Preterm Labour

Max Mongelli

Western Clinical School

University of Sydney

Nepean Hospital

Definitions

� Threatened pre-term labour

� Pre-term labour

� Pre-term delivery

Incidence

� Approx 5-6% in Australia

� More than 10% in the USA

� Second leading cause of mortality after congenital anomalies

Risk Factors (1)�

� Stress

� Occupational fatigue

� Smoking/substance abuse

� Poor antenatal care

Risk Factors (2)�

Excessive or impaired uterine distension:

� Multiple pregnancy

� Polyhydramnios

� Fibroids

� Uterine anomaly

Risk Factors (3)�

Cervical factors:

� History of second trimester loss

� Cervical surgery

� Premature cervical dilatation or effacement

Risk Factors (4)�

Infections:

� Systemic infections

� STD's

� Pyelonephritis

� Bacteriuria

� Periodontal disease

Risk Factors (5)�

Fetal & placental factors:

� Congenital anomalies

� IUGR

�Abruption

� Vaginal bleeding

� Placenta previa

Causes of Preterm Labour

� Major focus of O & G research.

� 80% spontaneous onset

� 50% PTL

� 30% PPROM

� 20% due to to intervention for maternal

or fetal indications

Four Major Categories

� Activation of hypothalamic/pituitary/adrenal axis:

� maternal or fetal

� Inflammation

� Decidual hemorrhage

� Uterine over-distention

Activation of HPA Axis

� Maternal physical/emotional stress

� Placental vasculopathy

� Increased secretion of CRH – fetal ACTH

� Increased secretion placental estrogen

� Increased secretion of placental PG's

� Activation of myometrium

Inflammation

� Both systemic and genital tract infections

� Chorioamnionitis in 50% of preterm labours before 30 weeks' gestation

� Can occur with intact membranes

� Raised cytokines (interleukins, TNF, GSF)�

� Enhanced prostaglandin production

Bacteria

� Some organisms have a direct role in PTL independent of inflammatory mediators

� Psudomonas, staph, strep, bacteroides,enterobacter produce proteases that can break down fetal membranes

� Can also produce phospholipase A2 andendotoxins, stimulating uterine contractions

Bacteria

� Increased rates of PTL noted in women with GBS, chlamydia and syphilis

� Risk of PTL reduced by treating:

� Asymptomatic bacteriuria

� Gonorrhea

� BV in high risk patients for PTL

Oral Bacteria

� Increased rates of PTL noted in women with periodontal disease

� ? intrauterine infection following “descent”from oral cavity

� Case report: Bergeyella bacterium isolated from both the mouth and amniotic fluid of patient with intact membranes having PTL at 24 weeks

Decidual hemorrhage

� Vaginal bleeding in more than one trimester increases risk of PTL 7-fold

� Placental histopathology: occult decidual hemorrhage noted in 36-38% of cases of PTB

� PPROM may be related to high concentrations of tissue factor

Decidual hemorrhage

� Decidual TF combines with FVIIa to activate FX, to generate thrombin

� Thrombin is a potent inducer of IL8, causing localised inflammatory reactions.

� Leads to degradation of fetal membraneextracellular matrix, PPROM

Uterine Over-distention

� Up-regulation of oxytocin receptors� Formation of gap junctions� PGE2 and PGF� Myosin light chain kinase

Uterine Over-distention

� Polyhydramnios� Multiple pregnancy

Cervical Incompetence

� In most cases a secondary effect� Cervical cone biopsy � LLETZ, laser cone� Increased risk of PTL -

� < 37 weeks: OR 3.4� <32 weeks: OR 4.6� <28 weeks: OR 12.4

Prevention of PretermLabour

Potentially effective interventions

� Progesterone supplements

� Smoking cessation

� Avoidance of drugs & alcohol

� Reduce rate of multiple pregnancy

� Cervical cerclage

� Reduce occupational stress

� Nutrition

� Early diagnosis & treatment of infection

Progesterone supplements

� Most trials use 17-alpha-hydroxyprogesterone caproate, weekly IMI

� Reduction in PTL rates by 15-70%

� Most effective in women with previous PTL at <34 weeks

� Increased risk of GDM (OR 2.9)�

� ACOG recommends use in women with previous PTL only

� No reduction in perinatal mortality

� More research needed

Stop smoking

� Cigarette smoking has a dose-dependent relationship with preterm labour

� Partially due to smoking-related complications

� Cessation of smoking likely to be beneficial, but not proven in RCT’s

Avoidance of drugs and alcohol

� Cocaine

� Alcohol

� ? Cannabis

Reduction in multiple pregnancies

� Multiple pregnancies six times more likely to deliver preterm

� Risk increases with increasing no. of fetuses

� Valid indication before starting ART

� Limit no. of embryos transferrred

Cervical Cerclage

� Cervical incompetence based on history or ultrasound findings

� RCOG study of 1292 women

� Significant reduction in preterm births<33 weeks

� NNT = 25 cerclages

� Increased risk of puerperal infection

� Increased risk of PTL in twins

Reduction of Work Fatigue

� Excessive physical demands related to increased risk (OR 1.63)�

� Working > 42 hrs/week

� Standing > 6 hrs/day

� Low job satisfaction

� No RCT’s available

Nutritional interventions

� No fish consumption linked to excess risk of PTL (OR 19.6)�

� Fish oil supplements: one multi-centre RCT in high risk women showed a significant reduction in PTL (OR 0.54)

� Trial with docosahexanoic acid supplements: significant prolongation of pregnancy

� CARRDIP trial: marked reduction in risk ofpreterm labour (1/141 vs 11/149)�

Early detection and treatment of infection

� Asymptomatic bacteriuria: treatment significantly reduces risk of PTL or LBW infants (OR 0.60)�

� Chlamydia, gonorrhea, BV: routine screening not indicated

� Women with previous PTL and +ve for BV may benefit from treatment

� Trichomonas: treatment of asymptomatic women may increase risk of PTL

Case Scenario 1

� 19 yo G3P1M1 late booking at 22 weeks

� Previous preterm delivery at 29 weeks

� Heavy smoker, nil alcohol

� Works in supermarket as check-out assistant, prolonged standing

� Offensive vaginal discharge

Case Scenario 2

� 35 yo G5P1M3 booking at 9 weeks

� Previous preterm delivery at 27 weeks due to placental abruption

� Three first trimester miscarriages

� Family history of thromboembolism

Diagnosis of Preterm Labor

� No universally accepted definition

� Regular uterine contractions and

� Cervical dilatation or effacement

Tests for Prediction of PretermDelivery

� Cervico-vaginalfibronectin

� Ultrasound measurement of cervical length

Treatment of Preterm Labor

� No generally accepted criteria for starting tocolysis

� About 30-50% of threatened pretermlabours spontaneously resolve

� Treat the underlying cause if possible

General Measures

No proven benefits for:

� Bed rest� Hydration� Sedation

Objectives of Tocolysis

� Delay delivery so that steroids may be given

� Allow safe transport of the mother if possible

� Prolong pregnancy when there are self-limiting causes of labour e.g. sepsis

Contraindications to Tocolysis

� APH with hemodynamic instability� Severe pre-eclampsia/eclampsia� Chorioamnionitis� Severe IUGR� Evidence of fetal compromise� Lethal fetal anomaly� Fetal demise

Benefits of Antenatal Steroids

Reduce risk of:

� RDS (RR 0.66)�

� NEC (RR 0.46)�

� IVH (RR 0.54)�

� Severe bruising

� Systemic infection in the first 48 hr of life (RR 0.56)�

� Admission to NICU (RR 0.80)�

� Neonatal mortality (RR 0.69)�

Antenatal Steroids

� Effective in women with SROM and PET

� Maximum effect at 48 hrs

� Betamethasone 11.4 mg IM 12 hrs apart

� Beneficial effects wear off after 2 weeks

� No significant maternal side effects

TOCOLYTIC AGENTS

� Betamimetic agents� Nifedipine� NSAIDS� Atosiban� Magnesium sulphate

BETA-ADRENERGIC RECEPTOR AGONISTS

BETA-ADRENERGIC RECEPTOR AGONISTS

Mechanism of action:

� Cause myometrial relaxation by binding with beta-2 receptors and increasing intracellular adenyl cyclase.

� Drop in intracellular calcium� Target cells eventually become desensitized

to the effect of beta-adrenergic agonists (tachyphylaxis).

BETA-ADRENERGIC RECEPTOR AGONISTS:EFFICACY

Meta-analyses:

� Reduction in no. of births within 48 hrs (RR 0.63).

� No decrease in no. of births within 7 days� No change in perinatal mortality� Marginal decrease in RDS cases

BETA-ADRENERGIC RECEPTOR AGONISTS:MATERNAL SIDE EFFECTS

� Tachycardia� Palpitations� Lowered blood pressure� SOB� Myocardial ischemia� Pulmonary oedema (0.3%)�� Hyperglycemia, hypokalemia

BETA-ADRENERGIC RECEPTOR AGONISTS:FETAL SIDE EFFECTS

� Tachycardia� Neonatal hypoglycemia

TERBUTALINE:DOSAGE

� Continuous iv infusion (2.5 mcg/min increased to max. of 25 mcg/min)�

� S.C.I. 25 mg stat� Stop if HR>120 or symptomatic� Monitor K+ and BSL

CALCIUM CHANNEL BLOCKERS

� Block the influx of Ca+ through the cell membrane

� Reduction of intracellular free calcium� Inhibition of myosin light chain kinase

phosphorylation� Relaxation of uterine muscle

EFFICACY OF NIFEDIPINE

Meta-analysis of 12 RCT’s:

� Reduction in no. of births within 7 days (RR 0.76)�

� Reduction in no. of births before 34 weeks (RR 0.83) �� Lower risk of RDS (RR 0.63), NEC (RR 0.23), IVH

(RR 0.59), jaundice (RR 0.73)�� Fewer maternal side effects (RR 0.14)�

NIFEDIPINE :MATERNAL SIDE EFFECTS

Peripheral vasodilator:

� Nausea, flushing, headache� Palpitations� Reduction in MAP, reflex tachycardia� Rarely severe hypotension

NIFEDIPINE :FETAL SIDE EFFECTS

� Animal studies: reduced uterine and umbilical blood flow

� No evidence of toxicity in humans

NIFEDIPINE :CONTRAINDICATIONS

� Known allergy � LV dysfunction or cardiac failure� Hepatic dysfunction� Concomitant use of magnesium:

respiratory paralysis

NIFEDIPINE :DOSAGE

� Half-life 2-3 hrs, single dose lasts up to 6 hrs� 20 mg po stat� Repeat 30 mins later if still contracting� Maintenance 20-40 mg qid� Max dose 160 mg in 24 hrs

ROUTINE ANTIBIOTICS IN PRETERM LABOUR WITH INTACT MEMBRANES

Results of ORACLE and meta-analysis:

� No improvement in neonatal outcomes� Reduction in maternal infection (RR 0.74)�

� Uncertainty about optimal antibiotics and regime

MANAGEMENT FOLLOWING SUCCESSFUL TOCOLYSIS

Optimal approach unknown – limited data

� Prolonged hospitalisation probably of no value� Bed rest not proven effective� Avoid physically demanding work

MANAGEMENT FOLLOWING TOCOLYSIS:SEXUAL ACTIVITY

� Observational data only� Higher mortality amongst infected infants

associated with recent coitus: 11% vs 2.4%� Increased rates or RDS, jaundice, low Apgar

scores (x 2)�� Effect stronger among preterm births� Prudent to suggest avoidance of coitus after

successful tocolysis

MANAGEMENT FOLLOWING TOCOLYSIS:MAINTENANCE TOCOLYSIS

� Most RCT’s are small� Endogenous prostaglandins may increase

oxytocin receptor density� Cochrane review of maintenance oral beta-

agonists: no significant benefits� May be useful for temporary relief of painful

contractions

MANAGEMENT FOLLOWING TOCOLYSIS:REPEATED COURSES OF ANTENATAL

STEROIDS

� Repeat courses of steroids improve neonatal pulmonary outcomes, especially in earlier gestational ages

� Evidence of delayed neuronal maturation and increased risk of IUGR in animal studies

� Humans: reduced birth weight only with 4 or more courses

� Catch-up growth by time of discharge from hospital

MANAGEMENT FOLLOWING TOCOLYSIS:REPEATED COURSES OF ANTENATAL

STEROIDS

� Long-term neuro-developmental data not available

� Optimal number of courses of steroids unknown

� Two courses probably safe

MANAGEMENT FOLLOWING TOCOLYSIS:RISK OF IUGR

� Threatened PTL may be an indication of fetalstress arising from unfavourable intrauterine environment.

� Placental pathology: increased incidence offetal or maternal vascular lesions without inflammation

� Risk of giving birth to SGA infant (OR 2.2)�� Need closer surveillance with USS for growth

and Doppler studies

CASE SCENARIO 3

� 33 y.o G1P0 presents to rural hospital at 31 weeks

� Strong, painful contractions for 3 hours � Slight brownish PV loss� Normal recordings; cephlic presentation� CTG “irritable uterus” pattern� Cervix 2 cm long os closed� How would you manage?

CASE SCENARIO 4

� 21 y.o G2P1 at 29 weeks recently discharged from hospital following TPL successfully stopped with nifedipine

� Completed course of steroids� Single mother, smokes 20/day� How would you manage her?