1. “IMPACTO DE LA SEPSIS NEONATAL SOBRE EL NEURODESARROLLO EN RECIÉN NACIDOS DE MUY BAJO PESO.” Prof Titular Gerardo R. Robaina Castellanos, MD, PhD. Hospital Gineco-obstétrico Docente Provincial de Matanzas. Universidad de Ciencias Médicas de Matanzas, Cuba. E-mail: grcastellanos.mtz@infomed.sld.cugrcastellanos.mtz@infomed.sld.cu Infants care in Cuba & USA: Sharing experiences and making chances for collaboration. Havana, February 4-6, 2016.

2. Impact of neonatal sepsis on neurodevelopment in very low birth weight infants Authors:  DrC. Gerardo R. Robaina Castellanos. Hospital Gineco-obstétrico Docente Provincial de Matanzas.  MSc. Solangel de la Caridad Riesgo Rodríguez. Hospital Pediátrico Provincial de Matanzas, Cuba.

3. ↑ survival rates VLBW infants: >90% Motor impairments: 5-10% Other disabilities (cognition, behavior) 25-50% Preterm born: social dimensions

4. Risk factors Male sex Long mechanical ventilation Posnatal steroids ROP, BPD, PDA IVH, convulsions PVL NEC, perforation Malnutrition Long total parenteral nutrition Neurodevelopmental disorders in VLBW infants

5. Neonatal sepsis  Incidence: 1-12 x1000 newborn alive (20-40% in developing countries)  Mortality: 5-20% (↑ in developing countries)  Incidence in VLBWI: 9,8-31%  EOS: 1,5-2%  LOS: 21%  Mortality in VLBWI: 3 times > Infants born at term.  NICHD Neonatal Research Network survey (1998 to 2000). [Stoll B, et al. PEDIATRICS 2002;110 (2).  The Vermont Oxford Network 2001.

6. WMD-CPWMD-CP Neurodevelopmental disorders Neonatal infections Neonatal sepsis Chorioamnionitis WMD: White matter damage; CP: Cerebral Palsy.

7. Risk of neurodevelopmental disorders in VLBW & < 1000g. W/ neonatal sepsis 2-3 times > w/o neonatal sepsis. (OR 2,09; IC95% 1,65-2,65).  Schlapbach LJ et al. Pediatrics 2011; 128(2):e348-57. [Extreme premature]  Alshaikh B et al. J Perinatol. 2013;33(7):558-64. [VLBW]

8. The impact of neonatal sepsis on neurodevelopment in VLBW infants admitted in Cuban neonatal intensive care units is unknown.

9. To determine the impact of neonatal sepsis as a risk factor of neurodevelopmental disorders for VLBW infant’s discharged from a Cuban tertiary hospital.

10. SUBJECTS & METHODS Cohort study Study population: 89 VLBW infants discharged from the HGODP-Matanzas (2006-2010) Inclusion criteria:  GA<37 w, followed-up until 24 mo corrected age. Exclusion criteria:  Major malformations, hereditary syndromes, neonatal & post neonatal deaths. Study groups:  w/ neonatal sepsis----------- 19 patients  w/o neonatal sepsis--------- 70 patients

11. Research stages First: Cohort analysis→ to determine association between neonatal sepsis & neurodevelopment disorders 2nd: Regression logistic analysis (Previous univariate analysis) 3rd: Association between:  Onset of sepsis (EOS, LOS, EOS+LOS) & neurodevelopmental disorders  Exposition levels to neonatal sepsis episodes & neurodevelopmental disorders

12. NACS Prechtl Fenichel Neurological exam at term Amiel Tison (1, 3, 6, 9, 12 mo). Bayley (end 1rst y) Brain ecography & ABER. 1rst year, corrected age Classic neurological exam (trimesterly) Bayley (end 2nd y) 2 nd year, corrected age Follow-up:

13. Data search : Maternal and infant characteristics were recorded in a standardized data-collection form. Statistical processing: SPSS v 17.0  1rst stage: RR & CI95% (main measure) Means, % X 2 or Fisher test (qualitative data) t-test (continuous data)  2nd stage: LR analysis → OR & CI95%  3rd stage: Type of sepsis & ND: OR & CI 95% Episodes of sepsis & ND: RR & CI95%. P<0.05 were considered statistically significant

14. Results

15. General characteristics of VLBW infants involved on the study. (N=89) Variable% Sex (male/female)41.6/58.4 Birthweight (g)1278.0 [700-1490 ] Gestational age (weeks)31.4 [ 26-36] Birthweight < 1000 g7.9 Low birth weight for GA53.9 Cesarea section80.9 Low Apgar score 1rst min (<7)12.4 Low Apgar score 5th min (<7)6.7 Neonatal respiratory distress syndrome59.6 Bronchopulmonary dysplasia15.7 Hyperbilirrubinemia >15mg/dl29.2 Exogenous surfactant35.9 Mechanical ventilation39.3 Neonatal localized infections51.7 Neonatal sepsis21.3

16. NEURODEVELOPMENTAL OUTCOME

17. (p=0.02).

18. Risk of neurodevelopmental disorders according to presence of neonatal sepsis (N=89; with sepsis n=19; w/o sepsis n=79). Grade/ type of disordersRR (IC95%)p Neurodevelopmental disorders 2.7 (1.3-5.5)0.005 Major disorders1.8 (0.3-9.3)0.45 Cerebral palsy3.6 (0.5-24.4)0.15 Mod/severe motor developmental delay (IDP<70)3.6 (0.5-24.4)0.15 Mod/severe mental developmental delay (IDM<70) 3.6 (0.24-56.2)0.31 Minor disorders3.3 (1.4-8)0.005 Mild/transitory hypotonia4.4 (1.5-12.9)0.004 Mild motor insufficiency with increased muscle tone 3.6 (0.24-56.2)0.31 Mild/transitory motor developmental delay (IDP 70-84) 3.6 (1.18-11.4)0.01 Mild mental developmental delay (IDM 70-84)1.8 (0.17-19.2)0.60 Mild/unilateral visual disability7.3 (0.7-76.9)0.051 Mild/unilateral hypoacusia1.8 (0.17-19.2)0.60

19. Neonatal sepsis & neurodevelopmental disorders (2 years CE) in infants born <34 weeks and/or birthweight ≤1500 g. Neurodevelopmental disordersRR (IC95%)p Cerebral palsy1.98 (1.70-2.30)<0.001 Cognitive delay1.55 (1.36-1.76)<0.001 Psychomotor delay 1.85 (1.48-2.30)<0.001 Visual impairment 2.24 (1.55-3.23)<0.001 Auditory impairment 3.19 (2.30-4.42)<0.001  Bakhuizen S et al. Acta Pædiatr. 2014;103(12):1211-8.

20. Variables associated to neonatal sepsis, according to univariate analysis (N=89). Variable With sepsis n=19 Without sepsis n=70 p * RDS neonatal (%)17 (89.5)36 (51.4)0.003 Exogenous surfactant (%)12 (63.2)20 (28.6)0.005 Mechanical ventilation(%)13 (68.4)22 (31.4)0.03 Bronchopulmonary dysplasia (%)6 (31.6)8 (11.4)0.03 Hyperbilirrubinemia > 15mg/dl (%)10 (52.6)16 (22.9)0.01

21. Association of some variables with neurodevelopment disorders, according to logistic regression analysis (N=89). Sig.ORIC 95% InfSup Neonatal sepsis0.034.031.1314.37 Mechanical ventilation0.162.340.717.69 Bronchopulmonary dysplasia0.541.550.396.18 Hyperbilirrubinemia >15mg/dl0.290.500.141.79 Male sex0.291.800.615.31 Constant0.000.12

22. Type of sepsis & neurodevelopment disorders, according to logistic regression analysis (N=89). Sig.ORIC 95% InfSup EOS 0.990.0 LOS0.077.50.8269.5 EOS + LOS 0.044.51,02 20,3 Adjusted for mechanical ventilation, BPD, hyperbilirrubinemia >15mg/dl & male sex.

24. Conclusions The association power of neonatal sepsis with adverse neurodevelopmental outcomes in VLBW infants was similar in this study related to other performed in developed countries. Neonatal sepsis should be considered an important cause, among the multiple events of brain damage in the preterm newborn. It is possible that incidence of neurodevelopmental sequels in VLBW infants could be diminished with implementation of more effective interventional measures aimed to prevent neonatal sepsis.

25. Recommendations To carry out a collaborative multicenter study to determine, with a larger population of VLBW infants, the impact of neonatal sepsis on neurodevelopment in higher ages.