Biological basis of therapeutic agents for preterm labour
In recent times, the prevention, prediction and treatment of preterm labour has remained a
major focus for contemporary research in obstetrics (83). Generally, the use of tocolytics has become a fundamental pharmacological therapy in the clinical management of preterm labour(84). The biological basis for the use of tocolytics is to delay delivery for at least 48hours to allow for corticosteroids and magnesium sulphate administration to enhance foetal lung maturation and prevention cerebral palsy respectively and transfer to a tertiary healthcare facility with neonatal intensive care facilities(83,84).
Proinflammatory cytokines such as IL-1β, IL-6, and IL-8 have been strongly associated with cervical dilation in preterm labour and medications the decrease the concentration of these mediators constitutes potential preventive interventions(72). The common therapeutic agents which are currently used to abort uterine contractions or maintain uterine quiescence include beta adrenergic receptor agonists (ritodrine, isoxsuprine, salbutamol, terbutaline), prostaglandin -Synthase inbibitors [including NSAIDS (e.g indomethacin) and COX-2 inhibitors (e.g Celecoxib)], oxytocin receptor antagonists (atosiban), calcium channel blockers (nifedipine) and Magnesium sulphate. Tocolytics are usually administered as a monotherapy although a combination of more than one agent maybe required in some cases. However, a recent systematic review by Vogel et al did not support the use of a polytherapy of tocolytics over monotherapy and this is partly due to lack of trials of combination regimens of commonly used tocolytics(85).
Beta agonists (betamimetics) bind to beta 2 adrenergic receptors on surface membranous myometrial smooth muscle cells which activate adenyl cyclase leading to increased intracellular levels of cAMPs and activation of protein kinase A. Increased cAMPs levels decrease intracellular calcium which specifically suppresses spontaneous and oxytocin-induced uterine contractions. Three different subtypes of beta adrenergic receptors are located in the uterus and beta 2 adrenergic receptors constitutes approximately 80%(86). However, the use of beta 2 adrenergic receptors is associated significant maternal side effects such as palpitations, chest pain, breastlessness and pulmonary oedema in severe cases which limits their clinical use for extended duration(86).
Atosiban is a nona-peptide, desamino-oxytocin analogue and a competitive vasopressin/oxytocin receptor antagonist(87). Atosiban blocks oxytocin receptors and prevents oxytocin-induced hydrolysis of phosphati­dylinositol 4,5-bisphosphate (PIP2) to IP3 and calcium efflux into the cytoplasm(88). Thus, it inhibits signalling transduction on the uterine smooth muscle leading to uterine relaxation (83,89). Atosiban has minimal side effects with higher safety profile as compared to the other tocolytics(90).
Selective COX-2 inhibitors such as celecoxib and non-specific COX inhibitors such as indomethacin which are prostaglandin synthase-2 inhibitors inhibit the synthesis of prostaglandins (e.g. PGF2α & PGE2) but do not affect the production of pro-inflammatory mediators (e.g. IL-1β, IL-6, and TNFα) because the action of pro-inflammatory mediators is upstream of COX-2 expression(91,92). Prostaglandins induce uterine contraction via facilitation of myometrial gap junction formation and increasing the concentration of intracellular calcium concentration. Therefore, prostaglandin synthase inhibitors are considered effective tocolytics. However, their usage is limited because they cause premature constriction of the ductus arteriosus, inhibit platelets aggregation and impair renal function and decreased urine production resulting in oligohydramnios. Therefore, the duration of indomethacin use should be restricted and limited to gestational age of 32 weeks(93).
Magnesium sulphate is used broadly as a tocolytic and proven to be more effective in fetal neuroprotection and preventing cerebral palsy(94,95). Magnesium sulphate competitively blocks intracellular calcium influx and activation of myosin light chain kinase leading to decreased myometrial contractility. It also inhibits acetyl choline release by competing with calcium at the motor end plate of the neuromuscular junction. Perhaps, its usage is not primarily intended to delay delivery but to prevent cerebral palsy via neuroprotection(94–97). The common side effects include flushing, respiratory depression and cardiac arrest(88). Based on our review, all the tocolytic agents in recent use appear to act on areas that interfere with either calcium entry or prostaglandins production which are downstream of pro-inflammatory mediators’ production.