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Lange-termijn prognose na zeer premature geboorte: de POPS-19 studie Dr. Martijn J.J. Finken Afdelingen Kindergeneeskunde en Klinische Epidemiologie PAOG.

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Presentation on theme: "Lange-termijn prognose na zeer premature geboorte: de POPS-19 studie Dr. Martijn J.J. Finken Afdelingen Kindergeneeskunde en Klinische Epidemiologie PAOG."— Presentation transcript:

1 Lange-termijn prognose na zeer premature geboorte: de POPS-19 studie Dr. Martijn J.J. Finken Afdelingen Kindergeneeskunde en Klinische Epidemiologie PAOG nascholing Jeugdgezondheidszorg Maastricht 2009

2 Uitspraak van een “ex-prematuur” “Het is geen ziekte om te vroeg geboren te zijn, maar het is niet zomaar iets.”

3 CBS-gegevens Incidence of very preterm birth

4 CBS-gegevens Very preterm birth and in-hospital mortality

5 Changed characteristics over time of very preterm populations POPS 1983 National database 2005 Maternal characteristics Maternal age (y)27.3± ±4.9 Multiple pregnancy (%) Hypertensive disease (%) Chorioamnionitis (%) Delivery in center with NICU (%) Neonatal characteristics Gestational age (weeks)30.0±2.9 Birth weight (g) Mechanical ventilation (%) RDS (%) Intracranial hemorrhage (%) Sepsis (%)

6 POPS Project On Preterm and Small-for-gestational-age infants cohort: 94% of all liveborns in the Netherlands in 1983 with: gestational age <32 weeks and/or birth weight <1,500 g

7 Hille, et al. (Pediatrics 2005) Cohort retrieval Full response (N=596; 62%); Postal response (N=109; 11%) Alive at 19 y (N=959) Entire birth cohort (N=1,338)

8 Walther, et al. (Early Hum Dev 2000) Very preterm birth and development of handicaps

9 Hille, et al. (Pediatrics 2007) Very preterm birth and functional outcomes at 19 y POPS populationReference IQ97.8 (95% CI: 96.5 to 99.1)100 Significant hearing loss (%) Neuromotor score57.6 (95% CI: 56.8 to 58.4)60-66 Special education or lesser level (%) No paid job and not followed any education (%)

10 Hille, et al. (Pediatrics 2007) Very preterm birth and functional outcomes at 19 y

11 Hille, et al. (Pediatrics 2007)

12 Weisglas-Kuperus, et al. (Arch Dis Child Fetal Neonatal Ed 2008) Very preterm birth and IQ at 19 y

13 Causes of intrauterine and neonatal growth retardation Intrauterine growth: Maternal factors: Maternal height and parity Intoxications Medical conditions before or during pregnancy Placental factors: Anatomic and functional variants Fetal factors: Congenital infections Syndromes Hormones: IGF-I, IGF-II, insulin and cortisol Neonatal growth after preterm birth: Respiratory distress syndrome Bronchopulmonary dysplasia Infections Inadequate caloric intake Farmacologic effects: corticosteroids

14 Wit, et al. (Pediatrics 2006) Growth velocity

15 Finken, et al. (Pediatrics 2006) Very preterm birth and height development SGAAGA PGRAGA non-PGR N Birth weight SDS Birth length SDS Weight SDS at 3 mo Length SDS at 3 mo Length SDS at 1 y Length SDS at 2 y Height SDS at 5 y Height SDS at 19 y Target height SDS

16 Finken, et al. (Pediatrics 2006) Very preterm birth and perinatal morbidity SGAAGA PGRAGA non-PGR N Multiple pregnancy (%) Maternal hypertension (%) Maternal smoking (%) Mean gestational age (weeks) Respiratory distress syndrome (%) >7 Days on assisted ventilation (%) Intracranial hemorrhage (%) Postnatal glucocorticoids (%)7144

17 Finken, et al. (Pediatrics 2006) Very preterm birth, catch-up growth and adult height SGAAGA PGR Height SDS at 5 y≥-2<-2≥-2<-2 N Height SDS at 19 y % <-2 SDS

18 Hofman, et al. (NEJM 2004) Preterm birth and insulin resistance at 7 y

19 Hovi, et al. (NEJM 2007) Preterm birth and insulin resistance in adulthood

20 Euser, et al. (Am J Clin Nutr 2005); Finken, et al. (Diabetologia 2006) Very preterm birth and body composition at 19 y MenWomen N BMI SDS -0.17± ±1.24 Waist SDS 0.19± ±0.98 Waist-to-hip ratio SDS 0.70± ±0.97 HOMA-IR1.9 (1.4 to 2.6)1.8 (1.4 to 2.3)

21 Keijzer-Veen, et al. (Pediatrics 2005) Very preterm birth and blood pressure at 19 y JNC VII criteria RangeN (%) NormalSBP <120 or DBP <90 mmHg182 (43.5%) Prehypertensive stageSBP or DBP mmHg192 (45.9%) Hypertension stage 1SBP or DBP mmHg42 (10.0%) Hypertension stage 2SBP >160 or DBP >100 mmHg2 (0.5%)

22 Eriksson, et al. (BMJ 2001) Birth size, childhood growth and later coronary artery disease

23 Soto, et al. (JCEM 2003) Birth size, postnatal catch-up growth and insulin level at 1 y

24 Euser, et al. (Am J Clin Nutr 2005); Finken, et al. (Diabetologia 2006); Finken, et al. (Pediatr Res 2006) Very preterm birth and metabolic profile at 19 y OutcomeBirth weight SDS Early postnatal weight gain δSDS Height SDSPos BMI SDSPos Waist SDSAbsentPos Fat mass (kg)AbsentPos Fat-free mass (kg)Pos Fat percentage (%)AbsentPos Insulin (mU/l)AbsentPos HOMA-IR (mmol/l × mU/l)Absent Cholesterol (mmol/l)Absent Carotid IMT (mm)Absent

25 Finken, et al. (Diabetologia 2006) Very preterm birth and insulin resistance at 19 y

26 Catch-up growth and later disease: causal factor or epiphenomenon? Catch-up growth Nutrition Disease

27 Nutritional intervention in preterm infants 926 Infants born preterm Trial 1 (sole diet) Banked breast milk Preterm formula Trial 2 (supplement to breast milk) Standard term formula Preterm formula

28 Singhal, et al. (Lancet 2003); Singhal, et al. (Lancet 2004) Nutritional intervention in preterm infants OutcomeTrial 1Trial 2 Banked breast milkPreterm formula Standard term formula Preterm formula Neonatal weight gain (g/kg/d) Length at 18 mo. (cm)

29 Lucas, et al. (BMJ 1998) Nutritional intervention in preterm infants

30 Singhal, et al. (Lancet 2001); Singhal, et al. (Lancet 2003); Singhal, et al. (Lancet 2004) Nutritional intervention in preterm infants Outcome at yTrial 1Trial 2 Banked breast milkPreterm formula Standard term formula Preterm formula Split pro- insulin (pmol/l) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) LDL/HDL ratio

31 Maternal behaviour Epigenetic modifications Altered GR expression

32 Szathmari, et al. (Horm Res 2001) Preterm birth and adrenocortical function at 20 y

33 Finken, et al. (JCEM 2007) GR R23K polymorphism, very preterm birth and height development

34 Finken, et al. (JCEM 2007) GR R23K polymorphism, very preterm birth and metabolic profile at 19 y CharacteristicMean difference (95% CI) BMI SDS-0.03 (-0.48 to 0.43) Waist SDS-0.04 (-0.46 to 0.38) Waist-to-hip ratio SDS-0.30 (-0.61 to 0.02) Fat mass (kg)-0.1 (-2.9 to 2.7) Fat percentage (%)-0.4 (-4.3 to 3.5) 10 Log-Insulin (mU/l)-0.09 (-0.16 to -0.01) 10 Log-HOMA-IR (mmol/l × mU/l)-0.09 (-0.16 to -0.01) Systolic blood pressure (mmHg)-2 (-7 to 3) Diastolic blood pressure (mmHg)-2 (-6 to 1)

35 Long-term effects in animals of antenatal glucocorticoid treatment Raised blood pressure Hyperglycemia Renal morphology and function: Smaller kidneys with less glomeruli Lower GFR

36 Roberts & Dalziel (Cochrane Datab Syst Rev 2006) Short-term benefits of antenatal glucocorticoid treatment Outcome after maternal glucocorticoid treatment No. of studies No. of infants Pooled OR (95% CI) Neonatal mortality183, (0.58 to 0.81) Respiratory distress syndrome214, (0.59 to 0.73) Intracranial hemorrhage132, (0.43 to 0.69) Necrotizing enterocolitis81, (0.29 to 0.74) Respiratory support or NICU admission (0.65 to 0.99) Systemic infections <48 hours51, (0.38 to 0.85)

37 Verhaeghe, et al. (JCEM 2005); Moise, et al. (Pediatrics 1995) Short-term benefits of antenatal glucocorticoid treatment Higher glucose and insulin levels in cord blood Less often inotropic support

38 Long-term effects of antenatal glucocorticoid treatment First authorReferenceOutcome after maternal glucocorticoid treatment Blood pressure Fat mass Insulin sensitivity Cholesterol levels GFR Doyle, et al. Clin Sci (London) 2000 ↑---- Dessens, et al.Pediatrics 2000↓---- Dalziel, et al.Lancet 2005==↓=- Finken, et al.Arch Dis Child Fetal Neonatal Ed 2008 ↓=↑=↓

39 Finken, et al. (in preparation) GR N363S polymorphism, very preterm birth and waist circumference at 19 y

40 Conclusions (1) Preterm infants have a metabolic profile similar to that of children born SGA Preterm infants with neonatal growth retardation display a growth pattern similar to that of children born SGA At present, there is no trial data available suggesting a beneficial effect of rhGH therapy in short children born very preterm who had experienced neonatal growth retardation

41 Conclusions (2) Activation of the HPA axis may contribute to adverse metabolic health after preterm birth The GR R23K variant, associated with decreased sensitivity to glucocorticoids, protects against postnatal growth failure and insulin resistance after very preterm birth The GR N363S variant, associated with increased sensitivity to glucocorticoids, predisposes to adverse body composition after perinatal glucocorticoid treatment in indivduals born very preterm

42 Recommendations Children born very preterm and SGA or experiencing neonatal growth retardation should be flagged Body composition should be monitored throughout childhood Waist circumference is a more valuable tool than BMI for determination of body fatness


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