Tocolytic Drugs

Tocolytic drugs relax the uterus to delay preterm birth. They do not prevent preterm birth or improve outcomes on their own, but a delay of 48 hours allows antenatal corticosteroids to work, magnesium sulfate for neuroprotection to be given, and transfer to a unit with neonatal care. Nifedipine, atosiban and indomethacin are the main drugs.

Classification. Calcium channel blocker (nifedipine); oxytocin receptor antagonist (atosiban); cyclo-oxygenase inhibitor (indomethacin); beta-2 agonists (terbutaline, salbutamol, ritodrine) with more maternal harm; magnesium sulfate (not an effective tocolytic, used for neuroprotection).

Mechanism. Nifedipine blocks calcium entry into myometrial cells. Atosiban blocks oxytocin receptors. Indomethacin inhibits prostaglandin synthesis. Beta-2 agonists raise cyclic AMP.

Pharmacokinetics. Nifedipine is absorbed orally within 30 to 60 minutes; half-life 2 to 5 hours. Atosiban is intravenous with a half-life of about 1.7 hours. Indomethacin is given orally or rectally, crosses the placenta and shuts the ductus arteriosus.

Companion drugs.

• Antenatal corticosteroids: betamethasone 12 mg intramuscularly, 2 doses 24 hours apart (or dexamethasone 6 mg intramuscularly every 12 hours for 4 doses) between 24 and 34 weeks, where gestation is accurate and care for preterm infants is available.
• Magnesium sulfate for neuroprotection before 32 weeks: 4 g intravenously over 20 to 30 minutes, then 1 g/h until birth or for up to 24 hours.
• Antibiotics for preterm rupture of membranes (erythromycin 250 mg every 6 hours, with or without amoxicillin).

• First-line. Nifedipine to delay birth by 48 hours between 24 and 34 weeks in threatened preterm labour with intact membranes.
• Alternative. Atosiban when nifedipine is contraindicated (maternal cardiac disease, hypotension) or not tolerated; indomethacin before 32 weeks.
• Specialist. In utero transfer, external cephalic version, cervical cerclage and progesterone for prevention (separate indications).
• Emergency. Preterm labour in a woman too far from a neonatal unit.

Selection. Use tocolysis only for a clear, short purpose. Do not use maintenance tocolysis after 48 hours. Do not use for contractions without cervical change.

Contraindications. Placental abruption, chorioamnionitis, severe pre-eclampsia or eclampsia, foetal death, lethal anomaly, foetal compromise, haemodynamic instability, advanced labour; gestation over 34 weeks; indomethacin after 32 weeks, with renal disease, peptic ulcer or bleeding disorder; nifedipine with maternal aortic stenosis, hypotension.

Serious adverse effects.

• Nifedipine: flushing, headache, palpitations, hypotension, reflex tachycardia.
• Atosiban: nausea, headache, hyperglycaemia; rarely hypersensitivity.
• Indomethacin: premature ductal closure, oligohydramnios, necrotising enterocolitis and neonatal renal injury.
• Beta-2 agonists: pulmonary oedema, arrhythmia, hypokalaemia, hyperglycaemia, maternal deaths.

Major interactions. Nifedipine with magnesium sulfate (hypotension and neuromuscular weakness; use caution); nifedipine with CYP3A4 inhibitors; combining tocolytics (avoid, more adverse effects); beta-2 agonists with corticosteroids (pulmonary oedema).

Common prescribing errors.

• Giving tocolytics beyond 48 hours.
• Using sublingual or immediate-release nifedipine in severe hypotension.
• Starting tocolysis in pre-eclampsia or infection.
• Omitting corticosteroids and transfer.
• Using more than one tocolytic.

Special groups.

• Pregnancy: used only for acute threatened preterm labour.
• Breastfeeding: compatible after birth.
• Children and adolescents: dose as adults.
• Older adults: not applicable.
• Kidney: avoid indomethacin; magnesium sulfate is reduced in renal failure.
• Liver: nifedipine dose reduction.
• East Africa: antenatal corticosteroids help only when gestation is accurate and newborn care is available; nifedipine is inexpensive and available; transfer to a unit with neonatal support is the main benefit; monitor for malaria and urinary infection as triggers.

Monitoring. Maternal pulse and blood pressure every 15 to 30 minutes at first; foetal heart rate; contractions; respiratory rate, urine output and reflexes with magnesium sulfate; blood glucose with steroids.

Referral and escalation. Preterm labour at any gestation without neonatal facilities; ruptured membranes; abruption or bleeding; signs of infection; magnesium toxicity (loss of reflexes, respiratory depression, treated with calcium gluconate 1 g intravenously).

Comparison with alternative classes. Nifedipine matches atosiban and beta-2 agonists in delaying delivery with fewer maternal effects, and is cheap and oral. The real gains come from corticosteroids, magnesium sulfate and transfer rather than tocolysis alone.