Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics.

OBJECTIVE:To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia. STUDY DESIGN:Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC). RESULTS:Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822-0.959) training; 0.883 (0.804-0.963) testing). CONCLUSION:Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia

Single-nucleotide polymorphisms in genes involved in placental function and unexplained stillbirth.

OBJECTIVE: The purpose of this study was to evaluate the association between unexplained stillbirth (SB) and single-nucleotide polymorphisms (SNPs) in genes involved in placental function using a well-characterized cohort. STUDY DESIGN: Placentas were obtained from 50 unexplained SB and 46 live birth controls. Classification of stillbirth was by Wigglesworth criteria. SBs were stratified by weight: appropriate (AGA-SB) and small for gestational age (SGA-SB, less than the 10th percentile) and gestational age: before 32 and after 32 weeks. Placental DNA was extracted and various SNPs in the endothelial nitric oxide synthase (eNOS), Klotho, hypoxic inducible factor-1\u3b1, and and tumor necrosis factor-\u3b1 genes were evaluated. RESULTS: None of the SNPs were associated with SB overall. Significantly different genotype distribution emerged for eNOS-SNP rs1800783 when comparing AGA-SB with SGA-SB and control (P = .004). Its allele-A was more frequent in AGA-SB compared with both controls (P = .03) and SGA-SB (P = .001). No differences were seen accordingly to gestational age. CONCLUSION: Unexplained stillbirth in the setting of adequate growth is associated with carrier of allele A of rs1800783 eNOS gene in the placenta

Magnesium sulfate and diphenylhydantoin relax canine middle cerebral artery contracted with the thromboxane-A2 analogue U46619 by different mechanisms: Implications for the management of eclampsia

Objectives: To investigate the relaxant effect of MgSO4 and diphenylhydantoin on isolated canine middle cerebral artery (MCA) rings contracted with the thromboxane-A2 analogue U46619. Methods: Canine MCA rings, with and without endothelium, were suspended in organ chambers for isometric tension recording, they were contracted with U46619 in the presence of indomethacin, with and without nitro-L-arginine (NLA). Cumulative dose-response curves were performed using MgSO4 (10-8 M to 10-2 M) and diphenylhydantoin (10-9 M to 10-3 M). Main Outcome Measures: Tension at each concentration of the study drug expressed as a percentage of the maximum tension developed with U46619; area under the concentration response curve. Results: Both MgSO4 and diphenylhydantoin relaxed the MCA rings irrespective of the presence of endothelium. Diphenylhydantoin caused an endothelium-dependent relaxation at concentrations above 3x10-5 M, unaffected by NLA. Conclusions: MgSO4 relaxes canine MCA by a direct smooth muscle effect independent of the endothelium. Diphenylhydantoin causes an endothelium-dependent relaxation of canine MCA at concentrations above 3x10-5 M, unrelated to nitric oxide. MgSO4 and diphenylhydantoin may both help to prevent seizures in patients with eclampsia by reducing the potential for cerebral vasospasm.link_to_subscribed_fulltex

L-arginine supplementation in patients with gestational hypertension: A pilot study

Objective: To evaluate the effects of L-arginine (L-Arg) supplementation on clinical outcomes and blood pressure (BP) changes in patients with gestational hypertension. Methods: Patients with gestational hypertension and proteinuria (n = 28, > 300 mg/ 24 h) and those without proteinuria (n = 46) were randomized in a double-blind design to receive either L-Arg (20g/500 mL intravenously daily, for 5 days followed by 4g/day orally for 2 weeks) or placebo (PL). The primary outcome variable was time from randomization to delivery (Latency). Automated BP readings were obtained every 2 hours, between 8.00 am and 8.00 pm daily, untill the sixth day after treatment. Results: At inclusion, gestational age and proportions of patients with proteinuria did not differ significantly between the PL and L-Arg group, Latency was significantly longer in the L-Arg group compared with the PL group (19.5 +/- 16.9 vs. 31.7 +/- 25.2 days; p = 0.008). Compared with baseline, both systolic and diastolic BP 6 days after treatment were significantly reduced in the L-Arg group but not in the PL group. The subgroup of patients without proteinuria randomized to the group receiving L-Arg showed a trend to prolong pregnancy, to attenuate the evolution to PE, and to reduce the rate of low birth weight. Conclusions: The treatment with L-Arg seems promising in prolonging pregnancy and reducing blood pressure, particularly in patients with gestational hypertension and without proteinuria. This benefit should be confirmed in larger studies with the power to evaluate the effectiveness of L-Arg in preventing the development to preeclampsia

Regional and racial/ethnic differences in perinatal interventions among periviable gestations

OBJECTIVE: To examine whether there are: 1) regional differences in three perinatal interventions that reflect active treatment among periviable gestations and 2) racial–ethnic differences in the receipt of these perinatal interventions after accounting for hospital region. METHODS: We conducted a retrospective study on neonates born at 776 U.S. centers that participated in the Vermont Oxford Network (2006–2017) with a gestational age of 22–25 weeks. The primary outcome was postnatal life support. Secondary outcomes included maternal administration of antenatal corticosteroids and cesarean delivery. We examined rates and 99% CI of the three outcomes by region. We also calculated the adjusted relative risks (aRRs) and 99% CIs for the three outcomes by race and ethnicity within each region using modified Poisson regression models with robust variance estimation. RESULTS: Major regional variation exists in the use of the three interventions at 22 and 23 weeks of gestation but not at 24 and 25 weeks. For example, at 22 weeks of gestation, rates of life support in the South (38.3%; 99% CI 36.3–40.2) and the Midwest (32.7%; 99% CI 30.4–35.0) were higher than in the Northeast (20.2%; 99% CI 17.6–22.8) and the West (22.2%; 99% CI 20.0–24.4). Particularly in the Northeast, black and Hispanic neonates born at 22 or 23 weeks of gestation had a higher provision of postnatal life support than white neonates (at 22 weeks: black: aRR 1.84 [99% CI 1.33–2.56], Hispanic: aRR 1.80 [1.23–2.64]; at 23 weeks: black: aRR 1.14 [99% CI 1.08–1.20], Hispanic: aRR 1.12 [1.05–1.19]). In the West, black and Hispanic neonates born at 23 weeks of gestation also had a higher provision of life support (black: aRR 1.11 [99% CI 1.03–1.19]; Hispanic: aRR 1.10 [1.04–1.16]). CONCLUSION: Major regional variation exists in perinatal interventions when managing 22- and 23-week neonates. In the Northeast and the West regions, minority neonates born at 22 and 23 weeks of gestation had higher provision of postnatal life support

Effect of nitric oxide and carbon monoxide on uterine contractility during human and rat pregnancy

OBJECTIVE: We sought to study the effects of authentic nitric oxide and carbon monoxide on the contractile activity of pregnant human and rat myometrium. STUDY DESIGN: Strips were prepared from uterine biopsy specimens of 10 pregnant, nonlaboring women at term gestation undergoing cesarean delivery. In addition, rings were prepared from the uteri of pregnant rats at midterm (day 14) and at term (day 22) gestation (n = 10-12). The tissues were mounted in organ chambers filled with Krebs-Henseleit solution continuously aerated with 5% carbon dioxide in air (37 degrees C, pH similar to 7.4) for isometric tension recording. The effects of nitric oxide and carbon monoxide gases on spontaneous contractile activity were studied. Responses to hemin (hemoxygenase substrate), which produces endogenous carbon monoxide, were also examined. Responses to nitric oxide and carbon monoxide were also studied in aortic and tail artery rings from pregnant rats after contraction with phenylephrine. RESULTS: Nitric oxide significantly inhibited contractility of human myometrium at term (area under the concentration-response curve, 145.36 +/- 30.02 vs 40.56 +/- 22.81 in controls; P < .05) and rat myometrium at midterm gestation (264.23 +/- 47.86 vs 121.82 +/- 23.50; P < .05) but not at term. No statistically significant inhibition was induced in human or rat myometrium by carbon monoxide, whereas hemin significantly attenuated contractility in human myometrium at term and in rat myometrium at midterm gestation (P < .05). Nitric oxide, carbon monoxide, and hemin relaxed aortic and tail artery rings. CONCLUSIONS: Authentic nitric oxide inhibits rat uterine contractile activity at midterm gestation but not at term. However, nitric oxide inhibits human myometrium activity at term. Authentic carbon monoxide does not appear to modulate uterine contractility, whereas hemin may have some inhibitory properties

Enhanced growth and improved vascular function in offspring from successive pregnancies in endothelial nitric oxide synthase knockout mice

Objective: Transgenic mice that lack endothelial nitric oxide synthase have offspring with growth deficiency and abnormal vascular reactivity in later life. Our objective was to evaluate the role of parity in the modulation of the fetal programming of growth and vascular responses in these transgenic mice. Study design: Oligoparous (0-2 previous pregnancies) and multiparous (5-9 previous pregnancies) nitric oxide synthase knockout (-/-KO) female mice were bred with nitric oxide synthase(-/-KO) and wild type (+/+WT) male mice to produce nitric oxide synthase-/-KO and maternally derived heterozygous (+/-Mat) litters. The pups were weighed weekly. Carotid arteries of the adult females from these litters were used for in vitro vascular reactivity studies. Results: Nitric oxide synthase knockout and nitric oxide synthase maternal litters that were born to oligoparous mothers had significant growth lag compared with corresponding multiparous litters. Length-tension characteristics were not different between the groups. However, optimal diameter, which is a measure of vascular tensile properties and resistance, was decreased in oligoparous compared with multiparous female offspring. Acetylcholine-mediated vasorelaxation was abolished, and contraction by phenylephrine and Ca++ was increased in oligoparous, but not multiparous, female offspring (P <.05). Conclusion: These data support the role of abnormal uterine environment in the fetal programming of postnatal growth and vascular function in later life. Successive pregnancies may lead to maternal uterine adaptations that bypass the lack of a functional nitric oxide synthase, which leads to improvement in postnatal growth and vascular function in the offspring. Given the reported effect of parity on the risk of preeclampsia, similar mechanisms may be operative in human pregnancy. (C) 2004 Elsevier Inc. All rights reserved