DP van der Ham, MD VieCuri MC, Venlo, the Netherlands R van de Laar, MD ; JJ van Beek, MD PhD, C Willekes, MD PhD, BW Mo

1. Accuracy of C-reactive protein in predicting chorioamnionitis and neonatal sepsis in women with premature rupture of membranes: A systematic review DP van der Ham, MD VieCuri MC, Venlo, the Netherlands R van de Laar, MD; JJ van Beek, MD PhD, C Willekes, MD PhD, BW Mol MD PhD

2. PPROM affects approximately 2-4,5% of all pregnancies 1 Expectant management will increase the risk of neonatal sepsis 2 Induction of labour increases the risks of instrumental delivery and neonatal complications related to prematurity Background 1 Mercer (2000); Merenstein (1996); Furman (2000) 2 Neerhof (1999); Lieman (2005)

3. There is no consensus on the management of PPROM 1 Four small studies on management of PPROM between 30-37 weeks did no show a significant difference in treatment policy 2 A trend of an increased risk of maternal and neonatal infection was noticed in the expectant management group.2 Background 1 Guideline ACOG (2007); Guideline RCOG (2006); Guideline NVOG (2002) 2 Naef (1998); Cox (1995); Mercer (1993); Spinnato (1987)

4. Choice between expectant management or induction of labour depends on the prediction of clinical infection of mother and more important neonate C-reactive protein (CRP) is widely used to diagnose infection Background

5. In past CRP have been reported to positively correlate to predict chorioamnionitis 1 Wide variety in definition for chorioamnionitis and neonatal sepsis Many studies do not meet modern standards for studies on diagnostic tests 2 Background 1 Ibarra Chavarria (1989); Dodds (1987) Romem (1984) Evans (1980) 2 Whiting (2003)

6. Why? • Lack of evidence for CRP as a predictor for chorioamnionitis and/or neonatal sepsis • What? • Is C-reactive protein in maternal serum capable of predicting chorioamnionitis and neonatal sepsis in women with PPROM? • How? • Systematic review Study Question

7. Two independent reviewers Electronic search MEDLINE (1951-2007) and EMBASE (1974-2007) Reference list of primary studies Disagreement resolved by consensus with third reviewer Quality assessment: Data were extracted using a form according to the QUADAS-tool Material and Methods 1 Whiting (2003)

8. Predefined definitions (Endpoints) • Neonatal sepsis: positive blood culture or clinical signs of infection with positive surface cultures • Clinical chorioamnionitis: Temperature above 37,5oC (99,5 oF) combined with uterine tenderness and/or purulent AF and/or materal or fetal tachycardia • Histological chorioamnionitis: Presence of neutrophil infiltrate in extraplacental membranes Material and Methods

9. Statistical analysis • 2x2 tables • Receiver Operating Characteristic (ROC) Plot • Bivariate meta-regression model to calculate pooled estimates of sensitivity and specificity 1 Material and Methods 1 Van Houwelingen (1993); van Houwelingen (2002); Reitsma (2005)

10. Results

11. ResultsStudy selection process

12. Endpoints • Histological Chorioamnionitis (five studies) 1 • 306 patients (range: 24-100 patients/study) • Clinical Chorioamnionitis (four studies) 2 • 330 patients (range: 31-147 patients/study) • None of the studies could be included for neonatal sepsis Results 1 Berardi (1991) Fisk (1987) Farb (1983) Hawrylyshyn (1983) Ismail (1985) 2 Kurki (1990) Farb (1983) Hawrylyshyn (1983) Ismail (1985)

13. ResultsStudy characteristics

14. ResultsPPROM before ...

15. Incidence histological chorioamnionitis 47% Incidence clinical chorioamnionitis 26% Gestational age varied between 20 – 37 weeks Results

16. ResultsCRP and histological chorioamnionitis sensitivity 1 – specificity

17. ResultsCRP and histological chorioamnionitis sensitivity 1 – specificity

18. ResultsCRP and clinical chorioamnionitis sensitivity 1 – specificity

19. Discussion

20. Lack of blinding in 2 studies • Exclusion criteria not reported in 50% of studies • Large interval in gestational age (20-37 weeks) • Expectant management in (very) premature pregnancies, increasing risk of infection • Use of antibiotics varied among studies DiscussionStudy characteristics

21. Rather high incidence of chorioamnionitis 1 • Combined studies: Clinical Chorioamnionitis: 26% • Ramsey et al: Clinical Chorioamnionitis: 13% • Included studies on clinical chorioamnionitis were very heterogeneous • This limits the possibility to estimate a reliable sROC-curve DiscussionStudy characteristics 1 Ramsey (2005); Williams (1994)

22. In (very) preterm pregnancies incorrectly inducing labour may lead to serious complications for the neonate We should be focused on predicting clinical chorioamnionitis and even more importantly neonatal sepsis Predicting histological chorioamnionitis is clinically of limited use Discussion

23. Insufficient evidence to support or withdraw the accuracy of CRP in predicting chorioamnionitis Further research is required Research should be focused on predicting neonatal sepsis (infection) and clinical chorioamnionitis Conclusion

24. PPROMEXIL trial • Induction of Labour versus EXpectant management in women with Preterm Prelabour Rupture Of Membranes between 34 and 37 weeks • Multicentre randomized controlled trial • Primary endpoint: Neonatal sepsis • C-reactive protein and leucocytes determination www.studies-obsgyn.nl/ppromexil/