京都大学 / 新制・論文博士 / 博士(医学) / 乙第13439号 / 論医博第2238号 / 新制||医||1054(附属図書館) / (主査)教授 万代 昌紀, 教授 小杉 眞司, 教授 稲垣 暢也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

[Truncated abstract] In obstetric practice, pregnant women at risk of pre-term delivery between 24 and 34 weeks of gestation are administered synthetic glucocorticoids (betamethasone or dexamethasone) to induce fetal organ maturation. During this gestational period, the fetal kidney is undergoing a phase of rapid organogenesis with an increase in renal growth and active nephrogenesis occurring. The studies comprising this thesis examine the effects of prenatal betamethasone exposure on the fetal and adult ovine kidney. The central hypothesis of these studies was that exposure of the fetal kidney to betamethasone in late gestation would change renal structure and induce long-term alterations in the expression of glucocorticoid-sensitive genes and proteins. In the fetal studies, pregnant Merino ewes bearing single fetuses received single or repeated-weekly intra-muscular (i.m.) injections of betamethasone (0.5 mg/kg body weight) or saline commencing on day 104 of gestation (term is 150 days). Kidneys were collected from fetuses at 109, 116, 121 and 146 days of gestation (d). Using gold standard unbiased stereological techniques, the physical disector/fractionator method, total glomerular (nephron) number and glomerular volume were determined in 146 d fetal kidneys exposed to repeated maternal saline or betamethasone administration. In the adult study, kidneys were collected from 3.5-year-old sheep that had been exposed to ... In this thesis I have demonstrated that renal growth restriction as a result of betamethasone exposure is associated with a reduction in fetal nephron endowment. Although betamethasone does not appear to consistently alter nephron number or glomerular size, it may indirectly affect total nephron endowment through effects on renal growth. I have also provided evidence which suggests that lategestation betamethasone exposure in sheep does not program permanent alterations in the renal expression of genes or proteins involved in glucocorticoid hormone action or components of the renin-angiotensin system. Therefore, exposure of the fetal kidney to betamethasone during nephrogenesis may alter renal structure if kidney growth is perturbed; however, there are no persistent alterations in the expression of glucocorticoid-sensitive genes. These findings are consistent with the preservation of normal basal blood pressure in the adult sheep I studied and with the limited results from human studies of late-gestation maternal glucocorticoid administration.

Objective: Animal literature has suggested that the impact of antenatal corticosteroids (ACS) may vary by infant sex. Our objective was to assess the impact of infant sex on the use of multiple courses versus a single course of ACS and perinatal outcomes. Study Design: We conducted a secondary analysis of the Multiple Courses of Antenatal Corticosteroids (MACS) for Preterm Birth trial. Our primary outcome was a composite of perinatal mortality or clinically significant neonatal morbidity (including neonatal death, stillbirth, severe respiratory distress syndrome, intraventricular hemorrhage [grade III or IV], cystic periventricular leukomalacia, and necrotising enterocolitis [stage II or III]). Secondary outcomes included individual components of the primary outcome as well as anthropometric measures. Baseline characteristics were compared between participants who received multiple courses versus a single course of ACS. Multivariable regression analyses were conducted with adjustment for pre-defined covariates including an interaction between exposure to ACS and infant sex. Results: Data on 2304 infants were analyzed. The interaction term between treatment status (multiple courses versus a single course of ACS) and infant sex was not significant in the adjusted model for the primary outcome (p=0.86), nor for any of the secondary outcomes. Exposure to multiple courses versus a single course of ACS was not associated with the primary outcome either before or after adjustment (aOR 0.99, 95% CI 0.67 to 1.45, n=2292 infants). However, exposure to multiple courses versus a single course of ACS resulted in significantly lower birth length (p=0.02) and head circumference at birth (p=0.04) although not birthweight (p=0.06). Conclusions: Infant sex did not modify the association between exposure to ACS and perinatal outcomes including perinatal mortality or neonatal morbidity or anthropometric outcomes. However, animal literature indicates that sex specific differences after exposure to ACS may emerge over time and thus investigating long-term sex-specific outcomes warrants further attention. / Thesis / Master of Science (MSc) / Antenatal corticosteroids (ACS) are given in pregnancies at risk of early birth. ACS help the lungs and other organs, such as the brain and kidneys to mature. ACS help improve babies’ survival and reduce the risk of other health complications. Several animal studies suggest that infant sex can affect long-term outcomes after receiving a higher dose of ACS. The goal of our study was to look at the effect of infant sex on the relationship between the use of multiple courses (i.e., a higher dose) versus a single course of ACS and short-term outcomes. These outcomes include challenges with breathing, bleeding in the brain, problems in the bowel, and infant death. Our study found that infant sex did not significantly change the relationship between ACS and short-term infant outcomes, but further study is required on long-term outcomes as sex specific differences may emerge over time as reported in animal literature.

Hyaluronan is an important component of the lung extracellular matrix, with a high capacity for water immobilization, but information on perinatal changes in the lung hyaluronan concentration and their association with changes in the lung water content is limited. In this study, conducted both in rabbit pups and in human infants, we investigated changes in the hyaluronan concentration and distribution in the lung and in the lung water content after preterm or term birth, and changes produced by common antenatal and postnatal pathological conditions and treatments. In rabbit pups, we found a gradual decrease in lung hyaluronan concentration and in the intensity of alveolar hyaluronan staining with advancing gestational age at birth in late gestation, but no further changes during the first 7-9 days of life. The lung water content was uniformly high before birth, but decreased significantly after preterm delivery or at birth at term. Postnatal exposure of newborn preterm or term rabbit pups to hyperoxia for 4-9 days resulted in an increase in both lung hyaluronan concentration and lung water content. This was accompanied by more intense hyaluronan staining, mainly in the alveolar walls. Antenatal exposure of rabbit pups to betamethasone or terbutaline resulted in a lower lung hyaluronan concentration at preterm birth, associated with less intense hyaluronan staining in alveolar walls, without altering the lung water content. Betamethasone exposure had a maximal effect at 25 days of gestation (term = 31 days), decreasing thereafter with advancing gestation, while terbutaline exposure resulted in a gradually increasing effect during late gestation, with a maximum at 29 days. In deceased infants born at a gestational age of < 32 weeks, the lung hyaluronan concentration at death was most strongly associated with the gestational age at birth. It also covaried with sex, antenatal steroid administration, intrauterine bleeding, mode of delivery, birth weight, IRDS, and surfactant treatment. In infants born at a gestational age of > 33 weeks there was a weaker association between lung hyaluronan concentration and gestational age. In this group, the lung hyaluronan concentration was associated with administration of a high concentration of oxygen, and covaried with maximal ventilatory pressure, and lung water content.