An introduction to preterm labor

1. Preterm Labour
Max Mongelli
Western Clinical School
University of Sydney
Nepean Hospital

2. Definitions
Threatened pre-term labour
Pre-term labour
Pre-term delivery

3. Incidence
Approx 5-6% in Australia
More than 10% in the USA
Second leading cause of mortality after
congenital anomalies

4. Risk Factors (1)
Stress
Occupational fatigue
Smoking/substance abuse
Poor antenatal care

5. Risk Factors (2)
Excessive or impaired uterine distension:
Multiple pregnancy
Polyhydramnios
Fibroids
Uterine anomaly

6. Risk Factors (3)
Cervical factors:
History of second trimester loss
Cervical surgery
Premature cervical dilatation or
effacement

7. Risk Factors (4)
Infections:
Systemic infections
STD's
Pyelonephritis
Bacteriuria
Periodontal disease

8. Risk Factors (5)
Fetal & placental factors:
Congenital anomalies
IUGR
Abruption
Vaginal bleeding
Placenta previa

9. 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

10. Four Major Categories
Activation of hypothalamic/pituitary/adrenal axis:
maternal or fetal
Inflammation
Decidual hemorrhage
Uterine over-distention

11. 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

12. 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

13. 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 and
endotoxins, stimulating uterine contractions

14. 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

15. 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

16. 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

17. 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 membrane
extracellular matrix, PPROM

18. Uterine Over-distention
Up-regulation of oxytocin receptors
Formation of gap junctions
PGE2 and PGF
Myosin light chain kinase

19. Uterine Over-distention
Polyhydramnios
Multiple pregnancy

20. 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

21. Prevention of Preterm
Labour

22. 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

23. 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

24. 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

25. Avoidance of drugs and alcohol
Cocaine
Alcohol
? Cannabis

26. 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

27. 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

28. 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

29. 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 of
preterm labour (1/141 vs 11/149)

30. 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

31. 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

32. 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

33. Diagnosis of Preterm Labor
No universally accepted definition
Regular uterine contractions and
Cervical dilatation or effacement

34. Tests for Prediction of Preterm
Delivery
Cervico-vaginal
fibronectin
Ultrasound
measurement of
cervical length

35. Treatment of Preterm Labor
No generally accepted criteria for
starting tocolysis
About 30-50% of threatened preterm
labours spontaneously resolve
Treat the underlying cause if possible

36. General Measures
No proven benefits for:
Bed rest
Hydration
Sedation

37. 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

38. Contraindications to Tocolysis
APH with hemodynamic instability
Severe pre-eclampsia/eclampsia
Chorioamnionitis
Severe IUGR
Evidence of fetal compromise
Lethal fetal anomaly
Fetal demise

39. 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)

40. 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

41. TOCOLYTIC AGENTS
Betamimetic agents
Nifedipine
NSAIDS
Atosiban
Magnesium sulphate

42. BETA-ADRENERGIC RECEPTOR AGONISTS

43. 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).

44. 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

45. BETA-ADRENERGIC RECEPTOR AGONISTS:
MATERNAL SIDE EFFECTS
Tachycardia
Palpitations
Lowered blood pressure
SOB
Myocardial ischemia
Pulmonary oedema (0.3%)
Hyperglycemia, hypokalemia

46. BETA-ADRENERGIC RECEPTOR AGONISTS:
FETAL SIDE EFFECTS
Tachycardia
Neonatal hypoglycemia

47. 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

48. 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

49. 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)

50. NIFEDIPINE :
MATERNAL SIDE EFFECTS
Peripheral vasodilator:
Nausea, flushing, headache
Palpitations
Reduction in MAP, reflex tachycardia
Rarely severe hypotension

51. NIFEDIPINE :
FETAL SIDE EFFECTS
Animal studies: reduced uterine and
umbilical blood flow
No evidence of toxicity in humans

52. NIFEDIPINE :
CONTRAINDICATIONS
Known allergy
LV dysfunction or cardiac failure
Hepatic dysfunction
Concomitant use of magnesium:
respiratory paralysis

53. 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

54. 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

55. MANAGEMENT FOLLOWING SUCCESSFUL
TOCOLYSIS
Optimal approach unknown – limited data
Prolonged hospitalisation probably of no value
Bed rest not proven effective
Avoid physically demanding work

56. 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

57. 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

58. 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

59. 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

60. 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

61. 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?

62. 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?