Prenatal opioid-exposed infant extracellular miRNA signature obtained at birth predicts severity of neonatal opioid withdrawal syndrome

Abstract

Prenatal opioid exposure (POE) is commonly associated with neonatal opioid withdrawal syndrome (NOWS), which is characterized by a broad variability in symptoms and severity. Currently there are no diagnostic tools to reliably predict which infants will develop severe NOWS, while risk stratification would allow for proactive decisions about appropriate clinical monitoring and interventions. The aim of this prospective cohort study was to assess if extracellular microRNAs (miRNAs) in umbilical cord plasma of infants with POE could predict NOWS severity. Participants (n = 58) consisted of pregnant women receiving medications for opioid use disorder and their infants. NOWS severity was operationalized as the need for pharmacologic treatment and prolonged hospitalization (≥ 14 days). Cord blood miRNAs were assessed using semi-quantitative qRT-PCR arrays. Receiver operating characteristic curves and area under the curve (AUC) were estimated. The expression of three miRNAs (miR-128-3p, miR-30c-5p, miR-421) predicted need for pharmacologic treatment (AUC: 0.85) and prolonged hospitalization (AUC: 0.90). Predictive validity improved after two miRNAs (let-7d-5p, miR-584-5p) were added to the need for pharmacologic treatment model (AUC: 0.94) and another two miRNAs (let-7b-5p, miR-10-5p) to the prolonged hospitalization model (AUC: 0.99). Infant cord blood extracellular miRNAs can proactively identify opioid-exposed neonates at high-risk for developing severe NOWS.

Figure 1

miRNA Expression in Infants with NOWS Requiring Pharmacologic Treatment or Prolonged Hospitalization. Volcano plots of cord blood plasma extracellular miRNA expression (difference in normalized CT between groups, ΔΔCT) and effect size (Cohen’s d) comparing miRNA expression in neonates Pharmacologically-Treated compared to Not-Pharmacologically-Treated (A) and in LOS ≥ 14 days compared to LOS < 14 days neonates (B). White filled points denote miRNAs altered with a small effect size (d < 0.4), black filled points denote miRNAs with moderate or larger effect size (d > 0.4), and dashed line denotes d = 0.4.

Figure 2

Receiver Operator Characteristic (ROC) Curves for Five miRNAs Differentiating Pharmacologically-Treated and Not-Pharmacologically-Treated Infants. ROC curves for performance of Model 1, containing miR-let-7d-5p, miR-128-3p, miR-30c-5p, miR-421, and miR-584-5p and Model 2, containing the same miRNAs and gestational age. AUC area under the ROC curve.

Figure 3

Receiver Operator Characteristic (ROC) Curves for Five miRNAs Differentiating Infants with Prolonged Hospitalization (≥ 14 Days) from Those Hospitalized for < 14 Days. ROC curves for performance of Model 1, containing let-7b-5p, miR-10b-5p, miR-128-3p, miR-30c-5p, and miR-421, and Model 2, containing the same miRNAs and gestational age. For Model 2, miR-10b-5p was dropped from the model due to lack of convergence. AUC area under the ROC curve.