyl years. Decreased late pregnancy loss over the same period may be attributable to improvements in prenatal diagnostics. A notable weakness of this study is that missing data could not be complemented due to the decades that have passed since the incident.Conclusions: In conclusion, the present data suggest that the nuclear catastrophe in 1986 did not cause a significant increase in pregnancy loss or congenital malformations in Hungary.

Radiation exposure in Hungary caused by the Chernobyl nuclear power plant disaster did not results in increases in fetal death or congenital anomaly rates.

[Psychological aspects of induced abortion]. / A muvi abortusz pszichológiai vonatkozásai.

The present paper, based on the results of international studies, is focused on the reconsideration of the psychological aspects of induced abortion. By presenting a narrow cross-section of the Hungarian demographic data, we would like to emphasise the necessity and the significance of a deeper understanding of the subject. Factors behind the decision-making, short- and long term outcomes of the intervention influencing primarily the mental health of women and partner-relationship aspects are discussed in details. While acknowledging the complexity of the subject deriving from the legal, ethical, moral, religious, medical, social and sociological concerns, our aim is to call attention to the psychological aspects of induced abortion and the importance of psychological care of women undergoing surgical operation.

Investigation of pituitary adenylate cyclase activating polypeptide (PACAP) in human amniotic fluid samples.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide acting as a hormone, a neuromodulator, a neurotransmitter, a trophic factor and is involved in a variety of developmental and regenerative processes. PACAP is present in several human tissues and biological fluids. In many pathological conditions, changes in PACAP levels have been described to reflect disease progression, therefore PACAP has diagnostic value as a potential biomarker. Since PACAP has been shown to play an important role in reproductive physiology and development, it was of interest to examine whether this neuropeptide occurs in the human amniotic fluid. Amniotic fluid samples were collected between the 15-19th weeks of gestation from volunteering pregnant women undergoing amniocentesis as a prenatal diagnostic tool due to maternal age. Pathological cases were excluded after prenatal karyotype analysis. PACAP-like immunoreactivity was measured by radioimmunoassay and could be detected in all samples. The present study provides evidence for the presence of PACAP in human amniotic fluid, but determination of the exact physiological or pathological significance awaits further investigation.

Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial.

BACKGROUND: Pregnant women usually meet their increased energy needs but do not always meet their increased micronutrient requirements. The supply of both folic acid and docosahexaenoic acid (DHA) has been related to positive pregnancy and infant outcomes. OBJECTIVE: We aimed to assess whether fish-oil (FO) supplementation with or without folate from gestation week 22 to birth improves maternal and fetal n-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) status. DESIGN: We conducted a multicenter (Germany, Hungary, and Spain), randomized, double-blind, 2 x 2 factorial, placebo-controlled trial. From gestation week 22 until delivery, 311 pregnant women received daily a preparation with FO [0.5 g DHA and 0.15 g eicosapentaenoic acid (EPA)], 400 microg methyltetrahydrofolic acid (MTHF), FO with MTHF, or placebo. Outcome measures included maternal and cord plasma DHA and EPA contents at gestation weeks 20 and 30 and at delivery, indicators of pregnancy outcome, and fetal development. RESULTS: FO significantly (P<0.001) increased maternal DHA and EPA (% by wt), as shown by 3-factor repeated-measures ANOVA (ie, MTHF, FO, and time) with adjustment for maternal baseline DHA and EPA. In addition, FO significantly (P<0.001) increased cord blood DHA (% by wt; 2-factor ANOVA). MTHF was significantly (P=0.046) associated with increased maternal DHA (% by wt). There was no FO x MTHF interaction for the time course of DHA or EPA (P=0.927 and 0.893). Pregnancy outcomes and fetal development did not differ significantly among the intervention groups. CONCLUSIONS: FO supplementation from gestation week 22 until delivery improves fetal n-3 LC-PUFA status and attenuates depletion of maternal stores. MTHF may further enhance maternal n-3 LC-PUFA proportions.

Unaltered development of the archi- and neocortex in prematurely born infants: genetic control dominates in proliferation, differentiation and maturation of cortical neurons.

The development of cerebral cortex includes highly organized, elaborate and long-lasting series of events, which do not come to an end by the time of birth. Indeed, many developmental events continue after the 40th postconceptual week resulting in a long morphological, behavioral and cognitive development of children. Premature birth causes an untimely dramatic change in the environment of the human fetus and often results in serious threats for life. Cognitive abilities of prematurely born children vary, but a correlation between cognitive impairment and the time of birth is evident. In this study we review the morphological evidence of cortical maturation in preterm and full-term infants. Various aspects of postnatal cortical development including cell proliferation and maturation of neurons in the temporal archi- and neocortex are discussed and compared in preterm infants and age-matched full-term controls. Our results suggest that cell proliferation and maturation are not influenced by the preterm delivery. In contrast, the perinatal decrease of the number of Cajal-Retzius cells might be regulated by a mechanism that is affected by preterm birth. We demonstrate that cognitive deficiencies of the prematurely born infants cannot be explained with light microscopically observed alteration of proliferation and maturation of neurons.

[Rapid diagnosis of fetal chromosomal abnormalities by fluorescence in situ hybridization]. / Magzati kromoszóma-rendellenességek gyors diagnosztizálása interfázis fluoreszcens in situ hibridizációval.

INTRODUCTION: In the course of the Down-screening protocol there are possibilities today for rapid diagnosis of aneuploidies among high-risk pregnancies identified by non-invasive screening tests, however, the diagnostic value of these molecular genetic tests are debated. AIM OF THE STUDY: In this prospective study, data about the reliability of one of the rapid tests, namely; interphase fluorescence in situ hybridization (int-FISH) was to be gathered by the authors. METHODS: For the period between May 2002 and September 2006 all of the 1279 fetal sample were examined both with int-FISH and full karyotyping. RESULTS: Extra or absent signal was detected in 47 cases (3.7%) (trisomy 21 in 32, various other numerical abnormalities in 15 cases). All of these numerical aberrations were confirmed by metaphase analysis without false positivity or negativity. In 19 cases the finding of int-FISH was negative, however, full karyotyping disclosed abnormalities (in 12 of these 19 cases, the abnormality was balanced). Only 4 of the 1279 fetuses (0.3%) (3 small extra marker chromosomes, 1 de novo unbalanced translocation) were to be found, who would have been born with phenotypical abnormalities without metaphase analysis (2 of them had suspect ultrasound signs). CONCLUSION: Although more analysis are needed, based on the results of this study it is to be concluded that rapid molecular genetic methods like int-FISH might be accepted as a diagnostic tests of fetal aneuploidy, if its use were restricted to high risk pregnancies identified by advanced maternal age and non-invasive maternal screening only. However, full karyotyping is needed in cases with familial translocation and abnormal 2nd trimester ultrasound signs.

[Hydrops fetalis--a retrospective study]. / Hydrops foetus universalis, visszatekinto tanulmány.

In a retrospective study, the authors examined the occurrence of hydrops in foetal and neonatal cases in a five-year period. During this time, the clinical and pathologic diagnosis of hydrops was established in 28 cases. In three cases, the hydrops was caused by Rh incompatibility, and in 25 cases non-immune hydrops was discovered by clinical and pathologic examination. The cause of hydrops was recognised in 25 cases and no underlying disease was discernible in three. In 12 cases, the pregnancy was spontaneously terminated. Artificial abortion was performed in four cases. In this series, four hydropic newborns died on the first week of their life. The average age in artificial abortion was 16-20 gestational week and 24 in spontaneous abortion or stillbirth. Pathologic examination revealed increased weight, oedema, ascites, and hydrothorax in all cases. In half of the cases, there was also hydropericardium. Hepatosplenomegaly, cardiomegaly, pulmonary hypoplasia, increased extramedullary hemopoiesis, and placenta oedema were seen in all the cases. Causes of the non-immune hydrops were cardiac malformation in 4 cases, chromosome anomaly in 3, cystic hygroma in 2, skeletal anomaly in 1, foeto-foetal transfusion in 3, infection in 7 and sacrococcygeal teratoma in 1 case. In two cases, the underlying disease was reported to be of maternal origin. Comparing the clinical and pathologic findings there were only three cases with absolute agreement. The underlying disease revealed by pathologic examination was regarded to be significant from respect of inheritance, therapeutic approach, and further management in 10 cases. The authors emphasise the importance of pathologic examinations in foetal hydrops and point out the significance of clinico-pathological collaboration in the decision about further management of hydropic foetuses.

Sex ratio of congenital abnormalities in the function of maternal age: a population-based study.

Maternal age effect is well-known in the origin of numerical chromosomal aberrations and some isolated congenital abnormalities (CAs). The sex ratio (SR), i.e. number of males divided by the number of males and females together, of most CAs deviates from the SR of newborn population (0.51). The objective of this analysis was to evaluate the possible association of maternal age with the SR of isolated CAs in a population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. First, SR of 24 CA entities/groups was estimated in 21,494 patients with isolated CA. In the next step SR of different maternal age groups was compared to the mean SR of the given CA-groups. The SR of four CA-groups showed some deviation in certain maternal age groups. Cases with anencephaly had female excess in young mothers (<25 years). Cases with skull's CAs particularly craniosynostosis had a male excess in cases born to women over 30 years. Two other CA groups (cleft lip ± palate and valvar pulmonic stenosis within the group of right-sided obstructive defect of heart) had significant deviation in SR of certain maternal age groups from the mean SR, but these deviations were not harmonized with joining age groups and thus were considered as a chance effect due to multiple testing. In conclusion, our study did not suggest that in general SR of isolated CAs might be modified by certain maternal age groups with some exception such as anencephaly and craniosynostosis.

Possible association of first and high birth order of pregnant women with the risk of isolated congenital abnormalities in Hungary - a population-based case-matched control study.

OBJECTIVE: In epidemiological studies at the estimation of risk factors in the origin of specified congenital abnormalities in general birth order (parity) is considered as confounder. The aim of this study was to analyze the possible association of first and high (four or more) birth order with the risk of congenital abnormalities in a population-based case-matched control data set. STUDY DESIGN: The large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities included 21,494 cases with different isolated congenital abnormality and their 34,311 matched controls. First the distribution of birth order was compared of 24 congenital abnormality groups and their matched controls. In the second step the possible association of first and high birth order with the risk of congenital abnormalities was estimated. Finally some subgroups of neural-tube defects, congenital heart defects and abdominal wall's defects were evaluated separately. RESULTS: A higher risk of spina bifida aperta/cystica, esophageal atresia/stenosis and clubfoot was observed in the offspring of primiparous mothers. Of 24 congenital abnormality groups, 14 had mothers with larger proportion of high birth order. Ear defects, congenital heart defects, cleft lip± palate and obstructive defects of urinary tract had a linear trend from a lower proportion of first born cases to the larger proportion of high birth order. Birth order showed U-shaped distribution of neural-tube defects and clubfoot, i.e. both first and high birth order had a larger proportion in cases than in their matched controls. CONCLUSIONS: Birth order is a contributing factor in the origin of some isolated congenital abnormalities. The higher risk of certain congenital abnormalities in pregnant women with first or high birth order is worth considering in the clinical practice, e.g. ultrasound scanning.

Impaired myelination of the human hippocampal formation in Down syndrome.

Myelination is considered as one of the last steps of neuronal development and is essential to the physiologically matured function of afferent and efferent pathways. In the present study, myelin formation was examined in the human fetal, postnatal and adult hippocampal formation in Down syndrome and in age-matched controls with immunohistochemistry detecting a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelination is mainly a postnatal event in the hippocampal formation of both healthy controls and in patients with Down syndrome. In patients with Down syndrome the sequence of myelination of the hippocampal formation followed a similar developmental pattern to that in controls. However, myelin formation was generally delayed in Down syndrome compared to age-matched controls. In addition, in the hilus of the dentate gyrus a decreased density of myelinated axons was detected from the start of myelination until adulthood. The majority of local axons (mossy fibers) are not myelinated in the hilar region and myelinated fibers arriving in the hilus come mainly from the subcortical septal nuclei. Since intact septo-hippocampal connections are necessary for memory formation, we hypothesize that decreased myelination in the hilus may contribute to the mental retardation of Down syndrome patients.

Myelination in the human hippocampal formation from midgestation to adulthood.

Myelination, one of the last steps of neuronal development, was examined in the human fetal and postnatal hippocampal formation using immunohistochemistry to detect a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelin basic protein-immunoreactive oligodendroglial cells were first seen at the 20th gestational week in the fimbria fornicis and in the alveus. Between the 21st and 35th weeks, myelinated axons also appeared in the fimbria fornicis. At the age of 39 gestational weeks, short and thin myelinated fibers were present in the fimbria, in the alveus, and less so in the stratum oriens of the hippocampus, while the first oligodendroglial cells appeared in the stratum lacunosum-moleculare and in the hilus. By the 2nd postnatal week myelinated fibers appeared in the stratum lacunosum-moleculare of Ammon's horn. At the 3rd month, myelination was strong in the alveus, moderate in the strata oriens, lacunosum-moleculare and radiatum of Ammon's horn, while only a small number of myelinated fibers were detected in the hilus. By the 5th month, the first oligodendroglial cells were detected in the molecular layer of the dentate gyrus. Myelination continued in the following years, particularly in the dentate gyrus, where even at the age of 11 years the density of myelinated fibers did not reach the adult level. It appears that the first myelinated axons belong to the long-projecting large hippocampal pyramidal cells and/or to their subcortical and cortical afferents. The sequence of myelination follows the known developmental pattern of hippocampal afferent and efferent pathways, and the prolonged myelination might be a factor in the prolonged functional maturation of hippocampal circuitry.

Ontogeny of calbindin immunoreactivity in the human hippocampal formation with a special emphasis on granule cells of the dentate gyrus.

Calbindin (CB) is a calcium-binding protein that is present in principal cells as well as in interneurons of the hippocampal formation of various species including humans. Studies with transgenic mice revealed that CB is essential for long-term potentiation and synaptic plasticity which are the cellular basis of learning and memory. In a previous study we have shown that CB expression in granule cells of the dentate gyrus correlates with the functional maturation of the hippocampal formation in the rat. In the present study we examined the ontogeny of CB using immunohistochemistry in the human hippocampal formation paying special attention to the granule cells of the dentate gyrus. As early as the 14(th) week of gestation (GW), CB was being expressed by pyramidal cells of CA1-3 regions in the deepest cell rows of the pyramidal layer towards the ventricular zone. Later, CB sequentially appears in more superficial cell rows. After midgestation, CB disappears from CA3 pyramidal neurons. Expression of CB by granule cells starts at the 22(nd)-23(rd) GW, first by the most superficial neurons of the ectal end of the dorsal blade. At the 24(th) GW, CB is expressed by granule cells of the crest and medial portion of the ventral blade whereas later the entire ventral blade revealed CB immunoreactivity. At term, and in the first few postnatal months, CB-immunoreaction is detected in granule cells of both blades except for those neurons in the deepest cell rows at the hilar border. At around 2-3 years of age, all granule cells of the entire cell layer are CB-immunoreactive. Axons of granule cells, the mossy fibers, start to express CB around the 30(th) GW in stratum lucidum of CA3a. With further development, CB is expressed in CA3b and c, as well as in the hilus. An adult-like pattern of CB-immunoreactivity could be observed at 11 years of age. Our results indicate that (i) CB is expressed by hippocampal pyramidal cells a few weeks before midgestation; (ii) similarly to rodents, migration of postmitotic human hippocampal pyramidal cells follows the inside-out gradient; (iii) CB was expressed transiently in pyramidal cells of the CA3 area of the human hippocampus; (iv) granule cells of the dentate gyrus start to express CB as early as midgestation; (v) maturation and migration of human granule cells follow the outside-in migrational gradient described in rodents and non-human primates; (vi) CB-immunoreactivity in the axon terminals of granule cells could be observed a few weeks before birth with a long-lasting increase in staining intensity postnatally; (vii) the maturation pattern of the CB-positive mossy fiber system suggests that the development of connectivity and the mature topographical termination pattern between dentate gyrus and the CA3 area of Ammon's horn in humans resembles that previously described for rodents; (viii) the dorsal-ventral delay in development may explain the topography of neuropathologic alterations of the granule cell layer found in temporal lobe epilepsy related to febrile seizures.