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Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series
OBSTETRICS OBSTETRICS
Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series Laura M. Gaudet, MD,1 Michael Flavin, MB,2 Omar Islam, MD,3 Graeme N. Smith, MD, PhD1,3,4 1
Department of Obstetrics and Gynaecology, Division of Maternal-Fetal Medicine, Queen’s University, Kingston ON
2
Department of Pediatrics, Division of Neonatology, Queen’s University, Kingston ON
3
Department of Radiology, Queen’s University, Kingston ON
4
Department of Pharmacology and Toxicology, Queen’s University, Kingston ON
Abstract Objective: The primary objective of this study was to determine the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI) to assess white matter changes in high-risk neonates. Secondary objectives were to determine if exposure to chorioamnionitis (clinical or histopathologic) is associated with DWMRI findings in the neonatal brain, and to calculate the sample size required for a more definitive prospective cohort study. Methods: Seventeen women with PPROM (preterm premature rupture of the membranes) who delivered 18 infants not requiring ventilatory support were recruited to participate in this case series. When stable, infants underwent DWMRI scanning. All placentas were examined for evidence of histopathologic chorioamnionitis (HCA). Results: There was histopathologic evidence of chorioamnionitis in seven of the 18 placentas examined; three of these patients had clinical chorioamnionitis. Diffusion MRI revealed changes in both the diffusion-weighted imaging and the apparent diffusion coefficient in three of the seven infants confirmed to have HCA (43%), while only one of the 11 infants with normal placentas (9%) showed similar findings. Routine head ultrasound examination demonstrated abnormal cortical findings that would normally prompt further investigation in only one of these infants. Conclusion: Exposure to HCA may be associated with abnormal DWMRI findings on imaging of the neonatal brain within 96 hours of delivery. Further study is required to delineate the association of chorioamnionitis and white matter changes with long-term neurodevelopmental sequelae.
Résumé Objectif : Le principal objectif de cette étude était de déterminer la faisabilité de l’utilisation de l’imagerie de diffusion par résonance magnétique (IDRM) pour évaluer les modifications de la substance blanche chez les nouveau-nés exposés à des risques élevés. Nos objectifs secondaires étaient de déterminer si l’exposition à la chorioamnionite (clinique ou histopathologique) est associée aux résultats de l’IDRM, en ce qui concerne le
Key Words: Chorioamnionitis, neonatal white matter imaging, diffusion MRI, brain Competing Interests: None declared. Received on October 8, 2008 Accepted on December 5, 2008
cerveau néonatal, et de calculer la taille d’échantillon requise pour la tenue d’une étude de cohorte prospective plus précise. Méthodes : La participation de 17 femmes présentant une RPMP (rupture prématurée des membranes préterme) qui ont accouché de 18 enfants ne nécessitant pas une ventilation assistée a été sollicitée en ce qui a trait à cette série de cas. Une fois stables, ces enfants ont été soumis à une IDRM. Tous les placentas ont été examinés afin d’y dépister des signes de chorioamnionite histopathologique (CAH). Résultats : La présence de signes histopathologiques de chorioamnionite a été constatée chez sept des 18 placentas examinés; trois de ces patientes présentaient une chorioamnionite clinique. L’IDRM a révélé des modifications tant en ce qui concerne l’imagerie de diffusion qu’en ce qui concerne le coefficient de diffusion constaté chez trois des sept enfants pour lesquels la présence d’une CAH avait été confirmée (43 %), tandis que seulement un des 11 enfants ayant présenté un placenta normal (9 %) a obtenu des résultats semblables. L’échographie céphalique systématique a révélé des résultats corticaux anormaux qui, normalement, entraîneraient la tenue d’autres explorations chez seulement l’un de ces enfants. Conclusion : L’exposition à la CAH pourrait être associée à l’obtention de résultats IDRM anormaux à la suite de l’imagerie du cerveau néonatal dans les 96 heures suivant l’accouchement. D’autres études s’avèrent requises pour cerner l’association entre les séquelles neurodéveloppementales à long terme et la chorioamnionite et les modifications de la substance blanche. J Obstet Gynaecol Can 2009;31(6):497–503
INTRODUCTION
erebral palsy is a devastating adverse perinatal outcome, in part because of its long-term impact on the lives of those who are affected. Prematurity is the factor most strongly associated with the development of CP. Previous human and animal research has shown that chorioamnionitis may be a contributing factor for the development of CP in many cases, particularly in preterm infants.1–5 Chorioamnionitis is thought to further increase both the incidence (OR 2.03; 95% CI 1.24–3.30) and severity (OR 2.23; 95% CI 1.23–3.94) of CP in preterm infants.6 Intrauterine infection can be identified in up to 45% of
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pregnancies complicated by delivery between 23 and 26 weeks of gestation and 18% of pregnancies that deliver between 27 and 30 weeks of gestation.7 Histopathologic chorioamnionitis is commonly found on postpartum examination of the placentas of pregnancies complicated by PPROM. A survey of Canadian tertiary care centres found an overall incidence of PPROM of 2.3%.8 PPROM is defined as rupture of the fetal membranes prior to 37 weeks of gestation and before the onset of uterine contractions. When the placentas from the patients with PPROM in the Canadian study were examined, 53% exhibited evidence of HCA. The diagnosis of clinical chorioamnionitis is based on the relatively non-specific findings of maternal fever, maternal or fetal tachycardia, uterine tenderness, purulent vaginal discharge, and maternal leukocytosis.3 HCA, diagnosed postpartum by finding leukocytic polymorphonuclear infiltration in the placenta and membranes with edema and congestion of the vessels and corresponding umbilical cord vasculitis, is found more frequently than a clinical diagnosis of chorioamnionitis is made.7 A retrospective study of preterm infants found that the odds ratio for the development of CP in cases where chorioamnionitis was diagnosed clinically was 2.3 (95% CI 1.2–4.5).9 The authors also reported an increased risk for the development of CP (OR 4.2; 95% CI 1.4–12) when the diagnosis was made histologically. It is now recognized that bacterial invasion of the amniotic cavity can occur in the absence of an inflammatory response.10 Clinical signs of inflammation seem to be more predictive of adverse outcomes than the presence of bacteria alone.10 Recent research suggests that fetal genotype of the interleukin-6 gene promoter (a cytokine involved in the inflammatory cascade) plays a role in the development of chorioamnionitis and neonatal infection.11 Epidemiologic human data also suggest that, among preterm infants, children who develop CP are more likely to have been exposed to intrauterine infection.7,12,13 The immature brain of the preterm fetus is particularly vulnerable to inflammatory injury.14 Of children born preterm who were subsequently diagnosed with CP, 17% to 21% had been exposed to clinical chorioamnionitis.4–6 In control
ABBREVIATIONS ADC
apparent diffusion coefficient
CP
cerebral palsy
DWMRI diffusion-weighted magnetic resonance imaging HCA
histopathologic chorioamnionitis
PPROM preterm premature rupture of the membranes
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patients who did not develop CP, only 3% to 10% had been exposed to clinical chorioamnionitis. Umbilical cord inflammation (funisitis) also suggests more advanced fetal involvement in chorioamnionitis and has a stronger association with CP.15 Several studies have shown an association between chorioamnionitis and cerebral palsy or periventricular leukomalacia.16–18 Increased severity or length of exposure to infection in utero may be associated with an increased risk of neurodevelopmental abnormalities.15 Intrauterine inflammation and infection are associated with neonatal white matter injury, and it appears that this injury is mediated by inflammatory cytokines (such as interleukin-6, interleukin 1b, and tumour necrosis factor-a) released by the fetus in response to infection.19–21 Increased levels of inflammatory cytokines play a role in the development of acute organ injury, including to the white matter.22 These changes are accentuated in the presence of ischemiareperfusion processes that are not uncommon in the perinatal period of premature infants.23 Histopathologic chorioamnionitis, in combination with other insults, such as placental perfusion defects and maternal systemic infection, appears to increase the risk of poor long-term neurologic outcome in very preterm infants, even after adjustment for confounders.19 The standard modality for imaging the neonatal brain is ultrasound, despite the recognition that MRI is a more precise tool, particularly for the detection of periventricular leukomalacia and other white matter diseases.24–29 DWI is based on alterations in the random motion of water within tissues. With the initiation of the ischemic cascade, water proton diffusion decreases, and this is sensitively measured using high-gradient strength MRI units. DWI signal abnormalities can be detected within minutes following an acute ischemic insult, long before changes are noted on conventional MR imaging techniques.30 Reported sensitivities range from 88% to 100% and reported specificities range from 86% to 100%.31 It is well recognized that restriction of water motion, and therefore DWI signal changes, follow an expected temporal course related to the time interval from the onset of ischemic insult. The purpose of this study was to assess the feasibility of using diffusion-weighted magnetic resonance imaging to diagnose the presence of neonatal white matter changes in a high-risk population. Secondary objectives included DWMRI assessment of neonatal white matter changes following exposure to chorioamnionitis compared to non-exposure, and determination of the sample size necessary for a more definitive prospective cohort study.
Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series
Figure 1. Flow Diagram of Eligible Patients
Patients approached to participate 34
Patients declining to participate 3 Failure to meet inclusion criteria 8 Incomplete data 5 Infants studied 18 Chorioamnionitis 7
White matter injury 3
No chorioamnionitis 11
White matter injury 1
Log of patients approached to participate in the study
METHODS
All women who presented to Kingston General Hospital (the tertiary referral centre for south-eastern Ontario) with PPROM at between 30 and 34 weeks’ gestation from June 2004 to June 2005 were invited to participate and to consent to having their infant assessed according to the study protocol. Inclusion criteria for infants included spontaneous ventilation, stable clinical status, and having parental consent. In order to ensure MRI compatibility, infants requiring ventilatory support for more than seven days were excluded. Patients with confirmed PPROM were admitted to Kingston General Hospital and initiated on a standard protocol that included a single course of antenatal corticosteroids and broad spectrum antibiotics. Maternal temperature and leukocyte count were monitored in hospital, and fetal well-being was monitored using twice-daily non-stress tests and twice-weekly biophysical profiles. If chorioamnionitis was suspected, delivery was expedited as clinically indicated.
At least one cranial ultrasound examination of the infant was completed within the first week of life. As soon as the infant was stable enough for transport, DWMRI was performed. Neuroimaging was performed using a 1.5 Tesla Siemens Magnetom Avanto MRI system. Single shot EPI axial DWI was performed. Apparent diffusion coefficient maps were obtained. Total imaging time was less than one minute for the DW images. All scans were performed within the first four days of life. During imaging, the infants were fed and swaddled and had continuous heart rate and oxygen saturation monitoring. Each infant was accompanied for imaging by a neonatal nurse, respiratory therapist, and physician. All MRI scans were reported by the same neuroradiologist, who was blinded to placental pathology and obstetrical and neonatal courses. After delivery of the infant, histopathologic analysis of the placenta was carried out; the pathologist was blinded to the clinical status of the mothers and infants, as well as to the neonatal DWMRI findings. The placentas were fixed in 10% neutral buffered formalin, processed routinely through dehydration in graded ethanol, clearing in xylene, embedding in paraffin blocks, and staining with JUNE JOGC JUIN 2009 l
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Results White matter changes (4/18)
No white matter changes (14/18)
32
28
Maternal nulliparity*
2/4 (50%)
6/14 (43%)
Gestational age at PPROM, weeks (range)
31 (29–33)
31 (25–34)
Gestational age at delivery, weeks (range)
33 (32–34)
33 (30–35)
Parameter Maternal age, years, mean
13
14
1996 g
1986 g
Male gender
2/4 (50%)
6/14 (43%)
Delivery by Caesarean section
1/4 (25%)
3/14 (21%)
9 (7–9)
9 (8–9)
7.29
7.25
Any histopathologic chorioamnionitis, mild or severe
3/4 (75%)
4/14 (29%)
Severe histopathologic chorioamnionitis
2/4 (50%)
3/14 (21%)
Funisitis‡
1/4 (25%)
2/14 (14%)
Clinical chorioamnionitis§
0/4 (0%)
3/14 (21%)
Latency period, days† Birth weight, mean
Apgar score at five minutes, median (range) Cord artery pH, mean
*Proportion of women having their first baby (after 20 weeks of gestation) †Time from PPROM to delivery ‡Inflammation of the umbilical cord on histopathology §Presence of at least one of the following: maternal fever, sustained maternal or fetal tachycardia, acute maternal leukocytosis (other than within 7 days of administration of betamethasone), purulent vaginal discharge, or uterine tenderness
hematoxylin-phloxin-saffron stain. The resulting slides were reviewed, and the inflammatory response was graded as absent, mild or severe. The grading system was based on the stage (duration) of the maternal inflammatory response: stage 1 (early) corresponds to acute subchorionitis or acute chorionitis, stage 2 (intermediate) corresponds to acute chorioamnionitis, and stage 3 (late) corresponds to necrotizing chorioamnionitis. Stage 1 placentas were graded as showing mild chorioamnionitis and stage 2 and 3 placentas were graded as showing severe chorioamnionitis. The fetal inflammatory response was also taken into consideration, with the presence of acute funisitis resulting in a designation of severe chorioamnionitis. Statistical analysis consisted of unpaired t test for continuous variables and Fisher exact test for categorical variables. Research ethics approval was obtained from the Health Sciences Research Ethics Board of Queen’s University prior to initiation of the study. RESULTS
Seventeen patients completed participation in the study, including one patient with a dichorionic, diamniotic twin gestation. This resulted in 18 infants being included in the 500
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study population (Figure 1). Of women presenting to hospital with PPROM, 31/34 (92%) agreed to have their newborns undergo DWMRI for study purposes only (neonatologists were not aware of the MRI findings). Eight of these infants did not meet the inclusion criteria because of ongoing ventilatory support. In an additional six cases, incomplete data were obtained (5 neonates did not undergo ultrasound assessment of the head, and 1 placenta did not undergo histopathologic assessment). There was no difference between infants with white matter changes on MRI and infants without such changes with regard to gestational age at the time of PPROM, gestational age at delivery, latency period (time from PPROM to delivery), cord artery pH, and birth weight (Table). At the time of delivery, there were no significant clinical differences between the neonates with white matter changes and those without. Apgar scores at five minutes and cord artery pH levels were similar (Table). DWMRI revealed acute white matter changes in 4/18 infants (22%) (Figure 2), as demonstrated by DW and ADC imaging. The changes observed in the infant presented in Figure 2 are representative of those observed in the other three infants. No other abnormalities were noted. Routine
Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series
Figure 2. DWMR images of one study infant. The first image results from the apparent diffusion coefficient sequence and shows a solitary focus of dark signal representing restriction of water motion within a region of acute deep white matter infarction adjacent to the trigone of the left lateral ventricle. The second image demonstrates the same focus, now as an increased signal on DWI sequencing. The final image from the same patient is taken using DWI sequencing and demonstrates more extensive patchy hyperintense signal changes within the right fronto-parietal corona radiate. There was corresponding low signal on the ADC sequence (not included), confirming acute infarction.
ultrasound examination of the head demonstrated abnormal cortical findings that would prompt further investigation for only one of these four infants. All infants tolerated MRI well with no adverse events.
MRI is the very short time required to complete the imaging sequence. Infants were fed and swaddled for the MRI, with none requiring sedation. All babies tolerated the imaging well, with no adverse events occurring.
Histopathology of the placenta revealed chorioamnionitis of any grade (mild or severe) in 7/18 cases (39%). Five patients were given a diagnosis of severe histopathologic chorioamnionitis, either on the basis of stage 2 or 3 maternal inflammatory response, or because fetal inflammatory response in the form of funisitis was confirmed. Three patients had a diagnosis of clinical chorioamnionitis.
The use of MRI-compatible ventilatory equipment would add valuable information to future studies. This would allow the extension of the eligibility criteria potentially to 24 weeks’ gestational age, provided the neonates are hemodynamically stable enough for transportation to the MRI. It is anticipated that the implications of exposure to chorioamnionitis and/or inflammatory cytokines are even more profound in very preterm infants, with more damage to the immature white matter. This may, in part, explain the increased incidence of cerebral palsy in this group. The eight babies who were excluded from our study were generally more clinically unstable than their counterparts who underwent DWMR imaging. Infants who require extended ventilatory support are intuitively at higher risk for white matter changes as they are generally more clinically unstable. MRI compatible equipment would allow such infants to undergo imaging.
Of the four infants with white matter changes on DWMRI, three had a placental diagnosis of any histopathologic chorioamnionitis (mild or severe). Two were confirmed to have severe chorioamnionitis, and one had funisitis. Of the 14 neonates without white matter changes, four had any histopathologic chorioamnionitis, three had severe chorioamnionitis and two had funisitis. All of the women with clinical chorioamnionitis had histopathologic chorioamnionitis, and none of their neonates had white matter changes. No statistically significant differences were observed. DISCUSSION
The results of this study confirm that it is feasible to use DWMRI for research purposes to assess high-risk neonates for white matter changes in the immediate postpartum period. The majority of women approached agreed to the study, and most neonates were stable enough to undergo imaging. One advantage of DWMRI over conventional
The results of this observational study confirm previous findings that exposure to chorioamnionitis may be associated with an increase in risk of changes in white matter that are demonstrable by diffusion MR within the first week of birth,32 but not all studies demonstrated this relationship.33 Ongoing research is needed in order to establish this association definitively. In our study, DWMRI appeared to be more sensitive than routine head ultrasound in demonstrating white matter JUNE JOGC JUIN 2009 l
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changes. One infant studied had findings of bilateral periventricular white matter acute infarcts and a left parietal peripheral hemorrhage on routine neonatal ultrasound. The DWMR imaging of that infant confirmed acute white matter changes. For the remaining three infants with white matter changes found on DWMR imaging, the routine head ultrasound examination was reported as normal. The clinical significance of the white matter changes identified in this study is uncertain. Information for affected neonates is not available outside the initial admission to the neonatal intensive care unit. The babies with white matter changes followed benign neonatal courses, with no differences in five-minute Apgar scores (a better indicator of long-term morbidity than one-minute Apgar scores) or cord artery pH. Furthermore, none of those infants showed abnormal neurologic symptoms, such as seizures. All were discharged, with routine follow-up for preterm infants arranged. The observed white matter changes result from an unknown cause, and the evolution of these changes is unknown. A major limitation of this study is the small sample size. As a result, we are unable to comment on the significance of any association between chorioamnionitis and neonatal white matter changes. Our preliminary data suggest a trend towards an increase in the incidence of white matter changes in preterm infants exposed to histopathologic chorioamnionitis. On the basis of this study, a preliminary sample size calculation can be completed. Our study has shown that it is reasonable to expect that 40% of neonates with histopathologic chorioamnionitis will develop white matter changes. In the absence of histopathologic chorioamnionitis, approximately 20% of patients demonstrate similar changes. Assuming an alpha level of 0.05 and a power of 90%, a sample size of 218 patients (109 per group) would be required to show a difference of 20% in the proportion of patients with white matter changes associated with exposure to histopathologic chorioamnionitis. Early diagnosis of chorioamnionitis continues to be a challenge in obstetric practice. There is an increased incidence of subacute chorioamnionitis in women who deliver prematurely, even in the absence of PPROM. Many of the changes that result in neonatal white matter injury likely result from inflammatory mediators that are released early in the process, before any clinical evidence of chorioamnionitis is apparent. In future studies, it would be prudent to compare infants exposed to histologically confirmed chorioamnionitis with infants having iatrogenic prematurity (e.g., those born to mothers with preeclampsia). This would presumably minimize any contribution to white matter changes by inflammatory mediators due to infection. It should be recognized, however, that inflammatory mediators are 502
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produced through other pathways including hypoxia, ischemia, trauma, and labour itself.34,35 This may preclude the confirmation of a definitive causal relationship between chorioamnionitis, white matter injury, and cerebral palsy. There is a need for long-term follow-up, both clinical and radiological, of infants in future studies in order to determine the significance of observed white matter changes. Without long-term follow-up, it is impossible to know if the changes we have observed represent a significant white matter injury or merely a reversible process. Epidemiologic studies have linked chorioamnionitis with an increased risk of fetal brain injury and subsequent adverse neurodevelopmental outcomes. Additional research through multi-centre study is required to achieve an adequate sample size to determine the relationship between chorioamnionitis and DWMRI changes. If white matter changes are shown to be a marker for brain injury, early identification, close clinical follow-up, and intensive stimulation programs may improve longer term neurodevelopmental outcomes. ACKNOWLEDGEMENTS
Support for this work was provided by a grant from the Physician’s Services Incorporated (PSI) Foundation and by the Canadian Institute for Health Research. The authors would like to thank Dr Tim Childs for assisting with the placental histopathology, Ms Heather Ramshaw for her data organization, and Mr Patrick Gaudet for preparing the figures for publication. REFERENCES 1. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R, et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997;176(2):275–81. 2. Watts DH, Krohn MA, Hillier SL. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labour. Obstet Gynecol 1992; 79:351–7. 3. Gibbs RS, Sweet LT. Maternal and fetal infectious disorders. In: RK Creasy, R Resnick, eds. Maternal fetal medicine. Toronto: WB Saunders;1999:664–6. 4. Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998;91(5):725–9. 5. Smulian, JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Anath CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol 1999; 94(6):1000–5. 6. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278(3):207–11. 7. Elimian, A. Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes. Obstet Gynecol 2000;96:333–6. 8. Smith GN, Rafuse C, Anand, N, Brennan B, Connors G, Crane J, et al. Prevalence, management, and outcomes of preterm premature rupture of the membranes of women in Canada. J Obstet Gynaecol Can 2005;27:547–53.
Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series
9. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346:1449–54. 10. Steel JH, Malatos, S, Kennea H, Edwards a.d., Miles L, Duggan P, et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res 2005;57:404–11. 11. Reiman M, Kujari H, Ekholm E, Lapinleimu H, Lehtonen L, Haataja L; PIPARI Study Group. Interleukin-6 polymorphism is associated with chorioamnionitis and neonatal infections in preterm infants. J Pediatr 2008;153:19–24. 12. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA 2000; 284:1417–24. 13. Wu YW. Systematic review of chorioamnionitis and cerebral palsy. Ment Retard Dev Disabil Res Rev 2002;12:99–104. 14. Back SA, Luo NL Borenstein NS, Levine JM, Volpe JJ, Kinney HC, et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 2001;21:1302–12.
22. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194–202. 23. Fanaroff AA, Hack M. Periventricular leukomalacia—prospects for prevention. N Engl J Med 1999; 341:1229–31. 24. Maalouf EF, Duggan PJ Counsell SJ, Rutherford MA, Cowan F, Azzopardi D et al. Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants. Pediatrics 2001; 107:719–27. 25. Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. et al. White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol 2003; 24:805–9. 26. Bozzao A, Di Paolo A, Mazzolent C, Fasoli F, Simonetti A, Fantozzi LM, et al. Diffusion-weighted MR imaging in the early diagnosis of periventricular leukomalacia. Eur Radiol 2003;13:1571–6. 27. Miller SP, Vigneron DB, Henry RG, Bohland MA, Ceppi-Cozzio C, Hoffman C, et al. Serial quantitative diffusion tensor MRI of the premature brain: development in newborns with and without injury. J Magn Reson Imaging 2002;16:621–32.
15. Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000;182(3):675–81.
28. Kim MJJ, Provenzale J, Law M. Magnetic resonance and diffusion tensor imaging in pediatric white matter diseases. Top Magn Reson Imaging 2006;17:265–74.
16. Hagberg H, Wennerholm UB, Savman K. Sequelae of chorioamnionitis. Curr Opin Infect Dis 2002;15:301–6.
29. Rutherford MA, Ward P, Malamatentiou C. Advanced MR techniques in the term-born infant with perinatal brain injury. Semin Fetal Neonatal Med 2005;10:445–60.
17. O’Shea TM, Klinepeter KL, Meis PJ, Dillard RG. Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants. Paediatr Perinat Epidemiol 1998;12:72–83. 18. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R, et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low birth-weight neonate. Am J Obstet Gynecol 1997;176:275–81. 19. Kaukola T, Herva R, Perhomaa M, Paakko E, Kingsmore S, Vainionpaa L, et al. Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants. Pediatr Res 2006;59(3):478–83. 20. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis for acute inflammatory lesions of preterm placenta and prediction of perinatal mortality. Am J Obstet Gynecol 1995;172: 960–70. 21. Yoon BH, Romero R, Park KH, Gomez R, Choi JH, Kim IO. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gyncecol 1996;174:1433–40.
30. Lansberg MG, Thijs VN, O’Brien MW, Ali JO, DeCrespigny AJ, Tong DC, et al. Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke. AJNR Am J Neuroradiol 2001;22:637–44. 31. Lutsep HL, Albers GW, DeCrespigny A, Kamar GN, Marks MP, Moseley ME. Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Ann Neurol 1997;41(5):574–80. 32. Sorenson LC, Skogstrand K, Hougaard DM, Albrectsen J, Borch K, Lou HC, et al. Cord blood inflammatory markers, coetal vasculitis and cerebral MRI abnormalities in preterm infants. Acta Paediatr 2006;96:1360–4. 33. Reiman M, Kujari H, Maunu J, et al. Does placental inflammation relate to brain lesions and volume in preterm infants? J Pediatr 2008;152:642–7. 34. Savman K, Biennow M, Gustafson K, Tarkowski E, Hagberg H. Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr Res 1998;43:746–51. 35. Bona E, Andersson AL, Blomgren K, Gilland E, Puka-Sundvall M, Gustafson K, et al. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res 1999;45: 500–9.
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Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series Laura M. Gaudet, MD,1 Michael Flavin, MB,2 Omar Islam, MD,3 Graeme N. Smith, MD, PhD1,3,4 1
Department of Obstetrics and Gynaecology, Division of Maternal-Fetal Medicine, Queen’s University, Kingston ON
2
Department of Pediatrics, Division of Neonatology, Queen’s University, Kingston ON
3
Department of Radiology, Queen’s University, Kingston ON
4
Department of Pharmacology and Toxicology, Queen’s University, Kingston ON
Abstract Objective: The primary objective of this study was to determine the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI) to assess white matter changes in high-risk neonates. Secondary objectives were to determine if exposure to chorioamnionitis (clinical or histopathologic) is associated with DWMRI findings in the neonatal brain, and to calculate the sample size required for a more definitive prospective cohort study. Methods: Seventeen women with PPROM (preterm premature rupture of the membranes) who delivered 18 infants not requiring ventilatory support were recruited to participate in this case series. When stable, infants underwent DWMRI scanning. All placentas were examined for evidence of histopathologic chorioamnionitis (HCA). Results: There was histopathologic evidence of chorioamnionitis in seven of the 18 placentas examined; three of these patients had clinical chorioamnionitis. Diffusion MRI revealed changes in both the diffusion-weighted imaging and the apparent diffusion coefficient in three of the seven infants confirmed to have HCA (43%), while only one of the 11 infants with normal placentas (9%) showed similar findings. Routine head ultrasound examination demonstrated abnormal cortical findings that would normally prompt further investigation in only one of these infants. Conclusion: Exposure to HCA may be associated with abnormal DWMRI findings on imaging of the neonatal brain within 96 hours of delivery. Further study is required to delineate the association of chorioamnionitis and white matter changes with long-term neurodevelopmental sequelae.
Résumé Objectif : Le principal objectif de cette étude était de déterminer la faisabilité de l’utilisation de l’imagerie de diffusion par résonance magnétique (IDRM) pour évaluer les modifications de la substance blanche chez les nouveau-nés exposés à des risques élevés. Nos objectifs secondaires étaient de déterminer si l’exposition à la chorioamnionite (clinique ou histopathologique) est associée aux résultats de l’IDRM, en ce qui concerne le
Key Words: Chorioamnionitis, neonatal white matter imaging, diffusion MRI, brain Competing Interests: None declared. Received on October 8, 2008 Accepted on December 5, 2008
cerveau néonatal, et de calculer la taille d’échantillon requise pour la tenue d’une étude de cohorte prospective plus précise. Méthodes : La participation de 17 femmes présentant une RPMP (rupture prématurée des membranes préterme) qui ont accouché de 18 enfants ne nécessitant pas une ventilation assistée a été sollicitée en ce qui a trait à cette série de cas. Une fois stables, ces enfants ont été soumis à une IDRM. Tous les placentas ont été examinés afin d’y dépister des signes de chorioamnionite histopathologique (CAH). Résultats : La présence de signes histopathologiques de chorioamnionite a été constatée chez sept des 18 placentas examinés; trois de ces patientes présentaient une chorioamnionite clinique. L’IDRM a révélé des modifications tant en ce qui concerne l’imagerie de diffusion qu’en ce qui concerne le coefficient de diffusion constaté chez trois des sept enfants pour lesquels la présence d’une CAH avait été confirmée (43 %), tandis que seulement un des 11 enfants ayant présenté un placenta normal (9 %) a obtenu des résultats semblables. L’échographie céphalique systématique a révélé des résultats corticaux anormaux qui, normalement, entraîneraient la tenue d’autres explorations chez seulement l’un de ces enfants. Conclusion : L’exposition à la CAH pourrait être associée à l’obtention de résultats IDRM anormaux à la suite de l’imagerie du cerveau néonatal dans les 96 heures suivant l’accouchement. D’autres études s’avèrent requises pour cerner l’association entre les séquelles neurodéveloppementales à long terme et la chorioamnionite et les modifications de la substance blanche. J Obstet Gynaecol Can 2009;31(6):497–503
INTRODUCTION
erebral palsy is a devastating adverse perinatal outcome, in part because of its long-term impact on the lives of those who are affected. Prematurity is the factor most strongly associated with the development of CP. Previous human and animal research has shown that chorioamnionitis may be a contributing factor for the development of CP in many cases, particularly in preterm infants.1–5 Chorioamnionitis is thought to further increase both the incidence (OR 2.03; 95% CI 1.24–3.30) and severity (OR 2.23; 95% CI 1.23–3.94) of CP in preterm infants.6 Intrauterine infection can be identified in up to 45% of
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pregnancies complicated by delivery between 23 and 26 weeks of gestation and 18% of pregnancies that deliver between 27 and 30 weeks of gestation.7 Histopathologic chorioamnionitis is commonly found on postpartum examination of the placentas of pregnancies complicated by PPROM. A survey of Canadian tertiary care centres found an overall incidence of PPROM of 2.3%.8 PPROM is defined as rupture of the fetal membranes prior to 37 weeks of gestation and before the onset of uterine contractions. When the placentas from the patients with PPROM in the Canadian study were examined, 53% exhibited evidence of HCA. The diagnosis of clinical chorioamnionitis is based on the relatively non-specific findings of maternal fever, maternal or fetal tachycardia, uterine tenderness, purulent vaginal discharge, and maternal leukocytosis.3 HCA, diagnosed postpartum by finding leukocytic polymorphonuclear infiltration in the placenta and membranes with edema and congestion of the vessels and corresponding umbilical cord vasculitis, is found more frequently than a clinical diagnosis of chorioamnionitis is made.7 A retrospective study of preterm infants found that the odds ratio for the development of CP in cases where chorioamnionitis was diagnosed clinically was 2.3 (95% CI 1.2–4.5).9 The authors also reported an increased risk for the development of CP (OR 4.2; 95% CI 1.4–12) when the diagnosis was made histologically. It is now recognized that bacterial invasion of the amniotic cavity can occur in the absence of an inflammatory response.10 Clinical signs of inflammation seem to be more predictive of adverse outcomes than the presence of bacteria alone.10 Recent research suggests that fetal genotype of the interleukin-6 gene promoter (a cytokine involved in the inflammatory cascade) plays a role in the development of chorioamnionitis and neonatal infection.11 Epidemiologic human data also suggest that, among preterm infants, children who develop CP are more likely to have been exposed to intrauterine infection.7,12,13 The immature brain of the preterm fetus is particularly vulnerable to inflammatory injury.14 Of children born preterm who were subsequently diagnosed with CP, 17% to 21% had been exposed to clinical chorioamnionitis.4–6 In control
ABBREVIATIONS ADC
apparent diffusion coefficient
CP
cerebral palsy
DWMRI diffusion-weighted magnetic resonance imaging HCA
histopathologic chorioamnionitis
PPROM preterm premature rupture of the membranes
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patients who did not develop CP, only 3% to 10% had been exposed to clinical chorioamnionitis. Umbilical cord inflammation (funisitis) also suggests more advanced fetal involvement in chorioamnionitis and has a stronger association with CP.15 Several studies have shown an association between chorioamnionitis and cerebral palsy or periventricular leukomalacia.16–18 Increased severity or length of exposure to infection in utero may be associated with an increased risk of neurodevelopmental abnormalities.15 Intrauterine inflammation and infection are associated with neonatal white matter injury, and it appears that this injury is mediated by inflammatory cytokines (such as interleukin-6, interleukin 1b, and tumour necrosis factor-a) released by the fetus in response to infection.19–21 Increased levels of inflammatory cytokines play a role in the development of acute organ injury, including to the white matter.22 These changes are accentuated in the presence of ischemiareperfusion processes that are not uncommon in the perinatal period of premature infants.23 Histopathologic chorioamnionitis, in combination with other insults, such as placental perfusion defects and maternal systemic infection, appears to increase the risk of poor long-term neurologic outcome in very preterm infants, even after adjustment for confounders.19 The standard modality for imaging the neonatal brain is ultrasound, despite the recognition that MRI is a more precise tool, particularly for the detection of periventricular leukomalacia and other white matter diseases.24–29 DWI is based on alterations in the random motion of water within tissues. With the initiation of the ischemic cascade, water proton diffusion decreases, and this is sensitively measured using high-gradient strength MRI units. DWI signal abnormalities can be detected within minutes following an acute ischemic insult, long before changes are noted on conventional MR imaging techniques.30 Reported sensitivities range from 88% to 100% and reported specificities range from 86% to 100%.31 It is well recognized that restriction of water motion, and therefore DWI signal changes, follow an expected temporal course related to the time interval from the onset of ischemic insult. The purpose of this study was to assess the feasibility of using diffusion-weighted magnetic resonance imaging to diagnose the presence of neonatal white matter changes in a high-risk population. Secondary objectives included DWMRI assessment of neonatal white matter changes following exposure to chorioamnionitis compared to non-exposure, and determination of the sample size necessary for a more definitive prospective cohort study.
Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series
Figure 1. Flow Diagram of Eligible Patients
Patients approached to participate 34
Patients declining to participate 3 Failure to meet inclusion criteria 8 Incomplete data 5 Infants studied 18 Chorioamnionitis 7
White matter injury 3
No chorioamnionitis 11
White matter injury 1
Log of patients approached to participate in the study
METHODS
All women who presented to Kingston General Hospital (the tertiary referral centre for south-eastern Ontario) with PPROM at between 30 and 34 weeks’ gestation from June 2004 to June 2005 were invited to participate and to consent to having their infant assessed according to the study protocol. Inclusion criteria for infants included spontaneous ventilation, stable clinical status, and having parental consent. In order to ensure MRI compatibility, infants requiring ventilatory support for more than seven days were excluded. Patients with confirmed PPROM were admitted to Kingston General Hospital and initiated on a standard protocol that included a single course of antenatal corticosteroids and broad spectrum antibiotics. Maternal temperature and leukocyte count were monitored in hospital, and fetal well-being was monitored using twice-daily non-stress tests and twice-weekly biophysical profiles. If chorioamnionitis was suspected, delivery was expedited as clinically indicated.
At least one cranial ultrasound examination of the infant was completed within the first week of life. As soon as the infant was stable enough for transport, DWMRI was performed. Neuroimaging was performed using a 1.5 Tesla Siemens Magnetom Avanto MRI system. Single shot EPI axial DWI was performed. Apparent diffusion coefficient maps were obtained. Total imaging time was less than one minute for the DW images. All scans were performed within the first four days of life. During imaging, the infants were fed and swaddled and had continuous heart rate and oxygen saturation monitoring. Each infant was accompanied for imaging by a neonatal nurse, respiratory therapist, and physician. All MRI scans were reported by the same neuroradiologist, who was blinded to placental pathology and obstetrical and neonatal courses. After delivery of the infant, histopathologic analysis of the placenta was carried out; the pathologist was blinded to the clinical status of the mothers and infants, as well as to the neonatal DWMRI findings. The placentas were fixed in 10% neutral buffered formalin, processed routinely through dehydration in graded ethanol, clearing in xylene, embedding in paraffin blocks, and staining with JUNE JOGC JUIN 2009 l
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Results White matter changes (4/18)
No white matter changes (14/18)
32
28
Maternal nulliparity*
2/4 (50%)
6/14 (43%)
Gestational age at PPROM, weeks (range)
31 (29–33)
31 (25–34)
Gestational age at delivery, weeks (range)
33 (32–34)
33 (30–35)
Parameter Maternal age, years, mean
13
14
1996 g
1986 g
Male gender
2/4 (50%)
6/14 (43%)
Delivery by Caesarean section
1/4 (25%)
3/14 (21%)
9 (7–9)
9 (8–9)
7.29
7.25
Any histopathologic chorioamnionitis, mild or severe
3/4 (75%)
4/14 (29%)
Severe histopathologic chorioamnionitis
2/4 (50%)
3/14 (21%)
Funisitis‡
1/4 (25%)
2/14 (14%)
Clinical chorioamnionitis§
0/4 (0%)
3/14 (21%)
Latency period, days† Birth weight, mean
Apgar score at five minutes, median (range) Cord artery pH, mean
*Proportion of women having their first baby (after 20 weeks of gestation) †Time from PPROM to delivery ‡Inflammation of the umbilical cord on histopathology §Presence of at least one of the following: maternal fever, sustained maternal or fetal tachycardia, acute maternal leukocytosis (other than within 7 days of administration of betamethasone), purulent vaginal discharge, or uterine tenderness
hematoxylin-phloxin-saffron stain. The resulting slides were reviewed, and the inflammatory response was graded as absent, mild or severe. The grading system was based on the stage (duration) of the maternal inflammatory response: stage 1 (early) corresponds to acute subchorionitis or acute chorionitis, stage 2 (intermediate) corresponds to acute chorioamnionitis, and stage 3 (late) corresponds to necrotizing chorioamnionitis. Stage 1 placentas were graded as showing mild chorioamnionitis and stage 2 and 3 placentas were graded as showing severe chorioamnionitis. The fetal inflammatory response was also taken into consideration, with the presence of acute funisitis resulting in a designation of severe chorioamnionitis. Statistical analysis consisted of unpaired t test for continuous variables and Fisher exact test for categorical variables. Research ethics approval was obtained from the Health Sciences Research Ethics Board of Queen’s University prior to initiation of the study. RESULTS
Seventeen patients completed participation in the study, including one patient with a dichorionic, diamniotic twin gestation. This resulted in 18 infants being included in the 500
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study population (Figure 1). Of women presenting to hospital with PPROM, 31/34 (92%) agreed to have their newborns undergo DWMRI for study purposes only (neonatologists were not aware of the MRI findings). Eight of these infants did not meet the inclusion criteria because of ongoing ventilatory support. In an additional six cases, incomplete data were obtained (5 neonates did not undergo ultrasound assessment of the head, and 1 placenta did not undergo histopathologic assessment). There was no difference between infants with white matter changes on MRI and infants without such changes with regard to gestational age at the time of PPROM, gestational age at delivery, latency period (time from PPROM to delivery), cord artery pH, and birth weight (Table). At the time of delivery, there were no significant clinical differences between the neonates with white matter changes and those without. Apgar scores at five minutes and cord artery pH levels were similar (Table). DWMRI revealed acute white matter changes in 4/18 infants (22%) (Figure 2), as demonstrated by DW and ADC imaging. The changes observed in the infant presented in Figure 2 are representative of those observed in the other three infants. No other abnormalities were noted. Routine
Diffusion MRI Brain Findings in Neonates Exposed to Chorioamnionitis: A Case Series
Figure 2. DWMR images of one study infant. The first image results from the apparent diffusion coefficient sequence and shows a solitary focus of dark signal representing restriction of water motion within a region of acute deep white matter infarction adjacent to the trigone of the left lateral ventricle. The second image demonstrates the same focus, now as an increased signal on DWI sequencing. The final image from the same patient is taken using DWI sequencing and demonstrates more extensive patchy hyperintense signal changes within the right fronto-parietal corona radiate. There was corresponding low signal on the ADC sequence (not included), confirming acute infarction.
ultrasound examination of the head demonstrated abnormal cortical findings that would prompt further investigation for only one of these four infants. All infants tolerated MRI well with no adverse events.
MRI is the very short time required to complete the imaging sequence. Infants were fed and swaddled for the MRI, with none requiring sedation. All babies tolerated the imaging well, with no adverse events occurring.
Histopathology of the placenta revealed chorioamnionitis of any grade (mild or severe) in 7/18 cases (39%). Five patients were given a diagnosis of severe histopathologic chorioamnionitis, either on the basis of stage 2 or 3 maternal inflammatory response, or because fetal inflammatory response in the form of funisitis was confirmed. Three patients had a diagnosis of clinical chorioamnionitis.
The use of MRI-compatible ventilatory equipment would add valuable information to future studies. This would allow the extension of the eligibility criteria potentially to 24 weeks’ gestational age, provided the neonates are hemodynamically stable enough for transportation to the MRI. It is anticipated that the implications of exposure to chorioamnionitis and/or inflammatory cytokines are even more profound in very preterm infants, with more damage to the immature white matter. This may, in part, explain the increased incidence of cerebral palsy in this group. The eight babies who were excluded from our study were generally more clinically unstable than their counterparts who underwent DWMR imaging. Infants who require extended ventilatory support are intuitively at higher risk for white matter changes as they are generally more clinically unstable. MRI compatible equipment would allow such infants to undergo imaging.
Of the four infants with white matter changes on DWMRI, three had a placental diagnosis of any histopathologic chorioamnionitis (mild or severe). Two were confirmed to have severe chorioamnionitis, and one had funisitis. Of the 14 neonates without white matter changes, four had any histopathologic chorioamnionitis, three had severe chorioamnionitis and two had funisitis. All of the women with clinical chorioamnionitis had histopathologic chorioamnionitis, and none of their neonates had white matter changes. No statistically significant differences were observed. DISCUSSION
The results of this study confirm that it is feasible to use DWMRI for research purposes to assess high-risk neonates for white matter changes in the immediate postpartum period. The majority of women approached agreed to the study, and most neonates were stable enough to undergo imaging. One advantage of DWMRI over conventional
The results of this observational study confirm previous findings that exposure to chorioamnionitis may be associated with an increase in risk of changes in white matter that are demonstrable by diffusion MR within the first week of birth,32 but not all studies demonstrated this relationship.33 Ongoing research is needed in order to establish this association definitively. In our study, DWMRI appeared to be more sensitive than routine head ultrasound in demonstrating white matter JUNE JOGC JUIN 2009 l
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changes. One infant studied had findings of bilateral periventricular white matter acute infarcts and a left parietal peripheral hemorrhage on routine neonatal ultrasound. The DWMR imaging of that infant confirmed acute white matter changes. For the remaining three infants with white matter changes found on DWMR imaging, the routine head ultrasound examination was reported as normal. The clinical significance of the white matter changes identified in this study is uncertain. Information for affected neonates is not available outside the initial admission to the neonatal intensive care unit. The babies with white matter changes followed benign neonatal courses, with no differences in five-minute Apgar scores (a better indicator of long-term morbidity than one-minute Apgar scores) or cord artery pH. Furthermore, none of those infants showed abnormal neurologic symptoms, such as seizures. All were discharged, with routine follow-up for preterm infants arranged. The observed white matter changes result from an unknown cause, and the evolution of these changes is unknown. A major limitation of this study is the small sample size. As a result, we are unable to comment on the significance of any association between chorioamnionitis and neonatal white matter changes. Our preliminary data suggest a trend towards an increase in the incidence of white matter changes in preterm infants exposed to histopathologic chorioamnionitis. On the basis of this study, a preliminary sample size calculation can be completed. Our study has shown that it is reasonable to expect that 40% of neonates with histopathologic chorioamnionitis will develop white matter changes. In the absence of histopathologic chorioamnionitis, approximately 20% of patients demonstrate similar changes. Assuming an alpha level of 0.05 and a power of 90%, a sample size of 218 patients (109 per group) would be required to show a difference of 20% in the proportion of patients with white matter changes associated with exposure to histopathologic chorioamnionitis. Early diagnosis of chorioamnionitis continues to be a challenge in obstetric practice. There is an increased incidence of subacute chorioamnionitis in women who deliver prematurely, even in the absence of PPROM. Many of the changes that result in neonatal white matter injury likely result from inflammatory mediators that are released early in the process, before any clinical evidence of chorioamnionitis is apparent. In future studies, it would be prudent to compare infants exposed to histologically confirmed chorioamnionitis with infants having iatrogenic prematurity (e.g., those born to mothers with preeclampsia). This would presumably minimize any contribution to white matter changes by inflammatory mediators due to infection. It should be recognized, however, that inflammatory mediators are 502
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produced through other pathways including hypoxia, ischemia, trauma, and labour itself.34,35 This may preclude the confirmation of a definitive causal relationship between chorioamnionitis, white matter injury, and cerebral palsy. There is a need for long-term follow-up, both clinical and radiological, of infants in future studies in order to determine the significance of observed white matter changes. Without long-term follow-up, it is impossible to know if the changes we have observed represent a significant white matter injury or merely a reversible process. Epidemiologic studies have linked chorioamnionitis with an increased risk of fetal brain injury and subsequent adverse neurodevelopmental outcomes. Additional research through multi-centre study is required to achieve an adequate sample size to determine the relationship between chorioamnionitis and DWMRI changes. If white matter changes are shown to be a marker for brain injury, early identification, close clinical follow-up, and intensive stimulation programs may improve longer term neurodevelopmental outcomes. ACKNOWLEDGEMENTS
Support for this work was provided by a grant from the Physician’s Services Incorporated (PSI) Foundation and by the Canadian Institute for Health Research. The authors would like to thank Dr Tim Childs for assisting with the placental histopathology, Ms Heather Ramshaw for her data organization, and Mr Patrick Gaudet for preparing the figures for publication. REFERENCES 1. Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R, et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997;176(2):275–81. 2. Watts DH, Krohn MA, Hillier SL. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labour. Obstet Gynecol 1992; 79:351–7. 3. Gibbs RS, Sweet LT. Maternal and fetal infectious disorders. In: RK Creasy, R Resnick, eds. Maternal fetal medicine. Toronto: WB Saunders;1999:664–6. 4. Alexander JM, Gilstrap LC, Cox SM, McIntire DM, Leveno KJ. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998;91(5):725–9. 5. Smulian, JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Anath CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol 1999; 94(6):1000–5. 6. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278(3):207–11. 7. Elimian, A. Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes. Obstet Gynecol 2000;96:333–6. 8. Smith GN, Rafuse C, Anand, N, Brennan B, Connors G, Crane J, et al. Prevalence, management, and outcomes of preterm premature rupture of the membranes of women in Canada. J Obstet Gynaecol Can 2005;27:547–53.
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30. Lansberg MG, Thijs VN, O’Brien MW, Ali JO, DeCrespigny AJ, Tong DC, et al. Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke. AJNR Am J Neuroradiol 2001;22:637–44. 31. Lutsep HL, Albers GW, DeCrespigny A, Kamar GN, Marks MP, Moseley ME. Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Ann Neurol 1997;41(5):574–80. 32. Sorenson LC, Skogstrand K, Hougaard DM, Albrectsen J, Borch K, Lou HC, et al. Cord blood inflammatory markers, coetal vasculitis and cerebral MRI abnormalities in preterm infants. Acta Paediatr 2006;96:1360–4. 33. Reiman M, Kujari H, Maunu J, et al. Does placental inflammation relate to brain lesions and volume in preterm infants? J Pediatr 2008;152:642–7. 34. Savman K, Biennow M, Gustafson K, Tarkowski E, Hagberg H. Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr Res 1998;43:746–51. 35. Bona E, Andersson AL, Blomgren K, Gilland E, Puka-Sundvall M, Gustafson K, et al. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res 1999;45: 500–9.
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