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Neonatal Respiratory Distress Syndrome After Repeat Exposure to Antenatal Corticosteroids: A Randomized Controlled Trial
Abstract
The risk of neonatal lung disease such as respiratory distress syndrome (RDS) is increased in preterm births. Considerable morbidity may be expected both immediately and in the longer term. The best management has been a course of maternal steroid therapy, but this has not proved effective for infants born more than 1 week after initial treatment. Repeat doses of prenatal steroids have not been endorsed outside of clinical trials. There is some concern that prenatal steroids may increase the risk of maternal infection after preterm prelabor membrane rupture. The investigators conducted a hospital-based trial in 982 women, seen at 23 hospitals in Australia and New Zealand, who remained at risk of preterm birth at less than 32 weeks gestation 1 week or longer after an initial course of steroids. They were randomly assigned to receive either a repeat intramuscular dose of Celestone Chronodose (7.8 mg betamethasone sodium phosphate and 6 mg of betamethasone acetate) or a saline placebo injection. Fewer infants exposed to multiple steroid treatments had RDS. The NNTB (number needed to treat to benefit) was 14 with a 95% confidence interval (CI) of 8 to 50. Multiply exposed infants had less severe lung disease in general (NNTB, 14; 95% CI, 9–29). These infants required less oxygen therapy and less protracted mechanical ventilation than did placebo recipients. Birth weight, length, and head circumference did not differ between in the treatment and control groups. Z scores of weight-adjusted mean difference and head circumference—but not length—were lower at birth when infants were repeatedly exposed to steroids, but no such differences were evident at the time of hospital discharge. Major causes of infant deaths in the hospital were comparable in the 2 groups. Average gestational ages at birth also were similar. Apgar scores, rates of admission to neonatal intensive care, and rates of intracerebral disorders, retinopathy of prematurity, necrotizing enterocolitis, and all neonatal infections were similar in the 2 management groups. Similar numbers of women required treatment for clinical chorioamnionitis. More women given repeat steroid therapy had operative delivery. The investigators conclude that a repeat course of antenatal maternal steroid therapy clearly is beneficial for women who are still at risk of preterm birth 1 week or longer after an initial course.
... Several excellent structured reviews, including that by Crowther and colleagues for the Cochrane Collaboration, provide an in-depth composite picture of the outcomes. The repeated administration of corticosteroids is associated with a small but significant decrease in RDS and a reduction in serious adverse infant outcomes ( Crowther et al., 2006;Peltoniemi et al., 2011). One of the central issues relating to the repeated administration of ANS is that the dose for repeated courses of antenatal steroids has not been empirically optimized. ...
... The study reported reduced respiratory distress, and reduced severe lung injury with repeated doses of corticosteroids. Interestingly, the significant reductions in weight, length and head circumference at birth in babies exposed to repeated corticosteroid treatment were not maintained at discharge ( Crowther et al., 2006). Of note is the authors' observation that there was no difference in perinatal mortality between the repeated steroid and placebo groups, and that the causes of death were (p.1916) 'much the same between the two groups' ( Crowther et al., 2006). ...
... Interestingly, the significant reductions in weight, length and head circumference at birth in babies exposed to repeated corticosteroid treatment were not maintained at discharge ( Crowther et al., 2006). Of note is the authors' observation that there was no difference in perinatal mortality between the repeated steroid and placebo groups, and that the causes of death were (p.1916) 'much the same between the two groups' ( Crowther et al., 2006). This finding is a significant departure from the original trial conducted by Liggins and Howie, which demonstrated a significant reduction in perinatal mortality between a single ANS course infants and those receiving placebo control (3.2 versus 15%, respectively; P ¼ 0.01) ( Liggins and Howie, 1972). ...
BACKGROUND The use of antenatal steroid therapy is common in pregnancy. In early pregnancy, steroids may be used in women for the treatment
of recurrent miscarriage or fetal abnormalities such as congenital adrenal hyperplasia. In mid-late pregnancy, the antenatal
administration of corticosteroids to expectant mothers in anticipation of preterm birth is one of the most important advances
in perinatal medicine; antenatal corticosteroids are now standard care for pregnancies at risk of premature delivery in high-
and middle-income countries. The widespread uptake of this therapy is due to a compelling body of evidence demonstrating improved
neonatal outcomes following antenatal corticosteroid exposure, stemming most notably from corticosteroid-driven maturation
of fetal pulmonary function. As we approach the 50th anniversary of landmark work in this area by Liggins and Howie, it is
apparent that much remains to be understood with regards to how we might best apply antenatal corticosteroid therapy to improve
pregnancy outcomes at both early and mid to late gestation.
... Observational studies, with their inherent risk of bias, have given conflicting results, some suggesting adverse effects of repeat corticosteroids on measures of foetal growth [15] and on delayed development in early child- hood [16] , whilst others have indicated a possible reduction in cerebral palsy [17]. Given the need for better quality evidence about the benefits and harms of repeat prenatal corticosteroids, randomised clinical trials have now been reported18192021222324252627. A recent Cochrane systematic review of published aggregate data was unable to answer some important clinical questions which this individual participant data (IPD) meta-analysis will address [28]. ...
... The most recent Cochrane systematic review that assesses the use of repeat prenatal corticosteroids for women at risk of preterm birth to prevent neonatal respiratory disease included ten trials (over 4,730 women and 5,650 babies) with low to moderate bias [28]. Five of the trials were conducted in the US [20,21,23,26,27]; one in each of Canada [18], India [22] and Finland [25]; one in Australia and New Zealand [19]; and one involved 20 countries [24]. Six trials [18,19,21222326] gave repeat corticosteroids at seven day intervals if risk of preterm birth remained, one trial [24] at 14 day intervals and three trials [20,25,27] specifically targeted women for 'rescue therapy' (repeat doses only given when preterm birth was considered imminent). ...
... Five of the trials were conducted in the US [20,21,23,26,27]; one in each of Canada [18], India [22] and Finland [25]; one in Australia and New Zealand [19]; and one involved 20 countries [24]. Six trials [18,19,21222326] gave repeat corticosteroids at seven day intervals if risk of preterm birth remained, one trial [24] at 14 day intervals and three trials [20,25,27] specifically targeted women for 'rescue therapy' (repeat doses only given when preterm birth was considered imminent). There was diversity in the inclusion and exclusion criteria for the ten included trials, with wide variation in the reasons women were at risk of preterm birth (preterm labour, preterm prelabour rupture of the membranes , antepartum haemorrhage, pre-eclampsia, foetal growth restriction, cervical incompetence and multiple pregnancy); the gestational age women were eligible (from 24 to 34 weeks); and the time of treatment prior to expected preterm birth. ...
The aim of this individual participant data (IPD) meta-analysis is to assess whether the effects of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies are modified in a clinically meaningful way by factors related to the women or the trial protocol.
The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. The primary study outcomes for the infants will be serious neonatal outcome (defined by the PRECISE International IPD Study Group as one of death (foetal, neonatal or infant); severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia); use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support); and birth weight (Z-scores). For the children, the primary study outcomes will be death or any neurological disability (however defined by trialists at childhood follow up and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (for example, corrected visual acuity worse than 6/60 in the better eye) or deafness (for example, hearing loss requiring amplification or worse)). For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal pyrexia).
Data analyses are expected to commence in 2011 with results publicly available in 2012.
... We also compared neonatal outcomes of one dose versus two doses ACS in preterm infants. Preterm babies who have been exposed to repeated courses of ACS had a lower incidence of RDS than those who have been exposed to one course of ACS in few welldesigned randomized controlled studies [16][17][18] and in some other studies. [17,19] However, some studies [20,21] showed that there was no significant difference between repeated courses and a single course of ACS treatment. ...
... Preterm babies who have been exposed to repeated courses of ACS had a lower incidence of RDS than those who have been exposed to one course of ACS in few welldesigned randomized controlled studies [16][17][18] and in some other studies. [17,19] However, some studies [20,21] showed that there was no significant difference between repeated courses and a single course of ACS treatment. As such, there are no reports on the neonatal outcomes of one dose versus double dose of ACS and preterm infants. ...
... Five of the trials were conducted in the United States of America (Guinn 2001, McEvoy 2002, McEvoy 2010, Wapner 2006, Garite 2009) one in Canada Aghajafari 2002, India (Mazumder 2008) and Finland (Peltoniemi 2007), one in Australia and New Zealand (Crowther 2006), and one involved 20 countries (Murphy 2008). ...
... Most trials (Aghajafari 2002, Crowther 2006, Guinn 2001, Mazumder 2008, McEvoy 2002, Wapner 2006) (6) gave repeat corticosteroids at 7 day intervals if risk of preterm birth remained, one trial (Murphy 2008) at 14 day intervals and three trials (Garite 2009, McEvoy 2010, Peltoniemi 2007 specifically targeted women for "rescue therapy" (repeat doses only given when preterm birth was considered imminent). ...
PRECISE IPD-MA.
Repeat prenatal corticosteroid prior to preterm birth: a systematic review and IPD-MA for the PRECISE study group Study Protocol. IPD, individual participant data; MA, meta-analysis; PRECISE, Prenatal Repeat Corticosteroid International IPD-MA Study: assessing the effects using the best level of Evidence.
(PDF)
... [2][3][4][5] En varios estudios se investigaron los beneficios a corto plazo de la administración de dosis semanales de corticosteroides prenatales en comparación con el suministro de placebo, en mujeres que ya habían recibido una dosis de corticosteroides. [6][7][8] En general, los estudios reducidos iniciales no revelaron ningún beneficio. 6,8 Sin embargo, en el estudio de la Red de Unidades de Medicina Materno-Fetal del Instituto Nacional de Salud Infantil y Desarrollo Humano (NICHD), 8 se observó una tendencia de mejoría del resultado compuesto para los neonatos expuestos a dosis semanales de corticosteroides prenatales nacidos antes de las 32 semanas de gestación (23% de los neonatos del grupo de corticosteroides prenatales y 39% del grupo de placebo, p= 0,08). ...
... 6,8 Sin embargo, en el estudio de la Red de Unidades de Medicina Materno-Fetal del Instituto Nacional de Salud Infantil y Desarrollo Humano (NICHD), 8 se observó una tendencia de mejoría del resultado compuesto para los neonatos expuestos a dosis semanales de corticosteroides prenatales nacidos antes de las 32 semanas de gestación (23% de los neonatos del grupo de corticosteroides prenatales y 39% del grupo de placebo, p= 0,08). En el estudio Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) 7 , se incluyeron 982 pacientes y se observaron beneficios después de la administración de dosis semanales de corticosteroides prenatales. En el grupo de tratamiento hubo menos neonatos con síndrome de dificultad respiratoria que en el grupo de placebo (33% y 41%, riesgo relativo [RR] 0,82 [95% IC 0,71-0,95], p= 0,01) y menos casos de enfermedad pulmonar grave (12% y 20%; 0,60 [0,79], p= 0,0003). ...
Un tratamiento con una dosis de corticosteroides prenatales reduce el riesgo de síndrome de dificultad respiratoria y muerte neonatal. La administración de dosis semanales a pacientes que no dieron a luz después de una tanda de corticosteroides puede presentar beneficios (menor morbilidad respiratoria) o causar daños (reducción del crecimiento en el útero). Nuestro objetivo fue determinar si la administración de varias dosis de corticosteroides prenatales reduce los valores de morbilidad y mortalidad neonatales sin afectar el crecimiento fetal. Métodos. 1.858 mujeres entre 25 y 32 semanas de gestación, que no habían dado a luz entre 14 y 21 días después de una dosis inicial de corticosteroides prenatales y seguían presentando un riesgo elevado de parto prematuro, fueron asignadas de forma aleatoria a un tratamiento con múltiples tandas de corticosteroides prenatales (n= 937) o placebo (n= 921), cada 14 días hasta la semana 33 o el momento del parto, lo que ocurriera primero. El resultado primario fue un cuadro compuesto de mortalidad perinatal o neonatal, síndrome de dificultad respiratoria grave, hemorragia intraventricular (grado III o IV), leucomalacia periventricular, displasia broncopulmonar o enterocolitis necrosante. El análisis se realizó según la "intención de tratar". Ninguno de los pacientes o los profesionales conocían el tratamiento aplicado. Este estudio se registró con el número ISRCTN2654148. Resultados. Los neonatos expuestos a varias dosis de corticosteroides prenatales presentaron niveles de morbilidad y mortalidad similares a los neonatos expuestos a placebo (150 [12,9%] y 143 [12,5%]). Quienes recibieron múltiples dosis de corticosteroides también presentaron un peso al nacer inferior al de los neonatos expuestos a placebo (2.216 g y 2.330 g, p= 0,0026), una talla menor (44,5 cm y 45,4 cm, p< 0,001) y una circunferencia cefálica menor (31,1 cm y 31,7 cm, p< 0,001). Conclusiones. La administración de múltiples dosis de corticosteroides prenatales cada 14 días no mejoró el desenlace del parto prematuro y está asociada con valores menores de peso, talla y circunferencia cefálica al nacer. Por lo tanto, no se recomienda esta frecuencia de tratamiento. Financiamiento. Canadian Institutes of Health Research.
... As a result of the increasing contribution of neonatal deaths to overall child mortality, it is critical to address the determinants of poor outcomes related to preterm birth through interventions delivered to the mother before or during pregnancy, and to the preterm infant after birth. However, the most beneficial set of maternal interventions are those that are aimed at improving outcomes for preterm infants when preterm birth is inevitable which include tocolysis, antenatal corticosteroids, magnesium sulfate and antibiotic prophylaxis [6][7][8]. ...
Background:
Preterm birth is the leading cause of neonatal deaths and the second leading cause of death in children under five after pneumonia. The study aimed at improving the management of preterm birth through the development of protocols for standardization of care.
Methods:
The study was conducted in Mulago National Referral Labor ward in two phases. A total of 360 case files were reviewed and mothers whose files had missing data interviewed for clarity for both the baseline audit and the re-audit. Chi squares were used to compare results for the baseline and the re-audit.
Results:
There was significant improvement in four parameters out of the six that were used to assess quality of care and these were 32% increase in administration of Dexamethasone for fetal lung maturity, 27% increase in administration of Magnesium Sulphate for fetal neuroprotection and 23% increase in anti-biotic administration. A 14% reduction noted in patients who received no intervention. However, there was no change in the administration of Tocolytic.
Conclusion:
The results of this study have shown that protocols standardize care and improve the quality of care in preterm delivery to optimize outcomes.
... Zastosowanie pojedynczego kursu steroidoterapii jest uznaną metodą w stymulacji dojrzewania płuc płodu, która nie zwiększa śmiertelności poporodowej wśród noworodków, ponadtowedług Roberts D. i wsp.nie stanowi również zagrożenia dla zdrowia ciężarnej [9]. Udowodniono natomiast, że powtarzane kursy steroidoterapii zmniejszają częstość powikłań okresu noworodkowego, takich jak zespół zaburzeń oddychania (RDS) [10]. Stosowanie steroidoterapii nie pozostaje jednak bez wpływu na szereg parametrów kardiotokograficznych, takich jak FHR czy parametry cyfrowej analizy MONAKO zapisu LTV, STV, co potwierdza badanie Piazze'a i wsp. ...
Wstęp
Podawanie steroidów w ciąży do 34 hbd przyspiesza rozwój dojrzałości płuc płodu i stymuluje wydzielanie surfaktantu, przez co zapobiega występowaniu zespołu zaburzeń oddychania. Udowodniono, że podawanie steroidów prenatalnie powoduje czasowe obniżenie akcji serca płodu o adekwatnej masie ciała (AGA). W pracy podjęto próbę odpowiedzi na pytanie: jak długo utrzymuje się czasowe obniżenie akcji serca płodu (fetal heart rate – FHR) po podaniu steroidów u płodów z wewnątrzmacicznym ograniczeniem wzrastania?
Materiał i metody
Badanie przeprowadzono z udziałem 152 pacjentek Kliniki Ginekologii i Położnictwa SUM w Katowicach, hospitalizowanych w latach 2013–2016, podzielonych na dwie grupy: AGA – 109 przypadków, IUGR – 43 przypadki. W obu grupach została włączona profilaktyka steroidowa – betametazon lub deksametazon. Przeanalizowano zapisy KTG oraz MONAKO wykonane przy przyjęciu pacjentki oraz 24 i 48 godzin po podaniu steroidów, oceniając linię podstawową, epizody bradykardii oraz parametry zmienności LTV i STV. Wyniki opracowano w programie Statistica 12PL.
Wyniki
Bradykardia posteroidowa występowała częściej w grupie AGA niż w grupie IUGR. Po podaniu pierwszej dawki steroidów zauważono istotnie niższą wartość FHR w czasie trwania epizodów bradykardii w grupie AGA niż w grupie IUGR (p = 0,0001). Obniżenie FHR bez bradykardii było znamiennie większe w grupie AGA niż w grupie IUGR (p = 0,0001). Średnia wartość STV po podaniu drugiej dawki steroidów była znamiennie niższa w grupie AGA niż w grupie IUGR (p = 0,006). Ciśnienie parcjalne tlenu było wyższe w grupie IUGR (p = 0,001).
Wnioski
W świetle powyższych wyników wydaje się, że płody z IUGR wykazują lepszą tolerancję podawanych steroidów manifestującą się rzadszym występowaniem bradykardii i wyższymi wartościami STV oraz mniejszymi wahaniami wartości FHR.
... Difficulty in accurate prediction of preterm delivery in the short term and a possible diminishing effect of ACS over time, with an optimal interval of 7–14 days between ACS and delivery, resulted in routinely repetition of ACS in the 1990s1011121314151617. However no long-term benefit of repeat courses were found18192021222324 . Furthermore a lower neonatal birth weight and smaller head circumference were reported, although the long-term outcomes at 2–3 years of age seemed to be reassuring. ...
... Fetal exposure to exogenous GC levels higher than appropriate for the current stage of fetal maturation produces intrauterine growth restriction (IUGR) in multiple species including sheep, nonhuman primates, and from data of retrospective analyses, in human pregnancy (Johnson et al., 1981; Jobe et al., 1998; Banks et al., 1999; French et al., 1999; Bloom et al., 2001; Long et al., 2013). Besides reduced fetal growth, long-term adverse effects on brain development, neuroendocrine function, blood pressure, glucose homeostasis (Aghajafari et al., 2002), endocrine, renal, and metabolic function (Aghajafari et al., 2002; Crowther et al., 2006 Crowther et al., , 2007 Crowther et al., , 2011) have also been reported in vivo. These similarities across multiple species suggest common underlying mechanisms that result in adverse outcomes that need to be better understood (McKinlay et al., 2012). ...
... Both study groups At weekly intervals, if the woman has not yet given birth, and remains at continued risk of preterm birth, justifying the use of repeat antenatal corti- costeroids343536, a 'repeat treatment pack' containing a single syringe from the same treatment group will be allocated using the telephone randomisation service. Care during the antenatal period, labour and postnatal stay will be managed by the obstetric team caring for the woman. ...
Background:
Both dexamethasone and betamethasone, given to women at risk of preterm birth, substantially improve short-term neonatal health, increase the chance of the baby being discharged home alive, and reduce childhood neurosensory disability, remaining safe into adulthood. However, it is unclear which corticosteroid is of greater benefit to mother and child.This study aims to determine whether giving dexamethasone to women at risk of preterm birth at less than 34 weeks' gestation increases the chance of their children surviving free of neurosensory disability at two years' corrected age, compared with betamethasone.
Methods/design:
Design randomised, multicentre, placebo controlled trial.Inclusion criteria women at risk of preterm birth at less than 34 weeks' gestation with a singleton or twin pregnancy and no contraindications to the use of antenatal corticosteroids and who give informed consent.Trial entry & randomisation at telephone randomisation eligible women will be randomly allocated to either the dexamethasone group or the betamethasone group, allocated a study number and corresponding treatment pack.Study groups women in the dexamethasone group will be administered two syringes of 12 mg dexamethasone (dexamethasone sodium phosphate) and women in the betamethasone group will be administered two syringes of 11.4 mg betamethasone (Celestone Chronodose). Both study groups consist of intramuscular treatments 24 hours apart.Primary study outcome death or any neurosensory disability measured in children at two years' corrected age.Sample size a sample size of 1449 children is required to detect either a decrease in death or any neurosensory disability from 27.0% to 20.1% with dexamethasone compared with betamethasone, or an increase from 27.0% to 34.5% (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).
Discussion:
This study will provide high-level evidence of direct relevance for clinical practice. If one drug clearly results in significantly fewer deaths and fewer disabled children then it should be used consistently in women at risk of preterm birth and would be of great importance to women at risk of preterm birth, their children, health services and communities.
Trial registration:
Trial registration number:
ACTRN12608000631303.
... Pregnancy is a physiological condition associated with endogenous hypercortisolism. In modern obstetrics antenatal steroids (betamethazone or dexamethazone) are widely administered to improve neonatal survival when delivery before 34 weeks' gestation is a distinct possibility, however both of these steroid formulations have low mineralocorticoid activity [23]. ...
Pre-eclampsia is associated with ocular changes. The aim of this study was to examine the macular changes of patients with early-onset severe pre-eclampsia using optical coherence tomography (OCT).
This prospective study was performed at Tygerberg Academic Hospital, a secondary and tertiary referral centre in Cape Town, South Africa. Twenty women with early onset pre-eclampsia and 20 women without hypertensive or vascular complications, matched for gestational age, were examined before and after delivery.
There was a trend showing a positive correlation between increased central retinal thickness and increasing proteinuria in patients with pre-eclampsia antepartum (left eye r=0.52, p=0.04) and postpartum (left eye r=0.60, p=0.01). A positive correlation between average central 1mm and proteinuria was noted antepartum (left eye r=0.63, p=0.01) and postpartum (right eye r=0.52, p=0.03). There were no significant correlations between blood pressure and any of the retinal parameters. Two of the 23 patients with pre-eclampsia developed serous retinal detachments, both of which resolved completely postpartum.
Macular thickness parameters measured using OCT correlated with the degree of proteinuria in pre-eclampsia. These changes reversed soon after delivery.
Copyright © 2012 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
... Over the last decade, a number of multicenter, prospective trials comparing a single course of antenatal corticosteroid treatment to multiple courses have been published. 59,60,61 The results of ten randomized controlled trials, involving 4730 women and 5650 neonates have been summarized recent in a Cochrane review. 62 Treatment of women who remained at risk of preterm birth seven or more days after an initial course of antenatal corticosteroids with repeat dose(s) compared with no repeat treatment reduced the risk of infant respiratory distress syndrome (RR 0.83, 95%CI 0.75-0.91). ...
Though the preterm birth rate in the United States has finally begun to decline, preterm birth remains a critical public health problem. The administration of antenatal corticosteroids to improve outcomes after preterm birth is one of the most important interventions in obstetrics. This article summarizes the evidence for antenatal corticosteroid efficacy and safety that has accumulated since Graham Liggins and Ross Howie first introduced this therapy. Although antenatal corticosteroids have proven effective for singleton pregnancies at risk for preterm birth between 26 and 34 weeks’ gestation, questions remain about the utility in specific patient populations such as multiple gestations, very early preterm gestations, and pregnancies complicated by IUGR. In addition, there is still uncertainty about the length of corticosteroid effectiveness and the need for repeat or rescue courses. Though a significant amount of data has accumulated on antenatal corticosteroids over the past 40 years, more information is still needed to refine the use of this therapy and improve outcomes for these at-risk patients.
... 1,2 The administration of repeated-course antenatal corticosteroids has been the subject of recent clinical trials, and has been found to further reduce neonatal respiratory morbidity, relative to singlecourse regimens. [3][4][5] However, these studies have also supported concerns regarding the impact of repeated-course antenatal corticosteroids on fetal growth, head circumference, and neurodevelopment. 3,4,6,7 The clinical effects of antenatal corticosteroids may be mediated, in part, by their antiinflammatory effects. ...
... Prospective studies are currently underway examining the effects of repeated sGC administration during pregnancy in human cohorts. A large Australian trial found that infants born of mothers administered repeated doses of sGCs exhibited decreased RDS and severe lung disease compared to those whose mothers had received a single course (Crowther et al. 2006). Based on those results, the authors concluded that multiple courses were beneficial for respiratory function in preterm infants. ...
Preterm delivery occurs in approximately 10% of all pregnancies. Prenatal exposure to synthetic glucocorticoids (sGCs) reduces the incidence of respiratory distress syndrome (RDS) in these babies. Therefore, administration of multiple courses of sGCs became common practice. Animal and human studies have demonstrated that multiple courses of sGCs can have long-term effects. While the majority of animal studies have been undertaken in male offspring, it is emerging that there are profound sex differences in the consequences of prenatal sGC exposure. To our knowledge, no studies have determined the effects of prenatal sGC exposure on hypothalamic-pituitary-adrenal (HPA) axis function in female offspring while accounting for reproductive cycle status, or determined if there are effects on pregnancy parameters. Pregnant guinea pigs were administered three courses of betamethasone (Beta), dexamethasone (Dex) or vehicle on gestational days 40/41, 50/51 and 60/61. In adulthood (age range: postnatal days 126-165), basal and activated HPA axis function were assessed at various stages of the reproductive cycle. The female offspring were then mated and underwent an undisturbed pregnancy. Females were killed in the luteal phase of the reproductive cycle following litter weaning, and molecular analysis undertaken. In the luteal phase, Beta-exposed females exhibited significantly lower basal salivary cortisol levels (P < 0.05). Dex-exposed females also exhibited significantly lower basal salivary cortisol levels during the luteal phase (P < 0.05), but increased basal salivary cortisol levels during the ostrous phase (P < 0.01). The Beta-exposed females exhibited increased glucocorticoid receptor (GR) mRNA expression in the CA1/2 region of the hippocampus (P < 0.05) and MC2R mRNA in the adrenal cortex (P < 0.05). The Dex-exposed animals exhibited higher hippocampal GR and mineralocorticoid receptor (MR) mRNA levels (P < 0.05). Beta-exposed females showed reduced fecundity (P < 0.05). In Dex-exposed females there was a lower male to female sex ratio. In conclusion, prenatal sGC exposure affects HPA axis activity, in a cycle-dependent manner, and long-term reproductive success. The clinical implications of the findings on endocrine function and pregnancy in females are profound and further follow-up is warranted in human cohorts. Furthermore, we have shown there are considerable difference in phenotypes between the Beta- and Dex-exposed females and the specific endocrine and maternal outcome is contingent on the specific sGCs administered during pregnancy.
The recommended fixed dosage of betamethasone for pregnancies at risk of preterm‐birth was determined in the 1970s, regardless of gestational age (GA), number of fetuses and maternal weight. We aimed to examine the association between maternal and neonatal betamethasone serum levels and neonatal respiratory distress syndrome (RDS) and to examine whether levels correlate with maternal weight, GA or number of fetuses. Prospective study conducted at a single academic medical center between August‐2016 and February‐2019. Women received betamethasone and delivered between 28+0 and 34+6 weeks were included. Maternal serum levels (MSL), and neonatal serum levels (NSL) of betamethasone at delivery were analyzed using Corticosteroid ELISA kit. RDS was diagnosed according to clinical and radiographic findings. We assumed that the sensitivity of NSL to detect RDS is 95%; hence, 150 neonates were needed (power 80%, alpha 0.05). Overall 124 women were included; 96 (77.4%) singletons, 26 (21.0%) twins and 2 (1.6%) triplets, corresponding to 154 neonates. RDS was diagnosed in 35 (22.7%). After adjusting for GA, time elapsed from last dose and number of doses, NSL were associated with RDS (RR: 0.97; 95%CI: 0.94‐0.99; p=0.011). A level of 6.00 ng/mL predicted RDS with a sensitivity of 80.0% and specificity of 64.7%. Adjusted MSL were not associated with RDS. Both maternal and neonatal serum levels were not associated with the number of fetuses and maternal weight. In conclusion, NSL are associated with RDS while MSL are not.
Objectives
To assess the relationship of time interval between antenatal corticosteroid administration and delivery with respiratory distress in premature newborns.
Settings
Tertiary level teaching hospital
Population
Preterm deliveries between 28 and 34 weeks in the period of April 2011 to January 2013 where the mothers received one course of corticosteroid prophylaxis and fulfilled the selection criteria.
Materials and methods
Perusal of the hospital records was made to gather antenatal information and the details of delivery and the newborn. The patients were divided based on the number of doses of steroids received into three groups. The patients receiving complete steroid prophylaxis was further divided based on the time interval between steroid administration and delivery into five groups: 0 to 7 days, 8 to 14, 15 to 21, 22 to 28, 29 days and beyond. We looked for association between neonatal respiratory outcomes and steroid-delivery intervals using Statistical Package for the Social Sciences version 16 (SPSS, Chicago, USA). Regression model was used to control for the confounding variables.
Results
There were 284 women who delivered preterm (up to 34 weeks of gestation) between April 2011 and January 2013 and fulfilled the selection criteria. The babies who received one (48) or no dose of steroids (14) had a higher incidence of respiratory distress than the ones who received a complete dose. This was statistically significant for babies born up to 32 weeks.
Among the rest 222 babies who received complete steroid prophylaxis, 138 (62%) of the neonates born were admitted in NICU, respiratory distress was seen in 62 (28%). Eleven (5%) of the babies required intubation and 22 (9%) required surfactant therapy; there were 12 (5%) neonatal deaths. Multivariable logistic regression analysis showed a slightly increased risk of respiratory morbidity with increased interval from administration to delivery (OR–0.87 for 8–14 days, 1.79 for 15–21 days and 0.16 for 22–28 days).
Conclusion
The risk of respiratory distress in preterm newborns increases beyond 2 weeks interval between antenatal corticosteroid administration and delivery.
How to cite this article
Guruvare S, Basu B, Rai L, Lewis L, Hebbar S, Adiga P. Relationship of Time Interval between Antenatal Corticosteroid Administrations to Delivery with Respiratory Distress in Preterm Newborns. Int J Infertil Fetal Med 2015;6(3): 128-132.
Preterm delivery is an important cause of morbidity and mortality. The administration of a single course of corticosteroids antepartum in women at risk of preterm delivery (24+0 - 34+6 weeks of gestation) is associated with a significant reduction of these complications without increasing the short and long term maternal and neonatal risks. There is less certainty about the administration of repeated cycles where the woman remains at high risk of preterm delivery 7 days after the initial treatment. Repeated cycles seem to be beneficial in the short term, but there is no agreement and sufficient information on what might be the long-term effects on the infant exposed to multiple cycles during intrauterine life. Therefore, the administration of repeated cycles should be reserved to women involved in randomized controlled trials. Finally, further studies should be conducted to clarify many questions still with no definitive answer: duration of effect of corticosteroids, necessity of repeated cycles, risks of repeated administration, ideal medication and dosage, long-term effects, the role of corticosteroids in particular situations (elective caesarean section, intrauterine growth restriction, diabetes in pregnancy).
Preterm labor is the most common complication of the pregnancy in the second trimester and has been suggested as the cause of two-thirds of neonatal mortality. Antenatal corticosteroid is used for fetal lung maturity in preterm labor and makes a significant reduction in the incidence of respiratory distress syndrome (RDS). The aim of this study was to compare the prenatal administration of single and multiple courses of betamethasone and neonatal outcomes, effectiveness and safety of its weekly administration.
A randomized, double-blind placebo-control clinical trial study conducted in pregnant women at risk for preterm birth by gestational age between 28 and 35 weeks. The women received a course of betamethasone at first, and then divided into a single course and multiple betamethasone courses. They evaluated for the incidence of RDS, need for oxygen, surfactant administration, the need for ventilation, duration of hospitalization and neonatal mortality. Data were analyzed using SPSS-version 16 and Chi-square test and t-test.
The need for O2, the incidence of RDS, the need for hospitalization, days of hospitalization, the need for continuous positive airway pressure, ventilation and surfactant and the mortality significantly lower in the multiple course groups and betamethasone had a clear positive effect in this regard. Mean weight, height and head circumferences were significantly lower in the multiple course group.
Despite a positive impact of multiple betamethasone usage on mortality and morbidity in neonates, it is recommended to avoid routinely using of betamethasone multiple courses until the adequate data of studies prove the safety of reduction in weight, height, and head circumference in a long period.
AimTo investigate the impact of antenatal exposure to a single course or repeated courses of dexamethasone (DEX) on neonatal anthropometrics, placental morphometry and potential effect on maternal plasma levels and placental expression of vascular endothelial growth factor (VEGF).Methods
Pregnant women between 27 and 32 weeks of gestation who delivered between 28 and 40 weeks and received a single course (n = 38) or repeated courses (n = 33) of DEX were compared to gestational age-matched controls (n = 30). Maternal blood samples were obtained, and placental biopsy was taken. Area percent of VEGF immunostaining and villous capillarization index were evaluated using image analysis.ResultsInfants exposed to repeated courses of DEX were significantly associated with decreased birthweight, body length, head circumference and placental weight compared with controls (P = 0.011, P < 0.001, P = 0.004, P < 0.001, respectively) and with the group that received a single course of DEX (P = 0.021, P = 0.020, P = 0.049, P = 0.010, respectively). There was a significant decrease in maternal VEGF plasma levels and percentage of VEGF immunostained area after repeated courses of DEX compared with controls (P < 0.001 and P = 0.001, respectively) or a single course (P = 0.028 and P = 0.002, respectively). Notably, repeated courses of DEX impaired normal increase in villous capillarization index compared with controls or a single course (P = 0.001 and P = 0.041, respectively).Conclusion
Repeated antenatal courses of DEX compromised fetal and placental growth compared with a single course of DEX, and these effects were potentially mediated by altered maternal plasma levels and placental expression of VEGF with consequent decrease in placental vascularization. Because of continuing uncertainties, several key messages for clinicians are provided.
Objective:
To investigate the duration of effects and health consequences of earlier antenatal corticosteroid exposure in infants born late preterm or term.
Design:
Observational cohort study.
Setting:
Children born after gestational week 34 in Sweden, 1976-1997, whose mothers were hospitalized for imminent preterm delivery. The children were followed to their 11th birthday.
Sample:
The cohort consisted of 11 873 infants, of whom 8620 were exposed.
Methods:
Exposure was estimated at hospital level. Infants born at a hospital practicing antenatal corticosteroid administration were classified as exposed. Estimation of hospital routines was based on questionnaire data, telephone interviews with physicians and pharmacy sales, validated in a random sample of medical records. Logistic regression was used to assess associations with adjustments for pregnancy length, birth year and hospital level.
Main outcome measures:
Rates and odds ratios of mortality, respiratory distress syndrome, bronchopulmonary dysplasia, epilepsy, cerebral palsy, childhood diabetes, birthweight, length and head circumference for all infants, and for preterm and term infants, respectively.
Results:
Exposed infants had reduced risks of respiratory distress syndrome (odds ratio 0.54, 95% confidence interval 0.35-0.83) and small head circumference (odds ratio 0.47, 95% confidence interval 0.36-0.61), and an increased risk of low Apgar scores (odds ratio 1.40, 95% confidence interval 1.01-1.94), most pronounced in infants born after gestational week 37.
Conclusions:
Infants born after gestational week 34 seem to benefit from earlier antenatal corticosteroid administration, with reduced risks of respiratory distress syndrome. However, the treatment was less beneficial for term infants, because they also had increased risk of low Apgar scores.
Respiratory distress syndrome (RDS) caused by preterm delivery is a major clinical problem with limited mechanistic insight. Late stage embryonic lung development is driven by hypoxia and hypoxia inducible transcription factors Hif-1α and Hif-2α, which act as important regulators for lung development. Expression of BTB-kelch protein KLEIP (Kelch-like ECT2 interacting protein; also named Klhl20) is controlled by two hypoxia response elements and KLEIP regulates stabilization and transcriptional activation of Hif-2α. Based on the data, we hypothesised an essential role for KLEIP in murine lung development and function. Therefore, we have performed a functional, histological, mechanistic and interventional study in embryonic and neonatal KLEIP(-/-) mice. Here we show that half of the KLEIP(-/-) neonates die due to respiratory failure that is caused by insufficient aeration, septal thickness, reduced glycogenolysis, type II pneumocyte immaturity and reduced surfactant production. Expression analyses in E18.5 lungs identified KLEIP in lung capillaries and strongly reduced mRNA and protein levels for Hif-2α and VEGF, which is associated with embryonic endothelial cell apoptosis and lung bleedings. Betamethasone injection in pregnant females prevented respiratory failure in KLEIP(-/-) neonates, normalized lung maturation, aeration and function and increased neonatal Hif-2α expression. Thus, the experimental study shows that respiratory failure in KLEIP(-/-) neonates is determined by insufficient angiocrine Hif-2α/VEGF signaling and that betamethasone activates this new identified signaling cascade in late stage embryonic lung development.
Prenatal glucocorticoids (GCs) are routinely used for pregnant women in preterm labor to prevent respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, the effect of antenatal GCs on neurogenesis in preterm neonates remains elusive. Herein, we hypothesized that prenatal GCs might suppress both glutamatergic and GABAergic neurogenesis in preterm rabbits and that this treatment would induce distinct changes in the expression of transcription factors regulating these developmental events. To test our hypotheses, we treated pregnant rabbits with betamethasone at E27 and E28, delivered the pups at E29 (term=32d), and assessed neurogenesis at birth and postnatal day 3. We quantified radial glia (Sox2(+)) and intermediate progenitor cells (Tbr2(+)) in the dorsal cortical subventricular zone to assess glutamatergic neuronal progenitors, and counted Nkx2.1(+) and Dlx2(+) cells in the ganglionic eminence to evaluate GABAergic neurogenesis. In addition, we assayed transcription factors regulating neurogenesis. We found that prenatal GCs did not affect the densities of radial glia and intermediate progenitors of glutamatergic or GABAergic neurons. The number of GABA(+) interneurons in the ganglionic eminence was similar between the prenatal GC treated pups compared to untreated controls. Moreover, the mRNA expression of transcription factors, including Pax6, Ngn1/2, Emx1/2, Insm1, Dlx1, Nkx2.1, and Gsh2, were comparable between the two groups. However, there was a transient elevation in Mash1 protein in betamethasone treated pups relative to controls at birth. This data suggests that prenatal GC treatment does not significantly impact the balance of glutamatergic and GABAergic neurogenesis in premature infants.
We aimed to evaluate the effects of single and double courses of antenatal corticosteroid administration on neonatal mortality and morbidity.
232 preterm babies delivered between 01. April 2007 and 31. March 2008 with gestational ages of 26-34 weeks were evaluated prospectively. Infants were divided into three groups. The first group did not receive any antenatal betamethasone therapy. The second group received single (two doses of 12 mg betamethasone administered at 24 hour intervals) and the third group received double (repeated course after one week) courses of betamethasone therapy.
156 (67.2%) infants received at least one dose of corticosteroid treatment whereas 76 (37.8%) did not. Of 156 infants who had received antenatal betamethasone, 36 (23.1%) developed respiratory distress syndrome (RDS), while the incidence of RDS was 35.5% in 76 preterms who received no antenatal betamethasone (27/76) (p<0.05). When single and double courses of bethamethasone administration were compared, 20 (24.7%) infants with single course and 16 (21.3%) infants with two course developed RDS (p>0.05).
When single and two courses of antenatal steroid therapy were compared, there was no statistically significant difference between groups regarding the incidence of RDS and mechanical ventilator treatment.
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.
The effectiveness of antenatal corticosteroid therapy for foetal lung maturation in pre-term infants is well known, but there is uncertainty about the time that the treatment remains effective. A descriptive, longitudinal study was conducted to determine whether the need for surfactant administration was determined by the time-lapse between corticosteroids administration and delivery, and when repeating the doses of maternal corticosteroids should be considered. A total of 91 premature infants ≤32 weeks and/or ≤1,500 g (limit 34+6 weeks) whose mothers had received a complete course of corticosteroids were included. In patients at 27-34+6 weeks, we found that the longer the time elapsed between delivery and administration of corticosteroids, most likely were the babies to require treatment with surfactant (P=.027). The resulting ROC curve determined an 8-days cut-off after which repeating a dose of corticosteroids should be assessed.
Diabetic pregnancy is a precarious situation, both for mother and fetus, because it increases the risk of prematurity and respiratory distress. We report 3 cases of severe acute complications following antenatal betamethasone treatment in mothers presenting with severe diabetes. Corticosteroids are strongly recommended to prevent prematurity complications in newborns. We highlight the high risk profile of theses pregnancies, the effect of this treatment on the mother and the child, and question the real benefit of corticotherapy for these fragile newborns. The metabolic and blood pressure balance is dangerously disturbed in such pregnancies by this treatment. This brings the question of how justified are corticosteroids in such cases?
Objective:
The purpose of this study was to estimate a gestational age threshold at which the benefits of treatment with weekly courses of antenatal corticosteroids (ACS) during preterm labor outweigh the risks.
Study design:
Risk-benefit ratios by gestational age were determined with the use of a Markov microsimulation decision-analysis model with a 1-week cycle length. Single course and multiple (weekly to a maximum of 4) courses of ACS by gestational age of entry (23 weeks to 31 weeks 6 days' gestation) were compared. Benefits were composite events (respiratory distress syndrome, chronic lung disease, severe intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, or stillbirth) averted. Risks were small head circumference and small for gestational age.
Results:
More composite events are averted (benefits) than risks acquired (ratio, 6:1) when multiple courses of ACS are initiated at 26 weeks' gestation. When multiple courses of ACS are initiated at 29 weeks' gestation, the risk-benefit ratio is 1. Beyond 29 weeks, there is a suggestion of more risk than benefit.
Conclusion:
The model suggests that multiple courses of ACS that are initiated at <29 weeks' gestation may have increased benefit compared with risks. Further analyses are needed to determine the long-term clinical significance of these findings.
Objective:
To investigate whether repeat courses of antenatal corticosteroids have long-term effects on cognitive and psychological functioning.
Study design:
In a prospective cohort study, 58 adolescents and young adults (36 males) who had been exposed to 2-9 weekly courses of betamethasone in utero were assessed with neuropsychological tests and behavior self-reports. Unexposed subjects (n = 44, 25 males) matched for age, sex, and gestational age at birth served as a comparison group. In addition, individuals exposed in utero to a single course (n = 25, 14 males) were included for dose-response analysis. Group differences were investigated using multilevel linear modeling.
Results:
Mean scores obtained in 2 measures of attention and speed were significantly lower in subjects exposed to 2 or more antenatal corticosteroids courses (Symbol Search, P = .009; Digit Span Forward, P = .02), but these were not dose-dependent. Exposure to repeat courses of antenatal corticosteroids was not associated with general deficits in higher cognitive functions, self-reported attention, adaptability, or overall psychological function.
Conclusions:
Although this study indicates that repeat exposure to antenatal corticosteroids may have an impact on aspects of executive functioning, it does not provide support for the prevailing concern that such fetal exposure will have a major adverse impact on cognitive functions and psychological health later in life.
Glucocorticoids are administered to pregnant women at risk of preterm labour to promote fetal lung surfactant maturation. Intrauterine growth restriction (IUGR) is associated with an increased risk of preterm labour. Hence, IUGR babies may be exposed to antenatal glucocorticoids. The ability of the placenta or blood brain barrier to remove glucocorticoids from the fetal compartment or the brain is compromised in the IUGR fetus, which may have implications for lung, brain, and heart development. There is conflicting evidence on the effect of exogenous glucocorticoids on surfactant protein expression in different animal models of IUGR. Furthermore, the IUGR fetus undergoes significant cardiovascular adaptations, including altered blood pressure regulation, which is in conflict with glucocorticoid-induced alterations in blood pressure and flow. Hence, antenatal glucocorticoid therapy in the IUGR fetus may compromise regulation of cardiovascular development. The role of cortisol in cardiomyocyte development is not clear with conflicting evidence in different species and models of IUGR. Further studies are required to study the effects of antenatal glucocorticoids on lung, brain, and heart development in the IUGR fetus. Of specific interest are the aetiology of IUGR and the resultant degree, duration, and severity of hypoxemia.
The developmental origins of disease or fetal programming model predict that early exposures to threat or adverse conditions have lifelong consequences that result in harmful outcomes for health. The maternal endocrine 'fight or flight' system is a source of programming information for the human fetus to detect threats and adjust their developmental trajectory for survival. Fetal exposures to intrauterine conditions including elevated stress hormones increase the risk for a spectrum of health outcomes depending on the timing of exposure, the timetable of organogenesis and the developmental milestones assessed. Recent prospective studies, reviewed here, have documented the neurodevelopmental consequences of fetal exposures to the trajectory of stress hormones over the course of gestation. These studies have shown that fetal exposures to biological markers of adversity have significant and largely negative consequences for fetal, infant and child emotional and cognitive regulation and reduced volume in specific brain structures.
Objective To estimate the efficacy of a rescue course of antenatal corticosteroids in twin pregnancies.
Design Retrospective cohort study.
Setting Tertiary-care centre.
Population Twins born from 24 to <34 weeks of gestation in a single maternal and fetal medicine practice from 2006 to 2011.
Methods We compared neonatal outcomes in 88 twins exposed to a single course of corticosteroids with outcomes in 42 twins exposed to two courses of corticosteroids: the initial course and a single rescue course. Analyses were adjusted to control for correlation between twins born to the same mother.
Main outcome measure Short-term neonatal respiratory morbidity.
Results Rescue corticosteroids were associated with fewer days of mechanical ventilation (7.3 ± 3.3 versus 33.9 ± 25.3 days, P = 0.003), fewer days with a fraction of inspired oxygen of >21% (6.3 ± 4.3 versus 33.3 ± 25.8 days, P = 0.003), a lower incidence of mechanical ventilation >14 days or death while on mechanical ventilation (0 versus 12.5%, P = 0.016), and a lower incidence of retinopathy of prematurity (0 versus 12.5%, P = 0.016). The proportion of neonates with respiratory distress syndrome did not differ between the groups (adjusted odds ratio 1.28, 95% confidence interval 0.50–3.26). There were no differences found for birthweight, head circumference and length.
Conclusions In twins born before 34 weeks of gestation, exposure to rescue corticosteroids may be associated with improved neonatal outcomes. Further studies are warranted to assess the effect of rescue corticosteroids in twin pregnancies.
Background Although the hope is that many perinatal interventions are performed with an ultimate aim to improve the long-term health and development of the child, long-term outcome is rarely used as a primary end-point in perinatal randomised controlled trials (RCTs).
Objective To evaluate how often and with which tools long-term follow-up is performed after large obstetric RCTs.
Search strategy We searched the Cochrane Library for Cochrane reviews published by the Cochrane Pregnancy and Childbirth Group for reviews on interventions that aimed to improve neonatal outcome.
Selection criteria Reviews on perinatal interventions that were not performed to improve the condition of the neonate were excluded. We limited our review to RCTs with more than 350 participating women. For each included study, we checked in Web of Science as to whether the researchers had reported on follow-up in subsequent publications.
Data collection and analysis Relevant information was extracted from these RCTs by two reviewers using a predefined data collection sheet. All information was analysed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA).
Main results We studied 212 reviews including 1837 RCTs on perinatal interventions, 249 (14%) of which included 350 participants. Only 40 of 249 RCTs (16%) followed the children after discharge from the hospital to evaluate the effect of a specific perinatal intervention. The number of RCTs with long-term follow-up remained stable, with 10 of 67 RCTs (15%) reporting follow-up before 1990, 17 of 115 (15%) between 1990 and 2000, and 13 of 67 (19%) after 2000 (P = 0.68).
Conclusions Only a small minority of large perinatal RCTs report the long-term follow-up of the child. Future obstetric RCTs should consider performing long-term follow-up at the start of the trial.
Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI), leading to the development of bronchopulmonary dysplasia (BPD). It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI.
Preterm lambs of 131 days' gestation (term = 147 d) were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13), 18 L/min (n = 12) or 28 L/min (n = 14). Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate.
High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung.
High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD.
To evaluate the effects on neonatal outcomes between very-low-birth-weight (VLBW) preterm newborns with and without maternal use of antenatal corticosteroids (ACS).
We retrospectively reviewed medical records of VLBW premature infants who were admitted to Kaohsiung Medical University Hospital between 1999 and 2008. A total of 256 infants were enrolled in this study. A total of 174 neonates did not receive any ACS, and 82 neonates received ACS. A total of 37 neonates received one dose of ACS, and 45 neonates received more than one dose of ACS, referred to as "multiple-dose ACS." In addition, these 82 infants were divided to betamethasone group (n=8) and dexamethasone group (n=50) with 24 infants excluded because of inadequate information.
Neonates with multiple-dose ACS had lower incidence of surfactant use and lower rate of intubation than neonates without ACS. There were no differences in the occurrences of intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and chronic lung disease with one-dose vs. multiple-dose ACS and in the betamethasone group vs. the dexamethasone group.
ACS reduces the need for exogenous surfactant, and the need for endotracheal tube insertion at birth in VLBW premature infants.
To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn.
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.
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.
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.
Repeated courses of antenatal steroids in women at risk of preterm delivery have beneficial effects on lung maturation, but concern exists about the effects on brain development. We aimed to determine whether repeated courses of corticosteroids increased the risk of neuropathology as compared with single courses or no treatment.
Single-course animals received a 6-mg dose of steroids at 123 and 124 d of gestation (dg; term, 185 dg; n = 6). Repeated-course animals received additional doses at 137 and 138 dg (n = 7). Controls received no steroids (n = 5). Baboons delivered naturally at term and necropsy was performed. Brains were assessed histologically for parameters of development and neuropathology.
Body weights did not differ between the groups (P > 0.05); neither did brain/body weight ratio. Density of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes in white matter (WM) was increased in the single- (P < 0.05) and repeated-course (P < 0.01) groups as compared with controls. Density of myelin basic protein (MBP)-IR oligodendrocytes was reduced in the repeated-course animals as compared with both the control and single-course groups (P < 0.05); oligodendrocyte transcription factor 2 (Olig2)-IR showed no difference between groups.
Repeated courses of antenatal corticosteroids have effects on myelination in the developing nonhuman primate brain, which should be taken into account when determining a dosing regimen.
Objective: This study was conducted to examine the frequency and clinical significance of a positive Amnisure test in patients with preterm labor and intact membranes by sterile speculum exam. Study design: A retrospective cohort study was performed including 90 patients with preterm labor and intact membranes who underwent Amnisure tests prior to amniocentesis (< 72 h); most patients (n = 64) also underwent fetal fibronectin (fFN) tests. Amniotic fluid (AF) was cultured for aerobic/anaerobic bacteria and genital mycoplasmas and assayed for matrix metalloproteinase-8. Results: (1) the prevalence of a positive Amnisure test was 19% (17/90); (2) patients with a positive Amnisure test had significantly higher rates of adverse pregnancy and neonatal outcomes (e.g., impending preterm delivery, intra-amniotic infection/inflammation, and neonatal morbidity) than those with a negative Amnisure test; (3) a positive test was associated with significantly increased risk of intra-amniotic infection and/or inflammation, delivery within 7, 14, or 28 days and spontaneous preterm birth (< 35 weeks) among patients with a negative fFN test. Conclusions: A positive Amnisure test in patients with preterm labor and intact membranes is a risk factor for adverse pregnancy outcome, particularly in patients with a negative fFN test. A positive Amnisure test in patients without symptoms or signs of ROM should not be taken as an indicator that membranes have ruptured.
In high-income countries, administration of antenatal steroids is standard care for women with anticipated preterm labour. However, although >1 million deaths due to preterm birth occur annually, antenatal steroids are not routine practice in low-income countries where most of these deaths occur.
To review the evidence for and estimate the effect on cause-specific neonatal mortality of administration of antenatal steroids to women with anticipated preterm labour, with additional analysis for the effect in low- and middle-income countries.
We conducted systematic reviews using standardized abstraction forms. Quality of evidence was assessed using an adapted GRADE approach. Existing meta-analyses were reviewed for relevance to low/middle-income countries, and new meta-analysis was performed.
We identified 44 studies, including 18 randomised control trials (RCTs) (14 in high-income countries) in a Cochrane meta-analysis, which suggested that antenatal steroids decrease neonatal mortality among preterm infants (<36 weeks gestation) by 31% [relative risk (RR) = 0.69; 95% confidence interval (CI) 0.58-0.81]. Our new meta-analysis of four RCTs from middle-income countries suggests 53% mortality reduction (RR = 0.47; 95% CI 0.35-0.64) and 37% morbidity reduction (RR = 0.63; 95% CI 0.49-0.81). Observational study mortality data were consistent. The control group in these equivalent studies was routine care (ventilation and, in many cases, surfactant). In low-income countries, many preterm babies currently receive little or no medical care. It is plausible that antenatal steroids may be of even greater effect when tested in these settings.
Based on high-grade evidence, antenatal steroid therapy is very effective in preventing neonatal mortality and morbidity, yet remains at low coverage in low/middle-income countries. If fully scaled up, this intervention could save up to 500 000 neonatal lives annually.
Infants born very prematurely often received corticosteroids to minimise the risk of developing bronchopulmonary dysplasia (BPD) but their long term impact on lung function at school age is unclear.
A cross-sectional study of 105 children [mean gestation of 27 weeks] was undertaken. Lung function assessments were conducted at a mean age of 10 years according to standard criteria. Corticosteroid dose was obtained from the medical record.
Spirometry in the BPD group was not significantly different to the non-BPD group, mean per-cent predicted (95% confidence interval) forced expiratory volume in 1 s (FEV1) 83% (79, 87) versus 86% (83, 90), FEF25%-75% 67% (60, 73) versus 75% (69, 81). Antenatal steroid treatment alone did not adversely affect airflow FEV1, 88% (84.92) versus 90% (82.97), and forced expiratory flow (FEF)25%-75%, 75% (69.81) versus 87% (70.104). Children who received post-natal corticosteroids had significantly lower flows than those who did not (FEV1 82% (78.85) vs. 88% (85.92), P = 0.006; FEF25%-75% 65% (59.71) vs. 78% (72.84), P = 0.003). Regression analysis revealed days on oxygen and days ventilated were statistically significant but weak predictors of airflow at 10 years of age.
A diagnosis of BPD did not predict reduced spirometry in middle childhood. Children who received post-natal corticosteroids as preterm infants had reduced expiratory flows compared with those who did not. While post-natal corticosteroids may be a marker of severity of lung disease, the potential of post-natal corticosteroids to influence lung development requires further investigation.
It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial.
To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2011), searched reference lists of retrieved studies and contacted authors for further data.
Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth.
We assessed trial quality and extracted data independently.
We included 10 trials (more than 4730 women and 5650 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNT 30, 95% CI 19 to 79).Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) -75.79 g, 95% CI -117.63 to -33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small-for-gestational age) did not differ between treatment groups.At early childhood follow-up no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or serious outcome) or in the secondary outcome growth assessments.
The short-term benefits for babies of less respiratory distress and fewer serious health problems in the first few weeks after birth support the use of repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. These benefits were associated with a small reduction in size at birth. The current available evidence reassuringly shows no significant harm in early childhood, although no benefit.Further research is needed on the long-term benefits and risks for the woman and baby. Individual patient data meta-analysis may clarify how to maximise benefit and minimise harm.
At birth, lung fluid produced during fetal life must be cleared immediately and efficiently before the first breath takes place, in order for infants to achieve a normal and successful transition from prenatal to postnatal life. Postnatal lung fluid resorption is mediated through activation of airway epithelial sodium channels (ENaC). The observation that ENaC expression is a gestational age-dependent process contributes to our understanding of the development of respiratory distress in both term and preterm infants due to impaired clearing of fluid from their lungs. As fluid absorption, mediated by ENaC activity, in postnatal life has a significant biological role in preventing respiratory distress, any strategy that enhances ENaC activity can potentially help to decrease its incidence and associated morbidity.
To systematically review the efficacy and safety of repeated antenatal corticosteroid on neonatal morbidity, growth and later development.
MEDLINE, Cochrane database and a bibliography of identified articles were searched for English language studies. Design. Meta-analysis of randomized controlled trials.
Randomized, controlled trials studying the efficacy and safety of repeat antenatal corticosteroid treatment on neonatal morbidity and early childhood development.
Respiratory distress syndrome, intrauterine growth, neurodevelopment.
Two reviewers independently assessed titles, abstracts and full studies, extracted data and assessed quality. Meta-analyses were performed, calculating risk ratios and weighted differences of means with 95% confidence intervals using a random-effects model.
Eight trials were included. Repeated betamethasone treatment decreased the risk of respiratory distress syndrome (relative risk 0.85, 95% confidence interval 0.77-0.93). Trials involving weekly or biweekly repeated betamethasone and those involving a single rescue dose decreased the risk of respiratory distress syndrome. Intrauterine growth was significantly restricted among preterm infants exposed to weekly or biweekly repeated betamethasone. A single rescue course did not affect growth. Four follow-up studies did not reveal any disturbances in neurodevelopment or growth at two years of corrected age.
Repeated corticosteroid treatment decreased the risk of respiratory distress syndrome among preterm infants. Weekly or biweekly repeated betamethasone restricted intrauterine growth, which raises concerns about long-term consequences on neurodevelopment and metabolism. More follow-up studies are needed to confirm the long-term safety of repeated betamethasone.
Ali Khan A, Rodriguez A, Kaakinen M, Pouta A, Hartikainen A-L, Jarvelin M-R. Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? A systematic review of current evidence in humans. Paediatric and Perinatal Epidemiology 2010.
Synthetic glucocorticoids are the mainstay treatment for stimulating lung maturation in threatened preterm delivery. Animal studies suggest that in utero exposure to glucocorticoids leads to a reduction in birth size. Smaller birthweight has been associated with higher risk of many chronic diseases. Therefore, the authors undertook a systematic review of human studies examining the association between synthetic glucocorticoid treatment and birth size. Medline, EMBASE, PubMed, Cochrane, Google scholar and Institute of Life Science databases were searched for studies published between 1978 and 2009 investigating the association between synthetic glucocorticoids and birthweight, head circumference, birth length and ponderal index. All studies controlling for gestational age were examined. Seventeen studies were included in the analysis. Nine out of 17 studies reported a reduction in birthweight (range 12–332 g), five of nine a reduction of head circumference (range 0.31–1.02 cm) and two of four a reduction of 0.8 cm in birth length. Despite methodological inconsistencies and limitations that impede clear conclusions, the evidence suggests an association between in utero exposure to synthetic glucocorticoids and reduced birth size.
This study was undertaken to evaluate the effects of repeated courses of antenatal corticosteroids (ACS) on foetal growth.
We studied 94 infants exposed to 2-9 courses of ACS. Mean gestational age (GA) at first exposure was 29 and at birth 34 weeks. Exposure data were retrieved from case record files. Information on potential confounders was collected from the Swedish Medical Birth Registry. Standard deviation scores (SDS) for birthweight (BW), birthlength (BL) and head circumference (HC) were calculated and considered as outcomes.
GA at start of ACS did not affect outcome. BW-SDS, BL-SDS and HC-SDS were -0.21, -0.19 and +0.25 in infants exposed to two courses, compared to -1.01, -1.04 and -0.23 in infants exposed to ≥ 4 courses of ACS (p = 0.04-0.07). In multiple regression analyses, ≥ 4 courses were associated with lower BW-SDS, BL-SDS and HC-SDS (p = 0.007-0.04) compared to SDS after 2-3 courses. The effects from ≥ 4 courses on BW and BL were comparable to reduction in birth size seen in twins and on HC to that observed after maternal smoking.
Multiple courses of ACS are associated with a dose-dependent decline in foetal growth, which may affect later development and health.
Enhancing functional maturity of the high-risk preterm fetus is aimed at decreasing the life-threatening neonatal disorders that increase the burden of chronic disease. A course of antenatal glucocorticoids before 35 weeks of pregnancy substitutes endogenous activation of the hypothalamic-adrenal axis that spontaneously enhances functional maturity and augments cytokine-induced preterm lung maturity. It is the main fetal therapy that decreases the functional prematurity-related neonatal morbidity in the era of surfactant therapy. Tocolytic agents potentiate the effect of glucocorticoids on the fetus. Repeating an antenatal glucocorticoid course may be recommended if the preterm fetus remains undelivered for more than 7 days and very preterm birth is imminent. However, the follow-up results are still incomplete, and available preliminary studies warn against adverse neurological and metabolic consequences following several antenatal repeat courses of glucocorticoids. Administration of glucocorticoids after 34 weeks of pregnancy may be considered in selected high-risk cases, preferably with documented lung immaturity. We recommend delaying elective delivery in low-risk pregnancies without established lung maturity until 40 weeks, unless labor starts earlier. In a selected high-risk population 17alpha-hydroxyprogesterone acetate decreases the prematurity rate. However, this drug has a limited impact on functional maturity of the preterm fetus and its effects on the development of the child remain to be studied further.
To compare respiratory compliance and functional residual capacity in infants randomized to a rescue course of antenatal steroids vs placebo.
Randomized, double-blinded trial. Pregnant women > or =14 days after initial antenatal steroids were randomized to rescue antenatal steroids or placebo. The primary outcomes were measurements of respiratory compliance and functional residual capacity. This study is registered with clinicaltrials.gov (NCT00669383).
Forty-four mothers (56 infants) received rescue antenatal steroids and 41 mothers (57 infants) received placebo. There was no significant difference in birthweight, or head circumference. Infants in the rescue group had an increased respiratory compliance (1.21 vs 1.01 mL/cm H(2)O/kg; adjusted 95% confidence interval, 0.01-0.49; P = .0433) compared with placebo. 13% in the rescue vs 29% in the placebo group required > or =30% oxygen (P < .05). Patients delivered at < or =34 weeks had greater pulmonary benefits.
Infants randomized to rescue antenatal steroids have a significantly increased respiratory compliance compared with placebo.
There are ongoing concerns that antenatal corticosteroids, which are administered to women at high risk of delivering preterm to reduce the incidence of respiratory distress syndrome, have adverse effects on foetal brain development and subsequent effects on behaviour and learning, when administered as repeated courses. The present study aimed to examine whether repeated betamethasone treatment alters the expression of the key-rate limiting enzyme, 5alpha-reductase, in the synthetic pathway of the potent neuroactive steroid allopregnanolone in the brain and placenta and whether this effect is potentiated in growth restricted foetuses. To investigate this, pregnant guinea pigs carrying either control (sham surgery) or growth-restricted foetuses were treated with vehicle or betamethasone (1 mg/kg/day) for 4 days prior to sacrifice (65d). Placental insufficiency was induced by the ablation of uterine artery branches supplying each placenta at mid gestation, resulting in foetal growth restriction characterised by 'brain sparing'. Real-time reverse transcriptase polymerase chain reaction was used to determine relative 5alpha-reductase type 1 and 2 mRNA expression in the placenta and brain. Immunohistochemistry was used to examine the glial fibrillary acidic protein (GFAP) expression in the subcortical white matter, CA1 and dentate regions of the hippocampus. 5alpha-reductase type 2 mRNA expression in the brain was markedly reduced by betamethasone treatment in male foetuses compared to vehicle-treated controls but not in female foetuses. In addition, 5alpha-reductase type 1 expression in the brain was increased by growth restriction and/or betamethasone treatment in female foetuses but expression in males foetuses did not increase. 5alpha-reductase type 2 expression in the placenta was markedly reduced by betamethasone treatment compared to vehicle-treated control. Intrauterine growth restriction and betamethasone treatment reduced GFAP expression in the CA1 region of the hippocampus in the brains of male but not female foetuses. These data indicate that betamethasone treatment suppresses placental expression and has sexually dimorphic effects on expression of neuroactive steroid synthetic enzymes in the brain. These actions may lead to adverse effects on the developing brain, particularly in male foetuses, such as the observed effects on GFAP expression.
Glucocorticoid administration to women in preterm labor improves neonatal mortality and morbidity. Fetal exposure to glucocorticoid levels higher than those appropriate to the current gestational stage has multiple organ system effects. Some, eg, fetal hypertension, are maximal at lower than the clinical dose. We hypothesized that the clinical dose has supramaximal lung maturational effects.
We evaluated the full, half, and quarter clinical betamethasone dose (12 mg/70 kg or 170 microg/kg intramuscularly twice 24 hours apart) on fetal sheep lung pressure volume curves (PVC) after 48 hours' exposure at 0.75 gestation. We measured key messenger RNAs and protein products that affect lung function and total lung dipalmitoyl phosphatidyl choline.
Full and half doses had similar PVC and total lung dipalmitoyl phosphatidyl choline effects. Messenger RNA for surfactant proteins A, B, and D and elastin increased in a dose-dependent fashion.
Half the clinical betamethasone dose produces maximal PVC improvement in fetal sheep at 0.75 gestation.
There are no randomized data on the effect of repeat courses of corticosteroids during pregnancy on newborn pulmonary function. Our objective was to compare the effect of a single remote course of antenatal steroids (AS) with weekly courses of AS on functional residual capacity (FRC) and respiratory compliance in preterm infants.
Pregnant women 25 to 33 weeks' gestation, who remained undelivered 1 week after their first course of antenatal corticosteroids (two 12-mg doses of betamethasone) were randomized to weekly courses of corticosteroids versus weekly placebo until delivery or 34 weeks' gestation. FRC was measured with the nitrogen washout technique and respiratory compliance with the single breath occlusion technique within 48 hours of life.
Thirty-seven infants (mean gestational age at delivery approximately 32.5 weeks) were studied. Maternal and infant demographics were similar. There was no significant difference in FRC (28.5 vs 27.5 mL/kg) or respiratory compliance between the infants who received a single remote course of antenatal corticosteroids and those who received weekly courses of corticosteroids until delivery. There was no significant difference in admission head circumference or birth weights between the groups.
Our results demonstrate that weekly repetitive courses of AS do not significantly increase FRC or respiratory compliance in preterm infants when compared with a single remote course of steroids given at a mean gestational age of 29 weeks.