SIDS: State of the Science and Initiatives in Perinatal Research

1. SIDS: State of the Science and Initiatives in Perinatal Research Marian Willinger, Ph.D. Pregnancy and Perinatology Branch NICHD

2. Critical Landmarks • Delineation of modifiable risk factors in the postnatal sleep environment • Public health campaigns to modify sleep position and their success in reducing SIDS rates • Identification of specific anatomic and neurochemical abnormalities in the brainstem

3. SIDS Rates, U.S.

4. Challenges • Plateau in SIDS rates • What are contributing factors? • Racial disparity remains • Unacceptable high rates among African Americans and American Indians

5. NISP, Position Placed: BackSubgroups, 1992-2005 Source: NICHD Household Survey

6. Challenges • Plateau in the adoption of supine position • Racial disparity in the adoption of supine position

7. Study of Barriers to Care • Interviews at WIC clinics in Boston, Dallas, New Haven and Los Angeles in 2004. http://www.pediatrics.org/cgi/doi/10.1542/peds.2005-2517 • Characteristics of women participating: • 64% Black, 7% white, 14% Hispanic, 15% other • 18% less than high school education; 44% high school education, 26% some college, 12% college or more • 16% less than 20 years old, 60% 20-29, 25% older than 29

8. Study of Barriers to Care • 59% usually placed their children on their back for sleep, ranging from 45% in Dallas to 78% in New Haven • 34% reported ever placing the baby on the stomach in the last 2 weeks • Only 42% reported that a nurse, only 36% a doctor and 15% a female friend or relative, recommended back. • If mothers trusted the opinion of their doctor or nurse about sleep position, they were more likely to place the baby on the back. • If a female friend or relative advised a position, mothers were 5 times more likely to place the baby in that position, than if no advice was given at all.

9. Study of Barriers to Care • Half of mothers believed their infants were more likely to choke on their backs and were less likely to place them on their backs. • 29% believed that having their infants sleep with an adult prevents SIDS • Only 43% believed that SIDS is related to sleep position

10. New AAP and “Back to Sleep” Recommendations • Keep your baby's sleep area close to, but separate from, where you and others sleep. Your baby should not sleep in a bed or on a couch or armchair with adults or other children, but he or she can sleep in the same room as you. If you bring the baby into bed with you to breastfeed, put him or her back in a separate sleep area, such as a bassinet, crib, cradle, or a bedside cosleeper (infant bed that attaches to an adult bed) when finished.Think about using a clean, dry pacifier when placing the infant down to sleep,but don't force the baby to take it. (If you are breastfeeding your baby, wait until your child is 1 month old or is used to breastfeeding before using a pacifier.) • Attitudes and behaviors in response to new recommendations will be followed.

11. Biologic VulnerabilityRegions with Decreased Serotinergic Receptors Kinney et al., 2000

12. New Brainstem Findings • Brainstem tissue from the SIDS infants contained more serotonin-using neurons than did the brainstem tissue from the infants dying of other causes. • However, these serotonin-using neurons appeared to contain fewer receptor proteins for serotonin than did the brainstems of infants dying from other causes. • For about 70% of the cases, SIDS infant brainstem tissue had very little serotonin receptor, known as “subtype 1A,” which inhibits nerve cell firing when serotonin binds to it.

13. New Brainstem Findings • Relative to the increased number of serotonin-using neurons in SIDS infants, there were fewer serotonin transporter proteins that recycle serotonin. • Therefore, the ability to use serotonin effectively appears to be significantly in impaired SIDS infants (JAMA 2006; 296:2124-2132). • While more serotonin neurons were observed in the SIDS infants, they appeared to be immature in their morphology, as well as abnormal in their functional properties. These results suggest that the observed abnormalities in the brainstem of SIDS infants originate in pregnancy, while the baby is developing in utero.

14. Developmental Changes in Physiology • If newborns are rapidly tilted from horizontal to head up, the reflexes that control blood pressure make the heart beat faster in response to the tilt. Recordings of brain waves done at the same time as the tilt show an increase in electrical activity in the cerebral cortex. The cerebral cortex integrates signals from all parts of the brain, including the brainstem. • Infants between two and four months of age, the peak age of SIDS risk, did not increase their heart rate in response to a head up tilt, and there was a smaller increase in brain wave activity compared to newborns (Acta Paediatr. 2005;94:1756-1763).

15. Developmental Changes in Physiology • There are many possible reasons for this developmental difference in response, and they are being investigated. The researchers suggest that the tilt test may be a good way to assess the brain’s control of blood pressure during the peak age of risk for SIDS (Acta Paediatr. 2006;95:77-81).

16. Genetics • Genes associated with the serotonin system • The serotonin transporter recovers serotonin from the extracellular space and regulates the strength and duration of interaction between serotonin and its receptor. • Polymorphisms in the promoter region that enhance the efficacy of the transporter (VL and L) are significantly in excess in SIDS cases and those reducing efficacy (S) are reduced in SIDS (Pediatrics 2001;107:690-692 and Am J Med Gen 2003;117A:268-274) • Another polymorphism (12-repeat intron-2), which also increases transporter efficacy is increased in African American SIDS cases. The combination of L and the 12 polymorphism may confer greater SIDS risk (Am J Med Gen 2003;122A:238-245).

17. Genetics • Genes associated with long Q-T syndrome (may be in the germ-line or arise spontaneously) • 2% of a population-based cohort of SIDS cases had mutations in the cardiac sodium channel gene that changed the transport of sodium through the channel (JAMA 2001;286:2264-2269) • Another sodium channel gene mutation, detected in an infant with prolonged QT interval, who died suddenly, showed that the loss of function was due to a defect in the “trafficking” of the channel protein within the cell. (Physiol Genomics 2003;12:187-193). • A SIDS case study detected a mutation in potassium channel gene associated with familial long Q-T (Lancet 2001;358:1342-1343)

18. Genetics • IL-10- Anti-Inflammatory cytokine • There are several known polymorphisms in IL-10 • A specific allele is significantly associated with 70% of SIDS cases and may be related to low IL-10 production. • This allele is associated with a 3.3 fold increased risk for SIDS. • The polymporphisms at this position are responsible for IL-10 production in macrophages and monocytes (Human Immun 2000:61:1270-1273)

19. Opportunities to Build on Existing Knowledge The SIDS Infant • How do the observed brainstem deficits translate into altered physiological function? • What are the mechanisms whereby the physiological response becomes deadly? • How do the sleep environment and other environmental risk factors, such as infection, influence these processes? • How does genetics play a role? • Can we use this information to develop screening tests and specific preventive strategies?

20. New Opportunities:The Maternal- Fetal Environment • Origin of vulnerability • The Mom: • Focus on pre-pregnancy maternal health • Focus on placental function • The Baby: • Prospective investigation of fetal development and transition through infancy • Influence of maternal factors such as cigarette smoking and alcohol use

21. Challenges for Research • Low incidence and heterogeneity of cases makes new research studies more difficult and expensive • Funds available for research very confined

22. Prenatal Alcohol in SIDS and Stillbirth (PASS) • Network of 6 cooperative agreements with NIAAA and NICHD • Phase II: Cohort study from pregnancy through infancy to assess the role of prenatal alcohol exposure in SIDS and stillbirth risk. • Based on an expansion of phase I pilot studies.

23. PASS Research Network Steering Committee Northern Plains Cape Town Data Coordinating And Analysis Center Developmental Biology and Pathology Center Science and Program Officers NICHD/NIAAA Physiology Assessment Center Advisory and Safety Monitoring Board

24. PASS – Phase II- Opportunities • Prospective study of the regulation of fetal and infant brain development • Potential public health impact through the development of preventive strategies to identify babies at risk in utero and after birth • Elaboration of genetic susceptibility and molecular mechanisms of SIDS, stillbirth, and fetal alcohol related neurological disorders • Potential to shed light on the etiology and pathogenesis of SIDS and some categories of stillbirth.

25. PASS – Phase II- Opportunities • By carefully documenting the alcohol exposure we will learn about the timing, quantity, and the mediators of the toxic affects of alcohol. • Potential for public health impact to reduce the racial disparity in SIDS and alcohol related neurological defects. • First longitudinal study beginning in the prenatal period to examine the effects of fetal alcohol exposure, and provides the opportunity to obtain markers in infancy to identify babies at risk for FAS and ARND.

26. 5 Clinical sites • Data center • NICHD • Emory University • U North Carolina • U Texas-Galveston • U Texas SanAntonio • U Utah • Women and Infants • About 300 SB /year NICHD Stillbirth Research Collaborative Network 2003-2008

27. Stillbirth Collaborative Research Network (SCRN) • Standard Protocol: The use of a prospectively implemented standardized postmortem protocol will establish that half of all stillbirths have explainable causes • Incidence: The use of standardized surveillance in a geographic catchment will show that the stillbirth rates are greater than those reported in the vital statistics catchment • Risk Factors:E.g. Maternal biologic and environmental risk factors in combination with genetic predisposition increase the risk for stillbirth • Identifying risk factors and/or • Delineating mechanism(s)

28. Stillbirth Collaborative Research Network • Population-based, hypothesis-driven, case-control study • Prospective enrollment of stillbirths as cases and live births as controls in geographic catchments capturing >=90% of deliveries. • Standard placental pathology and fetal autopsy protocols were developed and are implemented centrally at each clinical site. • Hypotheses address: surveillance and epidemiology; fetal and placental pathology; maternal disease mechanisms; immunology and infectious diseases; and genetics. • To date, 58 hospitals are participating in the SCRN protocol. • 189 cases and 522 controls have been enrolled; one -third of the total sample size (500 cases of stillbirth with complete information including autopsy and 1850 controls)

29. Examples of Other NICHD PPB Perinatal Initiatives • Maternal-Fetal Medicine Units Network (MFMU) • Neonatal Research Network (NRN) • Community Child Health Network • Genomic and Proteomic Network for premature birth research (GPN)

30. NICHD MFMU Vision Statement The MFMU Network conducts clinical studies to improve maternal, fetal and neonatal health emphasizing randomized-controlled trials. • Reduce the rates of • Preterm birth • Maternal complications of pregnancy • Fetal growth abnormalities • Neurologic sequelae of the newborn • Evaluate maternal and fetal interventions including efficacy, safety and cost-effectiveness. • Includes: translational research, genetics, evaluation of new technologies in the promotion of maternal-child health/prevention of disease Specific aims: NICHD MFMU 2006

31. 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

32. 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 • 1o outcome: delivery <37 wks • Sample: 463 pregnant women Meis et al, N Engl J Med 2003

33. Progesterone: Rates of Preterm Birth P<0.0001 P=0.004 P=0.010 P<0.016 P<0.018 Placebo Progesterone Meis et al, N Engl J Med 2003 Meis et al, N Engl J Med 2003

34. 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

35. 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 Meis et al, N Engl J Med 2003

36. Recommends the use of progesterone to prevent PTD for women with prior sPTD Obstet Gynecol 2003;102:1115-6

37. NICHD NRN Mission The Neonatal Research Network is designed to conduct studies to investigate the safety and efficacy of treatment and management strategies to care for newborn infants.

38. NICHD NRN Mission Aims • Identify priority issues for research • Evaluate interventions including efficacy, safety, and cost-effectiveness. • Included: translational research, genetics, evaluation of new technologies in the promotion of infant health/prevention of disease

39. -Data center - 16 Clinical Sites- NICHD NICHD NRN NETWORK CENTERS 2001-2006 • > 60,000 admissions/yr • Recompetition every 5 years • Case Western Reserve University • Univ. Texas – Southwestern • Univ. Texas – Houston • Wayne State • Emory • Univ. Cincinnati • Indiana Univ. • Yale • Brown • Stanford • Univ. Alabama • Tufts • Univ of Iowa • Univ of Utah • Univ of New Mexico

40. HYPOTHERMIA RCT • To assess safety and efficacy of whole body hypothermia in term infants with acute perinatal hypoxic ischemic encephalopathy • Multicenter, randomized, unmasked trial • pH < 7.0 or base deficit > 16 mEq/L or history of acute perinatal event and either a 10 minute apgar < 5 or continued need for ventilation. Infants must have signs of encephalopathy within 6 hours of age. • NEJM October 13, 2005

41. HYPOTHERMIA RCT • Intervention – cooling to 33-34ºC for 72 hours • Outcome – death or moderate/severe disability at 18 months of age • N = 208 • Follow-up completed on 98% of enrolled subjects

42. HYPOTHERMIA RCT IN HIE Primary Outcome: Death or Mod-Severe Disability RR = 0.71 (0.57,0.93); Number needed to treat = 6 Percent (%) RR with Center/HIE severity adjustment = 0.76 (0.60,0.97)

43. Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy Lillian R. Blackmon, MD, Ann R. Stark, MD, the Committee on Fetus and Newborn, American Academy of Pediatrics http://www.pediatrics.org/cgi/doi/10.1542/peds.2005-2950 Recommendations: 1. Therapeutic hypothermia is a promising therapy that should be considered investigational until the short term safety and efficacy have been confirmed in the additional human trials underway. Long-term safety and efficacy remain to be defined. 2. Completion of the 3 large RCTs in progress should be supported so that projected enrollment is accomplished. 3. Additional trials are needed that would define the most effective cooling strategies.

44. Hypothermia: A Neuroprotective Therapy forNeonatal Hypoxic-Ischemic EncephalopathyLillian R. Blackmon, MD, Ann R. Stark, MD, the Committee on Fetus and Newborn, American Academy of Pediatrics Recommendations cont’d. 4. Registries of infants with perinatal encephalopathies should be established to facilitate data collection regarding diagnoses, treatments, and outcomes. 5. If therapeutic hypothermia is to be implemented outside of an RCT, clinicians should follow published protocols, ensure systematic follow-up of survivors validated neurodevelopmental tests, and submit patient data to national or international registries as they are established. Parents should be informed of the current status of hypothermia therapy and consent for the procedure obtained. 6. Longer-term follow-up at least through early school is essential.

45. Community Child Health Research Network • Five community partnership clinical sites and a data center funded under cooperative agreement. This is the first community partnership in perinatal research. • Eastern NC Baby Love Project (Healthy Start)- UNC, Chapel Hill • Baltimore Healthy Start- Johns Hopkins SPH • Lake County HD Community Health Center- Northwestern U • Several DC community organizations- Georgetown U • Healthy African American Families- UCLA • Penn State, Data Coordinating and Analysis Center

46. Community Child Health Research Network • Planning a study that examines how community, family, and individual level factors interact with biological influences and result in health disparities in pregnancy outcome and infant mortality and morbidity • Funded for phase II with focus on the inter-pregnancy period to measure predictors of allostatic load and its affect on pregnancy outcomes. • Projected sample size of 2400 births

47. Genomic and Proteomic Network for Premature Birth (GPN) • Use wide-scale, high-output genomic and proteomic strategies to accelerate knowledge in the mechanisms responsible for premature birth • Act as a resource to the scientific community by providing genomic and proteomic data quickly for secondary analysis and creating, as well as maintaining, a public genomic and proteomic database dedicated to premature birth research • Clinical Core- 3 sites UAB, Utah, UTMB • Analytical Core - U Penn • Data Mgmt, Statistics and Informatics Core - Yale Univ

48. GPN Study Designs • A Longitudinal Cohort Studyof 500 women with a history of previous spontaneous preterm delivery before 37 weeks recruited at or before 18 weeks of pregnancy and followed to delivery. • PURPOSE: The prediction of sPTB using global proteomic/metabolomic profiling (i.e., serum, cervical-vaginal fluid, amniotic fluid, etc.). • Case-Control Study of 1000 spontaneous preterm deliveries before 34 weeks with and without history of prior spontaneous preterm delivery and 1000 term deliveries (39 - <42 weeks) without prior spontaneous PTD. Specimen collection at or after delivery. • PURPOSE:To determine a genetic susceptibility profile using a genome-wide association study. • Expression Profiling Studyof four groups of 20 women for scheduled C/S, in labor and not in labor, at term and preterm before 34 weeks; and two groups of 20 women with pPROM in spontaneous labor before 34 weeks and induced labor at 34 weeks. • PURPOSE: Global expression profiling for insight into mechanisms that underlie spontaneous preterm delivery.