Insulin-like growth factor-binding protein 1 and insulin-like growth factor-binding protein 3 in pre-eclampsia

Objective To investigate circulating levels of insulin-like growth factor-binding protein 1 (IGFBP-1) and IGFBP-3 in the mother and the fetus in pregnancies complicated by pre-eclampsia, and the relationship between serum levels of IGFBPs and fetal birthweight.
Design A prospective study over an 18 month period.
Setting A tertiary care academic medical centre.
Participants Sixty-six pregnant women with pre-eclampsia (35 cases of mild/moderate pre-eclampsia and 31 cases of severe pre-eclampsia) and 78 nonpra-eclamptic pregnant women of matched gestational weeks and maternal ages.
Main outcome measures Serum concentrations of IGFBP-1 and IGFBP-3 at the time of delivery.
Results In pre-eclampsia associated with intrauterine growth retardation (IUGR), maternal and cord serum IGFBP-1 levels at the time of delivery were elevated. By contrast, circulating IGFBP-3 levels in both the mother and the fetus were lower in pre-eclampsia with IUGR than in nonpre-eclamptic pregnancy. However, there was no difference in serum IGFBP-1 and IGFBP-3 levels between pre-eclampsia without IUGR and nonpre-eclamptic pregnancy in both the mother and the fetus.
Conclusions In pre-eclampsia, elevated concentrations of circulating IGFBP-1 and decreased serum IGFBP-3 levels were observed in both the mother and the fetus. However, these changes may simply reflect low birthweight in pre-eclampsia.     

NK cells and pre-eclampsia

The immunological interaction between the mother and fetus has classically been thought of as one between paternal antigen and maternal T cells. However, the MHC antigen expression on human trophoblast and the immune cell populations present in the decidua suggest that this interaction primarily involves decidual NK cells rather than T cells, and this is supported by new functional studies. It is becoming apparent also that the maternal systemic immune response in pregnancy (Th1/Th2 shift) primarily involves NK cells. Aberrant NK cell activation both locally in the decidua and systemically in the maternal blood may be the cause of pre-eclampsia.     

Serum uric acid levels as an index of fetal prognosis in pregnancies complicated by pre-existing hypertension and pre-eclampsia of pregnancy

The relation of perinatal mortality to plasma-urate concentration and blood pressure was studied in 200 patients with pre-existing hypertension and 200 patients with pre-eclampsia of pregnancy. Perinatal mortality was markedly increased when maternal plasma-urate concentrations were raised, generally in association with severe pre-eclampsia of early onset or superimposed on pre-existing hypertension. Maternal hypertension, even severe, without hyperuricemia was associated with good prognosis for the fetus. When there was hyperuricemia, the prognosis for the fetus was poor irrespective of the level of blood pressure. Pre-eclampsia of pregnancy was associated with high perinatal mortality rate when compared with the rate in pre-existing hypertension. This study suggests that serum urate is a reliable index of fetal welfare when pregnancy is complicated by pre-eclampsia and pre-existing hypertension.     

The pathogenesis of pre-eclampsia: new aspects

The etiology of pre-eclampsia, a disorder specific to pregnancy, has not yet been clearly established. Generalized endothelial dysfunction is thought to occur. Inadequate trophoblast invasion at the feto-maternal junction has also been postulated as the cause. However, recent findings are more suggestive of an inappropriate maternal inflammatory response within the framework of placentation, the innate immune system being primarily involved. This exaggerated maternal intravascular inflammatory reaction to the invading trophoblast leads to the manifestations of pre-eclampsia in the mother and feto-placental unit. The extent of the inflammatory reaction, which is also present in normal pregnancy, is probably determined by genetic factors and any pre-existing disorder affecting the mother or fetus. The process is very complex and cannot be attributed to any one single cause.     

Alpha-fetoprotein, human placental lactogen, and pregnancy-specific beta 1-glycoprotein in pregnant women who drink: relation to fetal alcohol syndrome

To determine the usefulness of the assays of maternal serum alpha-fetoprotein, human placental lactogen, and pregnancy-specific beta 1-glycoprotein in prenatal diagnosis of fetal alcohol syndrome, these proteins were followed in 35 problem drinkers (greater than 100 gm of ethanol weekly) and in 14 abstinent women throughout gestation. Thirteen women gave birth to infants with fetal alcohol syndrome, and these women had low levels of alpha-fetoprotein and pregnancy-specific beta 1-glycoprotein but levels of human placental lactogen were normal. Low alpha-fetoprotein correctly predicted fetal alcohol syndrome in 59% with a relative risk of 2.46. Low pregnancy-specific beta 1-glycoprotein predicted fetal alcohol syndrome in 56%, and a relative risk was 3.29. Low alpha-fetoprotein and pregnancy-specific beta 1-glycoprotein may reflect primary or secondary effects of ethanol abuse in pregnancy and appear to be useful in predicting fetal alcohol syndrome.     

血小板参数及凝血功能相关指标预测子痫前期的研究进展

子痫前期是导致孕产妇及围生儿死亡的主要妊娠期特发性疾病。近年来,随着早产儿救治水平的提高,妊娠34周后子痫前期的积极治疗会获得良好母儿结局,但早发型子痫前期患者的治疗仍然差强人意,因此预测子痫前期的发生成为研究热点。研究发现子痫前期的发病与凝血-纤溶系统失衡有关。其中血小板参数、凝血四项、纤溶酶原激活物抑制剂1(PAI-1)、血管性血友病因子(vWF)、P-选择素和D-二聚体对子痫前期具有预测价值。综述这些指标用于预测子痫前期的研究进展。     

Origins of fetal growth restriction

Regulation of growth of the fetus and its placenta begins before pregnancy. Early in pregnancy the mother sets the rate of growth of the fetus on a trajectory, which may be modified by events later in pregnancy.Low maternal weight for height, history of previous small babies, maternal undernutrition, pregnancy disorders, e.g. pre-eclampsia, are associated with low birthweight. Maternal smoking is a major factor in developed countries; infections and undernutrition in developing countries.Recently, there has been emphasis on adverse long-term outcomes including ischaemic heart disease, hypertension and diabetes associated with poor fetal growth. Experimental studies in animals show that some of these outcomes can readily be induced by restriction of fetal growth.Progress in determining successful treatments to improve the growth of the fetus has lagged behind these epidemiological and experimental findings. However, nutrient supplements improve growth in undernourished women and smoking cessation also improves fetal size and outcome.     

Impact of progesterone on cytokine-stimulated nuclear factor-kappaB signaling in HeLa cells.

OBJECTIVE: A key event in the pathways leading to preterm labor may be the activation of nuclear factor-kappaB (NF-kappaB) in the fetal membranes and the cervix. Anti-inflammatory agents, such as the corticosteroids, inhibit the activation of NF-kappaB. We proposed to investigate the effects of progesterone pretreatment on cytokine-stimulated activation of NF-kappaB in HeLa cells, a human cervical epithelial cell line. METHODS: HeLa cells were pretreated with 10(-7) M progesterone for 24 hours and exposed to 1 ng/mL interleukin-1beta (IL-1beta) for 1 hour. Nuclear and cytosolic extracts were subjected to Western blot analysis using anti-p65 and anti-inhibitory protein-kappaBalpha (anti-IkappaBalpha) antibodies. Densitometric data (n=5) were compared using Kruskal-Wallis test. RESULTS: Pretreatment with progesterone interfered with IL-1beta-induced IkappaBalpha degradation. However, progesterone pretreatment resulted in a significant decrease in NF-kappaB protein subunit p65 in the cytoplasm. Pretreatment with progesterone did not reduce the amount of nuclear p65 and did not interfere with nuclear translocation of p65. CONCLUSION: Our observations suggest that any possible role played by progesterone in preterm labor prevention is not exerted through anti-inflammatory mechanisms of NF-kappaB down-regulation.     

Maternal serum activin A levels in association with intrauterine fetal growth restriction

Objective To assess maternal serum activin A as a potential marker of fetal growth restriction.
Design A cohort study.
Setting A maternal–fetal medicine unit, university teaching hospital.
Population Fifty-seven women with a small fetus (less than 10th centile for gestation) referred for assessment of fetal size by ultrasound biometry.
Methods At the time of presentation for fetal biometry, maternal blood was collected for activin A measurement. The case records of each woman were independently reviewed after delivery and the pregnancy grouped into one of three groups: constitutionally small fetus, intrauterine growth restricted (IUGR) fetus or IUGR fetus and maternal pre-eclampsia (IUGR–pre-eclampsia). Activin A levels in the three groups were compared.
Main outcome measures Maternal serum activin A levels.
Results Sixteen of the 57 pregnancies were classified as constitutionally small, 17 as IUGR and 24 as IUGR–pre-eclampsia. Expressed as multiples of a normal median (MoMs), the median (95% CI) activin A level in the constitutionally small pregnancies was 1.12 (0.72–1.39) MoMs significantly lower than the level in both the IUGR pregnancies, 3.00 (1.84–4.11) MoMs, and the IUGR–pre-eclampsia pregnancies, 7.96 (5.73–10.62) MoMs (   P = 0.002 and 0.0001 for IUGR vs constitutionally small and IUGR–pre-eclampsia vs constitutionally small, respectively  ).
Conclusions Maternal serum activin A may be useful in the assessment of the small for gestational age fetus.     

Psychosocial correlates of health-promoting and health-impairing behaviors in pregnancy

Abstract

Behaviors during pregnancy including eating, exercise, cigarette smoking, and other substance use affect the health of a pregnant woman and her fetus. However, little is known about what influences pregnant women to engage in these health behaviors. Based upon relevant theory, we hypothesized that because health-promoting behaviors require continuous efforts that may depend upon a reliable, stable set of resources, intrapersonal traits, namely self-esteem and optimism, would be associated with the practice of health-promoting behaviors during pregnancy. In addition, we hypothesized that variables reactive to the more immediate context, pregnancy-specific stress and perceived control over pregnancy, would be associated with the practice of health-impairing behaviors. We distinguished health-promoting and health-impairing behaviors in a diverse sample of 165 pregnant women and investigated whether such behaviors are associated with distinct psychosocial factors. Results supported study hypotheses and provide evidence that even after controlling for maternal age, income, body mass index, and gestation, a stable, self-relevant disposition, self-esteem, is associated with the practice of health-promoting behaviors in pregnancy whereas pregnancy-specific stress, a situationally-evoked factor, is associated with the practice of health-impairing prenatal behaviors. Perceived control over pregnancy, which may reflect stable disposition and situational perceptions, was associated with health-promoting and health-impairing behaviors.     

Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between 'self' and 'non-self'. Accordingly, the fetus activates the mother's immune system because the fetus is in part 'non-self'. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint. Instead, the danger model suggests that normal pregnancy, regardless of the expression of 'non-self' antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome. Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

Mouse model for allogeneic immune reaction against fetus recapitulates human pre-eclampsia

AIM: We have previously demonstrated that mRNA expression and enzyme activity levels of placental indoleamine 2,3-dioxygenase (IDO), which degrades L-tryptophan and blocks the proliferation of T cells, are significantly low in patients with severe pre-eclampsia. From this observation, we hypothesized that induction of maternal allogeneic immune reaction by reduced IDO activity is one of the causes of pre-eclampsia. METHODS: To examine this hypothesis, we administered an IDO inhibitor to pregnant female mice carrying allogeneic concepti. Since administration of an IDO inhibitor to pregnant mice starting at E4.5 is already reported to cause allogeneic fetal rejection, we modified the regimen and started the administration at E6.5 when the fetus and placenta have already been established. RESULTS: Pregnant mice treated with an IDO inhibitor developed high blood pressure and proteinuria in addition to local circulation impairment in the placenta, which is analogous to the lesions that are characteristic of human pre-eclampsia. In contrast, pregnant mice carrying syngeneic concepti did not manifest such symptoms. CONCLUSIONS: Our findings reveal a pivotal role for IDO activity in the etiology of pre-eclampsia. These data also lend support to the current hypothesis that pre-eclampsia is one of the possible manifestations of a maternal immunological reaction against an allogeneic fetus.     

Tumor necrosis factor-alpha activates nuclear factor-kappaB but does not regulate progesterone production in cultured human granulosa luteal cells.

BACKGROUND: The role of tumor necrosis factor-alpha (TNF-alpha) in granulosa luteal cell function and steroidogenesis is still controversial. Our aim was to examine the steroidogenic response, together with the simultaneous expression and activation of nuclear factor-kappaB (NF-kappaB), in cultured human granulosa luteal cells (GLCs) following administration of TNF-alpha. MATERIALS AND METHODS: This prospective controlled study was conducted in the Human Reproduction Division at the Institute of Maternal and Child Research, Faculty of Medicine, University of Chile and the San Borja Arriarán Hospital, National Health Service, Santiago, Chile. GLCs were obtained from aspirates of follicles from women undergoing in vitro fertilization (IVF). Thirty-two women undergoing IVF for tubal-factor and/or male-factor infertility participated in this study. Protein levels of NF-kappaB, the NF-kappaB inhibitor IkappaBalpha and steroidogenic acute regulatory protein (StAR) were determined by Western blot and localization of NF-kappaB was studied by indirect immunofluorescence. Progesterone production was determined by radioimmunoassay. RESULTS: TNF-alpha did not affect the expression of StAR protein or the synthesis of progesterone. NF-kappaB was expressed in the GLCs and activated by TNF-alpha, resulting in degradation of IkappaBalpha and mobilization of the p65 NF-kappaB subunit into the nucleus. CONCLUSIONS: These results indicate that TNF-alpha did not modulate steroidogenesis in cultured human GLCs. However, NF-kappaB was activated by TNF-alpha. Therefore the activation of NF-kappaB via the TNF-alpha pathway is likely associated with other preovulatory granulosa cell processes important for human ovarian function.     

Preeclampsia: a view through the danger model

Classical thinking suggests that the immune system undergoes activation on the basis of discrimination between ‘self’ and ‘non-self’. Accordingly, the fetus activates the mother's immune system because the fetus is in part ‘non-self’. Thus, successful pregnancy depends on constraint of maternal immunity. Preeclampsia is an outcome of lost constraint.Instead, the danger model suggests that normal pregnancy, regardless of the expression of ‘non-self’ antigens, does not activate the maternal immune system unless that pregnancy expresses danger signals. Thus, preeclampsia stems from stress or abnormal cell death in pregnancy-related tissues. This compels expression of specific danger signals and potential activation of anti-fetal immunity, which secondarily feeds the syndrome.Study of preeclampsia from this perspective may bring forth novel mechanisms and indicators of vascular and metabolic dysfunction during pregnancy.     

Obesity in pregnancy

Overweight and obesity are common findings in women of reproductive age in the UK; as 32% of 35- to 64-year-old women are overweight and 21% obese. Obesity causes major changes in many features of maternal intermediary metabolism. Insulin resistance appears to be central to these changes and may also be involved in increased energy accumulation by the fetus. Maternal obesity is associated with many risks to the pregnancy, with increased risk of miscarriage (three-fold) and operative delivery (20.7 versus 33.8% in the obese and 47.4% in the morbidly obese group). Other risks to the mother include an increased risk of pre-eclampsia (3.9 versus 13.5% in the obese group) and thromboembolism (0.05 versus 0.12% in the obese group). There are risks to the fetus with increased perinatal mortality (1.4 per 1000 versus 5.7 per 1000 in the obese group) and macrosomia (>90th centile; 9 versus 17.5% in the obese group). Maternal obesity is associated with an increased risk of obesity in the long term. Obese woman should try to lose weight before pregnancy but probably not during pregnancy. There is no real evidence base for the management of maternal obesity but some practical suggestions are made.     

子痫前期PI3K/Akt通路相关非编码RNA的研究进展

子痫前期（pre-eclampsia）是妊娠期常见并发症之一,是导致孕产妇和围生儿死亡的重要原因。子痫前期的发生与胎盘滋养细胞功能障碍密切相关。胎盘滋养细胞侵袭不全和子宫螺旋动脉重铸异常是子痫前期发生的主要病理机制。磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol-3 kinase/protein kinase B,PI3K/Akt)通路对胎盘滋养细胞的增殖、存活、凋亡、迁移和侵袭等过程具有重要调节作用。非编码RNA(non-coding RNA,ncRNA)中的微小RNA、长链非编码RNA和环状RNA具有重要的多水平基因调控功能,在PI3K/Akt通路中发挥重要调节作用,影响胎盘滋养细胞的功能,与子痫前期的发生、发展相关。综述近年子痫前期PI3K/Akt通路相关ncRNA的研究进展,为探索和发现子痫前期发病机制中的关键分子提供参考。     

Maternal and fetal plasma zinc in pre-eclampsia.

Zinc is important for fetal growth and is involved in several important enzyme systems. Maternal and umbilical plasma zinc concentrations were determined in 52 parturient women with mild and severe pre-eclampsia, and were compared with those obtained from 20 women in labor whose pregnancies had progressed normally. A decrease in maternal as well as umbilical plasma zinc concentrations was observed in pre-eclamptic women, and this decrease was statistically significant in severe pre-eclampsia. The causes of these changes in plasma zinc concentrations in pre-eclampsia were discussed, and the possible adverse effects of zinc deficiency on the mother and fetus were mentioned. Low plasma zinc concentrations in pre-eclampsia may be a sign of zinc deficiency, implying possible risks to the mother and her fetus. It is recommended that maintenance of adequate dietary zinc nutrition during pregnancy, and particularly in pre-eclampsia, is important.     

The human tumor-associated antigen RCAS1 in pregnancies complicated by pre-eclampsia

The human tumor-associated antigen RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is considered to play a role in the escape of tumor cells from immune surveillance and, at the same time, participates in the inhibition of the maternal immune response during pregnancy. The aim of our study was to investigate the expression of tumor-associated RCAS1 protein in the placenta and amniotic membranes and to assess and compare its concentration in amniotic fluid, maternal and cord blood sera in pregnancies complicated by pre-eclampsia. Samples were obtained from women with pre-eclampsia (N=9), pre-eclampsia with IUGR (N=4), normotensive IUGR (N=7) and healthy term controls (N=25) after delivery. Placentas were studied by immunohistochemistry, Western blot analysis and real-time (RT)-PCR. For assessment of RCAS1 protein concentrations in biological fluids, ELISA was performed. RCAS1 mRNA expression in the placentas of pre-eclamptic patients was significantly lower than in controls (p<0.01). The maternal blood serum RCAS1 protein concentration in the pre-eclampsia cases was also significantly lower than in controls (p=0.0207). The other study groups did not differ significantly. This study reveals the possible role of the RCAS1 protein in the development of pre-eclampsia through an immunological pathway.     

Current knowledge on natural killer cells, pregnancy and pre-eclampsia. Introduction

The introduction to this review discusses briefly why immunology, perceived as difficult by assisted reproduction technology clinicians, need nevertheless be envisaged as a central actor in the reproduction process, and how the maternal immune system, initially perceived as a threat to the fetoplacental unit, is in fact utterly necessary for successful pregnancy. The key cells in such a process are uterine natural killer cells, which can act as friend or foe to the fetus, but are now known to play a key role in local vasculogenesis. As an ultimate consequence in cases of dysfunction/dysregulation, these factors result in implantation failure, abortion or pre-eclampsia.