Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate

Kemp, Matthew W.; Saito, Masatoshi; Usuda, Haruo; Molloy, Timothy J.; Miura, Yoshio; Sato, Shinichi; Watanabe, Shimpei; Clarke, Michael; Fossler, Michael J.; Scmidt, Augusto; Kallapur, Suhas G.; Kramer, Boris W.; Newnham, John P.; Jobe, Alan H.

doi:10.1016/j.ajog.2016.08.017

Cited by 34 publications

(40 citation statements)

References 46 publications

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“…After surgery, the ewes were unrestrained and housed in individual cages, with free access to water and food. The ewes received a single intravenous infusion of sterile saline (90 mL total volume) over 12 h as part of an unrelated experiment, with which these control animals were shared to minimize the use of animals undergoing surgical procedures . The infusion of a small volume of sterile saline over a period of 12 h was likely of minimal impact on these animals.…”

Section: Methodsmentioning

confidence: 99%

Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy

et al. 2017

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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.

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Section: Methodsmentioning

confidence: 99%

Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy

et al. 2017

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“…Recent data from our group demonstrated that the optimization of ACS therapy based on chronic, low-amplitude betamethasone exposures, or the use of single doses of betamethasone acetate may be an alternative therapy that promotes fetal lung maturation in women at risk of preterm delivery while minimizing fetal exposure to ACS [14, 26]. …”

Section: Discussionmentioning

confidence: 99%

“…Medroxyprogesterone acetate was given prior to treatment to minimize the risk of preterm labor and abortion induced by corticosteroids in sheep. Betamethasone doses of 0.5 mg/kg were deemed an effective dose for sheep as the fetal-to-maternal betamethasone plasma ratio in sheep is lower (1: 10) relative to data from human studies (1: 3) [14]. …”

Section: Methodsmentioning

confidence: 99%

Antenatal Corticosteroid Exposure Disrupts Myelination in the Auditory Nerve of Preterm Sheep

Rittenschober-Böhm

Rodger²,

Jobe

et al. 2018

Neonatology

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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.

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“…In cord blood, betamethasone is detectable as early as one hour after maternal administration, with a maternofetal steroid concentration gradient of approximately 1:3. Animal studies have suggested that the initial peak generated by betamethasone phosphate is not necessary for fetal lung maturation (36)(37)(38)(39). Using an ovine model of pregnancy, it has been shown that maintaining a low fetal betamethasone exposure of 1-4ng/mL for ~26 hours, (either by constant maternal betamethasone phosphate infusion or by maternal injection of low-dose betamethasone acetate) achieves lung maturation equivalent to that given with a standard clinical course of ACS (2 x 0.25mg/kg doses of betamethasone phosphate/acetate spaced by 24h).…”

Section: Antenatal Corticosteroid Regimensmentioning

confidence: 99%

“…As late preterm births are much more common than extreme and early preterm births, they are overall the biggest contributor to burden of disease that results from prematurity (5). The cost of late preterm deliveries (34)(35)(36) weeks gestation) on the health service from birth until 24 months has been estimated at £5823 compared with £2056 for children born at term (6). Overall, the economic burden of preterm birth is considerable with the total cost to the public sector estimated to be £2.9 billion in the UK and $26 billion in the US (7,8).…”

Section: Introductionmentioning

confidence: 99%

Antenatal Corticosteroids for Fetal Lung Maturity - Too Much of a Good Thing?

Hrabálková

Takahashi

Kemp

et al. 2019

CPD

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Background: Between 5-15% of babies are born prematurely worldwide, with preterm birth defined as delivery before 37 completed weeks of pregnancy (term is at 40 weeks of gestation). Women at risk of preterm birth receive antenatal corticosteroids as part of standard care to accelerate fetal lung maturation and thus improve neonatal outcomes in the event of delivery. As a consequence of this treatment, the entire fetal organ system is exposed to the administered corticosteroids. The implications of this exposure, particularly the long-term impacts on offspring health, are poorly understood. Aims: This review will consider the origins of antenatal corticosteroid treatment and variations in current clinical practices surrounding the treatment. The limitations in the evidence base supporting the use of antenatal corticosteroids and the evidence of potential harm to offspring are also summarised. Results: Little has been done to optimise the dose and formulation of antenatal corticosteroid treatment since the first clinical trial in 1972. International guidelines for the use of the treatment lack clarity regarding the recommended type of corticosteroid and the gestational window of treatment administration. Furthermore, clinical trials cited in the most recent Cochrane Review have limitations which should be taken into account when considering the use of antenatal corticosteroids in clinical practice. Lastly, there is limited evidence regarding the long-term effects on the different fetal organ systems exposed in utero, particularly when the timing of corticosteroid administration is sub-optimal. Conclusion: Further investigations are urgently needed to determine the most safe and effective treatment regimen for antenatal corticosteroids, particularly regarding the type of corticosteroid and optimal gestational window of administration. A clear consensus on the use of this common treatment could maximise the benefits and minimise potential harms to offspring.

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Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate

Cited by 34 publications

References 46 publications

Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy

Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy

Antenatal Corticosteroid Exposure Disrupts Myelination in the Auditory Nerve of Preterm Sheep

Antenatal Corticosteroids for Fetal Lung Maturity - Too Much of a Good Thing?

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