Population-based case-control teratogenic study of hydroxyprogesterone treatment during pregnancy

Hydroxyprogesterone, a synthetic progestin, was used for the treatment of pregnant women with threatened abortion and preterm delivery. Previous studies showed some association between hydroxyprogesterone use during early pregnancy and some specific congenital abnormalities. The population-based large Hungarian data set seemed to be appropriate to check this possible association. The Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996 includes 22 843 cases with congenital abnormalities and 38 151 controls without any defect. 318 (1.4%) cases, while 433 (1.1%) controls had mothers with hydroxyprogesterone treatment during pregnancy (adjusted POR with 95% CI: 1.3, 1.1-1.5). However, there was no association between risk for any congenital abnormality group and a higher use of maternal hydroxyprogesterone treatment during the second and third month of gestation. On the other hand hydroxyprogesterone is not effective in the prevention of preterm delivery. In conclusion, there was no detectable risk for congenital abnormalities in the offspring of mothers with hydroxyprogesterone treatment during early pregnancy, however, there is no reasonable indication of this treatment during pregnancy.     

Population-based case-control teratologic study of topical miconazole

Miconazole cream is used in Hungary to treat fungal genital and skin infections in pregnant women, but it causes anxiety for both patients and medical doctors due to the category C classification of the drug regarding teratogenic or fetotoxic risk. The objective of this case-control study was to analyze the teratogenic potential of topical miconazole used during pregnancy in the mothers of babies with congenital abnormalities and in matched control mothers of babies without congenital abnormalities. The population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996 included 22 843 women who had newborns or fetuses with congenital abnormalities, and 38 151 pregnant women who had newborn infants without any defects (controls). In the case group, 24 (0.11%) and in the control group, 46 (0.12%) pregnant women were treated with miconazole (crude odd ratio [OR]: 0.9 with 95% confidence interval [CI]: 0.6-1.6). Different congenital abnormality groups were evaluated in case-control pairs and a higher prevalence of miconazole treatment was not found during the second or third month of pregnancy. Thus, treatment with topical miconazole during pregnancy does not increase the risk of congenital abnormalities.     

The Safety of Penicillin V: Oral Penamecillin Use During Pregnancy The Importance and Limitation of Recall Bias

The purpose of the study was to check the human teratogenic potential of penicillin V: oral penamecillin treatment during pregnancy in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. The pairs of cases with congenital abnormalities and their matched population controls without congenital abnormalities were evaluated, in addition the data of total population and of patient control groups as referents were compared with the data of congenital abnormality groups. In the three study groups there were 38,151 pregnant women who had newborn infants without any defects (population control group), 22,865 pregnant women who had newborns or fetuses with congenital abnormalities, and 812 mothers of informative offspring with Down syndrome (patient controls). In the population control group 2,246 (5.9%) pregnant mothers were treated with penamecillin, in the case group 1,597 (7.0%) pregnant women had penamecillin treatment while in the patient control group 63 (7.9%) mothers used penamecillin during pregnancy. The use of penamecillin treatments during pregnancy was higher in the total case (i.e., congenital abnormality) group, than in the total population control group. However, the highest use of oral penamecillin was found in the patient control group. The case-matched population control pair analysis did not show a higher use of medically documented penamecillin during the second-third months of pregnancy, i.e., in the critical period for most major congenital abnormalities. In addition, an association between medically documented penamecillin use during the second and third months of gestation and different congenital abnormality groups was not found when total population control group or patient control groups were used as referent. Thus, the reported higher use of penamecillin among the mothers of cases and patient controls can be explained mainly by recall bias. Thus, treatment with oral penamecillin during pregnancy did not indicate detectable teratogenic risk to the fetus.     

Population-based case-control study of oxoline acid use during pregnancy for birth outcomes

The objective of the study was to check the effect of oxoline acid, a bactericidal drug for the treatment of urinary tract infection during pregnancy, on congenital abnormalities of informative offspring and fetal development. Human data of oxoline acid use during pregnancy have not been reported, but the use of this quinolone derivative is not recommended during pregnancy by the US Food and Drug Administration. The teratogenic and fetotoxic potential of oxoline acid was evaluated in the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. Observed and expected numbers of congenital abnormalities were compared in the newborn infants and fetus of case mothers with oxoline acid treatment. In addition, gestational age and birthweight were evaluated in control newborn infants born to mothers with or without oxoline acid treatment. Of 38,151 newborn infants without any congenital abnormalities (control group), 13 (0.03%) had mothers who were treated with oxoline acid, while of 22,843 cases with congenital abnormalities, five (0.02%) had mothers who were treated with oxoline acid during pregnancy (POR with 95% CI: 0.6, 0.2-1.8). The comparison of observed and expected number of different congenital abnormalities did not show the teratogenic potential of oxoline acid. There was a 0.9 weak shorter gestational age without a smaller birthweight in the newborn infants born to mothers with oxoline acid treatment. Our data did not indicate teratogenic and fetotoxic effect of oxoline acid, however, the number of cases and controls was limited.     

Birth outcomes of cases with unclassified multiple congenital abnormalities and pregnancy complications in their mothers depending on the number of component defects. Population-based case-control study

Multiple congenital abnormalities (MCA) represent the most severe category of structural birth defects, (i.e. congenital abnormalities [CA]). Unfortunately, most MCA are not recognized and/or identified as MCA syndromes or MCA associations in the clinical practice. The term unclassified MCA (UMCA) is used for this category of MCA. We decided to evaluate the component CA of UMCA cases. The population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996) was evaluated. 'False' MCA, such as complex CA, polytopic field defects and sequences were excluded from the category of MCA. In addition, MCA syndromes caused by chromosomal aberrations and major mutant genes with preconceptional origin were excluded from the dataset of the Surveillance. MCA syndromes caused by teratogens and MCA associations with well-defined component CA were also excluded in the study. Thus, only UMCA cases (i) without the recognition of previously delineated MCA syndromes (ii) and/or without the identification of new MCA syndromes or (iii) caused by random combination of CA were included in the study. We compared data from 1349 cases with UMCA, 2405 matched population controls without any CA, and 21 494 malformed controls with isolated CA. There was a higher rate of stillbirth and a moderate male excess in UMCA cases, a somewhat shorter gestational age at delivery and an obvious reduction in birthweight. The intrauterine fetal growth retardation and rate of low-birthweight newborns showed an association with the number of component CA in UMCA cases. A similar association was not found with gestational age and the rate of preterm birth. UMCA represent one of the most severe categories of CA. The degree of intrauterine fetal growth retardation depends on number of component CA in UMCA cases.     

Population-based case-control study of oral ketoconazole treatment for birth outcomes

The objective of the study presented here was to check the effect of oral ketoconazole treatment on fetal development. Ketoconazole has been given a teratogenic classification of C by the US Food and Drug Administration, but human controlled epidemiological studies of the treatment's effects have not been reported. The occurrence of ketoconazole use in the second to third months of gestation was compared between cases with congenital abnormalities and their matched controls in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Birth weight and gestational age were evaluated in control newborn infants born to mothers with or without ketoconazole treatment. The case group comprised 22,843 cases with congenital abnormalities, while the control group contained 38,151 newborn infants without any defects. Six infants (0.03%) and 12 controls (0.03%) had mothers who had received oral ketoconazole treatment (prevalence odds ratio: with 95% confidence interval: 0.8, 0.3-2.2). No group of infants with congenital abnormalities had mothers with a higher incidence of use of the drug. The mean gestational age was somewhat longer while birth weight was somewhat larger in controls with ketoconazole treated mothers. Our study failed to demonstrate a higher rate of congenital abnormalities in infants with mothers who had received oral ketoconazole treatment during pregnancy.     

Population-based case-control study of mebendazole in pregnant women for birth outcomes

The objectives of the study was to check the embryotoxic-teratogenic and fetotoxic effect of mebendazole (Vermox; Richter, Budapest, Hungary) treatment during pregnancy. Mebendazole use during pregnancy was evaluated in mothers of babies born with congenital abnormalities and in matched control mothers of babies born without congenital abnormalities in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. Of 22,843 women who had newborns or fetuses with congenital abnormalities, 14 were found to have been treated with mebendazole for intestinal nematoda infections/diseases during pregnancy (crude POR: 1.8 with 95% CI: 0.7-4.2). Of 38,151 women who had newborns without any defects (controls), the same number (14) were found to have been treated with mebendazole during pregnancy. Six different congenital abnormality groups were evaluated and a higher prevalence of mebendazole use in these mothers throughout pregnancy was not found. Gestational age and birth weight were analyzed in control infants born to mothers with or without mebendazole treatment. The mean gestational age was somewhat longer and mean birth weight was larger in newborn infants born to mothers with mebendazole treatment. Thus, treatment with mebendazole during pregnancy did not indicate a teratogenic and fetotoxic risk to the embryo or fetus, though the numbers of treated cases and controls in this study were limited.     

Acute respiratory infections during pregnancy and congenital abnormalities: a population-based case-control study

Diseases of respiratory system caused by acute infections are among the most common maternal diseases during pregnancy. The objective of the study was to estimate the association between congenital abnormalities and acute respiratory infections during the first trimester of pregnancy. The data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities including 22 843 cases with congenital abnormalities, 38 151 population controls without congenital abnormalities and 834 malformed controls with Down syndrome between 1980 and 1996 was evaluated. 2118 cases with congenital abnormalities (9.3%), 3455 population controls (9.1%) and 92 malformed controls with Down syndrome (11.0%) had mothers with acute respiratory infections. Of 25 different congenital abnormality groups, esophageal atresia/stenosis showed a high adjusted prevalence odds ratios (POR) with 95% confidence interval (CI) for acute respiratory infections during the first trimester of pregnancy in case mothers compared with population controls (3.6, 1.4-9.1) and malformed controls (1.9, 1.0-3.5), respectively. In addition there was an association between medically recorded acute respiratory infections during the first trimester of pregnancy and a higher risk for some other congenital abnormalities, such as posterior cleft palate and multiple congenital abnormalities. In conclusion a possible association between some congenital abnormalities, particularly esophageal atresia/stenosis and maternal acute respiratory infections cannot be excluded due to the interactions of the microbial agents, related drug treatments and last but not least the indirect effect of maternal diseases, such as fever-hyperthermia, hypoxia and dietary deficiency. However, periconceptional multivitamin/folic acid supplementation during the early pregnancy was able to reduce the acute respiratory infection related risk for congenital abnormalities.     

No association between severe constipation with related drug treatment in pregnant women and congenital abnormalities in their offspring: A population-based case-control study

Constipation is a common pathological condition in pregnant women; nevertheless, its possible association with structural birth defects (i.e. congenital abnormalities [CA]) in their offspring has not been studied in controlled epidemiological studies. We evaluated the possible association between severe constipation with laxative treatment in pregnant women and congenital abnormalities in their offspring. The dataset of the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities (HCCSCA) 1980–1996 contained 22 843 cases with CA and 38 151 matched controls without CA. Only pregnant women with prospectively and medically recorded constipation were included in the study and 13 CA groups were compared in cases and all their matched controls. A total of 78 (0.34%) cases had mothers with severe constipation and treatment during pregnancy compared to 144 (0.38%) controls (adjusted OR with 95% CI = 1.0, 0.7–1.3). Specified groups of CA were also assessed versus controls, but a higher occurrence of pregnant women with severe constipation and related treatment was not found in any CA group. Among laxative drugs, senna has no teratogenic potential; thus, if severe constipation requires laxative drug treatment in pregnant women, senna is not contraindicated. A higher rate of CA was not found in the offspring of pregnant women with severe constipation and related senna treatment.     

Excess of congenital abnormalities in French-Canadian children with neuroblastoma: A case series study from Montreal

Neuroblastoma is one of the most common cancers of childhood. Some studies have shown an excess of congenital abnormalities in children who have been diagnosed with neuroblastoma. In this study we examined the medical records of all children with neuroblastoma seen at St. Justine Children's Hospital between the years 1977 and 1993. A total of 141 children (131 of French-Canadian ancestry) were included in this study. Twelve children (8.5%) had 21 defined congenital abnormalities (1,490 per 10,000 children). This compared with a rate of 444.3 children with abnormalities per 10,000 live births (4.44%) for all congenital abnormalities in the British Columbia Health Surveillance Registry, 1979–1988 (relative risk 1.91, P = 0.03). Six of the 12 children had cardiovascular malformations. These and previous results suggest that there may be a common developmental origin to neuroblastoma and to some congenital malformations. Genes that control development may be worthy of further study in these children. Med. Pediatr. Oncol. 29:272–279, 1997. © 1997 Wiley-Liss, Inc.     

A novel phenotype variant of severe congenital neutropenia caused by G6PC3 deficiency

Severe congenital neutropenia type 4 (SCN4) is associated with mutations in the G6PC3 gene. To date, all patients bearing the p.Gly260Arg variant of the G6PC3 gene show heart defects. Here, we present a case of the p.Gly260Arg variant in a patient who did not have structural or functional heart anomalies. Treatment with granulocyte colony‐stimulating factor recovered the absolute neutrophil count and neutrophil functional competence. Pediatr Blood Cancer 2013; 60: E29–E31. © 2013 Wiley Periodicals, Inc.     

Symptomatic infant characteristics of congenital cytomegalovirus disease in Australia

BACKGROUND: Human cytomegalovirus (CMV) is the most common cause of viral intrauterine infection. In utero transmission can occur during primary maternal infection, reactivation or reinfection of seropositive mothers. OBJECTIVE: To describe the aetiology and clinical features of infants diagnosed with congenital CMV and to document maternal factors that were presented. METHODS: Active national surveillance was initiated in 1999 in collaboration with the Australian Paediatric Surveillance Unit. RESULTS: Monthly notifications resulted in 70 cases of congenital CMV being identified between 1999 and 2003. Nearly all of the cases were symptomatic with the most common clinical sequelae reported in infected infants being jaundice, thrombocytopaenia, hepatomegaly, petechiae, purpura and splenomegaly. Almost half (43.5%) of the infants had central nervous system (CNS) complications, such as microcephaly, chorioretinitis, sensorineural hearing loss, intracranial calcifications, developmental delay or seizures, with over half presenting two or more CNS abnormalities. Maternal febrile illness was noted in 54.8% of the cases. The majority of mothers were primiparous (46.4%) or secundiparous (39.3%), indicating two different population groups at risk of primary CMV infection. CONCLUSION: This study documents symptomatic congenital CMV cases in Australia.     

Clinical outcomes of congenital lung abnormalities

Individually, congenital abnormalities of the lung are rare but collectively they form an important group of conditions. The range of malformations is broad and the clinical impact is very variable, depending on the degree of malformation. This article groups these conditions under their traditional headings and considers their management. However, in conditions that are atypical, it is often useful to adopt a clear anatomical approach. Consider investigations that will clearly identify the structure of the bronchial tree, lung parenchyma and the vascular supply and drainage. Describe each in logical and simple terms. Similarly, an individual assessment of function will assist in planning appropriate management. The natural history of some of the congenital lung lesions is often unknown. This gap in our knowledge has widened with the advent of detailed antenatal ultrasound scanning. Paediatricians are now faced with an increasing cohort of completely asymptomatic antenatally diagnosed congenital lung lesions and the best post-natal management is unclear. Long-term follow-up studies are required to document their natural history.     

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.     

TRIGLYCERIDE STORAGE DISEASE A Report of Two Affected Children Associated with Neurological Abnormalities

ABSTRACT. Two children are described with congenital abnormalities (microcephaly, nystagmus, deafness, hepatomegaly) and the anomalous feature of triglyceride deposits in peripheral adipose tissue associated with severe malnutrition. Peripheral adipose tissue of one of these children displayed: (a) reduced sensitivity of adenyl cyclase to stimulation by noradrenaline ( b ) no response in tissue levels of cyclic AMP when stimulated by isoprenaline and ( c ) impaired release of glycerol following stimulation with isoprenaline. The other child, with similar clinical features, showed abnormal deposits of glycogen in the liver. It is postulated that a primary metabolic defect occurs in peripheral adipose tissue (and possibly at other sites such as the liver) that interferes with triglyceride (and glycogen) mobilization during prolonged malnutrition.     

功能性遗粪症儿童心理发育特点的病例对照研究

目的探讨功能性遗粪症(FE)儿童的心理行为发育特点,为其心理干预提供理论依据。方法采用分层随机整群抽样法从青岛市城区抽取4044名4～5岁儿童。男2196名,女1848名。应用自制的儿童一般情况与遗粪症影响因素调查问卷、Achenbach儿童行为量表(CBCL)、3～7岁儿童气质量表与家庭环境量表-中文版(FES-CV)调查抽样儿童的家庭环境和生长发育状况,将调查发现的90例FE儿童作为病例组,其他儿童作为健康对照组,采用病例对照研究的方法探讨FE儿童的气质、行为和家庭环境特征。FE诊断依据中国精神疾病分类手册第3版(CCMD-3)标准。结果4～5岁儿童FE的患病率为2.23%(90/4044例),其中男童患病率为1.46%(32/2196例),女童患病率为3.14%(58/1848例)。FE儿童气质维度方面规律性、趋避性、适应度和坚持度的得分均高于健康对照组(Pa<0.05),注意分散度得分低于健康对照组(Pa<0.05);家庭环境特征方面病例组亲密度和组织性得分均低于健康对照组(Pa<0.05),而矛盾性得分高于健康对照组(P<0.01);FE儿童发生行为问题的风险较健康对照组大(OR=1.931)。FE是男童发生不成熟、分裂样、攻击和行为总分异常的危险因素(OR=2.96,3.94,8.26,3.22),是女童发生体诉、攻击性和多动的危险因素(OR=4.35,3.47,2.14);FE儿童患注意缺陷多动障碍(ADHD)的风险大于健康对照组(OR=2.650)。结论FE的实际患病率远远超过临床医师的估计。FE儿童有其气质特点,发生行为问题及患ADHD的风险较高。FE对儿童的行为发展和家庭环境造成不良影响,为改善FE儿童的生命质量,对其进行心理干预是必要的。     

A Quarter Century of Thalidomide Embryopathy*

Abstract Some 137 patients with thalidomide embryopathy have been registered. Of them, 65 were male and 72 female. The age of patients who had a medical examination from 1976 to 1983, ranged from 7 to 22 years. The mean age was 17.0 ± 2.3 (mean ± SD) years. The number of hearing impairments were 35 (25.6%), limb defects were 55 (40.1%) and combined defects were 47 (34.3%). In order to determine the mutual relationships of 34 abnormal symptoms, the correlation coefficient was calculated, and cluster analysis was carried out by utilizing the result. There was a strong inverse correlation between deformities and hearing impairments. The 34 symptoms were divided into three groups. In the first group 11 symptoms were included, but there was little mutual relationship. Fifteen symptoms belonged to the second group, which evidenced strong mutual relationships. The 8 symptoms belonging to the third group were central to all of the symptoms.     

Three cases of congenital adrenal hypoplasia: A cause of salt-wasting and mortality in the neonatal period

Three infants with congenital adrenal hypoplasia are described. The two surviving infants were detected and successfully treated in the neonatal period due to a suggestive family history (Case 1) and antenatal maternal oestriol screening (Case 2). The modes of inheritance, diverse clinical presentation, associated conditions, diagnostic work-up and pathology of congenital adrenal hypoplasia in these three infants is discussed.