NICHD Maternal-Fetal Medicine What ’ ’ s New That Will Help You ’ ’ Units Network MFMU Research Network • Started in 1986. • Competitively renewed every 5 years. • Priorities include: – Reduce the rates of preterm birth, fetal growth abnormalities, neurologic sequelae of the newborn, and maternal complications of pregnancy, and, Bob Silver – Evaluate maternal and fetal interventions for efficacy, safety, and cost-effectiveness. University of Utah • Has become the premiere obstetric clinical trials network on the planet. Salt Lake City, Utah • Has accumulated 30 years of data and biologic samples. 1
When is the best time for delivery? Increasing maternal and perinatal risks after 39 weeks < 39 wks ≥ 42 wks Expectant Delivery management 39 - 41 wks ? 2
Maternal Complications * * * * • Pregnancies that continue beyond * 39 weeks are associated with increased risks of: – Cesarean delivery – Operative vaginal delivery – 3 rd and 4 th degree lacerations – Febrile morbidity – Hemorrhage Statistical significance as compared to rate of cesarean delivery in the previous week gestation *p<.05 MFMU FOX: Cesarean * * * * * * * P < .001 % * * * * * 39w 40w 41w Statistical significance as compared to rate of outcome in the previous week gestation: *p<.05 3
MFMU FOX: Maternal Perinatal Complications adverse composite • Pregnancies that continue beyond 39 weeks are associated with increased risks of: – Stillbirth P < .001 – Meconium aspiration syndrome % – Mechanical ventilation – Birth trauma – Neonatal seizures/ICH/ encephalopathy – Neonatal sepsis 39w 40w 41w – UA pH ≤ 7/BE < -12 Prospective fetal mortality ratio by single weeks of gestation: United States, 2005 Perinatal Death • Perinatal death nadirs between 37-38 weeks and increases steadily thereafter Gestational Age Loss Rate 37 0.7/1000 38 1.3/1000 39 1.4/1000 40 2.4/1000 43 41 2.8/1000 MacDorman et al; NVSS 2009;57:1-20 4
Cord Gas Abnormalities Severe Neonatal Complications 39 vs. 41 weeks Adjusted OR 6% 1.6 (1.4, 1.9) 40 vs. 39 weeks: adjusted OR 1.47 (1.1, 2.0) 41 vs. 39 weeks : adjusted OR 2.04 (1.5, 2.78) 5% Adjusted OR 4% 1.59 (1.17, Adjusted OR 2.16) 1.65 (1.01, 3% 2.77) 2% 1% 0% Hemistad et al, Caughey et al, 2005 Caughey et al, 2005 2006 UA pH<7.0 BE< -12 UA pH<7.10 39 weeks 0.78% 1.02% 3.40% 41 weeks 1.09% 1.72% 5.30% MFMU FOX: Neonatal When is the best time for adverse composite delivery? P = 0.047 % Expectant Delivery management 39w 40w 41w 39 - 41 weeks 5
Induction and cesarean delivery: Elective inductions only Common wisdom • Retrospective cohort studies – Induction of labor prior to 41 weeks of gestation is associated with an approximately 2-fold higher risk of cesarean delivery in nulliparous women When is the best time for Standard of Care delivery? • Patients undergoing induction of labor should be counseled about a 2 – fold increased risk of cesarean Expectant Delivery management 39 - 41 weeks ACOG #107 Obstet Gynecol 2009; 114:386-97 6
The problem Spontaneous labor CS rate=20% N=20 39 weeks N= 100 • Spontaneously laboring women are not the right comparison group IOL – Cannot choose between EIOL (strategy) and spontaneous labor (event) – Choice is between EIOL and expectant management • The latter may lead to spontaneous labor CS rate=35% N=35 • Also conveys downstream possibilities that may increase the CS rate Induction vs. Expectant N=100 30% Spontaneous labor Management CS rate=20% at 39 weeks N=6 70 – RCT of women at 41 weeks of gestation (N = 3407) 50% labor at 40 CS rate=30% weeks CS rate= N=11 31% 35 39 weeks CS Medical or Post dates IOL CS rate=40% % N= 100 N=14 IOL CS rate=35% N=35 Hannah et al, NEJM, 1992 7
IOL prior to 41 weeks: Induction vs. Expectant HYPITAT Management (CS%) • IOL vs. expectant management for mild hypertensive disease after 36 weeks (N = 756) Week of IOL Spontaneous Induction – IOL • Adverse maternal composite: RR 0.71 (0.59-0.86) 38 weeks 11.9% 7.0% Cesarean Delivery 39 weeks 14.3% 9.1% P = .09 40 weeks 20.4% 10.9% % 41 weeks 24.3% 14.9% Caughey et al, AJOG 2006;195:700-5 Koopmans et al. Lancet 2009; 374:979-88 EIOL vs. expectant Induction vs. Expectant management Management (CS%) • Retrospective Cohorts: Northwestern Week of IOL Spontaneous Expectant aOR (95% CI) – 588 women at 39 weeks with favorable cervix Induction • Power: 1/3 reduction in CS from 38 weeks 11.9% 7.0% 13.3% 1.80 (1.29-2.53) 30% at EIOL 39 weeks 14.3% 9.1% 15.0% 1.39 (1.08-1.80) – 204 women at 39 weeks with unfavorable cervix 40 weeks 20.4% 10.9% 19.0% 1.24 (1.27-1.62) • Power: 1/2 reduction in CS from 41 weeks 24.3% 14.9% 26.0% 1.26 (0.99-1.61) 40% at EIOL Osmundson et al. Obstet Gynecol 2010; 116:601-5 Caughey et al, AJOG 2006;195:700-5 Osmundson et al. Obstet Gynecol 2011; 117:583-7 8
EIOL vs. expectant Cesarean Delivery management at 39 weeks Cesarean delivery 30 25 20 % % Expectant 15 IOL 10 5 0 Cheng et al Stock et al 10% decreased odds of cesarean in EIOL group Osmundson et al. Obstet Gynecol 2010; 116:601-5 Osmundson et al. Obstet Gynecol 2011; 117:583-7 Cheng et al AJOG 2012; Stock et al BMJ 2012 EIOL vs. expectant management at 39 weeks RCT of EIOL prior to 41 weeks Perinatal mortality and morbidity 0.35 • Six small RCT ’ ’ ’ ’ s 0.3 0.25 0.2 % Expectant 0.15 IOL • None have found an increase 0.1 in cesarean delivery 0.05 – Poor quality 0 Cheng et al Stock et al – Underpowered 70% decreased odds of mec aspiration and mortality, respectively, in EIOL group Cheng et al AJOG 2012; Stock et al BMJ 2012 9
Elective Induction IOL & adverse neonatal outcome vs Expectant Management • Retrospective cohort study • California deliveries in 2006 • IOL/augmentation associated with ASD • No prior cesareans (OR 1.13) • 37 – 40 weeks gestation – Not supported consistently by other studies (e.g., Gale et al.) • Elective induction compared to expectant management at each – Incorrect control group for clinical relevance gestational age – Inadequate adjustment for confounding • Vertex, non-anomalous, singleton – Use of incorrect coding for ASD deliveries (N = 362, 154) Darney et al. Obstet Gynecol 2013; 122:761-9 Elective Induction Elective Induction vs Expectant Management vs Expectant Management • Overall CS rate: 16% • OR for CS with EIOL • Perinatal mortality: 0.2% – 37 weeks: 0.44 (0.34 – 0.57) • NICU admission: 6.2% – 38 weeks: 0.43 (0.38 – 0.50) • OR for CS was LOWER at all – 39 weeks: 0.46 (0.41 – 0.52) gestational ages and parity – 40 weeks: 0.57 (0.50 – 0.65) for EIOL!! • EIOL increased • EIOL NOT associated with severe hyperbilirubinemia at 37 and lacerations, operative vaginal delivery, shoulder dystocia, etc. 38 weeks gestation Darney et al. Obstet Gynecol 2013; 122:761-9 Darney et al. Obstet Gynecol 2013; 122:761-9 10
When is the best time for Trends in IOL delivery? • 2005 National Vital Statistics Report Birth Data Expectant Delivery management 39 - 41 weeks ?? Conclusions Conclusions • We know that at 41-42 weeks, IOL better than EM • We know that before 39 weeks, EM better than IOL • Between 39 and 41 weeks: An adequately powered study of elective – Common wisdom that EM is better than IOL induction of nulliparous women is needed • Maternal and neonatal outcomes worsen with delivery after 39 weeks • The concern that IOL increases CD is founded on methodologically flawed study design – We actually don ’ ’ ’ t know whether EM or IOL is better ’ – Common practice is moving away from EM 11
Design Summary • N = 6000 � target 167 per month for 3 years Induction in Nulliparous Women at 39 • Nulliparous women with a Weeks to Prevent Adverse Outcomes: A singleton pregnancy Randomized Controlled Trial • Randomized to one of two arms: � Elective IOL A Randomized Trial of Induction Versus � Expectant management Expectant Management (ARRIVE) Inclusion Criteria Outcomes 1. Nulliparous - no previous pregnancy beyond 20 weeks • Composite perinatal morbidity 2. Singleton gestation - twin gestation • Cesarean delivery reduced to singleton is not eligible • Maternal and fetal outcomes unless reduced before 14 weeks project gestational age • Cost (including hospital) • Patient satisfaction 3. Project gestational age at randomization is between 38,0 and 38,6 12
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