Effect of different squatting exercises on menstrual aspects, pelvic mechanics and uterine circulation in primary dysmenorrhoea: a randomised controlled trial.

This was a randomised trial aimed to determine squatting exercises' effects on menstruation, pelvic mechanics, and uterine circulation in primary dysmenorrhoea. A total of 120 females with primary dysmenorrhoea were assigned into group (A), receiving yoga protocol, or groups (B, C & D), receiving yoga protocol added to modified wall squat, sumo squat, or deep squat, respectively. Menstrual pain and distress, pelvic inclination, and uterine circulation were measured before and after interventions using a pain scale, a questionnaire, palpation metre, and Doppler ultrasonography, respectively. There was a significant reduction in pain intensity in groups B & C (effect size = 3.97 & 5.89, respectively), compared to group A (effect size = 3.68), and in group C (effect size = 5.89) compared to group D (effect size = 3.94), pain subscale in the groups B, C & D (effect size = 1.69, 3.3 & 3.41, respectively), compared to group A (effect size= 2.47), water retention subscale in group D effect size 0.90 compared to group A (effect size =0.41) and in the questionnaire total scores in the groups C &D (effect size = 2.3 & 2.46, respectively) when compared to group A (effect size =1.94). Adding squatting exercises to yoga is more effective than yoga alone in reducing menstrual pain and distress.IMPACT STATEMENTWhat is already known on this subject? Physical exercises positively affect primary dysmenorrhoea in terms of decreased pain and distress, possibly through altering faulty posture. Squatting exercises affect lumbopelvic mechanics.What do the results of this study add? This study explores the effect of squatting exercises on pelvic inclination, menstrual aspects, and circulation.What are the implications of these findings for clinical practice and/or further research? Squatting exercises can be utilised to affect pelvic mechanics leading to decreased menstrual pain and distress, because of decreased pelvic congestion.

The risk of hyperbilirubinemia in term neonates after placental transfusion - a randomized-blinded controlled trial.

OBJECTIVE: We aimed to demonstrate non-inferiority of delayed cord clamping (DCC) and cord milking (CM) in comparison to early cord clamping (ECC) in the incidence of hyperbilirubinemia requiring phototherapy. MATERIAL AND METHODS: 467 of maternal-foetal dyads were screened for eligibility. 389 term infants, of breastfeeding, non-smoking mothers were randomized to receive ECC ( < 40 s), DCC (1-2 min) or CM (4 times towards the neonate). The primary outcome was defined as hyperbilirubinemia requiring phototherapy. RESULTS: 307 patients were included in the analysis. CM did not increase the risk of phototherapy RR 11.27 95% CI (0.80; 2.04). Similar results were achieved when comparing DCC and ECC, RR 1.29 95% CI (0.82; 2.05). This was also true for CM vs DCC, RR 0.99 95% CI (0.64; 1.52). The prevalence of total serum bilirubin (TSB) at 24-48 hours was 10.8 mg/dL; 10.33 mg/dL and 11.39 in ECC, CM and DCC group respectively. Transcutaneous bilirubin (TcB) levels at 24-48 h were 7.58 mg/dL, 7.89 mg/dL and 7.60 mg/dL in the ECC, CM and DCC respectively. None of the neonates met exchange transfusion criteria or symptomatic polycythaemia. CONCLUSIONS: Our study suggests that placental transfusion is not associated with hyperbilirubinemia requiring phototherapy or exchange transfusion.

Umbilical cord milking in preterm infants: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of the efficacy and safety of umbilical cord milking in preterm infants. DESIGN: Randomised controlled trials comparing umbilical cord milking with delayed cord clamping/immediate cord clamping in preterm infants were identified by searching databases, clinical trial registries and reference list of relevant studies in November 2019. Fixed effects model was used to pool the data on various clinically relevant outcomes. MAIN OUTCOME MEASURES: Mortality and morbidities in preterm neonates. RESULTS: Nineteen studies (2014 preterm infants) were included. Five studies (n=922) compared cord milking with delayed cord clamping, whereas 14 studies (n=1092) compared milking with immediate cord clamping. Cord milking, as opposed to delayed cord clamping, significantly increased the risk of intraventricular haemorrhage (grade III or more) (risk ratio (RR): 1.95 (95% CI 1.01 to 3.76), p=0.05). When compared with immediate cord clamping, cord milking reduced the need for packed RBC transfusions (RR:0.56 (95% CI 0.43 to 0.73), p<0.001). There was limited information on long-term neurodevelopmental outcomes. The grade of evidence was moderate or low for the various outcomes analysed. CONCLUSION: Umbilical cord milking, when compared with delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants, especially at lower gestational ages. Cord milking, when compared with immediate cord clamping, reduced the need for packed RBC transfusions but did not improve clinical outcomes. Hence, cord milking cannot be considered as placental transfusion strategy in preterm infants based on the currently available evidence.

Implementing Delayed Umbilical Cord Clamping in Cesarean Birth Using a Novel Method: A Pilot Study of Feasibility and Safety.

INTRODUCTION: Although delayed cord clamping (DCC) is regarded as the standard of care for all vigorous newborns, those born via cesarean birth are less likely to be afforded this option, especially for longer than 30 to 60 seconds. This pilot study was undertaken to determine whether removal of the placenta before cord clamping to allow for DCC of at least 3 minutes during term, uncomplicated cesarean birth is feasible and without apparent safety issues in order to support a large prospective study on the benefits of this method. METHODS: Women having a term, uncomplicated cesarean birth who consented to the study were enrolled. Safety was assessed by comparing estimated maternal blood loss, newborn Apgar scores, temperatures, transcutaneous bilirubin levels, need for phototherapy, and neonatal intensive care unit admissions with a matched historical control group of women whose newborns had immediate cord clamping. Feasibility was measured by evaluating staff and maternal comfort with the intervention and by the ability to complete the protocol steps. RESULTS: Seventeen women consented to participate. The protocol was successfully completed in 94% of births. There were no differences in maternal and neonatal safety outcome measures between groups. There was high comfort level with the protocol among staff, and there was universal maternal satisfaction. DISCUSSION: This method of DCC in cesarean birth appears feasible and safe in this small pilot study and was associated with high maternal satisfaction and clinician comfort. Major organizations such as the American College of Nurse-Midwives and the World Health Organization have called for DCC of up to 3 to 5 minutes in all births, and this simple method has the potential to reach that goal in cesarean birth with minimal apparent risk. A large randomized controlled trial is warranted to determine the neonatal and maternal benefits and safety of this technique compared with a 30-to-60-second delay.

Effect of alternative positions of neonates prior to delayed cord clamping on placental transfusion: a randomized control trial.

Objective: To determine the effect of alternative positions (relative to placenta) of normal term neonates, prior to the recommended delayed cord clamping, on placental transfusion and short-term neonatal outcome.Methods: Normal term neonates born vaginally were randomly assigned to be placed either on mother's abdomen (Group AL, n = 97) or 20 cm below the introitus (Group BL, n = 102) for 90 seconds after delivery. Subsequently the cord was clamped. Outcome measures were anthropometry, hematological profile including ferritin at birth and at 3-4 months; and adverse effects, polycythemia, and jaundice.Results: Both groups had comparable outcome measures at birth. At 3-4 months, mean hemoglobin (AL: 12.0 ± 0.9 g/dl, BL: 12.3 ± 1.1 g/dl; p = .02, 95% CI: 0.03-0.58) and hematocrit (AL: 36.1 ± 2.7%, BL: 37 ± 3.2%; p = .01, 95% CI: 0.1-1.75) were significantly higher in BL group. Anthropometry, serum ferritin, incidence of anemia and iron deficiency at 3-4 months were similar in both groups. There was no significant difference in polycythemia, jaundice requiring phototherapy or respiratory distress between the two groups.Conclusions: Placing the baby below the placenta resulted in a statistically significant increase in hemoglobin and hematocrit at 3-4 months without any adverse outcomes. However, this meager quantum of increase did not translate into reduction of risk of anemia or improvement in iron stores.

Histological and biochemical changes induced by gibberellic acid in the livers of pregnant albino rats and their offspring: ameliorative effect of Nigella sativa.

Gibberellic acid (GA3), a plant growth regulator, is widely used in agriculture in many countries to accelerate the growth of fruits and vegetables. We designed histological, immunohistochemical, and biochemical studies to evaluate the deleterious effects of GA3 on the livers of adult pregnant rats and their offspring and to assess the possible ameliorative effect of Nigella sativa Linn. (NsL.oil) against these effects. Twenty-four pregnant albino rats were utilized, randomly divided into four groups: The first group was used as a negative control group, while the second group (positive control group) was provided NsL.oil at a dose of 100 mg/kg of bodyweight. Animals in the third group (GA3 group) were provided 200 ppm of GA3 dissolved in distilled water from the 7th day of pregnancy until 1 day after delivery. Animals in the last group (GA3 + NsL.oil group) were provided GA3 and NsL-oil at the same doses as mentioned above. One day after delivery, each group of lactating mothers and their pups were sacrificed. Liver specimens were subjected to histopathological, immunohistochemical, and biochemical examinations. The livers of rats from the GA3 group showed various degenerative changes, being predominant in the livers of the mothers compared with the offspring. The pathological changes in the livers of the offspring suggested transplacental passage of GA3. The results reveal that GA3 ingestion induced a significant increase in alanine aminotransferase (ALT) and aspartate transaminase (AST) activities in the serum of both groups of mothers and their pups, with a significant increment in lipid peroxidation as evidenced by enhanced malondialdehyde (MDA) levels with significant decrements in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) enzymatic activities in comparison with control groups in the liver of mothers and their offspring. Histopathological examination showed hydropic degeneration and inflammatory cellular infiltration. Additionally, there was fibrosis around the portal area. Moreover, immunolocalization revealed downregulation of the expression of the antiapoptotic marker Bcl-2 in hepatocytes and upregulation of the expression of the apoptotic marker Bax in the treated group. Concomitant use of NsL.oil along with GA3 exerted a considerable reversing effect on histopathological and biochemical changes in the livers of mother groups and their pups. The results of the present study highlight the consequences of exposure to GA3 during pregnancy on hepatic tissue in both mothers and their offspring. Furthermore, the study suggests use of NsL.oil as a potential protective strategy against GA3-induced liver toxicity.

Effect of Milking Maneuver in Preterm Infants: A Randomized Controlled Trial.

OBJECTIVE: To assess the short and medium-term effects of milking maneuver (MM) compared with early cord clamping for infants born before 37 weeks of pregnancy. MATERIAL AND METHODS: 138 infants between 24+0 and 36+6 weeks of gestation were allocated to MM or early cord clamping. Primary outcomes were the requirement of red blood cell transfusions or phototherapy. RESULTS: Initial hemoglobin was significantly higher in the MM group by 1.675 g/dL (p < 0.05) and initial hematocrit by 5.36% (p < 0.05), but no differences in the need of transfusion during the first 30 days after delivery were found (RR 0.8; 95% CI 0.22-2.85). Peak serum bilirubin was similar in both groups (11,097 ± 3.21 vs. 11,247 ± 3.56 mg/dL, p = 0.837). Phototherapy requirements were higher in the MM group (RR 1.62; 95% CI 1.1-2.38). No differences regarding the need of oral iron supplementation, platelet transfusion, respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, meconium aspiration syndrome, use of surfactant, days of oxygen supplementation, need of vasopressors, length of stay in the neonatal intensive care unit, or postpartum hemorrhage were found. CONCLUSION: MM does not reduce the need for red blood cell transfusions and increases phototherapy requirements in preterm infants.

HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation.

Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women.

Evaluation of the effectiveness of low-dose aspirin and omega 3 in treatment of asymmetrically intrauterine growth restriction: A randomized clinical trial.

OBJECTIVE: To test the effect of aspirin and omega 3 on fetal weight as well as feto-maternal blood flow in asymmetrical intrauterine growth restriction (IUGR). STUDY DESIGN: This study is a clinically registered (NCT02696577), open, parallel, randomized controlled trial, conducted at Assiut Woman's Health Hospital, Egypt including 80 pregnant women (28-30 weeks) with IUGR. They were randomized either to group I: aspirin or group II: aspirin plus omega 3. The primary outcome was the fetal weight after 6 weeks of treatment. Secondary outcomes included Doppler blood flow changes in both uterine and umbilical arteries, birth weight, time and method of delivery and admission to NICU. The outcome variables were analyzed using paired and unpaired t-test. RESULTS: The estimated fetal weight increased significant in group II more than group I (p=0.00). The uterine and umbilical arteries blood flow increased significantly in group II (p<0.05). The birth weight in group II was higher than that observed in group I (p<0.05). CONCLUSION: The using of aspirin with omega 3 is more effective than using aspirin only in increasing fetal weight and improving utero-placental blood flow in IUGR.

Nifedipine increases fetoplacental perfusion.

AIM: Our aim is to evaluate the effect of nifedipine on fetoplacental hemodynamic parameters. METHODS: A retrospective study was conducted at a tertiary center with 30 patients for whom nifedipine treatment was used as a tocolytic therapy for preterm labor. Initiation of this treatment was at 31.6±2.5 weeks of gestation. We combined the pulse Doppler imaging parameters with grayscale imaging via the Bernoulli theorem, which is called the "continuity equation", to get the fetoplacental perfusion (FPP). Evaluated parameters were the resistance index (RI), the pulsatility index (PI), systole/diastole ratios (S/D), the velocity-time integral of the umbilical artery (VTI), the radius of the umbilical artery, the peak systolic velocity and the mean pressure gradient in the umbilical artery. From these parameters, the FPP was acquired. RESULTS: We found that the RI, the PI and the S/D ratio did not change after treatment with nifedipine. The mean pressure gradient, the VTI and the peak systolic velocity increased after treatment with nifedipine. Nifedipine increases FPP from 166±73.81 beat.cm3/min to 220±83.3 beat.cm3/min. DISCUSSION: Although nifedipine had no effect on the PI, the RI or the S/D, it increased the mean pressure gradient, the VTI and FPP.

The benefits of optimal cord clamping.

Optimal cord clamping is known and now widely recognised as having positive consequences for the neonate in the short- and medium-term. This review of some of the key literature published over the last five years on the effects of both ECC and OCC provides an insight into the evidence on this topic. The aim of this article is to summarise the key papers on the topic of the effect of timing of cord clamping, including some of those included in the Cochrane Review as well as the majority that have been published since, to provide an up-to-date overview.

Effects of transcutaneous electrical nerve stimulation on fetal and placental development in an experimental model of placental insufficiency.

OBJECTIVE: To elucidate the effects of transcutaneous electrical nerve stimulation (TENS) in pregnancies with placental insufficiency. METHODS: Pregnant rats were subjected to uterine artery ligation and to TENS according to the following groups: ligated stimulated (LS); ligated non-stimulated (LN), control stimulated (CS); and control non-stimulated (CN). Fetal external measurements, such as crown-rump length (CRL), fronto-occipital distance (FOD), thoracic ventral-dorsal (TVDD) and abdominal ventral-dorsal (AVDD) distances were analyzed together with the area occupied by fetal internal organs. Glucose transporter 1 (GLUT-1) expression was evaluated by immunohistochemistry in fetal organs. Thickness of junctional, labyrinth and intermediate placental zones was analyzed by morphometric evaluation in HE-stained slides, and placental hypoxia-inducible factor 1 alfa expression was measured by real-time polymerase chain reaction. RESULTS: In LN and CS groups compared to the CN group, CRL was reduced (27.51/28.95 versus 30.16 mm), as well as FOD (6.63/6.63 versus 7.36 mm), AVDD (7.38/8.00 versus 8.61 mm) and TVDD (6.46/6.87 versus 7.23 mm). Brain GLUT-1 expression was higher in LS (1.3%) and CS (1.8%). The area occupied by placental vessels in the labyrinth zone (29.67 ± 3.51 versus 20.83 ± 7.63) and intermediate zone (26.46 ± 10.21 versus 10.86 ± 8.94) was larger in the LS group than in the LN group. CONCLUSIONS: Our results suggest a negative effect of TENS on placental development, thus compromising the maintenance of adequate blood flow to the fetus.

Effect of Delayed Cord Clamping Above Versus Below the Perineum on Neonatal Hematocrit: A Randomized Controlled Trial.

OBJECTIVE: The purpose of this study was to determine if there is a difference in neonatal hematocrit at 24 hours of life in full-term newborns for which delayed cord clamping is performed above versus below the perineum. MATERIALS AND METHODS: One hundred one patients with singleton pregnancies >37 weeks of gestation presenting for delivery were randomized to delayed cord clamping above or below the perineum. At 24 hours of life, neonatal hematocrit was determined, and the difference was compared using statistical analysis. Secondary outcomes measured were need for phototherapy, transfusion, and neonatal intensive care unit (NICU) admission. RESULTS: Of 101 patients recruited for the study, 53 were randomized to the above group, and 48 were randomized to the below group. Twenty-seven patients in the above group and 26 patients in the below group completed the study. The above group had an average neonatal hematocrit of 52.7% (± 2.58%). The below group had an average neonatal hematocrit of 55.8% (± 2.42%). There was no statistical difference between groups (p = 0.10). Similarly, differences in secondary outcomes did not reach statistical significance. Three infants in the above group and one infant in the below group required phototherapy. None of the infants required blood transfusion. Three infants in the above group and one infant in the below group required NICU admission. CONCLUSIONS: When comparing delayed cord clamping above versus below the perineum, there is no difference in the neonatal hematocrit at 24 hours of life.

Periconceptional multiple-micronutrient supplementation and placental function in rural Gambian women: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Maternal micronutrient deficiencies are commonly associated with clinical indicators of placental dysfunction. OBJECTIVE: We tested the hypothesis that periconceptional multiple-micronutrient supplementation (MMS) affects placental function. DESIGN: We conducted a double-blind, randomized, placebo-controlled trial of MMS in 17- to 45-y-old Gambian women who were menstruating regularly and within the previous 3 mo. Eligible subjects were pre-randomly assigned to supplementation with the UNICEF/WHO/United Nations University multiple micronutrient preparation (UNIMMAP) or placebo on recruitment and until they reached their first antenatal check-up or for 1 y if they failed to conceive. Primary outcome measures were midgestational indexes of utero-placental vascular-endothelial function [ratio of plasminogen-activator inhibitor (PAI) 1 to PAI-2 and mean uterine-artery resistance index (UtARI)] and placental active transport capacity at delivery [fetal to maternal measles antibody (MMA) ratio]. RESULTS: We recruited 1156 women who yielded 415 pregnancies, of which 376 met all of the inclusion criteria. With adjustment for gestational age at sampling, there were no differences in PAI-1 to PAI-2 or MMA ratios between trial arms, but there was a 0.02-unit reduction in UtARI between 18 and 32 wk of gestation (95% CI: -0.03, -0.00; P = 0.040) in women taking UNIMMAP. CONCLUSIONS: Placental vascular function was modifiable by periconceptional micronutrient supplementation. However, the effect was small and supplementation did not further affect other variables of placental function. This trial was registered at www.controlled-trials.com as ISRCTN 13687662.

Amino acids and conceptus development during the peri-implantation period of pregnancy.

The dialogue between the mammalian conceptus (embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients, collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of Developmental Origins of Health and Disease (DOHAD). Although mechanisms responsible for differential growth and development of the conceptus resulting in DOHAD phenomena remain unclear, epigenetic events involving methylation of DNA are likely mechanisms. Histotroph includes serine and methionine which can contribute to the one carbon pool, and arginine, lysine and histidine residues which may be targets of methylation. It is also clear that supplementing the diet with arginine enhances fetal-placental development in rodents, swine and humans through mechanisms that remain to be elucidated. However, molecules secreted by conceptuses such as interferon tau in ruminants, estrogens and interferons in pigs and chorionic gonadotrophin, along with progesterone, regulate expression of genes for nutrient transporters. Understanding mechanisms whereby select nutrients regulate expression of genes in cell signaling pathways critical to conceptus development, implantation and placentation is required for improving successful establishment and maintenance of pregnancy in mammals.

Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates.

OBJECTIVE: We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. STUDY DESIGN: Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. RESULTS: Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. CONCLUSION: Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy.

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation.

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.

Effect of maternal nutrient restriction and melatonin supplementation from mid to late gestation on vascular reactivity of maternal and fetal placental arteries.

INTRODUCTION: Maternal nutrient restriction and decreased scotophase concentrations of melatonin have been associated with severely compromised pregnancies. We hypothesized that melatonin supplementation in a compromised pregnancy enhances the bradykinin (BK)-induced relaxations of placental arteries thereby ensuring sufficient umbilical blood flow to the developing fetus. METHODS: Pregnant ewes (n = 31) were fed an adequate (ADQ) or nutrient restricted (RES) diet supplemented with 5 mg of melatonin (MEL) or without melatonin (CON) from day 50 to 130 of gestation. On day 130 of gestation, the maternal (caruncular; CAR) and fetal (cotyledonary; COT) placental arteries were suspended in organ chambers for isometric tension recording. RESULTS: There were no treatment or dietary effects on CAR arteries for any vasoactive agent. However, in COT arteries, MEL ewes were more sensitive (P < 0.01) to bradykinin-induced relaxation than CON ewes. There was a melatonin by nutritional level interaction (P < 0.01) with sodium nitroprusside-induced relaxation of COT arteries where CON-RES were more sensitive to sodium nitroprusside compared to CON-ADQ, which was in contrast to when ewes were fed MEL. There was a significant melatonin by nutritional interaction (P = 0.04) for responsiveness to norepinephrine. The sensitivity of the COT arteries to norepinephrine in CON-RES ewes was decreased compared to CON-ADQ. Melatonin supplementation, regardless of maternal dietary intake, resulted in COT arteries having similar responsiveness to CON-RES ewes. CONCLUSION: An increase in placental vessel sensitivity to bradykinin-induced relaxation may contribute to melatonin-induced increases in umbilical artery blood flow.

Improving amino acid nutrition to prevent intrauterine growth restriction in mammals.

Intrauterine growth restriction (IUGR) is one of the most common concerns in human obstetrics and domestic animal production. It is usually caused by placental insufficiency, which decreases fetal uptake of nutrients (especially amino acids) from the placenta. Amino acids are not only building blocks for protein but also key regulators of metabolic pathways in fetoplacental development. The enhanced demands of amino acids by the developing conceptus must be met via active transport systems across the placenta as normal pregnancy advances. Growing evidence indicates that IUGR is associated with a reduction in placental amino acid transport capacity and metabolic pathways within the embryonic/fetal development. The positive relationships between amino acid concentrations in circulating maternal blood and placental amino acid transport into fetus encourage designing new therapies to prevent or treat IUGR by enhancing amino acid availability in maternal diets or maternal circulation. Despite the positive effects of available dietary interventions, nutritional therapy for IUGR is still in its infancy. Based on understanding of the underlying mechanisms whereby amino acids promote fetal growth and of their dietary requirements by IUGR, supplementation with functional amino acids (e.g., arginine and glutamine) hold great promise for preventing fetal growth restriction and improving health and growth of IUGR offspring.

Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates.

Resveratrol has been proposed as a potential therapeutic to improve metabolic health during pregnancy, yet little is known about the fetal effects of this maternal dietary supplement. We hypothesized that when administered to pregnant nonhuman primates (NHPs), resveratrol would increase uterine blood flow and mitigate the harmful consequences of maternal Western-style diet (WSD) consumption. NHPs were fed a WSD (36% fat) supplemented with 0.37% resveratrol throughout pregnancy. Outcomes were compared with cohorts fed WSD alone and control chow (14% fat) to distinguish between WSD and resveratrol-specific effects in these animals. In the early third trimester, uterine blood flow was measured by Doppler ultrasound before fetal delivery and tissue collection. Resveratrol resulted in 30% maternal weight loss and improved glucose tolerance, increased uterine artery volume blood flow, and decreased placental inflammation and liver triglyceride deposition. In addition, fetal pancreatic mass was enlarged by 42%, with a 12-fold increase in proliferation by Ki67 immunohistochemistry. These results demonstrate that resveratrol use during pregnancy yields improvements in maternal and placental phenotype with beneficial effects in the fetal liver but an unexplained and concerning alteration in fetal pancreatic development, which strongly cautions against the use of resveratrol by pregnant women.