Preterm Labour

Definition

• Extreme prematurity: <28 weeks
• Very preterm: 28-32 weeks
• Moderate-to-late preterm: 32-37 weeks

Pathophysiology

1. Decidual/fetal membrane inflammation - infection or sterile inflammation (the most common pathway, ~25-40% of cases). Ascending genital tract infection activates the innate immune system, producing cytokines (IL-1β, IL-6, TNF-α) that stimulate prostaglandin synthesis (PGE2, PGF2α) and upregulate oxytocin receptors.
2. Activation of the maternal-fetal hypothalamic-pituitary-adrenal axis - fetal or maternal stress (placental insufficiency, uteroplacental ischemia) elevates CRH and cortisol, which promote prostaglandin production and uterine contractility.
3. Decidual hemorrhage and abruption - thrombin generated from abruption directly activates myometrial contractions and promotes cervical ripening.
4. Pathological uterine distension - multiple gestation, polyhydramnios, or Mullerian anomalies cause mechanical stretching that upregulates contraction-associated proteins (gap junctions, oxytocin receptors).

Risk Factors

Obstetric/Uterine

• Prior preterm birth (single strongest predictor; risk increases as prior gestational age falls and number of prior PTBs rises)
• Multiple gestation (>50% of twins, >75% of triplets deliver preterm)
• Uterine anomalies (bicornuate uterus, fibroids)
• Cervical insufficiency / short cervix (<25 mm at 16-24 weeks)
• Prior cervical surgery (LEEP, conisation, D&E)
• Polyhydramnios

Infection/Inflammation

• Bacterial vaginosis, trichomoniasis, STIs
• Chorioamnionitis, urinary tract infection
• Periodontal disease

Maternal Demographics

• Black race (2x higher risk vs. White; persists after adjusting for socioeconomic factors)
• Age <17 or >35
• Low socioeconomic status, low education level
• Smoking, substance abuse, underweight BMI

Pregnancy Complications

• Placenta previa, placental abruption (decidual bleeding)
• Preeclampsia / gestational hypertension (associated with both spontaneous and indicated PTB)
• Diabetes mellitus
• ART-conceived pregnancies, especially with multiple embryo transfer

Genetic

• Maternal family history of preterm birth; variants in EBF1, EEFSEC, AGTR2 loci; collagen gene polymorphisms (associated with Ehlers-Danlos syndrome phenotype and cervical insufficiency)

Clinical Presentation

• Pelvic pressure or heaviness
• Menstrual-like cramps
• Low backache
• Increased or changed vaginal discharge
• Painless or painful uterine tightenings/contractions
• Vaginal spotting

• Contractions ≥6/hour PLUS cervical dilation ≥3 cm OR effacement ≥80%
• OR spontaneous rupture of membranes

Diagnosis

Clinical Assessment

• Digital cervical examination (dilation, effacement, station)
• Speculum exam to exclude PPROM (pooling, ferning, nitrazine)
• Uterine contraction monitoring (tocometry)

Diagnostic Tests for Equivocal Cases (cervical dilation <2 cm or effacement <80%)

• Gold standard for non-invasive cervical assessment
• Cervical length ≥30 mm - preterm delivery unlikely despite symptoms (high negative predictive value)
• Cervical length <15 mm - high risk of imminent delivery
• Cervical length 15-30 mm - intermediate risk; combine with fFN

• Glycoprotein at the decidual-chorionic interface; normally absent in cervicovaginal secretions between 22-34 weeks
• Negative result (<50 ng/mL) before 34 weeks: very high NPV for delivery within 7 days (~99%)
• Positive result has low PPV in isolation; most valuable when combined with cervical length
• Must be obtained before digital exam, lubricants, or intercourse within 24 hours

• CL ≥30 mm → low risk, consider discharge
• CL <15 mm → high risk, admit and treat
• CL 15-30 mm → test fFN; if negative, low risk; if positive, treat as high risk

Management

1. General Measures

• Confirm gestational age and fetal presentation
• Exclude contraindications to conservative management (PPROM, chorioamnionitis, severe preeclampsia, abruption, fetal compromise, lethal anomaly)
• Hydration (correct dehydration but routine IV hydration does not stop PTL)
• Bed rest: NOT recommended as evidence-based therapy - routine bed rest does not prolong pregnancy

2. Antenatal Corticosteroids

• Betamethasone 12 mg IM, two doses 24 hours apart (preferred)
• Dexamethasone 6 mg IM every 12 hours for 4 doses (alternative)
• Indicated for gestations 24 to 34 weeks at high risk of delivery within 7 days
• Benefits: reduced risk of neonatal death, RDS, IVH, NEC, PDA
• A single rescue course may be considered if initial course given >14 days prior and GA still <34 weeks
• Mechanism: promotes surfactant synthesis, increases lung compliance, reduces vascular permeability; also maturational effects on brain, kidneys, gut

3. Tocolysis

• Severe preeclampsia/gestational hypertension
• Antepartum hemorrhage (significant abruption or previa)
• Chorioamnionitis
• Fetal compromise or non-reassuring fetal status
• Lethal fetal anomaly
• Significant maternal cardiac disease

Calcium Channel Blockers (First Line)

• Nifedipine - most used agent
• Mechanism: inhibits voltage-dependent calcium channels in smooth muscle
• Onset: within minutes orally; peak 15-90 min; half-life ~81 min
• Evidence: Cochrane meta-analysis (23 trials vs. β-agonists) - reduced delivery <34 weeks (RR 0.78), reduced NICU admission (RR 0.74), reduced NEC, RDS, IVH; fewer maternal side effects than β-agonists
• Side effects: headache (20%), flushing (8%), dizziness, nausea, hypotension; rare: MI (reported)
• Avoid concurrent MgSO4 (skeletal muscle blockade) or β-agonists

β-Agonists

• Terbutaline (most used); ritodrine
• Mechanism: β2-receptor stimulation → increased cAMP → reduced myosin light-chain kinase activity → reduced intracellular calcium
• Evidence: effective for 48-hour and 7-day delay (Cochrane); more side effects than CCBs
• Side effects: maternal tachycardia, palpitations, tremor, pulmonary oedema, hypokalemia; fetal tachycardia
• Subcutaneous terbutaline for acute tocolysis; long-term oral/pump use is not recommended (no benefit, increased risk)

NSAIDs (Indomethacin)

• Mechanism: COX inhibitor → reduced prostaglandin synthesis → reduced uterine contractility
• Typically used <32 weeks (avoid beyond 32 weeks due to premature ductal closure)
• Fetal concerns: premature constriction of ductus arteriosus (especially >32 weeks), neonatal pulmonary hypertension, oligohydramnios, renal impairment
• Periodic fetal echocardiography monitoring required

MgSO4

• Not recommended as a tocolytic (Cochrane: ineffective for inhibiting preterm labour)
• Still used for neuroprotection (reduces risk of cerebral palsy) in gestations <32 weeks when delivery is imminent

Oxytocin Receptor Antagonists

• Atosiban - available in Europe (not FDA-approved in the US)
• Cochrane: shown to be ineffective vs. placebo for improving neonatal outcomes; fewer maternal side effects
• Not superior to CCBs in efficacy

4. Magnesium Sulfate for Neuroprotection

• MgSO4 4 g IV loading dose then 1-2 g/hr infusion for gestations <32 weeks (or <34 weeks per some protocols)
• Reduces risk of cerebral palsy and gross motor dysfunction in surviving preterm infants
• Monitor for magnesium toxicity: loss of deep tendon reflexes, respiratory depression (antidote: calcium gluconate)

5. GBS Prophylaxis

• Intrapartum antibiotic prophylaxis for Group B Streptococcus if unknown or positive screen status at <37 weeks

6. Antibiotics

• Indicated for PPROM (prolongs latency: erythromycin/ampicillin ± azithromycin)
• NOT indicated for PTL with intact membranes in the absence of infection - antibiotics do not prolong pregnancy or improve outcomes in intact-membrane PTL (except for GBS prophylaxis)

Prevention in High-Risk Women (Singleton)

Progesterone Supplementation

• 17-hydroxyprogesterone caproate (17OHPC) - 250 mg IM weekly starting at 16-20 weeks until 36 weeks
  • Note: FDA withdrew approval in 2023 based on re-analysis; ACOG currently recommends either formulation pending further data
• Vaginal progesterone - 200 mg/night or 90 mg gel; also recommended for asymptomatic women with cervical length <25 mm in midtrimester (regardless of prior PTB history)
• Mechanism: maintains uterine quiescence, modulates inflammatory cytokines, promotes cervical integrity

Cervical Cerclage

• Indicated for women with cervical insufficiency or prior second-trimester loss with painless dilation
• Also considered for women with prior preterm birth who develop short cervix (<25 mm) on TVU in current pregnancy (history-indicated or ultrasound-indicated)
• Prophylactic cerclage in multiple gestations is NOT recommended - evidence does not support benefit and may increase risk

Cervical Pessary

• Not recommended for multiple gestations (two large multicenter RCTs showed no benefit)

Multiple Gestation-Specific Points

• 50% of twins and 75% of triplets deliver preterm

• TVU cervical length <20 mm at 20-24 weeks → 10-fold increased risk for delivery <32 weeks (LR+ ~10)
• Progesterone, cerclage, and pessary do NOT reliably prevent PTB in twin pregnancies based on current evidence
• Acute tocolysis still appropriate to allow corticosteroid benefit and maternal transport
• Risk of pulmonary oedema is higher with tocolytics in multiple gestations (already elevated blood volume)

Regionalized Care

• Level I: normal deliveries
• Level II: most maternal/neonatal complications; NICU for infants >1500 g
• Level III: sickest/smallest infants; complex maternal critical care
• Level IV: ECMO, complex neonatal cardiothoracic surgery

Neonatal Complications of Prematurity

Summary Table: Key Tocolytic Agents