Premature Labor Premature Labor and Deliveryand Delivery

Honor M. WolfeHonor M. Wolfe

Associate Professor Associate Professor

Maternal Fetal MedicineMaternal Fetal Medicine

Objectives: Objectives:

To review theTo review the– Definition, frequency and consequence of Definition, frequency and consequence of

preterm deliverypreterm delivery– Modifiable and non modifiable risks for Modifiable and non modifiable risks for

Preterm deliveryPreterm delivery– Pathogenesis of Preterm deliveryPathogenesis of Preterm delivery– Prediction of Preterm deliveryPrediction of Preterm delivery– Management of Preterm laborManagement of Preterm labor

Preterm Labor: DefinitionPreterm Labor: Definition

““Regular” uterine contractions With

– Cervical “change” or– > 2 cm dilation or– > 80% effacement

Preterm DeliveryPreterm Delivery

- Preterm birth:< 37completed weeks- Preterm birth:< 37completed weeks

- Very Preterm birth: < 32 weeks - Very Preterm birth: < 32 weeks

- Extremely Preterm birth: < 28 - Extremely Preterm birth: < 28 weeksweeks

Incidence/DefinitionsIncidence/Definitions

12.5% USA (2004) 12.5% USA (2004) 2% < 32 weeks2% < 32 weeks Fetal growthFetal growth

– Small for gestational age < 10Small for gestational age < 10thth % for GA % for GA Birthweight:Birthweight:

– Low BWT Low BWT < 2500 grams < 2500 grams– Very low BWT Very low BWT < 1500 grams < 1500 grams– Extremely low BWT < 1000 gramsExtremely low BWT < 1000 grams

IncidenceIncidence

13% Rise in PTB since 199213% Rise in PTB since 1992 Multiple gestation (20% increase)Multiple gestation (20% increase)

– 50 % twins, 90% triplets born preterm50 % twins, 90% triplets born preterm

Changes in Obstetric managementChanges in Obstetric management– Ultrasound, inductionUltrasound, induction

Sociodemographic factorsSociodemographic factors– AMA!AMA!

No improvement with physician interventions!No improvement with physician interventions!

Leading Causes of Neonatal Death (USA)

  

Neonatal Neonatal deathsdeaths

Percentage of Percentage of neonatal deathsneonatal deaths

Disorders related to prematurity and low birth Disorders related to prematurity and low birth weightweight

4,3184,318 23.023.0

Congenital malformations, chromosomal Congenital malformations, chromosomal abnormalitiesabnormalities

4,1444,144 22.122.1

Maternal complicationsMaternal complications 1,3941,394 7.47.4

Placenta, cord, and membrane complicationsPlacenta, cord, and membrane complications 1,0491,049 5.65.6

Respiratory distressRespiratory distress 929929 4.94.9

Bacterial sepsisBacterial sepsis 737737 3.93.9

Intrauterine hypoxia and birth asphyxiaIntrauterine hypoxia and birth asphyxia 589589 3.13.1

Neonatal hemorrhageNeonatal hemorrhage 563563 3.03.0

AtelectasisAtelectasis 483483 2.6 2.6

Necrotizing enterocolitisNecrotizing enterocolitis 313313 1.71.7

Neonatal deaths: death within 28 days of birth .Data adapted from: the Centers for Disease Control and Prevention, 2000.

SignificanceSignificance

Infant mortalityInfant mortality– Over 50% of infant deaths occur among the Over 50% of infant deaths occur among the

1.5% infants < 1500 grams1.5% infants < 1500 grams– 70 % of infant deaths occur among the 7.7% of 70 % of infant deaths occur among the 7.7% of

infants < 2500 gramsinfants < 2500 grams MorbidityMorbidity

– 60%: 26 weeks60%: 26 weeks– 30%: 30 weeks30%: 30 weeks

Risk Factors for Preterm Birth Non-modifiableNon-modifiable

Prior preterm birthPrior preterm birth

African-American raceAfrican-American race

Age <18 or >40 yearsAge <18 or >40 years

Poor nutrition/low prepregnancy weightPoor nutrition/low prepregnancy weight

Low socioeconomic statusLow socioeconomic status

Cervical injury or anomalyCervical injury or anomaly

Uterine anomaly or fibroidUterine anomaly or fibroid

Premature cervical dilatation (>2 cm) orPremature cervical dilatation (>2 cm) oreffacement (>80 percent)effacement (>80 percent)

Over distended uterus (multiple pregnancy, Over distended uterus (multiple pregnancy, polyhydramnios)polyhydramnios)

? Vaginal bleeding? Vaginal bleeding

? Excessive uterine activity? Excessive uterine activity

Modifiable Modifiable

Cigarette smokingCigarette smoking

Substance abuseSubstance abuse

Absent prenatal careAbsent prenatal care

Short interpregnancy intervalsShort interpregnancy intervals

AnemiaAnemia

Bacteriuria/urinary tract infectionBacteriuria/urinary tract infection

Genital infectionGenital infection

? Strenuous work? Strenuous work

? High personal stress? High personal stress

Risk factors for preterm birthRisk factors for preterm birthStressStress Single womenSingle women Low socioeconomic statusLow socioeconomic status AnxietyAnxiety DepressionDepression Life events (divorce, separation, death)Life events (divorce, separation, death) Abdominal surgery during pregnancyAbdominal surgery during pregnancyOccupational fatigueOccupational fatigue Upright postureUpright posture Use of industrial machinesUse of industrial machines Physical exertionPhysical exertion Mental or environmental stressMental or environmental stressExcessive or impaired uterine distentionExcessive or impaired uterine distention Multiple gestationMultiple gestation PolyhydramniosPolyhydramnios Uterine anomaly or fibroidsUterine anomaly or fibroids DiethystilbesterolDiethystilbesterol

Cervical factorsCervical factors History of second trimester abortionHistory of second trimester abortion History of cervical surgeryHistory of cervical surgery Premature cervical dilatation or Premature cervical dilatation or

effacementeffacementInfectionInfection Sexually transmitted infectionsSexually transmitted infections PyelonephritisPyelonephritis Systemic infectionSystemic infection BacteriuriaBacteriuria Periodontal diseasePeriodontal diseasePlacental pathologyPlacental pathology Placenta previaPlacenta previa AbruptionAbruption Vaginal bleedingVaginal bleeding

Risk factors for preterm birthRisk factors for preterm birth

MiscellaneousMiscellaneous Previous preterm deliveryPrevious preterm delivery Substance abuseSubstance abuse SmokingSmoking Maternal age (<18 or >40)Maternal age (<18 or >40) African-American raceAfrican-American race Poor nutrition and low body mass indexPoor nutrition and low body mass index Inadequate prenatal careInadequate prenatal care Anemia (hemoglobin <10 g/dL)Anemia (hemoglobin <10 g/dL) Excessive uterine contractilityExcessive uterine contractility Low level of educational achievementLow level of educational achievement GenotypeGenotypeFetal factorsFetal factors Congenital anomalyCongenital anomaly Growth restrictionGrowth restriction

Prior preterm birthPrior preterm birth

- Increases risk in subsequent Increases risk in subsequent pregnancypregnancy

- Risk increases withRisk increases with- more prior preterm birthsmore prior preterm births- earlier GA of prior preterm birth (s)earlier GA of prior preterm birth (s)

Prediction/RecurrencePrediction/Recurrence

Prior PTD @ (23-27 wks) 27%Prior PTD @ (23-27 wks) 27% Prior PPROM 13.5%Prior PPROM 13.5%

FIRST BIRTH

SECOND BIRTH

SUBSEQUENT PRETERM

BIRTH (%)

Not preterm 4.4

Preterm 17.2 Not Preterm Not Preterm 2.6

Preterm Not Preterm 5.7

Not preterm Preterm 11.1

Preterm Preterm 28.4

PathogenesisPathogenesis

80% of Preterm births are spontaneous80% of Preterm births are spontaneous– 50% Preterm labor50% Preterm labor

– 30% Preterm premature rupture of the membranes30% Preterm premature rupture of the membranes

Pathogenic processesPathogenic processes– Activation of the maternal or fetal hypothalamic Activation of the maternal or fetal hypothalamic

pituitary axispituitary axis

– InfectionInfection

– Decidual hemorrhageDecidual hemorrhage

– Pathologic uterine distentionPathologic uterine distention

Activation of the HPA AxisActivation of the HPA Axis

Premature activationPremature activation Major maternal physical/psychologic stressMajor maternal physical/psychologic stress Stress of uteroplacental vasculopathyStress of uteroplacental vasculopathy MechanismMechanism

– Increased Corticotropin-releasing hormoneIncreased Corticotropin-releasing hormone– Fetal ACTHFetal ACTH– Estrogens (incr myometrial gap junctions)Estrogens (incr myometrial gap junctions)

InflammationInflammation

Clinical/subclinical chorioamnionitisClinical/subclinical chorioamnionitis– Up to 50% of preterm birth < 30 wks GAUp to 50% of preterm birth < 30 wks GA

Proinflammatory mediatorsProinflammatory mediators– maternal/fetal inflammatory responsematernal/fetal inflammatory response– Activated neutrophils/macrophagesActivated neutrophils/macrophages– TNF alpha, interleukins (6)TNF alpha, interleukins (6)

BacteriaBacteria– Degradation of fetal membranesDegradation of fetal membranes– Prostaglandin synthesisProstaglandin synthesis

Prediction of Preterm DeliveryPrediction of Preterm Delivery

History: Current and Historical Risk FactorsHistory: Current and Historical Risk Factors MechanicalMechanical

– Uterine contractionsUterine contractions– Home uterine activity monitoringHome uterine activity monitoring

BiochemicalBiochemical– Fetal fibronectinFetal fibronectin

UltrasoundUltrasound– Cervical lengthCervical length

Fetal fibronectin-Fetal fibronectin-Glycoprotein in amnion, decidua,Glycoprotein in amnion, decidua,

cytotrophoblastcytotrophoblast

Increased levels secondary to Increased levels secondary to breakdown of the chorionic-breakdown of the chorionic-

decidual decidual interfaceinterface

Inflammation, shear, movementInflammation, shear, movement

Fetal fibronectin as a predictor for delivery Fetal fibronectin as a predictor for delivery within 7 and 14 days after sampling, combined results within 7 and 14 days after sampling, combined results

Delivery <7 daysDelivery <7 days Delivery <14 days Delivery <14 days

Sensitivity Specificity SensitivitySensitivity Specificity Sensitivity Specificity Specificity (percent), (percent), 95 (percent), 95 (percent), 95(percent), (percent), 95 (percent), 95 (percent), 95 95 percent CI percent CI percent CI percent CI95 percent CI percent CI percent CI percent CI

Study groupStudy group

All studies 71 (57-84) 89 (84-93) 67 (51-82) 89 (85-94)All studies 71 (57-84) 89 (84-93) 67 (51-82) 89 (85-94)

Women with Women with

preterm labor 77 (67-88) 87 (84-91) 74 (67-82) preterm labor 77 (67-88) 87 (84-91) 74 (67-82) . .

87 (83-92) 87 (83-92)

Asymptomatic 63 (26-90)* 97 (97-98) 51 (33-70) Asymptomatic 63 (26-90)* 97 (97-98) 51 (33-70) . .

96 (92-100) 96 (92-100)(low risk or (low risk or high-risk) high-risk) women women

CI: confidence interval.CI: confidence interval.* Only one study included in analysis.* Only one study included in analysis.

. . Fixed-effects model used (homogeneity test P >0.10).Fixed-effects model used (homogeneity test P >0.10).Data from: Leitich, H, Kaider, A. Fetal fibronectin - how useful is it in the prediction of preterm Data from: Leitich, H, Kaider, A. Fetal fibronectin - how useful is it in the prediction of preterm birth? BJOG 2003; 110 (Suppl 20):66. birth? BJOG 2003; 110 (Suppl 20):66.

Fetal fibronectin vs. Clinical assessment of Fetal fibronectin vs. Clinical assessment of Preterm LaborPreterm Labor

Parameter Sensitivity (percent) PPV (percent) NPV (percent)Parameter Sensitivity (percent) PPV (percent) NPV (percent)

Fetal fibronectin 93 29 99Fetal fibronectin 93 29 99

Cervical Cervical dilatation >1 cm 29 11 94 dilatation >1 cm 29 11 94

Contraction Contraction frequency 8/h 42 9 94frequency 8/h 42 9 94

PPV: positive predictive value; NPV: negative predictive value.PPV: positive predictive value; NPV: negative predictive value. Data derived from symptomatic women and reflect the ability to predict delivery within Data derived from symptomatic women and reflect the ability to predict delivery within

seven days.seven days. Adapted from: Iams, JD, Casal, D, McGregor, JA, et al. Am J Obstet Gynecol 1995; Adapted from: Iams, JD, Casal, D, McGregor, JA, et al. Am J Obstet Gynecol 1995;

173:141. 173:141.

Sonographic assessment Sonographic assessment of of cervical length cervical length

- Transvaginal- Reproducible- Simple

(Dijkstra et al Am J Obstet Gynecol 1999)(Dijkstra et al Am J Obstet Gynecol 1999)

Assessment of Risk:Assessment of Risk:

Integration of Integration of

History, History,

Cervical lengthCervical length

FibronectinFibronectin

Prediction of spontaneous preterm delivery before 35 Prediction of spontaneous preterm delivery before 35 weeks gestation among asymptomatic low risk womenweeks gestation among asymptomatic low risk women

Cervical length Fetal fibronectin Both testsCervical length Fetal fibronectin Both tests <<25mm (percent) (percent) (percent)25mm (percent) (percent) (percent) Positive test Positive test Result 8.5 3.6 0.5Result 8.5 3.6 0.5

Sensitivity 39 23 16 Sensitivity 39 23 16

Specificity 92.5 97 99.5 Specificity 92.5 97 99.5

Positive predictive Positive predictive Value 14 20 50 Value 14 20 50

Negative predictiveNegative predictivevalue 98 98 94.4value 98 98 94.4

Adapted from: Iams, JD, Goldenberg, RL, Mercer, BM, et al. Am J Obstet Gynecol 2001; Adapted from: Iams, JD, Goldenberg, RL, Mercer, BM, et al. Am J Obstet Gynecol 2001; 184:652. 184:652.

Risk of Preterm birth < 35 Risk of Preterm birth < 35 weeksweeks

History of History of DeliveryDelivery

18-18-2626

27-27-3131

32-32-3636

>> 37 37

FFN (-)FFN (-)

CL CL << 25 25 25%25% 25%25% 25%25% 6%6%

CL 26-35CL 26-35 14%14% 14%14% 13%13% 3%3%

CL > 35CL > 35 7%7% 7%7% 7%7% 1%1%

FFN (+)FFN (+)

CL CL << 25 25 64%64% 64%64% 63%63% 25%25%

CL 26-35CL 26-35 46%46% 45%45% 45%45% 14%14%

CL > 35CL > 35 28%28% 28%28% 27%27% 7%7%

Clinical Diagnosis Preterm LaborClinical Diagnosis Preterm Labor

Clinical CriteriaClinical Criteria– Persistent Ctx 4 q 20 min or 8 q 60 minPersistent Ctx 4 q 20 min or 8 q 60 min– Cervical change/80% effacement/> 2cm dil.Cervical change/80% effacement/> 2cm dil.

Among the most common admission DxAmong the most common admission Dx Inexact diagnosis: PTL is not PTDInexact diagnosis: PTL is not PTD

– 30% PTL resolves spontaneously30% PTL resolves spontaneously– 50% of hospitalized PTL deliver @ term50% of hospitalized PTL deliver @ term

Management of Preterm LaborManagement of Preterm Labor

Bedrest, hydration, sedationBedrest, hydration, sedation NO evidence to support in the literatureNO evidence to support in the literature

Beta adrenergic receptor agonists Beta adrenergic receptor agonists (terbutaline)(terbutaline)

MechanismMechanism– Interferes w/ myosin light chain kinaseInterferes w/ myosin light chain kinase– Inhibits actin myosin interactionInhibits actin myosin interaction

EfficacyEfficacy– ? 48 hours. No change in perinatal outcome? 48 hours. No change in perinatal outcome

Side EffectsSide Effects– Tachycardia, palpitations,hypotension,SOB, pulmonary Tachycardia, palpitations,hypotension,SOB, pulmonary

edema, hyperglycemiaedema, hyperglycemia ContraindicationsContraindications

– Maternal cardiac disease, uncontrolled diabetes and Maternal cardiac disease, uncontrolled diabetes and hyperthyroidismhyperthyroidism

Magnesium SulfateMagnesium Sulfate

Mechanism of ActionMechanism of Action– Competes with Calcium at plasma memb (?)Competes with Calcium at plasma memb (?)

EfficacyEfficacy– UnprovenUnproven

Side EffectsSide Effects– Diaphoresis, flushing, pulmonary edemaDiaphoresis, flushing, pulmonary edema

ContraindicationsContraindications– Myasthesthenia gravis, renal failureMyasthesthenia gravis, renal failure

Calcium Channel BlockersCalcium Channel Blockers

Mechanism of ActionMechanism of Action– Directly block influx of Ca thru cell membraneDirectly block influx of Ca thru cell membrane

EfficacyEfficacy– UnprovenUnproven

Side EffectsSide Effects– Nausea, flushing, HA, palpitationsNausea, flushing, HA, palpitations

ContraindicationsContraindications– Caution: LV dysfunction, CHFCaution: LV dysfunction, CHF

Cyclooxygenase InhibitorsCyclooxygenase Inhibitors

Mechanism of ActionMechanism of Action– Decrease prostaglandin productionDecrease prostaglandin production

EfficacyEfficacy– UnprovenUnproven

Side EffectsSide Effects– Nausea, GI reflux, spasm fetal DA, oligoNausea, GI reflux, spasm fetal DA, oligo

ContraindicationsContraindications– Platelet or hepatic dysfunction, GI ulcerPlatelet or hepatic dysfunction, GI ulcer

– Renal dysfunction, asthmaRenal dysfunction, asthma

Antenatal SteroidsAntenatal Steroids

Recommended for:Recommended for:– Preterm labor 24 – 34 weeksPreterm labor 24 – 34 weeks– PPROM 24 – 32 weeksPPROM 24 – 32 weeks

Reduction in:Reduction in:– Mortality, IVH, NEC, RDSMortality, IVH, NEC, RDS

Mechanism of action:Mechanism of action:– Enhanced maturation lungsEnhanced maturation lungs– Biochemical maturationBiochemical maturation

Antenatal SteroidsAntenatal Steroids

Dosage:Dosage:– Dexamethasone 6 mg q 12 hDexamethasone 6 mg q 12 h– Betamethasone 12.5 mg q 24 hBetamethasone 12.5 mg q 24 h

Repeated doses - NORepeated doses - NO Effect: Effect:

– Within several hoursWithin several hours– Max @ 48 hoursMax @ 48 hours

Progesterone for History of PTB Progesterone for History of PTB

17 alpha OH Progesterone17 alpha OH Progesterone– Women with prior PTB (singleton) 24 – 26 wksWomen with prior PTB (singleton) 24 – 26 wks– (16 – 20 wks) – 36 weeks(16 – 20 wks) – 36 weeks

Reduces the risk of recurrent preterm birthReduces the risk of recurrent preterm birth– < 37 wks 36% vs 55%< 37 wks 36% vs 55%– < 35 wks 21% vs 31%< 35 wks 21% vs 31%– < 32 wks 11% vs 20%< 32 wks 11% vs 20%

Case # 1Case # 1

A 36 year old black female G2 P 0101 A 36 year old black female G2 P 0101 presents at 8 weeks gestation. presents at 8 weeks gestation.

HistoryHistory: Chronic hypertension, no meds: Chronic hypertension, no meds–Smokes 1 ppd, Drugs (-) ETOH (+)Smokes 1 ppd, Drugs (-) ETOH (+)–STI – history of chlamydia, HIV positiveSTI – history of chlamydia, HIV positive–Surgical history : LEEP, tubal ligation Surgical history : LEEP, tubal ligation