These potent smooth-muscle relaxants afect the vasculature, gut, and uterus. In randomized clinical trials, nitroglycerin administered orally, transdermally, or intravenously was ineffective or showed no superiority over other tocolytics. In addition, maternal hypotension was a common side efect (Bisits, 2004; EI-Sayed, 1999; Lees, 1999).
Discussed in Chapter 21 (p. 404), myometrial aCtlVIty is directly related to cytoplasmic free calcium, and reduced calcium concentrations inhibit contractions. Calcium-channel blockers act to inhibit, by various mechanisms, calcium entry through cell membrane channels. Although they were developed to treat hypertension, their ability to arrest pre term labor has been evaluated.
From study results, calcium-channel blockers, especially nifedipine, are safer and more efective tocolytic agents than 3-agonist drugs (King, 2003; Papatsonis, 1997). Lyell and colleagues (2007) randomized 192 women at 24 to 33 weeks' gestation to either magnesium sulfate or nifedipine and found no substantial diferences in eicacy or adverse efects. In another randomized study, 145 women with preterm labor between 24 and 33 weeks received nifedipine or atosiban. Neither proved superior to delay delivery, and neonatal morbidity was equivalent (Salim, 2012).
Flenady and coworkers (20 14b) reviewed 38 trials of calciumchannel blockers (mainly nifedipine) for preterm labor. These investigators suggested that calcium-channel blockers have beneits compared with placebo or no treatment. But, this conclusion stemmed from a trial with unclear risk of selection bias and a three-arm study of 84 women that was not blinded (Ara, 2008; Zhang, 2002). We are currently performing a randomized, double-blind, placebo-controlled trial of nifedipine for acute tocolysis of preterm labor at Parkland Hospital.
Importantly, the combination of nifedipine with magnesium for tocolysis is potentially dangerous. Ben-Ami (1994) and Kurtzman (1993) and their coworkers reported that nifedipine enhances the neuromuscular blocking efects of magnesium, which can interfere with pulmonary and cardiac function. In one small study of 54 women with preterm labor who received either magnesium sulfate plus nifedipine or no tocolytic, neither beneit nor harm was found (How, 2006).
This nonapeptide oxytocin analogue is an oxytocin-receptor antagonist (ORA). Goodwin and colleagues (1995) described its pharmacokinetics in pregnant women. In randomized clinical trials, atosiban failed to improve relevant neonatal outcomes and was linked with signiicant neonatal morbidity (Moutquin, 2000; Romero, 2000). he FDA has denied approval of atosiban because of concerns regarding eicacy and fetal-newborn safety. Further, in 2014, a metaanalysis did not demonstrate superiority of ORAs (largely atosiban) as a tocolytic compared with placebo, 3-mimetic drugs, or calcium-channel blockers in terms of pregnancy prolongation or neonatal outcomes. But, ORAs were associated with fewer maternal adverse efects (Flenady, 20 14a). Recently, van Vliet and coworkers (2016) conducted a randomized trial comparing nifedipine with atosiban in 510 women with threatened preterm birth. Using a composite of adverse perinatal outcomes, no diferences were reported between the two study groups.