Effectiveness of routine ultrasonography in detecting fetal structural abnormalities in a low risk population.

OBJECTIVE--To review the efficacy of routine prenatal ultrasonography for detecting fetal structural abnormalities. DESIGN--Retrospective study of the ultrasonographic findings and outcome of all pregnancies in women scanned in 1988-9. SETTING--Maternity ultrasonography department of a district general hospital. SUBJECTS--8785 fetuses. MAIN OUTCOME MEASURES--Correlation of prenatal ultrasonographic findings with outcome in the neonate. RESULTS--8733 babies were born during 1988-9, and 52 pregnancies were terminated after a fetal malformation was identified. 8432 (95%) of the fetuses were examined by ultrasonography in the second trimester. 130 fetuses (1.5%) were found to have an abnormality at birth or after termination of pregnancy, 125 of which had been examined in the second trimester. In 93 cases the abnormality was detected before 24 weeks (sensitivity 74.4%, 95% confidence interval to 66.7% to 82.1%. Two false positive diagnoses occurred, in both cases the pregnancies were not terminated and apparently normal infants were born. This gives a specificity of 99.98% (99.9% to 99.99%). The positive predictive value of ultrasonography in the second trimester was 97.9% (92.6% to 99.7%). Of the 125 abnormalities, 87 were lethal or severely disabling; 72 of the 87 were detected by the routine screening programme (sensitivity 82.8%, 73.2% to 90.0%). CONCLUSION--Routine fetal examination by ultrasonography in a low risk population detects many fetal structural abnormalities but can present several dilemmas in counselling.     

Developmental toxicity evaluation of Bendectin in CD rats

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).     

Induction of external abnormalities in offspring of male mice irradiated with 252Cf neutron.

To assess the genetic effects of fission neutron, the induction of external malformations was studied in F1 fetuses after F0 male mice were irradiated. Male mice of the ICR:MCH strain were irradiated with 252Cf neutron at doses of 0.238, 0.475, 0.95 and 1.9 Gy. They were mated with non-irradiated female mice at 71-120 days after the irradiation. Pregnant females were autopsied on day 18 of gestation and their fetuses were examined for deaths and external abnormalities. No increases of pre- and post-implantation losses were noted at any dose. External abnormalities were observed at rates of 1.40% in the 0.238 Gy, 2.23% in the 0.475 Gy, 3.36% in the 0.95 Gy and 3.26% in the 1.9 Gy groups; the rate in the control group was 1.65%. The dose-response curve was linear up to 0.95 Gy, and then flattened out; the induction rate of external abnormalities was 2.7 x 10(-4)/gamete/cGy based on the linear regression. These results indicated that fission neutron effectively induces external abnormalities in F1 fetuses after spermatogonial irradiation.     

Congenital malformations in rats with the semilethal mutation fused pulmonary lobes

It has been demonstrated that an autosomal recessive gene, fused pulmonary lobes (fpl), causes fusion of the right pulmonary lobes with several associated malformations and a high incidence of death in homozygous newborns (Aoyama et al. Teratology 1988; 37:159-166). The aim of the present study was to investigate whether the deaths of fpl/fpl newborns were caused by functional abnormalities of the malformed lung or other associated malformations. Day-20 fpl/fpl and fpl/+ fetuses were weighed and examined for gross abnormalities. The lungs of selected fetuses were further examined for histological abnormalities. A wide variety of associated external, visceral, and skeletal anomalies as well as relatively lower body weights than those of phenotypically normal fpl/+ littermates were observed in the fpl/fpl fetuses. The associated anomalies consisted of hematomas and/or subcutaneous hemorrhages in the head, truncus and limbs, eyelid anomalies, CNS defects, lobation anomalies of the liver, hypoplasia of the spleen, partial absence of the skull bones, and dorsi- or ventriflexion of the phalanges of the limbs. Among them, CNS defects and partial absence of the skull bones were considered to be possible causes of newborn deaths. However, the incidence of these malformations was approximately 10% and was lower than the neonatal mortality, which had been estimated to be approximately 50% in the previous study (Aoyama et al. Teratology 1988; 37:159-166). The lungs of fpl/fpl fetuses consistently had hypoplasia of the intermediate lobe and fusion of the right pulmonary lobes. No histological changes suggesting postnatal respiratory insufficiency were found in the lungs of day-20 fpl/fpl fetuses, and the cause of newborn death remains unclear.     

Effects of prenatal exposure to 50 Hz magnetic fields on development in mice: I. Implantation rate and fetal development

Pregnant CD1 mice were exposed or sham-exposed from day 0 to day 17 of gestation to a 50 Hz sinusoidal magnetic field at 20 mT (rms). Preimplantation and postimplantation survival were assessed and fetuses examined for the presence of gross external, internal, and skeletal abnormalities. There were no statistically significant field-dependent effects on preimplantation or postimplantation survival, sex ratio, or the incidence of fetuses with internal or skeletal abnormalities. Magnetic field exposure was, however, associated with longer and heavier fetuses at term, with fewer external abnormalities. The results lend no support to suggestions of increased rates of spontaneous abortion or congenital malformation following prenatal exposure to power frequency magnetic fields. © 1994 Wiley-Liss, Inc.     

Maternal influenza during pregnancy and risk of congenital abnormalities in offspring

BACKGROUND: The teratogenic effect of influenza viruses is currently being debated, and we examined the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) to study the possible association between maternal influenza and various congenital abnormalities (CAs). METHODS: The 1980-1996 HCCSCA includes 22,843 newborns or fetuses with CAs, and 38,151 matched controls (newborn infants without any abnormalities). RESULTS: In the case group, 1328 (5.8%) mothers had influenza at some time during their pregnancies compared to 1838 (4.8%) mothers in the control group (adjusted prevalence odds ratios [PORs], 1.3; 95% confidence interval [CI], 1.2-1.4). In the calculation of the adjusted PORs, the use of antifever drugs and maternal employment status were considered. When cases and their matched controls were compared, there was a higher prevalence of maternal influenza during the second and/or third month of pregnancy for the group of newborns with cleft lip +/- palate (adjusted POR, 3.2; 95% CI, 2.0-5.3), neural-tube defects (adjusted POR, 1.9; 95% CI, 1.1-3.3), and cardiovascular malformations (adjusted POR, 1.7; 95% CI, 1.3-2.3). However, a direct teratogenic effect from influenza viruses appears to be unlikely, and we suggest that the higher prevalence of the CAs indicated above can be explained mainly by fever, because this risk was reduced by the use of antifever drugs. Periconceptional folic acid supplementation also showed some preventive effect for these CAs. CONCLUSIONS: The indirect teratogenic effect of maternal influenza during pregnancy may be restricted by appropriate medical treatment (e.g., antifever drugs) and periconceptional folic acid supplementation.     

Tissue-specific effects of in vitro fertilization procedures on genomic cytosine methylation levels in overgrown and normal sized bovine fetuses

Epigenetic perturbations are assumed to be responsible for phenotypic abnormalities of fetuses and offspring originating from in vitro embryo techniques. We studied 29 viable Day-80 bovine fetuses to assess the effects of two in vitro fertilization protocols (IVF1 and IVF2) on fetal phenotype and genomic cytosine methylation levels in liver, skeletal muscle, and brain. The IVF1 protocol employed 0.01 U/ml of FSH and LH in oocyte maturation medium and 5% estrous cow serum (ECS) in embryo culture medium, whereas the IVF2 protocol employed 0.2 U/ml of FSH and no LH for oocyte maturation and 10% ECS for embryo culture. Comparisons with in vivo-fertilized controls (n=14) indicated an apparently normal phenotype for IVF1 fetuses (n=5), but IVF2 fetuses (n=10) were significantly heavier (19.9%) and longer (4.7%), with increased heart (25.2%) and liver (27.9%) weights, and thus displayed an overgrowth phenotype. A clinicochemical screen of 18 plasma parameters revealed significantly increased levels of insulin-like growth factor 1 (40.8%) and creatinine (37.5%) in IVF2, but not in IVF1, fetuses. Quantification of genomic 5-methylcytosine (5mC) by capillary electrophoresis indicated that both IVF1 and IVF2 fetuses differed from controls. We observed significant DNA hypomethylation in liver and muscle of IVF1 fetuses (-16.1% and -9.3%, respectively) and significant hypermethylation in liver of IVF2 fetuses (+11.2%). The 5mC level of cerebral DNA was not affected by IVF protocol. Our data indicate that bovine IVF procedures can affect fetal genomic 5mC levels in a protocol- and tissue-specific manner and show that hepatic hypermethylation is associated with fetal overgrowth and its correlated endocrine changes.     

A low rate of trisomy 21 in twin-pregnancies: a cytogenetics retrospective study of 278 cases

From January 1st 1990 until December 31st 2001, we collected 19686 prenatal diagnosis (on amniocentesis and chorius villus sampling). Five hundred twelve samples (2.6%) concerned 278 twin pregnancies. The most frequent indications were maternal age > or = 35 years (108/278 = 38.8%), medically assisted procreation (34/278 = 12.3%), positive ultrasound (20/278 = 7.2%). Chromosome abnormalities were found in eight twin-pregnancies (2.9%): five with only one fetus affected [47,XX,+ 18; 45,XX,t( 13;14); 47,XYY; 47,XXX; 45,XX, t(13;14)], two with both fetuses showing the same chromosomal abnormality [inv(11)(q21q25); 47,XX,+ 18] and one with only one fetus tested [47,XX,+ 18]. In total, we found eight autosomal abnormalities, four inherited balanced rearrangements (two robertsonian translocations and two paracentric inversions of chromosome 11) and four trisomies 18. We also observed two sex chromosome abnormalities interesting only one of the two fetuses. Surprisingly, we did no detect any Down Syndrome among this population. The frequency of Down Syndrome was significantly (p < 0.05) lower in our population of twin pregnancies (0.0%) as compared to the observed incidence in singleton pregnancies during the same period (163/19162 = 0.9%).     

Pulmonary Hypoplasia Associated with Congenital Heart Diseases: A Fetal Study

Background

Abnormalities of the fetal pulmonary vasculature may affect lung morphogenesis. Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).

Objective

To determine the prevalence of PH associated with CHDs, and to evaluate whether CHDs with right outflow obstruction were associated with the highest risk of lung growth impairment.

Methods

Between January 2006 and December 2010, fetuses with CHD obtained following the termination of pregnancies due to fetal abnormalities were examined in a prospective manner for the detection of heart and lung defects. CHDs were classified into five pathophysiological groups. Lung weight (LW), body weight (BW), and LW/BW ratio were analyzed for each case. The expression of CD31 and VEGF in the lung was evaluated by immunohistochemistry.

Results

Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age. When defining PH as a fetal LW/BW ratio <0.015 before 28 weeks, and <0.012 after 28 weeks, PH was detected in 15 of the 119 fetuses analyzed (13%). It was significantly associated with CHD with right outflow obstruction, independently of chromosomal abnormalities and associated extracardiac abnormalities (p<0.03). Right outflow obstruction was detected in 60% of the fetuses with CHD and PH, but in only 32% of those with CHD but no PH. In fetuses with right outflow obstruction, no difference was observed between those with PH and those without PH, in terms of the ratio of pulmonary artery diameter to aortic diameter, lung CD31 expression, or lung VEGF expression.

Conclusion

CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH. The occurrence of fetal PH is not correlated with abnormalities of the pulmonary vasculature, suggesting the involvement of perfusion-independent mechanisms.     

Induction of congenital anomalies in offspring of female mice exposed to varying doses of X-rays

Female mice were exposed to varying absorbed doses (108–504 rad) of X-rays and mated at different intervals after irradiation (1–7, 8–14, 15–21 and 22–28 days). Uterine contents were examined at late pregnancy in order to detect early fetal deaths (dominant lethality) and malformations in the live fetuses.Two trends were apparent from data on abnormal fetuses. At each weekly interval, the incidence of abnormalities tended to rise with increase in dose, and, at any given dose, the incidence tended to increase with time after irradiation. Dwarfism and exencephaly were the two most common malformations found.The changes in incidence of dominant lethality and of abnormal fetuses with time and with dose follow each other closely, the highest incidence for both being reached in week 3 (59±4.7% for dominant lethals and 12.5±3.1% for abnormal fetuses, after 504 rad) indicating increased radiosensitivity of less mature oocytes. These results parallel those obtained from known genetic effects reported by other workers and suggest that testing for incidence of congenital malformations among offspring of treated animals may prove a useful means of assessing genetic hazards of radiation of chemicals.     

系统和四维超声对胎儿器质性异常筛检价值分析

摘要 目的：探究系统及四维超声在胎儿器质性异常筛选中的应用价值。方法：回顾性分析2018年3月至2019年3月于我院接受检查的887例中晚期产妇超声检测资料,所有产妇均行系统及四维超声检测,对比系统超声、四维超声和联合检测在胎儿器质性异常筛查中的特异性、敏感性和准确性,分析上述检查方式对不同胎儿器质性异常筛查的价值。结果：（1）887例产妇共娩出899例胎儿,其中87例存在器质性异常,异常率9.68 %（87/899）,联合检测对器质性异常检出率为94.25 %（82/87）,系统超声检出率为68.97 %（60/87）,四维超声检出率为79.31 %（69/87）,联合检测明显优于单独检测（P<0.05）;（2）系统超声检测一致性为96.05 %,灵敏度为70.59 %,特异度为98.54 %,四维超声一致性为96.47 %,灵敏度为75.40 %,特异度为98.54 %,联合检测一致性为99.57%,灵敏度为96.26 %,特异度为99.90 %,对比发现联合检测一致性、灵敏度均优于单独检测。结论：系统及四维超声对胎儿器质性异常具有较好的筛查效果,联合检测筛查效果优于单独检测。     

A scanning electron microscope study of fetal eyelid closure accelerated by cortisone in SWV/Bc mice

Eyelid closure occurs earlier in SWV/Bc and CBA/J mouse fetuses whose mothers were treated with cortisone on day 14 of gestation than it does in fetuses from untreated mothers. Similar treatment prevents the open-eyes defect of lidgap-Miller mutant mice, but examination by scanning electron microscope (SEM) has shown differences in the periderm of the closing eyelids of the cortisone-treated mutant compared with those of untreated genetically normal fetuses. (Untreated mutant eyelids remain wide open and very abnormal). The present study has examined at the SEM level the accelerated eyelid closure of cortisone-treated normal strain, SWV/Bc, fetuses to investigate whether the differences from normal in the eyelids of treated lidgap-Miller fetuses are part of the mechanism of the cortisone "cure." At the SEM level, cortisone-accelerated eyelid closure of SWV/Bc fetuses is indistinguishable from that in untreated fetuses. This suggests that the early eyelid closure induced by cortisone in normal strain fetuses represents acceleration of the normal coordinated sequence of events that leads to closure, rather than an abnormality that fortuitously leads to closure. The data also indicate that the cellular abnormalities seen previously in treated lidgap-Miller mutant fetuses are a combination of 1) abnormalities due to the mutation that are not completely reversed by cortisone and 2) normal developmental stages that have become concurrent with the cortisone-induced late closure in lidgap-Miller mutant fetuses.     

Maternal severe migraine and risk of congenital limb deficiencies

BACKGROUND: Migraines occurs frequently during pregnancy; however, there are no published data on their possible teratogenic potential in a controlled epidemiological study. Therefore, we examined the risk of congenital abnormalities in infants born to women who had migraines and other headaches during pregnancy. METHODS: Between 1980 and 1996, the Hungarian Case-Control Surveillance of Congenital Abnormalities evaluated 22,843 cases (newborns or fetuses) with congenital abnormalities, 38,151 control newborn infants without any abnormalities, and 834 malformed controls with Down syndrome. RESULTS: Migraines anytime during pregnancy occurred in 565 (2.5%) mothers of the case group compared with 713 (1.9%) mothers in the control group (crude prevalence odds ratio [POR], 1.3; 95% confidence interval [CI], 1.2-1.5) and 24 (2.9%) pregnant women in the malformed control group (crude POR, 0.9; 95% CI, 0.6-1.3) The mothers of 247 cases, 533 controls, and 21 malformed controls had severe migraines during the second and/or third months of pregnancy. There was only 1 congenital abnormality group: limb deficiencies, which had a higher rate of maternal migraines during the second and third months of pregnancy both at the comparison of cases and matched controls (adjusted POR, 2.5; 95% CI, 1.1-5.8) and of cases and malformed controls (adjusted POR, 1.7; 95% CI, 1.3-3.0). There was no association between other headaches and different congenital abnormalities at the comparison of cases and controls. CONCLUSIONS: Our data showed that maternal severe migraines during the second and/or third months of pregnancy were associated with an increased risk of congenital limb deficiencies. A similar association was not detected between congenital anomalies and other headaches during pregnancy. Our study was not based on a prior hypothesis; therefore, these data can be considered only as a signal that needs confirmation by independent data sets.     

Evaluation of routine prenatal ultrasound examination in detecting fetal chromosomal abnormalities in a low risk population

Prenatal diagnosis performed by fetal ultrasound scan is now a routine part of antenatal care in many countries. We have used our registry of congenital malformations to determine how many fetal anomalies and consequently how many chromosomal abnormalities are detected by this procedure. In our region, evaluation of prenatal diagnosis of chromosomal abnormalities in women of 38 years and younger (chromosomal prenatal diagnosis is offered to women 38 years) with no personal or familial history of chromosomal anomaly was performed in 119 099 consecutive pregnancies of known outcome from 1980 to 1987. At least one ultrasonographic examination seeking congenital malformations was performed in more than 95% of the pregnant women studied. The total number of chromosomal anomalies during the study period was 199, 123 of these being Down syndrome. Only 41 (34.5%) of the 119 fetuses with chromosomal abnormalities and congenital malformation examined had been found to have a malformation at ultrasound examination. This low sensitivity was different for the diverse chromosomal abnormalities. Only 10 out of the 54 fetuses with Down syndrome and malformations (18.5%) were detected and only 3 out of 24 (12.5%) atrioventricular canal defects in those trisomie 21 patients were detected. Only 5 out of 11 (45.4%) fetuses with trisomy 13, 13 out of 26 (50.0%) fetuses with trisomy 18, 7 out of 12 patients with monosomy X (58.3%) and 6 out of 27 (22.2%) fetuses with other chromosomal abnormalities were diagnosed. Moreover, the time of detection of these anomalies was early enough to allow amniocentesis and termination of pregnancy in the case of a chromosomal abnormality in only 15 out of these 41 patients, including 7 cases of cystic hygroma in fetuses with monosomy X. This low sensitivity is not the result of the quality of the ultrasound equipment. It may be explained by the inadequate qualification of some operators and by the insufficient duration of the routine examination. In conclusion, our study has shown that the sensitivity of the detection of chromosomal abnormalities by routine prenatal ultrasound screening is low. Other screening methods are needed.     

Rate of chromosomal aberrations in prenatally detected hydrops fetalis and hygroma colli

Summary Chromosome analyses were carried out in a series of 775 fetuses with morphological abnormalities diagnosed by ultrasound. Among these cases, 57 demonstrated non-immune hydrops fetalis with hygroma colli (group 1) and a further 116 non-immune hydrops fetalis without hygroma colli (group 2). Different chromosome abnormalities were found in 54.5% of cases of group 1 where chromosome analyses could be performed, and in 27.6% of cases of group 2. The most common aberrations were monosomy X and trisomy 21.     

Exposure of the pregnant rat to warfarin and vitamin K1: an animal model of intraventricular hemorrhage in the fetus

Pregnant Sprague-Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg) and concurrent intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did not have any apparent deleterious effect on the dams and did not affect the fetuses when administered from day 1 to day 12 of pregnancy. However, similar treatment from day 9 to 20 caused hemorrhage in the fetuses examined on day 21 of gestation. There were no hemorrhages in the control fetuses from dams receiving vitamin K1 only. The lowest effective dose of warfarin, in conjunction with daily doses of vitamin K1, was 3 mg/kg. This dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal brain, face, eyes, and ear and occasionally the limbs. Brain hemorrhages were frequently intraventricular and caused various degrees of hydrocephaly. Bony defects were not a feature of prenatal exposure to warfarin. These results show that prenatal exposure of the rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology associated with prenatal exposure to warfarin in the human. It did not induce bony or facial defects probably because the vitamin K-dependent components of bone development occur postnatally in the rat. This model should allow detailed determination of the role of vitamin K-dependent proteins in development.     

Spontaneous malformations in JW-NIBS rabbits

The frequency of spontaneous anomalies among JW-NIBS rabbits in our laboratory is reported. The study was based on 1217 live fetuses obtained from 185 of an origin sample of 195 pregnant females; the remaining 10 (5.1%) aborted. Seven (0.57%) of the fetuses had the following external anomalies: multiple anomalies with craniofacial anomalies and thoraco-, gastroschisis (3 cases), microcephaly with open eyelids and microstomia (1), microphthalmia (1), anury (1) and brachyury (1). Among 1213 fetuses, 2 (0.16%) had abdominal visceral anomalies: agenesis of gall bladder and hypoplasia of the ovary were each found in one animal. Head and thoracic visceral anomalies were found in 6 (1.73%) of 347 fetuses, and skeletal anomalies in 6 (0.69%) of 867 fetuses. 4.03% of fetuses had 13 ribs.     

Fetal development in mice exposed to isoflurane

The developmental toxicity of trace (0.006%), subanesthetic (0.06%), and light anesthetic (0.6%) exposure to isoflurane was examined in Swiss/Webster mice. No adverse effects were demonstrated following exposure of dams to 0.006% (n = 26) and 0.06% (n = 27) isoflurane for 4 hr daily on days 6-15 of pregnancy. Exposure to 0.6% isoflurane (n = 23) for the same period resulted in significantly decreased fetal weight, decreased skeletal ossification, minor hydronephrosis, and increased renal pelvic cavitation. The incidence of cleft palate also was significantly increased, abnormalities occurring in 12.1% of fetuses and affecting 11 of 23 litters. This incidence was considerably higher than that of the combined treatment and colony control groups (0.75%) and those that we have found in previous experiments with this mouse strain following exposure to halothane (1.2%) or enflurane (1.9%).