Caffeine and Clinical Outcomes in Premature Neonates

Abstract

Caffeine is the most widely used drug by both adults and children worldwide due to its ability to promote alertness and elevate moods. It is effective in the management of apnea of prematurity in premature infants. Caffeine for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia in very-low-birth-weight infants and improves survival without neurodevelopmental disability at 18-21 months. Follow-up studies of the infants in the Caffeine for Apnea of Prematurity trial highlight the long-term safety of caffeine in these infants, especially relating to motor, behavioral, and intelligence skills. However, in animal models, exposure to caffeine during pregnancy and lactation adversely affects neuronal development and adult behavior of their offspring. Prenatal caffeine predisposes to intrauterine growth restriction and small growth for gestational age at birth. However, in-utero exposure to caffeine is also associated with excess growth, obesity, and cardio-metabolic changes in children. Caffeine therapy is a significant advance in newborn care, conferring immediate benefits in preterm neonates. Studies should help define the appropriate therapeutic window for caffeine treatment along with with the mechanisms relating to its beneficial effects on the brain and the lung. The long-term consequences of caffeine in adults born preterm are being studied and may depend on the ability of caffeine to modulate both the expression and the maturation of adenosine receptors in infants treated with caffeine.

Keywords: Caffeine; Neuroprotection; Newborn; Premature infant; bronchopulmonary dysplasia.

Figure 1

Mechanism of action of caffeine (C₈H₁₀N₄O₂). The illustration depicts the distinct actions of caffeine on (A). Blood Vessel, (B). Neurons, and (C). Myocytes. (A). In the vasculature of smooth muscle, caffeine inhibits myosin light-chain kinase via the cAMP pathway and stimulates myosin light-chain phosphatase, inhibiting the myosin-actin interaction. The A₁/A₃ receptors inhibit cAMP production, whereas A_2a/A_2b receptors stimulate cAMP production by adenylate cyclase. Caffeine increases endothelial cell (EC) Ca²⁺, stimulating endothelial nitric oxide synthase to produce nitric oxide, dilating the vascular smooth muscle cells through the cGMP pathway. (B). Caffeine antagonizes the actions of adenosine at the adenosine receptor, specifically at the A₁/A_2a receptors, resulting in increased wakefulness coupled with altered activity of neurotransmitters such as dopamine, epinephrine, norepinephrine, and serotonin in the nervous system. (C). Caffeine mobilizes intracellular calcium by activating the ryanodine receptor on the sarcoplasmic reticulum of skeletal and smooth muscles, facilitating excitation-contraction coupling. A₁, A₃, A_2a, and A_2b, adenosine receptors; cAMP-cyclic Adenosine Monophosphate; AC-adenylate cyclase; PDEs-Phosphodiesterase; AMP-adenosine monophosphate; GTP-Guanosine triphosphate; cGMP-cyclic Guanosine Monophosphate; sGC-soluble guanylate cyclase; C-Caffeine molecules; A-Adenosine molecules; ER/SR-Endoplasmic-sarcoplasmic reticulum; TM-tropomyosin; A-actin; M-myosin; ECC-excitation-contraction coupling; NT-neurotransmitters; GABA-gamma-aminobutyric acid (copyright:Vasantha H.S. Kumar, MD).

Figure 2

The spectrum of effects when caffeine is consumed prenatally, postnatally, and during adolescence. Caffeine consumed during pregnancy and adolescence may have adverse effects. However, in premature infants, caffeine is remarkably safe and has substantial benefits on the lungs and the brain. Caffeine reduces bronchopulmonary dysplasia, improves survival and neurodevelopmental outcomes at 18 months in premature infants ≤1250 g at birth. Infants should be monitored for cardio-metabolic, neurobehavioral, and other adult-oriented disorders as the long-term effects of caffeine are not known. Caffeine consumption offers substantial benefits in adults [108,109,110].