1. Outcomes of preterm birth Stefan Johansson Department of Neonatology, Karolinska university hospital Department of Medical Epidemiology and Biostatistics, Karolinska institutet Stockholm, Sweden

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4. 25 October 2006Stefan Johansson4 Studies of outcomes of preterm birth - subjected to errors! systematic errors random errors What are systematic and random errors?

5. 25 October 2006Stefan Johansson5 Studies of outcomes - random errors  Measurement errors may be random  few meaurements - the average value could be wrong  Outcome differences may be a random finding  uneven sampling of study subjects may result in spurious results  Differences in outcomes are not detected  study sample to small

6. 25 October 2006Stefan Johansson6 BIG IS BEAUTIFUL

7. 25 October 2006Stefan Johansson7 Studies of outcomes - systematic errors  Selection bias  Information bias  Confounding

8. 25 October 2006Stefan Johansson8 Studies of outcomes - selection bias  The optimal study would be to include the world’s entire population, but every study have to select their subjects.  What happens if the selected study subjects are not similar to the general population?  RISK OF SELECTION BIAS!!

9. 25 October 2006Stefan Johansson9 Studies of outcomes - selection bias  ”Cardiovascular risk and running - new insight”  marathon runners.  ”Low mortality among preterm infants”  infants in a specialized center

10. 25 October 2006Stefan Johansson10 Studies of outcomes - information bias  The collection of information is not properly done; misclassification:  a preterm infant has several infections but only one is recorded.  Misclassification can be…  non-differential: the error is the same for all study subjects  differential: the error is not the same for different study groups  Recall bias is a common type of differential information bias:  Cancer patients report more stress than healthy control, but both groups are similarly stressed according to objective stress tests.

11. 25 October 2006Stefan Johansson11 Studies of outcomes - confounding  Confounding means… something (measured or unmeasured) is important for the associations between you measurements. Neonatal nursePregnancy

12. 25 October 2006Stefan Johansson12 Studies of outcomes - confounding  The association is confounded by age of neonatal nurses. Neonatal nursePregnancy Young female

13. 25 October 2006Stefan Johansson13 Good design pays off

14. 25 October 2006Stefan Johansson14  Parental characteristics  Hospital setting  Gestational age  Apgar scores  Blood testing  X-rays  Lung diseases  Blood pressure  Nutrition  Infections  Drugs  Neurological symtoms  Noise  Death  Motor skills  Vision  Hearing  Blood pressure  Blood glucose  Allergies  Cognitive functions  Academic performace  Life span Exposures and outcomes of preterm infants

15. 25 October 2006Stefan Johansson15 In addition… cohort effects…  Neonatal intensive care is a ”new” speciality.  1970’smechanical ventilation  1980’snew treatment of premature lung disease maternal steriod treatment for threatening labour  1990’shigh frequency ventilation gentle nursing strategies treatment of pain nutrition  Preterms born in the 60’s, 70’s, 80’s and 90’s do not represent the same group of people.

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17. What do we know from the literature!?

18. 25 October 2006Stefan Johansson18 Preterm birth and mortality - world-wide  One million infants born preterm die during the first four weeks (26% of neonatal mortality). Lawn et al, Lancet 2005;365:891-900

19. 25 October 2006Stefan Johansson19 Contribution of preterm birth to infant mortality Relative risk [95% CI]*Etiologic fraction % < 28 weeks126,7 [124,0-129,5]35,7 28-31 weeks16,2 [15,4-17,0]7,3 32-33 weeks6,6 [6,1-7,0]3,2 34-36 weeks2,9 [2,8-3,0]6,3 Infant mortality in live born infants < 37 weeks, Canada 1992-1994 *adjusted for age, parity, race, and education Reference group: infants born at term Kramer et al, JAMA 2000;284:843

20. 25 October 2006Stefan Johansson20 Contribution of preterm birth to infant mortality  34% of infants deaths attributed to preterm birth (USA 2002)  Of deaths attributed to preterm birth  95% of occured in infants > 32 weeks and <1500 grams  two thirds occured during the first 24 hours Callaghan et al, Pediatrics 2006;118:1566

21. 25 October 2006Stefan Johansson21 Gestational age and mortality - Sweden Perinatal mortality (%) in Sweden 2003, by gestational age.

22. 25 October 2006Stefan Johansson22 Trend in mortality of infants < 1500 grams Horbar et al, Pediatrics 2002;110:143

23. 25 October 2006Stefan Johansson23 Infant mortality related to preeclampsia Basso et al, JAMA 2006;296:1357

24. 25 October 2006Stefan Johansson24 The impact of level-of-care on mortality Liveborn infants MortalityOdds ratio95% CI Unadjusted - university hospital - county hospital 924 1320 14.2 % 10.3 % 1.00 0.700.54 - 0.90 Adjusted - university hospital - county hospital 924 1320 14.2 % 10.3 % 1.00 1.330.98 - 1.81 Johansson et al, Pediatrics 2004;113:1230

25. 25 October 2006Stefan Johansson25 The impact of level-of-care on mortality Liveborn infants MortalityOdds ratio95% CI 24 - 26 weeks - university hospital - county hospital 262 125 29.0 % 43.2 % 1.00 1.841.11 - 3.04 27 - 31 weeks - university hospital - county hospital 662 1195 8.3 % 6.9 % 1.00 1.090.74 - 1.61 Johansson et al, Pediatrics 2004;113:1230

26. 25 October 2006Stefan Johansson26 What kind of picture emerges…  Many preterm infants die.  Mortality risk is inversely associated with gestation/birth weight.  Preterm birth contribute greatly to infant mortality rates.  Mortality among the most immature infants has decreased.  Preeclampsia related mortality has decreased.  Centralizing care of the most immature infants may improve survival rates.

27. 25 October 2006Stefan Johansson27 What about outcome in surviving preterm infants?

28. 25 October 2006Stefan Johansson28 Outcome in adults born preterm  166 adults BW <1000 g vs 145 adults with normal BW, born 1977-1982 in Canada.  Mean gestational age 27 weeks.  Neurosensory impairment/-s identified in 40 adults (27%)  Cerebral palsyn=20  Autismn=2  Blindnessn=11  Cognitive impairmentn=14 Saigal et al, JAMA 2006;295:667

29. 25 October 2006Stefan Johansson29 Outcome in adults born preterm  Educational attainments was similar in both groups (”highest achievement” excluded those with neurosensory impairment) <1000 gNormal BWp-value Total years of completed eduaction 13.914.5.02 Highest achievement.06 < high school17%12% high school54%56% college24%18% university5%14%

30. 25 October 2006Stefan Johansson30 Outcome in adults born preterm  Current employment (”Job classification” excluded those with neurosensory impairment) <1000 gNormal BWp-value Full time work83%84%.85 Job classification.25 un-/semi-skilled52%40% skilled, technical35%41% management professional 13%20%

31. 25 October 2006Stefan Johansson31 Outcome in adults born preterm  Independent living, marital status and parenthood <1000 gNormal BWp-value Independent living42%53%.19 Marital status.33 single77%75% married10%7% cohabitating13%18% Parenthood11%14%.36

32. 25 October 2006Stefan Johansson32 Outcome in 6 year old children <26 weeks  Infants <26 weeks, born in the UK in 1995.  Severe disability defined as  Cerebral palsy  IQ less than -3 SD  Profound hearing loss  Blindness  Mild disability defined as  Neurologic signs, minimal functional impairment  IQ between -1 and -2 SD  Mild hearing impairment  Squint or refractive error Marlow et al, NEJM 2005;352:9

33. 25 October 2006Stefan Johansson33 What kind of picture emerges…  Studies of adults born preterm – good outcomes?  Studies of children born preterm – poor outcomes?  Why contradicting results…  different populations with different different health care systems?  a reversed ”healthy worker” effect - children born < 26w represent a new group of survivors?

34. 25 October 2006Stefan Johansson34 Conclusions  Outcome of preterm birth… consider methods!  High mortality, although decreasing rates/risks.  Conflicting results on long term outcome.  More knowledge needed, to predict and promote good outcomes.