Description of the condition
Preterm birth, defined as birth prior to 37 weeks estimated gestation (WHO 1992), is a leading cause of perinatal mortality (Beck 2010). Preterm infants are at significant risk of short-term and long-term morbidity (How 2006). The costs to individual families and to the community are great, and the burden on modern healthcare systems is significant. Spontaneous preterm labour contributes to 40% to 50% of all preterm birth (Goldenberg 2008). The prevention of spontaneous preterm labour using tocolysis has been a focus of obstetric research (Tsatsaris 2004).
Description of the intervention
Various pharmacological agents have been used in an attempt to arrest spontaneous preterm labour and therefore prolong pregnancy. Betamimetics (Neilson 2014), calcium channel blockers (King 2003), magnesium sulphate (Crowther 2002; update forthcoming) and oxytocin receptor antagonists (Papatsonis 2005) have each been the subject of Cochrane systematic reviews. Other drugs advocated for tocolysis include the prostaglandin inhibitor, indomethacin (Klauser 2012), selective COX-2 inhibitors, rofecoxib and celecoxib (Borna 2007; McWhorter 2004), progesterone (Borna 2008), nitrates and ethanol. Controversy remains as to which agent is preferable. A meta-analysis of 55 randomised controlled trials of tocolytic therapy (Haas 2012) found prostaglandin inhibitors and magnesium sulphate to have the highest probability of delaying delivery by 48 hours. However, prostaglandin inhibitors and calcium channel blockers were most likely to be the best class of therapy in terms of effectiveness, maternal side-effect profile and neonatal outcomes. The American College of Obstetrics and Gynaecology has supported ‘first-line tocolytic treatment with beta-adrenergic receptor agonists, calcium channel blockers, or NSAIDs for short-term prolongation of pregnancy’ (ACOG 2012).
Magnesium sulphate when given for tocolysis has not been demonstrated to significantly prolong pregnancy (risk ratio 0.87; 95% confidence interval 0.61 to 1.24, nine trials). Its tocolytic efficacy has been found to be similar to that of calcium channel blockers and betamimetics (Crowther 2002; update forthcoming). The side-effect profile of magnesium sulphate when given for tocolysis is greater than that of other tocolytic agents such as the calcium channel blocker, nifedipine (Lyell 2007).
There has been limited evaluation of the efficacy and safety of alternative treatment regimens of magnesium sulphate given for tocolysis. One systematic review has included treatment regimens given for tocolysis in an evaluation of different antenatal magnesium sulphate regimens with respect to maternal adverse effects (Bain 2013).
Alternatively, magnesium sulphate is used widely in other obstetric and perinatal contexts. Magnesium sulphate has an established role in the prevention and treatment of eclampsia (Duley 2010a; Duley 2010b; Duley 2010c), and in fetal neuroprotection for women at risk of preterm birth (Doyle 2009). In each setting, the efficacy and safety of different treatment regimens have been examined in Cochrane systematic reviews (Duley 2010d and Bain 2012 respectively).
Clinical trials have evaluated magnesium sulphate administered for both acute tocolysis (Crowther 2002; update forthcoming) and maintenance tocolysis (Han 2013). Treatment regimens have differed with respect to dose, route, duration, and timing of administration (James 2010).
Dosing of magnesium sulphate when given for tocolysis has varied between clinical trials. Low-dose regimens have typically included a loading dose of 4 g followed by an infusion of 2 g per hour. Early trials limited maximum dosing according to total dose administered in 24 hours (usually 10 g to 12 g). More aggressive regimens have included loading doses of 6 mg (Glock 1993; Haghighi 1999; Larmon 1999; Morales 1993; Schorr 1997), and maintenance infusion rates with incremental rate increases (usually by 0.5 g at 30- or 60-minute intervals) until cessation of contractions is achieved or a maximum hourly rate of up to 5 g is reached. Current obstetric standard for use in preterm labour indicates administration of intravenous magnesium sulphate with a loading dose of 4 g to 6 g followed by a maintenance infusion of 2 g per hour until uterine quiescence is established (James 2010).
Timing of administration has varied between treatment regimens. Loading doses have been given either as a bolus, over 15 minutes or over 30 minutes. Duration of therapy has extended from six hours to 24 hours, or until tocolysis has been achieved.
Different routes of administration have been evaluated. Oral magnesium therapy has been trialled for maintenance tocolysis either according to study protocol or when it has been established that preterm labour has been arrested (Han 2013). Intramuscular magnesium therapy has been limited in its use for tocolysis by the potential for adverse reaction at the injection site (Bain 2013).
Monitoring of magnesium sulphate therapy has been performed clinically or by evaluating serum magnesium levels. Evidence of magnesium sulphate toxicity can allow appropriate administration of calcium gluconate as an antidote (Tsatsaris 2004). Concerns have been raised over the utility of serum monitoring (Lurie 2004): monitoring is resource-expensive; and serum levels increase slowly and unpredictably after intramuscular administration.
Clinical adverse side effects of magnesium sulphate have been evaluated extensively. For the mother, the most common adverse side effect reported after drug administration is flushing. Other maternal adverse side effects include gastrointestinal disturbance, muscle weakness, thirst, headache, drowsiness and confusion. Serious cardiorespiratory events including pulmonary oedema and cardiac or respiratory arrest have been reported (James 2010).
Common neonatal side effects include increased time to established respiration, lethargy and poor sucking (Klauser 2012). An association between the administration of high-dose magnesium sulphate and an increased total death rate (fetal, neonatal and infant) has been reported (Mittendorf 1997).
Additionally, it has been suggested that prolonged administration of magnesium sulphate affects fetal calcium metabolism, increasing the risk of hypocalcaemia (Nassar 2006). In May 2013, the US Food and Drug Administration (FDA) issued a statement warning against prolonged (more than five to seven days), continuous administration of magnesium sulphate for the prevention of preterm birth given the risk of fetal hypocalcaemia, osteopaenia and fractures (FDA 2013).
While magnesium sulphate has been deemed to be safe when used for the prevention and treatment of eclampsia (FDA 2013), and for fetal neuroprotection in the setting of preterm birth (Doyle 2009), many clinicians and researchers have cautioned against use of magnesium sulphate for tocolysis (Grimes 2006). Tocolytic regimens typically involve high-dose and prolonged intravenous administration of magnesium sulphate (Pryde 2009). While low-dose regimens of magnesium sulphate offer fetal neuroprotection (Doyle 2009), high-dose regimens have been associated with increased fetal, neonatal and infant death rate (Mittendorf 1997) and fetal osteopaenia (Nassar 2006). It has been suggested that this may reflect a dose-response relationship and a potential 'therapeutic window' (Pryde 2009). Further delineation of this dose-response relationship is required.
How the intervention might work
Magnesium sulphate was first described for use as a tocolytic agent in 1977 (Steer 1977). An association between magnesium sulphate and uterine quiescence has long been established (Abarbanel 1945; Hall 1957). However, the mechanism of action of magnesium sulphate tocolysis remains incompletely defined. Evidence suggests the tocolytic effect of magnesium has both an intracellular and extracellular component (Lurie 2004). It is suggested that magnesium alters calcium uptake, binding and distribution in uterine smooth muscle cells, thereby reducing the frequency of cell depolarisation and inhibiting myometrial contraction (Lewis 2005). More recent evidence suggests the tocolytic effect of magnesium might have an anti-inflammatory component (Dowling 2012; Tam Tam 2011).
Why it is important to do this review
Magnesium sulphate has been trialled as a tocolytic agent in the context of threatened preterm labour for the prevention of preterm birth. Controversy exists regarding the benefits of magnesium sulphate therapy when given for tocolysis (Grimes 2006). There has been limited evaluation of the efficacy and safety of alternative regimens of magnesium sulphate when given for tocolysis. In order to determine the optimal dose, duration, route and timing of administration, evaluation of different regimens of magnesium sulphate given for tocolysis is warranted. Given its widespread availability and use in other obstetric contexts, further review of the safety profile of magnesium sulphate will be of value.