Ljungan virus: a commentary on its association with fetal and infant morbidity and mortality in animals and humans

Epidemiologic and experimental data support the notion that Ljungan virus (LV), endemic in some rodent populations in Sweden, Denmark, and the United States, can cause morbidity and mortality in animals and humans. LV infection can cause type I diabetes mellitus, myocarditis, and encephalitis in bank voles and experimental mice, and lemmings. Mouse dams infected with LV experience high rates of stillbirth that may persist across generations, and their fetuses may develop cranial, brain, and limb malformations. In humans, epidemiologic and serologic data suggest that LV infection correlates with intrauterine fetal death, malformations, placental inflammation, myocarditis, encephalitis, and Guillain-Barré syndrome. The proposed role of LV infection in SIDS is unconvincing. Further research is necessary to clarify the role of LV infection in animal and human disease.     

Association of zoonotic Ljungan virus with intrauterine fetal deaths

BACKGROUND: It has recently been shown that Ljungan virus (LV) is associated with disease in its wild rodent reservoir. In addition, it has been demonstrated that LV causes malformations and perinatal death in a mouse model. The question was therefore raised whether LV is a zoonotic agent in humans. METHODS: Population fluctuations of native rodents in Sweden were compared to the incidence of intrauterine fetal deaths (IUFDs) using the Swedish national hospitalization database. Formalin-fixed tissues from cases of IUFD were investigated using LV-specific immunohistochemistry. RESULTS: Variation in the incidence of IUFDs closely tracked the fluctuations in native rodent populations. LV was detected in the brain tissue in 4 of 10 cases of IUFDs investigated by immunochemistry. LV was also detected in the placenta in 5 of the 10 IUFD cases, but in none of 20 placentas from normal pregnancies. CONCLUSIONS: LV may play an important role in IUFDs.     

Comparative analysis of the frequency and type of chromosomal aberrations in somatic cells in maternal-fetal infections

Fetal infections have high specific gravity in the structure of perinatal diseases and mortality. The gravity of infection processes in pregnancies and degree of fetal pathology are not correlated. Latent asymptomatic forms of pregnant's diseases can often be the cause of the congenital malformations and fetal death. We present here results of the analysis of the frequencies and types of chromosome aberrations in pregnancies with latent infections. The chromosome structure damages, mainly chromatide-type aberrations, were registered with higher frequency in the studied group.     

Correlations of developmental end points observed after 2,4,5-trichlorophenoxyacetic acid exposure in mice.

A large-scale developmental toxicology study of 2,4,5-trichlorophenoxyacetic acid was conducted in four inbred strains and one outbred strain of mice. The most significant developmental effects observed were reduced fetal weight and increased incidences of cleft palate (malformation) and prenatal death (deaths/resorptions). The correlation coefficients among the proportion of deaths/resorptions, proportion of malformations, average fetal weights, and number of viable fetuses were investigated, with each variable measured on a per-litter basis. Generally, the correlation coefficients between average fetal weight and number of viable fetuses were negative for the control and low-dose groups in the C57BL/6, C3H/He, and BALB/c strains. Overall, the correlation coefficients between proportion of malformations and number of viable fetuses were not significant. The correlation coefficients between proportion of malformations and average fetal weight were negative for all but one case. The correlations were weak in the control and low-dose groups, in which the malformation rates were very low, and were strong in the high-dose groups. The correlation coefficients between proportion of deaths/resorptions and proportion of malformations were generally positive at the high doses; some negative correlations were observed in control and low-dose groups. The correlation coefficients between proportion of deaths/resorptions and average fetal weight were negative for the A/JAX and CD-1 strains. In summary, the strongest relationship observed was the negative correlation between fetal weight and malformation.     

Relationship between fetal weight and malformation in developmental toxicity studies

Exposure to developmental toxicants may cause fetal malformations, increase prenatal death rates and reduce fetal weight at term. However, there has been little formal study of the relationship among these effects. Certainly, no statistical methods are currently available to jointly analyze these effects of exposure. As a preliminary step in developing such methods, simple exploratory analyses were conducted using a series of ten studies conducted for the National Toxicology Program. Because fetal weight and malformation status were both reported for all live fetuses, the data permitted an exploration of the correlation between these two outcomes. The data show a clear pattern wherein malformed fetuses tended to be lighter at term than nonmalformed fetuses. While these patterns cannot be used to draw inferences regarding the biological relationship between fetal weight and malformation, they do suggest the potential value in developing statistical models for the joint effect of exposure on fetal weight and malformations.     

Quantitative risk assessment for developmental toxicity.

Pharmaceutical companies and governmental regulatory agencies are becoming increasingly aware of the need for improved statistical methods for developmental toxicity experiments. Although a number of statisticians have become interested in this area, activity has centered mostly on the development of methods to analyze binary outcomes, such as malformations among live pups, while accounting appropriately for the correlation induced by the litter effect. In contrast, the topic of quantitative risk assessment has received relatively little attention. This paper addresses the specific question of how to assess risk appropriately when exposure causes a variety of adverse effects, including resorption and fetal death, in addition to malformations. It will be seen that risk assessments based on a single developmental outcome, such as malformation, may be conservative. A method is proposed for estimating an exposure level at which the overall risk of any adverse effect is acceptably low. The method is based on a continuation ratio formulation of a multinomial distribution, with an additional scale parameter to account for overdispersion. Comparisons are made with binary models on prenatal death and malformation, as well as a binary model that makes no distinction between death and malformation, but simply classifies each fetus as normal or abnormal. Data from several developmental toxicity studies illustrate the results and findings.     

Inhibitory effect of caffeine on 5-azacytidine-induced digital malformations in the rat

The effect of caffeine on 5-azacytidine (5-AC)-induced digital malformations in rat fetuses was investigated. Caffeine suppressed all types of digital defects in the fore- and hindlimbs except for syndactyly induced by 1.0 mg/kg of 5-AC; it was still effective when administered 24 hours after 5-AC treatment. However, fetal mortality increased as the frequency of malformations decreased. While the malformation results support the view that caffeine inhibits the processes leading to malformation expression, the relation between its suppressive effect on malformations and its enhancing effect on fetal mortality is unclear.     

Combined effects of radiation and caffeine on embryonic development in mice

The combined effect of radiation and caffeine has been studied in mouse embryos. Radiation and/or caffeine were administered to ICR mice on Day 11 of gestation. Intrauterine death, gross malformation, and fetal body weight were selected as indicators of effects. Doses of whole-body gamma irradiation were 0.5 to 2.5 Gy and those of caffeine were 100 and 250 mg/kg maternal body wt. Intrauterine mortality increased with increasing radiation dose; this trend was more remarkable in combination with caffeine. Gross malformations such as cleft palate and defects of forelegs and hindlegs appeared frequently in the fetuses treated with both radiation and caffeine. Decreased fetal weight was observed even in mice treated with 0.5 Gy of radiation or 100 mg/kg caffeine. There was a linear relationship between dose and reduction of fetal weight. The fetal weight was a sensitive, precise, and easy-to-handle indicator for the effects of growth retardation. Intrauterine mortality and frequencies of cleft palate and defects of forelegs and hindlegs were higher than the sum of those induced by radiation and by caffeine separately. The results indicated that the combined action of radiation and caffeine on intrauterine death and malformations was synergistic.     

Mitigation of caffeine-induced teratogenicity in mice by prior chronic caffeine ingestion.

Pregnant A/J female mice, which had drunk tap water or a 0.05% caffeine solution for 8-19 weeks after weaning, were each injected sc with 150 or 250 mg/kg caffeine once on day 13 of gestation. After 150 mg/kg caffeine the frequencies at term of fetal death, external malformation, and subcutaneous hematomas were significantly lower in the caffeine- than water-drinking group. After 250 mg/kg caffeine the frequency of fetal death but not of malformations and hematomas was lower in the group with caffeine pretreatment. These findings were explained by assuming that long-term ingestion of caffeine induced and increased rate of degradation of caffeine administered during pregnancy.     

Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy.

Ninety-nine insulin-dependent diabetic women with regular menstrual histories were examined by ultrasonic scanning in the seventh to 14th weeks of pregnancy. As judged by the crown-rump length 38 fetuses were smaller than normal. The term early growth delay is suggested for this phenomenon. Nine fetuses had major congenital malformations, and seven of them were smaller than normal in early pregnancy (p less than 0.02). The risk of fetal malformation in diabetic pregnancy increases with the severity of the diabetes. Early fetal growth delay is apparently another risk marker, in this series indicating a risk of 18% (7/38). The combination of severe maternal diabetes (White''s classes D and F) and early growth delay yielded a risk of major congenital malformation of 27% (6/22). These observations suggest a common mechanism behind early growth delay and induction of abnormal embryogenesis (and maybe even fetal death). The mechanism is unknown but probably influenced by the quality of regulation of diabetes.     

Numeric Estimates of Teratogenic Severity from Embryo–Fetal Developmental Toxicity Studies

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo–fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two‐ to <fivefold higher than control have detectable but a low level of teratogenic severity, and scores ≥fivefold higher than control have increasingly more severe teratogenicity. Such scores may help refine the concept of an exposure‐based validation list for use by proponents of screening assays (Daston et al., 2014) by estimating the severity of “positive” exposures, or in other situations by defining the severity of a LOAEL (lowest observed adverse effect level)     

Potentialities of magnetic resonance imaging in the complex of prenatal radiation diagnosis of fetal malformations

The purpose of the study was to investigate the potentialities of magnetic resonance imaging (MRI) in the complex of prenatal radiation diagnosis of fetal malformations. Twenty-eight female patients with suspected fetal malformations were examined. Ultrasound study was supplemented by MRI according to a specially developed protocol. Various fetal CNS malformations were diagnosed. These included the Arnold-Chiari syndrome, the Dandy-Walker syndrome, occlusive hydrocephaly, lobular holoprosencephaly, porencephaly, diaphragmatic hernias, anomalies of the abdomen and retroperitoneal space, as well as anomalies of facial structures, including median clefts, and dacryocystocele. The use of MRI in the complex prenatal radiation diagnosis makes it possible to visualize fetal malformation more clearly, contributes to the more adequate prediction of the outcome of pregnancy and to the choice of a management policy for a female patient.     

Antibodies to rubellavirus, herpes simplex virus and Toxoplasma gondii in serial serum samples of pregnant and non-pregnant women.

By testing serial serum samples of 213 pregnant women for rubellavirus, of 196 for herpes simplex virus and of 134 for Toxoplasma gondii, it was found that during pregnancy there was a fall in the humoral antibody level. Presence and titre of antibodies were lower in sera of pregnant than of non-pregnant women. Alteration of the humoral antibody level during pregnancy may influence serological studies aimed at clarifying the role of infections in fetal malformations. Serial serum samples (4 samples from each pregnant woman involved) should be tested for obtaining reliable data regarding the frequency of infections during pregnancy.     

The Archipelago of Fernando de Noronha: An Intriguing Malformed Toad Hotspot in South America

Malformed anurans raise concern among scientists, because deformities may relate to the recent global crisis among amphibian populations, although declining populations also may be associated with other causes (e.g., diseases, over-exploitation, and land use/land cover change). We examined a sample of toads (Rhinella jimi, Bufonidae) from an introduced population in the Archipelago of Fernando de Noronha, Brazil where malformations of anurans were thought to be high. Our sample of 159 specimens from the site revealed that 44.6% of all specimens had one or more malformations. Incidence of malformed toads on the mainland sites was substantially lower: 10.5% at Itamaracá, and 3.7% at Propriá. We describe the malformations observed, including six undescribed types of malformation of anurans, and we pose possible hypotheses to explain this high incidence of malformed toads. In addition to existing hypotheses, we suggest for the first time the hypothesis that lack of predation pressures contributes to numbers of malformed toads. We indicate the need of specific studies to understand the causes of malformations in the R. jimi population of Fernando de Noronha, which is thought to be extreme foci of malformed amphibians in the world. Our results may improve local conservation action plans as this is an alien population that may be affecting endemic fauna, and may affect populations in other parts of the world, because toad species of the genus Rhinella are recognized as exceptional colonizers. More importantly, unknown variables in these toads’ environment are evidently affecting toads during development, which should be a concern for all species that inhabit the area, perhaps even humans.     

Sequelae and support after termination of pregnancy for fetal malformation.

A retrospective study examined the reactions to the termination of pregnancy for fetal malformation and the follow up services that were available. Women resident in Mid Glamorgan who had had a termination between 1977 and 1981 because of positive findings after midtrimester prenatal diagnostic tests for neural tube defect or chromosome abnormalities were interviewed at home using a semistructured interview schedule. Three retrospective internal comparison groups were formed from those women who had also had a spontaneous abortion, previous stillbirth, or neonatal death or previous termination for medicosocial reasons early in pregnancy. Of the 48 women interviewed, 37 (77%) experienced an acute grief reaction after the index pregnancy was ended. This reaction was akin to that documented after stillbirth or neonatal death. Twenty two women (46%) remained symptomatic six months after the pregnancy had been ended, some requiring psychiatric support, compared with no such reaction after spontaneous abortion or termination for medicosocial reasons. All the women who had previously had a stillbirth or neonatal death were visited at home either by the general practitioner or by the midwife after that event but such follow up was limited to only eight of the study group after termination for fetal malformation. The findings suggest that support is inadequate for these patients and that improved follow up and counselling services may lessen the adverse sequelae of termination for fetal malformation.     

Congenital malformations in offspring of Vietnamese women in California, 1985-97

BACKGROUND: Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S. METHODS: Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women. RESULTS: The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, "other" limb, and "other" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or 相似文献   

The present and future of whole-exome sequencing in studying and treating human reproductive disorders

The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.     

The dependency of fetal left ventricular biomechanics function on myocardium helix angle configuration

The helix angle configuration of the myocardium is understood to contribute to the heart function, as finite element (FE) modeling of postnatal hearts showed that altered configurations affected cardiac function and biomechanics. However, similar investigations have not been done on the fetal heart. To address this, we performed image-based FE simulations of fetal left ventricles (LV) over a range of helix angle configurations, assuming a linear variation of helix angles from epicardium to endocardium. Results showed that helix angles have substantial influence on peak myofiber stress, cardiac stroke work, myocardial deformational burden, and spatial variability of myocardial strain. A good match between LV myocardial strains from FE simulations to those measured from 4D fetal echo images could only be obtained if the transmural variation of helix angle was generally between 110 and 130°, suggesting that this was the physiological range. Experimentally discovered helix angle configurations from the literature were found to produce high peak myofiber stress, high cardiac stroke work, and a low myocardial deformational burden, but did not coincide with configurations that would optimize these characteristics. This may suggest that the fetal development of myocyte orientations depends concurrently on several factors rather than a single factor. We further found that the shape, rather than the size of the LV, determined the manner at which helix angles influenced these characteristics, as this influence changed significantly when the LV shape was varied, but not when a heart was scaled from fetal to adult size while retaining the same shape. This may suggest that biomechanical optimality would be affected during diseases that altered the geometric shape of the LV.

     

Associated malformations in cases with congenital diaphragmatic hernia

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).     

小波阈值降噪的超声多普勒技术在胎儿中枢神经系统畸形筛查中的临床应用价值

摘要 目的：探究小波阈值降噪的超声多普勒技术在胎儿中枢神经系统（CNS）畸形筛查中的临床应用价值。方法：选择2018年1月-2021年1月于本院进行规范化妊娠早期超声结构筛查的1092例11-13+6周单胎妊娠孕妇,所有孕妇均进行常规超声和小波阈值降噪的超声多普勒技术的检查,并对其妊娠过程和结果进行随访。结果：1092例胎儿产后病理或超声检查显示,胎儿CNS畸形共计19例,发生率为1.74％（19/1092）。其中,露脑畸形8例,无脑畸形5例,前脑无裂畸形3例,脑膜膨出2例,脊柱裂1例。基于小波阈值降噪的超声多普勒技术对胎儿CNS畸形检出的符合率94.74%（18/19）显著高于常规超声63.16%（12/19）,差异有统计学意义（P<0.05）;且基于小波阈值降噪的超声多普勒技术检出胎儿CNS畸形的准确性、敏感度、特异度、阳性预测值、阴性预测值均显著高于常规超声,差异均均有统计学意义（P<0.05）。结论：小波阈值降噪的超声多普勒技术对妊娠早期孕妇进行规范化结构筛查更有助于及早发现胎儿CNS畸形,对降低畸形胎儿的出生率以及指导临床治疗方案的选择具有重要指导意义。