Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction.

BACKGROUND: Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR. METHODS: Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected. RESULTS: Study groups were control (n = 5), FGR (n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined (p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule (p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex. CONCLUSIONS: Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation. IMPACT: Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination. This preclinical study adds to the body of work on this topic, and informs clinical translation. Neuroprotection likely to improve long-term outcomes of this vulnerable infant group.

Nanomedicines: An approach to treat placental insufficiency and the current challenges.

INTRODUCTION: Preeclampsia and fetal growth restriction are common pregnancy complications that significantly impact perinatal health and offspring development later in life. The origin of these complex syndromes overlap in placental insufficiency. Progress in developing treatments for maternal, placental or fetal health is mainly limited by the risk of maternal and fetal toxicity. Nanomedicines are a promising approach to safely treat pregnancy complications since they can regulate drug interaction with the placenta to enhance efficacy of the treatment while minimizing exposure of the fetus. METHODS: This narrative review discusses the current developments and challenges of nanomedicines during pregnancy with a focus on preclinical models of placenta insufficiency syndromes. Firstly, we outline the safety requirements and potential therapeutic maternal and placental targets. Secondly, we review the prenatal therapeutic effects of the nanomedicines that have been tested in experimental models of placental insufficiency syndromes. RESULTS: The majority of liposomes and polymeric drug delivery system show promising results regarding the prevention of trans-placental passage nanomedicines in uncomplicated and complicated pregnancies. The others two studied classes, quantum dots and silicon nanoparticles, have been investigated to a limited extent in placental insufficiency syndromes. Characteristics of the nanoparticles such as charge, size, and timing of administration have been shown to influence the trans-placental passage. The few available preclinical therapeutic studies on placental insufficiency syndromes predominantly show beneficial effects of nanomedicines on both maternal and fetal health, but demonstrate contradicting results on placental health. Interpretation of results in this field is complicated by the fact that results are influenced by the choice of animal species and model, gestational age, placental maturity and integrity, and nanoparticle administration route. CONCLUSION: Nanomedicines form a promising therapeutic approach during (complicated) pregnancies mainly by reducing fetal toxicity and regulating drug interaction with the placenta. Different nanomedicines have been proven to effectively prevent trans-placental passage of encapsulated agents. This can be expected to dramatically reduce risks for fetal adverse effects. Furthermore, a number of these nanomedicines positively impacted maternal and fetal health in animal models for placental insufficiency. Demonstrating that effective drug concentrations can be reached in the target tissue. While these first animal studies are encouraging, more research is needed to better understand the influence of the pathophysiology of this multi-factorial disease before implementation in clinical practice can be considered. Therefore, extensive evaluation of safety and efficacy of these targeted nanoparticles is needed within multiple animal, in vitro, and/or ex vivo models. This may be complemented by diagnostic tools to assess the disease status to identify the best time to initiate treatment. Together these investigations should contribute to building confidence in the safety of nanomedicines for treating mother and child, as safety has, understandably, the highest priority in this sensitive patient groups.

The role of melatonin in pregnancies complicated by placental insufficiency: A systematic review.

Placental insufficiency affects about 10% of pregnancies and can lead to pre-eclampsia, fetal growth restriction, and preterm birth. Despite significant advances in early prediction and prevention of preterm pre-eclampsia with aspirin, the effects of prophylaxis on fetal growth restriction are less certain, and the rates of late-onset pre-eclampsia are not influenced by aspirin treatment. Pregnancies complicated by placental insufficiency are characterized by increased oxidative stress, and recent studies suggest that melatonin has antioxidant properties and contributes to maintaining placental homeostasis. We aimed to systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. PubMed (Medline) and Scopus were searched until December 2020. Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in qualitative evidence synthesis. The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency reflected by lower production of melatonin, with consequent lower systemic and placental concentrations and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Small intervention studies also suggest that treatment is safe and may lead to prolongation of pregnancy and better outcomes, but double-blind, randomized placebo-controlled trials are lacking.

Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency.

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Pravastatin plus L-arginine prevents adverse pregnancy outcomes in women with uteroplacental vascular dysfunction.

BACKGROUND: Uteroplacental vascular dysfunction, characterized by diminished uterine artery (UtA) blood flow in the second trimester is a clinically useful predictor of the further development of preeclampsia, fetal growth restriction and stillbirth. Efforts to develop effective treatments to protect pregnancies with abnormal UtA Dopplers would be of significant clinical benefit for mothers and their fetuses. OBJECTIVE: The aim of this pilot non randomized control study was to use pravastatin +L-arginine to improve uteroplacental haemodynamics and prevent adverse maternal and neonatal outcomes in women with abnormal Dopplers and high risk for developing adverse pregnancy outcomes. STUDY DESIGN: This study was performed between 2015 and 2018. All women received primary care at OB/GYN Polyclinic Jurisic and Narodni Front University Hospital, University of Belgrade Medical School, Serbia. Approval for investigational drug use was obtained and all women gave informed consent. 10 pregnant women with a poor obstetric history that developed uteroplacental dysfunction (UtA pulsatility index (PI) above the 95th percentile and notching) at 20.5 weeks IQR [17.7-22] gave consent to be treated daily with pravastatin (40 mg) and L-arginine (1.5 g) to improve placental blood flow and pregnancy outcomes. 5 women remained untreated after diagnosis at 21 weeks [20-22] (control group). Due to presence of risk factors for pregnancy complications, close maternal and fetal monitoring was undertaken in all patients. Doppler examinations were performed to monitor changes in placental vascular resistance and fetal well-being and growth. RESULTS: PRAV+L-arginine improved uteroplacental haemodynamics, increased fetal growth and prevented early onset preeclampsia leading to delivery close to term (delivery date: median 38 weeks, IQR[36.5-39]) and appropriate weight for gestational age compared to controls, in which placental blood flow did not improve and 2 women developed severe early onset preeclampsia. Neonates from the control group were born preterm (25 weeks IQR[23.5-25]), growth restricted and spent several months at NICU. Two neonates died due to prematurity-associated complications. PRAV+L-arginine treatment prolonged pregnancies for 4.1 months, compared to 26 days in the untreated group, preventing neonatal complications associated with prematurity. The infants are now 1-3 years old and show normal growth and development. CONCLUSION: This study describes the successful management with pravastatin+L-arginine of 10 pregnant patients with uteroplacental vascular dysfunction and high risk of adverse maternal and fetal outcomes. A larger study is being organized to confirm these observations.

Heparin therapy in placental insufficiency: Systematic review and meta-analysis.

INTRODUCTION: The objective of this study was to establish whether heparin improves the neonatal outcome of fetuses with suspected placental insufficiency. MATERIAL AND METHODS: Before data extraction, the project was registered in the PROSPERO International Prospective Register of Systematic Reviews (registration number: CRD42019117627). A systematic search was performed to identify relevant studies, using PubMed, SCOPUS, ISI Web of Knowledge, and PROSPERO database for meta-analysis. Suspected placental insufficiency was defined as either an estimated fetal weight or abdominal circumference below the 10th centile or when at least 2 of the following criteria were met: (1) abnormal biochemical markers, (2) sonographic evidence of abnormal placental morphology, or (3) abnormal uterine artery Doppler. Heparin in any commercial presentation was defined as the intervention. Mean difference (MD) by random effects model was used. Heterogeneity between studies was assessed using Cochran's Q, H, and I2 statistics. RESULTS: From 1159 assessed studies, two were retained for analysis. The results showed a significantly higher birthweight (MD 365; 95% CI 236 to 494; P < 0.001) and a significant increase of gestational age at birth by 1 week in those women treated with heparin (MD 0.806; 95% CI 0.354 to 1.258; P < 0.001). However, there were no significant differences in Apgar scores, neonatal admission, neonatal mortality, or composite neonatal morbidity. CONCLUSIONS: In women with very high suspicion of placental insufficiency, heparin may increase fetal growth and prolong pregnancy. There is no evidence for a beneficial effect of heparin in reducing neonatal adverse outcomes.

Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

BACKGROUND: Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated. METHOD: The trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI > 1.6, at 190 to 226 weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight < 10th percentile), severe FGR (birth weight < 3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34 weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery < 34 weeks` and 37 weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020. DISCUSSION: During the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR. TRIAL REGISTRATION: DRKS00011374 registered at September 29th, 2017 and NCT03669185 , registered September 13th, 2018.

Skeletal muscle amino acid uptake is lower and alanine production is greater in late gestation intrauterine growth-restricted fetal sheep hindlimb.

In a sheep model of intrauterine growth restriction (IUGR) produced from placental insufficiency, late gestation fetuses had smaller skeletal muscle mass, myofiber area, and slower muscle protein accretion rates compared with normally growing fetuses. We hypothesized that IUGR fetal muscle develops adaptations that divert amino acids (AAs) from protein accretion and activate pathways that conserve substrates for other organs. We placed hindlimb arterial and venous catheters into late gestation IUGR (n = 10) and control (CON, n = 8) fetal sheep and included an external iliac artery flow probe to measure hindlimb AA uptake rates. Arterial and venous plasma samples and biceps femoris muscle were analyzed by mass spectrometry-based metabolomics. IUGR fetuses had greater abundance of metabolites enriched within the alanine, aspartate, and glutamate metabolism pathway compared with CON. Net uptake rates of branched-chain AA (BCAA) were lower by 42%-73%, and muscle ammoniagenic AAs (alanine, glycine, and glutamine) were lower by 107%-158% in IUGR hindlimbs versus CON. AA uptake rates correlated with hindlimb weight; the smallest hindlimbs showed net release of ammoniagenic AAs. Gene expression levels indicated a decrease in BCAA catabolism in IUGR muscle. Plasma purines were lower and plasma uric acid was higher in IUGR versus CON, possibly a reflection of ATP conservation. We conclude that IUGR skeletal muscle has lower BCAA uptake and develops adaptations that divert AAs away from protein accretion into alternative pathways that sustain global energy production and nitrogen disposal in the form of ammoniagenic AAs for metabolism in other organs.

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress in a mouse model.

Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.

Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia.

Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates.

Overcoming impaired growth in an intrauterine growth-restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We subjected fetal sheep to chronic placental insufficiency and tested whether prolonged amino acid infusion would increase protein accretion in these IUGR fetuses. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg-1·day-1 (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in the IUGR-AA than IUGR-Sal group ( P < 0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were fourfold higher in the IUGR-AA group ( P < 0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus the total amino acid delivery rate (net umbilical amino acid uptake + infusion rate) was higher in the IUGR-AA than IUGR-Sal group (30 ± 4 vs. 19 ± 1 µmol·kg-1·min-1, P < 0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate, measured using a leucine tracer, was higher in the IUGR-AA than IUGR-Sal group (2.5 ± 0.3 vs. 1.7 ± 0.3 µmol·kg-1·min-1, P < 0.05). Fetal protein accretion rate was not statistically different between the IUGR groups (1.6 ± 0.4 and 0.8 ± 0.3 µmol·kg-1·min-1 in IUGR-AA and IUGR-Sal, respectively) due to variability in response to amino acids. Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency - The leading cause of preeclampsia.

INTRODUCTION: Placental insufficiency is one of the major risk factors for growth restriction and preeclampsia. The aim of this study is to investigate whether recombinant human Thrombomodulin(r-TM) improves fetal conditions and physiological outcomes. METHODS: We used CBA/J × BALB/C mice as a control and CBA/J × DBA/2 mice - a well-studied model of recurrent spontaneous miscarriage. Pregnant mice received daily subcutaneous injections of r-TM or saline from day 0-15. The fetal resorption rate, fetal weight, and litter size were calculated at day 15. Additionally, we analyzed the mRNA expression of angiogenic factors and the concentration of soluble Flt-1 (sFlt-1) using the ELISA kit. RESULTS: The rate of fetal resorption in CBA/J × DBA/2 mice treated with r-TM was significantly lower compared with mice without r-TM treatment. Additionally, fetal weight and litter size were also significantly higher in the r-TM treated mice. Fibrinogen deposition in the labyrinth area of the CBA/J × DBA/2 mice treated with r-TM was significantly lower compared with deposits in the mice untreated with r-TM. As well, r-TM significantly increased the gene expression level of VEGF and Flt-1 mRNA in the placentas of the CBA/J × DBA/2 mice. r-TM treatment also significantly decreased the production of sFlt-1 protein in the placentas of preeclampsia-like diseased mice. CONCLUSION: r-TM as an anticoagulation therapy has the potential for the medical treatment of recurrent miscarriage and fetal growth restriction due to improved angiogenic factors. Additionally, r-TM treatment has the potential for the recovery of preeclampsia.

Hyperbaric oxygenation and glucose/amino acids substitution in human severe placental insufficiency.

In the first case, the AA and glucose were infused through a perinatal port system into the umbilical vein at 30 weeks' gestation due to severe IUGR. The patient received daily hyperbaric oxygenation (HBO, 100% O2 ) with 1.4 atmospheres absolute for 50 min for 7 days. At 31+4  weeks' gestation, the patient gave birth spontaneously to a newborn weighing 1378 g, pH 7.33, APGAR score 4/6/intubation. In follow-up examinations at 5 years of age, the boy was doing well without any neurological disturbance or developmental delay. In the second case, the patient presented at 25/5  weeks' gestation suffering from severe IUGR received HBO and maternal AA infusions. The cardiotocography was monitored continuously during HBO treatment. The short-time variations improved during HBO from 2.9 to 9 msec. The patient developed pathologic CTG and uterine contractions 1 day later and gave birth to a hypotrophic newborn weighing 420 g. After initial adequate stabilization, the extremely preterm newborn unfortunately died 6 days later. Fetal nutrition combined with HBO is technically possible and may allow the prolongation of the pregnancy. Fetal-specific amino-acid composition would facilitate the treatment options of IUGR fetuses and extremely preterm newborn.

Maternal Choline Supplementation Alters Fetal Growth Patterns in a Mouse Model of Placental Insufficiency.

Impairments in placental development can adversely affect pregnancy outcomes. The bioactive nutrient choline may mitigate some of these impairments, as suggested by data in humans, animals, and human trophoblasts. Herein, we investigated the effects of maternal choline supplementation (MCS) on parameters of fetal growth in a Dlx3+/- (distal-less homeobox 3) mouse model of placental insufficiency. Dlx3+/- female mice were assigned to 1X (control), 2X, or 4X choline intake levels during gestation. Dams were sacrificed at embryonic days E10.5, 12.5, 15.5, and 18.5. At E10.5, placental weight, embryo weight, and placental efficiency were higher in 4X versus 1X choline. Higher concentrations of hepatic and placental betaine were detected in 4X versus 1X choline, and placental betaine was positively associated with embryo weight. Placental mRNA expression of Igf1 was downregulated by 4X (versus 1X) choline at E10.5. No differences in fetal growth parameters were detected at E12.5 and 15.5, whereas a small but significant reduction in fetal weight was detected at E18.5 in 4X versus 1X choline. MCS improved fetal growth during early pregnancy in the Dlx3+/- mice with the compensatory downregulation of Igf1 to slow growth as gestation progressed. Placental betaine may be responsible for the growth-promoting effects of choline.

Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices.

OBJECTIVES: To evaluate the effects of transdermal nitroglycerin (GTN) and sildenafil citrate on Doppler velocity waveforms of the uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) arteries in pregnancies with intrauterine growth restriction (IUGR). METHODS: This was a prospective study of 35 singleton pregnancies (gestational age, 24-31 weeks) with IUGR and abnormal UtA and UA Doppler waveforms. We compared maternal arterial blood pressure and Z-scores of the pulsatility index (PI) of UtA, UA and fetal MCA before and after application of a transdermal GTN patch (average dose, 0.4 mg/h), oral sildenafil citrate (50 mg) or placebo. Statistical analysis was performed by ANOVA for paired samples. RESULTS: There was a significant decrease in UtA-PI after application of GTN (21.0%) and sildenafil citrate (20.4%). A significant reduction in UA-PI was also observed for both GTN (19.1%) and sildenafil citrate (18.2%). There was no difference in UtA- and UA-PI when the GTN and sildenafil groups were compared. No changes in Doppler velocimetry were observed in the placebo group and no significant change in MCA-PI was observed in any group. Maternal arterial blood pressure decreased with administration of both GTN and sildenafil citrate in those with pre-eclampsia. CONCLUSION: The use of transdermal GTN or sildenafil citrate in pregnancies with IUGR is associated with a significant reduction in both UtA and UA Doppler PI, as well as maternal arterial blood pressure. Neither drug affected the MCA-PI. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Unfractionated heparin and placental pathology in high-risk pregnancies: secondary analysis of a pilot randomized controlled trial.

INTRODUCTION: Heparin is often prescribed during pregnancy with the intention of improving perinatal outcomes on the basis that it exerts an anticoagulant action in the inter-villous space. Accumulating in-vitro and in-vivo evidence indicates that heparin's beneficial effects in pregnancy may result from 'non-anticoagulant' effects including the promotion of angiogenesis. METHODS: To study the effect of heparin within the placenta, we performed secondary analyses on a pilot trial where 32 women with negative thrombophilia screens and second-trimester evidence of placental insufficiency were randomized to standard care or antenatal self-administration of unfractionated heparin (UFH) 7500 IU twice-daily. Serial placental ultrasound images were reviewed and compared with histo-pathologic findings following delivery. RESULTS: There were no differences between the two arms in either the evolution of abnormal placental lesions on ultrasound (p = 0.75) or evidence of maternal vascular under-perfusion on histopathology (p = 0.89). In pregnancies considered at increased risk for adverse pregnancy outcomes based on previous history or abnormal serum marker screen, early (second-trimester) placental ultrasound, reflecting developmental pathology had better test characteristics (sensitivity 77.8%; positive predictive value 80.8%) for predicting adverse pregnancy outcomes than third-trimester ultrasound that is reflective of placental thrombotic injury. CONCLUSIONS: Administration of UFH did not prevent the development or evolution of abnormal placental lesions on placental ultrasound or evidence of maternal vascular underperfusion on placental histo-pathology. Second-trimester placental ultrasound may be of value in predicting those at greatest risk of adverse outcomes.

Aspirin and Other COX-1 inhibitors.

Currently available antiplatelet drugs interfere with the process of platelet activation and aggregation by selectively blocking key enzymes involved in the synthesis of platelet agonists, or membrane receptors mediating activation signals. Pharmacological interference with critical molecular pathways of platelet activation and aggregation may reduce the risk of atherothrombotic complications through mechanisms that are also responsible for an increased risk of bleeding. Acetylsalicylic acid (aspirin) represents a prototypic antiplatelet agent. The aim of this chapter is to integrate our current understanding of the molecular mechanism of action of aspirin with the results of clinical trials and epidemiological studies assessing its efficacy and safety. Moreover, the antiplatelet properties of reversible inhibitors of the same drug target will also be reviewed.

High prevalence of hypertension and placental insufficiency, but no in utero HIV transmission, among women on HAART with stillbirths in Botswana.

BACKGROUND: Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth. METHODS: HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed. RESULTS: Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART). CONCLUSIONS: In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.