Obstetrics on the Cutting Edge: Research Information on the

Progress in OBGYN 2015Progress in OBGYN 2015

Horizon

Alan T. N. Tita, MD, PhDAlan T. N. Tita, MD, PhD

Professor Professor

University of Alabama at BirminghamUniversity of Alabama at Birmingham

Conflict of Interest

●PI for some these studies

Objective● Briefly review research that will likely

influence obstetric practice including:

– Selected UAB / MFMU Network research

– Other recently completed research

NICHD MFMU Network

• Columbia • Case Western• Colorado• Northwestern • Ohio State • Duke • U AlabamaU Alabama• U North Carolina• U Texas‐Houston• U Texas SW‐Dallas• U Utah• U TMB Galveston• Stanford U• Brown U

CESAREAN SECTION OPTIMAL CESAREAN SECTION OPTIMAL ANTIBIOTIC PROPHYLAXISANTIBIOTIC PROPHYLAXIS

(C/SOAP) TRIAL(C/SOAP) TRIAL

HypothesesHypotheses

ExtendedExtended--spectrum prophylaxis spectrum prophylaxis (with (with azithromycinazithromycin)) compared to compared to cefazolincefazolin alone reduces risk ofalone reduces risk ofcefazolincefazolin alone reduces risk of alone reduces risk of

1.1. PostPost--cesarean infectioncesarean infection

2.2. Neonatal morbidityNeonatal morbidity

Antibiotic ProphylaxisAntibiotic Prophylaxis

↓Infectious morbidity: ↓Infectious morbidity: 50%50%

CostCost--effectiveeffective CostCost--effectiveeffective

MugfordMugford: BMJ, 1989: BMJ, 1989SmaillSmaill: Cochrane, 2013: Cochrane, 2013ChelmowChelmow: AJOG, 2004: AJOG, 2004

Unscheduled cesareans: Unscheduled cesareans: Standard preStandard pre--incision incision cefazolincefazolin

FollowFollow--upup Puerperal InfectionPuerperal Infection

Di hDi h 5%5%DischargeDischarge 5%5%

6 weeks PP6 weeks PP 77--12%12%

Extended ProphylaxisExtended Prophylaxis

cefazolincefazolin ++

22ndnd AntibioticAntibiotic22ndnd AntibioticAntibiotic

•• AzithromycinAzithromycin

•• MetronidazolMetronidazol

Why Why AzithromycinAzithromycin??

Covers additional organismsCovers additional organisms

•• UreaplasmaUreaplasma sp. ++sp. ++

•• Most common organisms in Most common organisms in postpost--cesarean infectionscesarean infections

ExtendedExtended--spectrum Prophylaxis:spectrum Prophylaxis:

↓Total infection↓Total infection

↓Hospital stay↓Hospital stay

–– ↓ Costs ↓ Costs

Andrews: Andrews: O&G, 2003O&G, 2003N=597N=597

17%19%

25%28%

15

20

25

30

35

Per

cen

t

Extended

Standard

0.8%

17%

3.6%0

5

10

15

Endometritis Wound Infections Endometritis orWound Infection

P Standard

Tita: Tita: O&GO&G, 2008, 2008

15

20

25

30

met

riti

s (%

)

Narrow spectrum prophylaxis

Routine extended prophylaxis

Trial of extended spectrum prophylaxis

23%

16%

2.1%

0

5

10

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

Year

En

do

m

Extended Prophylaxis: Extended Prophylaxis: ConcernsConcerns

GeneralizabilityGeneralizability (1 center)(1 center)

No data on preNo data on pre--incision useincision usepp–– BenefitsBenefits

–– Neonatal exposureNeonatal exposure

CostCost--effectivenesseffectiveness

C/SOAP (N=2000)C/SOAP (N=2000)

NonNon--elective cesareanelective cesarean

RCTRCT

ExclusionsExclusions

RCTRCT(Routine cefazolin for all)(Routine cefazolin for all)

AzithromycinAzithromycin PlaceboPlacebo

C/SOAP TrialC/SOAP Trial

OutcomesOutcomesPostpartum infection (6 weeks)Postpartum infection (6 weeks)

Neonatal/infant morbidity (3 months)Neonatal/infant morbidity (3 months)

StatusStatus

●● N=2013 enrolled (13 sites)N=2013 enrolled (13 sites)

●● Completing followCompleting follow--upup

●● Results within the next yearResults within the next year

Antenatal Late Preterm Steroids Antenatal Late Preterm Steroids (ALPS) RCT(ALPS) RCT

Primary Research Question Primary Research Question --ALPSALPS

●● In patients with an anticipated In patients with an anticipated late late PTBPTB

–– Not previously received a steroids Not previously received a steroids

●● Does antenatal corticosteroids reduce risk ofDoes antenatal corticosteroids reduce risk of●● Does antenatal corticosteroids reduce risk of Does antenatal corticosteroids reduce risk of respiratory and other neonatal morbidity? respiratory and other neonatal morbidity?

Late Preterm Healthcare BurdenLate Preterm Healthcare BurdenDischarge Delays: 42% LP vs. 5% at termDischarge Delays: 42% LP vs. 5% at term

10

2030

40

50

60

Full termLate preterm

Mean difference in the cost of care for a LP infant: $ 3877Mean difference in the cost of care for a LP infant: $ 3877

US projections based on 9.1% LP rate: US projections based on 9.1% LP rate: $1.4 $1.4 billionbillion dollarsdollars

Wang et al, Pediatr 114:372, 2004

0

10

Temp Pro

blems

Hypoglycemia

IV Fl

uids

Resp D

istre

ss

Jaundice

Late preterm

McIntire and Leveno, Obstet Gynecol, 2008;111:35-41

US Late Preterm Singleton US Late Preterm Singleton BirthsBirths

7%

5%

14%

40%<32 weeks32 weeks33 weeks7%

13%

22%

33 weeks34 weeks35 weeks36 weeks

Source: NCHS, final natality dataPrepared by March of Dimes Perinatal Data Center, April 2006.

75% of all pts !

Late preterm infants populate the Late preterm infants populate the NICUNICU

15000

20000

25000

30000

of P

atients

0

5000

10000

15000

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Estimated Gestational Age (wks)

Num

ber

o

Clark R et.al, Pediatrix Database, 2005

Neonatal Mortality RatesNeonatal Mortality Rates

*p<0.001, †p=0.02 McIntire D, Leveno K. Obstet Gynecol, 2008;111:37-41

Can we improve outcome of LP Can we improve outcome of LP infants?infants?

Study Design Study Design –– Inclusion Inclusion CriteriaCriteria

●● RCT of BMZ vs. matching placeboRCT of BMZ vs. matching placebo●● Singleton at 34 0/7 to 36 5/7 weeks Singleton at 34 0/7 to 36 5/7 weeks ●● One of 3 categories:One of 3 categories:

–– ROMROM

–– Preterm laborPreterm labor

–– Planned delivery for any indicationPlanned delivery for any indication

●● Likely to deliver >12 hours from 1Likely to deliver >12 hours from 1stst dose dose

1100 Outcome: Outcome: Respiratory Support or Respiratory Support or

Death in 1Death in 1stst 72 hours72 hours●● CPAP or highCPAP or high--flow nasal flow nasal cannulacannula (HHFNC) (HHFNC)

●● Mechanical ventilationMechanical ventilation

●● Oxygen requirement of FiOOxygen requirement of FiO2 2 ≥ 0.3≥ 0.3

●● ECMOECMO

●● Stillbirth or neonatal deathStillbirth or neonatal death

ALPS StatusALPS Status

●● 2792 of planned 2800 enrolled (end 2/2015)2792 of planned 2800 enrolled (end 2/2015)

●● Completing followCompleting follow--up (3 and 6 months)up (3 and 6 months)

●● Expect results within next yearExpect results within next year

CONGENITAL CMV INFECTION PREVENTION

TRIAL(CMV Imm ne glob lin)(CMV Immune globulin)

Research Question

● Does antenatal administration of CMV immune globulin to pregnant women with primary CMV lower the risk of:

1. Congenital CMV infection

2. Infant neurologic morbidity at age 2

CMV●40,000 congenital infections / year

●Primary maternal infection

– 40% fetal transmission40% fetal transmission

● CMV Immune globulin may prevent transmission and reduce sequelae.

– Small observational study

HIG None p-value

CMV Hyperimmune Globulin Therapy

NIGRO, NEJM, 2005

Congenital CMV transmission

16% 40% 0.04

Symptomatic CMV 3.2% 50% <0.001

HIG (N=62)

Placebo (N=61)

P-value

RCT of Hyperimmune globulin

Revello, NEJM, 2014

Congenital CMV 30% 44% 0.13

Adverse obstetric event (PTB, SGA)

13% 2% 0.06

Design

● CMV serology – early (<24 weeks)

● Enroll into trial if positive for 10 CMV

– Sero-conversion

– IgM + low avidity IgG

● Randomization prior to 24 weeks

– CMV Hyperimmune globulin (100m/kg)

– Placebo (identical)

CMV RCT Status

●105,000 screened

●~200 enrolled (N=800)

●Open to all patients

ThyroxineThyroxine Therapy forTherapy forSubclinical Hypothyroidism orSubclinical Hypothyroidism or

HypothyroxinemiaHypothyroxinemia During During PregnancyPregnancy(TSH Trial)(TSH Trial)

Research QuestionIs thyroxine treatment of women withIs thyroxine treatment of women with

a) subclinical hypothyroidism or a) subclinical hypothyroidism or

b) b) hypothyroxinemiahypothyroxinemia

diagnosed in the first half of pregnancydiagnosed in the first half of pregnancydiagnosed in the first half of pregnancy diagnosed in the first half of pregnancy associated with intellectual improvement associated with intellectual improvement in their offspring at age 5 years?in their offspring at age 5 years?

●● Wechsler Preschool and Primary Scale Wechsler Preschool and Primary Scale of Intelligence (WPPSIof Intelligence (WPPSI--III)III)

Subclinical thyroid dysfunction● 3-4% of pregnant women

– Subclinical hypothyroidism: ↑TSH, ↔ FT4

– Hypothyroxinemia: ↔ TSH, ↓FT4

C● Controversy regarding:

– Association with low IQ in offspring

– Ameliorated by treatment during pregnancy

Haddow, NEJM 1999Pop, Clin Endo, 1999, 2003

Design● TFT screen – early (<21 weeks)

● Randomization prior to 21 weeks

– Levothyroxine vs. identical placebo

● 2 strata

– Subclinical hypothyroid (N=670)

– Hypothyroxinemia (N=500)

● 1o outcome: Neurodevelopment at 5 years

TSH RCT Status● 5-year follow-up complete this spring

● Results within 6-12 months

– Universal TFTs during pregnancy?

Automated Automated FetalFetal ECG ECG STSTANANalysisalysis (STAN) as adjunct (STAN) as adjunct

f FHR M it if FHR M it i

STAN TrialSTAN Trial

for FHR Monitoringfor FHR Monitoring(N=11000)(N=11000)

Intrapartum monitoring

Continuous Intrapartum FHR Monitoring

Cesarean delivery rate

%

66% 85% % US women cEFM in labor

%

Trends in CS and CP RatesTrends in CS and CP Rates

15

20

25

0

5

10

1970 1975 1980 1985 1990 1995 2000

Cesarean Section RateCerebral Palsy Rate

Clark SL, et al. Am J Obstet Gynecol 2003;188:628-33.

Sponsored by:NICHDACOGSMFM

Category II: IndeterminateCategory II: Indeterminate

●● All tracings not categorized as Category All tracings not categorized as Category I or III I or III

●● Appreciable fraction Appreciable fraction -- 33%33%

●● Management uncertainManagement uncertainE amples●● Management uncertainManagement uncertain

• Moderate variability with bradycardia• Minimal FHR variability• Absent variability with no recurrent decels• Recurrent variable decels with moderate variability• Recurrent late decels with moderate variability

Examples

A Cat II tracing A Cat II tracing needsneeds a back up test! a back up test!

●● Fetal scalp pH: < 3% of institutions in the U.S. Fetal scalp pH: < 3% of institutions in the U.S. (ACOG Survey of U.S. Hospitals)(ACOG Survey of U.S. Hospitals)

●● Others have never been proven or accepted: Others have never been proven or accepted: Continuous scalp pH, fetal pulse Continuous scalp pH, fetal pulse oximetryoximetry

●● ST AnalysisST Analysis–– developed for this purpose in minddeveloped for this purpose in mind

–– tested in these labor situationstested in these labor situations

–– the only currently FDA approved backupthe only currently FDA approved backup

Device Description Device Description (NEOVENTA)(NEOVENTA)

●● Std EFM capabilities:Std EFM capabilities:–– External ultrasound or fetal External ultrasound or fetal

spiral electrode (FSE)spiral electrode (FSE)

–– TOCO or IUPC TOCO or IUPC

& &

●● Fetal ECG (ST) AnalysisFetal ECG (ST) Analysis

Basis for STAN TechnologyBasis for STAN Technology

“Labor puts the fetus on a treadmill”

What is being recorded?What is being recorded?

30 ECG complexes

T-wave amplitude is divided by

the QRS amplitude which gives T/QRS ratio

average ECG

STAN clinical managementSTAN clinical management

Examples of STAN Tracings: Category II Examples of STAN Tracings: Category II FHRFHR

Second stage recording NVD, Apgar 9-10 CA pH 7.18 CV pH 7.27

CS FD, Apgar 8-9 CA pH 7.14, Bdecf 8.7 mmol/L CV pH 7.34, Bdecf 6.3mmol/L

STAN clinical experienceSTAN clinical experience

Cochrane ReviewCochrane ReviewNeonatal EncephalopathyNeonatal Encephalopathy

Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. during labour. Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2006, 2006,

Issue 3. Art. No.: CD000116. DOI: Issue 3. Art. No.: CD000116. DOI: 10.1002/14651858.CD000116.pub2.10.1002/14651858.CD000116.pub2.

Cochrane ReviewCochrane ReviewCord pH < 7.05 + Base Deficit > 12 mmol/LCord pH < 7.05 + Base Deficit > 12 mmol/L

Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. during labour. Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2006, 2006,

Issue 3. Art. No.: CD000116. DOI: Issue 3. Art. No.: CD000116. DOI: 10.1002/14651858.CD000116.pub2.10.1002/14651858.CD000116.pub2.

Cochrane ReviewCochrane ReviewOperative Vaginal DeliveryOperative Vaginal Delivery

Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. during labour. Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2006, 2006,

Issue 3. Art. No.: CD000116. DOI: Issue 3. Art. No.: CD000116. DOI: 10.1002/14651858.CD000116.pub2.10.1002/14651858.CD000116.pub2.

Cochrane ReviewCochrane ReviewCesarean DeliveryCesarean Delivery

Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. during labour. Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2006, 2006,

Issue 3. Art. No.: CD000116. DOI: Issue 3. Art. No.: CD000116. DOI: 10.1002/14651858.CD000116.pub2.10.1002/14651858.CD000116.pub2.

A study in US?A study in US?

●● No RCT in North AmericaNo RCT in North America●● Differences in practice patternsDifferences in practice patterns

F t l H liF t l H li–– Fetal pH samplingFetal pH sampling–– Operative deliveriesOperative deliveries–– Intermittent EFMIntermittent EFM

●● Differences in populationDifferences in population

Study Design Study Design -- STANSTAN

RCT: 2 groupsRCT: 2 groups

1. Fetal STAN electrode inserted and data available 1. Fetal STAN electrode inserted and data available to caregivers (open group)to caregivers (open group)

2. Fetal STAN electrode inserted, but data masked 2. Fetal STAN electrode inserted, but data masked to the caregivers (masked group)to the caregivers (masked group)

Primary OutcomePrimary Outcome

●● Any of the following:Any of the following:–– intrapartum fetal deathintrapartum fetal death

–– neonatal deathneonatal deathneonatal deathneonatal death

–– Apgar score ≤ 3 at 5 minutesApgar score ≤ 3 at 5 minutes

–– seizure(s)seizure(s)

–– cord artery pH ≤ 7.05 and BD cord artery pH ≤ 7.05 and BD >> 1212

–– neonatal encephalopathyneonatal encephalopathy

–– Intubation for ventilation at deliveryIntubation for ventilation at delivery

ResultsResults

●● N=11,108N=11,108Outcome Open STAN Masked STAN P-value

1o outcome 1.4% 1.3% 0.43

Cesarean 17% 16% 0.29

Operative VD 6.0% 6.0% 0.79

Effect of Expanded Effect of Expanded Midwifery and Hospitalist Midwifery and Hospitalist

Services on PrimaryServices on PrimaryServices on Primary Services on Primary Cesarean RatesCesarean Rates

Rosenstein, SMFM 2015

ObjectiveObjective

●● Impact of changing L&D care from: Impact of changing L&D care from: –– a private practice model (individual a private practice model (individual ObsObs))

–– to 24to 24--hr Obstetricianhr Obstetrician--midwife hospitalistmidwife hospitalistto 24to 24 hr Obstetricianhr Obstetrician midwife hospitalist midwife hospitalist model model

DesignDesign

●● Prospective (2005Prospective (2005--2014)2014)

●● Before and after designBefore and after design

●● SingletonsSingletons●● SingletonsSingletons

●● Single community hospitalSingle community hospital

ResultsResults

Outcome Before After p-value

Cesarean 32% 25% 0.007

VBAC 11% 23% 0.001

*Rates unchanged in publicly insured service with prior hospitalist model

PRESERVEPRESERVE--1 RCT1 RCT

GoalGoal

●● Test Test antithrombinantithrombin (recombinant) (recombinant) replacement for the treatment of replacement for the treatment of early onset preeclampsiaearly onset preeclampsia

PRESERVEPRESERVE--1 Rationale1 RationaleAntithrombinAntithrombin

●● Anticoagulant and antiAnticoagulant and anti--inflammatoryinflammatory

●● Deficient in preeclampsiaDeficient in preeclampsia

●● Promising preliminary studiesPromising preliminary studies●● Promising preliminary studiesPromising preliminary studies–– Pregnancy prolongation (1 week)Pregnancy prolongation (1 week)

–– Higher birth weightHigher birth weight

–– Lower SGA riskLower SGA risk

PRESERVEPRESERVE--1 Design1 Design

●● RCTRCT–– AntithrombinAntithrombin infusioninfusion

–– PlaceboPlacebo

●● Inclusion criteriaInclusion criteria–– Early onset preeclampsia Early onset preeclampsia

–– 23 0/7 to 29 6/7 weeks23 0/7 to 29 6/7 weeks

–– Expectant management plannedExpectant management planned

●● Outcomes: GA and Neonatal morbidityOutcomes: GA and Neonatal morbidity