PRETERM LABOR HOW CAN WE DO A BETTER JOB?. BACKGROUND Preterm defined as < 37 weeks Preterm defined as < 37 weeks PTD has continued to increase (until

PRETERM LABORPRETERM LABOR

HOW CAN WE DO A HOW CAN WE DO A BETTER JOB?BETTER JOB?

BACKGROUNDBACKGROUND

• Preterm defined as < 37 weeksPreterm defined as < 37 weeks• PTD has continued to increase PTD has continued to increase

(until recently?)(until recently?)• 1/8 births are preterm1/8 births are preterm• Earlier delivery associated with Earlier delivery associated with

increased risk of death and increased risk of death and disabilitydisability

• Leading cause of neonatal deaths Leading cause of neonatal deaths since 2001since 2001

Magnitude of the Magnitude of the ProblemProblem

• Definition (< 37 weeks)Definition (< 37 weeks)

• 2004: more than 500,000 2004: more than 500,000

neonates were born pretermneonates were born preterm

• Frequency: 12.5 % Frequency: 12.5 %

The Lancet Editorial 2006;368:339

Frequency of preterm Frequency of preterm birth by gestational age birth by gestational age

(1995-2000)(1995-2000)

• < 28 weeks : 0.82 %< 28 weeks : 0.82 %

• < 32 weeks: 2.2 % < 32 weeks: 2.2 %

• 33-36 weeks: 8.9 %33-36 weeks: 8.9 %

• < 37 weeks: 12.5%< 37 weeks: 12.5%

IOM Report-July 2006- page 72/2006Alexander GR et al 2006 (under review)

Survival by gestational age among live-born resuscitated infants

Mercer BM Obstet Gynecol 2003;101:178 –93.

Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

Acute morbidity by gestational age among surviving infants

Mercer BM Obstet Gynecol 2003;101:178 –93.

Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

BACKGROUNDBACKGROUND

• Preterm delivery accounts forPreterm delivery accounts for– 1 in 5 cases of mental retardation1 in 5 cases of mental retardation– 1 in 3 cases of visual impairment1 in 3 cases of visual impairment– 1 in 2 cases of cerebral palsy1 in 2 cases of cerebral palsy

• Also increases risk for adult diseasesAlso increases risk for adult diseases– MIMI– StrokeStroke– HypertensionHypertension– DiabetesDiabetes– ? cancer? cancer

Complications of “Late Complications of “Late Preterm or Near Term Preterm or Near Term

Infants”Infants”

• Cold StressCold Stress

• HypoglycemiaHypoglycemia

• RDSRDS

• JaundiceJaundice

• SepsisSepsis

IOM Report-July 2006- page 72/2006

Institute of Medicine of the National Academies, 2006

Richard E. Behrman, Adrienne Stith Butler, Editors

Institute of Medicine Report Preterm Birth: Causes, Consequences,

and Prevention

IOM Report – July 2006IOM Report – July 2006

• ““Babies born before 32 weeks have the Babies born before 32 weeks have the

greatest risk for death and poor health greatest risk for death and poor health

outcomes, however, infants born between 32 outcomes, however, infants born between 32

and 36 weeks, which make up the greatest and 36 weeks, which make up the greatest

number of preterm births, number of preterm births, are still at higher are still at higher

risk for health and developmental problems risk for health and developmental problems

compared to those infants born full term compared to those infants born full term

IOM Report page 72

Magnitude of the Magnitude of the ProblemProblem

• The infant mortality rate for very preterm The infant mortality rate for very preterm

infants (delivered < 32 weeks of gestation) infants (delivered < 32 weeks of gestation)

was 186.4, nearly 75 times the rate for was 186.4, nearly 75 times the rate for

infants born at term (2.5) (37–41 weeks of infants born at term (2.5) (37–41 weeks of

gestation)gestation)

• 20% all infants born <32 weeks do not 20% all infants born <32 weeks do not

survive the first year of lifesurvive the first year of life

Mathews TJ. et al. National Vital Statistics Reports 2004;53:1-32

RISK FACTORSRISK FACTORS

• Multiple gestationsMultiple gestations• Prior PTBPrior PTB• African American raceAfrican American race• SmokingSmoking• Substance abuseSubstance abuse• Poor oral hygienePoor oral hygiene• BMI < 20BMI < 20• Short inter-pregnancy intervalShort inter-pregnancy interval• ? Stress (physical/emotional)? Stress (physical/emotional)

RISK OF PRETERM BIRTHRISK OF PRETERM BIRTH

• Term/termTerm/term 4%4%

• PTD/termPTD/term 12% 12%

• Term/PTDTerm/PTD 23% 23%

• PTD/PTDPTD/PTD 32% 32%Carr-Hol RA BJOG 1985Carr-Hol RA BJOG 1985

• 50% of patients delivery within 1 week50% of patients delivery within 1 week

• 75% of patients delivery within 2 weeks75% of patients delivery within 2 weeks

Frequency of Preterm Birth by Ethnic Group

Source: CDC 2004 Births: Preliminary Data for 2003 http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr_09.pdf (accessed August 30, 2005)

Non-Hispanic African-American 17.8%

American Indians/Native Alaskans 13.5%

Hispanics 11.9%

Whites 11.5%

Asian and Pacific Islanders 10.5%

SERIOUSLY, WHY CAN’T WE FIGURE THIS OUT???

•Many different causes

•Patient demographics are different

•Socioeconomic factors

•Concerns regarding safety of medications

•Inability to do quality studies

The Preterm Parturition Syndrome

UterineUterineOverdistensioOverdistensio

nn

VascularVascular

InfectioInfectionn

Cervical Cervical DiseaseDisease

HormonalHormonal

ImmunologicalImmunological

© VR RR MM

UnknownUnknown

MAKING THE MAKING THE DIAGNOSIS OF DIAGNOSIS OF

PRETERM LABORPRETERM LABOR

CAN WE DO A BETTER JOB?CAN WE DO A BETTER JOB?

PREDICTORS OF PREDICTORS OF PRETERM DELIVERYPRETERM DELIVERY

• Very poorVery poor

• Often based on prior OB historyOften based on prior OB history– 50% of patients are nulliparous50% of patients are nulliparous

• Sensitivity and specificity are Sensitivity and specificity are lowlow

• Difficult to find interventions Difficult to find interventions that decrease preterm deliverythat decrease preterm delivery

PRETERM LABORPRETERM LABORMANAGEMENT GOALSMANAGEMENT GOALS

• Identify those at highest riskIdentify those at highest risk

• Eliminate those at a lower riskEliminate those at a lower risk

• Maximize condition of the fetus at Maximize condition of the fetus at birthbirth– short term tocolysis (neuroprotection?)short term tocolysis (neuroprotection?)– antenatal corticosteroidsantenatal corticosteroids– antibiotics to prevent early infectionantibiotics to prevent early infection– prevent birth trauma / asphyxiaprevent birth trauma / asphyxia

PRETERM LABORPRETERM LABORDIAGNOSISDIAGNOSIS

Gestational age 20 - 37 weeks Gestational age 20 - 37 weeks

with regular uterine contractionswith regular uterine contractions

andand

Ruptured membranes or intact membranesRuptured membranes or intact membranes

- cervical change- cervical change

- > 80% effaced- > 80% effaced

- - >> 2 cm. dilated 2 cm. dilated

DIAGNOSISDIAGNOSIS

• May be difficultMay be difficult

• Placebo/false labor 50+% of Placebo/false labor 50+% of

patientspatients

• Try to make diagnosis earlyTry to make diagnosis early– more successful tocolysismore successful tocolysis

– allow transfer to regional centerallow transfer to regional center

– maximize condition of fetus at birthmaximize condition of fetus at birth

PRETERM PREDICTORSPRETERM PREDICTORSOVERVIEWOVERVIEW

• None have stood the test of timeNone have stood the test of time

• 2 proven options2 proven options– ultrasound cervical lengthultrasound cervical length– fetal fibronectin (fFN)fetal fibronectin (fFN)

• Good at ruling out PTL (useful Good at ruling out PTL (useful NPV)NPV)

• PPV less usefulPPV less useful

Source: Iams JD et al. N Engl J Med. 1996;334:567-572.

Preterm Delivery <35 Weeks

Risk of PTD by Cervical Length

Pro

bab

ilit

y o

f P

rete

rm D

eliv

ery 0.5

0.4

0.3

0.2

0.1

0.0

0 20 40 60 80

Cervical Length (mm)

Cervix

NORMAL CERVIX

Fetal Head

CERVICAL LENGTH

•Most of the data for cervical length is in asymptomatic patients

•Not as much experience using in triaging of patients

•Limited accessibility, especially after hours

•Significant cost/charges•Delay in obtaining results

CERVICAL LENGTH

•Charges are variable between institutions.

•Costs, now that’s a whole nother matter

•At our 2 offices, charges are- $259.00- $380.00

Amnion

Chorion

FetalFibronectin

Decidua

Fetal Fibronectin

FETAL FIBRONECTINFETAL FIBRONECTINDOING THE TESTDOING THE TEST

• User friendly, all inclusive kitsUser friendly, all inclusive kits

• Normal speculum examinationNormal speculum examination

• Dacron swab in posterior fornix 10 Dacron swab in posterior fornix 10

sec.sec.

• Place in buffered solutionPlace in buffered solution

• Send to labSend to lab

Specimen Collection for fFN Testing

Lightly rotate swab across either the posterior fornix of the vagina or the ectocervical region of the external cerical os for 10 seconds.


Remove swab and immerse Dacron® tip in buffer

Break the shaft even with the top of the tube (at the score)


Align the shaft with the hole inside the tube cap and push down tightly over the shaft to seal the tube

Test Results

Rapid fFN for the TLi™ System

Analyzer produces results in 20 to 30 minutes

Around-the-clock availability

Moderately complex—requires CLIA approved laboratory

fFN Enzyme Immunoassay

24-hour turnaround through central laboratory

FETAL FIBRONECTINFETAL FIBRONECTINHOW GOOD IS IT?HOW GOOD IS IT?

• Multicenter trialMulticenter trial

• 763 symptomatic patients763 symptomatic patients

• Investigators blinded to resultsInvestigators blinded to results

• Treatment as deemed clinically Treatment as deemed clinically

indicatedindicated

• fFN gathered prior to examinationfFN gathered prior to examination

Peaceman et al, AJOG 1997;177:13-18

FETAL FIBRONECTINFETAL FIBRONECTINHOW GOOD IS IT?HOW GOOD IS IT?

Outcome (+) fFN (n = 150)

%

(-) fFN (n = 613)

%

Relative risk

Del < 7 d. 13.3 0.5 27.1

Del < 14 d. 16.7 0.8 20.4

BWT < 2500 38.0 11.2 3.4

NICU admit 29.3 11.1 2.6

Peaceman et al, AJOG 1997;177:13-18

Sum of the cost of steroids, tocolytics and hospitalization and the machine

To treat 91 patients without testing is approximately $106,000.00

To test and treat selectively is approximately $39,500.00

Estimation of Cost Estimation of Cost EffectivenessEffectiveness

..

CONCLUSIONSCONCLUSIONS

•Fetal Fibronectin testing is Fetal Fibronectin testing is reliable and can be used reliable and can be used effectively as an aid for the effectively as an aid for the diagnosis of preterm labordiagnosis of preterm labor

•The cost of avoidable The cost of avoidable admissions and treatment for admissions and treatment for those testing negative those testing negative outweighs the cost of the test.outweighs the cost of the test.

FETAL FIBRONECTINFETAL FIBRONECTINEFFECT ON TRANSPORTSEFFECT ON TRANSPORTS• 18 month prospective study18 month prospective study

• 9 referring hospitals, 1 university 9 referring hospitals, 1 university centercenter

• 151 patients with presumptive PTL151 patients with presumptive PTL

• 45 patients (30%) had (+) fFN45 patients (30%) had (+) fFN

• 25% delivered within 7 days25% delivered within 7 days

• 2% of (-) fFN’s delivered within 7 2% of (-) fFN’s delivered within 7 daysdays

FETAL FIBRONECTINFETAL FIBRONECTINEFFECT ON TRANSPORTSEFFECT ON TRANSPORTS• 90% of patients with a (-) fFN were 90% of patients with a (-) fFN were

not transportednot transported

• Cost savings: over $30,000 for Cost savings: over $30,000 for transports alonetransports alone

• Mean length of stay for Mean length of stay for antepartum: 7 daysantepartum: 7 days– Average hospital savings: > $150,000 Average hospital savings: > $150,000

• Cost of fFN tests: $5,000Cost of fFN tests: $5,000

FETAL FIBRONECTINFETAL FIBRONECTINPOSITIVE TESTS??POSITIVE TESTS??

• Unclear what is the best strategyUnclear what is the best strategy

• Many unproven optionsMany unproven options– bedrestbedrest– prophylactic tocolyticsprophylactic tocolytics– screen and treat for lower genital screen and treat for lower genital

infectionsinfections– antenatal corticosteroidsantenatal corticosteroids– close follow up and ongoing dialogueclose follow up and ongoing dialogue

COMBINATION COMBINATION APPROACHAPPROACH

(Goldenberg RL, Iams JD, AJOG (Goldenberg RL, Iams JD, AJOG 2000;182:636-43)2000;182:636-43)

• Serial fFN and cervical length in 2929 Serial fFN and cervical length in 2929 patientspatients

• Observational studyObservational study• Multiple exams and combination of Multiple exams and combination of

resultsresults• SummarySummary

– Isolated short cervix or (+) fFN increased Isolated short cervix or (+) fFN increased risk of PTB above baseline by factor of risk of PTB above baseline by factor of approximately 4approximately 4

– Both being abnormal increased risk by Both being abnormal increased risk by about 25about 25

COMPARISON OF TESTSCOMPARISON OF TESTS(Goldenberg RL, Iams JD, AJOG (Goldenberg RL, Iams JD, AJOG

2000;182:636-43)2000;182:636-43)

ModalityModality RRRR

(+) fFN and short cervix(+) fFN and short cervix 2525

(+) fFN alone(+) fFN alone 4.04.0

(+) short cervix alone(+) short cervix alone 4.04.0

* Of patients with a (+) fFN and short * Of patients with a (+) fFN and short cervix at 24-26 weeks, over 60% cervix at 24-26 weeks, over 60% delivered prior to 35 weeksdelivered prior to 35 weeks

AHRQ EVIDENCE REPORTAHRQ EVIDENCE REPORTDecember 2002December 2002

• Two biologic markers (fFN &EVUSD) Two biologic markers (fFN &EVUSD) are useful in identifying women in are useful in identifying women in PTL who are at a low risk of PTL who are at a low risk of experiencing a PTBexperiencing a PTB

• Certain tocolytics (beta-mimetics, Certain tocolytics (beta-mimetics, magnesium, calcium channel magnesium, calcium channel blockers, NSAID’s) appear effective in blockers, NSAID’s) appear effective in prolonging pregnancyprolonging pregnancy

• Beta-mimetics have a higher risk of Beta-mimetics have a higher risk of maternal harmmaternal harm

PROTOCOL(Mine anyway)

• Cervical length in high risk patients prior to 24 weeks

• Fetal fibronectin 24-34 weeks who are symptomatic for preterm labor

• Cervical length if fetal fibronectin (+) and no significant dilatation

• If short cervix is incidental finding, fetal fibronectin

PROTOCOL(Mine anyway)

• Steroids for maturity if fFN positive and cervix is short

• Observation if only one is abnormal

• Magnesium for tocolysis if necessary

• Repeat steroids if > 14 days from initial course and < 33 weeks

• Magnesium for neuroprotection until 32 weeks

INTRAPARTUMSTUFF

•Tocolytics

•Magnesium for neuroprotection

•Repeat steroids

LET’S TALKTOCOLYTICS!

MAGNESIUM VS. MAGNESIUM VS. NIFEDIPINENIFEDIPINE

• 192 patients randomized to 192 patients randomized to magnesium vs. nifedipinemagnesium vs. nifedipine

• 24 to 33 weeks24 to 33 weeks

• Magnesium: 4 gm bolus then 2 gm/hrMagnesium: 4 gm bolus then 2 gm/hr

• Nifedipine: 10 mg every 20 minutes x Nifedipine: 10 mg every 20 minutes x 3 then 20 mg every 4-6 hours3 then 20 mg every 4-6 hours

• Maintenance tocolysis at attending Maintenance tocolysis at attending discretiondiscretion

Lyell DJ Obstet Gynecol 2007;110:61-7

MAGNESIUM VS. MAGNESIUM VS. NIFEDIPINENIFEDIPINE


MAGNESIUM VSMAGNESIUM VSNIFEDIPINENIFEDIPINE

• No difference No difference – Delivery at < 48 hoursDelivery at < 48 hours– Delivery at < 32 weeks, 37 weeksDelivery at < 32 weeks, 37 weeks– EGA at deliveryEGA at delivery– Birth weightBirth weight– Recurrent preterm laborRecurrent preterm labor

• Shorter time to uterine quiescence with Shorter time to uterine quiescence with nifedipinenifedipine

• Slightly longer length of stay for infants in Slightly longer length of stay for infants in magnesium groupmagnesium group

• More maternal side effects in magnesium More maternal side effects in magnesium group but none life threateninggroup but none life threatening


REVIEW OF STUDIES SUGGESTING

MAGNESIUM IS NEUROPROTECTIVE

REVIEW OF MAG AND REVIEW OF MAG AND CP STUDIESCP STUDIES

FAVORING REDUCTIONFAVORING REDUCTION

SchendelSchendel JAMA 1996JAMA 1996

Grether Grether J Pediatr 1996J Pediatr 1996BoyleBoyle Am J Epidemiol 2000Am J Epidemiol 2000MatsudaMatsuda Euro J OB, GYN, Reprod 2000Euro J OB, GYN, Reprod 2000MurataMurata Brain & Develop 2005Brain & Develop 2005

AGAINST REDUCTIONAGAINST REDUCTIONPanethPaneth Pediatrics 1997Pediatrics 1997CanterinoCanterino OB/GYN 1999OB/GYN 1999GretherGrether AJOG 2000AJOG 2000

PROSPECTIVE STUDIESSUPPORTING MAGNESIUM

FORNEUROPROTECTION

ACTOMgSO4ACTOMgSO4– 1062 patients1062 patients

PreMagPreMag– 573 patients573 patients

Beam TrialBeam Trial– >2200 patients>2200 patients

SUMMARYSUMMARY

• Fairly clear that magnesium is Fairly clear that magnesium is neuroprotectiveneuroprotective

• Beneficial until 28-32 weeksBeneficial until 28-32 weeks• Optimal dosing is still unclearOptimal dosing is still unclear• RecommendRecommend

– 4 gram bolus4 gram bolus– Followed by 2 gram/hour infusionFollowed by 2 gram/hour infusion

• Try to wait 2 hours, if possibleTry to wait 2 hours, if possible• Continue until deliveryContinue until delivery

STEROIDSSTEROIDSBACKGROUNDBACKGROUND

• As early as the 1960’s, it was known As early as the 1960’s, it was known that steroids decrease RDS in animalsthat steroids decrease RDS in animals

• 1972 landmark study by Liggins/Howie1972 landmark study by Liggins/Howie– 2 doses of betamethasone2 doses of betamethasone– Reduced RDS from 15+% to 10%Reduced RDS from 15+% to 10%– Reduced mortality from 11+% to 6%Reduced mortality from 11+% to 6%

• Most of benefit in those 28-34 weeksMost of benefit in those 28-34 weeks• How long do they last?How long do they last?• Why no benefit after 34 weeks?Why no benefit after 34 weeks?


• Other studies confirmed findingsOther studies confirmed findings• Steroids slow to be implementedSteroids slow to be implemented• Study in 1992 showed less than 50% Study in 1992 showed less than 50%

of preterm infants received steroidsof preterm infants received steroids• In 1994, NIH released first consensus In 1994, NIH released first consensus

statement on steroidsstatement on steroids• Area of further researchArea of further research

– Repeat steroidsRepeat steroids– How long do they lastHow long do they last


• In 2000, NIH released their 2In 2000, NIH released their 2ndnd (and last) consensus statement(and last) consensus statement

• Repeat steroids should only be Repeat steroids should only be given to patient’s enrolled in a given to patient’s enrolled in a randomized controlled trial with randomized controlled trial with informed consent and in a dose informed consent and in a dose so as to minimize exposure of so as to minimize exposure of both the mother and fetusboth the mother and fetus

HOW LONG IS THE HOW LONG IS THE BENEFIT?BENEFIT?

• Retrospective chart reviewRetrospective chart review

• 197 infants received steroids197 infants received steroids– 98 delivered within 7 days98 delivered within 7 days– 99 delivered after 7 days99 delivered after 7 days

• Matched for everythingMatched for everything– RaceRace Payer mixPayer mix– GenderGender Route of deliveryRoute of delivery– EGA at deliveryEGA at delivery Birth weightBirth weight

Peaceman et al AJOG 2005;193:1165-9Peaceman et al AJOG 2005;193:1165-9

HOW LONG IS THE HOW LONG IS THE BENEFIT?BENEFIT?

DeliveryDelivery

< 7 days< 7 daysDelivery Delivery

> 7 days> 7 daysPP

Ventilation or Ventilation or CPAPCPAP

> 24 hours> 24 hours

63%63% 81%81% < 0.01< 0.01

Surfactant useSurfactant use 39%39% 47%47% .28.28

O2 at 28 daysO2 at 28 days 23%23% 22%22% .92.92

NEC, IVH, or NEC, IVH, or sepsissepsis

31%31% 28%28% .56.56

Length of stayLength of stay 34 days34 days 38 days38 days .80.80

Peaceman et al AJOG 2005;193:1165-9Peaceman et al AJOG 2005;193:1165-9

FINALLY, THE MEAT:FINALLY, THE MEAT:WHAT ABOUT A REPEAT DOSE?WHAT ABOUT A REPEAT DOSE?

• Now, 4 randomized controlled trials in Now, 4 randomized controlled trials in the literature looking at thisthe literature looking at this– Guinn 2001 (N = 502)Guinn 2001 (N = 502)– Wapner 2006 (N= 556)***Wapner 2006 (N= 556)***– Crowther 2006 (N= 1047)Crowther 2006 (N= 1047)– Garite 2009 (N= 437)Garite 2009 (N= 437)

• All suggest a modest reduction in All suggest a modest reduction in RDSRDS

• No improvement in other morbidities No improvement in other morbidities or in mortalityor in mortality– *** non-significant increase in CP at age 2*** non-significant increase in CP at age 2

IMPACT OF A ‘RESCUE IMPACT OF A ‘RESCUE COURSE’ COURSE’

OF STEROIDSOF STEROIDS• Multi-center randomized placebo trialMulti-center randomized placebo trial• 437 patients437 patients

– 223 in repeat group223 in repeat group– 214 in single course214 in single course

• Included multiple gestations (N = 141)Included multiple gestations (N = 141)• 25 to 33 weeks25 to 33 weeks• Randomized ifRandomized if

– Received 1Received 1stst course > 14 days earlier course > 14 days earlier– High likelihood of delivering in next 7 daysHigh likelihood of delivering in next 7 days

Garite et al AJOG 2009;200:248.e1-248.e9Garite et al AJOG 2009;200:248.e1-248.e9

IMPACT OF A ‘RESCUE IMPACT OF A ‘RESCUE COURSE’COURSE’

OF STEROIDSOF STEROIDS• No difference in demographicsNo difference in demographics• Significant reduction inSignificant reduction in

– Composite morbidity (44% vs 66%)Composite morbidity (44% vs 66%)– RDS (41% vs 61%)RDS (41% vs 61%)– Surfactant use (38% vs 55%)Surfactant use (38% vs 55%)– Ventilation (38% vs 53%)Ventilation (38% vs 53%)

• No difference in mortality or No difference in mortality or other significant morbidities other significant morbidities

Garite et al AJOG 2009;200:248.e1-248.e9Garite et al AJOG 2009;200:248.e1-248.e9

WHAT IS THE RISK OF WHAT IS THE RISK OF SEVERE RDS IN LEGACY SEVERE RDS IN LEGACY

NICU?NICU?• Let’s look at 30-32 weeksLet’s look at 30-32 weeks

• Northwest Newborn uses a lot of Northwest Newborn uses a lot of “gentler ventilation” i.e. nasal “gentler ventilation” i.e. nasal CPAPCPAP

• From 30-32 weeksFrom 30-32 weeks– About 1/3 do not require respiratory About 1/3 do not require respiratory

supportsupport– Failed CPAP is about 15%Failed CPAP is about 15%

WHAT IS THE RISK OF WHAT IS THE RISK OF SEVERE RDS IN OUR NICU?SEVERE RDS IN OUR NICU?

• So for counselingSo for counseling– 30% require no respiratory support30% require no respiratory support– 55-60% require nasal CPAP (duration 55-60% require nasal CPAP (duration

usually 2-6 days)usually 2-6 days)– About 15% require surfactant along with About 15% require surfactant along with

short term mechanical ventilationshort term mechanical ventilation

• In the VON, the rate is about 35%In the VON, the rate is about 35%

• Thus, the reason for limiting repeat Thus, the reason for limiting repeat steroids to those < 30 weekssteroids to those < 30 weeks

SUMMARYSUMMARY

• Steroid benefit probably does Steroid benefit probably does have limited time of efficacyhave limited time of efficacy

• Most studies consistently show Most studies consistently show this to be about 7-14 daysthis to be about 7-14 days

• Main benefit is in reduction of Main benefit is in reduction of short term respiratory short term respiratory complicationscomplications

• No reduction in death or serious No reduction in death or serious morbidities (severe IVH, NEC…)morbidities (severe IVH, NEC…)

SUMMARYSUMMARY

•Risk of severe RDS, chronic Risk of severe RDS, chronic lung disease is low after 30 lung disease is low after 30 weeksweeks

•Still some lingering concern Still some lingering concern about long term problems about long term problems with repeat doseswith repeat doses

•Consider giving repeat Consider giving repeat course up to 32-33 weekscourse up to 32-33 weeks

CAN WE PREVENT PRETERM BIRTH?

WHAT HAS BEEN TRIED?WHAT HAS BEEN TRIED?

• BedrestBedrest

• Prophylactic tocolyticsProphylactic tocolytics

• Prophylactic cerclageProphylactic cerclage

• HUAMHUAM

•PROGESTERONE!!PROGESTERONE!!

THE THE BANDWAGONBANDWAGON

NEVER BE THE 1NEVER BE THE 1STST ONE ONE

ON THE BANDWAGONON THE BANDWAGON

NORNOR

THE LAST ONE OFF IT!!THE LAST ONE OFF IT!!

PROGESTERONE STUDIESPROGESTERONE STUDIES

• Early studies with mixed resultsEarly studies with mixed results• Lumped SAB, PTL…. togetherLumped SAB, PTL…. together• Various progestational agentsVarious progestational agents• High risk vs. low riskHigh risk vs. low risk• Timing of initiation of therapyTiming of initiation of therapy• Risk of anomaliesRisk of anomalies

– Prior scaresPrior scares• DESDES• Repeat steroidsRepeat steroids• ThalidomideThalidomide• SSRI’sSSRI’s• TRHTRH• Continuous fetal monitoringContinuous fetal monitoring• MagnesiumMagnesium• IV alcoholIV alcohol

PROGESTERONE STUDIESPROGESTERONE STUDIES

• Studies currently usingStudies currently using– 17 hydroxyprogesterone caproate17 hydroxyprogesterone caproate– Vaginal progesterone 100 mg per dayVaginal progesterone 100 mg per day– Vaginal progesterone 200 mg per dayVaginal progesterone 200 mg per day– Vaginal progesterone 90 mg/dayVaginal progesterone 90 mg/day

• Limited randomized placebo Limited randomized placebo controlled trials (4 published)controlled trials (4 published)

Prevention of recurrent PTL by 17 Prevention of recurrent PTL by 17 alpha-hydroxyprogesterone alpha-hydroxyprogesterone

caproatecaproateNEJM June 2003 pp2379-2385NEJM June 2003 pp2379-2385

• Randomized prospective placebo Randomized prospective placebo controlled trialcontrolled trial

• Over 450 patients with 2:1 ratio Over 450 patients with 2:1 ratio of progesterone to placeboof progesterone to placebo

• All had prior preterm birthAll had prior preterm birth

• Singleton fetusSingleton fetus

• No significant medical problemsNo significant medical problems



• Initial part of study involving 150 Initial part of study involving 150 patients terminated due to violation patients terminated due to violation of manufacturing processof manufacturing process

• 86 completed treatment86 completed treatment– 57 (61%) with 17-P57 (61%) with 17-P– 29 (39%) with placebo29 (39%) with placebo

• Delivery at < 37 weeksDelivery at < 37 weeks– 17-P17-P 43%43%– PlaceboPlacebo 38%38%



CharacteristiCharacteristicc

ProgesteronProgesteronee

PlaceboPlacebo RRRR

# of PTD# of PTD 1.41.4 1.61.6 NSNS

Del. < 37 Del. < 37 wkswks

(%)(%)

36.336.3 54.954.9 0.660.66


(%)(%)

20.620.6 30.730.7 0.670.67


(%)(%)

11.411.4 19.619.6 0.580.58

IVH (%) IVH (%) 1.31.3 5.45.4 0.250.25

NEC (%)NEC (%) 0.00.0 2.62.6 NSNS

FDA ADVISORY PANELFDA ADVISORY PANELCOMMENTSCOMMENTS

Pregnancy Pregnancy outcomeoutcome

17-P17-P

N, (%)N, (%)PlaceboPlacebo

N, (%)N, (%)NominalNominal

P valueP value

SAB < 20 wksSAB < 20 wks 5 (1.6)5 (1.6) 00 0.170.17

StillbirthStillbirth 6 (2.0)6 (2.0) 2 (1.3)2 (1.3) 0.720.72

AntepartumAntepartum 5 (1.6)5 (1.6) 1 (0.6)1 (0.6) --------

IntrapartumIntrapartum 1 (0.3)1 (0.3) 1 (0.6)1 (0.6) --------

Neonatal deathsNeonatal deaths 8 (2.6)8 (2.6) 9 (5.9)9 (5.9) 0.120.12

Total deathsTotal deaths 19 (6.2)19 (6.2) 11 (7.2)11 (7.2) 0.690.69


• No difference in Apgar scores, No difference in Apgar scores, congenital malformations, median days congenital malformations, median days in NICU (9.1 vs 14.1), mean days in in NICU (9.1 vs 14.1), mean days in hospital (9.1 vs 14.1), and mean hospital (9.1 vs 14.1), and mean birthweight, and birthweight < 1500 birthweight, and birthweight < 1500 gms (8.6% vs 13.9%)gms (8.6% vs 13.9%)

• Percentage of babies < 2500 gms was Percentage of babies < 2500 gms was less in the 17-P group (27.2% vs 41.1%)less in the 17-P group (27.2% vs 41.1%)


• If adjusted for multiple comparisons, If adjusted for multiple comparisons, it is unlikely that any of the listed it is unlikely that any of the listed morbidities would have been morbidities would have been statistically lower in the 17-P groupstatistically lower in the 17-P group

• The composite neonatal morbidity The composite neonatal morbidity score, though numerically lower in score, though numerically lower in the 17-P group, it did not reach the 17-P group, it did not reach statistical significancestatistical significance

Prophylactic administration of Prophylactic administration of progesterone by vaginal suppositoriesprogesterone by vaginal suppositories

AJOG 2003;188:419-424AJOG 2003;188:419-424

• 142 high risk patients (mostly a 142 high risk patients (mostly a prior preterm birth)prior preterm birth)

• Randomized to daily suppository of Randomized to daily suppository of 100 mg progesterone vs. placebo100 mg progesterone vs. placebo

• Delivery: Progesterone PlaceboDelivery: Progesterone Placebo

< 37 wks 13.8% 28.5%< 37 wks 13.8% 28.5%

< 34 wks< 34 wks 2.8% 18.6% 2.8% 18.6%

PROGESTERONE GEL FOR PROGESTERONE GEL FOR RECURRENT PRETERM BIRTHRECURRENT PRETERM BIRTH

• Randomized placebo controlled Randomized placebo controlled trial of 659 patientstrial of 659 patients– 328 placebo328 placebo– 331 Prochieve (8% progesterone)331 Prochieve (8% progesterone)

• 60% in each group had prior 60% in each group had prior delivery at < 32 weeksdelivery at < 32 weeks

• No demographic differencesNo demographic differences

O’Brien JM Ultra OB/GYN, 2007;30(5):687

PROGESTERONE GEL FOR RECURRENT PRETERM

BIRTH•No difference between groups in:

– Mean gestational age at delivery– Deliveries < 37 weeks– Deliveries < 32 weeks– Mean birthweight– Neonatal morbidity– Neonatal mortality

O’Brien JM Ultra OB/GYN, 2007;30(5):687

META-ANALYSISMETA-ANALYSISMackenzie R. AJOG, 2006:194;1234Mackenzie R. AJOG, 2006:194;1234

• Progestational agents initiated in Progestational agents initiated in the 2the 2ndnd trimester reduce the risk of trimester reduce the risk of delivery at < 37 weeks but no delivery at < 37 weeks but no effects of perinatal outcomeseffects of perinatal outcomes

• Treatment with progestational Treatment with progestational agents should continue to be agents should continue to be limited to women enrolled in well-limited to women enrolled in well-designed randomized controlled designed randomized controlled trialstrials

TWINS AND 17-PTWINS AND 17-PRouse D, NEJM 2007;357:454Rouse D, NEJM 2007;357:454

• 655 sets of twins655 sets of twins– 325 17-P325 17-P– 330 placebo330 placebo

• Enrolled between 16.0 and 20.3 weeksEnrolled between 16.0 and 20.3 weeks• No other complicationsNo other complications• Nearly 50% nulliparousNearly 50% nulliparous• < 10% had prior PTB< 10% had prior PTB• 2/3’s spontaneous2/3’s spontaneous• 80% di-di placentation80% di-di placentation

TWINS AND 17-PTWINS AND 17-PRouse D, NEJM 2007;357:454Rouse D, NEJM 2007;357:454

• Delivery at < 35 weeksDelivery at < 35 weeks– 41% in 17-P41% in 17-P– 37% in placebo37% in placebo

• Composite neonatal morbidityComposite neonatal morbidity– 20.2% in 17-P20.2% in 17-P– 18.0% in placebo18.0% in placebo

• No improvement in outcomes No improvement in outcomes when using 17-P in twinswhen using 17-P in twins

SHORT CERVIX AND SHORT CERVIX AND VAGINAL PROGESTERONEVAGINAL PROGESTERONE

Fonseca, NEJM. 2007;357:462Fonseca, NEJM. 2007;357:462

• 413 patients with TVUSCL 413 patients with TVUSCL << 15 15 mmmm– 250 vaginal PG @ 200 mg nightly250 vaginal PG @ 200 mg nightly– 163 placebo163 placebo

• Mean EGA = 22 weeksMean EGA = 22 weeks• Randomized between 20 -25 weeksRandomized between 20 -25 weeks• Delivery at < 34 weeksDelivery at < 34 weeks

– ProgesteroneProgesterone 19.2%19.2%– PlaceboPlacebo 34.4%34.4%

SHORT CERVIX AND VAGINAL PROGESTERONE

Hassan et al. US OB/GYN 2011

• 458 patients randomized– 235 vaginal progesterone– 223 to placebo

• Progesterone: 90 mg at night

• TVUSCL: 1.0 to 2.0 cm

• EGA: 19.0 to 24 weeks

• Continued until 36 weeks

SHORT CERVIX AND VAGINAL PROGESTERONE

Hassan et al. US OB/GYN 2011

• Vaginal progesterone had less– < 35 weeks (14.5% vs 23.3%)– < 33 weeks (8.9% vs. 16.1%)– < 28 weeks (5.1% vs 10.3%)– RDS (3.0% vs. 7.6%)– BWT < 1500 gms (6.4% vs. 13.6%)– Any morbidity (7.7% vs. 13.6%)

Obstet Gynecol 2003;102:1115-6

Obstet Gynecol 2003;102:1115-6

SUMMARY

•Progesterone is safe

• It is probably effective is properly selected patients

•May not have a significant impact on the preterm delivery rate

•Legally, I think it needs to be offered to patients due to ACOG’s statement

SUMMARY OF THE SUMMARIES

• Preterm births are still a huge problem in the U.S.

• No clear, definitive way to decrease the overall rate due to the complexity of the problem

• Progesterone probably works to decrease the recurrence rate

• Vaginal progesterone may decrease the rate with a short cervix

SUMMARY OF THE SUMMARIES

• It is really, really, really important to make (or rule out) the diagnosis

• Liberal use of fetal fibronectin and cervical lengths to identify those at the highest risk so as to target therapy

• Magnesium is the tocolytic of choice for those under 28 weeks and probably 32 weeks due to its neuroprotection effects

• Steroids are a good thing!!!!

SUMMARY OF THESUMMARIES

• Effects of steroids fade after 14 days

• Strongly consider a repeat course (2 doses) if still at risk for preterm delivery, EGA < 33 weeks, and greater than 14 days from initial course

• Using fFN and cervical length to focus therapy can reduce the number of patients who needlessly get medications that they don’t really need

THANK YOU!!

QUESTIONS?

Documents

PRETERM LABOR HOW CAN WE DO A BETTER JOB?. BACKGROUND Preterm defined as < 37 weeks Preterm defined as < 37 weeks PTD has continued to increase (until