Experimental studies on vertical infection of mice with Japanese encephalitis virus. IV. Effect of virus strain on placental and fetal infection

An experiment was carried out to examine the effect of an inoculated strain of Japanese encephalitis virus on the establishment of experimental vertical infection of mice with this virus. In it, closed-colony mice of the CFW strain were inoculated intravenously with seven strains of the virus at 7 days of pregnancy. After that, an attempt was made to recover the virus from placenta and fetus, so that the infection rate of each strain might be determined. As a result, the infection rate was high for both placenta and fetus in the case of the AS-6 and Sagara strains both of which had undergone three passages in the mouse brain. The placental infection rate was high and the fetal infection rate relatively low in the case of the JaGAr01 and Fuji strains which had undergone 7 and 150 passages, respectively, in the mouse brain. The infection rate was very low for both placenta and fetus in the case of the Nakayama-Yakken strain which had undergone more than 100 passages in the mouse brain. There was no difference in the severity of viremia after inoculation between the AS-6 and Fuji strains. Both placental and fetal infection rates were low in the case of the JaTH160 strain which had undergone passages in mice by intraperitoneal inoculation and which presented a strong peripheral infectivity and induced a severe viremia after inoculation. Neither placental nor fetal infection occurred in the case of the S- strain used as live virus vaccine. These results indicated that placental and fetal infection rates varied from one virus strain to another.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hydrops fetalis caused by intrauterine human parvovirus infection

During a large outbreak of erythema infectiosum in 1987 in Toyama prefecture, Japan, a 32-year-old woman acquired a mild rash on her arms and legs at 18 weeks of gestation. At 26 weeks and 4 days of gestation, the fetus died by hydrops fetalis and pregnancy was terminated. Histological studies of the fetus revealed degeneration of erythroblastic cells in the liver and bone marrow. Extensive extramedullary hematopoiesis and hemosiderin deposits were observed in the liver. Antibody response to human parvovirus B19 virus was demonstrated in maternal sera by ELISA. Furthermore, dot hybridization with the molecularly cloned DNA probe revealed the presence of human parvovirus DNA sequence in the fetal liver, spleen, lung, kidney and placenta. This report describes the first case in Japan of hydrops fetalis caused by human parvovirus B19 infection.     

Effects of Trypanosoma vivax on pregnancy of Yankasa sheep and the results of homidum chloride chemotherapy

Three groups of pregnant Yankasa ewes, made up of six ewes in each group were assigned at random to first, second and third trimester of pregnancy studies. The ewes were experimentally infected with T. vivax to study the effects of the infection on pregnancy and the results of Novidium Chemotherapy. Three pregnant uninfected ewes served as controls. Fourteen days post infection, the ewes in each trimester study, were paired by weight and assigned to two groups of three ewes each. One group was treated with Novidium while the other group remained untreated. Of the three ewes in each group, one ewe was killed humanely at 21 days post infection and another at the end of the trimester period. In the first trimester, a ewe with partial fetal resorption was observed among the untreated ewes. Fetal death in-utero and expulsion of an autolyzed fetus was observed among the treated ewes. In the second trimester, abortion and almost complete fetal resorption were observed among the untreated ewes. Fetal death in-utero and expulsion of an autolyzed fetus was observed among the treated ewes. In the third trimester, abortions were observed among the untreated ewes. Abortion of a live fetus and a case of dystocia were observed among the treated ewes. Ewes in the second and third trimesters of pregnancy were more susceptible to the infection, with ewes in the third trimester being most susceptible, as measured by the number of abortions and death of ewes. Fetuses from the untreated ewes in the three trimesters of pregnancy were lower in body weights, than the fetuses from the treated ewes. The uninfected control ewes carried the pregnancies to term. Novidium chemotherapy at 14 days post infection was not beneficial in ameliorating the pathogenicity of T. vivax infection on pregnancy in Yankasa ewes. T. vivax infection of only 14 days was enough to cause irreversible pathology in Yankasa fetuses evidenced by death of fetuses in-utero, dystocia and abortions irrespective of Novidium chemotherapy.     

Experimental studies on vertical infection of mice with Japanese encephalitis virus. II. Effect of inoculation route on placental and fetal infection.

Studies were made on the effect of the route of inoculation on the establishment of experimental vertical infection of mice with Japanese encephalitis virus. Mice of the three strains, CFW, C3H/He, and C57BL/6, were inoculated with a field strain of the virus by the intravenous, intraperitoneal, or subcutaneous route. An attempt was made on them to recover the virus from the placenta and fetus. As a result, there were differences in rate of plancental and fetal infection among the route of inoculation. It was dependent the establishment of vertical infection. In general, the rates of placental and fetal infection were the highest in the case of intravenous inoculation, the second highest in the case of intraperitoneal inoculation, and the lowest in the case of subcutaneous inoculation, although there were small differences in this tendency among the mouse strains used. The differences in the rates of placental and fetal infection were presumed to be derived not from the difference in the severity of infection of the respective mothers, but from the degree of direct approach of virus to the placenta as one of the factors.     

Pathogenesis of in utero infections with abortogenic and non-abortogenic alphaviruses in mice.

The initial stages of infection of pregnant mice at gestation day 11 with either the T48 strain of Ross River virus or avirulent Semliki Forest virus are similar. With both infections, a hematogenous spread of virus to the placenta occurs. The viruses subsequently replicate to high titer in all placentas and are able to persist in the presence of specific maternal antiviral antibodies. There is a delay of at least 1 to 2 days between the initial detection of virus in the placenta and the onset of fetal infection. With Semliki Forest virus, abortion occurred in all mothers and appeared to be preceded by infection of all fetuses. However, when Semliki Forest virus was given at other stages of pregnancy, abortion was less common, and in all non-aborted pregnancies at least one uninfected fetus was observed. This situation was similar to that with Ross River virus, in which abortion was not observed and fetal infection and death were only seen in a proportion of fetuses. Within each pregnancy, the outcome of the two in utero infections appeared to result from similar mechanisms, with the fate of an individual fetus depending upon the timing of the passive transfer of anti-viral immunoglobulin G from the mother relative to the timing of fetal infection by virus from the placenta. Although the passive maternal immunoglobulin G protected susceptible fetuses against infection, antibody did not mediate in utero recovery of infected fetuses or clear placental infection.     

Prenatal and postnatal effects of dengue infection during pregnancy

The risk of dengue virus infection during pregnancy has increased due to the current rash of frequent and severe dengue epidemics. The effects of dengue virus in the fetus and newborn children have been studied only superficially and with contradictory results. Therefore, a retrospective cohort study was conducted in Medellin, Colombia, to describe the fetal and postnatal effects of dengue virus infection acquired during pregnancy. Twenty-two babies born from mothers who suffered dengue during the epidemics of 1998 were compared with babies from non-infected mothers. In the exposed cohort, three premature births occurred, three children suffered from fetal anomalies and four children were born with low weight. In the non-exposed children, none of these problems were found. Psychomotor development was normal in both groups. Only the low weight subgroup was statistically significant (Fisher test, p = 0.045). These results suggested that the children from women with dengue during pregnancy present low weight, greater frequency of premature birth and increased fetal distress. A larger sample is necessary to confirm these results.     

On the significance of true trisomy 20 mosaicism in amniotic fluid culture

Summary Nine new cases of prenatally detected true mosaic trisomy 20 (T20) are reported. In three instances the fetuses were aborted. One fetus showed multiple malformations associated with a high percentage of T20 cells among amniotic fluid (AF) cells and fibroblasts of different fetal tissues. In two other fetuses only a slight facial dysmorphy was seen which was accompanied by a low percentage of T20 cells among AF cells. In five instances the pregnancies were carried to term, and normal somatic and psychomotor development of the children has been observed, in one case up to the age of 24 months. In one case the pregnancy is continuing. The T20 cells were not detected among cultured lymphocytes of these children.A review of the hitherto known cases of prenatally detected mosaic T20 indicates a relationship between the prenatal findings and the fetal development. This may serve as a provisory basis for genetic counselling: in the case of a percentage above 50% of T20 cells among AF cells there seems to be a risk of about 50% for the fetus to be affected by severe anomalies. However, in cases of a prenatally detected mosaic T20 with a percentage equal to or less than 50, fetal or congenital malformations have not been observed among 23 individuals so far examined.     

Pregnancy and viral infections: Mechanisms of fetal damage,diagnosis and prevention of neonatal adverse outcomes from cytomegalovirus to SARS-CoV-2 and Zika virus

Some maternal infections, contracted before or during pregnancy, can be transmitted to the fetus, during gestation (congenital infection), during labor and childbirth (perinatal infection) and through breastfeeding (postnatal infection). The agents responsible for these infections can be viruses, bacteria, protozoa, fungi. Among the viruses most frequently responsible for congenital infections are Cytomegalovirus (CMV), Herpes simplex 1–2, Herpes virus 6, Varicella zoster. Moreover Hepatitis B and C virus, HIV, Parvovirus B19 and non-polio Enteroviruses when contracted during pregnancy may involve the fetus or newborn at birth. Recently, new viruses have emerged, SARS-Cov-2 and Zika virus, of which we do not yet fully know the characteristics and pathogenic power when contracted during pregnancy.Viral infections in pregnancy can damage the fetus (spontaneous abortion, fetal death, intrauterine growth retardation) or the newborn (congenital anomalies, organ diseases with sequelae of different severity). Some risk factors specifically influence the incidence of transmission to the fetus: the timing of the infection in pregnancy, the order of the infection, primary or reinfection or chronic, the duration of membrane rupture, type of delivery, socio-economic conditions and breastfeeding. Frequently infected neonates, symptomatic at birth, have worse outcomes than asymptomatic. Many asymptomatic babies develop long term neurosensory outcomes.The way in which the virus interacts with the maternal immune system, the maternal-fetal interface and the placenta explain these results and also the differences that are observed from time to time in the fetal?neonatal outcomes of maternal infections. The maternal immune system undergoes functional adaptation during pregnancy, once thought as physiological immunosuppression. This adaptation, crucial for generating a balance between maternal immunity and fetus, is necessary to promote and support the pregnancy itself and the growth of the fetus. When this adaptation is upset by the viral infection, the balance is broken, and the infection can spread and lead to the adverse outcomes previously described. In this review we will describe the main viral harmful infections in pregnancy and the potential mechanisms of the damages on the fetus and newborn.     

双胎妊娠一胎宫内死亡18 例临床分析

目的:探讨双胎妊娠中一胎宫内死亡的原因、对母亲和存活胎儿的影响及临床处理方法。方法:对2001年1月至2011年10月分娩的双胎妊娠之一胎宫内死亡的18例产妇临床资料进行回顾性分析。结果:双胎妊娠一胎宫内死胎的发生率占双胎的1.08%,其中单绒毛膜双羊膜囊双胎(monochorionic-diamniotic twin,MCDA)11例(61.11%),双绒毛膜双羊膜囊双胎(dichorionic-diamniotic twin,DCDA)7例(38.89%)。胎儿死因:胎盘脐带因素3例(16.67%),胎儿畸形1例(5.56%),妊娠并发症3例(16.67%),双胎输血综合征(twin-twin transfusion syndrome,TTTs)3例(16.67%),宫内感染3例(16.67%),不明原因5例(27.78%)。另一胎选择剖宫产者13例,阴道分娩3例。双胎一胎死亡后对母体的凝血功能影响不大(P>0.05)。结论:单绒毛膜双胎较双绒毛膜双胎母儿结局存在差别;双胎一胎宫内死亡对母体及存活儿有一定影响。对于孕周小,胎儿尚不成熟的病例,可严密监测存活胎儿宫内情况,行期待治疗延长孕龄至足月再分娩。     

The influence of fetoabdominal tissues on fetal ECGs and MCGs

Both fetal electrocardiography and fetal magnetocardiography are influenced by the volume conduction within the abdomen of the pregnant woman. In this paper, various models are used to simulate this influence. Such models are helpful to determine where to attach electrodes at the maternal abdomen in case fetal ECGs are measured and where to position the magnetocardiograph in case fetal MCGs are measured. Another goal is to assess the influence of individual differences, such as the amount of amniotic fluid. Seven models based on MR-images have been created, four for the third trimester of gestation, with the fetus in left occiput position, and three for the second trimester. The models consist of four compartments; the fetus, the vernix caseosa, the amniotic fluid, and the remainder of the maternal abdomen. It turns out that individual differences have a large impact on the fetal MCG and that the best measurement positions are expected over the centre of the abdomen near the fetal heart. The fetal ECG is dependent on the vernix caseosa and when this layer is present, the fetal ECG is best measured by two electrodes, one over the fetal mouth and the other over the bottom of the fetus.     

Plasmodium berghei: histology, immunocytochemistry, and ultrastructure of the placenta in rodent malaria

The pathological changes associated with malarial infection in pregnancy were studied in rats and mice infected with Plasmodium berghei at different stages of gestation. Histopathological and ultrastructural studies of infected placentae near term in both species revealed disruption of architecture with gross thickening and necrosis of cells in the labyrinthine zone and fibrosis of the trilaminar trophoblast separating the maternal and fetal circulations. In the mouse, the extent of histopathological alterations in infected placentae ranged from the presence of immature erythrocytes in the fetal circulation in low grade maternal infection, to the marked deposition of fibrinoid material on the trilaminar trophoblast and inflammatory masses in severely infected placentae. In the rat, histopathological aberrations in the placentae were marked by placental stroma edema, fibrosis, and cellular infiltration. Immunohistological studies of cryostat sections of placentae from infected animals showed more parasites and pigment in infected mouse placentae than in the corresponding rat organ, but in both species parasites and pigment were largely confined to the maternal blood spaces and were only occasionally found in necrotic areas of trophoblast. No clear differences were observed between infected and control placentae in terms of the amount of IgG, IgM, or IgA which were each present in various amounts. These observations and the rarity of congenital malaria in the animals indicate that the placenta constitutes a major barrier to infection of the fetus. However, the pathological aberrations in the infected placentae may impose a biochemical stress upon the fetus which may account for the low birthweight, the increased frequency of abortion, and the greatly increased maternal and fetal death rates observed in malaria.     

Bovine maternal,fetal and neonatal responses to bovine viral diarrhea virus infections

Due to the affinity of BVDV for the fetus and for cells of lymphatic organs of infected cattle, reproductive failure or immunosuppression, respectively, are likely consequences of BVDV infections of susceptible cattle. Infection of susceptible pregnant cattle with noncytopathic (ncp) BVDV results in transplacental infection with induction of maternal and fetal innate and adaptive immune responses. Differences in maternal innate and adaptive immune responses are evident in late gestation between cows carrying fetuses persistently-infected (PI) with BVDV and cows with fetuses transiently-infected with BVDV. Fetal innate and adaptive immune responses to ncp BVDV infection are defined by fetal age and developmental stage of the fetal immune system. Since a functional fetal adaptive immune response does not occur in the early fetus, immunotolerance to ncp BVDV is established, virus replicates unrestricted in fetal tissues and calves are born immunotolerant and PI with the virus. In the last trimester of gestation, the fetal immune system is adequately developed to respond in an efficacious manner, most commonly resulting in the birth of a clinically normal calf with pre-colostral antibodies. Immunosuppression due to postnatal acute ncp BVDV infections of susceptible calves may contribute to the occurrence and severity of multi-factorial respiratory tract and enteric diseases.     

In situ hybridization for the detection of human parvovirus B19 nucleic acid sequences in paraffin-embedded specimens

Parvovirus infection of pregnant women leading to a transplacentar infection of the fetus may result in hydrops fetalis, and ultimately in intrauterine death of the fetus. In situ hybridization with a biotinylated as well as with a 35S-labeled probe for human parvovirus B19 was performed on formalin-fixed paraffin-embedded (FFPE) tissue from a fetus suffering from non-immunologic hydrops fetalis. Histology was suggestive of viral infection probably with human parvovirus. Parvovirus DNA could be detected and precisely localized mainly in the nuclei of erythroid precursors cells within fetal blood vessels of all organs examined. There was no detection of B19 nucleic acid in parenchymal cells of the placenta or the fetal organs, nor within maternal blood cells. These findings are in agreement with the well-known properties of animal parvoviruses to replicate exclusively in proliferating cells. Taking into consideration the problems in diagnosing human parvovirus infection by light microscopy, we conclude that in situ hybridization with an appropriate non-radioactive probe is a valuable, rapid and safe complementary detection method for the diagnosis and study of human parvovirus infections. The 35S-labeled probe is more sensitive than the biotinylated probe, but has the disadvantages of lower resolution of the signal, longer duration of the assay, the hazard of radioactivity and the shorter shelf-life of the probe.     

Fetal immunization of baboons induces a fetal-specific antibody response

Neonates face a high risk of infection because of the immaturity of their immune systems. Although the transplacental transfer of maternal antibodies to the fetus may convey improved postnatal immunity, this transfer occurs late in gestation and may fail to prevent in utero infection. Both fetal immunization and in utero exposure to antigen can result in a state of immunologic tolerance in the neonate. Tolerance induction of fetal and premature infant lymphocytes has become a paradigm for neonatal responsiveness. However, fetal IgM responses have been demonstrated to maternal immunization with tetanus toxoid and to congenital infections such as rubella, toxoplasma, cytomegalovirus and human immunodeficiency virus. Moreover, 1-week-old infants can respond to standard pediatric vaccination, and neonates immunized with polysaccharide antigens do not develop immunologic tolerance. Here, direct immunization of the baboon fetus with recombinant hepatitis B surface antigen produced a specific fetal IgG antibody response. No specific maternal antibody response was detected, eliminating the possibility of vertical antibody transmission to the fetus. Some infants also responded to later vaccinations with hepatitis B surface antigen, indicating that no immunological tolerance was induced by prior fetal immunization. These results characterize the ability of the fetal immune system to respond to in utero vaccination. We demonstrate that active fetal immunization can serve as a safe and efficient vaccination strategy for the fetus and neonate.     

从乙型肝炎病毒表面抗原阳性母亲流产的胎儿查出乙型肝炎病毒标志

应用Southern blot杂交试验检测HBsAg及HBeAg均阳性母亲流产的9例胎儿肝细胞中HBV DNA的存在状态,并与其HBV血清学、免疫电镜及肝脏免疫组织化学的结果相比较。结果在3例胎肝高分子DNA中检出了整合的HBV DNA顺序,且此3例HBV DNA整合到胎肝细胞基因组并无特定部位,提示为随机整合。3例中2例的血清及肝匀浆都检出HBsAg颗粒,其胎肝细胞胞浆HBsAg也阳性;另1例受HBV感染的唯一标志是在胎肝细胞中存在着整合的HBVDNA。此外,另1例则仅胎肝细胞中HBsAg阳性而无整合的HBV DNA。在胎肝细胞中检出整合的HBV DNA进一步证实HBV子宫内传播途径的存在。     

Differential transmission of parvovirus B19 in a twin gestation: a case report.

Maternal infection with parvovirus B19 during pregnancy can cause aplastic anemia in the fetus. Severe anemia may lead to nonimmune hydrops or fetal demise. In the case reported, the demise of one twin was diagnosed by ultrasonography in an asymptomatic 21-year-old para 1-0-2-1 African American at the gestational age of 25 weeks. The deceased twin (A) was grossly hydropic with anasarca, ascites, pleural and pericardial effusions, and a thickened placenta. Parvovirus B19 DNA was found in the amniotic fluid of Twin A using the polymerase chain-reaction technique. Serial scans of Twin B showed normal growth and no evidence of hydrops. The pregnancy was managed expectantly until 29 weeks when delivery was indicated by maternal disseminated intravascular coagulation. Maternal IgM antiparvovirus B19 antibodies were detected at the time of delivery. Antiparvovirus B19 IgM antibodies were not present in Twin B. These serologic studies suggest a recent acute maternal infection and refute such an infection in Twin B. We present a case of differential transmission of parvovirus B19 in a twin pregnancy with in utero death of the infected twin and subsequent maternal disseminated intravascular coagulation.     

Fetal infection with Neospora caninum in dairy and beef cattle in Belgium

Neospora caninum is a protozoan parasite, which causes fetal and neonatal mortality in livestock and companion animals. In 224 abortions in Belgian cattle, different diagnostic methods were used to demonstrate infection, and the presence of N. caninum. An indirect fluorescent antibody test (IFAT) was used to analyze fetal and maternal sera and immunohistochemistry (IHC) was performed when lesions consistent with neosporosis were observed in the brain, heart or liver. Twenty dairy cattle sera out of 70 (29%) and 13 beef cattle sera out of 93 (14%) were positive by IFAT. A positive titer to N. caninum was found in seven and three fetuses born to beef and dairy cows, respectively. Lesions consistent with N. caninum infection were observed in 17 fetuses. Of nine positive beef fetuses, five were confirmed by IHC while, all but one dairy fetus were confirmed using the same technique.Age had no influence on the serological status of the mother (P = 0.486) whereas husbandry system had a borderline influence (P = 0.082). However, a strong association (P = 0.004) between the level of antibodies in the dam and the occurrence of lesions in the fetus was observed and lesions were more prominent in dairy than in beef fetuses. Additionally, the distribution of intra-cerebral lesions was more extensive in dairy than in beef fetuses (P < 0.0001). Age and serological status of the fetus were found to influence the occurrence of lesions in beef fetuses (both P < 0.001) but no such significant relationships could be demonstrated in dairy fetuses. The study indicated that N. caninum must be considered as an important cause of bovine abortion in Belgium.     

Comparison of cerebrospinal fluid transport in fetal and adult sheep

We quantified cerebrospinal fluid (CSF) transport (conductance) and CSF outflow resistance in late-gestation fetal and adult sheep using two methods, a constant pressure infusion method and a bolus injection technique into the lateral ventricles. No significant differences in CSF conductance (fetus 0.013 +/- 0.002, adult 0.014 +/- 0.003 ml x min(-1) x cm H(2)O(-1)) or CSF outflow resistance (fetus 83.7 +/- 9.8, adult 84.7 +/- 19.7 cm H(2)O x ml(-1) x min) were observed. To confirm CSF transport to plasma in fetal animals, (125)I- or (131)I-labeled human serum albumin (HSA) was injected into the lateral ventricles. The tracer entered fetal plasma with an average mass transport rate of 1.91 +/- 0.47% injected/h (n = 9). In two fetuses, we monitored the tracer appearance in plasma and cervical and thoracic duct lymph after injection of radioactive HSA into the ventricular CSF. As was the case in adult animals, fetal tracer concentrations increased in all three compartments over time, with the highest concentrations measured in lymph collected from the cervical lymphatics. These results 1) indicate that global CSF transport parameters in the late-gestation fetus and adult sheep are similar and 2) suggest an important role for extracranial lymphatic vessels in CSF transport before birth.     

In situ hybridization for the detection of human parvovirus B19 nucleic acid sequences in paraffin-embedded specimens

Parvovirus infection of pregnant women leading to a transplacentar infection of the fetus may result in hydrops fetalis, and ultimately in intrauterine death of the fetus. In situ hybridization with a biotinylated as well as with a³⁵S-labeled probe for human parvovirus B19 was performed on formalin-fixed paraffin-embedded (FFPE) tissue from a fetus suffering from non-immunologic hydrops fetalis. Histology was suggestive of viral infection probably with human parvovirus. Parvovirus DNA could be detected and precisely localized mainly in the nuclei of erythroid precursors cells within fetal blood vessels of all organs examined. There was no detection of B19 nucleic acid in parenchymal cells of the placenta or the fetal organs, nor within maternal blood cells. These findings are in agreement with the well-known properties of animal parvoviruses to replicate exclusively in proliferating cells. Taking into consideration the problems in diagnosing human parvovirus infection by light microscopy, we conclude that in situ hybridization with an appropriate non-radioactive probe is a valuable, rapid and safe complementary detection method for the diagnosis and study of human parvovirus infections. The³⁵S-labeled probe is more sensitive than the biotinylated probe, but has the disadvantages of lower resolution of the signal, longer duration of the assay, the hazard of radioactivity and the shorter shelflife of the probe.     

Trisomy 16 confined to chorionic villi and unfavourable outcome of pregnancy.

Two cases of trisomy 16 confined to placental tissue associated with an unfavourable outcome of the pregnancy are reported. In the first case, after a diagnosis of an apparent non-mosaic trisomy 16 at chorionic villi sample (CVS), an intrauterine fetal death occurred at the 22nd week. In the second case a mosaic with trisomy 16 was found in chorionic villi and the fetus was still-born at 38 weeks. From a comparison of their cases with those of the literature, the authors conclude that a trisomy 16 confined to placental tissue has a negative effect on fetal growth and pregnancy outcome.