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Our previous study showed an association between high fever-related maternal diseases during the second and/or third gestational months and a higher risk of multiple congenital abnormalities (MCA) in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities. The objective of our analysis is to attempt the delineation of the spectrum of the characteristic component defects of an MCA syndrome associated with high fever-related maternal diseases. Of 1349 cases with MCA without recognized genetic and teratogenic syndromes in the total dataset, 181 had a possible association with influenza, common cold with secondary complications, tonsillitis and recurrent orofacial herpes with high fever in the second and/or third gestational months. At the evaluation of component defects in these 181 MCA cases, an association was found between the components of the so-called two schisis-type defects, such as neural-tube defects and orofacial cleft, in addition to microphthalmos, neurogenic limb contractures, and indeterminate sex (i.e. maldevelopment of male external genital organs, such as hypoplasia of the penis and pseudohermaphroditism). In addition, previous findings that showed an association between high fever and facial anomalies (micrognathia and midfacial hypoplasia), microcephaly and defects of external ears, were confirmed in our dataset. Thus, we delineated the maternal high fever-related MCA syndrome, including the above component defects and this MCA syndrome was identified in 38 MCA (21.0%) among 181 MCA babies born to mothers with high fever-related diseases. In the total dataset of 1349 MCA, 2.8% of cases can be associated with high fever.

Two previous Hungarian intervention trials showed that periconceptional folic acid-containing multivitamin supplementation did not change the total (birth + fetal) prevalence of cases with multiple congenital abnormalities (MCAs). However, two US observational studies found an elevated risk for MCAs in the offspring of women who reported periconceptional use of multivitamins containing folic acid. These conflicting results stimulated us to evaluate the data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities and to check the possible association between the use of periconceptional multivitamin supplementations and the total prevalence of cases with MCAs. Of 1,349 cases with MCA, 69 (5.1%) had mothers who used multivitamins during the second and third month of pregnancy. Of 2,405 matched controls without any defect, 126 (5.2%) had mothers who used multivitamin supplementation in early pregnancy. Of 21,494 malformed controls with isolated congenital abnormalities, 1,052 (4.9%) mothers received supplementation with multivitamins during the critical period of CAs including MCAs. There was no difference in the use of multivitamins among the study groups either in the total data set or at the evaluation of only prospective medically recorded data. Medically recorded folic acid use without any multivitamins in the second and third gestational month showed some protective effect for MCAs. In conclusion, our observational case-control study did not detect a folic acid containing multivitamins during the early pregnancy as a risk factor for MCAs., ((c) 2006 Wiley-Liss, Inc.)

Objectives: It has recently been suggested that maternal ulcerative colitis is associated with an almost 4-fold increased risk of congenital abnormalities in offspring. We therefore examined the risk of congenital abnormalities in children born to women with ulcerative colitis., Methods: This was a case-control study within the Hungarian Case Control Surveillance of Congenital Abnormalities, 1980-1996, based on 22,843 newborn children or fetuses with congenital abnormalities and 38,151 children without any detected congenital abnormalities (the control group)., Results: Seventy-one pregnant women (0.3%) had ulcerative colitis in the case group and 95 (0.2%) in the control group. The adjusted overall risk for having a child with congenital abnormalities in women with ulcerative colitis was OR = 1.3 (95% CI = 0.9-1.8). The risk of limb deficiencies, obstructive urinary congenital abnormalities, and multiple congenital abnormalities was OR = 6.2 (95% CI = 2.9-13.1), OR = 3.3 (95% CI = 1.1-9.5), and OR = 2.6 (95% CI = 1.3-5.4), respectively. No association was found for cleft lip with or without cleft palate or cardiovascular defects., Conclusions: We found no significantly increased overall risk of congenital abnormalities in children born to women with ulcerative colitis. However, our results indicate an increased risk of some selected congenital abnormalities (limb deficiencies, obstructive urinary congenital abnormalities, and multiple congenital abnormalities). More data are needed to determine whether the association between maternal ulcerative colitis and an increased risk of certain congenital abnormalities is causal or is influenced by bias.

Limb deficiency defects (LD) occurring among 1,575,904 births in Hungary during 1975-1984 were reviewed. The overall birth prevalence of LD was 1 in 1,816. This paper discusses the nature and distribution of the limb and other defects in the 275 (32%) children who had structural malformations in other systems. Two main forms of classification were used: morphologic and causal. Additional malformations were most commonly seen in infants with amelia, rudimentary limb (RL), radial/tibial (RT), intercalary or central axis (CA) LD and rarely in those with terminal transverse (TT) or ulnar/fibular (UF) defects. Upper limbs (81%) were involved significantly more often than lower limbs (42%) and there were more right-sided defects (83% vs. 71%) due to an excess of right arm involvement especially with radial ray and split hand anomalies. Single limb involvement was relatively common with amelia (88%), UF (82%), RT (50%), and TT (50%) defects. With other LD, multimelic involvement was more characteristic. This was usually symmetric with intercalary and RL defects but asymmetric with CA anomalies and digital deficiencies (DD). From a causal perspective, 17% of cases had genetic disorders, 52% had recognized associations, anomalies, sequences, environmental causes or patterns of unknown origin, and 31% had unknown patterns of malformations. The commonest entities were amnion disruption sequence (16% of cases) and VACTERL association (8%). Both of these disorders showed unusual temporal distribution. As anticipated, patterns of malformations differed with the type of LD. Amelia and digital amputations were often seen with body wall defects, atypical anencephaly or encephalocele, and cleft lip reflecting amnion disruption. Rudimentary limb was seen with anencephaly, omphalocele, renal agenesis, aberrant genitalia, and imperforate anus, reflecting defects of blastogenesis including the cloacal exstrophy and caudal regression sequences and Schisis association. Radial/tibial defects were associated with different patterns depending on whether the limb defects were unilateral or bilateral. Unilateral defects occurred with anomalies suggesting VACTERL association or the facio-auriculo-vertebral anomaly, while bilateral defects occurred more often in genetic or potentially genetic disorders including VACTERL with hydrocephalus. Central axis defects showed three main patterns of association: one reflecting the ectrodactyly-ectodermal dysplasia-clefting syndrome; one with tongue anomalies representing a variant of oro-mandibular-limb (Hanhart) anomaly, and the last with hydronephrosis indicating a group of "acro-renal" syndromes. Strong associations with other anomalies were not seen in the groups with TT, UF, or intercalary defects.

A population-based and validated data set of 114 cases with isolated ulnar-fibular deficiency was evaluated in Hungary, 1975-1984. Ulnar-fibular type had the third most common birth prevalence (0.07 per 1000) among isolated congenital limb deficiency types. This type is relatively rarely associated with nonlimb defects, a single limb is affected in two-thirds of cases, nearly all other cases had femur-fibula-ulna (FFU) dysostosis. Upper and lower limbs, right and left sides, are equally affected, however, there is an obvious male excess (71%). Case-control analysis indicated a lower birth weight due to intrauterine growth retardation, higher birth order, lower socioeconomic status of parents, and a more frequent reported subfertility. The family study identified one familial cluster (one siboccurrence) among 331 first-degree relatives.

A case-control epidemiological and family study was organized of 2024 index patients born between 1970 and 1976 affected by isolated cleft lip +/- cleft palate, isolated posterior cleft palate and multiple congenital abnormalities including facial clefting and of their matched control cases. The specific rate of affected parents and sibs was 2.4% and 4.2% in the isolated cleft lip +/- cleft palate sample, while 2.2% and 3.2% in the isolated posterior cleft palate group. The proportion of polygenic liability was about 77 +/- 8% in isolated cleft lip +/- cleft palate cases. Among teratogens, the triggering impact of certain anticonvulsants was confirmed.

A nationwide programme for the evaluation of 1,339 newborns with multiple malformations (about 8% of all malformed babies) notified to the Hungarian Congenital Malformation Registry in the period 1973 to 1975, was launched on January 1st, 1973. As specific syndromes and anomalads, 696 cases (51.9%) were notified. On the basis of individual malformations, 87 cases were identified from 439 patients with notified associations, and 27 multiple malformations among 172 stillborns and infant deaths were recognized from autopsy records collected from pathologists. 341 surviving infants were officially referred to 'multiple malformation centres' for special examination. 57 infants of 129 cooperating families were identified. Benefits of this programme are (i) the proportion of specific syndromes and anomalads increased by 12.8%; (ii) the rate of unspecified multiple malformations decreased by 56.6%; (iii) examination of multiple malformations may be the most sensitive means to detect teratogens; (iv) 50.5% of the expected number of chromosome abnormalities in newborns was found; (v) the nationwide material of multiple malformed babies offers a possibility to clarify gene abnormalities and new syndromes.