Year: 2024
Type: article
Abstract: Sarah S. Osmundson, MD, MSJustin R. Lappen, MDThe ALPS (Antenatal Late Preterm Steroid) trial rapidly transformed the management of patients at high risk for late preterm delivery (34 0/7–36 6/7 weeks of gestation) due to key findings that antenatal corticosteroids reduced the need for neonatal respiratory support compared with placebo (11.6% vs 14.4%, relative risk 0.80, 95% 0.66–0.97).1 In the 9 months after publication of the ALPS trial, antenatal corticosteroid exposure more than doubled, from 5.0% to 11.7% of all late preterm deliveries in the United States.2 This increased exposure frequency appears to have been accompanied by a modest decrease in the transient use of assisted ventilation after delivery, from 8.9% to 8.2% (adjusted incident rate ratio 0.91, 95% CI 0.85–0.98).2 Even modest decreases in transient respiratory support could substantially decrease health care utilization and associated costs and potentially improve patient experience through earlier breastfeeding initiation and enhanced parental bonding.3,4 These forementioned data derive from patients who actually delivered in the late preterm period, but all obstetricians recognize the challenges in predicting birth timing. These data do not account for patients who received corticosteroids but ultimately delivered at term, which is documented to be as high as 40% in some studies.5–7 Recent observational studies suggest that antenatal corticosteroid exposure in children ultimately born at term is associated with increased risk for adverse neurodevelopmental outcomes.5,8 Observational studies have substantial limitations, especially confounding by indication and the inability to adjust for disease severity. Pregnant patients with more severe disease are more likely to receive antenatal corticosteroids, and fetuses of pregnant patients with more severe disease are at systematically higher risk for adverse neurodevelopmental outcomes in childhood than unexposed fetuses.9 Advanced statistical techniques may not be able to fully adjust for all confounding. The Maternal-Fetal Medicine Units’ ALPS follow-up study of a randomized controlled trial of betamethasone compared with placebo did not demonstrate any difference between groups for a general conceptual ability score measured by the Differential Ability Scales, 2nd Edition.10 However, in general, follow-up studies of randomized controlled trials are unlikely to fill this knowledge gap completely, because they will almost always be underpowered to assess rare but clinically important long-term outcomes after antenatal corticosteroid exposure.10 Ultimately, this leaves patients and clinicians weighing risks and benefits of late preterm antenatal corticosteroids to make decisions that center individual patient values and risk profiles. In this month's issue of Obstetrics & Gynecology (see page 747), Clapp and colleagues11 report a secondary analysis from the APLS trial documenting how the risk of respiratory morbidity varies by mode of delivery and gestational age with and without antenatal corticosteroid exposure. They intentionally did not use statistical testing to compare exposed with unexposed groups, because their aim was to quantify risk for patient decision making rather than to study efficacy of corticosteroid exposure within subgroups. In a world where P-values are often paramount, this approach is refreshing and patient-centered. Clapp and colleagues also selected planned rather than actual mode of birth and gestational age at enrollment rather than delivery. This approach mirrors the clinical setting that patients and clinicians face. Still, it is important to acknowledge that the ALPS trial had excellent success matching clinical predictions to observed reality; only 16.4% of enrolled patients delivered at 37 or more weeks of gestation, and 82.1% of patients with planned vaginal delivery had a vaginal delivery. To reproducing these findings outside the setting of a clinical trial would require strictly limiting use of late preterm steroids to patients with high anticipated probability of early delivery and may be challenging. The study findings from Clapp and colleagues are not surprising. The associations between cesarean birth, lower gestational age, and increased respiratory complications at delivery are well established and have a biological basis. Lung development of the terminal alveoli increases continuously with gestational age, even beyond 36 weeks. Biochemical changes during labor and with vaginal birth support resorption of alveolar fluid. In addition, surfactant, which increases with gestational age, is inactivated by retained fluid.12 Using the ALPS data, Clapp and colleagues constructed prediction models for respiratory morbidity that demonstrate the continuous association between advancing gestational age and decreasing respiratory morbidity, as well as the increased respiratory morbidity associated with cesarean delivery. However, as highlighted in their figures, the CIs for respiratory morbidity overlap for patients who received and did not receive antenatal corticosteroids throughout the late preterm period. In considering the etiologies of respiratory morbidity in this population, planned cesarean delivery most commonly affects the risk of transient tachypnea of the newborn and not respiratory distress syndrome, which is related primarily to gestational age at delivery and is affected directly by steroid administration. Given consideration of these underlying biologic mechanisms and the modest effect of steroid exposure reported by Clapp and colleagues, the incorporation of mode of delivery into decisions regarding the administration of antenatal corticosteroids should be interpreted cautiously. Outcomes of clinical studies that are relevant to clinicians and policy makers do not always translate into outcomes that are meaningful to patients. The primary outcome for the ALPS trial and, hence, for the study by Clapp and colleagues was respiratory morbidity, a combination of several endpoints: 1) need for high-flow nasal cannula or continuous positive airway pressure for at least 2 hours, 2) FIO2 0.30 or higher for at least 4 hours, 3) extracorporeal membrane oxygenation (ECMO), or 4) mechanical ventilation. In the ALPS trial, there were no cases of ECMO use. We do not know that patients value the remaining outcomes or weigh different components equally. For one, patients may find mechanical ventilation distressing but be accepting of transient respiratory support. They may not readily distinguish high-flow oxygen from more concentrated oxygen, both of which comprise the majority of adverse respiratory outcomes experienced in the trial (79% of all primary outcome events). Patients also may need more information on the long-term effects of transient respiratory support when weighing this outcome with the possible long-term effects of corticosteroid exposure on childhood neurodevelopmental outcomes. Lastly, patients may consider whether late antenatal steroids influence the nonrespiratory complications of prematurity. Although severe complications of prematurity are uncommon in the late preterm period, the most recent Cochrane review on antenatal corticosteroids highlights that exposure to steroids before 35 0/7 weeks of gestation was associated with a decrease in respiratory distress syndrome as well as perinatal death, neonatal death, and interventricular hemorrhage—benefits that were not evident when assessing all trials of late preterm corticosteroid exposure (34 weeks 0/7–36 weeks 6/7 weeks of gestation).13 Therefore, broader reduction in prematurity risks may be important for patient counseling and consideration of late antenatal corticosteroids, particularly in the earliest part of the late preterm gestational age window. Clapp and colleagues make a compelling case that patient-specific estimates of risk with and without antenatal corticosteroid treatment should inform shared decision making. The risks associated with declining corticosteroids at 36 weeks of gestation for a patient with regular contractions, dilated 4 cm, and planning vaginal delivery (excess risk 1.3 cases of respiratory morbidity/100 deliveries) may be acceptable, whereas these risks may not be acceptable to a patient with preeclampsia with severe features in breech presentation at 34 weeks of gestation planning cesarean delivery (excess risk 7.3 cases/100 deliveries). True shared decision-making requires individualized estimates and outcomes that center patient values.
Source: Obstetrics and Gynecology
Authors: Sarah S. Osmundson, Justin R. Lappen
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4404792229