Patient Impression of Improvement 1 year After Sacrospinous Hysteropexy Versus Vaginal Hysterectomy in Women with Pelvic Organ Prolapse Stage 2 or Higher.

INTRODUCTION AND HYPOTHESIS: Patient-reported outcomes are relevant outcomes in studies on pelvic organ prolapse (POP) surgery, as anatomical recurrence alone does not have a significant correlation with perceived improvement. In the present study, the patient's impression of improvement after 1 year is studied after vaginal hysterectomy (VH) versus sacrospinous hysteropexy (SSH) in large cohorts from daily clinical practice. We hypothesize that there is no difference between the groups. METHODS: This is a secondary analysis on prospectively collected data in a multicenter cohort of patients who underwent VH or SSH for symptomatic POP. All patients had a POP-Q stage ≥ 2 in at least one compartment at baseline and were treated with VH or SSH between 2002 and 2019. The primary outcome was the patient-reported score on the patient global impression of improvement index (PGI-I) 1 year after surgery. The secondary outcome was a composite outcome of surgical success, defined as the absence of recurrent POP beyond the hymen with bothersome bulge symptoms and/or repeat surgery. RESULTS: A total of 378 women (196 VH and 182 SSH) were included. The median score on the PGI-I did not differ between VH and SSH. At 1 year post-operatively, 77 women after VH (73%) and 77 women after SSH (75%) considered their condition (very) much improved (p = 0.86). There was no difference in composite outcome of surgical success (126 out of 137 women [92%] after VH, 118 out of 125 women [94%] after SSH; p = 0.44). CONCLUSIONS: Our study shows that there was no difference in the type of surgery, VH or SSH, with regard to the patient's impression of improvement 1 year postoperatively in a large cohort from daily clinical practice.

Statins prevent adverse effects of postnatal glucocorticoid therapy on the developing brain in rats.

BACKGROUND: Postnatal glucocorticoid therapy in the treatment of chronic lung disease benefits lung function, however it adversely affects brain development. We hypothesized that combined postnatal glucocorticoid and statin therapy diminishes adverse effects of glucocorticoids on the developing brain. METHODS: On postnatal days (P) 1-3, one male pup per litter received i.p. injections of saline control (C), n = 13) or dexamethasone (0.5, 0.3, 0.1 µg/g; D, n = 13), ± pravastatin (10 mg/kg i.p.; CP, n = 12; DP, n = 15). Statins or saline continued from P4-6. At P21, brains were perfusion fixed for histological and stereological analyses. RESULTS: Relative to controls, dexamethasone reduced total (837 ± 23 vs. 723 ± 37), cortical (378 ± 12 vs. 329 ± 15), and deep gray matter (329 ± 12 vs. 284 ± 15) volume (mm(3)), cortical neuronal number (23 ± 1 vs. 19 ± 1 × 10(6)), and hippocampal neuronal soma volume (CA1: 1,206 ± 32 vs. 999 ± 32; dentate gyrus: 679 ± 28 vs. 542 ± 24 µm(3); all P < 0.05). Dexamethasone increased the glial fibrillary acidic protein-positive astrocyte density in the white matter (96 ± 2 vs. 110 ± 4/0.1 mm(2)); P < 0.05. These effects no longer occurred in brains from pups treated with combined dexamethasone and pravastatin. Pravastatin alone had no effect on these variables. CONCLUSION: Concomitant dexamethasone with statins in premature infants may be safer for the developing brain than dexamethasone alone in the treatment of chronic lung disease.

Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth.

BACKGROUND: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. METHODS: We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. RESULTS: We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. CONCLUSIONS: Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.

Neonatal corticosteroid therapy affects growth patterns in early infancy.

OBJECTIVE: Although postnatal corticosteroid (CS) therapy has well established beneficial effects on pulmonary function, it may also result in growth restriction during treatment. The course of early childhood growth is believed to predict cardiovascular and metabolic diseases in adulthood. Therefore, we determined the effects of postnatal dexamethasone (DEX) or hydrocortisone (HC) treatment on patterns of postnatal growth until approximately four years of age. STUDY DESIGN: In an observational cohort study of children born prematurely (<32 weeks of gestation), we compared growth patterns for body weight, height, and head circumference from birth to age four years, of children who received DEX (boys: N = 30, girls: N = 14), HC (boys: N = 33, girls: N = 28) to a reference group that had not received postnatal CSs (boys: N = 52, girls: N = 53) using linear mixed-effects modeling. RESULTS: Growth velocity curves of CS-treated neonates showed a shift to the right, representing a delay in time. They had decreased absolute growth velocities during and shortly after treatment, followed by an increase in growth velocity thereafter. A shift to the right was also seen for the age at which maximal growth velocity of weight/height was reached in boys and girls. Fractional growth rates of weight, height, and head circumference were generally reduced in the CS-treated groups during the first two months of age, with catch-up growth in the following months. In DEX-treated infants these changes were more pronounced than in HC-treated infants. CONCLUSION: These data suggest that postnatal growth patterns of preterm born infants are affected by CS-treatment, more by DEX than by HC. Effects were observed mainly on growth velocities. This observation may have impact on health in later life for those individuals treated with CSs in the neonatal period. A definitive conclusion would require a randomized trial of these therapies.

Antenatal glucocorticoid treatment affects hippocampal development in mice.

Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

Maternal-to-fetal allopurinol transfer and xanthine oxidase suppression in the late gestation pregnant rat.

Fetal brain hypoxic injury remains a concern in high-risk delivery. There is significant clinical interest in agents that may diminish neuronal damage during birth asphyxia, such as in allopurinol, an inhibitor of the prooxidant enzyme xanthine oxidase. Here, we established in a rodent model the capacity of allopurinol to be taken up by the mother, cross the placenta, rise to therapeutic levels, and suppress xanthine oxidase activity in the fetus. On day 20 of pregnancy, Wistar dams were given 30 or 100 mg kg(-1) allopurinol orally. Maternal and fetal plasma allopurinol and oxypurinol concentrations were measured, and xanthine oxidase activity in the placenta and maternal and fetal tissues determined. There were significant strong positive correlations between maternal and fetal plasma allopurinol (r = 0.97, P < 0.05) and oxypurinol (r = 0.88, P < 0.05) levels. Under baseline conditions, maternal heart (2.18 ± 0.62 mU mg(-1)), maternal liver (0.29 ± 0.08 mU mg(-1)), placenta (1.36 ± 0.42 mU mg(-1)), fetal heart (1.64 ± 0.59 mU mg(-1)), and fetal liver (0.14 ± 0.08 mU mg(-1)) samples all showed significant xanthine oxidase activity. This activity was suppressed in all tissues 2 h after allopurinol administration and remained suppressed 24 h later (P < 0.05), despite allopurinol and oxypurinol levels returning toward baseline. The data establish a mammalian model of xanthine oxidase inhibition in the mother, placenta, and fetus, allowing investigation of the role of xanthine oxidase-derived reactive oxygen species in the maternal, placental, and fetal physiology during healthy and complicated pregnancy.

Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants.

OBJECTIVE: To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn. PATIENTS AND METHODS: Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids. The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage. RESULTS: The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage. CONCLUSION: We found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.

Oxidative stress in the developing brain: effects of postnatal glucocorticoid therapy and antioxidants in the rat.

In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1 mg x kg(-1) x day(-1)), with or without antioxidant vitamins C and E (DEXCE; 200 mg x kg(-1) x day(-1) and 100 mg x kg(-1) x day(-1), respectively), on postnatal days 1-6 (P1-6). Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4±34.7 mm(3) vs. 564.0±20.0 mm(3)), the soma volume of neurons in the CA1 (1172.6±30.4 µm(3) vs. 1002.4±11.8 µm(3)) and in the dentate gyrus (525.9±27.2 µm(3) vs. 421.5±24.6 µm(3)) of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%). Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5±43.1 mm(3)), and soma volume of neurons in the CA1 (1157.5±42.4 µm(3)) and the dentate gyrus (536.1±27.2 µm(3)). Hsp70 protein expression was unaltered in the cortex (+9%), however, 4-HNE (+95%) and NT (+24%) protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22%) and in the hippocampus (NT: +35%). Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.