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Perinatal Risk Factors for Neonatal Encephalopathy in Uganda: The Role of Materno-Fetal Infection/Inflammation

Presented at the Neonatal Society 2013 Summer Meeting.

Tann C1,2,3, Nakakeeto M, Kurinczuk JJ4, Mutuuza ED5, Nkurinziza P3, Willey B1, Cowan F6, Namiiro F5, Harris K7, Klein N7, Sewebaga M5, Sebire N7, Elliott AM1,3, Robertson NJ2

1 London School of Hygiene & Tropical Medicine (LSHTM), UK
2 University College London (UCL), Institute for Women’s Health, UK
3 MRC/UVRI Uganda Research Unit on AIDS, Uganda
4 NPEU, Oxford University, UK
5 Mulago Hospital, Uganda
6 Imperial College, London, UK
7 UCL, Institute for Child Health, London, UK

Background: Globally one quarter of neonatal deaths are related to perinatal asphyxia with survivors of the ensuing encephalopathy commonly developing sequelae, including cerebral palsy and seizures. Pre-clinical studies suggest that existing infection/inflammation may significantly increase the susceptibility of the developing brain to injury (1). We hypothesise that placental infection/inflammation significantly increases newborn susceptibility to brain injury and contributes to the pathogenesis of neonatal encephalopathy (NE) and poor outcome in low income settings.

Methods: Ethical approval was granted by IRB approved local and national ethics committees (UK & Uganda). Between Sept’11 and Oct’12 we recruited all 210 term infants with NE (defined as a Thompson score >5) and 420 randomly sampled unaffected term infants, to an unmatched case-control study at Mulago Hospital, Kampala, Uganda. Data from antepartum, intrapartum and postpartum periods were collected. Maternal-infant investigations to identify perinatal infection included species-specific qPCR (neonatal bacteraemia, malaria, cytomegalovirus, herpes simplex), point-of-care testing (HIV, Syphilis) and maternal and neonatal C-reactive protein (CRP). Placentas were examined for histological chorioamnionitis/funisitis. 

Results: The incidence of NE was 14.7 per 1000 live births and neonatal case fatality 34.3% (71/207). Clinical seizures affected 49.6% (104/210) of cases and 10.2% (21/206) were hypoglycaemic (<2.0mmol/L) on admission. Unadjusted risk factors from the preconception, antepartum and intrapartum periods were identified with the strongest associations seen with intrapartum complications. Real-Time PCR successfully identified bacteraemia in culture negative infants. Maternal HIV status (Odds Ratio (OR) 0.52; 95% confidence interval (CI) 0.29-0.95), prolonged rupture of membranes (OR 2.98; 95% CI 1.52-5.84), raised maternal CRP at delivery (p<0.0001), and clinical (OR 5.24; 95% CI 2.50-10.95) and histological chorioamnionitis (OR 2.38; 95% CI 0.92-6.11) were associated with NE in univariate analyses. Inflammation in the cord was associated with the highest risk of NE with a 10-fold increase in the crude odds of funisitis amongst encephalopathic infants when compared to controls (26.7% vs 3.9% respectively (OR 10.5; 95% CI 3.27-33.56). For cases, funisitis was associated with a doubling of the crude odds of neonatal death (43.8% vs 21.2%, OR 2.89; 95% CI 0.8-11.1).

Conclusion: Early results of this analysis suggest that perinatal infection/inflammation, and in particular fetal infection and inflammatory response, are important risk factors for neonatal encephalopathy and death in this low income setting.

Corresponding author: callytann@gmail.com

1. Eklind et al, Eur J Neurosci. 2001 Mar;13 (6):1101-6

The study is funded through the Wellcome Trust/LSHTM Clinical PhD Programme

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