Antenatal Corticosteroids in the Management of Preterm Birth: Are we back where we started?Babies born very early, or very preterm, are at risk of having breathing difficulties and antenatal steroids in preterm delivery serious health problems at winstrol gains, as a child and later in life. Some babies born very early do not survive these difficulties. Some babies have health antenatal steroids in preterm delivery that prevent them from developing as they should and can lead to problems with movement or learning. Corticosteroids are medicines given to women in early labour to help the babies' lungs to mature low t center houston cost quickly and so reduce the number of babies who die or suffer breathing problems at birth. Breathing problems are the main cause of death and serious health problems for babies born very early. Pregnant women who have ruptured membranes or spontaneous preterm labour can take corticosteroids to help mature the baby's lungs.
Editorial - Corticosteroids for preterm deliveries: missing evidence | Cochrane Library
Meeting the Healthy People goal of an The reasons for this recent downtrend in preterm birth are not entirely clear. The decrease has been demonstrated in both late preterm 34 to 36 completed weeks deliveries and early preterm deliveries less than 34 weeks. In addition, interventions such as alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth and vaginal progesterone for prevention of preterm birth in women with a short cervix may be effectively reducing the rate of spontaneous preterm birth.
Even with the recent decline, preterm birth remains a critical public health issue in this country. Primary prevention of preterm birth remains the ultimate goal. However, until a better understanding of the mechanisms underlying preterm birth leads to its effective and universal prevention, efforts to minimize the impact of preterm birth on neonatal morbidity and mortality are paramount.
Antenatal corticosteroid treatment for fetuses born preterm remains one of the most important antenatal interventions in obstetric practice. The story of antenatal corticosteroids - the discovery of this therapy for fetal maturation, the adoption into clinical practice and the evolution of corticosteroid administration in obstetrics - highlights several fascinating and universal truths about science and medicine.
The first being that scientific breakthroughs are often happened upon incidentally. In the s, the obstetrician Graham Liggins was investigating factors involved in the initiation of labor in a sheep model.
His goal was to solve the problem of preterm labor by determining what controls labor at term. While testing his hypothesis that steroid hormones might trigger labor, he found that preterm lambs exposed to corticosteroids in utero had structurally more mature lungs, were viable at an earlier gestational age, and had less severe respiratory distress at birth than expected. Liggins and Howie then designed and conducted a randomized controlled trial on maternal administration of betamethasone.
The results were published in a landmark article in The second point that the story of corticosteroids illustrates is that clinicians can be slow to adopt new therapies into clinical practice.
Over the next few decades additional studies corroborated the findings of Liggins and Howie. However, concerns about the quality of the evidence and fears about potential side effects made obstetrical providers hesitant to use this therapy routinely for women at risk for preterm birth. Subgroup analysis from the initial trial on antenatal corticosteroids suggested that effectiveness peaked between two and seven days from the initial injection.
Subsequent systematic reviews also suggested a waning of steroid effect at 7 days, prompting concern about the management of mothers who remained pregnant after seven days but were still at high risk for preterm delivery and adverse neonatal outcomes. Hence the third conclusion in the history of corticosteroids — clinicians can become overeager in the use of certain interventions before there is adequate supportive data.
The administration of repeat courses of corticosteroids to pregnant women at risk for preterm delivery quickly became common practice in the s. It is also interesting to note how arbitrary choices can insinuate themselves into standard clinical practice. The initial Liggins and Howie trial used betamethasone as a 1: In fact, this regimen has become such a standard practice that future clinical trials to test them will be difficult, or even impossible to conduct.
This review will take a critical look at the evidence for the efficacy and safety of antenatal corticosteroids that has accumulated over the past 40 years. The story of antenatal corticosteroids is ongoing, and there is much at stake as we continue to perfect the use of this vital therapy.
The most recent Cochrane review on antenatal corticosteroids for women at risk for preterm birth included 21 studies of patients and infants. Need for respiratory support and admission to the neonatal intensive care unit were also reduced by therapy. The longest specified duration of follow-up in these studies was six years. The authors concluded that a single course of antenatal corticosteroids should be considered routine for preterm delivery.
Though the efficacy of antenatal corticosteroids to improve outcomes after preterm birth may be established for singleton infants, there remain questions about efficacy in specific patient populations. Patients with multiple gestations are at significantly higher risk of delivering preterm.
Patients with multiple gestations are more likely to be delivered preterm for a multitude of reasons, including higher rates of obstetrical complications such as preterm labor and preterm rupture of membranes, and the increased incidence of maternal complications such as preeclampsia in these pregnancies.
In the most recent Cochrane review, antenatal corticosteroids were not effective in reducing the risk of RDS, IVH or neonatal death for women with multiple pregnancies. Smaller, retrospective studies have been divided on the effectiveness of antenatal corticosteroids to reduce neonatal morbidity and mortality in preterm twin versus singleton pregnancies.
There may be physiologic reasons for the diminished effectiveness of antenatal corticosteroids in multiple gestations. Some authors have suggested that the larger volume of distribution in the maternal and fetal compartments in multiple gestations would have a dilutional effect on the concentrations of drugs reaching the fetuses. More recently Gyamfi and colleagues demonstrated that maternal and umbilical cord serum betamethasone concentrations at delivery did not differ between singleton and twin gestations, suggesting that any apparent decrease in effectiveness of steroids in twin pregnancies is not due to inadequate fetal drug levels.
The most current evidence does not confirm the efficacy of antenatal corticosteroids in multiple gestations. Yet guidelines uniformly advocate for corticosteroid administration in these pregnancies at risk for preterm birth because of the weight of the evidence in singleton gestations.
The most likely reason that studies in multiple gestations have not demonstrated efficacy is the quality of the available data which does not include large prospective trials comparing corticosteroid treatment versus no treatment. Only two prospective trials totaling twins and controls supplied the data for the Cochrane review.
The remainder of the evidence comes from retrospective studies with multiple potential confounders. The Cochrane authors suggested that there may be additional unpublished data on twin pregnancies that may help clarify the benefit of treatment in this population, as further trials will be difficult to conduct. The problem of obesity has reached epidemic proportions across developed nations and even across the globe. Just as in multiple gestations, it has been hypothesized that obesity might influence the effectiveness of antenatal corticosteroids because of differences in tissue distribution and drug elimination.
However, Hashima and colleagues found that body mass index BMI did not influence neonatal outcome in women receiving a single course of antenatal corticosteroids. The literature appears to be conflicting on the efficacy of antenatal corticosteroids for pregnancies complicated by fetal growth restriction. As with the patient populations previously discussed, there are no randomized studies specifically designed to determine the benefits and risks of antenatal corticosteroid treatment in this group and therefore the evidence consists of observational and retrospective trials with their inherent limitations.
Largely because the first trial of Liggins and Howie suggested an increased risk of fetal death in pregnancies complicated by hypertension and fetal growth disorders, these patients have been excluded from most of the subsequent trials.
One large population-based study of infants with intrauterine growth restriction IUGR demonstrated that the benefits of antenatal corticosteroids were similar to those seen in normally grown infants.
This study included infants between 25 and 30 weeks gestation with outcomes reported in the Vermont Oxford Network database. Among the outcomes evaluated, only necrotizing enterocolitis was not reduced in neonates with IUGR. Another case control study looked at long-term outcomes of preterm infants with growth restriction secondary to placental insufficiency. Conversely, a recent systematic review of antenatal corticosteroid therapy for growth-restricted, preterm infants concluded that treatment has no effect on neonatal morbidity or mortality in this population.
Not only is there a degree of uncertainty about efficacy of antenatal corticosteroids for growth-restricted fetuses, but also there is some concern about the safety of use in this population. Intrauterine growth restriction is associated with alterations in cardiovascular function to maintain adequate blood flow to vital organs.
Glucocorticoids are powerful regulators of vascular tone, and it is possible that this has a particularly detrimental effect on brain development and long-term function. In a compelling study by Miller and colleagues using a sheep model, these investigators demonstrated that IUGR fetuses display significant carotid blood flow reperfusion in response to maternal betamethasone administration, which may lead to lipid peroxidation in the fetal brain, thereby contributing to an increased incidence of cell death.
Several investigators have advocated for a randomized controlled trial to examine whether treatment is truly beneficial for IUGR fetuses. Advances in neonatology and obstetrical care in the last few decades have resulted in increased survival of extremely premature infants. Because of this, resuscitation of preterm infants before 24 weeks gestation has become increasingly common. The administration of antenatal corticosteroids at 23 weeks gestation and even earlier has become more frequent, without clear evidence to support the benefit in this population.
In a post hoc analysis, the Cochrane review evaluated outcomes of antenatal corticosteroid treatment versus placebo by gestational age at entry to the trial. Similarly, RDS was reduced in all gestational ages with the exception of less than 26 weeks gestation. Unfortunately there are very few trials that included pregnancies less than 26 weeks gestation; only one study with less than 30 infants supplied the data for this group. Earlier this year, Onland and colleagues published an updated systematic review of randomized controlled trials on the effects of antenatal corticosteroids given before 26 weeks gestation.
Although none of the existing trials actually reported the outcomes in this particular subgroup, metaregression and subgroup meta-analysis revealed no significant reduction of neonatal mortality or morbidity in the corticosteroid group compared with no treatment.
Certainly these analyses may be underpowered to demonstrate effectiveness. It is also possible that antenatal corticosteroids can only improve lung function once adequate numbers of primitive alveoli and lamellar bodies have started to appear, which typically occurs in the saccular phase of lung development beginning at approximately 25 weeks gestation, though some in vitro studies would suggest a maturational effect can occur earlier in gestation.
However, if there is a beneficial effect of antenatal corticosteroids at very early gestational ages, it may be more evident in mortality rates and neurological morbidity than in prevention of RDS. Evidence from the EPICure study, a prospective cohort study of all infants born at less than 26 weeks gestation in the United Kingdom and Ireland in , showed that exposed newborns had decreased rates of death OR 0. While the results of observational cohort studies and retrospective analyses are sensitive to various biases, at times they represent the best of our understanding of the evidence, particularly when randomized studies are unavailable.
In a large prospective cohort of infants born at 22 to 25 weeks gestation published by Tyson and colleagues from the Neonatal Research Network of the National Institute of Child Health and Human Development, multivariable analyses showed that those who received intensive care, were exposed to antenatal corticosteroids, were of female sex, were from singleton pregnancies and of higher birth weight had reduced rates of death.
Long-term data from the EPICure investigators also showed that antenatal corticosteroids were associated with an increased mental development index assessed at 2.
Even with the most aggressive intervention, the neonatal mortality rate is high as is the chance of adverse long-term neurodevelopmental outcome. Despite the lack of randomized data on efficacy in the very preterm period, the suggestion of benefit for these preterm infants seems sufficient to recommend its use. However, in deciding whether antenatal corticosteroid use is appropriate at a specific gestational age, the frequency of disease must be balanced by the total number of infants that may benefit.
It is obvious that if antenatal corticosteroids work to improve respiratory function, there is likely to be a continuum of benefit across the preterm, and potentially even the early term period. It has been hypothesized that corticosteroids may be effective at later gestational ages not because of an increase in surfactant production from type II alveolar cells or acceleration in lung structural development reducing the incidence of classic RDS, but by increasing expression of epithelial sodium channels ENaC which allow the alveoli to convert from active fluid secretion to sodium and fluid absorption with subsequent reduction of fetal lung fluid.
To formally answer this question, the Maternal Fetal Medicine Units Network is currently conducting a prospective, randomized trial of antenatal corticosteroids for patients at risk for late preterm birth. The trial is expected to be completed in It will be particularly interesting to see if antenatal corticosteroids confer an overall benefit in this population, or if the benefit is dependent on mode and circumstances of delivery such as cesarean versus vaginal delivery or indicated preterm birth versus spontaneous preterm birth.
Multiple studies have suggested the potential benefit of antenatal corticosteroids to decrease respiratory morbidity even at term for patients delivered by elective cesarean.
A single course of antenatal corticosteroids is not associated with any significant short-term fetal or neonatal adverse effects.
Specifically, studies have shown no difference in the rate of fetal death in exposed versus unexposed. There have been no reports of serious maternal complications linked to antenatal corticosteroid treatment. The Cochrane review did not demonstrate any statistically significant difference in the rate of chorioamnionitis RR 0. For patients with poor glycemic control, inpatient observation during antenatal corticosteroid treatment may be required. Of note, patients with diabetes have universally been excluded from randomized controlled trials on antenatal corticosteroids, so the benefit of corticosteroid treatment has been extrapolated from the non-diabetic population.
There are no specific contraindications to a single course of antenatal corticosteroids. However, there is concern that the immunosuppressive effect would exacerbate systemic infection or activate latent disease.
Active tuberculosis has been suggested as a potential contraindication for antenatal corticosteroid treatment, although there is no evidence upon which this is based. Clearly this will not be as common a problem in developed countries as it will be in developing countries where antenatal corticosteroid administration is still a rare practice.
However, concern remains about use of corticosteroids in this population, because of the increased risk of chorioamnionitis and the strong association between clinical chorioamnionitis and cystic periventricular leukomalacia as well as cerebral palsy.
However, because of lingering concern about the preterm delivery in the setting of chorioamnionitis largely stemming from a trial of weekly antenatal corticosteroids, ACOG still does not fully endorse corticosteroid administration after 32 weeks gestation.
Certainly the etiology of periventricular leukomalacia and cerebral palsy after preterm birth is an active area of investigation. Infection and inflammation are believed to be important pathophysiologic factors.