The antithrombin binding regions of heparin mediate fetal growth and reduced placental damage in the RUPP model of preeclampsia†.

Preeclampsia is a serious hypertensive disorder of pregnancy, which is only cured with delivery of the placenta, thereby commonly necessitating preterm birth of the fetus. Low-molecular-weight heparin (LMWH) has demonstrated potential to reduce the incidence of preeclampsia in high-risk pregnant women, although the underlying mechanism by which LMWH protects against preeclampsia is unknown. Given the complex structure and biologic actions of heparin, we tested the hypothesis that heparin can mediate preeclampsia prevention via nonanticoagulant pathways. We compared the effects of a nonanticoagulant, glycol-split LMWH (gsHep)-rendered nonanticoagulant through disruption of the antithrombin binding regions-with the LMWH dalteparin in the rat reduced uterine perfusion pressure (RUPP) surgical model of preeclampsia. Although RUPP animals exhibit significantly elevated blood pressure and reduced plasma levels of placental growth factor (PGF) compared to sham, neither dalteparin nor gsHep treatment significantly impacted these parameters. However, the observed positive correlation between PGF levels and number of viable fetuses in RUPP-induced animals suggests that reduced PGF levels were predominately due to placental loss. Daily subcutaneous injections of low-dose dalteparin but not gsHep significantly restored fetal growth that was impaired by RUPP surgery. Placentas from RUPP animals exhibited an abnormal labyrinth structure, characterized by expanded sinusoidal blood spaces, relative to sham-operated animals. Morphometric analysis demonstrated that dalteparin but not gsHep treatment normalized development of the labyrinth in RUPP-exposed conceptuses. These data suggest that the antithrombin-binding regions of LMWH are required to confer its protective effects on fetal growth and placental development.

Periconception mHealth platform for prevention of placental-related outcomes and non-communicable diseases.

Most placental-related pregnancy complications originate during the first trimester of pregnancy where gene-environmental interactions play a role. The environmental factors also include parental behaviors that can be positive, such as folic acid supplement use, or negative, e.g. poor lifestyle choices like smoking, and nutritional choices that contribute to obesity or micronutrient deficits. The overlapping risk factors associated with non-communicable disease are poor nutrition, smoking, and obesity. These modifiable factors differ between individuals, populations and high, middle and low income countries, but have in common that they are extremely difficult to change. Parents-to-be however are most motivated to change poor behaviors when they are aware of short-term health benefits of having a healthy baby. Therefore, these couples should be empowered to use evidence-based and personalized effective tools to improve poor behaviors. Moreover, these tools should be implemented to support healthcare professionals in delivering 'nutrition and lifestyle care' in routine patient care. From this background the usability and effectiveness of the mHealth coaching program www.SmarterPregnancy.co.uk (Dutch version www.SlimmerZwanger.nl) is presented as an opportunity to further customize this tool for specific target groups, healthcare professionals and low resource settings with the potential to prevent placental-related and non-communicable disease during the life course.

Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta (MPFD).

Massive perivillous fibrin deposition of the placenta (MPFD) or maternal floor infarction (MFI) is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction. There is no method to evaluate the risk of adverse outcome in subsequent pregnancies, or effective prevention. Recent observations suggest that MFI is characterized by an imbalance in angiogenic/anti-angiogenic factors in early pregnancy; therefore, determination of these biomarkers may identify the patient at risk for recurrence. We report the case of a pregnant woman with a history of four consecutive pregnancy losses, the last of which was affected by MFI. Abnormalities of the anti-angiogenic factor, sVEGFR-1, and soluble endoglin (sEng) were detected early in the index pregnancy, and treatment with pravastatin corrected the abnormalities. Treatment resulted in a live birth infant at 34 weeks of gestation who had normal biometric parameters and developmental milestones at the age of 2. This is the first reported successful use of pravastatin to reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death.

Designing a VAR2CSA-based vaccine to prevent placental malaria.

Placental malaria (PM) due to Plasmodium falciparum is a major cause of maternal, fetal and infant mortality, but the mechanisms of pathogenesis and protective immunity are relatively well-understood for this condition, providing a path for vaccine development. P. falciparum parasites bind to chondroitin sulfate A (CSA) to sequester in the placenta, and women become resistant over 1-2 pregnancies as they acquire antibodies that block adhesion to CSA. The protein VAR2CSA, a member of the PfEMP1 variant surface antigen family, mediates parasite adhesion to CSA, and is the leading target for a vaccine to prevent PM. Obstacles to PM vaccine development include the large size (∼ 350 kD), high cysteine content, and sequence variation of VAR2CSA. A number of approaches have been taken to identify the combination of VAR2CSA domains and alleles that can induce broadly active antibodies that block adhesion of heterologous parasite isolates to CSA. This review summarizes these approaches, which have examined VAR2CSA fragments for binding activity, antigenicity with naturally acquired antibodies, and immunogenicity in animals for inducing anti-adhesion or surface-reactive antibodies. Two products are expected to enter human clinical studies in the near future based on N-terminal VAR2CSA fragments that have high binding affinity for CSA, and additional proteins preferentially expressed by placental parasites are also being examined for their potential contribution to a PM vaccine.

Alteration of placental haemostatic mechanisms in idiopathicintrauterine growth restriction / Alteración de los mecanismos hemostáticos de la placenta en restricción de crecimiento intrauterino idiopático / Alteração dos mecanismos hemostáticos da placenta em restrição de crescimento intra-uterino idiopático

La restriccióndel crecimiento intrauterino es una complicación del embarazo con alta probabilidad de morbilidad y mortalidad perinatal, que pareceser causada por desarrollo anormal de la vasculatura placentaria. Los procesos hemostáticos son importantes para el desarrollo de laplacenta y el desequilibrio entre factores procoagulantes y anticoagulantes se ha asociado con restricción del crecimiento intrauterino.Objetivo. Evaluar el compromiso hemostático en la placenta de los embarazos complicados con restricción del crecimiento intrauterinoidiopática. Materiales y métodos. Se estudiaron cinco placentas de embarazos con restricción de crecimiento intrauterino idiopática y 19controles. Se realizó examen macroscópico e histológico, y análisis de la expresión de factor tisular y trombomodulina a nivel de ARNmpor PCR en tiempo real y proteínas por ELISA. Resultados. Se evidenció compromiso hemostático en las placentas de embarazos conrestricción de crecimiento intrauterino idiopática, siendo la trombosis de los vasos coriales el hallazgo histológico más importante. Seencontró aumento en la expresión de la proteína del factor tisular (p=0,0411) y en la razón de factor tisular/trombomodulina a nivel deARNm (p=0,0411) y proteína (p=0,0215). No hubo diferencias estadísticamente significativas entre los grupos en los niveles de ARNmde factor tisular o trombomodulina, ni de trombomodulina a nivel de proteína. Conclusión. Se presenta evidencia de alteración de losmecanismos hemostáticos de la placenta, incluyendo la expresión anormal de factor tisular y de la razón factor tisular/trombomodulina,en embarazos complicados con restricción del crecimiento intrauterino idiopática...

Intrauterine growth restriction is a complication of pregnancy with a high probability of perinatal morbidity and mortality. It appears tobe caused by abnormal development of placental vasculature. Haemostatic processes are important for the development of the placenta,and an imbalance between procoagulant and anticoagulant factors has been associated with risk of intrauterine growth restriction.Objective. To evaluate coagulation abnormalities in placenta of pregnancies complicated with idiopathic intrauterine growth restriction.Materials and methods. Five placentas from pregnancies with idiopathic intrauterine growth restriction were compared to 19 controls.We performed gross and histological examination of the placenta. Analysis was made of both mRNA expression by real-time PCRand protein by ELISA of tissue factor and thrombomodulin in placental tissue. Results. Results based on histological evaluation wereconsistent with an increased prothrombotic state in placentas from pregnancies with idiopathic intrauterine growth restriction, andthrombosis of chorionic vessels was the most important finding. The study showed an increased expression of tissue factor protein(p=0.0411) and an increase in the ratio of tissue factor/thrombomodulin mRNA (p=0.0411) and protein (p=0.0215) in placentas frompregnancies with idiopathic intrauterine growth restriction. There were no statistically significant differences neither between cases andcontrols in the mRNA levels of tissue factor or thrombomodulin nor at the protein level of thrombomodulin. Conclusion. Evidence ofalteration of local haemostatic mechanisms at the level of the placenta, including abnormal expression of tissue factor and tissue factor/thrombomodulin ratio, in pregnancies that occur with idiopathic intrauterine growth restriction is presented...

A restrição do crescimentointra-uterino é uma complicação da gravidez com alta probabilidade de morbidade e mortalidade perinatal, que parece ser causada pelodesenvolvimento anormal da vasculatura placentária. Os processos hemostáticos são importantes para o desenvolvimento da placenta,e o desequilíbrio entre fatores pró-coagulantes e anticoagulantes têm sido associadas com a restrição de crescimento intra-uterino.Objetivo. Avaliar o compromisso hemostático na placenta com gestações complicadas com restrição de crescimento intra-uterinoidiopático. Materiais e métodos. Foram estudadas cinco placentas de gestações com restrição de crescimento intra-uterino idiopáticoe 19 controles. Foi realizada uma análise macroscópica e histológica e análise da expressão do factor tecidual e trombomodulina emARNm por PCR em tempo real e de proteína pelo método de ELISA. Resultados. Foi evidente o compromisso hemostático nas placentasde gestações com restrição de crescimento intra-uterino idiopático; a trombose dos vasos coriônicos é o descobrimento histológico maisimportante. Aumentaram a expressão de proteína do fator tecidual (p= 0,0411) e a proporção do fator tecidual/ trombomodulina aonível de ARNm (p= 0,0411) e de proteína (p= 0,0215). Não houve diferenças estatisticamente significativas entre os grupos nos níveisde ARNm do fator tecidual ou trombomodulina, nem de trombomodulina ao nível de proteína. Conclusão. Se apresenta evidência dealteração dos mecanismos hemostáticos da placenta, incluindo a expressão anormal de fator tecidual e da proporção do fator tecidual/trombomodulina, em gestações complicadas com restrição de crescimento intra-uterino idiopático...

Decrease in inflammatory response does not prevent placental dysfunction after fetal cardiac bypass in goats.

OBJECTIVE: One of the most significant responses to fetal cardiac bypass is severe placental dysfunction characterized by increased vascular resistance. We tested the hypothesis that fetal cardiac bypass triggers the activation of nuclear factor kappa-B (NF-KB), a major regulator of inflammatory response, and that pharmacologic inhibition of NF-KB activation by pyrrolidine dithiocarbamate alleviates fetal cardiac bypass-induced placental dysfunction. METHODS: Fifteen pregnant goats at 120 to 140 days' gestation were equally divided into the control group with a sham procedure of fetal sternotomy and cannulation (CG), the fetal bypass group (FB), and the fetal bypass group with 300 mg pyrrolidine dithiocarbamate before sternotomy (FP). Fetal cardiac bypass was performed for 30 minutes. Umbilical arterial flow rate was measured by ultrasonic flowmeter and placental vascular resistance was calculated. Fetal plasma levels of nitric oxide (NO), endothlin-1 (ET-1), 6-keto-prostaglandin F1α (6-K), thromboxane B(2) (TXB2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assayed. IL-6 and TNF-α mRNA were analyzed by real-time polymerase chain reaction. NF-KB activation was evaluated by electrophoretic mobility shift assay. RESULTS: Placental vascular resistance significantly increased in the FB and FP groups compared with the CG group. Increases in plasma levels of NO were observed in all 3 groups. Plasma levels of ET-1 rose significantly in the FB and FP groups without noticeable difference between them. Plasma levels of 6-K, TXB(2), IL-6, and TNF-α increased significantly in the FB group compared with the CG and FP groups. The transcription levels of IL-6 and TNF-α mRNA in the placental tissues of the FB group were significantly higher than in the FP and CG groups. The amount of activated NF-KB in the placental tissues of the FB group was also significantly higher than that in the FP and CG groups. CONCLUSIONS: Fetal cardiac bypass-induced inflammatory response possibly mediated by NF-KB caused placental dysfunction. Pharmacologic inhibition of NF-KB activation and decrease in the inflammatory response did not alleviate the placental dysfunction.

Placental malaria and low birth weight in pregnant women living in a rural area of Burkina Faso following the use of three preventive treatment regimens.

BACKGROUND: The weekly chemoprophylaxis of malaria during pregnancy with chloroquine (CQ) has become problematic with the increasing resistance of Plasmodium falciparum to this drug. There was a need to test the benefits of new strategies over the classical chemoprophylaxis. This study was conducted to provide data to the National Malarial Control Programme for an evidence-based policy change decision making process. It compares the efficacy of two IPT regimens, using chloroquine (CQ) or sulphadoxine/pyrimethamine (SP), with the classical chemoprophylaxis regimen using CQ in reducing the adverse outcomes of malaria infection, for the mother and the foetus. METHODS: Pregnant women attending the first antenatal care visit were randomly assigned to one of the three treatment regimens. They were subsequently followed up till delivery. Maternal, placental and cord blood samples were obtained upon delivery to check for P. falciparum infection. RESULTS: A total of 648 pregnant women were enrolled in the study. Delivery outcome were available for 423 of them. Peripheral maternal P. falciparum infection at delivery was found in 25.8% of the women. The proportion of women with maternal infection was significantly lower in the IPTp/SP group than in the CQ group (P << 0.000). The prevalence of placental malaria was 18.8% in the CWC/CQ group; 15.9% in the IPTp/CQ group and 10.6% in the IPTp/SP group. The incidence of LBW (weight < 2,500 g) was significantly higher among infants of mothers in the CWC/CQ group (23.9%) as compared with those of mothers in the IPTp/CQ (15.6%) and IPTp/SP (11.6%) groups (p = 0.02) CONCLUSION: Intermittent preventive treatment with SP has shown clear superiority in reducing adverse outcomes at delivery, as compared with intermittent preventive treatment with CQ and classical chemoprophylaxis with CQ.

Decline of placental malaria in southern Ghana after the implementation of intermittent preventive treatment in pregnancy.

BACKGROUND: Intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) has been adopted as policy by many countries in sub-Saharan Africa. However, data on the post-implementation effectiveness of this measure are scarce. METHODS: Clinical and parasitological parameters were assessed among women delivering at a district hospital in rural southern Ghana in the year 2000 when pyrimethamine chemoprophylaxis was recommended (n = 839) and in 2006 (n = 226), approximately one year after the implementation of IPTp-SP. Examinations were performed in an identical manner in 2000 and 2006 including the detection of placental Plasmodium falciparum infection by microscopy, histidine-rich protein 2, and PCR. RESULTS: In 2006, 77% of the women reported to have taken IPTp-SP at least once (26%, twice; 24%, thrice). In 2006 as compared to 2000, placental P. falciparum infection was reduced by 43-57% (P < 0.0001) and maternal anaemia by 33% (P = 0.0009), and median birth weight was 130 g higher (P = 0.02). In 2006, likewise, women who had taken > or = 1 dose of IPTp-SP revealed less infection and anaemia and their children tended to have higher birth weights as compared to women who had not used IPTp-SP. However, placental P. falciparum infection was still observed in 11% (microscopy) to 26% (PCR) of those women who had taken three doses of IPTp-SP. CONCLUSION: In southern Ghana, placental malaria and maternal anaemia have declined substantially and birth weight has increased after the implementation of IPTp-SP. Likely, these effects can further be increased by improving IPTp-SP coverage and adherence. However, the remnant prevalence of infection in women having taken three doses of IPTp-SP suggests that additional antimalarial measures are needed to prevent malaria in pregnancy in this region.

Trophoblast stem cells rescue placental defect in SOCS3-deficient mice.

Stem cells have important clinical and experimental potentials. Trophoblast stem (TS) cells possess the ability to differentiate into trophoblast subtypes in vitro and contribute to the trophoblast lineage in vivo. Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of cytokine signaling. Targeted disruption of SOCS3 revealed embryonic lethality on E12.5; it was caused by placental defect with enhanced leukemia inhibitory factor receptor signaling. A complementation of the wild-type (WT) placenta by using tetraploid rescue technique showed that the embryonic lethality in SOCS3-deficient embryo was due to the placental defect. Here we demonstrate that TS cells supplementation rescues placental defect in SOCS3-deficient embryos. In the rescued placenta, TS cells were integrated into the placental structure, and a substantial structural improvement was observed in the labyrinthine layer that was disrupted in the SOCS3-deficient placenta. Importantly, by supplying TS cells, living SOCS3-deficient embryos were detected at term. These results indicate a functional contribution of TS cells in the placenta and their potential application.

[The importance of specialised pathology service in diagnosis of ascending infection of the reproductive system in pregnant women].

Practical results of screening cytological diagnosis of urogenital infections in pregnant women and mass pathomorphological investigations of newborn placentas performed by bureaus of pathology in Leningrad region and Cheboksary city are reviewed. Important place of the ascending bacterial infection in the structure of reproductive mortality is emphasized.

Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali.

BACKGROUND: Malaria during pregnancy contributes to maternal anemia and low birth weight. In East Africa, several studies have demonstrated that intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) is more efficacious than weekly chloroquine (CQ) chemoprophylaxis in preventing these adverse consequences. To our knowledge, there are no published trials evaluating IPT in West Africa. METHODS: We undertook a randomized controlled trial of weekly CQ chemoprophylaxis, 2-dose IPT with CQ, and 2-dose IPT with SP; 1163 women were enrolled. RESULTS: In multivariate analyses, when compared with weekly CQ, IPT/SP was associated with a reduction in third-trimester anemia (adjusted odds ratio [AOR], 0.49; P<.001), placental parasitemia (AOR, 0.69; P=.04), and low birth weight (<2500 g) (AOR, 0.69; P=.04). The prevalence of placental infection remained unexpectedly high, even in the IPT/SP group (24.5%), possibly because of the intensity of seasonal transmission. There were no significant differences in stillbirths, spontaneous abortions, or neonatal deaths among the 3 groups. CONCLUSIONS: In Mali, IPT with SP appears more efficacious than weekly chloroquine chemoprophylaxis in preventing malaria during pregnancy. These data support World Health Organization recommendations to administer at least 2 doses of IPT during pregnancy. In intensely seasonal transmission settings in Mali, >2 doses may be required to prevent placental reinfection prior to delivery.

Association between funisitis and elevated interleukin-6 in cord blood.

OBJECTIVE: [corrected] To determine whether elevated plasma interleukin-6 (IL-6) in umbilical venous cord blood at delivery is associated with funisitis and whether IL-6 can be used to screen for funisitis in preterm neonates. METHODS: At the time of delivery, umbilical venous cord blood samples were collected from 92 infants for whom placental pathology results were also available. Interleukin-6 concentrations in the umbilical venous cord blood plasma were measured by immunoassay. Histologic examinations of the placenta and umbilical cord were done to determine the presence or absence of funisitis and chorioamnionitis. For a power of 90% with an alpha of.05, 12 subjects were required in each group. RESULTS: We found a significant association between the presence of histologic funisitis and elevated umbilical venous cord blood plasma IL-6 concentrations (defined as 10 pg/mL or greater). Of 15 infants whose umbilical cords showed funisitis, 93% (14 of 15) had elevated umbilical venous cord blood plasma IL-6 concentrations. Of 77 infants without funisitis, 32% (25 of 77) had elevated IL-6 concentrations in their cords (P <.001, two-sided Fisher exact test). The negative predictive value of IL-6 as a screening test for funisitis was 98%. CONCLUSION: In preterm neonates, screening for funisitis by using the immunoassay for IL-6 appears to be valid. In the near future, elevated umbilical venous cord blood IL-6 concentrations at delivery could be clinically useful to identify children who might benefit from early treatment for systemic fetal inflammatory syndrome.

Immunity to placental malaria. I. Elevated production of interferon-gamma by placental blood mononuclear cells is associated with protection in an area with high transmission of malaria.

In areas in which malaria is holoendemic, primigravidae and secundigravidae, compared with multigravidae, are highly susceptible to placental malaria (PM). The nature of gravidity-dependent immune protection against PM was investigated by measuring in vitro production of cytokines by placental intervillous blood mononuclear cells (IVBMC). The results demonstrated that interferon (IFN)-gamma may be a critical factor in protection against PM: production of this cytokine by PM-negative multigravid IVBMC was elevated compared with PM-negative primigravid and secundigravid and PM-positive multigravid cells. Low IFN-gamma responsiveness to malarial antigen stimulation, most evident in the latter group, was balanced by increased interleukin (IL)-4 production, suggesting that counter-regulation of these two cytokines may be a crucial determinant in susceptibility to PM. A counter-regulatory relationship between IL-10 and tumor necrosis factor-alpha was also observed in response to malarial antigen stimulation. These data suggest that elevated production of IFN-gamma, as part of a carefully regulated cytokine network, is important in the control of PM.

Congenital afibrinogenemia with successful delivery.

We experienced a case of congenital afibrinogenemia and successfully performed cesarean section with administration of fibrinogen. The patient was administered fibrinogen every week to sustain a fibrinogen level above 60 mg/ dl according to our previously reported first case. Pregnancy course was uneventful, and fetal growth was normal, but unfortunately placental abruption occurred after the spontaneous onset of labor at 37 weeks gestation. The fibrinogen level before labor was 96 mg/dl, but decreased to 33 mg/dl when placental abruption was diagnosed. During and after the operation, it was increased to 147 and 199 mg/dl, respectively, through infusion of 10 g of fibrinogen, and massive bleeding was stopped. Two grams of fibrinogen were infused daily after cesarean section, and postpartum hemorrhage was normal. It is obvious that fibrinogen is an extremely important factor in maintaining pregnancy, and we conclude that fibrinogen level must be at least 60 mg/dl during pregnancy, 120 mg/dl during surgery and 150 mg/dl during labor, if possible as high as 200 mg/dl under the continuous infusion of fibrinogen to prevent placental abruption.

Possible basis for primary prevention of birth defects with folic acid.

Prepregnancy counselling is efficient in cases of chronic maternal disease, selection of medication and avoiding bad life habits. A new policy is the use of folic acid in the periconceptional period for the purpose of reducing the chance of having a baby with neural tube defects (NTD). Research in progress at the Department of Obstetrics and Gynaecology in Nijmegen, the Netherlands, is presented demonstrating that a derangement of methionine-homocysteine metabolism could be the underlying mechanism of pathogenesis and prevention with folic acid. Such derangement was found in +/- 20% of cases with NTD, recurrent miscarriage and placental infarcts (abruption) and offers new possibilities for primary prevention in three major areas.