A combination therapy to prevent preterm birth

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Two tocolytic agents, nifedipine and indomethacin, were found to be more effective in combination versus a monotherapy for prevention of preterm birth (PTB) in a new randomized clinical trial (RCT).

Nifedipine is a calcium channel blocking agent that inhibits uterine contractions by preventing the entry of calcium through the cell membrane channels, whereas indomethacin is both a prostaglandin inhibitor and a nonsteroidal anti-inflammatory drug (NSAID).

Published in The Journal of Maternal-Fetal & Neonatal Medicine, the double-blind trial enrolled 152 pregnant women with a gestational age between 26 and 34 weeks who were referred to Akbarabadi Teaching Hospital in Tehran, Iran, between May 2016 and March 2018, with signs and symptoms of preterm labor.

Participants were randomly allocated to one of three initial treatment groups: 100 mg rectal indomethacin plus oral placebo (n = 50), 20 mg oral nifedipine plus rectal placebo (n = 52, of whom 2 did not receive treatment) and a combination of 100 mg rectal indomethacin and 200 mg oral nifedipine (n = 50). For those with cessation of contractions for two hours following initial treatment, maintenance therapy or placebo was initiated.

Inhibition of contractions for 2 hours and prevention of delivery for 48 hours and 7 days were evaluated. Duration of pregnancy, number of PTB, and the interval between entering the study and delivery were also compared among the three treated groups.

In both the indomethacin and nifedipine groups, 72% of women stopped having contractions within the first 2 hours of intervention, compared to 89.4% in the combination group (P = .002). 

For patients in the indomethacin group in whom contractions were inhibited after 2 hours, 25 mg of oral indomethacin was administered every 4 hours plus placebo, with maximum daily dosage of 200 mg over a maximum of 48 hours. Oral placebo was also repeated after 90 minutes of the first dosage and prescribed every 4 hours thereafter.

For patients in the nifedipine group, the initial protocol was repeated after 90 minutes. In instances of inhibition of contractions for 2 hours, 20 mg of oral nifedipine was continued every 4 hours for 48 hours, with a maximum daily dosage of 180 mg. Placebo was given the same as in the indomethacin group.

The combination group received a protocol similar to that used in the other two groups.

Inhibiting contractions for 2 hours occurred in 72.0% of patients in the  indomethacin group, the same percentage as in the nifedipine group, compared to 82.0% in the combination group (82.0%) (P = 0.002). 

Likewise, 83.3% of patients on indomethacin and 86.1% of those on nifedipine had contraction inhibition for 48 hours, versus 95.1% of patients on combination therapy (P = 0.003).

In the indomethacin group, 72.2% of women had inhibition of contractions for 7 days whereas 77.7% in the nifedipine group 90.2% of those in the combination group had a similar outcome (P = 0.021).

Gestational age at birth was also higher in the combination group (P = 0.001), with more pregnancies lasting beyond 37 weeks (P = 0.007), and increased neonatal weight (P = 0.020).

No severe gastrointestinal adverse events were observed in any of the three groups, except for epigastric pain in two women in the indomethacin group alone

“To the best of our knowledge, the present study is the first study on combination therapy with these two common tocolytic agents,” the authors wrote. Because no other study has compared combination therapy with indomethacin and nifedipine to monotherapy with either of these two drugs, the current study could not be compared to other studies.

The investigators advocate further studies combining different toxolytics and more popular agents, with a larger sample size and placebo-controlled studies. “Performing such studies will enable the researchers to find the best drug combinations, adverse effects, and advantages for neonates and mother alike,” the authors wrote.