Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the World Health Organization dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy

Usuda, Haruo; Fee, Erin L.; Carter, Sean; Furfaro, Lucy; Takahashi, Tsukasa; Takahashi, Yuki; Newnham, John P.; Milad, Mark A.; Saito, Masatoshi; Jobe, Alan H.; Kemp, Matthew W.

doi:10.1016/j.ajog.2022.06.058

Cited by 9 publications

(7 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown previously, both Beta‐P + Ac, Beta‐Ac, and Dex treatment improved fetal lung maturation compared to the saline control groups at 48 h from initial treatment (Table 1 ) (Takahashi et al, 2021 ; Usuda et al, 2022 ). SFTPA1 protein was significantly increased in treated groups compared to the saline control groups (Table 1 ).…”

Section: Resultssupporting

confidence: 73%

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Takahashi

Fee

et al. 2022

Physiological Reports

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultssupporting

confidence: 73%

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Takahashi

Fee

et al. 2022

Physiological Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…PD-end point model verification in pregnant sheep and monkeys. (A, B) Simulated and observed V40 results of fetal sheep with DEX intramuscular injection or not (control) of different literature studies. , The white column is the simulated result, and the gray column is the observed value; data are presented as mean ± SD.…”

Section: Resultsmentioning

confidence: 99%

“…However, around 28 GW, infants exposed to half-dose Beta had an increased risk of developing NRDS and requiring exogenous surfactant therapy. 32 Based on the above proof, we are undergoing another clinical trial involving the administration of half-dose DEX (2.5 mg Q12h for 4 times) to pregnant women after 34 GW, which aims to offer an 20,29 The white column is the simulated result, and the gray column is the observed value; data are presented as mean ± SD. optimal approach to enhance the effectiveness and safety of clinical DEX applications.…”

Section: Discussionmentioning

confidence: 99%

Systematic Quantitative Analysis of Fetal Dexamethasone Exposure and Fetal Lung Maturation in Pregnant Animals: Model Informed Dexamethasone Precision Dose Study

Song,

Wang

et al. 2024

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end point model of pregnant animals based on published data and then extrapolated to simulate fetal exposure and lung maturation in pregnant women. We first established the PK/PD/end point model for DEX in pregnant sheep. We considered the competitive effect of cortisol (Cort) and DEX binding with glucocorticoid receptor and then used the indirect response model to describe disaturated-phosphatidylcholine (DSPC) dynamics. Based on that, we established a regression relationship between DSPC and fetal lung volume (V40). We then extrapolated the PD/end point model of pregnant sheep to pregnant monkeys by corrected stages of morphologic lung maturation in two species. Finally, we utilized the interspecies extrapolation strategy to simulate fetal exposure (AUC0–48h) and V40 relationship in pregnant women. The current model could well describe the maternal-fetal PK of DEX in pregnant animals. Simulated DEX AUC0–24h values of the umbilical venous to maternal plasma ratio in pregnant sheep and monkeys were 0.31 and 0.27, respectively. The simulated Cort curve and V40 in pregnant sheep closely matched the observed data within a 2-fold range. For pregnant monkeys, model-simulated V40 were well fitted with external verification data, which showed good interspecies extrapolation performance. Finally, we simulated fetal exposure–response relationship in pregnant women, which indicated that the fetal AUC0–48h of DEX should not be less than 300 and 100 ng/mL·hr at GW28 and GW34 to ensure fetal lung maturity. The current model preliminarily provided support for clinical DEX dose optimization.

show abstract

“…In contrast, sheep models used to answer research questions for humans often did not focus on animal survival. Even in studies with a neonatal focus, lambs and/or ewes have often been sacrificed [ 3 , 15 , 16 , 34 ]. As a result, there is little detailed information on how to follow up sheep after a planned CD, which represents a hurdle for obstetric researchers in developing new sheep models while maintaining animal welfare.…”

Section: Discussionmentioning

confidence: 99%

“…As CD is an operation that both the ewe and the lambs can survive, contemporary ethical and animal welfare considerations—such as the 3R principle—demand an appropriate study design that promotes maternal as well as neonatal well-being [ 14 ]. However, information on these topics is scarce, as it is still a common practice to euthanize both ewes and lambs after experiments [ 15 , 16 ]. Existing veterinary publications deal with the technique of performing CD under field conditions [ 17 – 21 ] and focus on emergency CD of ewes under labor due to complications such as failure of the cervix to dilate, fetal-maternal disproportion, or fetal malpresentation [ 20 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

A Sustainable Translational Sheep Model for Planned Cesarean Delivery of Contraction-Free Ewes

Paping,

Ehrlich,

Melchior

et al. 2023

Reprod. Sci.

View full text Add to dashboard Cite

We evaluated whether the sheep constitutes a useful translational model to evaluate anatomical and surgical aspects of cesarean delivery (CD) from a human medical perspective with the aim of both maternal and neonatal well-being. Our hypothesis was that CD in contraction-free ewes is not associated with major complications. Primary endpoint was the transferability of anatomical conditions and surgical techniques of CD from the ewe to the human. Secondary endpoints were maternal and fetal survival, occurrence of retained fetal membranes, metritis, mastitis, or wound infections. Forty-eight Merino ewes were delivered by CD after 95% gestation (142–144 days). Both ewes and newborn lambs were cared for intensively after the delivery. Ovine uterine anatomy during CD appeared slightly different but comparable to the human uterus. Uterine incisions were mostly performed in the uterine horns, not in the uterine corpus. The ovine uterine wall is thinner than in humans. All ewes survived without any major complications. Seventy-seven (88.5%) out of 87 live-born lambs survived without any complications. The contraction-free ewe constitutes an appropriate and safe model to evaluate anatomical and surgical aspects of CD from a human medical perspective. We present a step-by-step manual for successfully planned cesarean delivery for sheep including the perioperative management illustrated with photographs and a five-minute video. With adequate planning and a reasonable number of staff, it is possible to safeguard both maternal and neonatal survival. This sustainable translational medicine model offers additional potential for the offspring to be used for further research studies (e.g., transgenerational inheritance research).

show abstract

Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the World Health Organization dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy

Cited by 9 publications

References 50 publications

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Systematic Quantitative Analysis of Fetal Dexamethasone Exposure and Fetal Lung Maturation in Pregnant Animals: Model Informed Dexamethasone Precision Dose Study

A Sustainable Translational Sheep Model for Planned Cesarean Delivery of Contraction-Free Ewes

Contact Info

Product

Resources

About