Preterm Labour & Tocolysis

Preterm birth is the single largest direct cause of neonatal mortality worldwide and a relentless NEET PG favourite. This topic concentrates on definitions, the cervical length and fetal fibronectin tests that triage true labour, the four tocolytic classes, and the two interventions that actually change neonatal outcome — antenatal corticosteroids and magnesium sulphate for neuroprotection.

Definition & classification

Preterm labour is the onset of regular uterine contractions with progressive cervical change (effacement and/or dilatation) occurring after the age of viability but before 37 completed weeks (i.e. before 36 weeks + 6 days) of gestation. Preterm birth is any delivery before 37 completed weeks.

Gestational-age subclassification (WHO) is heavily tested because corticosteroid and neuroprotection windows hinge on it:

Category	Gestational age	Notes
Late preterm	34 to <37 weeks	Largest group (~70–84%)
Moderate preterm	32 to <34 weeks
Very preterm	28 to <32 weeks
Extremely preterm	< 28 weeks	Highest mortality/morbidity

By clinical onset, preterm birth is divided into:

• Spontaneous (~70–80%): spontaneous preterm labour with intact membranes, or preterm premature rupture of membranes (PPROM).
• Indicated/iatrogenic (~20–30%): deliberate delivery for maternal or fetal indication (pre-eclampsia, IUGR with abnormal Dopplers, abruption).

High-yield: The threshold is 37 completed weeks. The lower limit is the locally defined limit of viability (commonly quoted as ~24 weeks, or fetal weight ~500 g / 20 weeks for "abortion vs preterm" distinction). A delivery at 36 weeks 6 days is preterm; at 37 weeks 0 days it is term.

Etiology & risk factors

Preterm labour is a syndrome, not a single disease. Four principal pathways converge on a final common pathway of myometrial activation, cervical ripening and decidual–membrane activation:

1. Activation of the maternal/fetal hypothalamic–pituitary–adrenal (HPA) axis — stress, raising CRH and cortisol.
2. Inflammation/infection — the best-understood pathway; ascending genital tract infection releases cytokines (IL-1, IL-6, IL-8, TNF-α) and prostaglandins. Subclinical intra-amniotic infection is a leading cause of early spontaneous preterm labour.
3. Decidual haemorrhage — abruption, thrombin generation.
4. Pathological uterine distension — multiple pregnancy, polyhydramnios.

Major risk factors (the most testable single factor first):

High-yield: A prior spontaneous preterm birth is the strongest single risk factor; recurrence risk rises with the number and earliness of previous preterm births.

• Short cervix on transvaginal ultrasound; history of cervical surgery (LEEP/cone, repeated D&C), Müllerian anomaly.
• Multiple gestation, polyhydramnios.
• Genital tract infection — bacterial vaginosis, asymptomatic bacteriuria, chorioamnionitis; periodontal disease.
• Short inter-pregnancy interval (< 6 months), extremes of maternal age, low BMI, smoking, substance abuse, low socioeconomic status.
• Vaginal bleeding (abruption, placenta praevia), PPROM, ART/IVF conception.

Pathophysiology in brief

The myometrium is held quiescent during pregnancy mainly by progesterone, nitric oxide and relaxin. Labour represents a functional progesterone withdrawal, a surge in oestrogen action, up-regulation of contraction-associated proteins (oxytocin receptors, connexin-43 gap junctions, prostaglandin receptors) and a rise in intracellular calcium driving actin–myosin cross-bridging. Inflammation accelerates every step — explaining why infection is such a potent trigger and why progesterone supplementation (which maintains quiescence) is used for prevention.

Clinical features

• Regular, painful uterine contractions (≥ 4 in 20 min or ≥ 8 in 60 min) with cervical change.
• Low dull backache, pelvic pressure/heaviness, menstrual-like cramps.
• Increased or changed vaginal discharge, mucoid "show", light vaginal bleeding.
• Leaking of fluid suggests PPROM (a distinct but overlapping entity).

The central clinical problem: most women with threatened preterm labour do NOT actually deliver preterm. Distinguishing true from false labour drives all the testing below and prevents over-treatment.

Diagnosis & investigation of choice

Diagnosis combines contractions + cervical change. Where the diagnosis is uncertain, two objective tests dominate exams.

Transvaginal cervical length (CL)

Transvaginal ultrasound (TVUS) is the gold-standard imaging for the cervix — far superior to transabdominal or digital assessment.

Cervical length (TVUS)	Interpretation
≥ 30 mm	Preterm labour very unlikely; high negative predictive value
15–30 mm	Indeterminate; use fFN to refine
< 25 mm before 24 weeks	"Short cervix" — risk marker for spontaneous preterm birth
< 15 mm	High risk of imminent delivery

High-yield: A short cervix is defined as < 25 mm before 24 weeks. Funnelling (dilatation of the internal os with protrusion of membranes — "U", "V", "Y", "T" shapes) further increases risk.

Fetal fibronectin (fFN)

Fetal fibronectin is an extracellular-matrix glycoprotein at the choriodecidual interface. It is normally undetectable in cervicovaginal secretions between ~22 and 35 weeks; its reappearance signals disruption of the interface.

• Sample the posterior fornix BEFORE digital exam, USG gel or intercourse (these cause false positives).
• Cut-off ≥ 50 ng/mL = positive.
• Its great value is its high NEGATIVE predictive value: a negative fFN means delivery within 7–14 days is very unlikely, allowing safe avoidance of admission, tocolysis and steroids.

High-yield: fFN and short CL are powerful for their NEGATIVE predictive value — they tell you who will not deliver soon, preventing unnecessary intervention. Positive predictive value is comparatively weak.

Other workup

• Speculum exam: confirm cervical dilatation, look for PPROM (pooling, nitrazine, ferning, or AmniSure/IGFBP-1/PAMG-1 if uncertain).
• Cultures: high vaginal swab, urine culture, group B Streptococcus status.
• CTG for fetal wellbeing and to quantify contractions; ultrasound for presentation, growth, liquor, placental localisation.

Diagnostic flow: Symptoms (contractions ± backache) → speculum to exclude PPROM and assess os → TVUS cervical length → if 15–30 mm, send fFN → if CL very short or fFN positive, admit and start corticosteroids ± tocolysis ± MgSO₄.

Management

The goals of intrapartum management are NOT primarily to prolong pregnancy for its own sake but to buy 48 hours to deliver the two genuinely outcome-changing interventions (steroids and, where indicated, magnesium) and to enable in-utero transfer to a unit with neonatal intensive care.

1. Antenatal corticosteroids — the single most important intervention

High-yield: A single course of antenatal corticosteroids is the intervention with the greatest proven reduction in neonatal mortality, respiratory distress syndrome (RDS), intraventricular haemorrhage and necrotising enterocolitis.

• Offer to all women at risk of preterm delivery between 24 and 34 weeks (and selectively up to ~36⁶/₇ in late-preterm per ALPS/ACOG).
• Drugs/doses (memorise exactly):
  • Betamethasone 12 mg IM, two doses 24 hours apart (total 24 mg), OR
  • Dexamethasone 6 mg IM, four doses 12 hours apart (total 24 mg).
• Maximal benefit appears 24 hours to 7 days after the first dose; some benefit even if delivery occurs before 24 h.
• A single rescue/repeat course may be considered if the first was > 7–14 days earlier and risk persists before 34 weeks. Avoid multiple repeated courses (reduced fetal growth/head circumference).

Drug	Dose & interval	Total
Betamethasone	12 mg IM × 2, 24 h apart	24 mg
Dexamethasone	6 mg IM × 4, 12 h apart	24 mg

2. Magnesium sulphate for fetal neuroprotection

High-yield: Magnesium sulphate given to the mother before 32 weeks when delivery is imminent reduces the risk of cerebral palsy in the surviving child (number needed to treat ≈ 60–63 for CP). Note this is a separate, lower gestational window than steroids.

• Indication: anticipated/imminent preterm birth < 32 weeks (some protocols < 30 or < 34 weeks).
• Regimen example: 4 g IV loading over 20–30 min, then 1 g/hour infusion (protocols vary), discontinued once delivery occurs or is no longer imminent.
• Monitor for toxicity: deep tendon reflexes, respiratory rate, urine output. Magnesium toxicity is treated with IV calcium gluconate.

3. Tocolysis

Tocolytics do not improve neonatal outcome by themselves and do not meaningfully reduce preterm birth; they buy roughly 48 hours, the window for steroids and transfer. Use only when this delay is useful and there is no contraindication.

Contraindications to tocolysis: intrauterine fetal death, lethal fetal anomaly, non-reassuring fetal status, chorioamnionitis, severe pre-eclampsia/eclampsia, significant antepartum haemorrhage/abruption, advanced cervical dilatation, and maternal contraindications to the specific drug.

Tocolytic agents

Agent (class)	Mechanism	Key adverse effects	Caution / contraindication
Nifedipine (Ca²⁺-channel blocker)	↓ Ca²⁺ influx into myometrium	Maternal hypotension, flushing, headache, tachycardia	Hypotension, cardiac disease; avoid combining with MgSO₄ (additive hypotension/block)
Atosiban (oxytocin-receptor antagonist)	Competitive block of oxytocin receptor	Best maternal/fetal safety, few side effects	Cost; not available everywhere
Indomethacin (NSAID / PG synthase inhibitor)	↓ Prostaglandin synthesis	Fetal: premature ductus arteriosus constriction, oligohydramnios	Limit to < 32 weeks and ≤ 48 h
Betamimetics — ritodrine, terbutaline, isoxsuprine, salbutamol (β₂-agonist)	↑ cAMP → myometrial relaxation	Maternal tachycardia, arrhythmia, hyperglycaemia, hypokalaemia, pulmonary oedema	Cardiac disease, diabetes; now largely abandoned

High-yield: First-line tocolytics today are the calcium-channel blocker NIFEDIPINE and the oxytocin antagonist ATOSIBAN. Betamimetics (ritodrine — the only FDA-approved tocolytic historically) are no longer first-line due to maternal cardiovascular toxicity (pulmonary oedema, arrhythmia).

High-yield: Indomethacin is favoured before 32 weeks (risk of premature ductal closure and oligohydramnios rises after 32 weeks). Do NOT combine nifedipine with magnesium sulphate — additive neuromuscular blockade and hypotension.

Atosiban dosing pattern (3-step): initial 6.75 mg IV bolus → 18 mg/hour loading infusion for 3 hours → 6 mg/hour maintenance for up to 45 hours.

4. Adjuncts

• Group B Streptococcus (GBS) intrapartum prophylaxis with IV penicillin/ampicillin if GBS unknown/positive and preterm delivery likely.
• In-utero transfer to a tertiary centre with NICU — better than postnatal transfer of a sick neonate.
• Mode of delivery individualised; preterm breech is often delivered by caesarean. Avoid routine episiotomy/forceps trauma to the fragile preterm head.

Prevention (in women with risk factors)

• Vaginal progesterone for asymptomatic short cervix (< 25 mm) on TVUS.
• 17-α-hydroxyprogesterone caproate (intramuscular) historically used for prior spontaneous preterm birth (note: its efficacy was questioned by the PROLONG trial and it has been withdrawn in some countries).
• Cervical cerclage for cervical insufficiency (history-, ultrasound-, or exam-indicated; McDonald or Shirodkar technique).
• Cervical pessary (Arabin) — used in selected short-cervix cases; evidence mixed.
• Treat asymptomatic bacteriuria and bacterial vaginosis; smoking cessation.

Complications

Neonatal (driven by organ immaturity):

• Respiratory distress syndrome (RDS) from surfactant deficiency — the prime target of antenatal steroids.
• Intraventricular haemorrhage (IVH) and periventricular leukomalacia → cerebral palsy (target of MgSO₄).
• Necrotising enterocolitis (NEC), retinopathy of prematurity, bronchopulmonary dysplasia, patent ductus arteriosus.
• Temperature instability, hypoglycaemia, hyperbilirubinaemia, sepsis, feeding difficulty.
• Long-term: neurodevelopmental delay, chronic lung disease.

Maternal/iatrogenic: drug-specific toxicity — pulmonary oedema (betamimetics, fluid overload, especially with multiple gestation and steroids), magnesium toxicity, nifedipine hypotension.

Key differentials

Condition	Distinguishing feature
False/Braxton-Hicks labour	Irregular, no cervical change; fFN negative, normal CL
PPROM	Leaking fluid; pooling, positive nitrazine/ferning, low liquor on USG
Placental abruption	Painful bleeding, tense tender uterus, fetal distress
Placenta praevia	Painless bleeding; low-lying placenta on USG
UTI / pyelonephritis	Dysuria, fever, loin pain; can itself trigger contractions
Round-ligament pain / red degeneration of fibroid	Localised, no cervical change
Chorioamnionitis	Maternal fever, tachycardia, uterine tenderness, foul liquor — a contraindication to tocolysis

Recently asked / exam angle

• First-line tocolytic → Nifedipine (or Atosiban). The "single FDA-approved" historical answer is ritodrine, but it is no longer preferred.
• Corticosteroid dose → Betamethasone 12 mg IM × 2, 24 h apart, or Dexamethasone 6 mg IM × 4, 12 h apart (total 24 mg); window 24–34 weeks.
• MgSO₄ for neuroprotection → reduces cerebral palsy; given < 32 weeks; toxicity reversed by calcium gluconate.
• Best test to rule OUT imminent delivery → fetal fibronectin / short cervical length on TVUS (high negative predictive value).
• Strongest risk factor → previous spontaneous preterm birth.
• Tocolytic to avoid after 32 weeks → indomethacin (premature ductus arteriosus closure, oligohydramnios).
• Drug combination to avoid → nifedipine + magnesium sulphate.
• Tocolytic causing pulmonary oedema/arrhythmia → betamimetics (ritodrine/terbutaline/isoxsuprine).
• Investigation of choice for short cervix → transvaginal ultrasound.
• Prevention with vaginal progesterone for short cervix; cerclage for cervical insufficiency.

Mnemonic for tocolytic classes — "NAIB": Nifedipine (CCB), Atosiban (oxytocin antagonist), Indomethacin (NSAID), Betamimetics. The first two (NA) are first-line; the last two are situational/abandoned.

Mnemonic for steroid effects — RIIN reduced: RDS, IVH, Intestinal NEC, Neonatal mortality.

Rapid revision

1. Preterm = birth before 37 completed weeks; late preterm 34–37 weeks is the commonest subgroup.
2. Previous spontaneous preterm birth is the strongest single risk factor.
3. Bacterial vaginosis / ascending infection is a leading trigger of early spontaneous preterm labour.
4. TVUS cervical length < 25 mm before 24 weeks = short cervix; funnelling adds risk.
5. Fetal fibronectin cut-off ≥ 50 ng/mL; its strength is the negative predictive value — sample before digital exam/USG gel.
6. Antenatal corticosteroids (24–34 weeks) are the most outcome-improving step: betamethasone 12 mg × 2 / 24 h or dexamethasone 6 mg × 4 / 12 h, total 24 mg; peak benefit 24 h–7 days.
7. MgSO₄ before 32 weeks for fetal neuroprotection (↓ cerebral palsy); toxicity → calcium gluconate.
8. Tocolytics only buy ~48 hours for steroids + in-utero transfer; they do not improve neonatal outcome alone.
9. First-line tocolytics: nifedipine and atosiban; betamimetics abandoned (pulmonary oedema, arrhythmia).
10. Indomethacin only < 32 weeks — risk of premature ductus arteriosus closure and oligohydramnios after.
11. Never combine nifedipine with magnesium sulphate (additive hypotension/neuromuscular block).
12. Chorioamnionitis, fetal death, severe pre-eclampsia, abruption, and non-reassuring fetal status are contraindications to tocolysis — deliver instead.