Preterm Labour

Dr Max Mongelli

Western Clinical School University of Sydney

Nepean Hospital

http://drmaxmongelli.weebly.com

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

congenital anomaliesafter

Risk Factors (1)

Stress Occupational fatigue Smoking/substance abuse Poor antenatal care

Risk Factors (2)

Excessive or impaired uterine Multiple pregnancy Polyhydramnios Fibroids Uterine anomaly

distension:

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 maternal or fetal

Inflammation Decidual hemorrhage Uterine over-distention

axis:

Activation of HPA Axis

Maternal physical/emotional stress Placental vasculopathy Increased Increased Increased

secretion

secretion secretion

of CRH – fetal ACTHplacental estrogenof 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 PTLindependent of inflammatory mediators

Psudomonas, staph, strep, bacteroides,enterobacter produce proteases that can breakdown fetal membranes

Can also produce phospholipase A2 andendotoxins, stimulating uterine contractions

Bacteria

Increased rates of PTL noted in womenGBS, chlamydia and syphilis

with

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 withperiodontal disease

? intrauterine infection following “descent”from

Case from

oral cavityreport: Bergeyella bacterium isolated both the mouth and amniotic fluid of

patient with intact membranes having PTL at24 weeks

Decidual hemorrhage

Vaginal bleeding in more than one trimesterincreases risk of PTL 7-fold

Placental histopathology: occult decidualhemorrhage noted in 36-38% of cases of PTB

PPROM may be related to high concentrationstissue factor

of

Decidual hemorrhage

Decidual TF combines with FVIIa to activateFX, to generate thrombin

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

Leads to degradation of fetal membrane extracellular 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 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

effect

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-hydroxyprogesteronecaproate, weekly IMIReduction in PTL rates by 15-70%Most effective in women with previous PTL at<34 weeksIncreased risk of GDM (OR 2.9)ACOG recommends use in women with previousPTL onlyNo reduction in perinatal mortalityMore research needed

Stop smoking

Cigarette smoking has a dose-dependentrelationship 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 todeliver preterm

Risk increases with increasing no. of fetuses Valid indication before starting ART Limit no. of embryos transferrred

Cervical Cerclage

Cervical incompetence based on historyultrasound findings

RCOG study of 1292 women

or

Significant reduction in preterm births<33weeks

NNT = 25 cerclages Increased risk of puerperal infection Increased risk of PTL in twins

Reduction of Work Fatigue

Excessive physical demandsincreased risk (OR 1.63)

Working > 42 hrs/week Standing > 6 hrs/day Low job satisfaction No RCT’s available

related to

Nutritional interventions

No fish consumption linked to excess risk ofPTL

Fish high

(OR 19.6)oil supplements: one multi-centre RCT in 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 of

preterm labour (1/141 vs 11/149)

Early detection and treatment ofinfection

Asymptomatic bacteriuria: treatment significantlyreduces risk of PTL or LBW infants (OR 0.60)

Chlamydia, gonorrhea, BV: routine screening notindicated

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

to placental abruption Three first trimester miscarriages Family history of thromboembolism

due

Diagnosis of Preterm Labor

No universally accepted definition Regular uterine contractions and Cervical dilatation or effacement

Tests for PredictionDelivery

Cervico-vaginal fibronectin

Ultrasound measurement of cervical length

of Preterm

Treatment of Preterm Labor

No generally accepted criteria forstarting tocolysis

About 30-50% of threatened preterm labours 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 begiven

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 AntenatalReduce risk of: RDS (RR 0.66) NEC (RR 0.46) IVH (RR 0.54) Severe bruising

Steroids

Systemic infection(RR 0.56)

in the first 48 hr of life

Admission to NICU (RR 0.80) Neonatal mortality (RR 0.69)

Antenatal Steroids

Effective in women with SROM Maximum effect at 48 hrs

and PET

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 bindingwith 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 RECEPTOREFFICACY

AGONISTS:

Meta-analyses:

Reduction in no. of births within0.63).

48 hrs (RR

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 uterineumbilical blood flow

and

No evidence of toxicity in humans

NIFEDIPINE :CONTRAINDICAT

IONS

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

respiratory paralysis

NIFEDIPINEDOSAGE

:

Half-life 2-3 hrs, single dose 20 mg po stat

lasts up to 6 hrs

Repeat 30 mins later if still contracting Maintenance 20-40 mg qid Max dose 160 mg in 24 hrs

ROUTINE ANTIBIOTICS IN PRETERMLABOUR 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 SUCCESSFULTOCOLYSIS

Optimal approach unknown – limited data

Prolonged hospitalisation probably Bed rest not proven effective Avoid physically demanding work

of no value

MANAGEMENT FOLLOWING TOCOLYSIS:SEXUAL ACTIVITY

Observational data only Higher mortality amongst infected

associated with recent coitus: 11%infants 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 fetal stress arising from unfavourable intrauterine environment.

Placental pathology: increased incidence of fetal 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 weeks

G1P0 presents to rural hospital at 31

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 dischargedfrom hospital following TPL successfully stopped with nifedipine

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