What are the recommended tocolytics (medications to suppress premature labor) for use in the third trimester?

Tocolytics for Third Trimester Preterm Labor

For women in preterm labor during the third trimester, calcium channel blockers (nifedipine) should be used as first-line tocolytic therapy, as they are highly effective in delaying delivery by 48 hours and 7 days, reduce neonatal respiratory and neurodevelopmental morbidity, and have a favorable maternal safety profile compared to other agents. 1

First-Line Tocolytic Agent

Calcium channel blockers (nifedipine) are the preferred first-line tocolytic for third trimester preterm labor based on the most recent and comprehensive network meta-analysis evidence 1:

• Nifedipine is possibly effective in delaying preterm birth by 48 hours (RR 1.16,95% CI 1.07 to 1.24) and probably effective in delaying birth by 7 days (RR 1.15,95% CI 1.04 to 1.27) 1
• Nifedipine prolongs pregnancy by approximately 5 days with high-certainty evidence 1
• Nifedipine possibly reduces neurodevelopmental morbidity (RR 0.51,95% CI 0.30 to 0.85) and respiratory morbidity (RR 0.68,95% CI 0.53 to 0.88) in neonates 1
• Nifedipine results in fewer neonates with birthweight less than 2000 g (RR 0.49,95% CI 0.28 to 0.87) 1
• The main maternal side effect is headache (RR 2.59,95% CI 1.39 to 4.83), which is generally well-tolerated 1

Alternative Tocolytic Options

Oxytocin Receptor Antagonists (Atosiban)

• Atosiban is probably effective in delaying preterm birth by 48 hours (RR 1.13,95% CI 1.05 to 1.22) and effective in delaying birth by 7 days (RR 1.18,95% CI 1.07 to 1.30) with high-certainty evidence 1
• Atosiban possibly prolongs pregnancy by 10 days (95% CI 2.3 to 16.7 more days) 1
• Atosiban has an excellent maternal safety profile with minimal side effects 1, 2

Magnesium Sulfate

• Magnesium sulfate is probably effective in delaying preterm birth by 48 hours (RR 1.12,95% CI 1.02 to 1.23) 1
• Magnesium sulfate is recommended as first-line therapy by some experts based on its safety profile 3
• Critical FDA warning: Continuous administration beyond 5-7 days can cause fetal hypocalcemia, skeletal demineralization, osteopenia, and neonatal fractures 4
• Magnesium sulfate probably causes treatment cessation due to side effects (RR 3.90,95% CI 1.09 to 13.93) 1

Cyclooxygenase (COX) Inhibitors (Indomethacin)

• Indomethacin is possibly effective in delaying preterm birth by 48 hours (RR 1.11,95% CI 1.01 to 1.23) 1
• Indomethacin is the only tocolytic class proven to decrease preterm birth before 37 weeks 5
• CRITICAL CONTRAINDICATION: Indomethacin is contraindicated after 32 weeks gestation due to risk of premature ductus arteriosus closure, oligohydramnios, pulmonary hypertension, and necrotizing enterocolitis 6, 7
• FDA labeling warns of constriction of ductus arteriosus prenatally, tricuspid incompetence, pulmonary hypertension, renal dysfunction/failure, oligohydramnios, gastrointestinal bleeding/perforation, and increased risk of necrotizing enterocolitis in the third trimester 6
• If used before 32 weeks, limit duration to 48 hours maximum 3

Betamimetics (Ritodrine, Terbutaline)

• Betamimetics are possibly effective in delaying preterm birth by 48 hours (RR 1.12,95% CI 1.05 to 1.20) and 7 days (RR 1.14,95% CI 1.03 to 1.25) 1
• Betamimetics have significant maternal side effects and are probably more likely to result in treatment cessation (RR 14.4,95% CI 6.11 to 34.1) 1
• Betamimetics probably cause dyspnoea (RR 12.09), palpitations (RR 7.39), vomiting (RR 1.91), possibly headache (RR 1.91), and tachycardia (RR 3.01) 1

Clinical Algorithm for Third Trimester Tocolysis

Step 1: Confirm Diagnosis and Gestational Age

• Confirm preterm labor with objective criteria including transvaginal ultrasound cervical length measurement 5
• Verify gestational age is between 24-34 weeks for tocolytic consideration 3

Step 2: Initiate First-Line Tocolytic

• Start nifedipine (calcium channel blocker) as first-line agent 1
• Alternative: Use atosiban if available, particularly if maternal cardiovascular concerns exist 1, 2

Step 3: Concurrent Interventions

• Administer corticosteroids for fetal lung maturation if gestational age is less than 34 weeks 8, 3
• Give corticosteroids for 48 hours to accelerate lung maturation 8
• Initiate magnesium sulfate for fetal neuroprotection (separate indication from tocolysis) 5

Step 4: Duration of Tocolysis

• The primary goal is to delay delivery by 48 hours to allow corticosteroid administration 3, 5
• Tocolytics are effective in stopping labor for 48-72 hours 3
• Prolonged tocolytic use beyond initial 48-72 hours has not been shown to prevent preterm birth and is not recommended 3

Critical Contraindications and Warnings

Indomethacin After 32 Weeks

• Absolutely avoid indomethacin after 32 weeks gestation due to severe fetal risks including ductus arteriosus closure, oligohydramnios, renal failure, and necrotizing enterocolitis 6, 7, 3

Magnesium Sulfate Duration

• Do not use magnesium sulfate continuously for more than 5-7 days due to risk of fetal skeletal demineralization, osteopenia, and neonatal fractures 4

NSAIDs in Late Pregnancy

• All NSAIDs must be discontinued after gestational week 28 to avoid premature ductus arteriosus closure and oligohydramnios 8, 9

Combination Therapy Caution

• Avoid combining calcium channel blockers with intravenous magnesium as myocardial depression may occur 8

Combination Tocolytic Therapy

• Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17,95% CI 1.07 to 1.27) and 7 days (RR 1.19,95% CI 1.05 to 1.34) 1
• Adjunctive use of indomethacin with magnesium sulfate may be used through 32 weeks for up to 48 hours at a time 3
• Combination tocolytics probably result in fewer neonates with birthweight less than 2500 g (RR 0.74,95% CI 0.59 to 0.93) 1
• However, combinations are probably more likely to result in treatment cessation due to side effects (RR 6.87,95% CI 2.08 to 22.7) 1

Key Pitfalls to Avoid

• Do not use prolonged prophylactic tocolytics after cessation of intravenous medications, as this has not been shown to prevent preterm birth and increases maternal risks 3
• Do not use indomethacin beyond 32 weeks or for more than 48 hours due to severe fetal complications 6, 3
• Do not continue magnesium sulfate tocolysis beyond 5-7 days due to fetal skeletal toxicity 4
• Ensure maternal and fetal well-being is established before initiating tocolytic therapy 3
• Re-evaluate the risk/benefit ratio on an ongoing basis during tocolytic therapy 3