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1.
Am J Obstet Gynecol ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31494126

RESUMO

OBJECTIVE: Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. ACS dosing remains un-optimized, and there is little understanding of how different treatment to delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with ACS do not deliver within the widely accepted 1-7 day window of treatment efficacy. We used a sheep model to test duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days. METHODS: For infusion studies, ewes with single fetuses were randomised to receive an intravenous bolus and maintenance infusion of betamethasone phosphate to target 1-4ng/mL fetal plasma betamethasone for 36 hours, with delivery at either 2, 4 or 7 days-post treatment or sterile saline as control. Animals receiving the clinical treatment were randomised to receive either:i) a single injection of 0.25mg/kg with a 1:1 mixture of betamethasone phosphate + betamethasone acetate with delivery at either 1 or 7 days post treatment; or ii) two treatments of 0.25 mg/kg betamethasone phosphate + betamethasone acetate spaced at 24 hours (giving approximately 48 hours of fetal steroid exposure) with delivery at 2, 5, 7 or 10 days post-treatment. Negative control animals were treated with saline. All lambs were delivered at 121±3 days gestational age and ventilated for 30 minutes to assess lung function. RESULTS: Preterm lambs delivered at 1 or 2 days post-ACS treatment had significant improvements in lung maturation for both intravenous and single dose intramuscular treatments. After 2 days the efficacy of 36 hour betamethasone phosphate infusions was lost. The single dose of 1:1 betamethasone phosphate + betamethasone acetate also was ineffective at 7 days. In contrast, animals treated with two doses had significant improvements in lung maturation at 2, 5 and 7 days, with treatment efficacy reduced by 10 days. CONCLUSION: In preterm lambs, the durability of ACS treatment depends on the duration of fetal exposure and is independent of the IV or IM maternal route of administration. For acute 24-48 hour post-treatment deliveries, a 24 hour fetal ACS exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single dose ACS treatment should be sufficient for women delivering within <48 hours of ACS treatment.

2.
Pediatr Res ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31365919

RESUMO

BACKGROUND: The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model. METHODS: We measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and betamethasone-acetate at 2, 5, and 7 days after initiation of ACS. RESULTS: Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability. CONCLUSION: Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.

3.
Am J Obstet Gynecol ; 221(1): 69.e1-69.e17, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30853365

RESUMO

BACKGROUND: Ex vivo uterine environment therapy is an experimental life support platform designed to reduce the risk of morbidity and mortality for extremely preterm infants born at the border of viability (21-24 weeks' gestation). To spare the functionally immature lung, this platform performs gas exchange via a membranous oxygenator connected to the umbilical vessels, and the fetus is submerged in a protective bath of artificial amniotic fluid. We and others have demonstrated the feasibility of extended survival with ex vivo uterine environment therapy therapy in late preterm fetuses; however, there is presently no evidence to show that the use of such a platform can support extremely preterm fetuses, the eventual translational target for therapy of this nature. OBJECTIVE: The objective of the study was to use our ex vivo uterine environment therapy platform to support the healthy maintenance of 600-700 g/95 days gestational age (equivalent to 24 weeks of human gestation) sheep fetuses. Primary outcome measures were as follows: (1) maintenance of key physiological variables; (2) absence of infection; (3) absence of brain injury; and (4) growth and cardiovascular function patterns matching that of noninstrumented, age-matched in utero controls. STUDY DESIGN: Singleton fetuses from 8 ewes underwent surgical delivery at 95 days' gestation (term, 150 days). Fetuses were adapted to ex vivo uterine environment therapy and maintained for 120 hours with real-time monitoring of key physiological variables. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, inflammation, and microbial load to exclude infection. Brain injury was evaluated by gross anatomical and histopathological approaches after euthanasia. Nine pregnant control animals were euthanized at 100 days' gestation to allow comparative postmortem analyses. Data were tested for mean differences with an analysis of variance. RESULTS: Seven of 8 ex vivo uterine environment group fetuses (87.5%) completed 120 hours of therapy with key parameters maintained in a normal physiological range. There were no significant intergroup differences (P > .05) in final weight, crown-rump length, and body weight-normalized lung and brain weights at euthanasia compared with controls. There were no biologically significant differences in hematological parameters (total or differential leucocyte counts and plasma concentration of tumor necrosis factor-α and monocyte chemoattractant protein 1) (P > .05). Daily blood cultures were negative for aerobic and anaerobic growth in all ex vivo uterine environment animals. There was no difference in airspace consolidation between control and ex vivo uterine environment animals, and there was no increase in the number of lung cells staining positive for the T-cell marker CD3. There were no increases in interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein 1 mRNA expression in lung tissues compared with the control group. No cases of intraventricular hemorrhage were observed, and white matter injury was identified in only 1 ex vivo uterine environment fetus. CONCLUSION: For several decades, there has been little improvement in outcomes of extremely preterm infants born at the border of viability. In the present study, we report the use of artificial placenta technology to support, for the first time, extremely preterm ovine fetuses (equivalent to 24 weeks of human gestation) in a stable, growth-normal state for 120 hours. With additional refinement, the data generated by this study may inform a treatment option to improve outcomes for extremely preterm infants.

4.
BMC Med ; 16(1): 201, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30396358

RESUMO

BACKGROUND: Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. METHODS: We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. RESULTS: We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. CONCLUSIONS: Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30396760

RESUMO

Late preterm and early term birth is associated with adverse short- and long-term consequences, particularly for neurodevelopment. A clear reduction in these births can be achieved by avoidance of non-medically indicated births prior to 39 weeks gestation, as shown following the introduction of prohibitive policies in the USA. However, clinicians and policy-makers must always consider the potential for unintended adverse consequences of such action, such as a potential for an increase in term stillbirth. Finding the balance between optimising long-term neurological outcomes and avoiding rare but devastating term stillbirths is one of the challenges of modern maternity care. In this article we review the current evidence for whether this balance can be found, where early births can be safely prevented, and what remains to be addressed to optimise this balance safely.

6.
Autism Res ; 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30230708

RESUMO

There is an emerging body of evidence demonstrating that maternal obesity at the time of conception increases the risk for Autism Spectrum Disorders (ASD) among offspring. We explored whether pre-pregnancy weight was related to autistic-like traits among offspring not diagnosed with ASD. A large sample of women, recruited during the second trimester of pregnancy, had their height measured and reported their pre-pregnancy weight. These measurements were then converted to a Body Mass Index (BMI) using the formula: (weight in kilograms)/(height in metres2 ). At 19-20 years of age, 1238 offspring of these women completed a measure of autistic-like traits, the Autism-Spectrum Quotient (AQ). Regression analyses identified a positive association between increasing maternal pre-pregnancy BMI and increasing AQ Total Score amongst offspring; this association was maintained even after controlling for a range of variables including maternal/obstetric factors (age at conception, education, smoking, alcohol consumption, hypertensive diseases, diabetes, threatened abortion), paternal BMI at pregnancy, and child factors (parity, sex) (P < .01, R2 =.03). Chi-square analyses found that women with pre-pregnancy obesity (BMI ≥ 30) were more likely to have offspring with high scores (≥26) on the AQ (P = .01). Follow-up binary logistic regression analyses also accounting for the same obstetric and sociodemographic variables found that the offspring of women with pre-pregnancy obesity were at a statistically significantly increased risk of having high scores (≥26) on the AQ (OR: 2.80; 95% CI: 1.06, 7.43). This study provides further evidence that maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring. LAY SUMMARY: The current study explored whether pre-pregnancy weight was related to autistic-like traits among offspring not diagnosed with ASD. We found that pre-pregnancy body mass index in women is associated with the amount of autistic-like traits in their children in early adulthood. Specifically, women who were obese at the time of conception were more likely to have a child who had high levels of autistic-like traits in early adulthood.

7.
Artigo em Inglês | MEDLINE | ID: mdl-29922230

RESUMO

Phthalates are ubiquitous environmental endocrine-disrupting chemicals suspected to interfere with developmental androgen action leading to adverse effects on male reproductive function. Prenatal exposure studies in rodents show cryptorchidism, hypospadias and reduced testicular volume (TV), testosterone and anogenital distance in males. It is postulated that there is a developmental window in utero when phthalate exposure has the most potent adverse effects. Some human studies show associations between prenatal phthalate exposure and reduced calculated "free" serum testosterone in infant boys and shorter anogenital distance. However, there are no data available yet which link antenatal exposure to long-term effects in men. We aimed to correlate antenatal phthalate exposure with adult TV, semen parameters and serum reproductive hormone concentrations. 913 men from the Western Australian (Raine) Pregnancy Cohort were contacted aged 20-22 years. 423 (56%) agreed to participate; 404 underwent testicular ultrasound examination; 365 provided semen samples, and reproductive hormones were measured in 384. Maternal antenatal serum phthalate metabolite measurements were available for 185 and 111 men, who provided serum and semen, respectively. Maternal serum collected at 18 and 34 weeks gestation, stored at -80°C, was pooled and analyzed for 32 phthalate metabolites by liquid chromatography-tandem mass spectrometry. TV was calculated, semen analysis performed by WHO approved methods, and serum concentrations of gonadotrophins, inhibin B, and testosterone measured. Eleven phthalate metabolites were detected. Primary and secondary metabolites of di-(2-ethyl-hexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were positively correlated. After correction for adult height, BMI, presence of a varicocele and exposure to maternal smoking mono-iso-nonyl phthalate (MiNP) (r = -0.22) and sums of DEHP and DiNP metabolites (r = -0.24) and the sum of the metabolites of the high molecular weight phthalates (r = -0.21) were negatively correlated with TV (all p < 0.05). After adjustment for BMI adult serum total testosterone was positively associated with exposure to the following antenatal serum phthalate metabolites: mono-(2-ethylhexyl) phthalate (r = 0.26), MiNP (r = 0.18), the sum of metabolites for DEHP (r = 0.21) and DiNP (r = 0.18), and the sum of high molecular phthalates (r = 0.20) (p = 0.0005 to p = 0.02). Given sample size, storage duration and confounding through postnatal exposures, further studies are required.

8.
Am J Obstet Gynecol ; 219(3): 301.e1-301.e16, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29758177

RESUMO

BACKGROUND: Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. OBJECTIVE: The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. STUDY DESIGN: Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of betamethasone phosphate to target 12-hour fetal plasma betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2 ng/mL. In a subsequent experiment, fetal plasma betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (betamethasone phosphate + betamethasone acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. RESULTS: The loading and maintenance doses were achieved and maintained the desired fetal plasma betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2 intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL betamethasone infusion group. Lambs from the 12-hour 2-ng/mL betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. CONCLUSION: In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose betamethasone phosphate infusion to achieve a fetal plasma betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.

9.
Neonatology ; 114(1): 62-68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29669335

RESUMO

BACKGROUND: Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. OBJECTIVES: We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. METHODS: Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA; (ii) betamethasone on day 104 and saline on days 111 and 118 GA; or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. RESULTS: Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group (p < 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value (p < 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas (p = 0.005; OR = 2.14, 95% CI 1.26-3.63; 31.6 vs. 18.2% in controls) and irregular myelin deposition (p = 0.001; OR = 5.91, 95% CI 2.16-16.19; 49.0 vs. 16.8% in controls) in the myelin sheath. CONCLUSIONS: In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition.

10.
Am J Physiol Regul Integr Comp Physiol ; 315(4): R825-R839, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29641233

RESUMO

Antenatal steroids (ANS) are among the most important and widely utilized interventions to improve outcomes for preterm infants. A significant body of evidence demonstrates improved outcomes in preterm infants (24-34 wk) delivered between 1 and 7 days after the administration of a single course of ANS. Moreover, ANS have the advantage of being widely available, low cost, and easily administered via maternal intramuscular injection. The use of ANS to mature the fetal lung is, however, not without contention. Their use in pregnancy is not FDA approved, and treatment doses and regimens remain largely unoptimized. Their mode of use varies considerably between countries, and there are lingering concerns regarding the safety of exposing the fetus to high doses of exogenous steroids. A significant proportion of women deliver outside the 1- to 7-day therapeutic window after ANS treatment, and this delay may be associated with an increased risk of adverse outcomes for both mother and baby. Today, animal-based studies are one means by which key questions of dosing and safety relating to ANS may be resolved, allowing for further refinement(s) of this important therapy. Complementary approaches using nonhuman primates, sheep, and rodents have provided invaluable advances to our understanding of how exogenous steroid exposure impacts fetal development. Focusing on these three major model groups, this review highlights the role of three key animal models (sheep, nonhuman primates, rodents) in the development of antenatal steroid therapy, and provides an up-to-date synthesis of current efforts to refine this therapy in an era of personalised medicine.

11.
Reprod Biomed Online ; 36(3): 340-347, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29291929

RESUMO

Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20-22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum samples for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay; testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum samples. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18; P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.


Assuntos
Compostos Benzidrílicos/farmacologia , Fertilidade , Depuradores de Radicais Livres/farmacologia , Hormônios Esteroides Gonadais/metabolismo , Exposição Materna , Fenóis/farmacologia , Motilidade Espermática/efeitos dos fármacos , Testículo/fisiologia , Adulto , Compostos Benzidrílicos/análise , Estudos de Coortes , Feminino , Fertilidade/efeitos dos fármacos , Depuradores de Radicais Livres/análise , Humanos , Masculino , Fenóis/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Análise do Sêmen , Testículo/efeitos dos fármacos , Adulto Jovem
12.
Am J Obstet Gynecol ; 218(1): 132.e1-132.e9, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29138038

RESUMO

BACKGROUND: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure. OBJECTIVE: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep. STUDY DESIGN: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours. RESULTS: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg. CONCLUSION: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.


Assuntos
Betametasona/administração & dosagem , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Pulmão/efeitos dos fármacos , Subfamília A de Transportador de Cassetes de Ligação de ATP/genética , Subfamília A de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Aquaporina 5/genética , Aquaporina 5/metabolismo , Betametasona/análogos & derivados , Betametasona/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacocinética , Modelos Animais , Gravidez , Proteínas Associadas a Surfactantes Pulmonares/genética , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , RNA Mensageiro/metabolismo , Ovinos
13.
Am J Obstet Gynecol ; 218(3): 349.e1-349.e10, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29274832

RESUMO

BACKGROUND: The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood. OBJECTIVE: We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings. STUDY DESIGN: Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n = 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone + lipopolysaccharide; and (4) intraamniotic + intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation. RESULTS: Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs. CONCLUSION: Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response.

14.
N Engl J Med ; 377(25): 2445-2455, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29081267

RESUMO

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).


Assuntos
Parto Obstétrico/métodos , Doenças do Prematuro/epidemiologia , Recém-Nascido Prematuro , Mortalidade Perinatal , Cordão Umbilical , Índice de Apgar , Constrição , Feminino , Hematócrito , Humanos , Incidência , Recém-Nascido/sangue , Masculino , Circulação Placentária , Gravidez , Fatores de Tempo
15.
Artif Organs ; 41(10): 959-968, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28891072

RESUMO

Ex vivo uterine environment (EVE) therapy is an experimental neonatal intensive care strategy wherein gas exchange is performed by membranous oxygenators attached to the umbilical vessels. Our aim was to assess the ability of a newly refined EVE system to maintain key physiological parameters in preterm lambs within optimal ranges for 48 h. EVE group; n = 6: Preterm lambs were delivered under general anesthesia at 115 ± 2 days of gestational age. Animals were submerged in a bath of artificial amniotic fluid on EVE therapy for 48 h. Physiological parameters were monitored in real-time over the length of the experiment. Control group; n = 11: Ewes carrying a single fetus (115 ± 2 days of gestational age) underwent recovery surgery to allow placement of a fetal carotid artery catheter. Fetuses received an infusion of sterile saline only. After euthanasia, EVE and Control group fetuses underwent necroscopy to perform static pressure-volume curves and for sampling of lung and cord blood plasma for molecular analyses. Five out of six fetuses in the EVE group completed the study period with key physiological variables remaining within their respective reference ranges for the duration of the 48 h study. Bacteremia was identified in four out of five EVE fetuses, and was associated with a systemic inflammatory response. Using our refined EVE therapy platform, preterm lambs were maintained in a stable physiological condition for 48 h. These findings represent a significant advance over earlier work with this system; however, the identification of bacteremia and a fetal inflammatory response suggests that further refinement to the EVE therapy platform is required.


Assuntos
Oxigenação por Membrana Extracorpórea/instrumentação , Sangue Fetal/fisiologia , Feto/irrigação sanguínea , Feto/fisiologia , Oxigenadores de Membrana , Nascimento Prematuro/veterinária , Animais , Animais Recém-Nascidos , Bacteriemia/complicações , Feminino , Inflamação/complicações , Gravidez , Nascimento Prematuro/terapia , Ovinos , Carneiro Doméstico , Cordão Umbilical/fisiologia
16.
Metabolism ; 75: 54-60, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28935125

RESUMO

BACKGROUND: Cytokines produced by adipose and placental tissues (adipokines) have been implicated in the development of gestational diabetes mellitus (GDM). There is, however, limited research regarding the relationship between advancing pregnancy, maternal adipokine profile, insulin resistance and the development of GDM. Furthermore, no studies have investigated these parameters in women with a history of GDM who are at the highest risk of recurrence. This study examined the circulating concentrations of a number of adipokines associated with insulin resistance at two points in pregnancy, and determined whether they were altered in women who developed GDM. METHODS: Non-diabetic women with a history of GDM in a previous pregnancy (n=123) had blood drawn at 14 and 28weeks of pregnancy for GDM diagnosis, together with assessment of a range of adipokine concentrations by multiplex assay (fatty acid-binding protein 4 [FABP4], leptin, chemerin, adiponectin and resistin). RESULTS: With advancing pregnancy, maternal adiponectin concentrations decreased, while leptin and resistin levels increased (p<0.05). In women who developed GDM at 28weeks of pregnancy (42%), fasting and postprandial glucose levels were already significantly elevated by 14weeks (p<0.05), while adiponectin concentrations were lower (p<0.05). Adiponectin remained lower at the time of GDM diagnosis (p<0.05), while the other adipokines were similar between groups at each timepoint. CONCLUSION: Maternal glucose and adipokine profile is altered early in pregnancy in women with a history of GDM who subsequently develop recurrent disease.


Assuntos
Adipocinas/sangue , Resistência à Insulina , Diabetes Gestacional/sangue , Feminino , Humanos , Leptina/sangue , Mães , Gravidez , Recidiva , Resistina/sangue , Medição de Risco
17.
F1000Res ; 62017.
Artigo em Inglês | MEDLINE | ID: mdl-28781747

RESUMO

Preterm birth (PTB) remains a major obstetric healthcare problem and a significant contributor to perinatal morbidity, mortality, and long-term disability. Over the past few decades, the perinatal outcomes of preterm neonates have improved markedly through research and advances in neonatal care, whereas rates of spontaneous PTB have essentially remained static. However, research into causal pathways and new diagnostic and treatment modalities is now bearing fruit and translational initiatives are beginning to impact upon PTB rates. Successful PTB prevention requires a multifaceted approach, combining public health and educational programs, lifestyle modification, access to/optimisation of obstetric healthcare, effective prediction and diagnostic modalities, and the application of effective, targeted interventions. Progress has been made in some of these areas, although there remain areas of controversy and uncertainty. Attention is now being directed to areas where greater gains can be achieved. In this mini-review, we will briefly and selectively review a range of PTB prevention strategies and initiatives where progress has been made and where exciting opportunities await exploitation, evaluation, and implementation.

18.
PLoS One ; 12(6): e0180114, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28666032

RESUMO

BACKGROUND: Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes. METHODS: Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed. RESULTS: LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone. CONCLUSION: Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Pulmão/irrigação sanguínea , Exposição Materna , Ovinos/crescimento & desenvolvimento , Ureaplasma/fisiologia , Animais , Vasos Sanguíneos/microbiologia , Feminino , Modelos Animais , Gravidez , Ovinos/embriologia
19.
BMC Pregnancy Childbirth ; 17(1): 207, 2017 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-28662683

RESUMO

BACKGROUND: Cohort studies may increase or decrease their selection bias as they progress through time. The Western Australian Pregnancy Cohort (Raine) Study has followed 2868 children for over two decades; from fetal into adult life. This paper analyses the cohort over time, assessing potential bias that may come and go with recruitment, retention and loss of participants. METHODS: Linked data from all births in Western Australian over the 3 years the Raine Cohort was recruited were obtained to compare perinatal characteristics and subsequent health outcomes between the Western Australian (WA) contemporaneous birth population and the Raine Cohort at five time points. Perinatal exposure-outcome comparisons were employed to assess bias due to non-participation in Raine Study subsets. RESULTS: There were demographic differences between the Raine Study cohort and its source population at recruitment with further changes across the period of follow up. Despite these differences, the pregnancy and infant data of those with continuing participation were not significantly different to the WA contemporaneous birth population. None of the exposure-outcome associations were significantly different to those in the WA general population at recruitment or at any cohort reviews suggesting no substantial recruitment or attrition bias. CONCLUSIONS: The Raine Study is valuable for association studies, even after 20 years of cohort reviews with increasing non-participation of cohort members. Non-participation has resulted in greater attrition of socially disadvantaged participants, however, exposure-outcome association analyses suggest that there is no apparent resulting selection bias.


Assuntos
Viés , Perda de Seguimento , Seleção de Pacientes , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Cesárea/estatística & dados numéricos , Estudos de Coortes , Feminino , Seguimentos , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Icterícia Neonatal/epidemiologia , Estudos Longitudinais , Idade Materna , Pré-Eclâmpsia/epidemiologia , Gravidez , Nascimento Prematuro/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fumar/epidemiologia , Fatores Socioeconômicos , Fatores de Tempo , Ultrassonografia Pré-Natal/estatística & dados numéricos , Vácuo-Extração/estatística & dados numéricos , Austrália Ocidental/epidemiologia
20.
Am J Obstet Gynecol ; 217(4): 457.e1-457.e13, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28646647

RESUMO

BACKGROUND: Extremely preterm infants born at the border of viability (22-24 weeks' gestation) have high rates of death and lasting disability. Ex vivo uterine environment therapy is an experimental neonatal intensive care strategy that provides gas exchange using parallel membranous oxygenators connected to the umbilical vessels, sparing the extremely preterm cardiopulmonary system from ventilation-derived injury. OBJECTIVE: In this study, we aimed to refine our ex vivo uterine environment therapy platform to eliminate fetal infection and inflammation, while simultaneously extending the duration of hemodynamically stable ex vivo uterine environment therapy to 1 week. STUDY DESIGN: Merino-cross ewes with timed, singleton pregnancies were surgically delivered at 112-115 days of gestation (term is ∼150 days) and adapted to ex vivo uterine environment therapy (treatment group; n = 6). Physiological variables were continuously monitored; humerus and femur length, ductus arteriosus directional flow, and patency were estimated with ultrasound; serial blood samples were collected for hematology and microbiology studies; weight was recorded at the end of the experiment. Control group animals (n = 7) were euthanized at 122 days of gestation and analyzed accordingly. Bacteremia was defined by positive blood culture. Infection and fetal inflammation was assessed with white blood cell counts (including differential leukocyte counts), plasma and lung proinflammatory cytokine measurements, and lung histopathology. RESULTS: Five of 6 fetuses in the treatment group completed the 1-week study period with key physiological parameters, blood counts remaining within normal ranges, and no bacteremia detected. There were no significant differences (P > .05) in arterial blood oxygen content or lactate levels between ex vivo uterine environment therapy and control groups at delivery. There was no significant difference (P > .05) in birthweight between control and ex vivo uterine environment groups. In the ex vivo uterine environment group, we observed growth of fetal humerus (P < .05) and femur (P < .001) over the course of the 7-day experimental period. There was no difference in airway or airspace morphology or consolidation between control and ex vivo uterine environment animals, and there was no increase in the number of lung cells staining positive for T-cell marker CD3+. CONCLUSION: Five preterm lambs were maintained in a physiologically stable condition for 1 week with significant growth and without clinically significant bacteremia or systemic inflammation. Although substantial further refinement is required, a life support platform based around ex vivo uterine environment therapy may provide an avenue to improve outcomes for extremely preterm infants.


Assuntos
Órgãos Artificiais , Placenta , Nascimento Prematuro/terapia , Animais , Animais Recém-Nascidos , Complexo CD3/metabolismo , Cuidados Críticos/métodos , Citocinas/genética , Citocinas/metabolismo , Feminino , Fêmur/diagnóstico por imagem , Fêmur/crescimento & desenvolvimento , Úmero/diagnóstico por imagem , Úmero/crescimento & desenvolvimento , Ácido Láctico/sangue , Pulmão/metabolismo , Modelos Animais , Oxigênio/sangue , Gravidez , RNA Mensageiro/metabolismo , Ovinos
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