CHUKWUMA I. ONYEIJE, MDATLANTA PERINATAL ASSOCIATES

TUESDAY, APRIL 22, 2014

PRETERM BIRTH:MODERN MANAGEMENT

Polling Courtesy of Poll Everywhere.

To participate in polling for this lecture:

1. Navigate to: http://pollev.com/onyeije

OR

2. Text the applicable CODE to:1-747-444-3548

Can You See this Poll Question?

What is the percentage of preterm deliveries in the US (all patients)?

What percentage of African American infant are born premature?

What has been the trend in preterm delivery in the last 6 years?

What is a Preterm birth

Any birth occurring before 37 weeks’ gestation

Subdivisions of Preterm birth: Late preterm birth (34 to 36 weeks) Early preterm (<34 weeks) Very preterm (<32 weeks) Extremely preterm (<28 weeks)

What is a Preterm birth

Any birth occurring before 37 weeks’ gestation

Subdivisions of Preterm birth: Late preterm birth (34 to 36 weeks) Early preterm (<34 weeks) Very preterm (<32 weeks) Extremely preterm (<28 weeks)

Prematurity Risks

Leading cause of infant death. 36% of infant deaths in 2005

Preterm infants are more likely to suffer: Neurologic impairment Chronic lung disease Cerebral palsy Developmental delay

Prematurity Risks

Leading cause of infant death. 36% of infant deaths in 2005

Preterm infants are more likely to suffer: Neurologic impairment Chronic lung disease Cerebral palsy Developmental delay

What has happened since 2006?

Prior to 2006, the U.S. preterm birth rate had been steadily rising for more than two

decades

Since 2006,

~176,000 FEWER babies have been born preterm

This improvement in the preterm birth rate has saved $9 billion

in health and societal costs.

2006 - 2012 The Trend in Preterm Birth

The US preterm birth rate DROPPED for the SIXTH consecutive year in 2012

Currently 11.5 %

This represents a 15-year LOW.

US preterm birth rate PEAKED in 2006 at 12.8 %

The Trend in Preterm Birth2006 – 2012

Racial disparities.

• Preterm birth rate African-American infants is the LOWER THAN IT HAS BEEN IN 20 YEARS

• African-American preterm birth rate is now 16.8%. Down from 18.5% in 2006; BUT…

• Remains the highest of all racial groups.

Our nations preterm birth rate is still the

HIGHEST rate of preterm birth of

any industrialized country.

Preterm Birth By Country

Papua New Guinea

Sierra Leone

Bangladesh

Malawi

Russia

Brazil

Turkey

Malaysia

Japan

United Kingdom

Germany

United States

Worldwide Average

0 2 4 6 8 10 12 14 16 18 20

Worldwide Low Income Middle Income High Income

Source: http://www.nature.com/news/pre-term-births-on-the-rise-1.10556

March of Dimes 2013 Preterm Delivery Report Card Results.

Source: http://www.marchofdimes.com/mission/prematurity-reportcard.aspx

Why have preterm births DECREASED?

?

Does prenatal care improve pregnancy outcome?

ANSWER: YES AND NO.

Does prenatal are improve pregnancy outcome?

Does prenatal care improve pregnancy outcome.

YES: Lower risk of preterm delivery among patients with

ANY kind of prenatal care than NO prenatal care.

BUT: This is NOT related to the kind of prenatal care

provided.

Behrman RE, Stith Butler A. Committee on understanding premature birth and assuring healthy outcomes: causes, consequences, and prevention. Washington, DC: National Academies Press, 2007

What DOES NOT seem to work…

Treating nutritional deficiencies Vitamin C, Vitamin E, Calcium, n-3 fatty acids.

Treating genitial tract microorganisms.

Treating periodontal disease

Iams et al, NEJM; 370;3 nejm.org january 16, 2014

What DOES seem to work?

Fewer uninsured women 37 states reduced the percentage of uninsured women

of childbearing ageLess smoking

35 states reduced the percentage of women of childbearing age who smoke

Fewer late preterm births 28 states lowered the late preterm birth rate (infants

born between 34 and 36 weeks gestation).

Source: http://www.marchofdimes.com/mission/prematurity-reportcard.aspx

Centers for Disease Control and Prevention. Youth tobacco surveillance-United States, 1998-1999. Morbidity and Mortality Weekly Report . 2000b;49(SS10):1–94

What DOES seem to work?

Increased interpregnancy intervals

Better IVF

Progesterone therapy

Cervical cerclage

Iams et al, NEJM; 370;3 nejm.org january 16, 2014

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508292/pdf/amjph00020-0040.pdf

Interpregnancy Interval

Shorter time for repletion of maternal nutrient stores.

Reduction in adverse birth outcomes. Pre-term infant Small for gestational age infant Neonatal death.

Other Risk Factors:

Tobacco use Dose-dependent increase in the risk of preterm birth

Substance abuseShort cervixCervical surgeryUterine malformationLarge (> 5cm) uterine fibroidsModerate to severe anemia in the first trimesterFetal factors

Growth restriction Congenital anomalies Male gender

Risk Factors for Preterm Birth

Previous preterm birthShort interpregnancy intervalAssisted reproductionMultifetal gestationDecidual hemorrhageInfection and inflammation

Asymptomatic bacteriuria Maternal periodontal disease

Previous preterm birth

Strongest risk factor for future preterm delivery

Data from McManemy et al: One preterm birth: 14-22 % risk. Two preterm births: 28 -42% Three or more: Up to 75%

A term birth decreases the risk of preterm birth in subsequent pregnancies

(McManemy et al, 2007)

RECALL

Papua New Guinea

Sierra Leone

Bangladesh

Malawi

Russia

Brazil

Turkey

Malaysia

Japan

United Kingdom

Germany

United States

Worldwide Average

0 2 4 6 8 10 12 14 16 18 20

Worldwide Low Income Middle Income High Income

THREE PREVIOUS PTD

TWO PREVIOUS PTD

ONE PREVIOUS PTD

United States

Worldwide Average

0 10 20 30 40 50 60 70 80

WorldwidePTD X 3PTD X 2PTD X 1Averages

Source: McManemy J., Cooke E., Amon E., Lee T.: Recurrence risk for preterm delivery. Am J Obstet Gynecol  2007; 196(6):576.e6-e7

Current Understanding:Pathology Underlying

Preterm Labor

Reversal of Progesterone to Estrogen Activity

Actions of progesterone Inhibits cervical ripening Reduces myometrial contractility Reduces oxytocin receptor synthesis Reduces oxytocin receptor function

Progesterone LevelsNormal vs. Threatened prematurity

Pathophysiologic Mechanisms for Prematurity

Activation of Maternal/FetalHPA Axis Maternal/Fetal

stress

Activation of Maternal/FetalHPA Axis Maternal/Fetal

stress

Inflammation/Infection Chorio-decidual Systemic

Inflammation/Infection Chorio-decidual Systemic

Decidual Hemorrhage Abruption

Decidual Hemorrhage Abruption

Pathological UterineDistension Multifetal pregnancy Polyhydramnios Uterine abnormality

Pathological UterineDistension Multifetal pregnancy Polyhydramnios Uterine abnormality

Preterm BirthPreterm Birth

Lockwood CJ, Kuczynski E. Paediatric Perinat Epidemiol. 2001;15(suppl 2):78-89.

Estimated at 40%Estimated at 30% Estimated at 20% Estimated at 10%

Premature Decidual Activation

Campbell S. Ultrasound Obstet Gynecol 2011

• Occult upper genital tract infection

• Release of proinflammatory cytokines in the cervix

• Release of proinflammatory cytokines at the choriodecidual interface

• Cervical softening and effacement

Pathophysiologic Mechanisms for Prematurity

Activation of Maternal/FetalHPA Axis Maternal/Fetal

stress

Activation of Maternal/FetalHPA Axis Maternal/Fetal

stress

Inflammation/Infection Chorio-decidual Systemic

Inflammation/Infection Chorio-decidual Systemic

Decidual Hemorrhage Abruption

Decidual Hemorrhage Abruption

Pathological UterineDistension Multifetal pregnancy Polyhydramnios Uterine abnormality

Pathological UterineDistension Multifetal pregnancy Polyhydramnios Uterine abnormality

Preterm BirthPreterm Birth

Lockwood CJ, Kuczynski E. Paediatric Perinat Epidemiol. 2001;15(suppl 2):78-89.

Estimated at 40%Estimated at 30% Estimated at 20% Estimated at 10%

Progesterone Mediation(?)

Is progesterone our new “Silver Bullet” ?

What is considered a “short” cervix (between 18 to 24 weeks)?

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“Prevention of Recurrent Preterm Delivery by 17 α-Hydroxyprogesterone Caproate”

“The NICHD Study”

Meis, Paul J. et al, N Engl J Med, June 12, 2003

(initially presented SMFM, Feb. 6, 2003)

17 α-hydroxyprogesterone caproate

Approved by FDA February 3, 2011Indicated to reduce the risk of preterm birth in

women with a singleton pregnancy who have a history of singleton spontaneous preterm birth

• MakenaTM • 17P content: 250 mg/ml

• 5 ml multi-dose vial with preservative

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Meis et al, New England Journal of Medicine, 2003

Maternal Outcomes

17P Plac. RR CI

N 306 153

< 37 w 36.3% 54.9% 0.66 .54 - .81

< 35 w 20.6% 30.7% 0.67 .48 - .93

< 32 w 11.4% 19.6% 0.58 .37 - .91

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Meis et al, New England Journal of Medicine, 2003

Neonatal Outcomes

Outcome 17P Placebo RR 95% CI

BW < 2500 27.2%

41.1% 0.66 0.51 – 0.87

IVH 1.3% 5.2% 0.25 0.8 – 0.82

NEC 0% 2.6% NA NA

Suppl O2 14.9% 23.8% 0.62 0.42 – 0.92

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Meis et al, New England Journal of Medicine, 2003

Study conclusion: “Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.”

Bibliography of Selected Publications (2007 – 2012) Data from Women Receiving Alere 17P Administration Nursing Service (17P-HAS) • Sibai 2012• Gonzalez-Quintero 2012• Timofeev 2012• Lucas 2012• Gonzalez-Quintero 2012• Rebarber 2012• Timofeev 2012• Timofeev 2012• Gonzalez-Quintero 2011• Unal 2011• Gonzalez-Quintero 2011• Coleman 2011• Barton 2011• Gonzalez-Quintero 2011• Gonzalez-Quintero 2011• Rittenberg 2011• Gonzalez-Quintero 2010

• Joy 2010• Rebarber 2010• O’Brien 2009• Eggerman 2009• Eggerman 2009• Page 2009• Rittenberg 2009• Rittenberg 2008• Ventolini 2008• Rebarber 2008• Guzman 2007• Rittenberg 2007• How 2007• Rebarber 2007• Rebarber 2007• Gonzalez-Quintero 2007

47

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17P: Side Effects and Precautions

Precautions Discontinue if thrombosis or

thromboembolism occurs Consider discontinuing if allergic reactions

occur Decreased glucose tolerance: Monitor pre-

diabetic and diabetic women Fluid retention: Monitor women with

conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction

Depression: Monitor women with a history of clinical depression; discontinue if depression recurs

MakenaTM Prescribing Information, Ther-Rx Corporation St. Louis, MO February, 2011

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Meis et al, New England Journal of Medicine, 2003

Fetal Safety

17P appeared to be safe. There was no increase in the rate of

congenital anomalies in the progesterone group.

These results are consistent with surveys of the literature that have indicated an absence of teratogenic effects from the use of 17P during pregnancy.”

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Progestins and Evidence of Fetal Harm

• Cohort of 988 progestin-exposed (90% 17P or progesterone; >60%: 17P only)

• Outcomes tabulated included GU, CNS, and CV anomalies; mean f/u: 11.5 years

• No significant detection of congenital anomalies with progestin exposure

• (“May not apply to androgenic progestins”)

Resseguie LJ et al. Congenital malformations among offspring exposed in utero to progestins, Olmsted County, Minnesota, 1936-1974.Fertility and Sterility 1985;43(4):514-9.

4-year Follow-up Safety Study

No significant differences were seen in health status or physical examination, including genital anomalies, between 17P and placebo children

Scores for gender-specific roles were within the normal range and similar between 17 alpha-hydroxyprogesterone caproate and placebo groups.

Northen AT. Obstet Gynecol 2007

No Evidence of 17P as Unsafe

Multi-Generational Developmental and Reproductive Toxicology study

Developmental and toxicology study in rats shows no evidence of a safety signal for hydroxyprogesterone caproate

Conclusions combined with the results of 11 trials showing fetal loss rates of 3.6% for 17P and 5.1% for placebo

Schardein J. Am J Obstet Gynecol 2012

Perinatal Mortality Reassuringly Low

17P (start) ≤18 wk(n = 3632)

18-20 wk(n = 1367)

>20/<21 wk(n = 494)

p

Stillbirth 6 (0.2%) 1 (0.1%) 1 (0.2%) 0.705

Miscarriage 10 (0.3%) 3 (0.2%) NA 0.492

NN death 18 (0.5%) 4 (0.3%) 3 (0.6%) 0.554

Total PNM 34 (0.9%) 8 (0.6%) 4 (0.8%) 0.478

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Sibai Am J Perinatoll 2012

17P: Contraindications

• Current or history of thrombosis or thromboembolic disorders

Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions

Undiagnosed abnormal vaginal bleeding unrelated to pregnancy

Cholestatic jaundice of pregnancy Liver tumors, benign or malignant, or

active liver disease Uncontrolled hypertension

MakenaTM Prescribing Information, Ther-Rx Corporation St. Louis, MO February, 2011

17P and Risk for Gestational Diabetes p-value OR (95% CI)

17OHPC initiated at 16-20 weeks

0.025 1.67 (1.07, 2.63)

17OHPC initiated at 21-24 weeks

0.515 1.22 (0.66,2.26)

Maternal age ≥ 35 years

0.001 2.11 (1.37,3.25)

Morbid obesity >

39.9 kg/m2

0.063 1.60 (0.97,2.63)

Eggerman R Am J Obstet Gynecol 2009

Cerclage Placement

Your text here

Cerclage: Controversies and Certainties

J. Owen et al, AmJOBG, 2009: Randomized trial Previous early preterm birth AND Cervix < 2.5 cm. Outcome: Birth at less than 35 weeks. Observation vs. Cerclage

Cervix < 2.5 cm: NO BENEFIT Cervix < 1.5 cm: BENEFIT

Cerclage: Controversies and Certainties

Berghella et al, Obstet Gynecol, 2011. Metaanalysis of 5 trials Cerclage for short cervix < 2.5 cm CERCLAGE EFFECTIVE

Relative risk, 0.70 Confidence interval: 0.55 – 0.89

Cerclage: Caution

The large trials for women with a short cervix were designed and performed BEFORE progestogens were used for that indication.

Available studies suggest vaginal progesterone and cervical cerclage are SIMILARLY effective in reducing the risk of preterm birth among high risk women.

Cerclage: Caution

There have been NO studies to directly compare cerclage and progesterone to date.

Progesterone vs. CerclageCurrent recommendations…

Short cervix who have NO previous preterm birth

Previous preterm birth.

For women with a previous preterm birth AND a short cervix.

Supplemental cerclage for short cervix and NO previous preterm birth?

Vaginal progesterone

17- alpha hydroxyprogesterone

Cervical cerclage

NO DATAAm J Obstet Gynecol 2012;206:376-86.

ACOG practice bulletin no. 130: Obstet Gynecol. 2012;120:964-73

Iams et al,

NEJMJanuary

16, 2014

Comprehensive obstetrical history

Ultrasound confirmation of EGA and number of fetuses

Initial prenatal visit

History of spontaneous preterm birth OR stillbirth

before 24 wk presenting as labor,

SROM or advanced dilation?

Prescribe 17- OHP, 250 mg IM

weekly from 16 to 37 weeks

Yes No

Is this a singleton pregnancy?

History of spontaneous preterm birth OR stillbirth

before 24 wk presenting as labor,

SROM or advanced dilation?

Prescribe 17- OHP, 250 mg IM

weekly from 16 to 37 weeks

Yes

Prescribe 17- OHP, 250 mg IM

weekly from 16 to 37 weeks

Measure TVCL every 14 days from 16–24 wk of

gestation, every 7 days if CL <30 mm

History of preterm birth:

If TVCL <25 mm before24 wk of gestation: 1. Consider CERCLAGE

(especially if patient had prior spontaneous preterm birth at <28 wk or if membranes are

visible)2. Continue progesterone

Is there a history of spontaneous preterm birth

or stillbirth before 24 wk presenting as labor,

SROM or advanced dilation? No

Is this a singleton

pregnancy?

No previous preterm birth

Is this a singleton

pregnancy?

Signs or symptomsof PTL ?

(e.g., persistent pelvic pressure,

cramps, spotting or vaginal discharge)?

Progestogens are ineffective

and cerclage may increasethe risk of preterm birth

Singleton vs. Multiple Gestation

Singleton Pregnancy, WITH symptoms of preterm labor

Signs or symptomsof PTL ?

(e.g., persistent pelvic pressure, cramps, spotting or vaginal

discharge)?

Have TVCLperformed bycredentialed

ultrasonographer

Next Slide

YES

Singleton Pregnancy, NO symptoms of preterm labor

Signs or symptomsof PTL ?

(e.g., persistent pelvic pressure,cramps, spotting or vaginal

discharge)?

Use one of the following site-specific screening

strategies.(S4)

Site-specific screening strategies.

(S4)

Universal TVCL screening at 18–24 wkUniversal TACL screening at 18–24 wk of gestation, until CL <35 mmSelective TVCL screening of women with the following risk factors:

Prior preterm birth at <34 wk with unknown cause, or twinsHistory of genitourinary infectionConception with fertility drugsBlack racePrevious cervical surgeryBMI <19.6 or >35.0Periodontal disease

Signs or symptomsof PTL ?

(e.g., persistent pelvic pressure, cramps, spotting or vaginal

discharge)?

The patient with “Symptomatic” preterm labor.

Have TVCLperformed bycredentialed

ultrasonographer

The Clinical

Evaluation of Preterm

Labor

Diagnosis of Preterm Labor

Difficult. “Regular painful uterine contractions AND cervical

dilatation or effacement at a preterm gestational age”Half of women HOSPITALIZED for preterm

labor deliver at TERM. Regardless of therapy.

•Signs and symptoms of preterm labor • Cramping• Back pain• Contractions• Bloody show

Tocodynamometry to evaluate

for the presence of uterine

contractions

Speculum exam to assess

for ruptured membranes or

bleeding

Initial laboratory evaluation

urinalysis & culture urine toxicology

GBS culture

FFN testing

High negative predictive valueMore than 99% of symptomatic patients

with a negative fFN did not deliver within 14 days

Cannot be performed with: Vaginal bleeding Ruptured membranes After recent intercourse After vaginal examination After transvaginal ultrasound

ONYEIJE’S 3, 2, 1 PRINCIPLE

Management of a Short Cervix

Iams J. N Engl J Med 1996

Cervix ~ 1.9 cm

Cervix ~ 2.0 - 3.0 cm

Cervix > 3.0 cm

United States

Worldwide Average

0 5 10 15 20 25

WorldwideCVX ~ 1.0 cmCVX ~ 2 - 3 cmCVX ~ 3.0 cmAverages

Source: The Length of the Cervix and the Risk of Spontaneous Premature Delivery. Jay D. Iams, M.D., Robert L. Goldenberg, M.D., et al. N Engl J Med 1996; 334:567-573February 29, 1996

Probability of Delivery before 32 weeksBased on Cervical Length before 24 weeks.

Cervical Length Triage for Preterm Labor

Cervical Length

< 1.9 cm

HighRisk

2.0 to 2.9 cm

Increased Risk

> 3.0 cm

LowRisk

Normal Cervix

Low Risk (> 3.0 cm)

 LOW risk of preterm birth.FFN testing NOT mandatory.Observe for 4 to 6 hours to confirm fetal well-

being. Reactive nonstress test Rule out abruption Rule out Infection. Rule out Cervical change

Arrange follow-up in one to two weeks Give PTL instructions

Bleeding, rupture of membranes, decreased fetal activity 

Increased Risk (2.0 to 3.0 cm)

Increased Risk (2.0 to 3.0 cm)

Most of these women do NOT deliver preterm.

FFN testing indicated.If FFN positive See High Risk Slide.If FFN negative See Low Risk Slide.

High Risk

The spectrum of cervical anatomy

High Risk

High risk of preterm birth Regardless of the fFN resultActive management recommended

Prevention of morbidity associated with preterm birth. 

Management of Preterm Labor

BetamethasoneVaginal progesteroneTocolysis for up to 48 hours.GBS ChemoprophylaxisAntibiotics for UTIMagnesium sulfate for neuroprotection

Between 24 and 32 weeks.

Summary

Preterm birth remains a leading cause of infant death in the United States, especially among African Americans.

Changes in IVF and reductions in scheduled births before 39 weeks have resulted in decreased preterm birth rates.

Summary

Strategies to identify and treat medical risk factors in early pregnancy have NOT been effective in reducing preterm birth rates.

Previous preterm birth and a short cervix (≤20 mm, as measured by transvaginal ultrasonography) are major risk factors for preterm birth.

Summary

The use of progesterone supplementation in women with a previous preterm birth, a short cervix, or both was shown in randomized trials to reduce the frequency of preterm birth and is recommended for women with these risk factors.

Cervical cerclage reduces the risk of recurrent preterm birth among women with a short cervix.

Thank you.

Periodontal Disease

Increases the risk of preterm labor and low birth weight.

Proposed mechanism: Seeding of the placenta or amniotic fluid by oral

pathogens and systemic inflammation. Oral bacteria associated with an increased risk of

preterm delivery: Bacteroides forsythus Porphyromonas gingivalis Actinobacillus actinomycetemcomitans Treponema denticola Fusobacterium nucleatum

Offenbacher S., Jared H.L., O’Reilly P.G., et al: Potential pathogenic mechanisms of periodontitis associated pregnancy complications. Ann Periodontol  1998; 3(1):233-250.

Periodontal Disease

Nonsurgical treatment of periodontal disease was NOT effective in reducing preterm births, low birth weight, or growth restriction.

Michalowicz B.S., Hodges J.S., DiAngelis A.J., et al: Treatment of periodontal disease and the risk of preterm birth. N Engl J Med  2006; 355(18):1885-1894.

Genital Infections

Associated with preterm birth

Causality has not been proved

Treatment for genital infections is often indicated, but has NOT been shown to reduce

the risk of preterm birth.

Preterm labor itself is NOT an indication for antibiotics in the absence of:Documented infection

or GBS prophylaxis

GBS CHEMOPROPHYLAXIS (< 37 WEEKS)

Repeat Doses of Steroids?

Administering a repeat course of therapy reduces the risk of respiratory distress syndrome (RDS). Repeat doses of prenatal corticosteroids for

women at risk of preterm birth for improving neonatal health outcomes.Cochrane Database Syst Rev. 2011 Jun 15;(6):CD003935. doi: 10.1002/14651858.CD003935.pub3.

This study did NOT evaluate the RISKS of repeat doses of steroids…

Repeat Dose Controversies

In the Maternal Fetal Medicine Units network (MFMU) trial, 63 percent of patients received 4 or more courses of therapy.

These patients had: More IUGR < 10th percentile More IUGR < 3rd percentile Smaller placenta size (?) Increased risk of cerebral palsy.

5 cases vs 1 case. REFERENCE: Am J Obstet Gynecol. 2006 Sep;195(3):633-42. Epub 2006 Jul 17. Single versus weekly courses of antenatal corticosteroids:

evaluation of safety and efficacy.

Repeat Dose Controversies

A small prospective cohort study reported lower measures of attention and speed in adolescence and young adults exposed in utero to multiple courses of antenatal corticosteroid therapy.

Rescue Dose Steroids

In 2011 and 2012, the American College of Obstetricians and Gynecologists (ACOG) endorsed the concept of a SINGLE course of rescue steroids in women who remain at risk of preterm delivery

These publications recommend AVOIDING regularly scheduled repeat courses or more than two courses of antenatal corticosteroids.

ACOG Committee Opinion No. 475: Antenatal corticosteroid therapy for fetal maturation.

Indications for Rescue Dose Steroids

Patient at high risk for delivery within the next 7 days

Initial course of antenatal corticosteroids at <28 weeks of gestation

Prior exposure to antenatal corticosteroids at least two weeks earlier