Post on 07-May-2015
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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?