Antenatal Betamethasone Therapy Research Articles

The Effect of Different Antenatal Betamethasone Regimens on Neonatal Outcomes

Objective: Preterm births sometimes occur before the completion of antenatal steroid therapy. Some specialists recommend administering betamethasone at 12-h intervals when birth is expected to occur quickly. The purpose of this study was to compare neonatal outcomes in pregnancies in which betamethasone was administered at 12-or 24-h intervals. Material and Methods: Neonates born at <34 gestational weeks were included in this retrospective study. They were assigned to groups based on antenatal betamethasone therapy: those receiving no steroid, a single dose, and two doses at 12 or 24-h intervals. Results: Six hundred forty-four babies were enrolled including 536 Turkish and 108 refugee pregnant women. The antenatal steroid treatment rate was lower in the refugee group (p<0.05), while 12-h interval treatment was similar between Turkish and refugee groups. Intubation at birth among no steroid, a single dose and two-dose treatment groups (12- or 24-h) were 53/136 (38.9%), 62/222 (28%), and 65/286 (22.7%), and mortality rates were 34/136 (27.9%), 48/222 (21.6%), and 50/286 (17.5%), respectively (p<0.05). Thirty-six (n: 286) of the patients received two doses of betamethasone as 12-h intervals (n:36) and 24-h intervals (n:250). Times elapsing from first betamethasone administration to birth in the 12 and 24-h groups were 22 h and 92 h, respectively (p<0,001). Median gestational week and birth weight were lower in the 24-h interval group than 12-h interval group (29 and 30 weeks, p=0.007; 1190 and 1362 g, p=0.015, respectively). Conclusion: Antenatal betamethasone administered at 12-h intervals may be a suitable option when preterm birth is expected within 24 hours. This regimen is associated with better neonatal outcomes, including lower intubation and mortality rates, as well as higher gestational age and birth weight, compared to the 24-h interval group.

Sex-dependent expression of brain medullary MAP and PI3 kinases in adult sheep with antenatal betamethasone exposure.

Antenatal betamethasone (BM) therapy for women in jeopardy of premature delivery accelerates the lung development in preterm infants and reduces infant mortality rates, but may induce early programming events with chronic cardiovascular consequences. In a sheep model of fetal programming, in utero BM-exposed (BMX) offspring as adults exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for the control of heart rate and insulin resistance accompanied by dysregulation of the brain renin-angiotensin (Ang) system (RAS). However, the status of signaling mechanisms in the brain dorsomedial medulla (DMM) of the BMX sheep that comprise both the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cellular pathways is unknown. Given the importance of these signaling pathways in the actions of Ang peptides as well as baroreflex function and autonomic integration, we applied both a kinase signaling array and associated individual immunoblots of the dorsomedial brain medulla from adult female and male sheep with antenatal BMX. MAPK and PI3K pathways were altered significantly in the BMX sheep in a sex-dependent manner. A protein array for kinases (PathScan® Intracellular Signaling Array Kit, Cell Signaling) and subsequent verification by immunoblot revealed that within the DMM, female BMX sheep exhibit lower expression of proteins in the PI3K pathway, while male BMX sheep show greater expression of p-MAPK pathway proteins extracellular signal regulated kinase (ERK) 1/2. We conclude that maladaptive changes in these two kinase pathways in the DMM may contribute to the chronic dysregulation of blood pressure in this model of fetal programming.

Conservative versus active management in HELLP syndrome: results from a cohort study

Objective HELLP syndrome exposes to severe maternal and fetal complications. Prompt delivery is thus recommended after 34 weeks of gestation, or earlier in case of nonreassuring maternofetal conditions. However, no consensus has been raised in the treatment of HELLP syndrome occurring before 34 weeks of gestation, when both maternal and fetal conditions are stable: it remains still unclear whether an active attitude should be prioritized over expectant management. Herein, we aimed to compare mother and child outcomes according to the type of obstetrical management, either active or conservative. Study design Retrospective and multicenter study involving two tertiary care units. In Center A, obstetrical attitude consisted in expectant management: all women received full antenatal betamethasone therapy and pregnancy was prolonged until maternal or fetal follow up indicated delivery. In Center B, management was active: all deliveries were initiated within 48 hours following diagnosis. Results From 2003 to 2011, 118 patients were included (87 in Center A, 31 in Center B). Both groups of patients were similar regarding maternal and fetal features at baseline. Active management led to increased risks of post-partum hemorrhage (relative risks (RR) = 5.38, 95%CI: 1.2–24.06) and neonatal morbidity including respiratory distress syndrome (RR = 3.1, 95%CI: 1.4–7.1), sepsis (RR = 2.5, 95%CI: 1.1–6.0), necrotizing enterocolitis (RR = 4.8, 95%CI: 1.1–21.2), intracerebral hemorrhage (RR = 5.4, 95%CI: 2.1–13.6), and blood transfusion (RR = 6.1, 95%CI: 1.7–21.7). Conclusions Conservative management may be beneficial for both mother and newborn in patients with stable HELLP syndrome. Identification of maternal and fetal specific prognostic factors would allow a better stratification of women with HELLP syndrome according to illness progressive potential, resulting in a more personalized management.

Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep.

Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.

Abstract 177: Antenatal Betamethasone Exposure Reduces Ang-(1-7) but Enhances Angiotensin-Converting Enzyme and a Thiol Peptidase to Metabolize Ang-(1-7) in the Cerebrospinal Fluid

Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these programming events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. The BM-exposed (BMX) offspring develop elevated blood pressure, decreased baroreflex sensitivity, and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6-months of age. While components of the RAS are present in cerebrospinal fluid (CSF), it is not known if BM exposure influences the CSF RAS to the same extent as other tissue compartments. Therefore, we characterized the CSF RAS in 6-month old male sheep, and established the impact of antenatal exposure on the RAS. Consistent with our previous findings of predominant ACE2 activity in the choroid plexus, CSF Ang-(1-7) levels are significantly higher than Ang I (320.8 ± 96.0 vs. 19.3 ± 4.6 pM; p&lt;0.01, N = 12) or Ang II (1.4 ± 0.5 pM; p&lt;0.01, N = 12). Moreover, Ang-(1-7) was 70% lower in the CSF of the BMX group (97.3 ± 31.4 pM; p&lt;0.05) without changes in Ang I or Ang II. We next assessed the metabolism of Ang-(1-7) in the CSF and demonstrate a trend for increased enzyme activity in BMX males. Further analysis revealed two peptidases that contribute to Ang-(1-7) degradation in CSF of both groups. ACE accounted for approximately 15% (85 out of 100) of the overall Ang-(1-7) metabolism that hydrolyzed the peptide to Ang-(1-5) in CSF and ACE was 1.4-fold higher in the BMX group (6.5 ± 0.5 vs. 8.8 ± 0.5 fmol/min/ml; p&lt;0.02, N = 4). We also identified a novel thiol peptidase activity (Ki = 4 μM PCMB) as the predominant activity that metabolized Ang-(1-7) to Ang-(1-4) in CSF; kinetic analysis of this peptidase in pooled CSF revealed Km and Vmax constants of 5.4 μM and 54 nmol/min/mg for control, and 4 μM and 60 nmol/min/mg for BMX. In summary, CSF levels of Ang-(1-7) were markedly lower following antenatal exposure. The reduced expression of central Ang-(1-7) potentially through an enhanced metabolism pathway may contribute to the long-term increase in blood pressure and an attenuated baroreflex in this model of fetal programming.

Do We Use Too Much Antenatal Betamethasone?

To review and rationalize the liberal use of antenatal betamethasone in the setting of threatened preterm birth. A retrospective review was performed using the charts of all patients at Ste-Justine Hospital, Montreal QC, who received antenatal betamethasone between 01 April 1997 and 31 March 1998. Initial treatment consisted of 2 doses of 12 mg IM given 24 hours apart. Repeat doses of 12 mg weekly were administered at the discretion of the treating physician. Optimal antenatal betamethasone therapy was defined as delivery within 1 week of initial treatment, prior to 34 weeks. Aside from number and timing of doses, other factors analyzed included: gestational age at admission and delivery, diagnosis associated with threatened preterm birth (PTB), number of hospital admissions, and delay between re-admission and delivery. Of the 334 patients identified, 82 (25%) received optimal treatment. Of the remaining 252 patients, 204 (81%) received repeat doses. In the repeat dose group, 112 (55%) women delivered after 34 weeks, while 70 of the 92 remaining patients were hospitalized until delivery. The other 22 patients who received serial doses were discharged at least once prior to delivery; of these patients, 8 were re-admitted more than 24 hours pre-delivery (i.e., adequate time for re-treatment), while 14 were not, but only 6 of these were delivered urgently. Thus, a maximum of 60 patients (25% of repeat doses) could potentially have benefited from this approach. Of the 48 patients not receiving repeat doses, 37 (77%) delivered after 34 weeks. Five remained hospitalized, and 6 were discharged prior to delivery and re-admitted (2 patients > 24 hr and 4 patients < 24 hr from delivery). This represented a potential underutilization of betamethasone by 3% (11/334) of the patients, but only 1.8% (6/334) were of less than 32 weeks' gestation. This study demonstrated the difficulty in predicting which of the patients presenting with threatened preterm birth would actually go on to deliver during the window of benefit of antenatal betamethasone therapy. Our desire to permit all premature fetuses to profit from the positive effects of this therapy must be balanced by a reserve in exposing too many to too much. Use of antenatal betamethasone in our unit has significantly decreased since this review.

The effect of multidose antenatal betamethasone on maternal and infant outcomes

Objective: This study was undertaken to determine whether prolonged betamethasone therapy is, as has been suggested, associated with adverse maternal or neonatal outcomes. Study Design: A secondary multivariate analysis of a randomized controlled trial was performed to determine whether duration of betamethasone therapy was associated with adverse maternal or neonatal outcomes. Results: There were 414 fetuses whose mothers were randomly assigned to trial groups. Final models included only valid cases without missing or averaged data (N = 367 to N = 412, depending on the model). Three or more sets of weekly betamethasone injections were given in 21.3% of cases and ≥4 sets were given in 12.3% of cases. Prolonged antenatal betamethasone therapy was not associated with increases in incidences of antenatal fever, chorioamnionitis, reduced birth weight, suppressed neonatal adrenal function, neonatal sepsis, or neonatal death. It was associated with larger birth weights (P <.05). Conclusion: Prolonged antenatal betamethasone therapy was not associated with higher risks of antenatal maternal fever, chorioamnionitis, reduced birth weight, neonatal adrenal suppression, neonatal sepsis, and neonatal death. (Am J Obstet Gynecol 2001;184:196-202.)

Neonatal sepsis and death after multiple courses of antenatal betamethasone therapy

Objective: This study was undertaken to compare the effects of single versus multiple courses of betamethasone therapy on the frequencies of neonatal outcomes and perinatal infectious morbidity among singleton pregnancies complicated by preterm delivery. Study Design: We performed a nonconcurrent prospective analysis of singleton pregnancies delivered between 24 and 34 weeks’ gestation after antenatal betamethasone exposure. Patients were categorized into two groups according to betamethasone exposure: (1) two 12-mg doses in a 24-hour interval on admission (single-course group) and (2) repeated dosing after the initial single course (multiple-course group). All patients received prophylactic antibiotics for group B streptococci. Any patients with ruptured membranes for >24 hours before delivery were excluded. Data were analyzed with the Student t test, the χ 2 test, and the Fisher exact test. Multiple logistic regression analyses were performed to examine the effect of each steroid dosing regimen on early-onset neonatal sepsis and neonatal death. P < .05 was considered significant for all 2-tailed tests. Results: A total of 453 patients were included, with 267 in the single-course group and 186 in the multiple-course group. The two groups were similar with respect to maternal demographic characteristics, gestational age at delivery, mode of delivery, birth weight, and maternal group B streptococcal colonization. Multiple courses were significantly associated with early-onset neonatal sepsis (odds ratio, 5.00; 95% confidence interval, 1.3-23.2), chorioamnionitis (odds ratio, 9.96; 95% confidence interval, 2.1-64.6), endometritis (odds ratio, 3.61; 95% confidence interval, 1.7-8.1), and neonatal death (odds ratio, 2.92; 95% confidence interval, 1.3-6.9). The frequencies of the other neonatal outcomes analyzed, including respiratory distress syndrome and grade III or IV intraventricular hemorrhage, were similar between the 2 groups. Multiple logistic regression analyses confirmed that multiple courses of antenatal betamethasone were independently associated with early-onset neonatal sepsis (odds ratio, 1.25; 95% confidence interval, 1.1-1.9) and neonatal death (odds ratio, 1.70; 95% confidence interval, 1.1-1.9). Conclusions: Multiple courses of antenatal betamethasone are associated with increased risks of perinatal infectious morbidity and neonatal death. (Am J Obstet Gynecol 2000;183:810-4.)

Antenatal betamethasone therapy augments isoproterenol and prostaglandin E2-mediated relaxation of preterm ovine pulmonary veins.

Antenatal glucocorticoid therapy improves pulmonary function in preterm newborns. We have determined the effect of antenatal glucocorticoid therapy on isoproterenol and prostaglandin (PG) E2-mediated relaxation in preterm ovine pulmonary veins after birth. Ovine fetuses (121 and 126 d of gestation; term = 150 d) received an ultrasound guided intramuscular injection of betamethasone, 0.5 mg/kg, or saline. Lambs were delivered 15 or 48 h later, ventilated for 3 h, and killed. Isolated fourth generation pulmonary veins were suspended in organ chambers filled with modified Krebs-Ringer solution (95% O2, 5% CO2) at 37 degrees C, and their isometric tension was recorded. During contractions to U46619, isoproterenol and PGE2 induced greater relaxations of pulmonary veins of betamethasone-treated lambs than those of control. Forskolin, an activator of adenylate cyclase, caused greater relaxation in veins of betamethasone-treated lambs than in those of controls. A greater relaxation of veins treated with betamethasone than that of control veins also occurred in the presence of isobutylmethylxanthine, an inhibitor of phosphodiesterases. All vessels relaxed similarly to 8-bromo-cAMP, a cell membrane-permeable analog of cAMP. When stimulated with isoproterenol, PGE2, and forskolin, adenylate cyclase activity of crude membrane preparations of pulmonary veins treated with betamethasone was greater than that of controls. These results demonstrate that antenatal betamethasone therapy potentiates isoproterenol and PGE2-mediated relaxation of pulmonary veins of preterm lambs; an enhanced adenylate cyclase activity explain in part the effect of antenatal glucocorticoid therapy on pulmonary veins of preterm lambs.

Changes in leukocyte, granulocyte and lymphocyte counts following antenatal betamethasone administration to pregnant women

Objective: Preterm labor and premature rupture of membranes are associated with a mild leukocytosis. However, we have observed a higher maternal leukocyte count after antenatal betamethasone therapy. We planned this study to evaluate the effects of antenatal betamethasone treatment on maternal leukocyte, granulocyte and lymphocyte count. Methods: Forty-six pregnant women with the diagnosis of preterm labor between 28 and 33 weeks of gestation age received 12 mg betamethasone at a 12-h interval. The control group consisted of 50 pregnant women between 28 and 33 weeks of gestational age with no medical or obstetrics problems. After a baseline venous sampling, serial leukocyte, granulocyte and lymphocyte counts were obtained every 6 h until it returned to baseline value. Results: There were no statistically significant differences in the control group with respect to the total leukocyte, lymphocyte, and neutrophil count. Total leukocyte and granulocyte counts were increased by 29.8% and 17.8% within 24 and 12 h after betamethasone injection, respectively ( P < 0.01). A significant reduction in lymphocyte count was observed within 12 h (45.4%) after betamethasone injection ( P < 0.01). All changes in leukocyte, granulocyte and lymphocyte counts returned to baseline values within 3 days. Conclusion: Antenatal betamethasone therapy leads to an increase in maternal leukocyte count and a decrease in lymphocyte count. This effect is transient and any leukocytosis persisting for more than 3 days is not due to betamethasone administration.

PLASMA CORTISOL CONCENTRATIONS AND LUNG DISEASE IN PREMATURE INFANTS.† 1934

Plasma cortisol concentrations are known to be relatively low at birth in premature infants and to be suppressed by antenatal betamethasone therapy. It has been suggested that low cortisol levels in the newborn period reflect adrenal insufficiency and are associated with respiratory disease. To further examine this relationship we determined plasma cortisol levels during the first 2 weeks of life in infants ≤32 wk gestation enrolled in an ongoing, blinded multi-center trial of antenatal thyrotropin releasing hormone (TRH). Women in premature labor at ≤30 wk gestation received betamethasone and either TRH or placebo and clinical data were obtained on the infants. Blood was collected at birth (cord) and postnatally from 145 infants ≤32 wk gestation at 8 participating sites and cortisol was assayed by immunoassay using enhanced chemiluminescence (Nichols Inst.). Natural log values for the data were used to evaluate correlations with lung disease. The geometric mean cortisol concentration in cord blood was 2.4 μg/dl (2.3 and 2.8 μg/dl for male and female infants, respectively), and there was a significant positive correlation with gestational age. Cortisol levels increased after birth with levels of 6.5, 11.2, 8.5, 8.2 and 6.4 μg/dl at 2 h and 1, 3, 7, and 14 days of age, respectively. Cortisol concentrations were significantly higher in infants with RDS at 2 h, 1 day and 3 days but not in cord blood(maximal levels on day 1, mean 13.6 vs 7.6 μg/dl, p=0.003). Levels were not significantly different at all time points for infants with and without chronic lung disease (CLD) at 28 days (ongoing requirement for oxygen or ventilator), CLD at 36 wk postconceptional age, or adverse outcome (death or CLD) at 36 wk postconceptional age. We conclude that very low birth weight infants exposed to betamethasone treatment in utero increase their plasma cortisol after birth and in response to the stress of RDS; low postnatal cortisol concentrations do not appear to be a predictor of CLD.

Antenatal betamethasone therapy potentiates nitric oxide-mediated relaxation of preterm ovine coronary arteries.

The present study was designed to test the hypothesis that betamethasone may potentiate nitric oxide-mediated relaxation of coronary arteries of preterm lambs. Isolated coronary arteries were obtained from lambs delivered at 128 days gestation. The lambs were treated intramuscularly with a single dose of betamethasone or saline 48 h before delivery and were killed after 3 h of ventilation after delivery. Vessel rings were suspended in organ chambers filled with modified Krebs-Ringer solution (95% O2-5% CO2, 37 degrees C), and their isometric tension was recorded. The endothelium-dependent relaxation induced by bradykinin and calcium ionophore A23187 was greater in arteries from antenatal betamethasone-treated lambs than in arteries from control lambs. The relaxation was abolished by N omega-nitro-L-arginine. Nitric oxide induced a greater relaxation in vessels from antenatal betamethasone-treated lambs and in vessels preincubated with betamethasone than in vessels from controls. Coronary arteries from control and antenatal betamethasone-treated lambs relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate. Nitric oxide induced a greater increase in guanosine 3',5'-cyclic monophosphate content in coronary arteries from antenatal betamethasone-treated lambs than in arteries from control lambs. Our data suggest that antenatal betamethasone therapy potentiates nitric oxide-mediated relaxation in coronary arteries from preterm lambs, probably by affecting the activity of soluble guanylate cyclase of vascular smooth muscle cells.

Antenatal betamethasone therapy augments nitric oxide-mediated relaxation of preterm ovine pulmonary veins.

Antenatal glucocorticoid therapy improves pulmonary function in preterm newborns. We have determined the effect of antenatal glucocorticoid therapy on nitric oxide-mediated relaxation in pulmonary vessels of preterm lambs. Ovine fetuses (126 days gestation; full term = 150 days) were injected with betamethasone (0.5 mg/kg body wt) or saline. After 48 h, lambs were delivered, ventilated for 3 h, and killed. Isolated fourth-generation pulmonary arteries (2-3 mm diameter) and veins (1.5-2 mm diameter) were suspended in organ chambers filled with modified Krebs-Ringer solution (95% O2-5% CO2) at 37 degrees C, and their isometric tension was recorded. During contractions to endothelin-1 or U-46619 (in the presence of indomethacin), acetylcholine and bradykinin induced endothelium-dependent nitro-L-arginine-inhibitable relaxation in arteries and veins. The relaxation was greater in veins of betamethasone-treated than in those of control lambs. Veins from lambs without endothelium treated with betamethasone were more sensitive to sodium nitroprusside than veins from controls. For arteries, there was no significant difference in relaxation between different groups. Relaxation induced by 8-bromoguanosine 3',5'-cyclic monophosphate was similar in arteries and veins of different groups. Radioimmunoassay showed that nitric oxide caused a greater increase in guanosine 3',5'-cyclic monophosphate in betamethasone-treated veins than in controls. These data suggest that antenatal betamethasone therapy augments nitric oxide-mediated relaxation of pulmonary veins of preterm lambs, probably by increasing soluble guanylate cyclase activity of vascular smooth muscle.

Invited editorial on "Antenatal betamethasone therapy augments nitric oxide-mediated relaxation of preterm ovine pulmonary veins".

ARTICLESInvited editorial on "Antenatal betamethasone therapy augments nitric oxide-mediated relaxation of preterm ovine pulmonary veins"J. R. Fineman, and H. W. TaeuschJ. R. Fineman, and H. W. TaeuschPublished Online:01 Feb 1996https://doi.org/10.1152/jappl.1996.80.2.388MoreSectionsPDF (491 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat "Invited editorial on "Antenatal betamethasone therapy augments nitric oxide-mediated relaxation of preterm ovine pulmonary veins"." Journal of Applied Physiology, 80(2), pp. 388–389 Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation More from this issue > Volume 80Issue 2February 1996Pages 388-389 Copyright & PermissionsCopyright © 1996 the American Physiological Societyhttps://doi.org/10.1152/jappl.1996.80.2.388PubMed8929573History Published online 1 February 1996 Published in print 1 February 1996 Metrics