MFMU - Background. MFMU - Background MFMU GOALS

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1 MFMU - Background Highlights From The MFM Units Network Ronald Wapner, MD Modern OB management (especially high risk pregnancies) has adopted principles of care, employed pharmaceuticals, applied methodologies without rigorous use of the controlled observation necessary for objective evaluation Their modification or replacement follows decades later after extensive experience fails to support their usefulness, or has shown unexpected consequences. MFMU - Background To respond to the need for well-designed clinical trials in MFM, the NICHD established a Network of Maternal-Fetal Medicine Units in Reduce the rates of: Preterm Birth MFMU GOALS Fetal Growth Abnormalities Neurologic Sequelae of the Newborn Maternal Complications of Pregnancy Evaluate maternal and fetal interventions for efficacy, safety, and cost-effectiveness 1

2 NICHD s MFMU Network centers Clinical sites Data center NICHD ~140,000 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 MFMU Completed Trials Post-Term Pregnancy Complications Pregnancy Outcomes with Antibiotics for Infections or PROM Antibiotics in pprom significantly prolongs pregnancy and improves neonatal outcomes Effectiveness of Aspirin to Prevent Preeclampsia Tx. low- or high-risk women with aspirin did not significantly reduce the incidence of preeclampsia; in fact, in low-risk women, there was a higher incidence of placental abruption. HUAM Varicella Zoster MFMU Completed Trials BV/TV Trial Treatment of asymptomatic BV did not reduce the rate of preterm birth. Therefore screening asymptomatic women for BV is not useful. Treatment of asymptomatic TV not only did not prevent preterm delivery, but the PTD rate was actually higher in the patients who received active drug Progesterone to Prevent Recurrent Preterm Birth ffn Trial Asthma Repeat Antenatal Steroids Cervical Ultrasound Cesarean Section (VBAC) Factor V Leiden MFMU Completed Trials Fetal Pulse Oximetry Progesterone in Twins and Triplets Omega 3 Fatty Acid to prevent Preterm Birth Beneficial Effects of Antenatal Magnesium (to prevent CP) 2

3 Patient presents to your office for her first prenatal exam at 5 weeks post LMP Do you screen for hypothyroidism by ordering a TSH and/or free T4 81% 1. Yes 2. No 19% Yes No Patients TSH is elevated and the total and free t4 are normal. Will you treat with thyroxine: 1. Yes 2. No 24% 76% Subclinical Hypothyroid: elevated TSH values but normal free-t4 Hypothyroxinemia: normal TSH levels but low free-t4 Yes No 3

4 Placental Transfer of Thyroid Hormones Nuclear T3 receptors in fetal brain by 10 weeks and increase 10-fold by 16 weeks before the fetal thyroid becomes fully functional During maximum growth velocity of developing brain structures, thyroid hormones of maternal origin Impact of Subclinical Hypothyroidism During Pregnancy Haddow, et al. NEJM 1999 TSH measured in stored samples of more than 25,000 women Located 62 women with high TSH levels and 124 controls 7-9 year old children evaluated by 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual motor performance 4

5 Haddow, et al. NEJM 1999 Full-scale IQ 4 points lower in children of hypothyroid women (P = 0.06) 15% with IQ 85 in hypothyroid vs. 5% in euthyroid women In 48 women not treated, IQs averaged 7 points lower than controls ( P = 0.005) 19% had IQs 85 TSH Study Impact Of Hypothyroxinemia Throughout Pregnancy POP 1999,2003 Impact Of Hypothyroxinemia Throughout Pregnancy POP 1999,2003 Infants of hypothyroxinemic mothers at 12 weeks gestation whose levels subsequently dropped further had the lowest developmental scores If the ft4 levels increased during pregnancy the children did not show any delay in development. Correction of maternal hypothyroxinemia by 24 weeks gestation prevented impaired neurodevelopment. 5

6 ACOG Practice Bulletin No. 37, Thyroid Disease in Pregnancy August, 2002 it would be premature to recommend universal screening for hypothyroidism in pregnancy The panel finds the evidence insufficient to recommend for or against routine determination of TSH levels in pregnant women or women planning to become pregnant. Surks et al., JAMA, 2004 TSH Study This study will address the dual primary research questions: in comparison with placebo is thyroxine treatment associated with an improvement in intellectual function of the children of women with: subclinical hypothyroidism or hypothroxinemia Primary Outcome: Percent of children with IQ 85 at 5years of age. 6

7 Prior to yesterday have you ever treated a pregnancy over 34 weeks with steroids 1. Yes 2. No 50% 50% Increasing incidence of late preterm birth %* 7.5% 8.5% 8.9% Yes No * % US Singleton live births Tomashek et al, J Peds in press US Preterm Singleton Births 40% 14% 75% of all pts! 22% 5% 7% 13% <32 weeks 32 weeks 33 weeks 34 weeks 35 weeks 36 weeks Number of Patients Late preterm infants populate the NICU Estimated Gestational Age (wks) Source: NCHS, final natality data Prepared by March of Dimes Perinatal Data Center, April Clark R et.al, Pediatrix Database,

8 Not All Respiratory Distress in Late Preterm Infants is Benign How can we improve the outcome of late preterm infants? CPAP Oxygen Nasal cannula HFV Ventilator Number of Patients Estimated Gestational Age (wks) Clark R et.al, Pediatrx Database, 2005 CS and Labor Induction Rates United States, 1992 and 2002 Columbia Data: Indication for Delivery in the LP Infant Late Preterm Spontaneous (PTL, PPROM) Acute (NRFHT, severe preeclampsia/hellp, abruption, previa) Planned (Repeat C/S, IUGR w/ normal testing, oligo, multiples) 229/ / / % 28.3% 29.9% Source: NCHS, final natality data Prepared by March of Dimes Perinatal Data Center, April

9 Neonatal transition Neonatal transition in the late preterm infant: Surfactant deficiency is NOT the only cause of respiratory distress in newborns AF testing does not accurately predict respiratory distress from other causes Delayed fetal lung fluid clearance is a significant part of RDS pathophysiology The Paradigm for Alveolar Salt Transport Impact of steroid exposure in late preterm infants Term labor Catecholamines Oxygen Steroids H2O AQP5 T1 Cell Interstitium Na+ ENaC Na+,K+ Cl- HSC CFTR ENaC NSC T2 Cell Cl- K+ Na+ K K+ CLC Channels Na,K-ATPase Salt and Paracellular Water Na+,K+,Cl- H2O AQP5 Rate of NICU admission among infants who received steroids at < 34 weeks and delivered weeks: 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% p < % Steroid Exposed 81% Steroid Unexposed Personal communication, Jain L,

10 Can antenatal steroids reduce neonatal morbidity in TERM infants: ASTECS Trial NICU Adm P=0.02 Neonatal Morbidity Resp Distress TTN RDS % 5.2% NICU Admissions 6.2% 2.8% 37 weeks 38 weeks STEROIDS PLACEBO Stutchfield P. BMJ 331:7518,