Maternal and fetal cord blood lipids in intrauterine growth restriction

Small for gestational age neonates (SGA) could be subdivided into two groups according to the underlying causes leading to low birth weight. Intrauterine growth restriction (IUGR) is a pathologic condition with diminished growth velocity and fetal compromised well-being, while non-growth restricted SGA neonates are constitutionally (genetically determined) small. Antenatal sonographic measurements are used to differentiate these two subgroups. Maternal metabolic changes contribute to the pathogenesis of IUGR. A disturbed lipid metabolism and cholesterol supply might affect the fetus, with consequences for fetal programming of cardiovascular diseases. We evaluated fetal serum lipids and hypothesized a more atherogenic lipoprotein profile in IUGR fetuses.

[How the bovine viral diarrhea virus outwits the immune system]

The interaction of bovine viral diarrhea virus (BVD virus) with its host has several unique features, most notably the capacity to infect its host either transiently or persistently. The transient infection stimulates an antiviral immune reaction similar to that seen in other transient viral infections. In contrast, being associated with immunotolerance specific for the infecting BVD viral strain, the persistent infection differs fundamentally from other persistent infections like those caused by lentiviruses. Whereas the latter are characterized by complex viral evasion of the host's adaptive immune response by mechanisms such as antigenic drift and interference with presentation of T cell epitopes, BVD virus avoids the immune response altogether by inducing both humoral and cellular immune tolerance. This is made possible by invasion of the fetus at an early stage of development. In addition to adaptive immunity, BVD virus also manipulates key elements of the host's innate immune response. The non-cytopathic biotype of BVD virus, which is capable of persistently infecting its host, fails to induce type I interferon. In addition, persistently infected cells are resistant to the induction of apoptosis by double-stranded RNA and do not produce interferon when treated with this pathogen-associated molecular pattern (PAMP) that signals viral infection. Moreover, when treated with interferon, cells persistently infected with non-cytopathic BVD virus do not clear the virus. Surprisingly, however, despite this lack of effect on persistent infection, interferon readily induces an antiviral state in these cells, as shown by the protection against infection by unrelated viruses. Overall, BVD virus manipulates the host's interferon defense in a manner that optimises its chances of maintaining the persistent infection as well as decreasing the risks that heterologous viral infections may carry for the host. Thus, since not all potential host cells are infected in animals persistently infected with BVD virus, heterologous viruses replicating in cells uninfected with BVD virus will still trigger production of interferon. Interferon produced by such cells will curtail the replication of heterologous viruses only, be that in cells already infected with BVD virus, or in cells in which the heterologous virus may replicate alone. From an evolutionary viewpoint, this strategy clearly enhances the chances of transmission of BVD virus to new hosts, as it attenuates the negative effects that a global immunosuppression would have on the survival of persistently infected animals.

[Antirheumatic therapy and reproduction. The influence on fertility, pregnancy and breast feeding]

Antirheumatic drugs can have a negative effect on reproduction in both men and women. Possible negative effects are impairment of fertility, harmful effects on the fetus and adverse effects on the breastfed child. In women non-steroidal antiinflammatory drugs (NSAID) and cyclophosphamide can impair fertility. In men infertility can result from the use of salazopyrine and cyclophosphamide. A desire for children should be taken into account before the start of disease modifying drugs (DMARD). Treatment with NSAID is possible at some stages of pregnancy as well as during lactation. A limited number of DMARD is compatible with pregnancy and is presented. Cytostatic drugs and leflunomide must be prophylactically withdrawn before a planned pregnancy. TNF alpha antagonists should be discontinued at the start of pregnancy. Safe birth control must be practised during therapy with drugs that are gonadotoxic or teratogenic. Treatment with immunosuppressive drugs during lactation is limited because of insufficient documentation of safety for the breastfed child.

[Search for Neospora caninum DNA in bull semen using PCR ]

Neospora caninum represents one of the most frequent abortifaciant organisms worldwide. The parasite is diaplacentally transmitted from the pregnant cow to the fetus, where it normally leads to the delivery of a healthy, however persistently infected calf. Abortion thus is a relative rare event. The transmission of bovine neosporosis occurs in more than 90% of the cases vertically due to the endogenous reactivation of a persistently infected mother. Exogenous infections are therefore responsible for less than 10% of the cases.The question arises about which infection sources may be relevant in this context. In Switzerland, the role of dogs as definitive hosts has been shown to be of low significance in that respect. Recently, discussion focused on the potential of infectious bull semen following natural or artificial insemination. Thus, a few years ago a report documented the detectability of N. caninum-DNA in the semen of naturally infected bulls by nested-PCR. As a consequence, we decided to gain own experience by investigating 5 separate semen specimens per animal, originating from 20 N. caninum-seropositive bulls used for artificial insemination in Switzerland. All probes turned out to be negative by nested PCR. Based upon our laboratory experiences, the potential bull semen-associated Neospora-problem seems not to affect the Swiss bull population, thus there is no evidence to include further respective means of control.

Modeling Breastmilk Infectivity in HIV-1 Infected Mothers

Estimation of breastmilk infectivity in HIV-1 infected mothers is difficult because transmission can occur while the fetus is in-utero, during delivery, or through breastfeeding. Since transmission can only be detected through periodic testing, however, it may be impossible to determine the actual mode of transmission in any individual child. In this paper we develop a model to estimate breastmilk infectivity as well as the probabilities of in-utero and intrapartum transmission. In addition, the model allows separate estimation of early and late breastmilk infectivity and individual variation in maternal infectivity. Methods for hypothesis testing of binary risk factors and a method for assessing goodness of fit are also described. Data from a randomized trial of breastfeeding versus formula feeding among HIV-1 infected mothers in Nairobi, Kenya are used to illustrate the methods.

C-reactive protein production in term human placental tissue

OBJECTIVE: C-reactive protein (CRP) is a marker of systemic inflammation. Recently, it has been shown that CRP is present in amniotic fluid and fetal urine, and that elevated levels are associated with adverse pregnancy outcome. However, the precise source of amniotic fluid CRP, its regulation, and function during pregnancy is still a matter of debate. The present in vivo and in vitro studies were designed to investigate the production of CRP in human placental tissues. MATERIAL AND METHODS: Ten paired blood samples from peripheral maternal vein (MV), umbilical cord artery (UA) and umbilical vein (UV) were collected from women with elective caesarean sections at term. The placental protein accumulation capacity of hCG, hPL, leptin and CRP was compared with the dual in vitro perfusion method of an isolated cotyledon of human term placentae and quantified by ELISA. Values for accumulation (release) were calculated as total accumulation of maternal and fetal circuits normalized for tissue weight and duration of perfusion. For gene expression, RNA was extracted from placental tissue and reverse transcribed. RT-PCR and real-time PCR were performed using specific primers. RESULTS: The median (range) CRP level was significantly different between UA and UV [50.1 ng/ml (12.1-684.6) vs. 61 ng/ml (16.9-708.1)]. The median (range) difference between UV and UA was 9.3 ng/ml (2.2-31.6). A significant correlation was found between MV CRP and both UA and UV CRP levels. Median (range) MV CRP levels [2649 ng/ml (260.1-8299)] were 61.2 (6.5-96.8) fold higher than in the fetus. In vitro, the total accumulation rates (mean+/-SD) were 31+/-13 (mU/g/min, hCG), 1.16+/-0.19 (microg/g/min, hPL), 4.71+/-1.91 (ng/g/min, CRP), and 259+/-118 (pg/g/min, leptin). mRNA for hCG, hPL and leptin was detectable using conventional RT-PCR, while CRP mRNA could only be demonstrated by applying real-time RT-PCR. In the perfused tissue the transcript levels for the four proteins were comparable to those detected in the native control tissue. CONCLUSIONS: Our results demonstrate that the human placenta produces and releases CRP mainly into the maternal circulation similarly to other analyzed placental proteins under in vitro conditions. Further studies are needed to explore the exact role of placental CRP during pregnancy.

A KEL gene encoding serine at position 193 of the Kell glycoprotein results in expression of KEL1 antigen

BACKGROUND: The KEL2/KEL1 (k/K) blood group polymorphism represents 578C>T in the KEL gene and Thr193Met in the Kell glycoprotein. Anti-KEL1 can cause severe hemolytic disease of the fetus and newborn. Molecular genotyping for KEL*1 is routinely used for assessing whether a fetus is at risk. Red blood cells (RBCs) from a KEL:1 blood donor (D1) were found to have abnormal KEL1 expression during evaluation of anti-KEL1 reagents. STUDY DESIGN AND METHODS: Kell genotyping methods, including KEL exon 6 direct sequencing, were applied. KEL cDNA from D1 was sequenced. Flow cytometry was used to assess KEL1 and KEL2 RBC expression. RESULTS: RBCs from the donor, her mother, and an unrelated donor gave weak or negative reactions with some anti-KEL1 reagents. Other Kell-system antigens appeared normal. The three individuals were homozygous for KEL C578 (KEL*2) but heterozygous for a 577A>T transversion, encoding Ser193. They appeared to be KEL*2 homozygotes by routine genotyping methods. Flow cytometry revealed weak KEL1 expression and normal KEL2, similar to that of KEL*2 homozygotes. CONCLUSION: Ser193 in the Kell glycoprotein appears to result in expression of abnormal KEL1, in addition to KEL2. The mutation is not detected by routine Kell genotyping methods and, because of unpredicted KEL1 expression, could lead to a misdiagnosis.

In utero haematopoietic stem cell transplantation. Experiences in mice, sheep and humans

Early prenatal diagnosis and in utero therapy of certain fetal diseases have the potential to reduce fetal morbidity and mortality. The intrauterine transplantation of stem cells provides in some instances a therapeutic option before definitive organ failure occurs. Clinical experiences show that certain diseases, such as immune deficiencies or inborn errors of metabolism, can be successfully treated using stem cells derived from bone marrow. However, a remaining problem is the low level of engraftment that can be achieved. Efforts are made in animal models to optimise the graft and study the recipient's microenvironment to increase long-term engraftment levels. Our experiments in mice show similar early homing of allogeneic and xenogeneic stem cells and reasonable early engraftment of allogeneic murine fetal liver cells (17.1% donor cells in peripheral blood 4 weeks after transplantation), whereas xenogeneic HSC are rapidly diminished due to missing self-renewal and low differentiation capacities in the host's microenvironment. Allogeneic murine fetal liver cells have very good long-term engraftment (49.9% donor cells in peripheral blood 16 weeks after transplantation). Compared to the rodents, the sheep model has the advantage of body size and gestation comparable to the human fetus. Here, ultrasound-guided injection techniques significantly decreased fetal loss rates. In contrast to the murine in utero model, the repopulation capacities of allogeneic ovine fetal liver cells are lower (0.112% donor cells in peripheral blood 3 weeks after transplantation). The effect of MHC on engraftment levels seems to be marginal, since no differences could be observed between autologous and allogeneic transplantation (0.117% donor cells vs 0.112% donor cells in peripheral blood 1 to 2 weeks after transplantation). Further research is needed to study optimal timing and graft composition as well as immunological aspects of in utero transplantation.

Multiple thromboembolic events in fetofetal transfusion syndrome in triplets contributing to the understanding of pathogenesis of hydranencephaly in combination with polymicrogyria

Over the last 180 years, several theories concerning the origin of hydranencephaly have been proposed with an emphasis on infectious, aplastic, and vascular etiologies. In this report, we present a case of triplets with fetofetal transfusion syndrome of which 2 fetuses (1 and 2) developed almost similar hydranencephaly, whereas the third exhibited the features of a fetus papyraceus (3). In the monochorial triamniotic placenta, multiple arteriovenous anastomoses were detected, representing a probable route for the transmission of thrombi originating from fetus 3 causing visceral lesions in fetus 2. Hydranencephaly was histologically characterized by necrosis, macrophage invasion, and endothelial proliferation. In addition, polymicrogyria was seen in fetuses 1 and 2. The combination of multiple visceral thromboembolic events and the death of fetus 3 approximately in the 11th week of gestation suggested a vascular thrombotic pathogenesis of hydranencephaly. Polymicrogyria can be considered as postmigratory laminar necrosis. Our findings contribute to the pathogenetic understanding of combined hydranencephaly and polymicrogyria.

Placental ABCA1 expression is reduced in primary antiphospholipid syndrome compared to pre-eclampsia and controls

The ATP binding cassette transporter A1 (ABCA1) mediates cellular cholesterol and phospholipid efflux, and is implicated in phosphatidylserine translocation and apoptosis. Loss of functional ABCA1 in null mice results in severe placental malformation. This study aimed to establish the placental localisation of ABCA1 and to investigate whether ABCA1 expression is altered in placentas from pregnancies complicated by pre-eclampsia and antiphospholipid syndrome. ABCA1 mRNA and protein localisation studies were carried out using in situ hybridization and immunohistochemistry. Comparisons of gene expression were performed using real-time PCR and immunoblotting. ABCA1 mRNA and protein was localised to the apical syncytium of placental villi and endothelia of fetal blood vessels within the villi. ABCA1 mRNA expression was reduced in placentas from women with APS when compared to controls (p<0.001), and this was paralleled by reductions in ABCA1 protein expression. There were no differences in ABCA1 expression between placentas from pre-eclamptic pregnancies and controls. The localisation of ABCA1 in human placenta is consistent with a role in cholesterol and phospholipid transport. The decrease in ABCA1 protein in APS may reflect reduced cholesterol transport to the fetus affecting the formation of cell membranes and decreasing the level of substrate available for steroidogenesis.

Floppy Baby mit makrozytärer Anämie und veganischer Mutter

We report the case of a 7 month-old girl that presented with acute anemia, generalized muscular hypotonia and failure to thrive. Laboratory evaluation revealed cobalamin deficiency, due to a vegan diet of the mother. The clinical triad of an acquired floppy baby syndrome with megaloblastic anemia and failure to thrive is pathognomic for infantile cobalamin deficiency. Neurological abnormalities are often irreversible and may be associated with delayed myelinization in the MRI. A normal cobalamin level in maternal serum and absence of anemia do not exclude subclinical deficiency. If cobalamin deficiency is suspected, e.g. in pregnant women on vegan diet, urinary methylmalonic acid excretion and plasma homocysteine levels should be determined and cobalamin substitution should be started at an early stage to avoid potentially irreversible damage of the fetus.

Perinatal adaptation in mammals: the impact of metabolic rate

Mammalian birth is accompanied by profound changes in metabolic rate that can be described in terms of body size relationship (Kleiber's rule). Whereas the fetus, probably as an adaptation to the low intrauterine pO2, exhibits an "inappropriately" low, adult-like specific metabolic rate, the term neonate undergoes a rapid metabolic increase up to the level to be expected from body size. A similar, albeit slowed, "switching-on" of metabolic size allometry is found in human preterm neonates whereas animals that are normally born in a very immature state are able to retard or even suppress the postnatal metabolic increase in favor of weight gain and O2 supply. Moreover, small immature mammalian neonates exhibit a temporary oxyconforming behavior which enhances their hypoxia tolerance, yet is lost to the extent by which the size-adjusted metabolic rate is "locked" by increasing mitochondrial density. Beyond the perinatal period, there are no other deviations from metabolic size allometry among mammals except in hibernation where the temporary "switching-off" of Kleiber's rule is accompanied by a deep reduction in tissue pO2. This gives support to the hypothesis that the postnatal metabolic increase represents an "escape from oxygen" similar to the evolutionary roots of mitochondrial respiration, and that the overall increase in specific metabolic rate with decreasing size might contribute to prevent tissues from O2 toxicity.

[Infections in pregnancy]

Infections in pregnancy may complicate its course and harm the fetus or newborn after vertical transmission. Treatment of asymptomatic bacteriuria is mandatory in pregnant women given the high risk of secondary pyelonephritis. Intraamniotic infection usually arises by the ascending route and is associated with premature rupture of membranes. Vaginal infections promote preterm labour or premature rupture of membranes and may be transmitted to the child during labour. They must therefore be treated although they often cause little discomfort to the pregnant woman. Systemic infections due to viral, protozoal and bacterial pathogens may be transmitted transplacentally and cause embryopathies, fetopathies or neonatal infections. Depending on the responsible agent the negative impact on the course of pregnancy and on the fetus' or neonate's health can be prevented or reduced by prophylactic or therapeutic interventions.

Leukaemia and pregnancy

In summary, the management of women diagnosed with leukaemia in pregnancy needs an interdisciplinary approach, including a careful oncological work-up as well as close monitoring of the pregnancy until delivery and beyond. Patients with acute leukaemias normally must receive anti-leukaemic treatment at full dosage prior to delivery, except for selected women diagnosed very close to term. Treatment should be avoided in the first trimester. The prognosis of pregnant women with acute leukaemia corresponds to that of an age-matched and diagnosis-matched non-pregnant cohort of patients, provided appropriate treatment is given. If given as of the second trimester, the typical chemotherapy regimes used for acute leukaemias imply acceptable acute toxicities to the fetus, with a somewhat increased risk of premature birth or developmental retardation, but no clear evidence of late sequelae in children and adolescents who were exposed to cytostatic agents whilst in utero. In chronic leukaemias and MDS, treatment may often be delayed until after delivery. In CML targeted therapy with imatinib mesylate is safe as of the second trimester, and possibly even before. Obstetric care and monitoring of women with leukaemia are essential throughout the pregnancy to ensure the best possible outcome for mother and child.

Regulation of fetal growth: consequences and impact of being born small

The first trimester of pregnancy is the time during which organogenesis takes place and tissue patterns and organ systems are established. In the second trimester the fetus undergoes major cellular adaptation and an increase in body size, and in the third trimester organ systems mature ready for extrauterine life. In addition, during that very last period of intrauterine life there is a significant increase in body weight. In contrast to the postnatal endocrine control of growth, where the principal hormones directly influencing growth are growth hormone (GH) and the insulin-like growth factors (IGFs) via the GH-IGF axis, fetal growth throughout gestation is constrained by maternal factors and placental function and is coordinated by growth factors. In general, growth disorders only become apparent postnatally, but they may well be related to fetal life. Thus, fetal growth always needs to be considered in the overall picture of human growth as well as in its metabolic development.