Associations Between Maternal Antenatal Corticosteroid Treatment and Mental and Behavioral Disorders in Children

Abstract

Importance: Maternal antenatal corticosteroid treatment is standard care to accelerate fetal maturation when birth before 34 weeks is imminent. Recently, expansion of the indications beyond 34 gestational weeks has been debated. However, data about long-term outcomes remain limited, especially among infants who after treatment exposure are born at term.

Objective: To study if antenatal corticosteroid treatment is associated with mental and behavioral disorders in children born at term (≥37 weeks 0 days' gestation) and preterm (<37 weeks 0 days' gestation) and if unmeasured familial confounding explains these associations.

Design, setting, and participants: Population-based retrospective cohort study using nationwide registries of all singleton live births in Finland surviving until 1 year and a within-sibpair comparison among term siblings. Children were born between January 1, 2006, and December 31, 2017, and followed up until December 31, 2017.

Exposures: Maternal antenatal corticosteroid treatment.

Main outcomes and measures: Primary outcome was any childhood mental and behavioral disorder diagnosed in public specialized medical care settings.

Results: Of the 674 877 singleton children born in Finland during the study period, 670 097 were eligible for analysis. The median length of follow-up was 5.8 (interquartile-range, 3.1-8.7) years. Of the 14 868 (2.22%; 46.1% female) corticosteroid treatment-exposed children, 6730 (45.27%) were born at term and 8138 (54.74%) were born preterm; of the 655 229 (97.78%; 48.9% female) nonexposed children, 634 757 (96.88%) were born at term and 20 472 (3.12%) were born preterm. Among the 241 621 eligible term-born maternal sibpairs nested within this population, 4128 (1.71%) pairs were discordant for treatment exposure. Treatment exposure, compared with nonexposure, was significantly associated with higher risk of any mental and behavioral disorder in the entire cohort of children (12.01% vs 6.45%; absolute difference, 5.56% [95% CI, 5.04%-6.19%]; adjusted hazard ratio [HR], 1.33 [95% CI, 1.26-1.41]), in term-born children (8.89% vs 6.31%; absolute difference, 2.58% [95% CI, 1.92%-3.29%]; HR, 1.47 [95% CI, 1.36-1.69]), and when sibpairs discordant for treatment exposure were compared with sibpairs concordant for nonexposure (6.56% vs 4.17% for within-sibpair differences; absolute difference, 2.40% [95% CI, 1.67%-3.21%]; HR, 1.38 [95% CI, 1.21-1.58]). 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 nonexposed children, but the HR was not significant (14.59% vs 10.71%; absolute difference, 3.38% [95% CI, 2.95%-4.87%]; HR, 1.00 [95% CI, 0.92-1.09]).

Conclusions and relevance: In this population-based cohort study, exposure to maternal antenatal corticosteroid treatment was significantly associated with mental and behavioral disorders in children. These findings may help inform decisions about maternal antenatal corticosteroid treatment.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Participant Flow of the Population-Based Sample

A, Entire cohort of children, including term (≥37 weeks 0 days’ gestation) and preterm-born (aTerm group included children born postterm at 42 weeks 0 days or more. bIn within-sibpair comparisons all maternal treatment exposure–discordant and nonexposure-concordant siblings are analyzed in consecutive order.

Figure 2.. Associations Between Maternal Antenatal Corticosteroid Treatment Exposure and Mental and Behavioral Disorders in Children

aNumber of cases with diagnosis of mental and behavioral disorders and cumulative incidences during follow-up of the entire cohort of children (N = 670 097) and term-born (n = 641 487) and preterm-born (n = 28 610) children eligible for data analyses. See Figure 1 for eligibility criteria for data analyses and definitions of term and preterm births. See eTable 2 in the Supplement for definitions of mental and behavioral disorders. bAbsolute differences may differ from the arithmetic difference of group totals because of rounding. cFrom χ2 statistics. dHazard ratios (HRs), 95% CIs, and P values are from multivariable Cox proportional hazard models adjusting for maternal age at delivery, parity, mode of delivery, maternal smoking during pregnancy, prepregnancy body mass index, premature rupture of membranes (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code O42), gestational diabetes (O24), hypertension in pregnancy (O10, O13-O15), and any lifetime mental disorder diagnosis (F00-F99), child sex, Apgar score (maximum of 1 and 5 minutes), admission to neonatal intensive care unit, weight, and gestational age at birth. eHazard ratios for entire cohort may fall outside the boundaries of HRs for term-born and preterm-born children as a result of differences in the proportion of treatment-exposed and nonexposed children between those born at term and preterm.

Figure 3.. Maternal Antenatal Corticosteroid Treatment Exposure and Probability of Any Mental and Behavioral Disorder in Children

Overall probability of any mental and behavioral disorder diagnosis of treatment-exposed and nonexposed children, from Kaplan-Meier analyses. See Figure 1 for definitions of term and preterm births. See eTable 2 in the Supplement for definition of any mental and behavioral disorder. See eTable 5 in the Supplement for the median age at first diagnosis of any mental and behavioral disorder in the entire cohort of children and in term and preterm children. Hazard ratios (HRs), 95% CIs, and P values are from multivariable Cox proportional hazard models adjusting for maternal age at delivery, parity, mode of delivery, maternal smoking during pregnancy, prepregnancy body mass index, premature rupture of membranes (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code O42), gestational diabetes (O24), hypertension in pregnancy (O10, O13-O15), and any lifetime mental disorder diagnosis (F00-F99), child sex, Apgar score (maximum at 1 and 5 minutes), admission to neonatal intensive care unit, weight, and gestational age at birth. The age of the oldest child at the last date of follow-up was 11.0 years.