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Study Authors: Katri Räikkönen, Mika Gissler, et al.; Sara B. DeMauro

Target Audience and Goal Statement: Obstetrician-gynecologists, pediatricians, psychiatrists

The goal of this study was to examine the associations between maternal antenatal corticosteroid treatment and mental and behavioral disorders in children born at term or preterm.

Questions Addressed:

• Was there an association between maternal antenatal corticosteroid treatment and risk of mental and behavioral disorders in their children?
• Was this risk similar in infants born at term and preterm?
• Did unmeasured familial confounding explain these associations?

Study Synopsis and Perspective:

Antenatal corticosteroids should be considered for women with threatened late preterm birth and for women undergoing elective cesarean delivery, according to from the American College of Obstetricians and Gynecologists (ACOG). Updates to the U.S. guidelines recommended treatment for pregnant women between 34 weeks 0 days and 36 weeks 6 days who are at risk for preterm delivery within 7 days and who have not received a prior course of antenatal corticosteroids.

Maternal antenatal corticosteroid treatment decreases risks of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, a need for mechanical ventilation, systemic infections, and death in infants born before 34 weeks 0 days.

However, a new population-based retrospective cohort study published in showed that exposure to antenatal corticosteroids was significantly associated with increased rates of mental and behavioral disorders during childhood. Katri Räikkönen, PhD, of the University of Helsinki, and colleagues observed these results both in the entire study population (12.01% in exposed vs 6.45% in unexposed; adjusted hazard ratio [HR] 1.33, 95% CI 1.26-1.41, P<0.001) and among children born at term (8.89% vs 6.31%; HR 1.47, 95% CI 1.36-1.69, P<0.001).

In addition, mental or behavioral disorders were diagnosed a median 1.4 years earlier in exposed children than in unexposed children.

Antenatal corticosteroid treatment is regarded as a major advance in perinatal care. analyzed the effectiveness of antenatal corticosteroids among women at risk for late preterm (34-36 weeks) delivery and for women undergoing elective full-term (≥37 weeks) cesarean delivery. Infants born to women who received this treatment had lower rates of respiratory distress syndrome and transient tachypnea.

However, corticosteroids can cross the placenta and the blood-brain barrier and may harm fetal brain development. As it is difficult to predict the timing of birth, many treatment-exposed children are not born within 7 days and go on to be born at term.

In addition, a separate trial involving 98,137 infants in 101 distinct geographical settings showed increased neonatal mortality when antenatal corticosteroids were given to women at risk of preterm birth in .

Therefore, knowledge gaps exist with respect to the optimal use of antenatal corticosteroids, including the of this treatment in other populations at high risk for neonatal morbidity and mortality.

In the current study, Räikkönen and team linked registry data for children born from 2006-2017 in Finland who survived the first year of life. The birth register did not include data on the number or timing of treatments, although Finnish national guidelines recommended 12 mg betamethasone administered twice, 24 hours apart, up to 34 weeks until 2009 and then up to 34 weeks and 6 days after 2009.

The data were controlled for infant characteristics such as birth year, admission to the neonatal intensive care unit, and weight and gestational age, as well as maternal characteristics (delivery mode, smoking, gestational diabetes, and mental health disorders).

Of the 670,097 children included in the analysis, 14,868 (46.1% female) were exposed to corticosteroids in utero, of which 6,730 (45.27%) were born full term. In contrast, 655,229 children (48.9% female) were not exposed, of which 96.88% were born at term. The cohort was followed up for a median 5.8 years.

In preterm-born children, the cumulative incidence rate of any mental and behavioral disorder was also significantly higher for the treatment-exposed compared with the unexposed children, but the HR was not significant (14.59% vs 10.71%; HR 1.00, 95% CI 0.92-1.09, P=0.97).

In an analysis of 241,621 sibling pairs within this population, siblings exposed to maternal prenatal corticosteroids also had a significantly increased risk for developing mental or behavioral disorders versus unexposed siblings (HR 1.38, 95% CI 1.21-1.58, P<0.001).

In the entire cohort and when the analysis was restricted to term-born children, exposure to corticosteroids was associated with attention deficit-hyperactivity or conduct disorders, emotional disorders, and sleep disorders, among others, although "these findings should be regarded as exploratory because of the possibility of type I error," Räikkönen and team noted.

In addition to the lack of data on the timing of corticosteroid exposure and dose, and mental disorder diagnoses made in primary care, "residual confounding cannot be ruled out," the researchers said. The study's generalizability is limited due to the Finnish population sampled, they added.

Source References: 2020; DOI: 10.1001/jama.2020.3937

Editorial: 2020; DOI: 10.1001/jama.2020.3935

Study Highlights and Explanation of Findings:

Together, the findings suggest "unmeasured familial confounding did not explain these associations," and that corticosteroids "may not pose a risk for mental and behavioral disorders independent of complications and illnesses related to preterm birth," Räikkönen and colleagues wrote. "The risk associated with treatment exposure appeared to be comparable in magnitude to the risk of key covariates, such as maternal smoking during pregnancy."

"This is an observational study, and the results do not prove that antenatal corticosteroids are the cause of the increased risks found in the study. However, we conclude that it is important to weigh the balance between the long-term benefits and harms, in particular when considering whether to expand the treatment indications to later gestational weeks. The prognosis of babies who are born preterm at later gestational weeks is very good in high-income countries," said senior author Eero Kajantie, MD, DMSc, of the University of Oulu and THL Finnish Institute for Health and Welfare, in a .

"Of the mothers who were treated with antenatal corticosteroids, 45% went on to deliver a term baby. This means that prediction of preterm birth is often very difficult," he continued.

"Even though experimental studies in animals have shown that antenatal corticosteroid treatment has harmful effects on the neurodevelopment of the offspring, population-based cohort studies, like ours, cannot verify if any of the harmful effects on child disorders are accounted for by maternal corticosteroid treatment or if some other factor explains these associations. We tested for several candidates, but none of these factors explained the associations," added Räikkönen.

Prior studies have shown prenatal exposure to corticosteroids to be associated with fetal development, with downstream cardiovascular, metabolic, endocrine, and neurologic outcomes, noted Sara B. DeMauro, MD, of the University of Pennsylvania in Philadelphia, in an .

However, research has also suggested the "abnormal pregnancy events that lead clinicians to administer steroids also predispose the exposed children to adverse cognitive outcomes, potentially through similar pathways of fetal programming," she wrote.

Notably, fewer than 40% of preterm children in this study were exposed to prenatal corticosteroids and the authors did not report how many infants born very preterm (<32 weeks) were exposed, raising the possibility that the infants who needed this treatment the most did not receive it, DeMauro said.

On the other hand, among the fewer than 45% of infants who were exposed and delivered at term, "minor short-term benefit may have been outweighed by significant longer-term risks," she added.

"Although benefits of this therapy outweigh risks in the most vulnerable infants, this may not be true for all infants," she concluded. "Recommendations to administer this therapy to broader populations of pregnant women may need to be reexamined until sufficient safety data, particularly among more mature infants, are available."