Antepartum trials that changed clinical practice Catherine Y Spong, MD Pregnancy and Perinatology...

Antepartum trials that changed clinical practice

Catherine Y Spong, MD

Pregnancy and Perinatology Branch, NICHD

National Institutes of Health

Objectives

To describe antepartum trials and studies that resulted in stopping a practice that was not beneficial (BV/TV; HUAM, FOX)

To describe trials that provided evidence for a new treatment or preventative therapy (Abx in PPROM, progesterone, BEAM, GDM)

To describe other studies and trials that result in changes in practice

The mission of the NICHD is to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives, free from disease or disability, and to ensure the health, productivity, independence, and well-being of all people through optimal rehabilitation.

Obstetrical management, especially for high-risk patient, has often adopted practices without objective evaluation

In an attempt to respond to the need for well-designed clinical trials in maternal fetal medicine, the NICHD established the MFMU Network in 1986

NICHD MFMU Origins

NICHD’s MFMU Network centers 2006-11• 14 Clinical sites• Data center • NICHD

• ~120,000 deliveries/yr• Re-competition: 5 yrs

• Columbia • Case Western• Magee Women• Northwestern • Ohio State • Oregon HSU • U Alabama• U North Carolina• U Texas-Houston• U Texas SW-Dallas• U Utah• U TMB Galveston• Wayne State• Women and Infants

NICHD MFMU Trials & clinical practice BEARS trial BV/TV PPROM antibiotic trial HUAM FOX trial Progesterone trial BEAM trial

Fox: Bloom et al NEJM 2006Progesterone: Meis et al NEJM 2003BEAM: Rouse et al NEJM 2008

BEARS: Wapner et al, AJOG 2006 Wapner et al, NEJM 2007PPROM: Mercer et al JAMA 1997

BEARS Beneficial Effects of Antenatal Repeat corticoSteroids

Aim: To determine if repeat courses of antenatal corticosteroids will decrease neonatal morbidity vs single course

Design: double-masked, placebo-controlled trial Eligibility criteria: 23 - 316 wks gestation at risk for

PTD who are pregnant >7d after initial steroid course Intervention: weekly betamethasone or placebo Primary outcome: composite outcome including

mortality, severe RDS, CLD, grade III/IV IVH, PVL Secondary outcome: 2yr followup Wapner et al, AJOG 2006

Wapner et al NEJM 357: 1190-8 Sep 20 2007

BEARS Beneficial Effects of Antenatal Repeat corticoSteroids

Wapner et al, AJOG 2006Wapner et al NEJM 357: 1190-8 Sep 20 2007

495 randomized No reduction in composite (8% vs 9%, P=0.67) Reduction in surfactant with repeat ACS (P=.02) <10th centile (24% vs 15%, P=.02)

Repeat ACS significantly reduced specific neonatal morbidities but do not improve composite neonatal

outcome with reduction in birthweight and increase in SGA

BEARS Followup At 24 to 36 months infants exposed

to weekly courses show no significant difference in: Anthropometric Measurements

Weight, Length, Head circumference Neurodevelopmental Evaluation

Bayley II PDI and MDI results

A non significant increase in cerebral palsy in infants exposed to 4 or more courses

RR: 5.7 (0.7 – 46.8)


Ronald J. Wapner, MD

Is it correct that thereis no increase in CP in <4group?what number are needed to be significant ie whats the power?

BEARS Followup

Caution Is Warranted In Using Repeat Courses Of Antenatal Corticosteroids

Until Additional Information Is Available


Repeat courses should not be used routinely but should be reserved for

women enrolled in clinical trials.


Stopped a practice



Infection/inflammation and sPTD Evidence supports infection cause of PTD:

Clinical & subclinical chorioamnionitis Bacterial vaginosis in pregnancy associated with poor

perinatal outcome, in particular an increased risk of PTD

Antibiotic trials RCT metronidazole +BV with hx prior sPTD

PTD 18% v 39%, p<.05 Morales et al 1994

RCT metronidazole+erythromycin in high risk women, +BV

PTD 23% v 37%, p<.001 Hauth et al 1994

McGregor 1990, Kurki 1992, Hay 1994, Hillier 1995

NICHD: MFMU BV/TV Trials

Aim: To establish whether metronidazole therapy will reduce the risk of PTD in women with asymptomatic bacterial vaginosis or trichomonas vaginalis

Design: double-masked, placebo-controlled trial Eligibility criteria: <24 wks, BV or TV positive Intervention: Four doses of 2g metronidazole or placebo Primary outcome: delivery at < 37 weeks’ Sample: BV: 1900 pregnant women (950/group)

BV: Carey et al, N Engl J Med 2000TV: Klebanoff et al, N Engl J Med 2001

TV: 1900 pregnant women (950/group)

Rates of Preterm Birth

0%

4%

8%

12%

16%

20%

<37 <35 <32

0%

4%

8%

12%

16%

20%

<37 <35 <32

Asymptomatic BVAsymptomatic BV Asymptomatic TVAsymptomatic TV

PlaceboMetronidazole

PTD


P<0.004

BV/TV trials TV trial stopped by DSMC after interim

analysis found increased PTD in metronidazole group

Effectiveness of treatment BV: 78% negative for BV TV: 93% negative for trichonomiasis


BV/TV trials: Conclusions Treatment of asymptomatic

BV does not reduce PTD or adverse perinatal outcomes

TV increased the risk of PTD

Results from these trials changed the practice of indiscriminate use of antibiotics in pregnancy



Stopped a practice



Stopped a practice

Preterm PROM (<32 w) Occurs in 3% of pregnancies Responsible for one third of PTD Important cause of perinatal morbidity/mortality >70% deliver within one week of ROM

Complications of prematurity & related to pPROM

Antibiotic therapy Treat/prevent ascending decidual infection to prolong

pregnancy Offer opportunity for reduced neonatal infectious and

GA dependent morbidity

n= 611 pPROM <32 w RCT antibiotics vs conservative mgmt

Antibiotics: Prolonged latency Reduced neonatal complications Reduced gestational age dependent morbidity

Broad spectrum antibiotic therapy in pPROMprolongs latency and improves neonatal outcome

The NICHD PPROM Study

Ampicillin 2gm + Erythromycin 250mg IV q6h x 48hAmoxicillin 250mg q8h + erythromycin base 333mg q8h po x 5d

Mercer et al JAMA 1997

Preterm PROM:Antibiotics are recommended to prolong latency if there are no contraindications


Stopped a practice

Therapy / treatment



Stopped a practice

Home Uterine Activity Monitoring

Premise: Uterine activity higher in women destined for PTD Uterine activity increases 24-48h before an episode

of PTL RCTs: No difference in PTB

Dyson et al 2,400 high risk women NEJM 1998

CHUMS: 1,292 high risk women AJOG 1995

NICHD MFMU

The NICHD HUAM Prediction Study Blinded monitoring of women w/ risk of PTD

Contraction frequency was related to risk of PTD

Contractions predicted PTD poorlySensitivity = 9.3% for 4 Contractions / hr PPV = 26.7% to predict birth < 35 weeks

Iams et al NEJM 2002

Deliver < 35 w

Deliver > 35 w

UC frequency is increased in women who will deliver < 35 w

Magnitude too small to be clinically useful Contractions are common in pregnancy Contractions occur late in process

HUAM not clinically useful to predict patients who will deliver preterm

The NICHD HUAM Prediction Study

HUAM not clinically useful to predict patients who will

deliver preterm


Stopped a practice

Therapy / treatment



Stopped a practice

Stopped a practice

FOX Fetal Pulse Oximetry trial

Aim: To determine if fetal pulse oximetry affects overall cesarean delivery rate; CS for FD

Design: RCT, 2-arm trial Eligibility criteria: Singleton, >36 wks Primary outcome: Cesarean delivery Status: 5087 patients enrolled Findings: Fetal oximetry not beneficial in

reducing CD or CD for fetal distress

Bloom et al, NEJM 11/2006

Background

• May 2000 – Conditional FDA approval*

• Randomized trial by Garite et al (Am J Obstet Gynecol 2000;183:1049)

* Conditional requires post-marketing surveillance

Women Enrolledn = 1010

EFM alonen = 502

EFM + Oximetryn = 508

C/S Distress 10%

C/S Dystocia 9%

C/S Total 26%

5%

19%

29%

P = 0.007

P < 0.001

P = 0.49

Garite et al, AJOG 2000

ACOG cannot endorse adoption…encourages trials

Eligible, consented participant

EFM + “Open”Fetal Oximetry

EFM + “Masked”Fetal Oximetry

STUDY DESIGN


Women screenedn = 27,570

Women consenting to study and sensor

insertion attemptedn = 5,553

Exclusioncriteria

n = 10,804

Randomizedn = 5,341

Not randomizedn = 212

Prolonged FHR decelerations during

sensor insertion n = 42

Open arm

n = 2,629

Masked arm

n = 2,712

Declined participationn = 11,425

Failed sensor insertionn = 170

0.310.300.59

747 (27.5)214 ( 7.9)521 (19.2)

692 (26.3)187 ( 7.1)490 (18.6)

Cesarean delivery: Overall Non-reassuring FHR Dystocia

0.76 400 (15) 380 (15)Forceps or vacuum

0.261565 (58)1557 (59)Spontaneous birth

Pvalue

Masked Armn=2712 (%)

Open Armn=2629 (%)

Method of Delivery


Infant Composite Outcome

0.7592 (3.4)85 (3.2)Composite outcome*

P value

Masked Armn=2712 (%)

Open Armn=2629 (%)

Characteristic

* Composite outcome includes one or more of:• 5-minute Apgar ≤ 3• Umbilical artery pH < 7.0• Seizures• Ventilator use > 24 hours• Admission to neonatal intensive care > 48 hours


Conclusions

Fetal Oximetry:

• Did not lower cesarean rates

• Did not modify infant outcomes


Fetal pulse oximetry not clinically useful as FHR monitoring adjunct to prevent Cesarean delivery


Stopped a practice

Stopped a practice

Therapy / treatment



Stopped a practice

Stopped a practice

Progesterone

•Steroid hormone•In target cells (endometrium)

•becomes tightly bound to progesterone receptor•forms a transcription factor.

•Actions of Progesterone on the MyometriumDecreases conduction of contractionsIncreases threshold for stimulationDecreases spontaneous activityDecreases number of oxytocin receptorsPrevents formation of gap junctions

NICHD: MFMU Progesterone Trial Aim: To establish if weekly progesterone injections

in women with prior spontaneous preterm delivery (sPTD) reduces the risk of PTD

Design: double-masked, placebo-controlled trial Eligibility criteria: singleton pregnancy 16-20 wks

with documented previous sPTD Intervention: progesterone or placebo

Meis et al, N Engl J Med 2003

1o outcome: delivery <37 wks Sample: 463 pregnant women

Characteristics

Qualifying delivery (wks) 30.5 31.3 Maternal age (yrs) 26.0 26.5 Married 51% 46% African American 59% 58% Mean BMI 26.9 25.9 Smoking 22% 19%

17-P Placebo


Progesterone: Rates of Preterm Birth

0%

10%

20%

30%

40%

50%

60%

70%

< 37 <35 <32 Afr.American

Non Afr-Am

P<0.0001 P<0.016 P<0.018

Meis et al, N Engl J Med 2003Meis et al, N Engl J Med 2003

17P

17P17P

17P

17P

P=0.010 P=0.004

AfricanAmerican

Non AfricanAmerican

Progesterone prevents neonatal complications

0%

2%

4%

6%

8%

10%

12%

14%

16%

neonataldeath

RDS BPD IVH* NEC*

17 P

17 P17 P 17 P

Placebo

Placebo

Placebo

Placebo

Placebo


Effectiveness of Progesterone 5-6 women with a previous sPTB would need

to be treated to prevent one birth <37 wks

12 women with a previous sPTB birth would need to be treated to prevent one birth <32 wks

Low dose ASA to prevent CVA, NNT=102B-blocker use in MI patients to prevent cardiac death NNT=42

Progesterone prevents recurrent preterm delivery

Weekly injections of progesterone prevented recurrent preterm birth and improved the neonatal outcome for pregnancies at risk

Effective in preventing very early as well as later preterm birth

Effective in both African American and Non-African American women


ACOG Committee Opinion:Use of Progesterone to Reduce Preterm Birth

Obstet Gynecol 2003;102:1115-6

Recommends the use of progesterone to prevent PTD for women with prior sPTD

Impact of progesterone to prevent recurrent preterm birth

10,000 preterm births could have been prevented in 2002 if all eligible pregnant women at high risk for PTD received 17P

Resulting in reduction of preterm birth of ~2%

Petrini et al, Obstet Gynecol 2005; 105(2)

STTARS Seventeen alpha-hydroxyprogesterone caproate in Twins and Triplets: A Randomized Study)

Double-masked placebo-controlled trial to determine whether 17 hydroxyprogesterone prevents preterm birth in multifetal pregnancies.

Intervention: 17-OHPC (250mg IM) or placebo weekly beginning at 16-20 weeks

Primary outcome: Preterm delivery < 35 wks Status: complete, 661 women randomized

Rouse et al, NEJM 2007; 357:454-61

0%

20%

40%

60%

80%

100%

<37 wks <35 wks <32 wks <28 wks

Twins: Delivery or Fetal Death Prior to 37, 35, 32 or 28 weeks

Rouse et al, NEJM 2007; 357:454-61

17-OHPC

Placebo

Delivery or Fetal Death Before 35 WeeksBy Conception Method & Chorionicity

0%

20%

40%

60%

80%

100%

Spont. ART MonoChor DiChor

17-OHPC Placebo

Rouse et al, NEJM 2007; 357:454-61

STTARS Seventeen alpha-hydroxyprogesterone caproate in Twins and Triplets: A Randomized Study)

17P did not reduce the rate of PTB in women with twins

This lack of benefit applied: - whether conception was spontaneous or after ART or - whether there was a di- or monochorionic placentation - regardless of gestational age cutoff

17-OHPC was well tolerated with side effects limited to the injection site

The rate of PTB in the placebo group was similar to national norms (34.9 vs 35.2 weeks)

Rouse et al, NEJM 2007; 357:454-61

Recommends the use of progesterone to prevent PTD for women with prior sPTD

May be considered for use in asymptomatic women with a very short cervix

Obstet Gynecol 2008;112:963-5


Stopped a practice

Stopped a practice

Preventative therapy

Therapy / treatment



Stopped a practice

Stopped a practice

BEAM Beneficial Effects of Antenatal Magnesium

Aim: To determine if antenatal MgSo4 can reduce the risk of cerebral palsy in offspring

Design: double-masked, placebo-controlled trial Eligibility criteria: 24 - 31 wks gestation with

PROM, PTL or planned delivery Intervention: MgSo4 or placebo

Primary outcome: composite outcome of death <1 yr or cerebral palsy at 24 months

Sample size: 2220, 2241 enrolled!co-funded by NINDS

BEAM To determine if antenatal MgSO4 can reduce the risk of cerebral palsy

*co-funded by NINDS0%

2%

4%

6%

8%

10%

12%

14%

Placebo MgSO4

Cerebral Palsy Death

Beneficial Effects of Antenatal Magnesium

N Engl J Med. 2008 August 28; 359

• 2,241 women randomized

• 95.6% follow up

• Significant reduction in moderate/severe CP from 3.5% to 1.9%RR(95%CI) 0.55(0.32-0.95)

• Risk of death not different

• NNT=63

NICHD MFMU Trials & clinical practice BEARS trial BV/TV PPROM antibiotic trial HUAM FOX trial Progesterone trial BEAM trial GDM trial

Stopped a practice

Stopped a practice


Therapy / treatment


Potential preventative therapy


Stopped a practice

Stopped a practice

Mild gestational diabetes trial Aim: To test whether identification and dietary

treatment of mild GDM reduces composite outcome Design: RCT with additional observational cohorts Eligibility criteria: 24-29 wks gestation,

normal FBS, abnormal 3h-GTT Intervention: treatment (counseling, dietary

management) vs standard non-GDM care Primary outcome: Fetal composite Status: 1,889 patients enrolled Submitted to SMFM 2008

Mild gestational diabetes trial

Treatment of mild GDM reduced• Birthweight

• Macrosomia by 50%• Neonatal fat mass• Shoulder dystocia • Cesarean delivery • Preeclampsia and gestational hypertension

Treatment of mild GDMTreatment of mild GDM

0

2

4

6

8

10

12

14

16

BW>4000g LGA SGA

Treated Untreated

%

P<.001 P<.001

P>.4

n=28 n=65 n=34 n=65 n=29n=36

SECONDARY OUTCOMESSECONDARY OUTCOMES

05

10152025303540

Induction CD CD adj Shoulderdystocia

Treated Untreated

%

P=.021

P=.011

P=.019

P=.86

Shoulder dystocia:

7/476 Treated

18/455 Untreated

P=0.019

NNT 95% CI

Macrosomia 12 (8, 22)

Shoulder Dystocia 40 (21, 262)

Cesarean Delivery 14 (8, 95)

Gest HTN/ Preeclampsia 20 (11, 103)

Identification and treatment of mild GDM associated with significant benefits:

NICHD MFMU Trials & clinical practice BEARS trial BV/TV PPROM antibiotic trial HUAM FOX trial Progesterone trial BEAM trial GDM trial

Stopped a practice

Stopped a practice


Therapy / treatment


Potential preventative therapy


Stopped a practice

Stopped a practice

Provided data to support therapy

Findings that Impact Clinical Practice

Timing repeat CD – ACOG Committee Opinion Induction of labor/VBAC – ACOG committee opinion Periviable calculator – website calculator Inhaled NO – limitation of use in preterm infants SIDS – AAP initiatives, policy statements Cesarean on maternal request – ACOG Committee Opinion Late preterm infants – AAP+ACOG committee opinion Perinatal risks + ART – ACOG committee opinion Screening for fetal chromosomal abN – ACOG com opinion Subclinical hypothyroidism – ACOG committee opinion Hypothermia for HIE – AAP statement

Timing of Repeat Elective CD 13,258 women with elective repeat CD >37 35.8% delivered before 39 weeks Complications increased

2 fold at 37 weeks 20% increase still at 38 4/7- 38 6/7 15% at 37w; 11% at 38w; 8% 39wks

Tita, A for MFMU. NEJM, Vol. 360, No. 2, January 8, 2009;111-20

Respiratory, mechanical ventilation, sepsis, hypoglycemia, NICU, >5d hospitalizedAffirmed ACOG recommendation of delivery at/after 39 weeks

N Engl J Med, 2008;358, 1672-1681

http://www.nichd.nih.gov/about/org/cdbpm/pp/prog_epbo/epbo_case.cfm?renderforprint=1

23555

NRN: Extremely Preterm Birth Outcome Data

N Engl J Med, 2008;358, 1672-1681

http://www.nichd.nih.gov/about/org/cdbpm/pp/prog_epbo/epbo_case.cfm?renderforprint=1

24780

NRN: Extremely Preterm Birth Outcome Data

NICHD NRN: Whole Body Hypothermia To assess the safety and

effectiveness of whole body hypothermia in term infants with moderate or severe HIE.

Infants enrolled between July 2000 and May 2003 Randomized to whole body cooling or standard care.

Cooling blanket to esophageal temperature 33.50 C for 72 hours then slow re-warming

Standard ICU care for control infants.

N Engl J Med. 2005 Oct 13;353(15):1574-84

Hypothermia TrialWhole Body Cooling

N Engl J Med. 2005 Oct 13;353(15):1574-84

0%

10%

20%

30%

40%

50%

60%

70%

Standard care Hypothermia

n=106 n=102

RR(95%CI) 0.72 (0.55-0.93)

Death or Moderate/Severe disability• Significant reduction in

moderate/severe disability from 62% to 45%

• Effect persistent after adjustment for clinical site and level of HIE at randomization

• NNT=6

Combined Death Or Disability Rates

0

10

20

30

40

50

60

70

80

90

COOL CAP NICHD

Standard Care Hypothermia

PE

RC

EN

T O

F IN

FA

NT

S

Higgins, Ob Gyn 2005

Current evidence supports the conclusion that mild to moderate hypothermia holds promise for the amelioration of neural injury after a perinatal hypoxic-ischemic insult

Electronic Fetal Heart Rate Monitoring: Revisited

Obstet Gynecol2008:112661-665

ART & Pregnancy OutcomesObstet Gynecol 2007:109; 967-977

Weight Gain During Pregnancy:Reexamining the Guidelines

Committee to Reexamine IOM Pregnancy Weight Guidelines

New recommendationsPrepregnancy BMI category

Total weight gain

(lb, kg)

Rate of weight gain

2nd and 3rd trimester

(lb/wk, kg/wk)

Underweight

(< 18.5 kg/m2)

28-40, 12.5-18 1.0 (1.0-1.3),

0.51 (0.44-0.58)

Normal-weight

(18.5-24.9 kg/m2)

25-35, 11.5-16 1.0 (0.8-1.0),

0.42 (0.35-0.50)

Overweight

(25.0-29.9 kg/m2)

15-25, 7-11.5 0.6 (0.5-0.7),

0.28 (0.23-0.33)

Obese

(≥ 30.0 kg/m2)

11-20, 5-9 0.5 (0.4-0.6),

0.22 (0.17-0.27)

*Calculations assume a first-trimester weight gain of 1.1-4.4 lb (0.5-2.0 kg)

Use of WHO BMI categories

Closed interval for obese women

Category names changed from “low” “normal” “high” and “obese”

Provisional guidelines*:mothers of twins

Prepregnancy BMI category Weight gain at term

Normal-weight 37-54 lb,17-25 kg

Overweight 31-50 lb,14-23 kg

Obese 25-42 lb,11-19 kg

*Based on the interquartile (25th-75th percentile) of gains of women who delivered twins at term (37-42 wk gestation) with birth weights ≥ 2,500 gNote: Insufficient data are available to offer a guideline for underweight women

Recommendations for special populations Short stature: no modification Young age: no modification; use adult BMI

tables Racial/ethnic subgroups: no modification Primiparity: no modification, but trade-off

should be studied further Smokers: no modification, but stop smoking

Consensus Conference:Vaginal Birth After Cesarean (VBAC)

Consensus Conference March 8-10, 2010

Bethesda, Marylandhttp://consensus.nih.gov/future.htm

MOMS Centers The Children’s Hospital

Of Philadelphia University Of California-

San Francisco Vanderbilt University

Medical Center Coordinating Center

The George Washington University Biostatistics Center

NICHD Pregnancy and

Perinatology Branch

Management of Myelomeningocele Study

(MOMS) Aim: To compare the safety and efficacy of in utero repair of

open neural tube defects with standard postnatal repair Intervention: Unmasked randomized clinical trial Primary outcome: Infant death or need for ventricular shunt

by 1 year of life; Bayley Scales of Infant Developmental MDI and functional anatomic level of lesion at 30 months corrected age

Sample size: 200 (100/group) Screening and randomization: Central preliminary

screening and central randomization to MOMS center Outcome evaluation by blinded independent investigators

MOMS Study Update

Recruitment started in March 2003 As of August 2010, 178 patients randomized 12 and 30-month follow-up exams underway

with 99% compliance Supplemental funding for more extensive

urological follow-up began April 2005

MOMS Screening and Recruitment

>240 referred to MOMS center

16% refused consent

21% not eligible

178 randomized

-Other fetal anomaly found (31%)-No hindbrain herniation (25%)

-Risks too high (30%)-Cannot comply with travel/FU (23%)-Termination/likely termination (23%)

MOMS Contact for Potential Patients

Call toll free: 1-866-ASK-MOMS e-mail: [email protected]

web: http://www.spinabifidamoms.com

The George Washington University Biostatistics Center 6110 Executive Blvd, Suite 750 Rockville, MD 20852

Objectives Accomplished!

To describe trials and studies that resulted in stopping a practice that was not beneficial (BV/TV; HUAM, FOX)

To describe trials that provided evidence for a new treatment or preventative therapy (Abx in PPROM, progesterone, BEAM, GDM)

To describe other studies and trials that result in changes in practice

The goal: healthy children, mothers and families

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Antepartum trials that changed clinical practice Catherine Y Spong, MD Pregnancy and Perinatology...

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