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UPDATE ON PREMATURITY Charlotte Clausen, MD September 13th, 2013

Disclosures • I have nothing to disclose

Objectives • To assess the risk factors for preterm labor and birth • To define the tools we have to evaluate the risk of preterm

labor and birth • To apply the appropriate treatment to those diagnosed

with preterm labor to optimize outcome

“A great deal of intelligence can be invested in ignorance when the need for illusion is deep”.Saul Bellow

Scope of the problem • Preterm birth (PTB)

• Birth prior to 37w0d gestation • 12.18% in United States

• Largest contributor to infant mortality • Morbidity of PTB primarily in < 32w • Rising due to more multiple gestation, late PTB

• 75% occur between 34-36w gestation

• Societal cost of PTB $26.2 billion

PTB rate

Very PTB rate

SCOPE OF THE PROBLEM • 1:5 infants with developmental delay were born preterm.

• 1:3 infants with vision impairment were born preterm

• ~50% of infants with CP were born preterm • Long term, LBW infants are at an increased risk cardiovascular diseases, such as MI,stroke, Htn, and increased risk for diabetes, and cancer as adults.

Pathogenesis •~70 - 80% of PTBs occur spontaneously

• Preterm labor accounts for 40 to 50% of all PTBs •PPROM accounts for 20 - 30% of all PTBs

•~ 20 - 30% of PTBs are due to intervention for maternal or fetal problems.

•4 primary processes are: •Activation of the maternal or fetal hypothalamic-pituitary-adrenal

axis. • Infection •Decidual hemorrhage. •Pathologic uterine distention.

Prevention • Primary prevention: aimed at all pregnant women • Secondary prevention: aimed at reducing risk in women

with prior preterm birth. • Tertiary prevention: aimed at preterm infants. • IN THE VAST MAJORITY OF CASES IT IS BEYOND THE CAPABILITITES OF OBSTETRIC MEDICINE TO PREVENT PTB.

Risk Factors Historical

• Prior preterm birth • Prior PPROM • Prior multiple D&E’s • Previous cervical surgery • Uterine anomalies • DES exposure • Significant myomata • Pre-existing medical conditions • Stress • Smoking or drug use* • African-American

*modifiable

Current pregnancy • Multifetal gestation* • Short inter-pregnancy interval* • Poor weight gain • Invasive testing • Polyhydramnios • Oligohydramnios • Maternal anemia* • Asymptomatic bacturia • Pyelonephritis* • Peronidontal disease • Abdominal surgery • Antepartum bleeding • Short cervix • Congenital anomalies • No prenatal care*

Interpregnancy Interval • Highest risk for PTB with intervals of less than 6 months

• Rates lowest at 18-23 months, then gradually rise

• When maternal age and SES adjusted for: • Progressive increase as interval decreased < 18mo

• < 6mo: PTB OR 1.40, LBW OR 1.26, SGA OR 1.2 • > 60mo: PTB OR 1.20, LBW OR 1.43, SGA OR 1.29

• Greater contributor to PTB in Native Americans, Puerto-Ricans, African-Americans

• Overall contribution short IP interval makes to PTB rate is small, but it is CONTROLLABLE

• Counsel your patients on this, and encourage delivery spacing/family planning

Multiple Gestation • 60% twins deliver preterm • Increase largely due to assisted reproduction • 2 to 3 percent of all births

• 15-20% of births under 37 weeks

• Nearly 1/4 of births under 32 weeks

• Uterine overdistention, fetal signaling • Reduction

• Responsible ART • Limiting number of embryos transferred

• Selective reduction of higher-order multiple gestations

Weight/nutrition • Both low and high BMI associated with increased risk

PTB • Inconsistent evidence of benefit with nutritional

supplementation in patients with PTB • Obese patients often have indicated PTB

• Weight loss prior to pregnancy may improve medical co-morbidities

Substance abuse • Smoking

• Modest does-dependent relationship between smoking and PTB • Greater than 10 cigarettes/d PTB OR 1.7 • Contribution of smoking-related complications such as abruption,

previa, PPROM, IUGR • Brief counseling sessions with pregnancy-specific discussion has

been shown to decrease smoking rates • 16% reduction in rate of PTB with smoking cessation programs

• Cocaine most common substance in subjects with PTL and positive urine tox screen

• Smoking and cocaine are bad for so many reasons, so just advocate for cessation

Asymptomatic Bacteriuria • Antibiotic treatment of asymptomatic bacteriuria is

effective in: • Reducing incidence of pyelonephritis • Reducing incidence PTB and LBW infants*

• Regular screening of women w high risk ASB • Sickle cell trait, diabetes, recurrent UTI, renal d/o

Peridontal Disease • Associated with variety of adverse pregnancy outcomes

• Independent risk factor for PTB

• Mechanisms • Seeding of the placenta by oral flora • Systemic inflammation • Could also be marker for exaggerated inflammatory response with

PTB as a result

• RCT of 1800 subjects treated prior to 24w • No reduction in PTB w tx (gingival scaling, root planing, oral

hygiene instruction)

Bacterial vaginosis • Screening and treatment of low risk women has not

demonstrated benefit • 2007 metanalysis showed increased risk of PTB with tx. OR

2.16(1.56-3.0)

• High risk groups • 2011 meta-analysis showed decreased risk PTB <37 weeks if

treated <22 weeks with clindamycin • 2013 Cochrane review

• 21 trials of 7847 women • Effective at eradicating infection, but no <PTB in high-risk patients OR

0.78(0.62-1.17)

• ACOG, USPSTF and CDC recommend no routine screening.

• Treat if symptomatic

Stress • Biologic plausibility in that stress can increase

corticotropin-releasing hormone which enhances prostaglandin production

• Hard to study because it is hard to define stress, confounders, acute vs chronic stress and timing in pregnancy

• Social support in pregnancy has not decrease PTB in these women

Risk PTB in subsequent pregnancies 1st birth 2nd birth Risk PTB (%)

Not preterm 4-9

Preterm 17-22

Not preterm Not preterm 2-5

Preterm Not preterm 5-13

Not preterm Preterm 11-22

Preterm Preterm 28-42

Bakketeig et al. in Elder MG et al. Preterm Labor, 1987.

PROGESTERONE

Progesterone: Meis trial Progesterone Placebo RR

<37w 36.3% 54.9% 0.66

<35w 20.6% 30.7% 0.67

<32w 11.4% 19.6% 0.58

• 459 subjects • Documented h/o spontaneous

PTB • 250 mg 17α-

hydroxyprogesterone caproate IM or placebo

• Start 16-20w, continued weekly to 36w

• Progesterone-exposed infants had less perinatal morbidity • Lower NEC, IVH, need for

supplemental O2

Progesterone: da Fonseca trial

Progesterone Placebo RR

<37w 13.8% 28.5% 0.66

<34w 2.7% 18.5% 0.67

• 142 subjects • History of PTB(90%),

uterine abnormality(6%), or cervical incompetence(5%)

• 100mg progesterone vaginal suppository

• Start at 24w, continue nightly to 34w

Progesterone: O’Brien trial Progeste

rone Placebo OR

<37w 41.7 40.7 1.08

<35w 22.7 26.5 0.9

<32w 10% 11.3% 0.9

• 659 subjects • h/o PTB 20-35 weeks • No twins

• 90 mg progesterone vaginal gel

• Start 18-22.9w, every morning until 37w

Meta-analyses • 5 different meta-analyses

• Reduction in PTB rates • 20-40% reduction in PTB with progesterone • NNT to prevent one PTB: 10

• Reduction in NEC and RDS in neonates • Decrease neonatal death

Progesterone • 2% reduction in overall PTB rate if all eligible pts receive

progesterone • Regimens

• 17 alpha-hydroxyprogesterone caproate 250 mg/ml IM once a week starting at 16-20 weeks until 36 weeks

• 100 mg vaginal suppository of micronized progesterone nightly starting at 16-20 weeks until 34-36 weeks: cost 1 USD per suppository

Cervical shortening • Cannot measure before 14

weeks • Transvaginal better than

transabdominal • Watch for dynamic change • <25mm is considered short • The shorter the length, the

greater the risk

Cervical length measurements • Cervical length is not significantly affected by parity. • Cervical length normally declines slightly between 20 and 32 weeks

and more substantially after 32 weeks. Between 22 and 32 weeks gestation the length of the cervix is described by a normal bell shaped curve: • 5th centile at 20 mm • 10th centile at 25 mm • 50th centile at 35 mm • 90th centile at 45 mm • Median cervical length is 40 mm before 22 weeks, 35 mm at 22 to 32

weeks, and 30 mm after 32 weeks • It is important to remember that cervical shortening precedes preterm

birth by several weeks (3-8 weeks) in most cases, rather than imminent PTB.

• Great negative predictive value

Progesterone + short cervix • Fonseca 2007

• RCT 250 subjects • No exclusion for prior PTB (15%) or twins (10%)

• 200mg capsules micronized progesterone to those with TVCL 15mm • Start at between 20-25w, nightly until 33w6d • Outcome PTB before 34w

• 19.2% progesterone v 34.4% placebo, RR 0.56 • Hassan 2011

• RCT 458 women • 90 mg vaginal progesterone gel to those with TVCL 10-20mm • Del <33 weeks 9% vs 16%, RR 0.55(0.33-0.92) • Still significant with hx PTB excluded

• Grobman 2012 • IM progesterone for CL <30mm • Nulliparous pts • PTB <37 weeks 25.1% vs 24.2%

Progesterone + short cervix

CERCLAGE

Cerclage with hx PTB: Owen trial • 1014 subjects w prior PTB < 34w

• 301 with cervix < 25mm randomized, with outcomes

• Primary outcome PTB < 35w • Surveillance between 16w-21.9w • Every 2w unless 25-29mm, in which case every week • If <25mm, randomized to McDonald cerclage

• Antibiotics and tocolytics not standardized

• Results • PTB <35 weeks no significant difference RR 0.71(0.58-1.04) • <24 weeks RR 0.44 (0.21-0.92) 6.1% vs 14% • <37 weeks RR 0.75 (0.60-0.93) • Perinatal death RR 0.54 (0.29-0.99)

Cerclage with hx PTB: Berghella meta-analysis • Included 5 RCTs of cerclage and short cervix(<25mm) • Hx of prior PTB, 502 women • Primary outcome PTB prior to 35w • 30% reduction in PTB(28% vs 41%) RR 0.7(0.55-0.89) • 36% reduction in composite perinatal mortality and

morbidity(16% vs 25%) RR 0.64 (0.45-0.91)

Cerclage for short cervix Berghella meta-analysis • 4 RCT of cerclage for short cervix(n=607) • Individual patient data compiled

• Combination of low- and high-risk subjects • Differing cervical length cutoffs for intervention

• Primary outcome PTB <35 weeks • All singletons RR 0.74(0.57-0.96) • No hx of PTB RR 0.84(0.60-1.17) • Hx PTB RR 0.61(0.40-0.92) • Hx prior 2nd tri loss RR 0.57(0.33-0.99) • Twins RR 2.15(1.15-4.01)

• If no hx PTB, start with progesterone, then move to cerclage for dilation or progressive shortening.

ACOG Bulletin

Where progesterone use is unclear • Multiple gestation

• IM has not been shown to prolong gestation in twins or triplets • Vaginal showed ns decrease in PTB <33 weeks in twins

• Significant decrease in neonatal morbidity and mortality 23.9% vs 39.7% • History of singleton PTB with current multiples

• +FFN • With cerclage

• No large studies to show additional benefit • Post-hoc of Berghella study showed benefit for del <28 weeks

• Arrested preterm labor • Maybe? • Small trial, 70 subjects with vaginal progesterone showed

prolonged latency, but no ss decrease in neonatal outcomes • Not currently recommended

ACTIVITY MODIFICATION?

Work • Minimal relationship between work and PTB

• In some series, duration standing or total hours worked correlated with increased risk PTB

• No relationship in other studies

• Effects of reducing occupational fatigue have not been evaluated

Play • No evidence that bedrest decreases the incidence of PTB

• In low risk population, physical activity associated with a reduced risk for PTB

• Coitus leads to increased uterine activity, but not PTB

Bedrest • Has not been shown to decrease the incidence of PTB

• Cochrane review 2004- no evidence for strict bedrest. 1 RCT • Even in short cervix

• Grobman WA. • Fox NS

• After acute PTL • Yost NP- mainly showed no difference in HBR vs Home

• Has negative psychosocial effects • Increased risk for thromboembolic event, bone

demineralization, muscle deconditioning, depression

Bedrest • Green journal article discussing ethical concerns

• Autonomy, Informed consent • Beneficence • Justice

Preterm labor: Diagnosis • One of the most common reasons for hospitalization of

pregnant women. • Using clinical criteria alone: - menstrual like

camps,constant low back pain, uterine contractions, bloody show - • 30% of patient diagnosed with preterm labor resolve

spontaneously. • 50% of patients hospitalized for PTL deliver at term.

• Uterine contractions: threshold not identified. • Digital cervical examination (80% effacement, and or

cervical dilation > 2 cm dilation, regular painful contractions associated with cervical changes).

Initial evaluation

BIOCHEMICAL ASSAYS AND ULTRASOUND EVALUATIONS OF THE CERVIX ARE NOT SUBSTITUTES FOR SOUND CLINICAL JUDGEMENT.

Fetal fibronectin • Well over 500 publications on the use of fFN in the

management of PTL. • In 2008 over 40,000 fFN were performed each month in

the US. • Used in 2 ways:

• To predict the risk of PTB in symptomatic patients. • To identify asymptomatic women who are most likely to deliver

preterm.

Use of ffn in symptomatic women • Systematic review of 32 cohort studies:

• PPV for predicting PTB within 7 days of the test is between 20% and 50%

• NPV for delivery within 7 days, within 14 days, and at < 37 weeks gestation were 99.5%, 99.2%, and 84>% respectively.

• Sample collection: • Intact fetal membranes • Cervical dilation < 3 cm • Gestational age 22-34 weeks • Use a sterile speculum exam • No lubricants, hx of coitus, vaginal bleeding or SVE • > 50 ng/mL is considered (+)

Combining cervical length and ffn • Triage based upon cervical length:

• Cervical length > 30 mm: • No fFN is needed. • Exclude acute precipitating events. • Cervix not dilating or effacing. • D/C home.

• Cervical length 20 to 30 mm: • Send for fFN if (+) treat the patient actively.

• Cervical length < 20 mm: • These patients are at risk for PTB regardless of the results of the

fFN.

NICHD Neonatal Research Network (NRN): Extremely Preterm Birth Outcome Data Gestational Age (Best Obstetric Estimate in

Completed Weeks): 24 weeks

Birth Weight: 650 grams

Sex: Female

Singleton Birth: Yes

Antenatal Corticosteroids: Yes

Outcomes Outcomes for All Infants Outcomes for Mechanically Ventilated Infants

Survival 66% 68% Survival Without Profound Neurodevelopmental Impairment

52% 55%

Survival Without Moderate to Severe Neurodevelopmental Impairment

38% 40%

Death 34% 32% Death or Profound Neurodevelopmental Impairment

48% 45%

Death or Moderate to Severe Neurodevelopmental Impairment

62% 60%

Treatment of preterm labor • Hospitalize if under 34 weeks gestation • Transport of the mother if necessary • Tocolytic drugs for up to 48 hours • Appropriate antibiotics for GBS chemoprophylaxis • Antenatal glucocorticoids. • MgSO4 for neuroprotection. • Appropriate antibiotics to women with positive urine

culture results, GC or chlamydia.

Choice of tocolytics:

• Beta-mimetics. • Magnesium sulfate. • Calcium channel blockers. • Prostaglandin synthetase inhibitors.

Beta-mimetics Dosage and administration

Contraindications Maternal side effects

Fetal and neonatal side effects

Terbutaline, .25 mg subcutaneously every 20 min to 3 hrs (hold for pulse > 120 bpm)

Cardiac arrhythmias, tachy sensitive cardiac disease FDA Warning for use >48-72 hours

Cardiac or cardiopulmonary, arrhythmias, pulmonary edema, myocardial ischemia, hypotension, tachycardia

Fetal tachycardia, hyperinsulinemia, hyperglycemia, myocardial and septal hypertrophy, myocardial ischemia

Ritodrine initial dose of 50-100 mcg/min, increase 50 mcgevery 10 min until uc’s stopor side effects, max dose 350mcg/min

Poorly controlled hyperthyroid disease Poorly controlled DM

Hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, abnormal thyroid function. Physiologic tremor plapitations, hallucinations, N&V

Neonatal tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, IVH

Magnesium Sulfate Dosage and administration

Contraindications Maternal side effects

Fetal and neonatal side effects

4 - 6 grams bolus for 20 minutes then 2 - 3 grams/hour

Myasthenia gravis FDA warning for use >5-7 days for fetal effects

Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest

Lethargy, hypotonia, respiratory depression, demineralization with prolonged use

Calcium channel blockers

Dosage and administration

Contraindications Maternal side effects

Fetal and neonatal side effects

NIFEDIPINE: 30 mg loading dose, then 10 - 20 mg every 4 to 6 hours

Cardiac disease, caution with renal disease, maternal hypotension (90/50), avoid concomitant use with magnesium sulfate

Flushing, headaches, dizziness, nausea, transient hypotension

None noted as yet

Prostaglandin Syntestase Inhibitors

Dosage and administration

Contraindications Maternal side effects

Fetal and neonatal side effects

INDOMETHACIN: loading dose of 50 mg rectally or 50 - 100 mg orally, then 25 - 50 mg orally every 6 hours for 48 hours

Significant hepatic or renal impairment, platelet dysfunction

Nausea, heartburn

Constriction of ductus arteriosus, pulmonary hypertension, reversible decrease in renal function with oligohydramnios, IVH, hyperbilirubinemia, NEC

Antibiotics • Is there a role for adjunctive antibiotics?

• Evidence than empiric treatment with broad spectrum antibiotics is not only less effective than placebo in prolonging gestation, but is also associated with long term abnormal CNS development.

• Treat for GBS prophylaxis while awaiting for culture results, discontinue treatment if GBS culture is negative.

Antenatal steroids • 24-34 weeks • Reductions in

• Respiratory distress syndrome OR 0.55 • Intraventricular hemorrhage OR 0.54 • Necrotizing enterocolitis OR 0.46 • Neonatal mortality OR 0.69 • Neurologic handicap

Crowley P. Cochrane Database 2;2002.

Antenatal steroids • 34-36 6/7 weeks

• Shanks A. • BMZ in those with documented lung immaturity between 34-37 weeks • Increased level of test for FLM: 28.4 vs 9.8%, too small to draw

conclusions about clinical outcomes • Brazilian RCT showed no difference • Concern with neurologic effect on more mature fetal brain

• Await results of ALPS(antenatal late preterm steroids)

Antenatal steroids • “Rescue dose”

• 3 RCT’s • 1 no benefit, 2 benefit in <RDS • No data on long-term outcome • Small number of patients

• Australian study • Single dose decreased RDS

• ACOG • Consider if 7 days have passed since 1st dose and <34 weeks

MgSO4 For “Neuroprotection” • Australasian Collaborative Trial of Magnesium Sulfate (ACTOMgSO4) published in 2003.

• PREMAG study from France published in 2007

• MFM Network study published in 2008 (BEAM).

MgSO4 For “Neuroprotection”: Crowther et al JAMA, 2003;290: 2669

• (ACTOMgSO4) published in 2003. • 1,060 preterm laboring women at < 30 weeks gestation expected to

deliver within 24 hours.

• Randomly assigned to receive MgSO4 (4 g over 30 minutes, followed by 1g/hr up to 24 hrs maximum) or saline placebo.

• CP was 6.8% vs 8.2%: RR: 0.83(0.54 - 1.27)

• Pediatric mortality 13.8% vs 17.1%: RR: 0.83(0.64 -1.09)

• Composite outcome of death or CP 19.8% vs 24% : RR: 0.83(0.66 -1.03)

MgSO4 For “Neuroprotection” Marret et al Gynecol Obstet Fertil 2008; 36: 278

• PREMAG study from France published in 2007. • 573 preterm laboring women at < 33 weeks gestation with

delivery planned or anticipated within 24 hours • Randomly assigned to receive a single dose of MgSO4 (4 g

bolus infusion) or saline placebo with NO maintenance. • Infants were followed for 2 years after discharge. • Primary outcome was white matter injury detected on

neonatal cranial ultrasound. • Secondary outcomes were “cerebral palsy or death” severe

motor dysfunction or death” • CP or death OR 0.65, (0.42-1.03) 16.1% vs 20.2% • Severe motor function or death 0.62 (0.41-0.93)

MgSO4 For “Neuroprotection” Rouse et al: N Engl J Med 2008; 358: 895

• MFMU Network study published in 2008. • Multicenter placebo controlled trial of MgSO4 for the prevention of CP

• 2,241 preterm laboring women at 24 to 31 weeks gestation at risk of imminent delivery.

• Randomly assigned to receive MgSO4 (6 g bolus infusion, followed by 2g/hr infusion for 12 hours) or saline placebo.

• Primary outcome was the composite outcome of “stillbirth or infant death by one year of corrected age or moderate or severe Cp at or beyond 2 years of corrected age” 11.3 vs 11.9%

• Rate of moderate or severe CP was 1.9% vs 3.5%: RR: 0.55; 95% CI 0.32 - 0.95. Only < 28 weeks showed a significant reduction.

• The risk of death was similar in both groups 9.5 % vs 8.5%RR 1.12; 95% CI 0.85 - 1.47

MgSO4 For “Neuroprotection” Doyle et al: Cochrane Database Syst Rev 2009, CD004661

• 4 studies explicitly designed to assess neuroprotective effect of MgSo4(4,446 children)

• Primary outcomes were fetal or infant death by age 1, neurological impairment, major neurological disability, and the composite outcome of “ death or an adverse neurological outcome” by age 2.

• Results: • Significant reduction in “death or CP” RR 0.85(0.74 - 0.98) • No significant effect on stillbirth or pediatric mortality rates RR 0.95(0.80

- 1.12) • Risk of any CP RR 0.71(0.55 - 0.91) • CP 3.7% vs 5.4% • Moderate /severe CP RR 0.64(0.44 - 0.92)

MgSO4 For “Neuroprotection” • Treat 63 women threatening to deliver prior to 32 weeks gestation to prevent 1 case of moderate to severe CP.

• Treat 29 women to prevent 1 case of moderate to severe CP if restricted to delivery under 28 weeks gestation.

• Compare to 100 women with preeclampsia treated to prevent 1 case of eclampsia.

MgSO4 For “Neuroprotection” • PROTOCOL:

• 24 to 32 weeks gestation for both preterm labor and PPROM

• Imminent risk of preterm birth within 24 hours. • 4 gram dose in 20 to 30 minutes

After initial stabilization • Progesterone? No evidence • Bedrest? • Is there a role for maintenance treatment after completing

acute treatment? • Meta-analysis fails to demonstrate any benefit of maintenance

tocolysis in terms of gestational age at birth, pregnancy prolongation, or birth weight.

• Is tocolysis warranted for recurrent preterm labor?