Diagnosis and Treatment of Preterm Labor How Far Have We Come?

1
Diagnosis and Treatment of Preterm Labor How Far
Have We Come?

• Siri Kjos, MD
• Harbor-UCLA Medical Center
• Good Samaritan Hospital

2
Objectives

• State the different etiologies of indicated and
  spontaneous preterm birth
• State various tocolytic agents which are used to
  prevent preterm birth
• Give the reasons why Calcium Channel Blockers are
  the best option for tocolysis compared to other
  agents
• Explain the difference between the
  recommendations for antibiotic therapy in
  preventing preterm birth in intact and ruptured
  membranes.

3
Preterm Labor and Delivery

• Labor or delivery occurring after 20 and before
  37 completed weeks
• ?10 of births are preterm
• 75 of neonatal deaths, excluding malformations
• Rates complications unchanged
• ?? Including earlier gestational ages as viable
  (now 23 weeks)

4
Preterm delivery ? Low birth weight

• Birth weight is commonly used confused
• Low birth weight (LBW) lt2500g
• Very-Low Birth Weight (VLBW)lt1500g
• Micropremie (lt750g)
• lt29 weeks gestational age is better predictor of
  survival
• gt29 weeks birthweight is better predictor,
• less influence of gender, ethnicity, plurality

5
Survival by Gestational Age
Creasy RK, Iams JD in Maternal Fetal Medicine,
4th Ed, 1999
6
Preterm Delivery

• Indicated preterm delivery
• Follow medical or obstetrical disorders that
  place mother or fetus at risk (20-30)
• hypertension, placenta previa or abruption, IUGR,
  cardiac disease, etc
• Spontaneous preterm delivery
• In absence of overt maternal or fetal illness
• spontaneous labor, rupture of membranes
• associated with multiple gestation, 2nd trimester
  bleeding, history of preterm delivery

Meis PJ, Am J Obstet Gynecol 173597, 1995
7
Spontaneous Preterm Birth Risk Factors

• ?75 of Preterm Births,
• Predisposing Risk Factors
• Multiple gestation
• Bleeding in 2nd trimester
• Prior spontaneous preterm birth(s)
• Low Socioeconomic status
• Non-white ethnicity
• Low prepregnancy weight (BMI lt19.8)
• Smoking, cocaine use
• Lack of prenatal care
• Preterm, premature rupture of membranes

8
Spontaneous Preterm Birth Etiology

• Primarily unknown gt 50
• Uterine malformations
• Unicorniuate or bicornuate (reduction of space
  for fetal growth)
• Myomas (submucosal, subplacental)
• Poor implantation, increased antepartum bleeding
  and preterm labor
• Cervical Incompetence 0.1-2.0
• Prior 2nd trimester abortion
• Prior gynecological surgery
  (cervical dilatation or conization)
• Maternal exposure to DES

9
Spontaneous Preterm Birth Etiology

• Vaginal Infectious
• association but no proven etiology
• Genital tract colonization infection
• Poorly defined association between
  chorioamnionitis and preterm labor
• Sexually transmitted disease and preterm labor
  have common risk factors
• Increased preterm delivery with colonization of
• Group B streptococcus N. gonorrhoeae T.
  pallidum
• C. trachomatis G. vaginalis T.
  vaginalis
• Ureaplasma urealyticum

10
Spontaneous Preterm Birth Etiology Infection

• Positive amniotic fluid cultures in 20-30 of
  cases of preterm labor
• ? if refractory to tocolysis
• ? infection with earlier gestational age
• ? 90 of PTB lt28 weeks with culture or
  histological evidence of infection
• ? Inflammatory markers
• in 2nd trimester amniotic fluid in pregnancies
  destined to deliver preterm
• Suggest subclinical infection in chorioamnion
  fetus before presentation of preterm labor

11
Spontaneous Preterm Birth Etiology

• 2nd Trimester Vaginal Bleeding
• ?PROM, RR 15.1
• ? Preterm labor, RR 19.7
• Etiology
• not associated with previa or abruption
• ? Maternal serum AFP
• (consistent with placental hemorrhage)
• ?Inflammatory markers in 2nd trimester
• ?Decidual vascular abnormalities

12
Risk Assessment Can we identify women at high
risk for preterm birth?

• Scoring Systems
• Sensitivity (ability to predict who will deliver
  preterm) of scoring systems lt50
• Positive predictive value (correctly identifying
  those pregnancies at risk) ?20
• Best predictors
• History of prior preterm birth
• Multiple gestation
• Vaginal bleeding in 2nd trimester
• Low pre-pregnancy weight

13
Risk of Preterm Birth in Subsequent Births
Bakketeig LS, Hoffman HJ, 1981
14
Management of Preterm LaborEstablishing the
Diagnosis

• No universal definition of preterm labor
• Frequent contractions ALONE does not define
  preterm labor
• Suggested Definition gt1 criteria meet
• 1. Cervical Change gt 1 cm
• 2. Cervical Dilatation gt 2 cm
• 3. Positive Fibronectin level
• If none of the above are present transvaginal
  cervical length gt3cm very low risk of preterm
  delivery (gt2)

15
Management of Preterm LaborAssessment

• Evaluate for vaginal infection, ruptured
  membranes, fever, etc.
• Detailed history for medical complications which
  may limit or prohibit tocolysis
• Estimate fetal weight, position (ultrasound)
• Intravenous or oral hydration
• Widely used, not supported by trials1,2

1. Helfgott AW, Matern Fetal Med 337, 1994. 2.
Guinn DA, Am J Obstet Gynecol 177814,1997
16
Management of Preterm LaborTocolysis

• No established criteria of when to initiate
• Most common criteria
• Regular uterine contractions plus
• Change in dilatation or effacement
• Cervical dilatation gt3 cm
• ? rate for successful tocolysis
• Goal Delay of 24-48 hours to permit
  corticosteroid therapy or transport to tertiary
  perinatal center

17
Management of Preterm LaborTocolysis

• General Guidelines
• lt 34 weeks begin tocolytics
• 34-37 weeks rarely tocolyze, must individualize
• Cost benefit studies gt 33 weeks, no improvement
  in neonatal survival or decrease in cost with
  tocolysis compared with no intervention
• Assess certainty of data criteria, fetal weight,
  maternal disease, lung maturation

18
Contraindications to Tocolysis
19
Evaluating the Efficacy of Tocolysis

• No uniform criteria to accurately establish the
  diagnosis of preterm labor
• Heterogeneous etiology of preterm labor
• More than one treatment modality likely needed
• Different measures of successful tocolysis
• Delay in delivery to 37 weeks or to 34 weeks
• Delay in delivery for 48 hours (allow
  corticosteroids)
• ?Neonatal morbidity or mortality
• Improved long-term newborn outcomes

20
Tocolysis and Preterm Labor The Drug Options

• Magnesium Sulfate
• ?-mimetic Agents (Ritodrine, Terbutaline)
• Calcium Channel Blockers (Nifedipine)
• Cyclo-oxygenase (COX) inhibitors (Indomethacin)
• Oxytocin antagonists (Atosiban)
• Antibiotics (Intact vs. ruptured membranes)
• Contraindications, Complications and Efficacy

21
Pharmocologic Therapy for Preterm Labor
Contraindications to Magnesium Sulfate
Intravenous administration Load4-6 g 1-4
g/H--titrate to response
22
Complications from Tocolysis with Magnesium
Sulfate

• Toxicity
• Inhibition of myometrial contractility (5-8
  mg/dl)
• Loss of deep tendon reflexes (9-13 mg/dl)
• Respiratory depression (gt13 mg/dl)
• Pulmonary edema (similar to ?-adrenergics)
• ? Twins (?volume expansion) ? Anemia
• ?Urinary output (renal excretion)
• Tocolysis gt24 hours (? colloid oncotic pressure)
• Fluid overload (overhydration)
• Careful attention to fluids decreases risk
• Corticosteroids do not affect risk

23
Magnesium Sulphate for Preventing PTB Cochrane
Meta-analysis 2002 Evaluated 23 RCTs 9 RCTs
included Rx vs Control

Primary outcome RR (95 CI) N
Preterm delivery lt48 Hr Preterm delivery lt37 weeks Preterm delivery lt34 weeks Difference in GA_at_ delivery Perinatal Death CVH 0.85 (0.58, 1.25) 0.91 (0.75, 1.11) 0.82 (0.45, 1.50) -0.43 (1.72, 0.87) 2.82 (1.20, 6.62) 1.07 (0.56, 2.05) 881 424 80 361 727 495
Conclusion Magnesium Sulfate is ineffective at
delaying or preventing preterm birth and its
use is associated with increased mortality for
the infant.
Crowther CA, Hiller JE Doyle LW. Cochrane
Collaboration 2002
24
A RCT of Magnesium Sulfate for Prevention of
Cerebral Palsy

Primary outcome RR (95 CI)
Composite (CP or Death) Moderate/severe Cerebral Palsy (gt 2 yr) Death (stillbirth or infant) 0.91 (0.75, 1.11) 0.55 (0.32, 0.95) 1.12 (0.85, 1.47) 11.3 vs. 11.7 1.9 vs. 3.5 9.5 vs. 8.5
Conclusion Fetal exposure to Magnesium Sulfate
before anticipated Early preterm deliver did not
reduce the combined risk of moderate or severe
cerebral palsy or death, although the rate of
cerebral palsy was reduce in survivors.
Study N 2241, multi-center (20 sites), 22-31
weeks, 6 g load, 2 g/H Rouse DJ, et al. New Eng
J Med 359895-905
25
Pharmocologic Therapy for Preterm Labor
Contraindications to ?-mimetic Agents
Intravenous administration Increase dose every
20-30 min, titrate to response
26
Complications from Tocolysis with Ritrodrine

• Cardiovascular ?1 and ?2
• Hypotension (?2 ), arrhythmias (?1 ), chest pain
  (?1 ),
• Pulmonary edema (?1 and ?2)
• Twins (?volume expansion) Anemia
• Maternal heart rate gt130 beats/min (?1)
• ?Urinary output (? renin-?2)
• Tocolysis gt24 hours (? colloid oncotic pressure)
• Fluid overload (overhydration)
• Careful attention to fluids decreases risk
• Rate in Canadian trial 0.3
• Corticosteroids do not affect risk

27
Treatment of preterm labor with Ritrodine The
Canadian Preterm Labor Investigators Group

• 708 women randomized to ritodrine vs. placebo
  (stratified by gestational age)
• No difference in Perinatal outcome
• Neonatal death (6.1 vs. 6.4)
• Delay in delivery (days or lt 37 weeks)
• Low birth weight infants (lt2500g) or birth weight
• Any neonatal morbidity
• Increased maternal morbidity with ritodrine
• chest pain, arrhythmias
• No significant beneficial effect from ritrodrine

The Canadian Preterm Labor Investigators Group, N
Engl J Med 327308, 1992
28
?-mimetic Agents for Preventing Preterm
BirthCochrane Meta-analysis 2004 Included 17
RCTs 11 with Placebo as Control

Primary outcome RR (95 CI) N
Preterm delivery lt48 Hr Preterm delivery lt7 days Preterm delivery lt37 weeks Perinatal Death RDS Discontinue 2 to adverse reaction Chest pain, dyspnea, tachycardia, tremor, palpitation, headache, NV, hypotension 0.63 (0.53, 0.75) 0.78 (0.68, 0.90) 0.95 (0.88, 1.03) 0.84 (0.46, 1.55) 0.87 (0.71, 1.08) 11.38 (5.21, 24.86) 1209 911 1112 1332 1239 1081
Conclusion ß-mimetics help delay preterm birth
for women transferred to tertiary center or
complete a course of antenatal corticosteroids.
However its use is associated with multiple
adverse effects.
Anotayanonth S, Subhedar NV, Neilson JP, Hargopal
S. Cochrane Collaboration 2004
29
?-mimetic Agents for Maintenance Therapy after
Preterm Labor Cochrane Meta-analysis
2006Included 11 RCTs with Placebo as Control

Primary outcome RR (95 CI) N
Preterm delivery lt37 weeks NICU admission Perinatal mortality IVH Discontinue 2 to adverse reaction Chest pain, dyspnea, tachycardia, tremor, palpitation, headache, NV, hypotension 1.08 (0.88, 1.32) 1.29 (0.64, 2.60) 2.41 (0.86, 6.78) 0.97 (0.27, 3.58) 2.71 (0.11, 64.79) 384 140 681 468 141
Conclusion Available evidence does not support
the use of Oral ß-mimetics For Maintenance
Therapy after threatened Preterm labor.
Dodd JM, Crowther CA, Middleton P. Cochrane
Collaboration 2006
30
Prophylactic Oral ?-mimetic Agents for
preventing PTL in high-risk singleton
pregnanciesCochrane Meta-analysis 2008Included
1 RCTs with Placebo as Control

Conclusion Insufficient evidence to support or
refute the use of Prophylactic oral ß-mimetics
(prior to PTL) For Primary Prevention of Preterm
Labor in Singleton pregnancies at high
risk Preterm labor.
Primary outcome RR (95 CI) N
Onset of Preterm labor lt37 weeks BW lt 2500 g Neonatal mortality Discontinue 2 to adverse reaction Study entry (28-32 wk, Hx PTD or previous infant lt 5 ½ lb) 1.07 (0.14, 8.09) 1.74 (0.44, 6.87) 4.74 (0.50, 45.0) 2.51 (0.59, 10.76) 64 64 64 64
Whitworth M, Siobhan Q. Cochrane Collaboration
2008
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Pharmocologic Therapy for Preterm Labor
Contraindications to Calcium Channel Blockers
oral administration 20-40 mg po load then 10-20
mg every 4-6 hours
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Treatment Protocols for Tocolysis

• Calcium Channel Blockers Nifedipine
• Up to 40 mg orally in 1st hour
• Many loading protocols 10 mg repeat in 15-20
  minutes xs 3 or 4 (total 30 to 40 mg),
• then 10-20 mg every 4-6 hours
• Side effects less than ritodrine
• Maternal flushing, vasodilation

33
Calcium Channel Blockers for Inhibiting Preterm
Labour Cochrane Meta-analysis 2003 Included 12
RCTs with other Tocolytics as Control

Primary outcome RR (95 CI) N
Preterm delivery lt48 Hr Preterm delivery lt7 days Preterm delivery lt34 weeks Preterm delivery lt37 weeks Discontinue 2 to adverse reaction Adverse Maternal drug Reaction 0.80 (0.61, 1.05) 0.76 (0.60, 0.97) 0.83 (0.69, 0.99) 0.95 (0.83, 1.09) 0.14 (0.05, 0.36) 0.32 (0.24, 0.41) 761 453 619 558 833 717
King JF, Papatonis DNM, Dekka GA, Carbonne B.
Cochrane Collaboration 2003
34
Calcium Channel Blockers for Inhibiting Preterm
Labour Cochrane Meta-analysis 2003 Included 12
RCTs 9 used ß-mimetics as Control
Primary outcome RR (95 CI) N
?Mean gestational age _at_ birth (wk) Necrotising Enterocolitis Respiratory Distress Syndrome Intraventricular Hemorrhage Neonatal Jaundice Subanalysis 9 RCT w/ ß-mimetics Preterm delivery lt48 Hr ?Mean birthweight (g) Also ?RDS, ?jaundice 0.70 (0.19, 1.20) 0.21 (0.05, 1.96) 0.63 (0.46, 0.88) 0.59 (0.36, 0.98) 0.73 (0.57, 0.93) 0.72 (0.53, 0.97) 122.7 (3.50, 241.9)

Conclusion When tocolysis is indicated, Calcium
Channel Blockers are preferable to other
tocolytic agents compared, mainly ß-mimetics.
Further research should address effects of
different dosing regimens and formulations.
King JF, Papatonis DNM, Dekka GA, Carbonne B.
Cochrane Collaboration 2003
35
Maintenance Therapy with Calcium Channel Blockers
for preventing PRB after threatened Pretern
Labor Cochrane Meta-analysis 2004 Included 1
RCT with placebo control (excluded 11 trials)

Conclusion The role of maintenance therapy with
Calcium Channel Blockers for preventing preterm
birth is not clear. Well designed trials with
sufficient size are needed.
Primary outcome RR (95 CI) N 74
Preterm delivery lt37 weeks Mean G.A. _at_ birth (wk) Pregnancy prolongation (d) No difference in RDS, SGA, Birthweight, IVH, NEC 1.00 (-1.37, 1.56) 1.00 (-1.36, 1.56) 4.20 (-5.90, 14.30) 35.4 vs. 35.3 37.0 vs. 32.8
Carr DB, Maintenance oral nifedipin for PTL a
RCT. Am J Obstet Gynecol 1999, 181822 Gaunekar
nn, Crowther CA, Carbonne B. Cochrane
Collaboration 2004
36
Pharmocologic Therapy for Preterm Labor
Contraindications to Indomethacin
oral or rectal administration 50 mg rectally,
then 25 mg every 6 H up to 48H
37
Cyclo-oxygenase (COX) Inhibitors

• Prostaglandin Synthesis Inhibitors e.g.
  Indomethacin
• Rectal or oral, crosses placenta
• 50-100 mg rectal suppository loading, 25 mg every
  6 hours for up to 48 hours
• Similar efficacy to ritrodrine in controlled
  trials
• Fetal risk
• Oligohydramnios (?Urinary output)
• Possible primary pulmonary hypertension, IVH
• Limit to 24-32 weeks

38
Cyclo-oxygenase (COX) Inhibitors for Treating
Preterm Labor Cochrane Meta-analysis 2005
Included 13 RCTs 10 used Indomethacin
Primary outcome RR (95 CI) N
Preterm delivery lt37 wk (c.f. placebo) Preterm delivery lt37 wk (c.f. ßmimetic) ?Mean gestational age _at_ birth (placebo) (wk) ?Mean gestational age _at_ birth (ßmimetic) (wk) Perinatal mortality (c.f. placebo) Perinatal mortality (c.f. ßmimetic) Premature PDA Closure (c.f. placebo) Premature PDA Closure (c.f. ßmimetic) Maternal Drug Rxn w/ Cessation Rx (ßmimetic) 0.21 (0.07, 0.62) 0.53 (0.31, 0.94) 3.53 (1.13, 5.92) 0.59 (-0.20, 1.38) 0.80 (0.25, 2.58) 1.46 (0.57, 3.74) Not estimable 3.05 (0.13, 73.39) 0.07 (0.02, 0.29) 36 168 67 411 106 660 106 337 355

Conclusion There is insufficient information to
base decisions about the role of COX inhibition
in preterm labor Further well designed trials are
needed. Review eliminated trials which used
indomethacin when 1 tocolytic therapy failed
King JF, Flenady V, Cole S, Thorton S. Cochrane
Collaboration 2005
39
Effect of Antenatal Indomethacin on Neonatal
Outcomes Meta-analysis 2007 Included 15
Retrospective cohort studies and 6
case-controlled studies.

• Inclusion examined Neonatal outcomes
• Retrospective cohort and Observational studies
• Gestational age lt37 weeks
• Used standard diagnostic criteria for PTL
• Permitted studies with indomethacin after failed
  1 tocolytic therapy, permitted multiple
  combinations of tocolytic Rx, not matched for
  steroid exposure
• Results
• ?Risk Periventricular leukomalacia OR 2.0 (1.3,
  3.1)
• ?Risk Necrotizing enterocolitis OR 2.2 (1.1,4.2)
• No effect on IVH, PDA, RDS, BPD, or mortality

King JF, Flenady V, Cole S, Thorton S. Cochrane
Collaboration 2005
40
Oxytocin Antagonists (Atosiban)

• Mechanism Oxytocin receptor antagonists
• Block oxytocin receptors in myometrium? prevent
  ?Ca2 ? relax myometrium
• Low incidence side effects
• NV, Headache, chest pain, hypotension

41
Oxytocin receptor antagonists for Inhibiting
Preterm Labour Cochrane Meta-analysis 2005
Included 2 RCTs w/ Placebo 4 RCT w/ ßmimetic
Control
Conclusion this review failed to demonstrate
superiority of atosiban over ßmimetics or placebo
in tocolytic efficacy or perinatal outcome. The
finding of increased infant death in one placebo
trial warrants caution.
Primary outcome RR (95 CI) N
Perinatal mortality (c.f. placebo) Infant Death (c.f. placebo) Perinatal mortality (c.f. ßmimetic) Preterm delivery lt37 wk (c.f. placebo) Preterm delivery lt37 wk (c.f. ßmimetic) Mean birth weight (placebo) (g) Mean birth weight (ßmimetic) (g) Mat Drug RxnCessation Rx (placebo) Mat Drug RxnCessation Rx (ßmimetic) 2.25 (0.79, 6.40) 6.15 (1.39, 27.22) 0.66 (0.24, 1.83) 1.017 (0.99, 1.37) 0.90 (0.71, 1.13) -138.3 (-248.8, -27.9) 26.3 (-82.2, 134.8) 4.02 (2.05, 7.85) 0.04 (0.02, 0.11) 583 583 836 501 244 692 836 613 1034
Papatsonis D, Flenady, Cole, Liley H. Cochrane
Collaboration 2005
42
Antibiotic Therapy

• To Prevent Group B Streptococcus
• Should be given to prevent neonatal infection at
  least 4 hours before delivery
• Different from prolongation of latency!
• Without rupture of membranes
• No clear benefit demonstrated to prolong latency
  (time between onset of labor and delivery) with
  antibiotic therapy.
• Antibiotics not recommended in routine preterm
  labor management
• Cochrane Review (Feb 2002)
• American College of Obstetricians Gynecologists
  (2001)
• ORACLE trial

King J. Cochrane Database, Feb 2002
43
ORACLE II Randomize Trial Broad Spectrum
Antibiotics for Spontaneous PTL with Intact
Membranes

• 6295 women randomized to 4 study arms, 80
  received steroids
• Erythromycin 250 mg (n1611)
• Co-amoxiclav (250mg amoxicillin 125 mg
  clavulanic acid) (n1550)
• Both Erythromycin Co-amoxiclav (n1565)
• Placebo (n1569)
• 1Outcome
• Composite measure neonatal death or major
  adverse outcome (chronic lung disease, major
  cerebral abnormality)
• 2 Outcome
• Delivery lt48H, lt7 d, GA _at_ delivery

Kenyon SL, ORACLE Group, Lancet 2001, 357981-90
44
ORACLE II Randomize Trial Broad Spectrum
Antibiotics for Spontaneous PTL with Intact
Membranes Results

• 1. No evidence that any antibiotic regimen
  prolonged pregnancy
• 2. Most women did not deliver lt48H (89.9) or
  lt7days (84.6)
• 3. ? CD wound infection with all antibiotic
  groups (0.7-0.8) c.f. placebo (1.5)
• 4. No difference in median birthweight, in NICU
  admission
• 5. ?proven/suspected NEC with any co-amoxiclav
  (1.4/0.6) c.f. placebo (0.9/0.3) p
  0.0.8/0.06
• 6. No difference in composite outcome rates
• Erythro 5.6 Co-amoxiclav 5.0 Both 5.9
  Placebo 5.0

Conclusion This trail provides evidence that
antibiotics should not be routinely prescribed in
women for spontaneous PTL without evidence of
clinical infection.
Kenyon SL, ORACLE Group, Lancet 2001, 357981-90
45
ORACLE I Randomize Trial Broad Spectrum
Antibiotics for Spontaneous PTL with Ruptured
Membranes

• 4826 women randomized to 4 study arms,
• Erythromycin 250 mg (n1197)
• Co-amoxiclav (250mg amoxicillin 125 mg
  clavulanic acid) (n1212)
• Both Erythromycin Co-amoxiclav (n1192)
• Placebo (n1225)
• Q.i.d. dose for 10 days
• 1Outcome
• Composite measure neonatal death or major
  adverse outcome (chronic lung disease, major
  cerebral abnormality)
• 2 Outcome
• Delivery lt48H, lt7 d, GA _at_ delivery

Kenyon SL, ORACLE Group, Lancet 2001, 357979-88
46
ORACLE I Randomize Trial Broad Spectrum
Antibiotics for Spontaneous PTL with Ruptured
Membranes

• Any Erythro vs. placebo
• 1. ?Composite outcome (singletons) 11.2 vs.
  14.4 (p 0.02)
• 2. ? Delivery lt48H 34.8 vs. 40.7 (p0.004)
• 3. ?surfactant Rx, Use of oxygen gt21d, ?cerebral
  abnormalities, ?blood cultures
• Any Co-amoxiclav vs. placebo
• 1. No difference in composite outcome 13.8 vs.
  14.0
• 2. ? Delivery lt48H 30.9 vs. 37.8 (p0.0001)
• 3. ?suspect/proven NEC 3.8 vs. 2.4 (p0.004)

Conclusion Erythromycin for PROM is associated
with range of health benefits for neonate.
Co-amoxiclav cannot be recommended due to
association with NEC.
Kenyon SL, ORACLE Group, Lancet 2001, 357979-88
47
Childhood Outcomes 7 year follow-up of ORACLE I
Trial Broad Spectrum Antibiotics for PROM

• Follow-up of 4148 children at 7 years for
  outcome 3298 assessed
• -Child health status, functional impairment,
  Educational outcomes (national curriculum tests)
• Any Erythro (/- Co-amoxiclav) vs. placebo
• 1. No difference in functional impairment 38.3
  vs. 38.1
• Any Co-amoxiclav (/- Erythro) vs. placebo
• 1. No difference in functional impairment 40.6
  vs. 38.1

Conclusion The prescription of antibiotics for
women with PROM seems to have little effect on
health of children at 7 years of age.
Kenyon SL, ORACLE Group, Lancet 2008, 1310
48
Glucocorticosteroid Therapy

• All women at risk of preterm delivery at 24-34
  weeks of gestations should receive corticosteroid
  therapy regardless of fetal gender, race or
  availablity of surfactant therapy.
• ? 50 Reduction in
• Respiratory distress syndrome
• Periventricular hemorrhage
• Necrotizing enterocolitis
• Neonatal mortality
• If preterm rupture of membranes 24-32 weeks

NIH Consensus Conference on Antenatal Steroids
1994
49
Evaluating the Efficacy of Tocolysis SUMMARY

• Calcium channel blockers are recommended for
  tocolytic Rx based on RCTs showing
• Less deliveries lt48H, lt7d c.f. ?-mimetics
• Less discontinuation 2 mat adverse reaction
• Less RDS, IVH and neonatal jaundice
• ß-mimetics help delay preterm birth for women
  transferred to tertiary center or complete a
  course of antenatal corticosteroids. However its
  use is associated with multiple adverse effects.
• No evidence that Magnesium Sulfate is effective
  in delaying or preventing preterm birth and its
  use is associated with increased mortality for
  the infant

50
Evaluating the Efficacy of Tocolysis SUMMARY

• Insufficient evidence for COX inhibitor Rx to
  prevent PTL.
• No evidence to support Atosiban (no advantage
  over ß-mimetics) and may be associated with
  ?infant death.
• No evidence for antibiotic therapy to prevent PTL
  in intact membranes.
• Evidence for Erythromycin to prevent PTB with
  PROM
• No evidence that ß-mimetics are effect in primary
  prevention of PTB in high risk women or in
  maintenance after threatened PTL
• Insufficient evidence for Calcium channel
  blockers in maintenance after threatened PTL

51
(No Transcript)
52
Risk Assessment Can we identify women at high
risk for preterm birth?

• Routine Cervical Examination
• Digital examination to identify early cervical
  dilatation not helpful
• If 1 cm cervical dilatation lt30 wk 20 risk PTB
• Large randomized trial (n5600) showed routine
  cervical examination not beneficial to predict or
  assess risk of preterm birth.
• Methods
• Bishops Score (effacement, dilatation, station,
  softness, position) gt 4
• Cervical Score (Cervical length - dilatation) lt
  1.5

53
Relative Risk of Preterm Delivery according to
percentiles of transvaginal cervical length at 24
weeks
Relative Risk of at or below percentile compared
to gt75th Percentile
Percentile
Cervical length 1.3 2.2 2.6
3.0 3.5 4.0 (mm)
Iams JD, NICHD, N Engl J Med 334567-72, 1996
54
Risk Assessment Can we identify women at high
risk for preterm birth?

• Routine Transvaginal Ultrasound
• Not useful as screening tool in asymptomatic
  women to predict who will deliver
• In symptomatic women with preterm contractions, a
  cervical length gt 30 mm has a NPV of 98-99
• Correctly identifies those who will NOT deliver
  within 2 weeks

55
Ultrasound and Digital Exam at 24 weeks to
predict spontaneous preterm birth lt35 weeks in
low risk population
N2916
Iams JD, N Engl J Med 334567, 1996 and Newman
RB, J Soc Gynecol Invest 4152A, 1997
56
Risk Assessment Can we identify women at high
risk for preterm birth?

• Fetal Fibronectin (cervical, 24-34 wk)
• Not useful as screening tool in asymptomatic
  women to predict who will deliver
• FFN, With prior preterm birth
• PPV 46, specificity 52, NPV 94
• FFN, with no prior preterm birth PPV 13
• In symptomatic women, a negative FFN correctly
  identifies those who will NOT deliver within 2
  weeks NPV 98-99

57
Probability of Spontaneous Preterm Birth
(lt35 wk) in parous women based on prior PTB,
cervical length and fibronectin at 24 weeks
Cervical length at 24 wk
Iams JD, Am J Obstet Gynecol 1781035, 1998
58
Risk Factors for Indicated Preterm Birth

• Rate 27.7 in a prospective study (n2929)
• Independent risk factors ORs
• Mullerian duct anomaly 7.02
• Proteinuria lt24 weeks 5.85
• Chronic hypertension 4.06
• Prior indicated preterm birth 2.79
• Lung disease 2.52
• Prior spontaneous preterm birth 2.45
• Age gt30 years 2.42
• African American 1.56
• Working during pregnancy 1.49
• Alcohol use 0.35

Meis PJ, Am J Obstet Gynecol 178562, 1998
59
Risk Factors for Indicated Preterm Birth

• NICHD Preterm Birth Prediction Study (n2929)
• 15.3 of Preterm Births,
• of which, 27.7 were indicated
• Most common diagnosis Percent Proteinuria
  lt24 weeks 42.5
• Fetal Distress 26.7
• IUGR 10.0
• Abrupio Placenta 6.7
• Fetal demise 6.7
• (Other causeshyperthyroidism, heart disease,
  cholestasis, appendicitis, pyelonephritis,
  cocaine)

Meis PJ, Am J Obstet Gynecol 178562, 1998